Handbook of Pharmaceutical Excipients

Fifth Edition 
Edited by 
Raymond C Rowe, Paul J Sheskey and Sian C Owen
London . Chicago 


Contents 
International Steering Committee ix 
Editorial Staff ix 
Contributors x 
About the Editors xii 
New Monographs xiii 
Related Substances xiv 
Preface xvi 
Arrangement xvii 
Acknowledgments xix 
Notice to Readers xix 
Bibliography xx 
Abbreviations xx 
Units of Measurement xxii 
Monographs 
Acacia 1 
Acesulfame Potassium 4 
Acetic Acid, Glacial 6 
Acetone 8 
Acetyltributyl Citrate 10 
Acetyltriethyl Citrate 12 
Agar 14 
Albumin 16 
Alcohol 18 
Alginic Acid 21 
Aliphatic Polyesters 24 
Alitame 28 
Almond Oil 30 
Alpha Tocopherol 32 
Aluminum Hydroxide Adjuvant 36 
Aluminum Oxide 38 
Aluminum Phosphate Adjuvant 40 
Aluminum Stearate 42 
Ammonia Solution 44 
Ammonium Alginate 46 
Ascorbic Acid 48 
Ascorbyl Palmitate 51 
Aspartame 53 
Attapulgite 56 
Bentonite 58 
Benzalkonium Chloride 61 
Benzethonium Chloride 64 
Benzoic Acid 66 
Benzyl Alcohol 69 
Benzyl Benzoate 72 
Boric Acid 74 
Bronopol 76 
Butylated Hydroxyanisole 79 
Butylated Hydroxytoluene 81 
Butylparaben 83 
Calcium Alginate 86 
Calcium Carbonate 89 
Calcium Phosphate, Dibasic Anhydrous 93 
Calcium Phosphate, Dibasic Dihydrate 96 
Calcium Phosphate, Tribasic 100 
Calcium Stearate 102 
Calcium Sulfate 105 
Canola Oil 108 
Carbomer 111 
Carbon Dioxide 116 
Carboxymethylcellulose Calcium 118 
Carboxymethylcellulose Sodium 120 
Carrageenan 124 
Castor Oil 128 
Castor Oil, Hydrogenated 130 
Cellulose, Microcrystalline 132 
Cellulose, Powdered 136 
Cellulose, Silicified Microcrystalline 139 
Cellulose Acetate 142 
Cellulose Acetate Phthalate 145 
Ceratonia 148 
Cetostearyl Alcohol 150

Cetrimide 152 
Cetyl Alcohol 155 
Cetylpyridinium Chloride 157 
Chitosan 159 
Chlorhexidine 163 
Chlorobutanol 168 
Chlorocresol 171 
Chlorodifluoroethane (HCFC) 174 
Chlorofluorocarbons (CFC) 176 
Chloroxylenol 180 
Cholesterol 182 
Citric Acid Monohydrate 185 
Colloidal Silicon Dioxide 188 
Coloring Agents 192 
Copovidone 201 
Corn Oil 204 
Cottonseed Oil 206 
Cresol 208 
Croscarmellose Sodium 211 
Crospovidone 214 
Cyclodextrins 217 
Cyclomethicone 222 
Denatonium Benzoate 224 
Dextrates 226 
Dextrin 228 
Dextrose 231 
Dibutyl Phthalate 234 
Dibutyl Sebacate 236 
Diethanolamine 238 
Diethyl Phthalate 240 
Difluoroethane (HFC) 242 
Dimethicone 244 
Dimethyl Ether 246 
Dimethyl Phthalate 248 
Dimethyl Sulfoxide 250 
Dimethylacetamide 253 
Disodium Edetate 255 
Docusate Sodium 257 
Edetic Acid 260 
Erythorbic Acid 264 
Erythritol 266 
Ethyl Acetate 268 
Ethyl Lactate 270 
Ethyl Maltol 272 
Ethyl Oleate 274 
Ethyl Vanillin 276 
Ethylcellulose 278 
Ethylene Glycol Palmitostearate 283 
Ethylene Vinyl Acetate 285 
Ethylparaben 287 
Fructose 290 
Fumaric Acid 293 
Gelatin 295 
Glucose, Liquid 299 
Glycerin 301 
Glyceryl Behenate 304 
Glyceryl Monooleate 306 
Glyceryl Monostearate 308 
Glyceryl Palmitostearate 311 
Glycofurol 313 
Guar Gum 315 
Hectorite 318 
Heptafluoropropane (HFC) 321 
Hexetidine 323 
Hydrocarbons (HC) 325 
Hydrochloric Acid 328 
Hydroxyethyl Cellulose 330 
Hydroxyethylmethyl Cellulose 334 
Hydroxypropyl Cellulose 336 
Hydroxypropyl Cellulose, Low-substituted 341 
Hydroxypropyl Starch 344 
Hypromellose 346 
Hypromellose Acetate Succinate 350 
Hypromellose Phthalate 354 
Imidurea 359 
Inulin 362 
Iron Oxides 364 
Isomalt 366 
Isopropyl Alcohol 371 
Isopropyl Myristate 374 
Isopropyl Palmitate 376 
Kaolin 378 
Lactic Acid 381 
Lactitol 383 
Lactose, Anhydrous 385 
Lactose, Monohydrate 389 
Lactose, Spray-Dried 396 
Lanolin 399 
vi Contents

Lanolin Alcohols 402 
Lanolin, Hydrous 404 
Lauric Acid 406 
Lecithin 409 
Leucine 412 
Linoleic Acid 414 
Macrogol 15 Hydroxystearate 416 
Magnesium Aluminum Silicate 418 
Magnesium Carbonate 422 
Magnesium Oxide 426 
Magnesium Silicate 428 
Magnesium Stearate 430 
Magnesium Trisilicate 434 
Malic Acid 436 
Maltitol 438 
Maltitol Solution 440 
Maltodextrin 442 
Maltol 445 
Maltose 447 
Mannitol 449 
Medium-chain Triglycerides 454 
Meglumine 457 
Menthol 459 
Methylcellulose 462 
Methylparaben 466 
Mineral Oil 471 
Mineral Oil, Light 474 
Mineral Oil and Lanolin Alcohols 476 
Monoethanolamine 478 
Monosodium Glutamate 480 
Monothioglycerol 482 
Myristic Acid 484 
Neohesperidin Dihydrochalcone 486 
Nitrogen 488 
Nitrous Oxide 490 
Octyldodecanol 492 
Oleic Acid 494 
Oleyl Alcohol 496 
Olive Oil 498 
Palmitic Acid 501 
Paraffin 503 
Peanut Oil 505 
Pectin 507 
Petrolatum 509 
Petrolatum and Lanolin Alcohols 512 
Phenol 514 
Phenoxyethanol 517 
Phenylethyl Alcohol 519 
Phenylmercuric Acetate 521 
Phenylmercuric Borate 524 
Phenylmercuric Nitrate 526 
Phosphoric Acid 530 
Polacrilin Potassium 532 
Poloxamer 535 
Polycarbophil 539 
Polydextrose 542 
Polyethylene Glycol 545 
Polyethylene Oxide 551 
Polymethacrylates 553 
Poly(methyl vinyl ether/maleic anhydride) 561 
Polyoxyethylene Alkyl Ethers 564 
Polyoxyethylene Castor Oil Derivatives 572 
Polyoxyethylene Sorbitan Fatty Acid Esters 580 
Polyoxyethylene Stearates 585 
Polyvinyl Acetate Phthalate 589 
Polyvinyl Alcohol 592 
Potassium Alginate 594 
Potassium Benzoate 596 
Potassium Bicarbonate 598 
Potassium Chloride 600 
Potassium Citrate 603 
Potassium Hydroxide 605 
Potassium Metabisulfite 607 
Potassium Sorbate 609 
Povidone 611 
Propionic Acid 617 
Propyl Gallate 619 
Propylene Carbonate 622 
Propylene Glycol 624 
Propylene Glycol Alginate 627 
Propylparaben 629 
2-Pyrrolidone 633 
Raffinose 635 
Saccharin 638 
Saccharin Sodium 641 
Saponite 644 
Sesame Oil 646 
Shellac 649 
Contents vii

Simethicone 652 
Sodium Acetate 654 
Sodium Alginate 656 
Sodium Ascorbate 659 
Sodium Benzoate 662 
Sodium Bicarbonate 665 
Sodium Borate 669 
Sodium Chloride 671 
Sodium Citrate Dihydrate 675 
Sodium Cyclamate 678 
Sodium Hyaluronate 681 
Sodium Hydroxide 683 
Sodium Lactate 685 
Sodium Lauryl Sulfate 687 
Sodium Metabisulfite 690 
Sodium Phosphate, Dibasic 693 
Sodium Phosphate, Monobasic 696 
Sodium Propionate 699 
Sodium Starch Glycolate 701 
Sodium Stearyl Fumarate 705 
Sodium Sulfite 708 
Sorbic Acid 710 
Sorbitan Esters (Sorbitan Fatty Acid Esters) 713 
Sorbitol 718 
Soybean Oil 722 
Starch 725 
Starch, Pregelatinized 731 
Starch, Sterilizable Maize 734 
Stearic Acid 737 
Stearyl Alcohol 740 
Sucralose 742 
Sucrose 744 
Sugar, Compressible 748 
Sugar, Confectioner’s 750 
Sugar Spheres 752 
Sulfobutylether b-Cyclodextrin 754 
Sulfuric Acid 758 
Sunflower Oil 760 
Suppository Bases, Hard Fat 762 
Talc 767 
Tartaric Acid 770 
Tetrafluoroethane (HFC) 772 
Thaumatin 775 
Thimerosal 777 
Thymol 780 
Titanium Dioxide 782 
Tragacanth 785 
Trehalose 788 
Triacetin 790 
Tributyl Citrate 792 
Triethanolamine 794 
Triethyl Citrate 796 
Vanillin 798 
Vegetable Oil, Hydrogenated 800 
Water 802 
Wax, Anionic Emulsifying 807 
Wax, Carnauba 809 
Wax, Cetyl Esters 811 
Wax, Microcrystalline 813 
Wax, Nonionic Emulsifying 815 
Wax, White 817 
Wax, Yellow 819 
Xanthan Gum 821 
Xylitol 824 
Zein 828 
Zinc Acetate 830 
Zinc Stearate 832 
Appendix I: Suppliers’ Directory 835 
Appendix II: List of Excipient ‘E’ Numbers 882 
Appendix III: List of Excipient ‘EINECS’ Numbers 884 
Appendix IV: List of Excipient Molecular Weights 886 
Index 889 
viii Contents

International Steering Committee 
Gregory E Amidon 
Pharmacia Corporation 
Kalamazoo, MI, USA 
Graham Buckton 
University of London 
London, UK 
Colin G Cable 
Western General Hospital 
Edinburgh, UK 
Brian A Carlin 
FMC Biopolymer 
Princeton, NJ, USA 
Walter Cook 
AstraZeneca 
Loughborough, UK 
Henk J de Jong 
Servier International Research Institute 
Courbevoie, France 
Stephen Edge 
DMV International 
Veghel, The Netherlands 
Roger T Guest 
GlaxoSmithKline 
Ware, Hertfordshire, UK 
Bruno Hancock 
Pfizer Inc 
Groton, CT, USA 
Stephen W Hoag 
University of Maryland at Baltimore 
Baltimore, MD, USA 
Arthur H Kibbe 
Wilkes University 
Wilkes-Barre, PA, USA 
William J Lambert 
Eisai Inc 
Research Triangle Park, NC, USA 
M Jayne Lawrence 
King’s College, University of London 
London, UK 
John MacLaine 
Boots Contract Manufacturing 
Nottingham, UK 
Colin P McCoy 
Queens University Belfast 
Belfast, UK 
R Christian Moreton 
Idenix Pharmaceuticals 
Cambridge, MA, USA 
Sandeep Nema 
Pfizer Inc 
Chesterfield, MO, USA 
Sia.n C Owen 
Royal Pharmaceutical Society of Great 
Britain 
London, UK 
Anthony Palmieri III 
University of Florida 
Gainesville, FL, USA 
Raymond C Rowe 
Intelligensys Ltd 
Billingham, UK 
Shirish A Shah 
Watson Pharmaceuticals 
Corona, CA, USA 
Bob Sherwood 
JRS Pharma 
Patterson, NY, USA 
Paul J Sheskey 
The Dow Chemical Co 
Midland, MI, USA 
Kamalinder K Singh 
SNDT Women’s University 
Mumbai, India 
Paul J Weller 
Royal Pharmaceutical Society of Great 
Britain 
London, UK 
Tim Wood 
GlaxoSmithKline 
Ware, Hertfordshire, UK 
Mukund Yelvigi 
Wyeth Research 
Pearl River, NY, USA 
Editorial Staff 
Editorial Staff of the Pharmaceutical Press: 
Laurent Y Galichet 
Louise ME McIndoe 
Sia.n C Owen 
Paul J Weller

Contributors 
O AbuBaker 
Pfizer Inc 
Ann Arbor, MI, USA 
KS Alexander 
University of Toledo 
Toledo, OH, USA 
LV Allen 
International Journal of Pharmaceutical 
Compounding 
Edmond, OK, USA 
GE Amidon 
Pharmacia Corporation 
Kalamazoo, Michigan, USA 
GP Andrews 
The Queen’s University of Belfast 
Belfast, UK 
NA Armstrong 
Harpenden, Hertfordshire, UK 
ME Aulton 
De Montford University 
Leicester, UK 
S Behn 
AstraZeneca 
Macclesfield, UK 
M Bond 
Danisco Sweeteners Ltd 
Redhill, Surrey, UK 
CG Cable 
Western General Hospital 
Edinburgh, UK 
E Cahill 
AstraZeneca 
Macclesfield, UK 
W Camarco 
ISP Corp 
Wayne, NJ, USA 
WG Chambliss 
University of Mississippi 
University, MS, USA 
RK Chang 
Shire Laboratory 
Rockville, MD, USA 
R Chen 
Pfizer Inc 
Groton, CT, USA 
JH Chu 
Pfizer Inc 
Groton, CT, USA 
JH Collett 
University of Manchester 
Manchester, UK 
JT Colvin 
Pfizer Inc 
Groton, CT, USA 
W Cook 
AstraZeneca 
Loughborough, UK 
DQM Craig 
The University of East Anglia 
Norwich, UK 
TC Dahl 
Gilead Sciences 
Foster City, CA, USA 
A Day 
AstraZeneca 
Loughborough, UK 
HJ de Jong 
Servier International Research Institute 
Courbevoie, France 
SP Denyer 
University of Cardiff 
Cardiff, UK 
X Duriez 
Roquette Fre`res 
Lestrem, France 
S Edge 
DMV International 
Veghel, The Netherlands 
K Fowler 
Schering-Plough Healthcare Products 
Memphis, TN, USA 
SO Freers 
Grain Processing Corporation 
Muscatine, IA, USA 
B Fritzsching 
Palatinit GmbH 
Mannheim, Germany 
G Frunzi 
Bristol-Myers Squibb 
New Brunswick, NJ, USA 
LY Galichet 
Royal Pharmaceutical Society of Great 
Britain 
London, UK 
SR Goskonda 
Sunnyvale, CA, USA 
JL Gray 
The Queen’s University of Belfast 
Belfast, UK 
RT Guest 
GlaxoSmithKline 
Ware, Hertfordshire, UK 
RR Gupta 
SNDT Women’s University 
Mumbai, India 
VK Gupta 
Tyco HealthCare Mallinckrodt 
St Louis, MO, USA 
G Haest 
Cargill Cerestar BVBA 
Mechelen, Belgium 
BC Hancock 
Pfizer Inc 
Groton, CT, USA 
RJ Harwood 
Bensalem, PA, USA 
S Hem 
Purdue University 
West Lafayette, IN, USA 
L Hendricks 
Rhodia Inc 
Cranbury, NJ, USA 
SE Hepburn 
Bristol Royal Infirmary 
Bristol, UK

NA Hodges 
University of Brighton 
Brighton, UK 
JT Irwin 
Perrigo Corporation 
MI, USA 
BR Jasti 
University of the Pacific 
Stockton, CA, USA 
R Johnson 
AstraZeneca 
Loughborough, UK 
DS Jones 
The Queen’s University of Belfast 
Belfast, UK 
AS Kearney 
GlaxoSmithKline 
King-of-Prussia, PA, USA 
SW Kennedy 
Morflex Inc 
Greensboro, NC, USA 
VL Kett 
The Queen’s University of Belfast 
Belfast, UK 
AH Kibbe 
Wilkes University 
Wilkes-Barre, PA, USA 
V King 
Rhodia Inc 
Cranbury, NJ, USA 
PB Klepak 
Reheis Inc 
Berkley Heights, NJ, USA 
JJ Koleng 
University of Texas at Austin 
Austin, TX, USA 
K Kussendrager 
DMV International 
Veghel, The Netherlands 
WJ Lambert 
Eisai Inc 
Research Triangle Park, NC, USA 
BA Langdon 
Pfizer Inc 
Groton, CT, USA 
MJ Lawrence 
King’s College, University of London 
London, UK 
JC Lee 
Cellegy 
San Jose., CA, USA 
MG Lee 
Medicines and Healthcare products 
Regulatory Agency 
London, UK 
X Li 
University of the Pacific 
Stockton, CA, USA 
EB Lindblad 
Brenntag Biosector 
Frederikssund, Denmark 
O Luhn 
Palatinit GmbH 
Mannheim, Germany 
PE Luner 
Pfizer Inc 
Groton, CT, USA 
HJ Mawhinney 
The Queen’s University of Belfast 
Belfast, UK 
CP McCoy 
The Queen’s University of Belfast 
Belfast, UK 
OS McGarvey 
The Queen’s University of Belfast 
Belfast, UK 
JW McGinity 
University of Texas at Austin 
Austin, TX, USA 
LME McIndoe 
Royal Pharmaceutical Society of Great 
Britain 
London, UK 
LA Miller 
Pfizer Inc 
Groton, CT, USA 
RW Miller 
Bristol-Myers Squibb 
New Brunswick, NJ, USA 
J-P Mittwollen 
BASF Aktiengesellschaft 
Ludwigshafen, Germany 
RC Moreton 
Idenix Pharmaceuticals 
Cambridge, MA, USA 
G Mosher 
CyDex Inc 
Lenexa, KS, USA 
C Mroz 
Colorcon Ltd 
Dartford, Kent, UK 
MP Mullarney 
Pfizer Inc 
Groton, CT, USA 
S Murdande 
Pfizer Inc 
Groton, CT, USA 
RA Nash 
St John’s University 
Jamaica, NY, USA 
S Nema 
Pfizer Inc 
Chesterfield, MO, USA 
SC Owen 
Royal Pharmaceutical Society of Great 
Britain 
London, UK 
A Palmieri 
University of Florida 
Gainesville, FL, USA 
D Parsons 
ConvaTec Ltd 
Clwyd, UK 
Y Peng 
University of Tennessee 
Memphis, TN, USA 
JD Pipkin 
CyDex Inc 
Lenexa, KS, USA 
D Pipkorn 
Pfizer Inc 
Ann Arbor, MI, USA 
JC Price 
University of Georgia 
Athens, GA, USA 
MA Repka 
University of Mississippi 
University, MS, USA 
B Sarsfield 
Bristol-Myers Squibb 
New Brunswick, NJ, USA 
T Schmeller 
BASF Aktiengesellschaft 
Ludwigshafen, Germany 
A Schoch 
Palatinit GmbH 
Mannheim, Germany 
CJ Sciarra 
Sciarra Laboratories Inc 
Hicksville, NY, USA 
Contributors xi

JJ Sciarra 
Sciarra Laboratories Inc 
Hicksville, NY, USA 
SA Shah 
Watson Pharmaceuticals 
Corona, CA, USA 
RM Shanker 
Pfizer Inc 
Groton, CT, USA 
PJ Sheskey 
The Dow Chemical Co 
Midland, MI, USA 
AJ Shukla 
University of Tennessee 
Memphis, TN, USA 
KK Singh 
SNDT Women’s University 
Mumbai, India 
R Steer 
AstraZeneca 
Loughborough, UK 
JT Stewart 
University of Georgia 
Athens, GA, USA 
Y Sun 
University of Tennessee 
Memphis, TN, USA 
AK Taylor 
Baton Rouge, LA, USA 
MS Tesconi 
Wyeth Research 
Pearl River, NY, USA 
D Thassu 
UCB Pharma Inc 
Rochester, NY, USA 
BF Truitt 
Pfizer Inc 
Groton, CT, USA 
CK Tye 
Pfizer Inc 
Kalamazoo, MI, USA 
HM Unvala 
Bayer Corporation 
Myerstown, PA, USA 
KD Vaughan 
Boots Healthcare International 
Nottingham, UK 
H Wang 
Pfizer Inc 
Groton, CT, USA 
PJ Weller 
Royal Pharmaceutical Society of Great 
Britain 
London, UK 
AJ Winfield 
Aberdeen, UK 
AW Wood 
GlaxoSmithKline 
Research Triangle Park, NC, USA 
M Yelvigi 
Wyeth Research 
Pearl River, NY, USA 
PM Young 
University of Sydney 
Sydney, Australia 
About the Editors 
Raymond C Rowe 
BPharm, PhD, DSc, FRPharmS, CChem, FRSC, CPhys, MInstP 
Raymond Rowe has been involved in the Handbook of 
Pharmaceutical Excipients since the first edition was published 
in 1986, initially as an author then as a Steering Committee 
member. In addition to his position as Chief Scientist at 
Intelligensys, UK, he is also Professor of Industrial Pharmaceutics 
at the School of Pharmacy, University of Bradford, UK. He 
was formerly Senior Principal Scientist at AstraZeneca, UK. In 
1998 he was awarded the Chiroscience Industrial Achievement 
Award, and in 1999 he was the British Pharmaceutical 
Conference Science Chairman. He has contributed to over 
350 publications in the pharmaceutical sciences including a 
book and eight patents. 
Paul J Sheskey 
BSc, RPh 
Paul Sheskey has been involved in the Handbook of Pharmaceutical 
Excipients as an author and member of the Steering 
Committee since the third edition. He is a Technical Service 
Leader in the Water Soluble Polymers, Pharmaceutical R&D 
Group at The Dow Chemical Company in Midland, Michigan, 
USA. Paul received his BSc degree in pharmacy from Ferris 
State University. Previously, he has worked as a research 
pharmacist in the area of solid dosage form development at the 
Perrigo Company and the Upjohn (Pharmacia) Company. Paul 
has authored numerous journal articles in the area of 
pharmaceutical technology. He is a member of the AAPS, 
Controlled Release Society, and the Institute for Briquetting and 
Agglomeration. 
Sia.n C Owen 
BSc, MA 
Sia.n Owen has been involved with the Handbook of 
Pharmaceutical Excipients since the fourth edition, as a 
contributor and Steering Committee member. Sia.n received 
her BSc degree in pharmacology from the University of 
Sunderland, and her MA in biotechnological law and ethics 
from the University of Sheffield. 
xii Contributors

New Monographs 
The following new monographs have been added to the Handbook of Pharmaceutical Excipients, 5th edition. 
Acetone 
Agar 
Aluminum Hydroxide Adjuvant 
Aluminum Oxide 
Aluminum Phosphate Adjuvant 
Ammonium Alginate 
Aluminum Stearate 
Boric Acid 
Calcium Alginate 
Cetylpyridinium Chloride 
Copovidone 
Dimethylacetamide 
Disodium Edetate 
Erythorbic Acid 
Erythritol 
Ethyl Lactate 
Ethylene Vinyl Acetate 
Hectorite 
Hydroxypropyl Starch 
Hypromellose Acetate Succinate 
Inulin 
Iron Oxides 
Isomalt 
Lactose, Anhydrous 
Lactose, Monohydrate 
Lactose, Spray-Dried 
Lauric Acid 
Leucine 
Linoleic Acid 
Macrogol 15 Hydroxystearate 
Myristic Acid 
Neohesperidin Dihydrochalcone 
Octyldodecanol 

Oleyl Alcohol 
Palmitic Acid 
Pectin 
Polycarbophil 
Poly(methylvinyl ether/maleic anhydride) 
Potassium Alginate 
2-Pyrrolidone 
Raffinose 
Saponite 
Sodium Acetate 
Sodium Borate 
Sodium Hyaluronate 
Sodium Lactate 
Sodium Sulfite 
Sulfobutylether b-Cyclodextrin 
Thaumatin 
Thymol 
Zinc Acetate

Related Substances 
Acetic acid 
Activated attapulgite 
Aleuritic acid 
d-Alpha tocopherol 
d-Alpha tocopheryl acetate 
dl-Alpha tocopheryl acetate 
d-Alpha tocopheryl acid succinate 
dl-Alpha tocopheryl acid succinate 
Aluminum distearate 
Aluminum monostearate 
Amylopectin 
a-Amylose 
Anhydrous citric acid 
Anhydrous sodium citrate 
Anhydrous sodium propionate 
Artificial vinegar 
Bacteriostatic water for injection 
Bentonite magma 
Beta tocopherol 
Beta-carotene 
n-Butyl lactate 
Butylparaben sodium 
Calcium ascorbate 
Calcium cyclamate 
Calcium polycarbophil 
Calcium propionate 
Calcium silicate 
Calcium sorbate 
Calcium sulfate hemihydrate 
Capric acid 
Carbon dioxide-free water 
Cationic emulsifying wax 
Ceratonia extract 
Cetylpyridinium bromide 
Chlorhexidine acetate 
Chlorhexidine gluconate 
Chlorhexidine hydrochloride 
Chlorodifluoromethane 
Chlorophenoxyethanol 
Corn syrup solids 
m-Cresol 
o-Cresol 
p-Cresol 
Crude olive-pomace oil 
Cyclamic acid 
De-aerated water 
Dehydrated alcohol 
Delta tocopherol 
Denatured alcohol 
Dextrose anhydrous 
Diazolidinyl urea 
Dibasic potassium phosphate 
Diethylene glycol monopalmitostearate 
Dilute acetic acid 
Dilute alcohol 
Dilute ammonia solution 
Dilute hydrochloric acid 
Dilute phosphoric acid 
Dilute sulfuric acid 
Dimethyl-b-cyclodextrin 
Dioctyl phthalate 
Dipotassium edetate 
Docusate calcium 
Docusate potassium 
Dodecyl gallate 
Dodecyltrimethylammonium bromide 
Edetate calcium disodium 
Eglumine 
Ethyl gallate 
Ethylene glycol monopalmitate 
Ethylene glycol monostearate 
Ethyl linoleate 
Ethylparaben potassium 
Ethylparaben sodium 
Extra virgin olive oil 
Fine virgin olive oil 
Fuming sulfuric acid 
Gamma tocopherol 
Hard water 
Hesperidin 
Hexadecyltrimethylammonium bromide 
High-fructose syrup 
Hyaluronic acid 
Hydrogenated lanolin 
Hydrogenated vegetable oil, type II 
2-Hydroxyethyl-b-cyclodextrin 
2-Hydroxypropyl-b-cyclodextrin 
3-Hydroxypropyl-b-cyclodextrin 
Indigo carmine 
Invert sugar 
Isotrehalose 
Lampante virgin olive oil 
Lanolin alcohols ointment 
DL-Leucine 
Liquefied phenol 
Liquid fructose 
Magnesium carbonate anhydrous 
Magnesium carbonate hydroxide 
Magnesium lauryl sulfate 
Magnesium metasilicate 
Magnesium orthosilicate 
Magnesium trisilicate anhydrous 
D-Malic acid 
L-Malic acid 
d-Menthol 
l-Menthol 
Methyl lactate 
Methyl linoleate 
Methyl methacrylate 
Methyl oleate

Methylparaben potassium 
Methylparaben sodium 
N-Methylpyrrolidone 
Microcrystalline cellulose and carboxymethylcellulose sodium 
Microcrystalline cellulose and carrageenan 
Microcrystalline cellulose and guar gum 
Modified lanolin 
Monobasic potassium phosphate 
Montmorillonite 
Myristyl alcohol 
Neotrehalose 
Normal magnesium carbonate 
Octyl gallate 
Oleyl oleate 
Olive-pomace oil 
Palmitin 
Pharmaceutical glaze 
Phenoxypropanol 
Polacrilin 
Poly(methyl methacrylate) 
Potassium bisulfite 
Potassium myristate 
Potassium propionate 
Powdered fructose 
Propan-1-ol 
(S)-Propylene carbonate 
Propylparaben potassium 
Propylparaben sodium 
Purified bentonite 
Purified stearic acid 
Quaternium 18-hectorite 
Rapeseed oil 
Refined almond oil 
Refined olive-pomace oil 
Saccharin ammonium 
Saccharin calcium 
Self-emulsifying glyceryl monostearate 
Shellolic acid 
Sodium bisulfite 
Sodium borate anhydrous 
Sodium edetate 
Sodium erythorbate 
Sodium laurate 
Sodium myristate 
Sodium palmitate 
Sodium sorbate 
Sodium sulfite heptahydrate 
Soft water 
Sorbitol solution 70% 
Spermaceti wax 
Stearalkonium hectorite 
Sterile water for inhalation 
Sterile water for injection 
Sterile water for irrigation 
Sunset yellow FCF 
Synthetic paraffin 
DL-(
)-Tartaric acid 
Tartrazine 
Theobroma oil 
Tocopherols excipient 
Tribasic sodium phosphate 
Trimethyl-b-cyclodextrin 
Trimethyltetradecylammonium bromide 
Trisodium edetate 
Virgin olive oil 
Water for injection 
White petrolatum 
Zinc propionate 
Related Substances xv

Preface 
Pharmaceutical dosage forms contain both pharmacologically 
active compounds and excipients added to aid the formulation 
and manufacture of the subsequent dosage form for administration 
to patients. Indeed, the properties of the final dosage 
form (i.e. its bioavailability and stability) are, for the most part, 
highly dependent on the excipients chosen, their concentration 
and interaction with both the active compound and each other. 
No longer can excipients be regarded simply as inert or inactive 
ingredients, and a detailed knowledge not only of the physical 
and chemical properties but also of the safety, handling and 
regulatory status of these materials is essential for formulators 
throughout the world. In addition, the growth of novel forms of 
delivery has resulted in an increase in the number of the 
excipients being used and suppliers of excipients have developed 
novel excipient mixtures and new physical forms to 
improve their properties. The Handbook of Pharmaceutical 
Excipients has been conceived as a systematic, comprehensive 
resource of information on all of these topics 
The first edition of the Handbook was published in 1986 and 
contained 145 monographs. This was followed by the second 
edition in 1994 containing 203 monographs, the third edition 
in 2000 containing 210 monographs and the fourth edition in 
2003 containing 249 monographs. Since 2000, the data has 
also been available on CD-ROM, updated annually, and from 
2004 online. This new printed edition with its companion CDROM, 
Pharmaceutical Excipients 5, contains 300 monographs 
compiled by over 120 experts in pharmaceutical formulation or 
excipient manufacture from Australia, Europe, India and the 
USA. All the monographs have been reviewed and revised in the 
light of current knowledge. There has been a greater emphasis 
on including published data from primary sources although 
some data from laboratory projects included in previous 
editions have been retained where relevant. Variations in test 
methodology can have significant effects on the data generated 
(especially in the case of the compactability of an excipient), 
and thus cause confusion. As a consequence, the editors have 
been more selective in including data relating to the physical 
properties of an excipient. However, comparative data that 
show differences between either source or batch of a specific 
excipient have been retained as this was considered relevant to 
the behavior of a material in practice. The Suppliers Directory 
(Appendix I) has also been completely updated with many more 
international suppliers included. 
In a systematic and uniform manner, the Handbook of 
Pharmaceutical Excipients collects essential data on the 
physical properties of excipients such as: boiling point, bulk 
and tap density, compression characteristics, hygroscopicity, 
flowability, melting point, moisture content, moisture-absorption 
isotherms, particle size distribution, rheology, specific 
surface area, and solubility. Scanning electron microphotographs 
(SEMs) are also included for many of the excipients. The 
Handbook contains information from various international 
sources and personal observation and comments from monograph 
authors, steering committee members, and the editors. 
All of the monographs in the Handbook are thoroughly 
cross-referenced and indexed so that excipients may be 
identified by either a chemical, a nonproprietary, or a trade 
name. Most monographs list related substances to help the 
formulator to develop a list of possible materials for use in a 
new dosage form or product. Related substances are not 
directly substitutable for each other but, in general, they are 
excipients that have been used for similar purposes in various 
dosage forms. 
The Handbook of Pharmaceutical Excipients is a comprehensive, 
uniform guide to the uses, properties, and safety of 
pharmaceutical excipients, and is an essential reference source 
for those involved in the development, production, control, or 
regulation of pharmaceutical preparations. Since many pharmaceutical 
excipients are also used in other applications, the 
Handbook of Pharmaceutical Excipients will also be of value to 
persons with an interest in the formulation or production of 
confectionery, cosmetics, and food products.

Arrangement 
The information consists of monographs that are divided into 
22 sections to enable the reader to find the information of 
interest easily. Although it was originally intended that each 
monograph contain only information about a single excipient, 
it rapidly became clear that some substances or groups of 
substances should be discussed together. This gave rise to such 
monographs as ‘Coloring Agents’ and ‘Hydrocarbons’. In 
addition, some materials have more than one monograph 
depending on the physical characteristics of the material, e.g. 
Starch versus Pregelatinized Starch. Regardless of the complexity 
of the monograph they are all divided into 22 sections as 
follows: 
1 Nonproprietary Names 
2 Synonyms 
3 Chemical Name and CAS Registry Number 
4 Empirical Formula and Molecular Weight 
5 Structural Formula 
6 Functional Category 
7 Applications in Pharmaceutical Formulation or 
Technology 
8 Description 
9 Pharmacopeial Specifications 
10 Typical Properties 
11 Stability and Storage Conditions 
12 Incompatibilities 
13 Method of Manufacture 
14 Safety 
15 Handling Precautions 
16 Regulatory Status 
17 Related Substances 
18 Comments 
19 Specific References 
20 General References 
21 Authors 
22 Date of Revision 
Descriptions of the sections appear below with information 
from an example monograph if needed. 
Section 1, Nonproprietary Names, lists the excipient names 
used in the current British Pharmacopoeia, European Pharmacopeia, 
Japanese Pharmacopeia, and the United States Pharmacopeia/
National Formulary. 
Section 2, Synonyms, lists other names for the excipient, 
including trade names used by suppliers (shown in italics). 
The inclusion of one supplier’s trade name and the absence of 
others should in no way be interpreted as an endorsement of 
one supplier’s product over the other. The large number of 
suppliers internationally makes it impossible to include all the 
trade names. 
Section 3, Chemical Name and CAS Registry Number, indicates 
the unique Chemical Abstract Services number for an 
excipient along with the chemical name, e.g., Acacia [9000- 
01-5]. 
Sections 4 and 5, Empirical Formula and Molecular Weight 
and Structural Formula, are self-explanatory. Many excipients 
are not pure chemical substances, in which case their composition 
is described either here or in Section 8. 
Section 6, Functional Category, lists the function(s) that an 
excipient is generally thought to perform, e.g., diluent, emulsifying 
agent, etc. 
Section 7, Applications in Pharmaceutical Formulation or Technology, 
describes the various applications of the excipient. 
Section 8, Description, includes details of the physical appearance 
of the excipient, e.g., white or yellow flakes, etc. 
Section 9, Pharmacopeial Specifications, briefly presents the 
compendial standards for the excipient. Information included 
is obtained from the British Pharmacopoeia (BP), European 
Pharmacopeia (PhEur), Japanese Pharmacopeia (JP), and the 
United States Pharmacopeia/National Formulary (USP/ 
USPNF). Information from the JP, USP and USPNF are 
included if the substance is in those compendia. Information 
from the PhEur is also included. If the excipient is not in the 
PhEur but is included in the BP, information is included from 
the BP. Pharmacopeias are continually updated with most 
now being produced as annual editions. However, although 
efforts were made to include up-to-date information at the 
time of publication of this edition, the reader is advised to 
consult the most current pharmacopeias or supplements. 
Section 10, Typical Properties, describes the physical properties 
of the excipient which are not shown in Section 9. All 
data are for measurements made at 208C unless otherwise 
indicated. Where the solubility of the excipient is described in 
words, the following terms describe the solubility ranges: 
Very soluble 1 part in less than 1 
Freely soluble 1 part in 1–10 
Soluble 1 part in 10–30 
Sparingly soluble 1 part in 30–100 
Slightly soluble 1 part in 100–1000 
Very slightly soluble 1 part in 1000–10 000 
Practically insoluble 1 part in more than 10 000 
or insoluble 
Where practical, data typical of the excipient or comparative 
data representative of different grades or sources of a material 
are included, the data being obtained from either the primary or 
the manufacturers’ literature. In previous editions of the 
Handbook a laboratory project was undertaken to determine 
data for a variety of excipients and in some instances this data 
has been retained. For a description of the specific methods

used to generate the data readers should consult the appropriate 
previous edition(s) of the Handbook. 
Section 11, Stability and Storage Conditions, describes the 
conditions under which the bulk material as received from 
the supplier should be stored. In addition some monographs 
report on storage and stability of the dosage forms that contain 
the excipient. 
Section 12, Incompatibilities, describes the reported incompatibilities 
for the excipient either with other excipients or with 
active ingredients. If an incompatibility is not listed it does 
not mean it does not occur but simply that it has not been 
reported or is not well known. Every formulation should be 
tested for incompatibilities prior to use in a commercial product. 
Section 13, Method of Manufacture, describes the common 
methods of manufacture and additional processes that are 
used to give the excipient its physical characteristics. In some 
cases the possibility of impurities will be indicated in the 
method of manufacture. 
Section 14, Safety, describes briefly the types of formulations 
in which the excipient has been used and presents relevant 
data concerning possible hazards and adverse reactions that 
have been reported. Relevant animal toxicity data are also 
shown. 
Section 15, Handling Precautions, indicates possible hazards 
associated with handling the excipient and makes recommendations 
for suitable containment and protection methods. A 
familiarity with current good laboratory practice (GLP) and 
current good manufacturing practice (GMP) and standard 
chemical handling procedures is assumed. 
Section 16, Regulatory Status, describes the accepted uses in 
foods and licensed pharmaceuticals where known. However, 
the status of excipients varies from one nation to another, 
and appropriate regulatory bodies should be consulted for 
guidance. 
Section 17, Related Substances, lists excipients similar to the 
excipient discussed in the monograph. 
Section 18, Comments, includes additional information and 
observations relevant to the excipient. Where appropriate, the 
different grades of the excipient available are discussed. Comments 
are the opinion of the listed author(s) unless referenced 
or indicated otherwise. 
Section 19, Specific References, is a list of references cited 
within the monograph. 
Section 20, General References, lists references which have 
general information about this type of excipient or the types 
of dosage forms made with these excipients. 
Section 21, Authors, lists the current authors of the monograph 
in alphabetical order. Authors of previous versions of 
the monograph are shown in previous printed editions of the 
text. 
Section 22, Date of Revision, indicates the date on which 
changes were last made to the text of the monograph. 
xviii Arrangement

Acknowledgments 
A publication containing so much detail could not be produced 
without the help of a large number of pharmaceutical scientists 
based world-wide. The voluntary support of over 120 authors 
has been acknowledged as in previous editions, but the current 
editors would like to thank them all personally for their 
contribution. Grateful thanks also go to the members of the 
International Steering Committee who advised the editors and 
publishers on all aspects of the Handbook project. Steering 
Committee members also diligently reviewed all of the 
monographs before their publication. Many authors and 
Steering Committee members have been involved in previous 
editions of the Handbook. For others, this was their first edition 
although not, we hope, their last. Walter Chambliss and John 
Hogan retired from the International Steering Committee 
during the preparation of this edition and we extend our 
thanks for their support over many years. Thanks are also 
extended to excipient manufacturers and suppliers who 
provided helpful information on their products. 
Thanks are also gratefully extended to the staff of the 
Pharmaceutical Press and American Pharmacists Association 
who were involved in the production of the Handbook: Eric 
Connor, Tamsin Cousins, Simon Dunton, Laurent Galichet, 
Julian Graubart, Louise McIndoe, Karl Parsons, Paul Weller, 
and John Wilson. Once again, the diligent copy-editing and 
challenging questions asked by Len Cegielka helped the authors 
and editors, we hope, to express their thoughts clearly, 
concisely, and accurately. 
Raymond C Rowe, Paul J Sheskey and Sia.n C Owen 
August 2005 
Notice to Readers 
The Handbook of Pharmaceutical Excipients is a reference 
work containing a compilation of information on the uses and 
properties of pharmaceutical excipients, and the reader is 
assumed to possess the necessary knowledge to interpret the 
information that the Handbook contains. The Handbook of 
Pharmaceutical Excipients has no official status and there is no 
intent, implied or otherwise, that any of the information 
presented should constitute standards for the substances. The 
inclusion of an excipient, or a description of its use in a 
particular application, is not intended as an endorsement of 
that excipient or application. Similarly, reports of incompatibilities 
or adverse reactions to an excipient, in a particular 
application, may not necessarily prevent its use in other 
applications. Formulators should perform suitable experimental 
studies to satisfy themselves and regulatory bodies that a 
formulation is efficacious and safe to use. 
While considerable efforts were made to ensure the accuracy 
of the information presented in the Handbook, neither the 
publishers nor the compilers can accept liability for any errors 
or omissions. In particular, the inclusion of a supplier within the 
Suppliers Directory is not intended as an endorsement of that 
supplier or its products and, similarly, the unintentional 
omission of a supplier or product from the directory is not 
intended to reflect adversely on that supplier or its product. 
Although diligent effort was made to use as recent 
compendial information as possible, compendia are frequently 
revised and the reader is urged to consult current compendia, or 
supplements, for up-to-date information, particularly as efforts 
are currently in progress to harmonize standards for excipients. 
Data presented for a particular excipient may not be 
representative of other batches or samples. 
Relevant data and constructive criticism are welcome and 
may be used to assist in the preparation of any future editions 
or electronic versions of the Handbook. The reader is asked to 
send any comments to the Editor, Handbook of Pharmaceutical 
Excipients, Royal Pharmaceutical Society of Great Britain, 1 
Lambeth High Street, London SE1 7JN, UK, or Editor, 
Handbook of Pharmaceutical Excipients, American Pharmacists 
Association, 2215 Constitution Avenue,NW,Washington, 
DC 20037-2985, USA.

Bibliography 
A selection of publications and websites which contain useful information on pharmaceutical excipients is listed below: 
Ash M, Ash I. Handbook of Pharmaceutical Additives, 2nd 
edn. Endicott, NY: Synapse Information Resources, 2002. 
Aulton ME, ed. Pharmaceutics: the Science of Dosage Form 
Design, 2nd edn. Edinburgh: Churchill Livingstone, 2002. 
Banker GS, Rhodes CT, eds. Modern Pharmaceutics, 4th edn. 
New York: Marcel Dekker, 2002. 
British Pharmacopoeia 2004. London: The Stationery Office, 
2004. 
Bugay DE, Findlay WP. Pharmaceutical Excipients Characterization 
by IR, Raman, and NMR Spectroscopy. New York: 
Marcel Dekker, 1999. 
European Pharmacopoeia, 5th edn. and supplements. Strasbourg: 
Council of Europe, 2005. 
Florence AT, Salole EG, eds. Formulation Factors in Adverse 
Reactions. London: Butterworth, 1990. 
Food and Drug Administration. Inactive Ingredient Guide. 
http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm 
(accessed 11 July 2005). 
Food Chemicals Codex, 4th edn. Washington, DC: National 
Academy Press, 1996. 
Health and Safety Executive. EH40/2002: Occupational 
Exposure Limits 2002. Sudbury: Health and Safety Executive, 
2001. 
Health Canada. Canadian List of Acceptable Non-medicinal 
Ingredients. (accessed 11 July 2005) 
Hoepfner E, Reng A, Schmidt PC, eds. Fiedler Encyclopedia of 
Excipients for Pharmaceuticals, Cosmetics and Related 
Areas. Aulendorf, Germany: Editio Cantor, 2002. 
Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004. 
Japanese Pharmacopeia, 14th edn. and supplement. Tokyo: 
Yakuji Nippo, 2001. 
Kemper FH, Luepke N-P, Umbach W, eds. Blue List Cosmetic 
Ingredients. Aulendorf, Germany: Editio Cantor, 2000. 
Lewis RJ, ed. Sax’s Dangerous Properties of Industrial 
Materials, 11th edn. New York: John Wiley, 2004. 
Lund W, ed. The Pharmaceutical Codex: Principles and 
Practice of Pharmaceutics, 12th edn. London: Pharmaceutical 
Press, 1994. 
National Library of Medicine. TOXNET. 
http://toxnet.nlm.nih.gov (accessed 11 July 2005) 
O’Neil MJ, Smith A, Heckelman PE, eds.The Merck Index: an 
Encyclopedia of Chemicals, Drugs, and Biologicals, 13th 
edn. Whitehouse Station, NJ: Merck, 2001. 
Smolinske SC. Handbook of Food, Drug and Cosmetic 
Excipients. Boca Raton, FL: CRC Press, 1992. 
Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical 
Technology, 2nd edn. New York: Marcel Dekker, 2002. 
Sweetman SC, ed. Martindale: the Complete Drug Reference, 
34rd edn. London: Pharmaceutical Press, 2005. 
United States Pharmacopeia 28 and National Formulary 23. 
and supplement. Rockville, MD: United States Pharmacopeial 
Convention, 2005. 
University of the Sciences in Philadelphia. Remington: the 
Science and Practice of Pharmacy, 21st edn. Baltimore: 
Lippincott Williams and Wilkins, 2005. 
Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation 
Agents: a Handbook of Excipients. New York: Marcel 
Dekker, 1989. 
Weiner ML, Kotkoskie LA, eds. Excipient Toxicity and Safety. 
New York: Marcel Dekker, 2000. 
Abbreviations 
Some units, terms, and symbols are not included in this list as they are defined in the text. Common abbreviations have been omitted. 
The titles of journals are abbreviated according to the general style of the Index Medicus. 
 approximately. 
Ad Addendum. 
ADI acceptable daily intake. 
approx approximately. 
atm atmosphere. 
BAN British Approved Name. 
bp boiling point. 
BP British Pharmacopoeia. 
BS British Standard (specification). 
BSI British Standards Institution. 
cal calorie(s). 
CAS Chemical Abstract Service. 
CFC chlorofluorocarbon. 
cm centimeter(s). 
cm2 square centimeter(s). 
cm3 cubic centimeter(s). 
cmc critical micelle concentration. 
CNS central nervous system. 
cP centipoise(s). 
cSt centistoke(s). 
CTFA Cosmetic, Toiletry, and Fragrance Association. 
D&C designation applied in USA to dyes permitted for use 
in drugs and cosmetics. 
DoH Department of Health (UK).

DSC differential scanning calorimetry. 
EC European Community. 
e.g. exemplit gratia, ‘for example’. 
EINECS European Inventory of Existing Commercial 
Chemical Substances. 
et al et alii, ‘and others’. 
EU European Union. 
FAO Food and Agriculture Organization of the United 
Nations. 
FAO/ Food and Agriculture Organization of the United 
WHO Nations and the World Health Organization. 
FCC Food Chemicals Codex. 
FDA Food and Drug Administration of the USA. 
FD&C designation applied in USA to dyes permitted for use 
in foods, drugs, and cosmetics. 
FFBE Flat face beveled edge. 
g gram(s). 
GMP Good Manufacturing Practice. 
GRAS generally recognized as safe by the Food and Drug 
Administration of the USA. 
HC hydrocarbon. 
HCFC hydrochlorofluorocarbon. 
HFC hydrofluorocarbon. 
HIV human immunodeficiency virus. 
HLB hydrophilic–lipophilic balance. 
HSE Health and Safety Executive (UK). 
i.e. id est, ‘that is’. 
IM intramuscular. 
INN International Nonproprietary Name. 
IP intraperitoneal. 
ISO International Organization for Standardization. 
IU International Units. 
IV intravenous. 
J joule(s). 
JP Japanese Pharmacopeia. 
JPE Japanese Pharmaceutical Excipients 
kcal kilocalorie(s). 
kg kilogram(s). 
kJ kilojoule(s). 
kPa kilopascal(s). 
L liter(s). 
LAL Limulus amoebocyte lysate. 
LC50 a concentration in air lethal to 50% of the specified 
animals on inhalation. 
LD50 a dose lethal to 50% of the specified animals or 
microorganisms. 
LdLo lowest lethal dose for the specified animals or 
microorganisms. 
m meter(s). 
m2 square meter(s). 
m3 cubic meter(s). 
M molar. 
max maximum. 
MCA Medicines Control Agency (UK). 
mg milligram(s). 
MIC minimum inhibitory concentration. 
min minute(s) or minimum. 
mL milliliter(s). 
mm millimeter(s). 
mM millimolar. 
mm2 square millimeter(s). 
mm3 cubic millimeter(s). 
mmHg millimeter(s) of mercury. 
mmol millimole(s). 
mN millinewton(s). 
mol mole(s). 
mp melting point. 
mPa millipascal(s). 
MPa megapascal(s). 
mg microgram(s). 
mm micrometer(s). 
N newton(s) or normal (concentration). 
nm nanometer(s). 
o/w oil-in-water. 
o/w/o oil-in-water-in-oil. 
Pa pascal(s). 
pH the negative logarithm of the hydrogen ion 
concentration. 
PhEur European Pharmacopeia. 
pKa the negative logarithm of the dissociation constant. 
pph parts per hundred. 
ppm parts per million. 
psia pounds per square inch absolute. 
RDA recommended dietary allowance (USA). 
rpm revolutions per minute. 
s second(s). 
SC subcutaneous. 
SEM scanning electron microscopy or scanning electron 
microphotograph. 
SI Statutory Instrument or SystU. me International 
d’Unites (International System of Units). 
TPN total parental nutrition. 
TWA time weighted average. 
UK United Kingdom. 
US or United States of America. 
USA 
USAN United States Adopted Name. 
USP The United States Pharmacopeia. 
USPNF The United States Pharmacopeia National 
Formulary. 
UV ultraviolet. 
v/v volume in volume. 
v/w volume in weight. 
WHO World Health Organization. 
w/o water-in-oil. 
w/o/w water-in-oil-in-water. 
w/v weight in volume. 
w/w weight in weight. 
Abbreviations xxi

Units of Measurement 
The information below shows imperial to SI unit conversions 
for the units of measurement most commonly used in the 
Handbook. SI units are used throughout with, where appropriate, 
imperial units reported in parentheses. 
Area 
1 square inch (in2) = 6.4516  10–4 square meter (m2) 
1 square foot (ft2) = 9.29030  10–2 square meter (m2) 
1 square yard (yd2) = 8.36127  10–1 square meter (m2) 
Density 
1 pound per cubic foot (lb/ft3) = 16.0185 kilograms per cubic 
meter (kg/m3) 
Energy 
1 kilocalorie (kcal) = 4.1840  103 joules (J) 
Force 
1 dyne (dynes) = 1  10–5 newton (N) 
Length 
1 angstrom (a.) = 10–10 meter (m) 
1 inch (in) = 2.54  10–2 meter (m) 
1 foot (ft) = 3.048  10–1 meter (m) 
1 yard (yd) = 9.144  10–1 meter (m) 
Pressure 
1 atmosphere (atm) = 0.101325 megapascal (MPa) 
1 millimeter of mercury (mmHg) = 133.322 pascals (Pa) 
1 pound per square inch (psi) = 6894.76 pascals (Pa) 
Surface tension 
1 dyne per centimeter (dyne/cm) = 1 millinewton per meter 
(mN/m) 
Temperature 
Celsius (8C) = (1.8  8C) . 32 Fahrenheit (8F) 
Fahrenheit (8F) = (0.556  8F) –17.8 Celsius (8C) 
Viscosity (dynamic) 
1 centipoise (cP) = 1 millipascal second (mPa s) 
1 poise (P) = 0.1 pascal second (Pa s) 
Viscosity (kinematic) 
1 centistoke (cSt) = 1 square millimeter per second (mm2/s) 
Volume 
1 cubic inch (in3) = 1.63871  10–5 cubic meter (m3) 
1 cubic foot (ft3) = 2.83168  10–2 cubic meter (m3) 
1 cubic yard (yd3) = 7.64555  10–1 cubic meter (m3) 
1 pint (UK) = 5.68261  10–4 cubic meter (m3) 
1 pint (US) = 4.73176  10–4 cubic meter (m3) 
1 gallon (UK) = 4.54609  10–3 cubic meter (m3) 
1 gallon (US) = 3.78541  10–3 cubic meter (m3)

Acacia 
1 Nonproprietary Names 
BP: Acacia 
JP: Acacia 
PhEur: Acaciae gummi 
USPNF: Acacia 
2 Synonyms 
Acacia gum; arabic gum; E414; gum acacia; gummi africanum; 
gum arabic; gummi arabicum; gummi mimosae; talha gum. 
3 Chemical Name and CAS Registry Number 
Acacia [9000-01-5] 
4 Empirical Formula and Molecular Weight 
Acacia is a complex, loose aggregate of sugars and hemicelluloses 
with a molecular weight of approximately 
240 000–580 000. The aggregate consists essentially of an 
arabic acid nucleus to which are connected calcium, magnesium, 
and potassium along with the sugars arabinose, 
galactose, and rhamnose. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Emulsifying agent; stabilizing agent; suspending agent; tablet 
binder; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Acacia is mainly used in oral and topical pharmaceutical 
formulations as a suspending and emulsifying agent, often in 
combination with tragacanth. It is also used in the preparation 
of pastilles and lozenges, and as a tablet binder, although if used 
incautiously it can produce tablets with a prolonged disintegration 
time. Acacia has also been evaluated as a bioadhesive;(
1) and has been used in novel tablet formulations,(2) and 
modified release tablets.(3) See Table I. 
Acacia is also used in cosmetics, confectionery, food 
products, and spray-dried flavors.(4) 
See also Section 18. 
Table I: Uses of acacia. 
Use Concentration (%) 
Emulsifying agent 10–20 
Pastille base 10–30 
Suspending agent 5–10 
Tablet binder 1–5 
8 Description 
Acacia is available as white or yellowish-white thin flakes, 
spheroidal tears, granules, powder, or spray-dried powder. It is 
odorless and has a bland taste. 
9 Pharmacopeial Specifications 
The PhEur 2005 provides monographs on acacia and spraydried 
acacia, while the USPNF 23 describes acacia in a single 
monograph that encompasses tears, flakes, granules, powder, 
and spray-dried powder. The JP 2001 also has monographs on 
acacia and powdered acacia. See Table II. 
Table II: Pharmacopeial specifications for acacia. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters . . . 
Microbial limit — 4104/g . 
Water 417.0% 415.0% 415.0% 
415.0%(a) 410.0%(b) — 
Total ash 44.0% 44.0% 44.0% 
Acid-insoluble ash 40.5% — 40.5% 
Insoluble residue 40.2% 40.5% 450mg 
Arsenic — — 43 ppm 
Lead — — 40.001% 
Heavy metals — — 40.004% 
Starch, dextrin, and agar . . . 
Tannin-bearing gums . . . 
Tragacanth — . — 
Sterculia gum — . — 
Glucose and fructose — . — 
Solubility and reaction — — . 
Organic volatile impurities — — . 
(a) Powdered acacia. 
(b) Spray-dried acacia. 
10 Typical Properties 
Acidity/alkalinity: pH = 4.5–5.0 (5% w/v aqueous solution) 
Acid value: 2.5 
Hygroscopicity: at relative humidities of 25–65%, the equilibrium 
moisture content of powdered acacia at 258C is 
8–13% w/w, but at relative humidities above about 70% it 
absorbs substantial amounts of water. 
Solubility: soluble 1 in 20 of glycerin, 1 in 20 of propylene 
glycol, 1 in 2.7 of water; practically insoluble in ethanol 
(95%). In water, acacia dissolves very slowly, although 
almost completely after two hours, in twice the mass of 
water leaving only a very small residue of powder. The 
solution is colorless or yellowish, viscous, adhesive, and 
translucent. Spray-dried acacia dissolves more rapidly, in 
about 20 minutes. 
Specific gravity: 1.35–1.49 
Viscosity (dynamic): 100 mPa s (100 cP) for a 30% w/v aqueous 
solution at 208C. The viscosity of aqueous acacia solutions 
varies depending upon the source of the material, processing,

storage conditions, pH, and the presence of salts. Viscosity 
increases slowly up to about 25% w/v concentration and 
exhibits Newtonian behavior. Above this concentration, 
viscosity increases rapidly (non-Newtonian rheology). 
Increasing temperature or prolonged heating of solutions 
results in a decrease of viscosity owing to depolymerization 
or particle agglomeration. See also Section 12. 
11 Stability and Storage Conditions 
Aqueous solutions are subject to bacterial or enzymatic 
degradation but may be preserved by initially boiling the 
solution for a short time to inactivate any enzymes present; 
microwave irradiation can also be used.(5) Aqueous solutions 
may also be preserved by the addition of an antimicrobial 
preservative such as 0.1% w/v benzoic acid, 0.1% w/v sodium 
benzoate, or a mixture of 0.17% w/v methylparaben and 
0.03% propylparaben. Powdered acacia should be stored in an 
airtight container in a cool, dry place. 
12 Incompatibilities 
Acacia is incompatible with a number of substances including 
amidopyrine, apomorphine, cresol, ethanol (95%), ferric salts, 
morphine, phenol, physostigmine, tannins, thymol, and vanillin.
An oxidizing enzyme present in acacia may affect preparations 
containing easily oxidizable substances. However, the 
enzyme may be inactivated by heating at 1008C for a short 
time; see Section 11. 
Many salts reduce the viscosity of aqueous acacia solutions, 
while trivalent salts may initiate coagulation. Aqueous solutions 
carry a negative charge and will form coacervates with 
gelatin and other substances. In the preparation of emulsions, 
solutions of acacia are incompatible with soaps. 
13 Method of Manufacture 
Acacia is the dried gummy exudate obtained from the stems 
and branches of Acacia senegal (Linne.) Willdenow or other 
related species of Acacia (Fam. Leguminosae) that grow mainly 
in the Sudan and Senegal regions of Africa. 
The bark of the tree is incised and the exudate allowed to dry 
on the bark. The dried exudate is then collected, processed to 
remove bark, sand, and other particulate matter, and graded. 
Various acacia grades differing in particle size and other 
physical properties are thus obtained. A spray-dried powder is 
also commercially available. 
14 Safety 
Acacia is used in cosmetics, foods, and oral and topical 
pharmaceutical formulations. Although it is generally regarded 
as an essentially nontoxic material, there have been a limited 
number of reports of hypersensitivity to acacia after inhalation 
or ingestion.(6,7) Severe anaphylactic reactions have occurred 
following the parenteral administration of acacia and it is now 
no longer used for this purpose.(6) 
The WHO has not set an acceptable daily intake for acacia 
as a food additive because the levels necessary to achieve a 
desired effect were not considered to represent a hazard to 
health.(8) 
LD50 (hamster, oral): >18 g/kg(9) 
LD50 (mouse, oral): >16 g/kg 
LD50 (rabbit, oral): 8.0 g/kg 
LD50 (rat, oral): >16 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Acacia can be irritant to the 
eyes and skin and upon inhalation. Gloves, eye protection, and 
a dust respirator are recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use in Europe as a food additive. 
Included in the FDA Inactive Ingredients Guide (oral preparations 
and buccal or sublingual tablets). Included in the 

Canadian List of Acceptable Non-medicinal Ingredients. 
Included in nonparenteral medicines licensed in the UK. 
17 Related Substances 
Ceratonia; guar gum; tragacanth. 
18 Comments 
Concentrated aqueous solutions are used to prepare pastilles 
since on drying they form solid rubbery or glasslike masses 
depending upon the concentration used. Foreign policy changes 
and politically unstable conditions in Sudan, which is the 
principal supplier of acacia, has created a need to find a suitable 
replacement.(10) Poloxamer 188 (12–15% w/w) can be used to 
make an oil/water emulsion with similar rheological characteristics 
to acacia. Other natural by-products of foods can also be 
used.(11) Acacia is also used in the food industry as an 
emulsifier, stabilizer, and thickener. A specification for acacia 
is contained in the Food Chemicals Codex (FCC). 
The EINECS number for acacia is 232-519-5. 
19 Specific References 
1 Attama AA, Adiknu MV, Okoli ND. Studies on bioadhesive 
granules. STP Pharma Sci 2003; 13(3): 177–181. 
2 Streubel A, Siepmann J, Bodmeier R. Floating matrix tablets based 
on low density foam powder. Eur J Pharm Sci 2003; 18: 37–45. 
3 Bahardwaj TR, Kanwar M, Lai R, Gupta A. Natural gums and 
modified natural gums as sustained-release carriers. Drug Dev Ind 
Pharm 2000; 26(10): 1025–1038. 
4 Buffo R, Reineccius G. Optimization of gum acacia/modified 
starch/maltodextrin blends for spray drying of flavors. Perfumer& 
Flavorist 2000; 25: 45–54. 
5 Richards RME, Al Shawa R. Investigation of the effect of 
microwave irradiation on acacia powder. J Pharm Pharmacol 
1980; 32: 45P. 
6 Maytum CK, Magath TB. Sensitivity to acacia. J Am Med Assoc 
1932; 99: 2251. 
7 Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 7–11. 
8 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirty-fifth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1990; No. 
789. 
9 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 289. 
10 Scheindlin S. Acacia – a remarkable excipient: the past, present, 
and future of gum arabic. JAMA 2001; 41(5): 669–671. 
11 I-Achi A, Greenwood R, Akin-Isijola A. Experimenting with a new 
emulsifying agent (tahini) in mineral oil. Int J Pharm Compound 
2000; 4(4): 315–317. 
2 Acacia

20 General References 
Anderson DMW, Dea ICM. Recent advances in the chemistry of acacia 
gums. J Soc Cosmet Chem 1971; 22: 61–76. 
Anderson DM, Douglas DM, Morrison NA, Wang WP. Specifications 
for gum arabic (Acacia Senegal): analytical data for samples 
collected between 1904 and 1989. Food Add Contam 1990; 7: 
303–321. 
Aspinal GO. Gums and mucilages. Adv Carbohydr Chem Biochem 
1969; 24: 333–379. 
Whistler RL. Industrial Gums. New York: Academic Press, 1959. 
21 Authors 
AH Kibbe. 
22 Date of Revision 
20 August 2005. 
Acacia 3

Acesulfame Potassium 
1 Nonproprietary Names 
PhEur: Acesulfamum kalicum 
2 Synonyms 
Acesulfame K; E950; 6-methyl-3,4-dihydro-1,2,3-oxathiazin- 
4(3H)-one 2,2-dioxide potassium salt; Sunett; Sweet One. 
3 Chemical Name and CAS Registry Number 
6-Methyl-1,2,3-oxathiazin-4(3H)-one-2,2-dioxide potassium 
salt [55589-62-3] 
4 Empirical Formula and Molecular Weight 
C4H4KNO4S 201.24 
5 Structural Formula 
6 Functional Category 
Sweetening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Acesulfame potassium is used as an intense sweetening agent in 
cosmetics, foods, beverage products, table-top sweeteners, 
vitamin and pharmaceutical preparations, including powder 
mixes, tablets, and liquid products. It is widely used as a sugar 
substitute in compounded formulations,(1) and as a toothpaste 
sweetener.(2) 
The approximate sweetening power is 180–200 times that 
of sucrose. It enhances flavor systems and can be used to mask 
some unpleasant taste characteristics. 
8 Description 
Acesulfame potassium occurs as a colorless to white-colored, 
odorless, crystalline powder with an intensely sweet taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for acesulfame potassium. 
Test PhEur 2005 
Characters . 
Identification . 
Appearance of solution . 
Acidity or alkalinity . 
Acetylacetamide . 
Impurity B and related substances 420 ppm 
Fluorides 43 ppm 
Heavy metals 45 ppm 
Loss on drying 41.0% 
Assay 99.0–101.0% 
SEM: 1 
Excipient: Acesulfame potassium 
Magnification: 150 Voltage: 5kV 
10 Typical Properties 
Bonding index: 0.007 
Brittle fracture index: 0.08(3) 
Flowability: 19% (Carr compressibility index)(3) 
Density (bulk): 1.04 g/cm3(3) 
Density (tapped): 1.28 g/cm3(3) 
Elastic modulus: 4000MPa(3) 
Melting point: 2508C 
Solubility: see Table II. 
Specific volume: 0.538 cm3/g(4) 
Tensile strength: 0.5MPa(3) 
Viscoelastic index: 2.6(3)

11 Stability and Storage Conditions 
Acesulfame potassium possesses good stability. In the bulk 
form it shows no sign of decomposition at ambient temperature 
over many years. In aqueous solutions (pH 3.0–3.5 at 208C) no 
reduction in sweetness was observed over a period of 
approximately 2 years. Stability at elevated temperatures is 
good, although some decomposition was noted following 
storage at 408C for several months. Sterilization and pasteurization 
do not affect the taste of acesulfame potassium.(5) 
The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
—
13 Method of Manufacture 
Acesulfame potassium is synthesized from acetoacetic acid tertbutyl 
ester and fluorosulfonyl isocyanate. The resulting 
compound is transformed to fluorosulfonyl acetoacetic acid 
amide, which is then cyclized in the presence of potassium 
hydroxide to form the oxathiazinone dioxide ring system. 
Because of the strong acidity of this compound, the potassium 
salt is produced directly. 
An alternative synthesis route for acesulfame potassium 
starts with the reaction between diketene and amidosulfonic 
acid. In the presence of dehydrating agents, and after 
neutralization with potassium hydroxide, acesulfame potassium 
is formed. 
14 Safety 
Acesulfame potassium is widely used in beverages, cosmetics, 
foods, and pharmaceutical formulations and is generally 
regarded as a relatively nontoxic and nonirritant material. 
Pharmacokinetic studies have shown that acesulfame potassium 
is not metabolized and is rapidly excreted unchanged in 
the urine. Long-term feeding studies in rats and dogs showed no 
evidence to suggest acesulfame potassium is mutagenic or 
carcinogenic.(6) 
The WHO has set an acceptable daily intake for acesulfame 
potassium of up to 15 mg/kg body-weight.(6) 
LD50 (rat, IP): 2.2 g/kg(5) 
LD50 (rat, oral): 6.9–8.0 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection, gloves, and a 
dust mask are recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide for oral and 
sublingual preparations. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. Accepted for use in 
Europe as a food additive. It is also accepted for use in certain 
food products in the USA and several countries in Central and 
South America, the Middle East, Africa, Asia, and Australia. 
17 Related Substances 
Alitame. 
18 Comments 
The perceived intensity of sweeteners relative to sucrose 
depends upon their concentration, temperature of tasting, and 
pH, and on the flavor and texture of the product concerned. 
Intense sweetening agents will not replace the bulk, textural, 
or preservative characteristics of sugar, if sugar is removed from 
a formulation. 
Synergistic effects for combinations of sweeteners have been 
reported, e.g., acesulfame potassium with aspartame or sodium 
cyclamate. A ternary combination of sweeteners that includes 
acesulfame potassium and sodium saccharin has a greater 
decrease in sweetness upon repeated tasting than other 
combinations.(7) 
Note that free acesulfame acid is not suitable for use as a 
sweetener. 
A specification for acesulfame potassium is contained in the 
Food Chemicals Codex (FCC). 
19 Specific References 
1 Kloesel L. Sugar substitutes. Int J Pharm Compound 2000; 4(2): 
86–87. 
2 Schmidt R, Janssen E, Haussler O, et al. Evaluating toothpaste 
sweetening. Cosmet Toilet 2000; 115: 49–53. 
3 Mullarney MP, Hancock BC, Carlson GT, Ladipo DD. The 
powder flow and compact mechanical properties of sucrose and 
three high-intensity sweeteners used in chewable tablets. Int J 
Pharm 2003; 257: 227–236. 
4 Birch GG, Haywood KA, Hanniffy GG, et al. Apparent specific 
volumes and tastes of cyclamates, other sulfamates, saccharins and 
acesulfame sweeteners. Food Chemistry 2004; 84: 429–435. 
5 Lipinski G-WvR, Huddart BE. Acesulfame K. Chem Ind 1983; 11: 
427–432. 
6 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirty-seventh report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1991; No. 806. 
7 Schiffman SS, Sattely-Miller EA, Graham BG, et al. Effect of 
repeated presentation on sweetness intensity of binary and tertiary 
mixtures of sweetness. Chem Senses 2003; 28: 219–229. 
20 General References 
Anonymous. Artificial sweetners. Can Pharm J 1996; 129: 22. 
Lipinski G-WvR, Lu. ck E. Acesulfame K: a new sweetener for oral 
cosmetics. Manuf Chem 1981; 52(5): 37. 
Marie S. Sweeteners. In: Smith J, ed. Food Additives User’s Handbook. 
Glasgow: Blackie, 1991: 47–74. 
Nutrinova. Technical literature: Sunett in Pharmaceuticals, 1998. 
21 Authors 
JH Chu. 
22 Date of Revision 
12 August 2005. 
Table II: Solubility of acesulfame potassium. 
Solvent Solubility at 208C 
unless otherwise stated 
Ethanol 1 in 1000 
Ethanol (50%) 1 in 100 
Water 1 in 7.1 at 08C 
1 in 3.7 
1 in 0.77 at 1008C 
Acesulfame Potassium 5

Acetic Acid, Glacial 
1 Nonproprietary Names 
BP: Glacial acetic acid 
JP: Glacial acetic acid 
PhEur: Acidum aceticum glaciale 
USP: Glacial acetic acid 
2 Synonyms 
E260; ethanoic acid; ethylic acid; methane carboxylic acid; 
vinegar acid. 
See also Sections 17 and 18. 
3 Chemical Name and CAS Registry Number 
Ethanolic acid [64-19-7] 
4 Empirical Formula and Molecular Weight 
C2H4O2 60.05 
5 Structural Formula 
6 Functional Category 
Acidifying agent. 
7 Applications in Pharmaceutical Formulations 
or Technology 
Glacial and diluted acetic acid solutions are widely used as 
acidifying agents in a variety of pharmaceutical formulations 
and food preparations. Acetic acid is used in pharmaceutical 
products as a buffer system when combined with an acetate salt 
such as sodium acetate. Acetic acid is also claimed to have some 
antibacterial and antifungal properties. 
8 Description 
Glacial acetic acid occurs as a crystalline mass or a clear, 
colorless volatile solution with a pungent odor. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for glacial acetic acid. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters . . — 
Freezing point 514.58C 514.88C 515.68C 
Nonvolatile matter 41.0mg 40.01% 41.0mg 
Sulfate . . . 
Chloride . . . 
Heavy metals 410 ppm 45 ppm 45 ppm 
Iron — 45 ppm — 
Readily oxidizable 
impurities 
. . . 
Assay 599.0% 99.5–100.5% 99.5–100.5% 
10 Typical Properties 
Acidity/alkalinity: 
pH = 2.4 (1M aqueous solution); 
pH = 2.9 (0.1M aqueous solution); 
pH = 3.4 (0.01M aqueous solution). 
Boiling point: 1188C 
Dissociation constant: pKa = 4.76 
Flash point: 398C (closed cup); 578C (open cup). 
Melting point: 178C 
Refractive index: nD
20 = 1.3718 
Solubility: miscible with ethanol, ether, glycerin, water, and 
other fixed and volatile oils. 
Specific gravity: 1.045 
11 Stability and Storage Conditions 
Acetic acid should be stored in an airtight container in a cool, 
dry place. 
12 Incompatibilities 
Acetic acid reacts with alkaline substances. 
13 Method of Manufacture 
Acetic acid is usually made by one of three routes: acetaldehyde 
oxidation, involving direct air or oxygen oxidation of liquid 
acetaldehyde in the presence of manganese acetate, cobalt 
acetate, or copper acetate; liquid-phase oxidation of butane or 
naphtha; methanol carbonylation using a variety of techniques. 
14 Safety 
Acetic acid is widely used in pharmaceutical applications 
primarily to adjust the pH of formulations and is thus generally 
regarded as relatively nontoxic and nonirritant. However, 
glacial acetic acid or solutions containing over 50% w/w acetic 
acid in water or organic solvents are considered corrosive and 
can cause damage to skin, eyes, nose, and mouth. If swallowed 
glacial acetic acid causes severe gastric irritation similar to that 
caused by hydrochloric acid.(1)

Dilute acetic acid solutions containing up to 10% w/w of 
acetic acid have been used topically following jellyfish stings.(2) 
Dilute acetic acid solutions containing up to 5% w/w of acetic 
acid have also been applied topically to treat wounds and burns 
infected with Pseudomonas aeruginosa.(3) 
The lowest lethal oral dose of glacial acetic acid in humans is 
reported to be 1470 mg/kg.(4) The lowest lethal concentration 
on inhalation in humans is reported to be 816 ppm.(4) Humans, 
are, however, estimated to consume approximately 1 g/day of 
acetic acid from the diet. 
LD50 (mouse, IV): 0.525 g/kg(4) 
LD50 (rabbit, skin): 1.06 g/kg 
LD50 (rat, oral): 3.31 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Acetic acid, particularly 
glacial acetic acid, can cause burns on contact with the skin, 
eyes, and mucous membranes. Splashes should be washed with 
copious quantities of water. Protective clothing, gloves, and eye 
protection are recommended. 
In the UK, the occupational exposure limits for acetic acid 
are 25 mg/m3 (10 ppm) long-term (8-hour TWA) and 37 mg/m3 
(15 ppm) short-term (15-minutes).(5) 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (injections, nasal, ophthalmic, 
and oral preparations). Included in parenteral and 
nonparenteral preparations licensed in the UK. 
17 Related Substances 
Acetic acid; artificial vinegar; dilute acetic acid. 
Acetic acid 
Comments: a diluted solution of glacial acetic acid containing 
30–37% w/w of acetic acid. See Section 18. 
Artificial vinegar 
Comments: a solution containing 4% w/w of acetic acid. 
Dilute acetic acid 
Comments: a weak solution of acetic acid which may contain 
between 6–10% w/w of acetic acid. See Section 18. 
18 Comments 
In addition to glacial acetic acid, many pharmacopeias contain 
monographs for diluted acetic acid solutions of various 
strengths. For example, the USPNF 23 has a monograph for 
acetic acid, which is defined as an acetic acid solution 
containing 36.0–37.0% w/w of acetic acid. Similarly, the BP 
2004 contains separate monographs for glacial acetic acid, 
acetic acid (33%), and acetic acid (6%). Acetic acid (33%) BP 
2004 contains 32.5–33.5% w/w of acetic acid. Acetic acid (6%) 
BP 2004 contains 5.7–6.3% w/w of acetic acid. The JP 2001 
also contains a monograph for acetic acid that specifies that it 
contains 30.0–32.0% w/w of acetic acid. 
A specification for glacial acetic acid is contained in the 
Food Chemicals Codex (FCC). 
The EINECS number for acetic acid is 200-580-7. 
19 Specific References 
1 Sweetman SC, ed. Martindale: The Complete Drug Reference, 
34th edn. London: Pharmaceutical Press, 2005: 1645. 
2 Fenner PJ, Williamson JA. Worldwide deaths and severe envenomation 
from jellyfish stings. Med J Aust 1996; 165: 658–661. 
3 Milner SM. Acetic acid to treat Pseudomonas aeruginosa in 
superficial wounds and burns. Lancet 1992; 340: 61. 
4 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 15–16. 
5 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002, Sudbury: Health and Safety Executive, 2002. 
20 General References 
—
21 Authors 
WG Chambliss. 
22 Date of Revision 
8 August 2005. 
Acetic Acid, Glacial 7

Acetone 
1 Nonproprietary Names 
BP: Acetone 
PhEur: Acetonum 
USPNF: Acetone 
2 Synonyms 
Dimethylformaldehyde; dimethyl ketone; b-ketopropane; pyroacetic 
ether. 
3 Chemical Name and CAS Registry Number 
2-Propanone [67-64-1] 
4 Empirical Formula and Molecular Weight 
C3H6O 58.08 
5 Structural Formula 
6 Functional Category 
Solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Acetone is used as a solvent or cosolvent in topical preparations, 
and as an aid in wet granulation.(1,2) It has also been used 
when formulating tablets with water-sensitive active ingredients, 
or to solvate poorly water-soluble binders in a wet 
granulation process. Acetone has also been used in the 
formulation of microspheres to enhance drug release.(3) Owing 
to its low boiling point, acetone has been used to extract 
thermolabile substances from crude drugs.(4) 
8 Description 
Acetone is a colorless volatile, flammable, transparent liquid, 
with a sweetish odor and pungent sweetish taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for acetone. 
Test PhEur 2005 
(Suppl. 5.1) 
USPNF 23 
Identification . . 
Characters . — 
Appearance of solution . — 
Acidity or alkalinity . — 
Relative density 0.790–0.793 40.789 
Related substances . — 
Matter insoluble in water . — 
Reducing substances . . 
Residue on evaporation 450 ppm 40.004% 
Water 43 g/L . 
Assay — 599.0% 
10 Typical Properties 
Boiling point: 56.28C 
Flash point: –208C 
Melting point: 94.38C 
Refractive index: nD
20 = 1.359 
Solubility: soluble in water; freely soluble in ethanol (95%) 
Vapor pressure: 185mmHg at 208C 
11 Stability and Storage Conditions 
Acetone should be stored in a cool, dry, well-ventilated place 
out of direct sunlight. 
12 Incompatibilities 
Acetone reacts violently with oxidizing agents, chlorinated 
solvents, and alkali mixtures. It reacts vigorously with sulfur 
dichloride, potassium t-butoxide, and hexachloromelamine. 
Acetone should not be used as a solvent for iodine, as it forms a 
volatile compound that is extremely irritating to the eyes.(4) 
13 Method of Manufacture 
Acetone is obtained by fermentation as a by-product of n-butyl 
alcohol manufacture, or by chemical synthesis from isopropyl 
alcohol; from cumene as a by-product in phenol manufacture; 
or from propane as a by-product of oxidation-cracking. 
14 Safety 
Acetone is considered moderately toxic, and is a skin irritant 
and severe eye irritant. Skin irritation has been reported due to 
its defatting action, and prolonged inhalation may result in 
headaches. Inhalation of acetone can produce systemic effects 
such as conjunctival irritation, respiratory system effects, 
nausea, and vomiting.(5) 
LD50 (mouse, oral): 3.0 g/kg(5) 
LD50 (mouse, IP): 1.297 g/kg 
LD50 (rabbit, oral): 5.340 g/kg 
LD50 (rabbit, skin): 0.2 g/kg

LD50 (rat, IV): 5.5 g/kg 
LD50 (rat, oral): 5.8 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Acetone is a skin and eye 
irritant (see Section 14), therefore gloves, eye protection and a 
respirator are recommended. In the UK, the long-term (8-hour 
TWA) exposure limit for acetone is 1210 mg/m3 (500 ppm). 
The short-term (15-minute) exposure limit is 3620 mg/m3 
(1500 ppm).(6) 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (inhalation 
solution; oral tablets; topical preparations). Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
Included in nonparenteral medicines licensed in the UK. 
17 Related Substances 
—
18 Comments 
A specification for acetone is included in the Japanese 
Pharmaceutical Excipients (JPE).(7) The EINECS number for 
acetone is 200-662-2. 
19 Specific References 
1 Ash M, Ash I. Handbook of Pharmaceutical Additives, 2nd edn. 
Endicott, NY: Synapse Information Resources, 2002: 282. 
2 Tang ZG, Black RA, Curran JM, et al. Surface properties and 
biocompatibility of solvent-cast poly[e-caprolactone] films. Biomaterials 
2004; 25(19): 4741–4748. 
3 Ruan G, Feng SS. Preparation and characterization of poly(lactic 
acid)–poly(ethylene glycol)–poly(lactic acid) (PLA-PEG-PLA) 
microspheres for controlled release of paclitaxel. Biomaterials 
2003; 24(27): 5037–5044. 
4 Todd RG, Wade A, eds. The Pharmaceutical Codex, 11th edn. 
London: Pharmaceutical Press, 1979: 6. 
5 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 22–23. 
6 Health and Safety Executive: EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
7 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004: 35–36. 
20 General References 
—
21 Authors 
AH Kibbe, SC Owen. 
22 Date of Revision 
23 August 2005. 
Acetone 9

Acetyltributyl Citrate 
1 Nonproprietary Names 
USPNF: Acetyltributyl citrate 
PhEur: Tributylis acetylcitras 
2 Synonyms 
Acetylbutyl citrate; acetylcitric acid, tributyl ester; ATBC; 
Citroflex A-4; tributyl acetylcitrate; tributyl O-acetylcitrate; 
tributyl citrate acetate. 
3 Chemical Name and CAS Registry Number 
1,2,3-Propanetricarboxylic acid, 2-acetyloxy, tributyl ester 
[77-90-7] 
4 Empirical Formula and Molecular Weight 
C20H34O8 402.5 
5 Structural Formula 
6 Functional Category 
Plasticizer. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Acetyltributyl citrate is used to plasticize polymers in formulated 
pharmaceutical coatings,(1–5) including capsules, 
tablets, beads, and granules for taste masking, immediate 
release, sustained-release and enteric formulations. 
8 Description 
Acetyltributyl citrate is a clear, odorless, practically colorless, 
oily liquid. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for acetyltributyl citrate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Appearance — . 
Characters — . 
Specific gravity 1.045–1055 — 
Refractive index 1.4410–1.4425 1.442–1.445 
Sulfated ash — 40.10% 
Acidity . . 
Water 40.25% 40.25% 
Heavy metals 40.001% 40.001% 
Assay (anhydrous basis) 599.0% 99.0–101.0% 
10 Typical Properties 
Acid value: 0.02 
Boiling point: 3268C (decomposes) 
Flash point: 2048C 
Pour point: 598C 
Solubility: miscible with acetone, ethanol, and vegetable oil; 
practically insoluble in water. 
Viscosity (dynamic): 33 mPa s (33 cP) at 258C 
11 Stability and Storage Conditions 
Acetyltributyl citrate should be stored in a well-closed 
container in a cool, dry location at temperatures not exceeding 
388C. When stored in accordance with these conditions, 
acetyltributyl citrate is a stable product. 
12 Incompatibilities 
Acetyltributyl citrate is incompatible with strong alkalis and 
oxidizing materials. 
13 Method of Manufacture 
Acetyltributyl citrate is prepared by the esterification of citric 
acid with butanol followed by acylation with acetic anhydride. 
14 Safety 
Acetyltributyl citrate is used in oral pharmaceutical formulations 
and films intended for direct food contact. It is also used in 
self-adhesive thin films used for topical delivery systems.(6) It is 
generally regarded as a relatively nontoxic and nonirritating 
material. However, ingestion of large quantities may be 
harmful. 
LD50 (cat, oral): >50 mL/kg(7) 
LD50 (mouse, IP): >4 g/kg 
LD50 (rat, oral): >31.5 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Acetyltributyl citrate is

slightly irritating to the eyes and may be irritating to the 
respiratory system as a mist or at elevated temperatures. Gloves 
and eye protection are recommended for normal handling, and 
a respirator is recommended when using acetyltributyl citrate at 
elevated temperatures. 
16 Regulatory Status 
Included in FDA Inactive Ingredients Guide (oral capsules and 
tablets). Included in nonparenteral medicines licensed in the 
UK. Approved in the USA for direct food contact in food films. 
17 Related Substances 
Acetyltriethyl citrate; tributyl citrate; triethyl citrate. 
18 Comments 
Acetyltributyl citrate is used as a plasticizer in food contact 
films, although it has been known to migrate from food-grade 
PVC films into high-fat foods such as olive oil.(8) 
Polylactide plasticized with acetyltributyl citrate has been 
investigated as a biodegradable barrier for use in guided-tissue 
regeneration therapy.(9) 
The EINECS number for acetyltributyl citrate is 201-067-0. 
19 Specific References 
1 Gutierrez-Rocca JC, McGinity JW. Influence of water soluble and 
insoluble plasticizer on the physical and mechanical properties of 
acrylic resin copolymers. Int J Pharm 1994; 103: 293–301. 
2 Lehmann K. Chemistry and application properties of polymethacrylate 
coating systems. In: McGinity JW, ed. Aqueous Polymeric 
Coatings for Pharmaceutical Dosage Forms. New York: Marcel 
Dekker, 1989: 153–245. 
3 Steurnagel CR. Latex emulsions for controlled drug delivery. In: 
McGinity JW, ed. Aqueous Polymeric Coatings for Pharmaceutical 
Dosage Forms. New York: Marcel Dekker, 1989: 1–61. 
4 Gutierrez-Rocca JC, McGinity JW. Influence of aging on the 
physical-mechanical properties of acrylic resin films cast from 
aqueous dispersions and organic solutions. Drug Dev Ind Pharm 
1993; 19(3): 315–332. 
5 Repka MA, Gerding TG, Repka SL. Influence of plasticisers and 
drugs on the physical-mechanical properties of hydroxypropylcellulose 
films prepared by hot melt extrusion. Drug Dev Ind Pharm 
1999; 25(5): 625–633. 
6 Lieb S, Szeimies RM, Lee G. Self-adhesive thin films for topical 
delivery of 5-aminolevulinic acid. Eur J Pharm Biopharm 2002; 
53(1): 99–106. 
7 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3512. 
8 Goulas AE, Riganakos KA, Ehlermann DA, et al. Effect of highdose 
electron beam irradiation on the migration of DOA and 
ATBC plasticizers from food-grade PVC and PVDC/PVC films, 
respectively, into olive oil. J Food Prot 1998; 61(6): 720–724. 
9 Dorfer CE, Kim TS, Steinbrenner H, et al. Regenerative periodontal 
surgery in interproximal intrabony defects with biodegradable 
barriers. J Clin Peridontol 2000; 27(3): 162–168. 
20 General References 
—
21 Authors 
SW Kennedy. 
22 Date of Revision 
15 August 2005. 
Acetyltributyl Citrate 11

Acetyltriethyl Citrate 
1 Nonproprietary Names 
USPNF: Acetyltriethyl citrate 
2 Synonyms 
ATEC; Citroflex A-2; triethyl acetylcitrate; triethyl O-acetylcitrate; 
triethyl citrate acetate. 
3 Chemical Name and CAS Registry Number 
1,2,3-Propanetricarboxylic acid, 2-acetyloxy, triethyl ester [77- 
89-4] 
4 Empirical Formula and Molecular Weight 
C14H22O8 318.3 
5 Structural Formula 
6 Functional Category 
Plasticizer. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Acetyltriethyl citrate is used to plasticize polymers in formulated 
pharmaceutical coatings.(1) The coating applications 
include capsules, tablets, beads and granules for taste masking, 
immediate release, sustained-release and enteric formulations.(
2–5) It is also used in diffusion-controlled release drug 
delivery systems.(6) 
8 Description 
Acetyltriethyl citrate occurs as a clear, odorless, practically 
colorless oily liquid. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for acetyltriethyl citrate. 
Test USPNF 23 
Identification . 
Specific gravity 1.135–1.139 
Refractive index 1.432–1.441 
Acidity . 
Water 40.3% 
Heavy metals 40.001% 
Assay (anhydrous basis) 599.0% 
10 Typical Properties 
Acid value: 0.02 
Boiling point: 2948C (decomposes) 
Flash point: 1888C 
Pour point: 438C 
Solubility: soluble 1 in 140 of water; miscible with acetone, 
ethanol, and propan-2-ol. 
Viscosity (dynamic): 54 mPa s (54 cP) at 258C. 
11 Stability and Storage Conditions 
Acetyltriethyl citrate should be stored in dry, closed containers 
at temperatures not exceeding 388C. When stored in accordance 
with these conditions, acetyltriethyl citrate is a stable 
product. 
12 Incompatibilities 
Acetyltriethyl citrate is incompatible with strong alkalis and 
oxidizing materials. 
13 Method of Manufacture 
Acetyltriethyl citrate is prepared by the esterification of citric 
acid with ethanol followed by acylation with acetic anhydride. 
14 Safety 
Acetyltriethyl citrate is used in oral pharmaceutical formulations 
and is generally regarded as a nontoxic and nonirritating 
material. However, ingestion of large quantities may be 
harmful. 
LD50 (cat, oral): 8.5 g/kg(7) 
LD50 (mouse, IP): 1.15 g/kg 
LD50 (rat, oral): 7 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Acetyltriethyl citrate may be 
irritating to the eyes or the respiratory system as a mist or at 
elevated temperatures. Gloves and eye protection are recommended 
for normal handling and a respirator is recommended 
if used at elevated temperatures.

16 Regulatory Status 
Approved in the USA for direct food contact in food films. 
17 Related Substances 
Acetyltributyl citrate; tributyl citrate; triethyl citrate. 
18 Comments 
The EINECS number for acetyltriethyl citrate is 201-066-5. 
19 Specific References 
1 Jensen JL, Appel LE, Clair JH, Zentner GM. Variables that affect 
the mechanism of drug release from osmotic pumps coated with 
acrylate/methacrylate copolymer latexes. J Pharm Sci 1995; 84: 
530–533. 
2 Gutierrez-Rocca JC, McGinity JW. Influence of water soluble and 
insoluble plasticizer on the physical and mechanical properties of 
acrylic resin copolymers. Int J Pharm 1994; 103: 293–301. 
3 Lehmann K. Chemistry and application properties of polymethacrylate 
coating systems. In: McGinity JW, ed. Aqueous Polymeric 
Coatings for Pharmaceutical Dosage Forms. New York: Marcel 
Dekker, 1989: 153–245. 
4 Steurnagel CR. Latex emulsions for controlled drug delivery. In: 
McGinity JW, ed. Aqueous Polymeric Coatings for Pharmaceutical 
Dosage Forms. New York: Marcel Dekker, 1989: 1–61. 
5 Gutierrez-Rocca JC, McGinity JW. Influence of aging on the 
physical-mechanical properties of acrylic resin films cast from 
aqueous dispersions and organic solutions. Drug Dev Ind Pharm 
1993; 19(3): 315–332. 
6 Siepmann J, Lecomte F, Bodmeier R. Diffusion-controlled drug 
delivery systems: calculation of the required composition to 
achieve desired release profiles. J Control Release 1999; 60(2–3): 
379–389. 
7 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 58–59. 
20 General References 
—
21 Authors 
SW Kennedy. 
22 Date of Revision 
15 August 2005. 
Acetyltriethyl Citrate 13

Agar 
1 Nonproprietary Names 
JP: Agar 
PhEur: Agar 
USPNF: Agar 
2 Synonyms 
Agar-agar; Bengal isinglass; Ceylon isinglass; Chinese isinglass; 
E406; gelosa; gelose; Japan agar; Japan isinglass; layor carang. 
3 Chemical Name and CAS Registry Number 
Agar [9002-18-0] 
4 Empirical Formula and Molecular Weight 
See Section 5. 
5 Structural Formula 
Agar is a dried, hydrophilic, colloidal polysaccharide complex 
extracted from the agarocytes of algae of the Rhodophyceae. 
The structure is believed to be a complex range of polysaccharide 
chains having alternating a-(1!3) and b-(1!4) linkages. 
There are three extremes of structure noted: namely neutral 
agarose; pyruvated agarose having little sulfation; and a 
sulfated galactan. Agar can be separated into a natural gelling 
fraction, agarose, and a sulfated nongelling fraction, agaropectin. 
6 Functional Category 
Emulsifying agent; stabilizing agent; suppository base; suspending 
agent; sustained-release agent; tablet binder; thickening 
agent; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Agar is widely used in food applications as a stabilizing agent. 
In pharmaceutical applications, agar is used in a handful of oral 
tablet and topical formulations. It has also been investigated in 
a number of experimental pharmaceutical applications including 
as a sustained-release agent in gels, beads, microspheres, 
and tablets.(1–4) It has also been reported to work as a 
disintegrant in tablets.(5) Agar has been used in a floating 
controlled-release tablet; the buoyancy in part being attributed 
to air entrapped in the agar gel network.(6) It can be used as a 
viscosity-increasing agent in aqueous systems. Agar can also be 
used as a base for nonmelting, and nondisintegrating suppositories.(
7) Agar has an application as a suspending agent in 
pharmaceutical suspensions.(8) 
8 Description 
Agar occurs as transparent, odorless, tasteless strips or as a 
coarse or fine powder. It may be weak yellowish-orange, 
yellowish-gray to pale-yellow colored, or colorless. Agar is 
tough when damp, brittle when dry. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for agar. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters . . — 
Swelling index — . — 
Arsenic — — 43 ppm 
Lead — — 40.001% 
Sulfuric acid . — — 
Sulfurous acid and 
starch 
. — — 
Gelatin — . . 
Heavy metals — — 40.004% 
Insoluble matter 415.0mg — 415.0mg 
Water absorption 475 mL — 475 mL 
Loss on drying 422.0% 420.0% 420.0% 
Microbial 
contamination 
— 41000/g(a) . 
Total ash 44.5% 45.0% 46.5% 
Acid-insoluble ash 40.5% 41.0% 40.5% 
Foreign organic matter — — 41.0% 
Limit of foreign starch — — . 
Organic volatile 
impurities 
— — . 
(a) Total viable aerobic count, determined by plate-count. 
10 Typical Properties 
Solubility: soluble in boiling water to form a viscous solution; 
practically insoluble in ethanol (95%), and cold water. A 
1% w/v aqueous solution forms a stiff jelly on cooling. 
11 Stability and Storage Conditions 
Agar solutions are most stable at pH 4–10. 
Agar should be stored in a cool, dry, place. Containers of 
this material may be hazardous when empty since they retain 
product residues (dust, solids). 
12 Incompatibilities 
Agar is incompatible with strong oxidizing agents. Agar is 
dehydrated and precipitated from solution by ethanol (95%). 
Tannic acid causes precipitation; electrolytes cause partial 
dehydration and decrease in viscosity of sols.(9)

13 Method of Manufacture 
Agar is obtained by freeze-drying a mucilage derived from 
Gelidium amansii Lamouroux, other species of the same family 
(Gelidiaceae), or other red algae (Rhodophyta). 
14 Safety 
Agar is widely used in food applications and has been used in 
oral and topical pharmaceutical applications. It is generally 
regarded as relatively nontoxic and nonirritant when used as an 
excipient. 
LD50 (hamster, oral): 6.1 g/kg(10) 
LD50 (mouse, oral): 16.0 g/kg 
LD50 (rabbit, oral): 5.8 g/kg 
LD50 (rat, oral): 11.0 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of the material handled. When heated to 
decomposition, agar emits acrid smoke and fumes. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral tablets). 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. Included in nonparenteral medicines licensed in the 
UK. 
17 Related Substances 
—
18 Comments 
The EINECS number for agar is 232-658-1. 
19 Specific References 
1 Bhardwaj TJ, Kanwar M, Lal R, Gupta A. Natural gums and 
modified natural gums as sustained release carriers. Drug Dev Ind 
Pharm 2000; 26(10): 1025–1038. 
2 Sakr FM, El-Said Y, El-Helw A. Design and evaluation of a dry 
solidification technique for preparing pharmaceutical beads. STP 
Pharma Sci 1995; 5(4): 291–295. 
3 Boraie NA, Naggar VF. Sustained release of theophylline and 
aminophylline from agar tablets. Acta Pharm Jugosl 1984; 
34(Oct–Dec): 247–256. 
4 Nakano M, Nakamura Y, Takikawa K, et al. Sustained release of 
sulfamethizole from agar beads. J Pharm Pharmacol 1979; 31: 
869–872. 
5 Fassihi AR. Characteristics of hydrogel as disintegrant in solid 
dose technology. J Pharm Pharmacol 1989; 54: 59–62. 
6 Desai S, Boston S. A floating controlled-release drug delivery 
system: in vitro–in vivo evaluation. Pharm Res 1993; 10: 1321– 
1325. 
7 Singh KK, Deshpande SG, Baichwal MR. Studies on suppository 
bases: design and evaluation of sodium CMC and agar bases. 
Indian Drugs 1994; 31(April): 149–154. 
8 Kahela P, Hurmerinta T, Elfving R. Effect of suspending agents on 
the bioavailability of erythromycin ethylsuccinate mixtures. Drug 
Dev Ind Pharm 1978; 4(3): 261–274. 
9 Gennaro AR, ed. Remington: The Science and Practice of 
Pharmacy, 20th edn. Baltimore: Lippincott Williams & Wilkins, 
2000: 1030. 
10 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 90–91. 
20 General References 
—
21 Authors 
VK Gupta. 
22 Date of Revision 
10 May 2005. 
Agar 15

Albumin 
1 Nonproprietary Names 
BP: Human albumin solution 
PhEur: Albumini humani solutio 
USP: Albumin human 
2 Synonyms 
Albuconn; albumin human solution; Albuminar; Albumisol; 
Albuspan; Albutein; Buminate; human serum albumin; normal 
human serum albumin; Plasbumin; plasma albumin; Pro- 
Bumin; Proserum. 
3 Chemical Name and CAS Registry Number 
Serum albumin [9048-49-1] 
4 Empirical Formula and Molecular Weight 
Human serum albumin has a molecular weight of about 66 500 
and is a single polypeptide chain consisting of 585 amino acids. 
Characteristic features are a single tryptophan residue, a 
relatively low content of methionine (6 residues), and a large 
number of cysteine (17) and of charged amino acid residues of 
aspartic acid (36), glutamic acid (61), lysine (59), and arginine 
(23). 
5 Structural Formula 
Primary structure: human albumin is a single polypeptide chain 
of 585 amino acids and contains seven disulfide bridges. 
Secondary structure: human albumin is known to have a 
secondary structure that is about 55% a-helix. The 
remaining 45% is believed to be divided among turns, 
disordered, and b structures.(1) 
Albumin is the only major plasma protein that does not 
contain carbohydrate constituents. Assays of crystalline 
albumin show less than one sugar residue per molecule. 
6 Functional Category 
Stabilizing agent; therapeutic agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Albumin is primarily used as an excipient in parenteral 
pharmaceutical formulations, where it is used as a stabilizing 
agent for formulations containing proteins and enzymes.(2) 
Albumin has also been used to prepare microspheres and 
microcapsules for experimental drug-delivery systems.(3) 
As a stabilizing agent, albumin has been employed in protein 
formulations at concentrations as low as 0.003%, although 
concentrations of 1–5% are commonly used. Albumin has also 
been used as a cosolvent(4) for parenteral drugs, as a 
cryoprotectant during lyophilization, and to prevent adsorption 
of other proteins to surfaces. 
Therapeutically, albumin solutions have been used parenterally 
for plasma volume replacement and to treat severe acute 
albumin loss. However, the benefits of using albumin in such 
applications in critically ill patients has been questioned.(5) 
8 Description 
The USP 28 describes albumin human as a sterile nonpyrogenic 
preparation of serum albumin obtained from healthy human 
donors; see Section 13. It is available as a solution containing 4, 
5, 20, or 25 g of serum albumin in 100mL of solution, with not 
less than 96% of the total protein content as albumin. The 
solution contains no added antimicrobial preservative but may 
contain sodium acetyltryptophanate with or without sodium 
caprylate as a stablizing agent. 
The PhEur 2005 similarly describes albumin solution as an 
aqueous solution of protein obtained from human plasma; see 
Section 13. It is available as a concentrated solution containing 
150–250 g/L of total protein or as an isotonic solution 
containing 35–50 g/L of total protein. Not less than 95% of 
the total protein content is albumin. A suitable stabilizer against 
the effects of heat, such as sodium caprylate (sodium octanoate) 
or N-acetyltryptophan or a combination of these two at a 
suitable concentration, may be added, but no antimicrobial 
preservative is added. 
Aqueous albumin solutions are slightly viscous and range in 
color from almost colorless to amber depending upon the 
protein concentration. In the solid state, albumin appears as 
brownish amorphous lumps, scales, or powder. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for albumin. 
Test PhEur 2005 USP 28 
Identification . — 
Characters . — 
pH (10 g/L solution) 6.7–7.3 . 
Polymers and aggregates . — 
Potassium 40.05 mmol/g — 
Sodium 4160 mmol/L 130–160 mEq/L 
Heme . . 
Aluminum 4200 mg/L — 
Sterility . . 
Hepatitis B surface antigen — . 
Pyrogens . . 
Total protein 95–105% 596% 
for 4 g in 100 mL — 93.75–106.25% 
for 5 to 25 g in 100 mL — 94.0–106.0% 
Protein composition . — 
Prekallikrein activator 435 IU/mL — 
10 Typical Properties 
Acidity/alkalinity: pH = 6.7–7.3 for a 1% w/v solution, in 
0.9% w/v sodium chloride solution, at 208C.

Osmolarity: a 4–5% w/v aqueous solution is isoosmotic with 
serum. 
Solubility: freely soluble in dilute salt solutions and water. 
Aqueous solutions containing 40% w/v albumin can be 
readily prepared at pH 7.4. The high net charge of the 
peptide contributes to its solubility in aqueous media. The 
seven disulfide bridges contribute to its chemical and spatial 
conformation. At physiological pH, albumin has a net 
electrostatic charge of about –17. Aqueous albumin solutions 
are slightly viscous and range in color from almost 
colorless to amber depending on the protein concentration. 
11 Stability and Storage Conditions 
Albumin is a protein and is therefore susceptible to chemical 
degradation and denaturation by exposure to extremes of pH, 
high salt concentrations, heat, enzymes, organic solvents, and 
other chemical agents. 
Albumin solutions should be protected from light and stored 
at a temperature of 2–258C or as indicated on the label. 
12 Incompatibilities 
See Section 11. 
13 Method of Manufacture 
Albumin human (USP 28) Albumin human is a sterile nonpyrogenic 
preparation of serum albumin that is obtained by 
fractionating material (source blood, plasma, serum, or placentas) 
from healthy human donors. The source material is 
tested for the absence of hepatitis B surface antigen. It is 
made by a process that yields a product safe for intravenous 
use. 
Albumin solution, human (PhEur 2005) Human albumin solution 
is an aqueous solution of protein obtained from plasma. 
Separation of the albumin is carried out under controlled conditions 
so that the final product contains not less than 95% 
albumin. Human albumin solution is prepared as a concentrated 
solution containing 150–250 g/L of total protein or as 
an isotonic solution containing 35–50 g/L of total protein. A 
suitable stabilizer against the effects of heat such as sodium 
caprylate (sodium octanoate) or N-acetyltryptophan or a 
combination of these two at a suitable concentration, may be 
added, but no antimicrobial preservative is added at any stage 
during preparation. The solution is passed through a bacteria-
retentive filter and distributed aseptically into sterile 
containers, which are then closed so as to prevent contamination. 
The solution in its final container is heated to 60 
 1.08C and maintained at this temperature for not less than 10 
hours. The containers are then incubated at 30–328C for not 
less than 14 days or at 20–258C for not less than 4 weeks 
and examined visually for evidence of microbial contamination. 
14 Safety 
Albumin occurs naturally in the body, comprising about 60% 
of all the plasma proteins. As an excipient, albumin is used 
primarily in parenteral formulations and is generally regarded 
as an essentially nontoxic and nonirritant material. Adverse 
reactions to albumin infusion rarely occur but include nausea, 
vomiting, increased salivation, chills, and febrile reactions. 
Urticaria and skin rash have been reported. Allergic reactions, 
including anaphylactic shock, can occur. Albumin infusions are 
contraindicated in patients with severe anemia or cardiac 
failure. Albumin solutions with aluminum content of less than 
200 mg/L should be used in dialysis patients and premature 
infants.(6) 
LD50 (monkey, IV): >12.5 g/kg(7) 
LD50 (rat, IV): >12.5 g/kg 
15 Handling Precautions 
Observe handling precautions appropriate for a biologically 
derived blood product. 
16 Regulatory Acceptance 
Included in the FDA Inactive Ingredients Guide (oral, tablets, 
film-coatings; IV injections). Included in parenteral products 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Albumins derived from animal sources are also commercially 
available, e.g., bovine serum albumin. 
18 Comments 
A 100mL aqueous solution of albumin containing 25 g of 
serum albumin is osmotically equivalent to 500mL of normal 
human plasma. The EINECS number for albumin is 310-127-6. 
19 Specific References 
1 Bramanti E, Benedetti E. Determination of the secondary structure 
of isomeric forms of human serum albumin by a particular 
frequency deconvolution procedure applied to Fourier transform 
IR analysis. Biopolymers 1996; 38(5): 639–653. 
2 Wang JUC, Hanson MA. Parenteral formulations of proteins and 
peptides: stability and stabilizers. J Parenter Sci Technol 1988; 
42(S): S1–S26. 
3 Arshady R. Albumin microspheres and microcapsules: methodology 
of manufacturing techniques. J Control Release 1990; 14: 
111–131. 
4 Olson WP, Faith MR. Human serum albumin as a cosolvent for 
parenteral drugs. J Parenter Sci Technol 1988; 42: 82–85. 
5 Cochrane Injuries Group Albumin Reviewers. Human albumin 
administration in critically ill patients: systematic review of 
randomised controlled trials. Br Med J 1998; 317: 235–240. 
6 Quagliaro DA, Geraci VA, Dwan RE, et al. Aluminum in albumin 
for injection. J Parenter Sci Technol 1988; 42: 187–190. 
7 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1970. 
20 General References 
Kragh-Hansen U. Structure and ligand properties of human serum 
albumin. Danish Med Bull 1990; 37(1): 57–84. 
Putnam FW, ed. The Plasma Proteins, Structure, Function and Genetic 
Control. London: Academic Press, 1975. 
21 Authors 
RT Guest. 
22 Date of Revision 
23 August 2005. 
Albumin 17

Alcohol 
1 Nonproprietary Names 
BP: Ethanol (96%) 
JP: Ethanol 
PhEur: Ethanolum (96 per centum) 
USP: Alcohol 
2 Synonyms 
Ethyl alcohol; ethyl hydroxide; grain alcohol; methyl carbinol. 
3 Chemical Name and CAS Registry Number 
Ethanol [64-17-5] 
4 Empirical Formula and Molecular Weight 
C2H6O 46.07 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; disinfectant; skin penetrant; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ethanol and aqueous ethanol solutions of various concentrations 
(see Sections 8 and 17) are widely used in pharmaceutical 
formulations and cosmetics; see Table I. Although ethanol is 
primarily used as a solvent, it is also employed in solutions as an 
antimicrobial preservative.(1,2) Topical ethanol solutions are 
also used as penetration enhancers(3–6) and as disinfectants. 
Ethanol has also been used in transdermal preparations in 
combination with Labrasol as a co-surfactant.(7) 
Table I: Uses of alcohol. 
Use Concentration (% v/v) 
Antimicrobial preservative 510 
Disinfectant 60–90 
Extracting solvent in galenical manufacture Up to 85 
Solvent in film coating Variable 
Solvent in injectable solutions Variable 
Solvent in oral liquids Variable 
Solvent in topical products 60–90 
8 Description 
In the BP 2004, the term ‘ethanol’ used without other 
qualification refers to ethanol containing 599.5% v/v of 
C2H6O. The term ‘alcohol’, without other qualification, refers 
to ethanol 95.1–96.9% v/v. Where other strengths are intended, 
the term ‘alcohol’ or ‘ethanol’ is used, followed by the 
statement of the strength. 
In the PhEur 2005, anhydrous ethanol contains not less than 
99.5% v/v of C2H6O at 208C. The term ethanol (96%) is used 
to describe the material containing water and 95.1–96.9% v/v 
of C2H6O at 208C. 
In the USP 28, the term ‘dehydrated alcohol’ refers to 
ethanol 599.5% v/v. The term ‘alcohol’ without other 
qualification refers to ethanol 94.9–96.0% v/v. 
In the JP 2001, ethanol (alcohol) contains 95.1–95.6% v/v 
(by specific gravity) of C2H6O at 158C. 
In the Handbook of Pharmaceutical Excipients, the term 
‘alcohol’ is used for either ethanol 95% v/v or ethanol 96% v/v. 
Alcohol is a clear, colorless, mobile, and volatile liquid with 
a slight, characteristic odor and burning taste. 
See also Section 17. 
9 Pharmacopeial Specifications 
See Table II. 
10 Typical Properties 
Antimicrobial activity: ethanol is bactericidal in aqueous 
mixtures at concentrations between 60% and 95% v/v; 
the optimum concentration is generally considered to be 
70% v/v. Antimicrobial activity is enhanced in the presence 
of edetic acid or edetate salts.(1) Ethanol is inactivated in the 
presence of nonionic surfactants and is ineffective against 
bacterial spores. 
Boiling point: 78.158C 
Flammability: readily flammable, burning with a blue, smokeless 
flame. 
Flash point: 148C (closed cup) 
Solubility: miscible with chloroform, ether, glycerin, and water 
(with rise of temperature and contraction of volume). 
Specific gravity: 0.8119–0.8139 at 208C 
Note: the above typical properties are for alcohol (ethanol 95% 
or 96% v/v). See Section 17 for typical properties of 
dehydrated alcohol. 
11 Stability and Storage Conditions 
Aqueous ethanol solutions may be sterilized by autoclaving or 
by filtration and should be stored in airtight containers, in a 
cool place. 
12 Incompatibilities 
In acidic conditions, ethanol solutions may react vigorously 
with oxidizing materials. Mixtures with alkali may darken in 
color owing to a reaction with residual amounts of aldehyde. 
Organic salts or acacia may be precipitated from aqueous 
solutions or dispersions. Ethanol solutions are also incompatible 
with aluminum containers and may interact with some 
drugs.

13 Method of Manufacture 
Ethanol is manufactured by the controlled enzymatic fermentation 
of starch, sugar, or other carbohydrates. A fermented 
liquid is produced containing about 15% ethanol; ethanol 95% 
v/v is then obtained by fractional distillation. Ethanol may also 
be prepared by a number of synthetic methods. 
14 Safety 
Ethanol and aqueous ethanol solutions are widely used in a 
variety of pharmaceutical formulations and cosmetics. It is also 
consumed in alcoholic beverages. 
Ethanol is rapidly absorbed from the gastrointestinal tract 
and the vapor may be absorbed through the lungs; it is 
metabolized, mainly in the liver, to acetaldehyde, which is 
further oxidized to acetate. 
Ethanol is a central nervous system depressant and ingestion 
of low to moderate quantities can lead to symptoms of 
intoxication including muscle incoordination, visual impairment, 
slurred speech, etc. Ingestion of higher concentrations 
may cause depression of medullary action, lethargy, amnesia, 
hypothermia, hypoglycemia, stupor, coma, respiratory depression, 
and cardiovascular collapse. The lethal human bloodalcohol 
concentration is generally estimated to be 400–500 mg/ 
100 mL. 
Although symptoms of ethanol intoxication are usually 
encountered following deliberate consumption of ethanolcontaining 
beverages, many pharmaceutical products contain 
ethanol as a solvent, which, if ingested in sufficiently large 
quantities, may cause adverse symptoms of intoxication. In the 
USA, the maximum quantity of alcohol included in OTC 
medicines is 10% v/v for products labeled for use by people of 
12 years of age and older, 5%v/v for products intended for use 
by children aged 6–12 years of age, and 0.5% v/v for products 
for use by children under 6 years of age.(8) 
Parenteral products containing up to 50% of alcohol 
(ethanol 95 or 96% v/v) have been formulated. However, 
such concentrations can produce pain on intramuscular 
injection and lower concentrations such as 5–10% v/v are 
preferred. Subcutaneous injection of alcohol (ethanol 95% v/v) 
similarly causes considerable pain followed by anesthesia. If 
injections are made close to nerves, neuritis and nerve 
degeneration may occur. This effect is used therapeutically to 
cause anesthesia in cases of severe pain, although the practice of 
using alcohol in nerve blocks is controversial. Doses of 1mL of 
absolute alcohol have been used for this purpose.(9) 
Preparations containing more than 50% v/v alcohol may 
cause skin irritation when applied topically. 
LD50 (mouse, IP): 0.93 g/kg(10) 
LD50 (mouse, IV): 1.97 g/kg 
LD50 (mouse, oral): 3.45 g/kg 
LD50 (mouse, SC): 8.29 g/kg 
LD50 (rat, IP): 3.75 g/kg 
LD50 (rat, IV): 1.44 g/kg 
LD50 (rat, oral): 7.06 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Ethanol and aqueous ethanol 
solutions should be handled in a well-ventilated environment. 
In the UK, the long-term 8-hour TWA exposure limit for 
ethanol is 1920 mg/m3 (1000 ppm).(11) Ethanol may be irritant 
to the eyes and mucous membranes and eye protection and 
gloves are recommended. Ethanol is flammable and should be 
heated with care. Fixed storage tanks should be electrically 
grounded to avoid ignition from electrostatic discharges when 
ethanol is transferred. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (dental 
preparations; inhalations; IM, IV, and SC injections; nasal 
and ophthalmic preparations; oral capsules, solutions, suspensions, 
syrups, and tablets; rectal, topical, and transdermal 
preparations). Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. Included in nonparenteral and 
parenteral medicines licensed in the UK. 
17 Related Substances 
Dehydrated alcohol; denatured alcohol; dilute alcohol; isopropyl 
alcohol. 
Dehydrated alcohol 
Synonyms: absolute alcohol; anhydrous ethanol; ethanol. 
Autoignition temperature: 3658C 
Boiling point: 78.58C 
Explosive limits: 3.5–19.0% v/v in air 
Flash point: 128C (closed cup) 
Melting point: 1128C 
Moisture content: absorbs water rapidly from the air. 
Table II: Pharmacopeial specifications for alcohol. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters . . — 
Specific gravity 0.814–0.816 0.805–0.812 0.812–0.816 
Acidity or alkalinity . . . 
Clarity of solution . . — 
Nonvolatile residue 41 mg/40 mL 425 ppm 41 mg/40 mL 
Water-insoluble 
substances 
— — . 
Volatile impurities . . — 
Aldehydes . 410 ppm v/v . 
Amyl alcohol, etc. — — . 
Absorbance — . — 
at 240 nm — 40.40 — 
at 250–260 nm — 40.30 — 
at 270–340 nm — 40.10 — 
Fusel oil constituents . — — 
Acetone and 
propan-2-ol 
— — . 
Methanol — 4200 ppm . 
Benzene — 42 ppm — 
Acetaldehyde and 
acetal 
— 410 ppm — 
Reducing 
substances 
. — — 
Organic volatile 
impurities 
— — . 
Chloride . — — 
Heavy metals 41.2 ppm — — 
Assay 95.1–95.6% 95.1–96.9% 92.3–93.8% 
by weight 
94.9–96.0% 
by volume 
Alcohol 19

Refractive index: nD
20 = 1.361 
Specific gravity: 0.7904–0.7935 at 208C 
Surface tension: 22.75 mN/m at 208C (ethanol/vapor) 
Vapor density (relative): 1.59 (air = 1) 
Vapor pressure: 5.8 Pa at 208C 
Viscosity (dynamic): 1.22 mPa s (1.22 cP) at 208C 
Comments: dehydrated alcohol is ethanol 599.5% v/v. See 
Section 8. 
Denatured alcohol 
Synonyms: industrial methylated spirit; surgical spirit. 
Comments: denatured alcohol is alcohol intended for external 
use only. It has been rendered unfit for human consumption 
by the addition of a denaturing agent such as methanol or 
methyl isobutyl ketone. 
Dilute alcohol 
Synonyms: dilute ethanol. 
Specific gravity: see Table III. 
Table III: Specific gravity of alcohol. 
Strength of alcohol (% v/v) Specific gravity at 208C 
90 0.8289–0.8319 
80 0.8599–0.8621 
70 0.8860–0.8883 
60 0.9103–0.9114 
50 0.9314–0.9326 
45 0.9407–0.9417 
25 0.9694–0.9703 
20 0.9748–0.9759 
Comments: the term ‘dilute alcohol’ refers to a mixture of 
ethanol and water of stated concentration. The BP 2004 lists 
eight strengths of dilute alcohol (dilute ethanol) containing 
90%, 80%, 70%, 60%, 50%, 45%, 25%, and 20% v/v 
respectively of ethanol. 
18 Comments 
Possession and use of nondenatured alcohols are usually 
subject to close control by excise authorities. 
A specification for alcohol is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for alcohol is 200-578-6. 
19 Specific References 
1 Chiori CO, Ghobashy AA. A potentiating effect of EDTA on the 
bactericidal activity of lower concentrations of ethanol. Int J 
Pharm 1983; 17: 121–128. 
2 Karabit MS, Juneskans OT, Lundgren P. Studies on the evaluation 
of preservative efficacy. IV. The determination of antimicrobial 
characteristics of some pharmaceutical compounds in aqueous 
solutions. Int J Pharm 1989; 54: 51–56. 
3 Liu P, Higuchi WI, Song W, et al. Quantitative evaluation of 
ethanol effects on diffusion and metabolism of b-estradiol in 
hairless mouse skin. Pharm Res 1991; 8(7): 865–872. 
4 Verma DD, Fahr A. Synergistic penetration enhancement of 
ethanol and phospholipids on the topical delivery of cyclosporin 
A. J Controlled Release 2004; 97(1): 55–66. 
5 Gwak SS, Oh IS, Chun IK. Transdermal delivery of ondansetron 
hydrochloride: effects of vehicles and penetration enhancers. Drug 
Dev Ind Pharm 2004; 30(2): 187–194. 
6 Williams AC, Barry BW. Penetration enhancers. Adv Drug 
Delivery Rev 2004; 56(5): 603–618. 
7 Kwean JH, Chi SC, Park ES. Transdermal delivery of diclofenac 
using microemulsions. Arch Pharmacol Res 2004; 27(3): 351–356. 
8 Jass HE. Regulatory review. Cosmet Toilet 1995; 110(5): 21–22. 
9 Lloyd JW. Use of anaesthesia: the anaesthetist and the pain clinic. 
Br Med J 1980; 281: 432–434. 
10 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1627–1628. 
11 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
Lund W, ed. The Pharmaceutical Codex: Principles and Practice of 
Pharmaceutics, 12th edn. London: Pharmaceutical Press, 1994: 
694–695. 
Spiegel AJ, Noseworthy MN. Use of nonaqueous solvents in parenteral 
products. J Pharm Sci 1963; 52: 917–927. 
Wade A, ed. Pharmaceutical Handbook, 19th edn. London: Pharmaceutical 
Press, 1980: 227–230. 
21 Authors 
SC Owen. 
22 Date of Revision 
10 February 2005. 
20 Alcohol

Alginic Acid 
1 Nonproprietary Names 
BP: Alginic acid 
PhEur: Acidum alginicum 
USPNF: Alginic acid 
2 Synonyms 
E400; Kelacid; L-gulo-D-mannoglycuronan; polymannuronic 
acid; Protacid; Satialgine H8. 
3 Chemical Name and CAS Registry Number 
Alginic acid [9005-32-7] 
4 Empirical Formula and Molecular Weight 
Alginic acid is a linear glycuronan polymer consisting of a 
mixture of b-(1!4)-D-mannosyluronic acid and a-(1!4)-Lgulosyluronic 
acid residues, of general formula (C6H8O)n. The 
molecular weight is typically 20 000–240 000. 
5 Structural Formula 
The PhEur 2005 describes alginic acid as a mixture of 
polyuronic acids [(C6H8O6)n] composed of residues of 
D-mannuronic and L-glucuronic acid, and is obtained mainly 
from algae belonging to the Phaeophyceae. A small proportion 
of the carboxyl groups may be neutralized. 
See also Section 4. 
6 Functional Category 
Stabilizing agent; suspending agent; sustained release adjuvant; 
tablet binder; tablet disintegrant; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Alginic acid is used in a variety of oral and topical 
pharmaceutical formulations. In tablet and capsule formulations, 
alginic acid is used as both a binder and disintegrating 
agent at concentrations of 1–5% w/w.(1,2) Alginic acid is widely 
used as a thickening and suspending agent in a variety of pastes, 
creams, and gels; and as a stabilizing agent for oil-in-water 
emulsions. Alginic acid has also been investigated for use in an 
ocular formulation of carteolol.(3) 
Therapeutically, alginic acid has been used as an antacid.(4) 
In combination with an H2-receptor antagonist, it has also been 
utilized for the management of gastroesophageal reflux.(5) 
Chemically modified alginic acid derivatives have been 
researched for their anti-inflammatory, antiviral, and antitumoral 
activities.(6) 
In the area of controlled release, the preparation of 
indomethacin sustained-release microparticles from alginic 
acid (alginate)–gelatin hydrocolloid coacervate systems has 
been investigated.(7) In addition, as controlled-release systems 
for liposome-associated macromolecules, microspheres have 
been produced encapsulating liposomes coated with alginic 
acid and poly-L-lysine membranes.(8) Alginate gel beads 
capable of floating in the gastric cavity have been prepared, 
the release properties of which were reported to be applicable 
for sustained release of drugs, and for tareting the gastric 
mucosa.(9) Alginic acid has also been used to improve the 
stability of levosimendan.(10) Mechanical properties, water 
uptake, and permeability properties of a sodium salt of alginic 
acid have been characterized for controlled-release applications.(
11) In addition, sodium alginate has been incorporated 
into an ophthalmic drug delivery system for pilocarpine 
nitrate.(12) It has also been reported that associated chains of 
alginic acid complexed with cations can bind to cell surfaces 
and exert pharmacological effects which depend on the cell type 
and the complexed cation. These complexes can be used to treat 
rheumatic disorders, diseases associated with atopic diathesis 
and liver diseases.(13) Furthermore, an alginic oligosaccharide, 
obtained from a natural edible polysaccharide, has been shown 
to suppress Th2 responses and IgE production by inducing 
IL-12 production, was found to be a useful approach for 
preventing allergic disorders.(14) 
SEM: 1 
Excipient: Alginic acid 
Magnification: 100 Voltage: 25 kV 
8 Description 
Alginic acid is a tasteless, practically odorless, white to 
yellowish-white, fibrous powder. 
9 Pharmacopeial Specifications 
See Table I.

SEM: 2 
Excipient: Alginic acid 
Magnification: 500 Voltage: 25 kV 
Table I: Pharmacopeial specifications for alginic acid 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Microbial limits 4102/g 4200/g 
pH (3% dispersion) — 1.5–3.5 
Loss on drying 415.0% 415.0% 
Ash — 44.0% 
Sulfated ash 48.0% — 
Arsenic — 43 ppm 
Chloride 41.0% — 
Lead — 40.001% 
Heavy metals 420 ppm 40.004% 
Acid value (dried basis) — 5230 
Assay (of COOH groups) 19.0–25.0% — 
10 Typical Properties 
Acidity/alkalinity: pH = 1.5–3.5 for a 3% w/v aqueous 
dispersion. 
Crosslinking: addition of a calcium salt, such as calcium citrate 
or calcium chloride, causes crosslinking of the alginic acid 
polymer resulting in an apparent increase in molecular 
weight. Films crosslinked with triphosphate (tripolyphosphate) 
and calcium chloride were found to be insoluble but 
permeable to water vapor. Drug permeability varies with pH 
and the extent of crosslinking.(11) 
Density (true): 1.601 g/cm3 
Moisture content: 7.01% 
Solubility: soluble in alkali hydroxides, producing viscous 
solutions; very slightly soluble or practically insoluble in 
ethanol (95%) and other organic solvents. Alginic acid 
swells in water but does not dissolve; it is capable of 
absorbing 200–300 times its own weight of water. 
Viscosity (dynamic): various grades of alginic acid are 
commercially available that vary in their molecular weight 
and hence viscosity. Viscosity increases considerably with 
increasing concentration; typically a 0.5% w/w aqueous 
dispersion will have a viscosity of approximately 20 mPa s, 
while a 2.0% w/w aqueous dispersion will have a viscosity 
of approximately 2000 mPa s. The viscosity of dispersions 
decreases with increasing temperature. As a general rule, a 
18C increase in temperature results in a 2.5% reduction in 
viscosity. At low concentrations, the viscosity of an alginic 
acid dispersion may be increased by the addition of a 
calcium salt, such as calcium citrate. See also Sections 11 
and 18. 
11 Stability and Storage Conditions 
Alginic acid hydrolyzes slowly at warm temperatures producing 
a material with a lower molecular weight and lower 
dispersion viscosity. 
Alginic acid dispersions are susceptible to microbial spoilage 
on storage, which may result in some depolymerization and 
hence a decrease in viscosity. Dispersions should therefore be 
preserved with an antimicrobial preservative such as benzoic 
acid; potassium sorbate; sodium benzoate; sorbic acid; or 
paraben. Concentrations of 0.1–0.2% are usually used. 
Alginic acid dispersions may be sterilized by autoclaving or 
filtration through a 0.22 mm filter. Autoclaving may result in a 
decrease in viscosity which can vary depending upon the nature 
of any other substances present.(15) 
Alginic acid should be stored in a well-closed container in a 
cool, dry place. 
12 Incompatibilities 
Incompatible with strong oxidizing agents, alginic acid forms 
insoluble salts in the presence of alkaline earth metals and 
group III metals with the exception of magnesium. 
13 Method of Manufacture 
Alginic acid is a hydrophilic colloid carbohydrate that occurs 
naturally in the cell walls and intercellular spaces of various 
species of brown seaweed (Phaeophyceae). The seaweed occurs 
widely throughout the world and is harvested, crushed, and 
treated with dilute alkali to extract the alginic acid. 
14 Safety 
Alginic acid is widely used in food products and topical and 
oral pharmaceutical formulations. It is generally regarded as a 
nontoxic and nonirritant material, although excessive oral 
consumption may be harmful. Inhalation of alginate dust may 
be irritant and has been associated with industrially related 
asthma in workers involved in alginate production. However, it 
appears that the cases of asthma were linked to exposure to 
unprocessed seaweed dust rather than pure alginate dust.(16) An 
acceptable daily intake of alginic acid and its ammonium, 
calcium, potassium, and sodium salts was not set by the WHO 
because the quantities used, and the background levels in food, 
did not represent a hazard to health.(17) 
LD50 (rat, IP): 1.6 g/kg(18) 
22 Alginic Acid

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Alginic acid may be irritant 
to the eyes or respiratory system if inhaled as dust; see Section 
14. Eye protection, gloves, and a dust respirator are recommended. 
Alginic acid should be handled in a well-ventilated 
environment. 
16 Regulatory Status 
GRAS listed. Accepted in Europe for use as a food additive. 
Included in the FDA Inactive Ingredients Guide (ophthalmic 
preparations, oral capsules, and tablets). Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
Included in nonparenteral medicines licensed in the UK. 
17 Related Substances 
Ammonium alginate; calcium alginate; potassium alginate; 
propylene glycol alginate; sodium alginate. 
18 Comments 
Alginic acid dispersions are best prepared by pouring the alginic 
acid slowly and steadily into vigorously stirred water. Dispersions 
should be stirred for approximately 30 minutes. Premixing 
the alginic acid with another powder, such as sugar, or a 
water-miscible liquid such as ethanol (95%) or glycerin, aids 
dispersion. 
When using alginic acid in tablet formulations, the alginic 
acid is best incorporated or blended using a dry granulation 
process. 
A specification for alginic acid is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for alginic acid is 232-680-1. 
19 Specific References 
1 Shotton E, Leonard GS. Effect of intragranular and extragranular 
disintegrating agents on particle size of disintegrated tablets. J 
Pharm Sci 1976; 65: 1170–1174. 
2 Esezobo S. Disintegrants: effects of interacting variables on the 
tensile strengths and disintegration times of sulfaguanidine tablets. 
Int J Pharm 1989; 56: 207–211. 
3 Tissie G, Sebastian C, Elena PP, Driot JY, Trinquand C. Alginic 
acid effect on carteolol ocular pharmacokinetics in the pigmented 
rabbit. J Ocul Pharmacol Ther 2002; 18(1): 65–73. 
4 Vatier J, Vallot T, Farinotti R. Antacid drugs: multiple but too often 
unknown pharmacological properties. J Pharm Clin 1996; 15(1): 
41–51. 
5 Stanciu C, Bennett JR. Alginate/antacid in the reduction of gastrooesophageal 
reflux. Lancet 1974; i: 109–111. 
6 Boisson-Vidal C, Haroun F, Ellouali M, et al. Biological activities 
of polysaccharides from marine algae. Drugs Future 1995; 
20(Dec): 1247–1249. 
7 Joseph I, Venkataram S. Indomethacin sustained release from 
alginate-gelatin or pectin-gelatin coacervates. Int J Pharm 1995; 
125: 161–168. 
8 Machluf M, Regev O, Peled Y, et al. Characterization of 
microencapsulated liposome systems for the controlled delivery 
of liposome-associated macromolecules. J Control Release 1997; 
43: 35–45. 
9 Murata Y, Sasaki N, Miyamoto E, Kawashima S. Use of floating 
alginate gel beads for stomach-specific drug delivery. Eur J Pharm 
Biopharm 2000; 50(2): 221–226. 
10 Larma I, Harjula M. Stable compositions comprising levosimendan 
and alginic acid. Patent No: WO9955337; 1999. 
11 Remunan-Lopez C, Bodmeier R. Mechanical, water uptake and 
permeability properties of crosslinked chitosan glutamate and 
alginate films. J Control Release 1997; 44: 215–225. 
12 Cohen S, Lobel E, Treygoda A, Peled Y. Novel in situ-forming 
opthalmic drug delivery system from alginates undergoing gelation 
in the eye. J Control Release 1997; 44: 201–208. 
13 Gradl T. Use of alginic acid and/or its derivatives and salts for 
combating or preventing diseases. Patent No: DE19723155; 1998. 
14 Tadashi Y, Aki H, Hanae W, Koji T, Makoto H. Alginic acid 
oligosaccharide suppresses Th2 development and IgE production 
by inducing IL-12 production. Int Arch Allergy Imm 2004; 133(3): 
239–247. 
15 Vandenbossche GMR, Remon J-P. Influence of the sterilization 
process on alginate dispersions. J Pharm Pharmacol 1993; 45: 
484–486. 
16 Henderson AK, Ranger AF, Lloyd J, et al. Pulmonary hypersensitivity 
in the alginate industry. Scott Med J 1984; 29(2): 90–95. 
17 FAO/WHO. Evaluation of certain food additives and naturally 
occurring toxicants. Thirty-ninth report of the joint FAO/WHO 
expert committee on food additives. World Health Organ Tech 
Rep Ser 1993; No. 837. 
18 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 101–102. 
20 General References 
Marshall PV, Pope DG, Carstensen JT. Methods for the assessment of 
the stability of tablet disintegrants. J Pharm Sci 1991; 80: 899–903. 
21 Authors 
JW McGinity, MA Repka. 
22 Date of Revision 
23 August 2005. 
Alginic Acid 23

Aliphatic Polyesters 
1 Nonproprietary Names 
See Table I. 
2 Synonyms 
See Table I. 
3 Chemical Name and CAS Registry Number 
See Table I. 
4 Empirical Formula and Molecular Weight 
Aliphatic polyesters are synthetic homopolymers or copolymers 
of lactic acid, glycolic acid, and e-hydroxycaproic acid. 
Typically, the molecular weights of homopolymers and 
copolymers range from 2000 to >100 000. 
5 Structural Formula 
6 Functional Category 
Bioabsorbable; biocompatible; biodegradable material. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Aliphatic polyesters are a group of synthesized, nontoxic, 
biodegradable polymers. In an aqueous environment, they 
undergo hydrolytic degradation, through cleavage of the ester 
linkages, into nontoxic hydroxycarboxylic acids. Aliphatic 
polyesters are eventually metabolized to carbon dioxide and 
water, via the citric acid cycle. Owing to their reputation as safe 
materials and their biodegradability, aliphatic polyesters are 
primarily used as biocompatible and biodegradable polymers 
for formulation of many types of implantable and injectable 
drug-delivery systems for both human and veterinary use. 
Examples of implantable drug delivery systems include rods, 
cylinders, tubing, films,(1) fibers,(2) pellets, and beads.(3) 
Examples of injectable drug-delivery systems include microcapsules,(
4) microspheres,(5) nanoparticles, and liquid injectable 
controlled-release systems. The rate of biodegradation and 
drug-release characteristics from these systems formulated with 
the aliphatic polyesters can be controlled by changing the 
physicochemical properties of the polymers, such as crystallinity, 
hydrophobicity, monomer stereochemistry, copolymer 
ratio, and polymer molecular weight. 
8 Description 
Aliphatic polyesters are a group of synthesized homopolymers 
or copolymers. They are nontoxic and can easily be fabricated 
into a variety of novel devices, such as rods, screws, nails, and 
cylinders. The polymers are commercially available in varying 
molecular weights as both homopolymers and copolymers. 
Molecular weights of polyesters range from 2000 to greater 
than 100 000. 
Co-monomer ratios of lactic acid and glycolic acid for 
poly(DL-lactide-co-glycolide) range from 85 : 15 to 50 : 50. 
Table I shows the chemical and trade names of different 
commercially available aliphatic polyesters. 
9 Pharmacopeial Specifications 
—
10 Typical Properties 
For typical physical and mechanical properties of the aliphatic 
polyesters, see Table II. 
Polymer composition and crystallinity play important roles 
in the solubility of these aliphatic polyesters. The crystalline 
homopolymers of glycolic acid are soluble only in strong 
solvents, such as hexafluoroisopropanol. The crystalline 
homopolymers of lactic acid also do not have good solubility 
in most organic solvents. However, amorphous polymers of DLlactic 
acid and copolymers of lactic acid and glycolic acid with a 
low glycolic acid content are soluble in many organic solvents 
(Table II). Aliphatic polyesters are slightly soluble or insoluble 
in water, methanol, ethylene glycol, heptane, and hexane.

Table I: Chemical names and CAS registry numbers of the aliphatic polyesters. 
Generic name Composition (%) Synonyms Trade name Manufacturer CAS name CAS number 
Lactide Glycolide Caprolactone 
Poly(D-lactide) 100 0 0 D-PLA Purasorb PD PURAC (3R-cis)-3,6-Dimethyl-1,4-dioxane-2,5-dione 
homopolymer 
[25038-75-9] 
Poly(L-lactide) 100 0 0 L-PLA Lactel L-PLA BPI Propanoic acid, 2-hydroxy-, homopolymer [26161-42-2] 
Medisorb 100 L Alkermes 
Purasorb PL PURAC 
Resomer L 206, 207, 209, 210, 
214 
BI 
Poly(DL-lactide) 100 0 0 DL-PLA Lactel DL-PLA BPI Propanoic acid, 2-hydroxy-, homopolymer [34346-01-5] 
Medisorb 100 DL Alkermes 
Pursasorb PDL PURAC 
Resomer R 202, 202H, 203, 206, 
207, 208 
BI 
Poly(glycolide) 0 100 0 PGA Lactel PGA BPI Acetic acid, hydroxy-, homopolymer [34346-01-5] 
Medisorb 100 PGA Alkermes 
Purasorb PG PURAC 
Resomer G 205 BI 
Poly(L-lactide-co-glycolide) 75 25 0 L-PLGA (75 : 25) Pursasorb PLG PURAC 1,4-Dioxane-2,5-dione, polymer with (3S-cis)- 
3,6-dimethyl-1,4-dioxane-2,5-dione 
[30846-39-0] 
Poly(L-lactide-co-glycolide) 50 50 0 L-PLGA (50 : 50) Purasorb PLG PURAC 1,4-Dioxane-2,5-dione,polymer with (3S-cis)- 
3,6-dimethyl-1,4-dioxane-2,5-dione 
[30846-39-0] 
Poly(DL-lactide-coglycolide) 
85 15 0 Polyglactin;DL-PLGA 
(85:15) 
Lactel 8515 DL-PLGA BPI Propanoic acid, 2-hydroxypolymer with 
hydroxyacetic acid 
[26780-50-7] 
Medisorb 8515 DL Alkermes 
Resomer RG 858 BI 
Poly(DL-lactide-coglycolide) 
75 25 0 Polyglactin;DL-PLGA 
(75 : 25) 
Lactel 7525 DL-PLGA BPI Propanoic acid, 2-hydroxypolymer with 
hydroxyacetic acid 
[26780-50-7] 
Pursasorb PDLG PURAC 
Resomer RG 752, 755, 756 BI 
Poly(DL-lactide-coglycolide) 
65 35 0 Polyglactin;DL-PLGA 
(65 : 35) 
Lactel 6535 DL-PLGA BPI Propanoic acid, 2-hydroxypolymer with 
hydroxyacetic acid 
[26780-50-7] 
Poly(DL-lactide-coglycolide) 
50 50 0 Polyglactin;DL-PLGA 
(50 : 50) 
Lactel 5050 DL-PLGA BPI Propanoic acid, 2-hydroxypolymer with 
hydroxyacetic acid 
[26780-50-7] 
Medisorb 5050 DL Alkermes 
Purasorb PDLG PURAC 
Resomer RG 502, 502H, 503, 
503H, 504, 504H, 505, 506 
BI 
Poly-e-caprolactone 0 0 100 PCL Lactel PCL BPI 2-Oxepanone, homopolymer [24980-41-4] 
Poly(DL-lactide-cocaprolactone) 
75 0 25 DL-PLCL (75 : 25) Lactel 7525 DL-PLCL BPI 1,4-Dioxane-2,5-dione,3,6-dimethyl-, 
polymer with 2-oxepanone 
[70524-20-8] 
Poly(DL-lactide-cocaprolactone) 
25 0 75 DL-PLCL (25 : 75) Lactel 2575 DL-PLCL BPI 1,4-Dioxane-2,5-dione,3,6-dimethyl-, 
polymer with 2-oxepanone 
[70524-20-8] 
Alkermes, Alkermes Inc.; BI, Boehringer Ingelheim; BPI, Birmingham Polymers Inc.; PURAC, PURAC America. 
Aliphatic Polyesters 25

Table II: Typical physical and mechanical properties of the aliphatic polyesters.(a) 
50/50 DL-PLG 65/35 DL-PLG 75/25 DL-PLG 85/15 DL-PLG DL-PLA L-PLA PGA PCL 
Molecular weight 40 000–100 000 40 000–100 000 40 000–100 000 40 000–100 000 40 000–100 000 >100 000 >100 000 80–150 000 
Inherent viscosity (mPa s) 0.5–0.8(b) 0.5–0.8(b) 0.5–0.8(c) 0.5–0.8(c) 0.5–0.8(c) 0.9–1.2(c) 1.1–1.4(b) 0.7–1.3(c) 
Melting point (8C) Amorphous Amorphous Amorphous Amorphous Amorphous 173–178 225–230 58–63 
Glass transition (8C) 45–50 45–50 50–55 50–55 55–60 60–65 35–40 –65 to –60 
Color White to light gold White to light gold White to light gold White to light gold White White Light tan White 
Solubility(d) MeCl2, THF, EtOAc, 
C3H6O, CHCl3 
MeCl2, THF, EtOAc, 
C3H6O, CHCl3 
MeCl2, THF, EtOAc, 
C3H6O, CHCl3 
MeCl2, THF, EtOAc, 
C3H6O, CHCl3, 
MeCl2, THF, EtOAc, 
C3H6O, CHCl3 
MeCl2, CHCl3 HFIP, HFASH MeCl2, CHCl3, 
C3H6O 
Specific gravity 1.34 1.30 1.30 1.27 1.25 1.24 1.53 1.11 
Tensile strength (psi) 6000–8000 6000–8000 6000–8000 6000–8000 4000–6000 8000–12 000 10 000. 3000–5000 
Elongation (%) 3–10 3–10 3–10 3–10 3–10 5–10 15–20 300–500 
Modulus (psi) 2–4  105 2–4  105 2–4  105 2–4  105 2–4  105 4–6  105 1  106 3–5  104 
Note: DL-PLG: DL-poly(lactic-co-glycolic acid); DL-PLA: DL-polylactic acid; L-PLA: L-polylactic acid; PGA: polyglycolic acid; PCL: poly-e-caprolactone. 
(a) Specifications obtained from Birmingham Polymers, Inc. 
(b) (HFIP) hexafluoroisopropanol. 
(c) (CHCl3) chloroform. 
(d) Partial listing only: MeCl2, methylene chloride; THF, tetrahydrofuran; EtOAc, ethyl acetate; HFIP, hexafluoroisopropanol; HFASH, hexafluoroacetone sesquihydrate; C3H6O, acetone. 
26 Aliphatic Polyesters

11 Stability and Storage Conditions 
The aliphatic polyesters are easily susceptible to hydrolysis in 
the presence of moisture. Hence, they should be properly 
stored, preferably refrigerated at below 08C. It is necessary to 
allow the polymers to reach room temperature before opening 
the container. After the original package has been opened, it is 
recommended to re-purge the package with high-purity dry 
nitrogen prior to resealing. 
12 Incompatibilities 
—
13 Method of Manufacture 
Generally, aliphatic polyesters can be synthesized via polycondensation 
of hydroxycarboxylic acids and catalytic ringopening 
polymerization of lactones. Ring-opening polymerization 
is preferred because polyesters with high molecular weights 
can be produced. Moreover, the dehydration of hydroxycarboxylic 
acids to form lactones does not have to be carried to a 
high degree of completion. Lactones can easily be purified 
owing to the differences of their physical and chemical 
properties from those of the corresponding hydroxycarboxylic 
acid. 
14 Safety 
Poly(lactide), poly(glycolide), poly(lactide-co-glycolide), and 
polycaprolactone are used in parenteral pharmaceutical formulations 
and are regarded as biodegradable, biocompatible, 
and bioabsorbable materials. Their biodegradation products 
are nontoxic, noncarcinogenic, and nonteratogenic. In general, 
these polyesters exhibit very little hazard. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Contact with eyes, skin, and 
clothing, and breathing the dust of the polymers should be 
avoided. Aliphatic polyesters produce acid materials such as 
hydroxyacetic and/or lactic acid in the presence of moisture; 
thus, contact with materials that will react with acids, especially 
in moist conditions, should be avoided. 
16 Regulatory Status 
GRAS listed. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Lactic acid. 
18 Comments 
Due to their ability to form complexes with heavy metal ions, 
aliphatic polyesters are added to skin-protective ointments.(6) 
19 Specific References 
1 Jackanicz TM, Nash HA, Wise DL, Gregory JB. Polylactic acid as a 
biodegradable carrier for contraceptive steroids. Contraception 
1973; 8: 227–233. 
2 Eenink MJD, Feijen J, Olijslager J, et al. In: Anderson JM, Kim SW, 
eds. Advances in Drug Delivery Systems. Amsterdam: Elsevier: 
1987: 225–247. 
3 Schwope AD,Wise DL, Howes JF. Lactic/glycolic acid polymers as 
narcotic antagonist delivery system. Life Sci 1975; 17: 1877–1886. 
4 Juni K, Ogata J, Nakano M, et al. Preparation and evaluation in 
vitro and in vivo of polylactic acid microspheres containing 
doxorubicin. Chem Pharm Bull 1985; 33(1): 313–318. 
5 Sanders LM, Burns R, Bitale K, Hoffman P. Clinical performance 
of nafarelin controlled release injectable: influence of formulation 
parameters on release kinetics and duration of efficacy. Proc Int 
Symp Control Rel Bioact Mater 1988; 15: 62–63. 
6 Hoeffner EM, Reng A, Schmidt PC, eds. Fiedler Encyclopedia of 
Excipients for Pharmaceuticals, Cosmetics and Related Areas, 5th 
edn. Munich, Germany: Editio Cantor Verlag Aulendorf, 2002: 
1270. 
20 General References 
Barrows T. Degradable implant materials: a review of synthetic 
absorbable polymers and their applications. Clin Mater 1986; 1: 
233–257. 
Chu CC. An in-vitro study of the effect of buffer on the degradation of 
poly (glycolide) sutures. J Biomed Mater Res 1981; 15: 19–27. 
Chu CC. The effect of pH on the in vitro degradation of poly (glycolide 
lactide) copolymer absorbable sutures. J Biomed Mater Res 1982; 
16: 117–124. 
Danckwerts M, Fassihi A. Implantable controlled release drug delivery 
systems: a review. Drug Dev Ind Pharm 1991; 17(11): 1465–1502. 
Gilding DK, Reed AM. Biodegradable polymers for use in surgerypolyglycolic/
poly(lactic acid) homo- and copolymers: 1. Polymer 
1979; 20: 1459–1464. 
Kissel T, Li YX, Volland C. Properties of block- and randomcopolymers 
of lactic acid and glycolic acid. Proc Int Symp Control 
Rel Bioact Mater 1993; 20: 127–128. 
Kitchell JP, Wise DL. Poly(lactic/glycolic acid) biodegradable drugpolymer 
matrix systems. Methods Enzymol 1985; 112: 436–448. 
Kulkarni RK, Moore EG, Hegyeli AF, Leonard F. Biodegradable 
poly(lactic acid) polymers. J Biomed Mater Res 1971; 5: 169–181. 
Lewis H. Controlled release of bioactive agents from lactide/glycolide 
polymers. In: Chasin M, Langer R, eds. Biodegradable Polymers as 
Drug Delivery Systems. New York: Marcel Dekker, 1990: 1–41. 
Li SM, Garreau H, Vert M. Structure–property relationships in the case 
of the degradation of massive aliphatic poly-(a-hydroxy acids) in 
aqueous media, Part 1: Poly(dl-lactic acid). J Mater Sci Mater Med 
1990; 1: 130–139. 
Nguyen TH, Higuchi T, Himmelstein J. Erosion characteristics of 
catalyzed poly(orthoester) matrices. J Controlled Release 1987; 5: 
1–12. 
Pitt CG, Gratzl MM, Jeffcoat AR, et al. Sustained drug delivery systems 
II: factors affecting release rates from poly (e-caprolactone) and 
related biodegradable polyesters. J Pharm Sci 1979; 68(12): 1534– 
1538. 
Reed AM, Gilding DK. Biodegradable polymers for use in surgerypoly(
glycolic)/poly(lactic acid) homo and copolymers: 2. In vitro 
degradation. Polymer 1981; 22: 494–498. 
Shah SS, Cha Y, Pitt CG. Poly(glycolic acid-co-dl lactic acid): diffusion 
or degradation controlled drug delivery? J Controlled Release 1992; 
18: 261–270. 
Vert M, Li S, Garreau H. New insights on the degradation of 
bioresorbable polymeric devices based on lactic and glycolic acids. 
Clin Mater 1992; 10: 3–8. 
Visscher GE, Robison RL, Maulding HV, et al. Biodegradation and 
tissue reaction to 50 : 50 poly(dl-lactide-co-glycolide) microcapsules. 
J Biomed Mater Res 1985; 19: 349–365. 
Williams DF. Mechanisms of biodegradation of implantable polymers. 
Clin Mater 1992; 10: 9–12. 
21 Authors 
RK Chang, AJ Shukla, Y Sun. 
22 Date of Revision 
26 August 2005. 
Aliphatic Polyesters 27

Alitame 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Aclame; L-aspartyl-D-alanine-N-(2,2,4,4-tetramethylthietan-3- 
yl)amide; 3-(L-aspartyl-D-alaninamido)-2,2,4,4-tetramethylthietane. 
3 Chemical Name and CAS Registry Number 
L-a-Aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alaninamide 
anhydrous [80863-62-3] 
L-a-Aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alaninamide 
hydrate [99016-42-9] 
4 Empirical Formula and Molecular Weight 
C14H25N3O4S 331.44 (for anhydrous) 
C14H25N3O4S21=2H2O 376.50 (for hydrate) 
5 Structural Formula 
6 Functional Category 
Sweetening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Alitame is an intense sweetening agent developed in the early 
1980s and is approximately 2000 times sweeter than sucrose. It 
has an insignificant energy contribution of 6 kJ (1.4 kcal) per 
gram of alitame. 
Alitame is currently primarily used in a wide range of foods 
and beverages at a maximum level of 40–300 mg/kg.(1) 
8 Description 
Alitame is a white nonhygroscopic crystalline powder; odorless 
or having a slight characteristic odor. 
9 Pharmacopeial Specifications 
—
10 Typical Properties 
Acidity/alkalinity: pH = 5–6 (5% w/v aqueous solution) 
Isoelectric point: pH 5.6 
Melting point: 136–1478C 
Solubility: see Table I. 
Table I: Solubility of alitame. 
Solvent Solubility at 208C 
unless otherwise stated 
Chloroform 1 in 5000 at 258C 
Ethanol 1 in 1.6 at 258C 
n-Heptane Practically insoluble 
Methanol 1 in 2.4 at 258C 
Propylene glycol 1 in 1.9 at 258C 
Water 1 in 8.3 at 58C 
1 in 7.6 at 258C 
1 in 3.3 at 408C 
1 in 2.0 at 508C 
Specific rotation [a]D
25: .408 to .508 (1% w/v aqueous 
solution) 
11 Stability and Storage Conditions 
Alitame is stable in dry, room temperature conditions but 
undergoes degradation at elevated temperatures or when in 
solution at low pH. Alitame can degrade in a one-stage process 
to aspartic acid and alanine amide (under harsh conditions) or 
in a slow two-stage process by first degrading to its b-aspartic 
isomer and then to aspartic acid and alanine amide. At pH 5–8, 
alitame solutions at 238C have a half-life of approximately 4 
years. At pH 2 and 238C the half-life is 1 year. 
Alitame should be stored in a well-closed container in a cool, 
dry place. 
12 Incompatibilities 
Alitame may be incompatible with oxidizing and reducing 
substances or strong acids and bases. 
13 Method of Manufacture 
Alitame may be synthesized by a number of routes.(2,3) For 
example, 3-(D-alaninamido)-2,2,4,4-tetramethylthietane is dissolved 
in water and L-aspartic acid N-thiocarboxyanhydride is 
then added in portions with vigorous stirring, maintaining the 
pH of 8.5–9.5. The pH is then adjusted to 5.5 and ptoluenesulfonic 
acid monohydrate is added over a period of 
one hour. The precipitated crystalline p-toluenesulfonate salt is 
collected by filtration. To obtain alitame from its salt, a mixture 
of Amberlite LA-1 (liquid anion exchange resin), dichloromethane, 
deionized water, and the salt is stirred for one hour, 
resulting in two clear layers. The aqueous layer is treated with 
carbon, clarified by filtration, and cooled to crystallize alitame. 
Alternatively, tetramethylthietane amine is condensed with 
an N-protected form of D-alanine to give alanyl amide. This is 
then coupled to a protected analogue of L-aspartic acid to give a 
crude form of alitame. The crude product is then purified.

14 Safety 
Alitame is a relatively new intense sweetening agent used 
primarily in foods and confectionary. It is generally regarded as 
a relatively nontoxic and nonirritant material. 
Chronic animal studies in mice, rats, and dogs carried out 
for a minimum of 18 months at concentrations >100 mg/kg per 
day exhibited no toxic or carcinogenic effects. In people, no 
evidence of untoward effects were observed following ingestion 
of 15 mg/kg per day for two weeks. 
Following oral administration 7–22% of alitame is unabsorbed 
and excreted in the feces. The remaining amount is 
hydrolyzed to aspartic acid and alanine amide. The aspartic 
acid is metabolized normally and the alanine amide excreted in 
the urine as a sulfoxide isomer, as the sulfone, or conjugated 
with glucuronic acid. 
TheWHOhas set an acceptable daily intake of alitame at up 
to 0.1 mg/kg body-weight.(4) 
LD50 (mouse, oral): >5 g/kg 
LD50 (rabbit, skin): >2 g/kg 
LD50 (rat, oral): >5 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. Alitame should be stored in tightly closed 
containers, and protected from exposure to direct sunlight and 
higher than normal room temperatures. 
16 Regulatory Status 
Alitame is approved for use in food applications in a number of 
countries worldwide including Australia, Chile, China, Mexico, 
and New Zealand. 
17 Related Substances 
Acesulfame potassium; aspartame; saccharin; saccharin 
sodium; sodium cyclamate. 
18 Comments 
—
19 Specific References 
1 FAO/WHO. Evaluation of certain food additives and contaminants. 
Fifty-ninth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 2002; No. 
913. 
2 Sklavounos C. Process for preparation, isolation and purification 
of dipeptide sweeteners. United States Patent No. 4,375,430; 1 
Mar, 1983. 
3 Brennan TM, Hendrick ME. Branched amides of L-aspartyl-Damino 
acid dipeptides. United States Patent No. 4,411,925; 25 
Oct, 1983. 
4 FAO/WHO. Evaluation of certain food additives and contaminants. 
Forty-sixth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1997; 
No.868. 
20 General References 
Anonymous. Use of nutritive and nonnutritive sweeteners—position of 
ADA. J Am Diet Assoc 1998; 98: 580–587. 
Hendrick ME. Alitame. In: Nabors L, Gelardi R, eds. Alternative 
Sweeteners. New York: Marcel Dekker, 1991: 29–38. 
Hendrick ME. In: Grenby TH, ed. Advances in Sweeteners. Glasgow: 
Blackie, 1996: 226–239. 
21 Authors 
LY Galichet. 
22 Date of Revision 
17 August 2005. 
Alitame 29

Almond Oil 
1 Nonproprietary Names 
BP: Almond oil 
PhEur: Amygdalae oleum virginum 
USPNF: Almond oil 
2 Synonyms 
Almond oil, bitter; artificial almond oil; bitter almond oil; 
expressed almond oil; huile d’amande; oleo de ame.ndoas; olio 
di mandorla; sweet almond oil; virgin almond oil. 
3 Chemical Name and CAS Registry Number 
Almond oil [8007-69-0] 
4 Empirical Formula and Molecular Weight 
Almond oil consists chiefly of glycerides of oleic acid, with 
smaller amounts of linoleic and palmitic acids. The PhEur 2005 
describes almond oil as the fatty oil obtained by cold expression 
from the ripe seeds of Prunus dulcis (Miller) DA Webb var. 
dulcis or Prunus dulcis (Miller) DA Webb var. amara (DC) 
Buchheim or a mixture of both varieties. A suitable antioxidant 
may be added. 
The USPNF 23 describes almond oil as the fixed oil obtained 
by expression from the kernels of varieties of Prunus amygdalus 
Batsch (Fam. Rosaceae). 
5 Structural Formula 
See above. 
6 Functional Category 
Emollient; oleaginous vehicle; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Almond oil is used therapeutically as an emollient(1) and to 
soften ear wax. As a pharmaceutical excipient it is employed as 
a vehicle in parenteral preparations,(2) such as oily phenol 
injection. It is also used in nasal spray,(3) and topical 
preparations.(4)Almond oil is also consumed as a food 
substance, see Section 18. 
8 Description 
A clear, colorless, or pale-yellow colored oil with a bland, nutty 
taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for almond oil. 
Test PhEur 2005 USPNF 23 
Identification . . 
Absorbance . — 
Acid value 42.0 — 
Characters . — 
Cottonseed oil — . 
Foreign kernel oils — . 
Foreign oils — . 
Iodine value — 95–105 
Mineral oil and fatty oils — . 
Peroxide value 415.0 — 
Saponification value — 190–200 
Sesame oil — . 
Specific gravity — 0.910–0.915 
Unsaponifiable matter 40.7% — 
Free fatty acids . . 
Saturated fatty acids < C16 40.1% — 
Arachidic acid 40.2% — 
Behenic acid 40.2% — 
Eicosenoic acid 40.3% — 
Erucic acid 40.1% — 
Linoleic acid 20.0–30.0% — 
Linolenic acid 40.4% — 
Margaric acid 40.2% — 
Oleic acid 62.0–86.0% — 
Palmitic acid 4.0–9.0% — 
Palmitoleic acid 40.6% — 
Stearic acid 43.0% — 
Sterols . — 

5-Avenasterol 510.0% — 

7-Avenasterol 43.0% — 
Brassicasterol 40.3% — 
Cholesterol 40.7% — 
Campesterol 44.0% — 
Stigmasterol 43.0% — 
b-Sitosterol 73.0–87.0% — 

7-Stigmasterol 43.0% — 
10 Typical Properties 
Flash point: 3208C 
Melting point: 188C 
Refractive index: nD
40 = 1.4630–1.4650 
Smoke point: 2208C 
Solubility: miscible with chloroform, and ether; slightly soluble 
in ethanol (95%). 
11 Stability and Storage Conditions 
Almond oil should be stored in a well-closed container in a 
cool, dry place away from direct sunlight and odors. It may be 
sterilized by heating at 1508C for 1 hour. Almond oil does not 
easily turn rancid.

12 Incompatibilities 
—
13 Method of Manufacture 
Almond oil is expressed from the seeds of the bitter or sweet 
almond, Prunus dulcis (Prunus amygdalus; Amygdalus communis) 
var. amara or var. dulcis (Rosaceae).(5) See also Section 
4. 
14 Safety 
Almond oil is widely consumed as a food and is used both 
therapeutically and as an excipient in topical and parenteral 
pharmaceutical formulations, where it is generally regarded as 
a nontoxic and nonirritant material. However, there has been a 
single case reported of a 5-month-old child developing allergic 
dermatitis attributed to the application of almond oil for 2 
months to the cheeks and buttocks.(6) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
Included in nonparenteral and parenteral medicines licensed in 
the UK. Widely used as an edible oil. 
17 Related Substances 
Canola oil; corn oil; cottonseed oil; peanut oil; refined almond 
oil; sesame oil; soybean oil. 
Refined almond oil 
Synonyms: amygdalae oleum raffinatum. 
Comments: refined almond oil is defined in some pharmacopeias 
such as the PhEur 2005. Refined almond oil is a clear, 
pale yellow colored oil with virtually no taste or odor. It is 
obtained by expression of almond seeds followed by 
subsequent refining. It may contain a suitable antioxidant. 
18 Comments 
A 100 g quantity of almond oil has a nutritional energy value of 
3700 kJ (900 kcal) and contains 100 g of fat of which 28% is 
polyunsaturated, 64% is monounsaturated and 8% is saturated 
fat. 
Studies have suggested that almond consumption is 
associated with health benefits, including a decreased risk of 
colon cancer.(7) 
A specification for bitter almond oil is contained in the Food 
Chemicals Codex (FCC). 
19 Specific References 
1 Pesko LJ. Peanut recipe softens brittle, split nails. Am Drug 1997; 
214(Dec): 48. 
2 Van Hoogmoed LM, Agnew DW, Whitcomb M, et al. Ultrasonographic 
and histologic evaluation of medial and middle patellar 
ligaments in exercised horses following injection with ethanolamine 
oleate and 2% iodine in almond oil. Am J Vet Res 2002; 
63(5): 738–743. 
3 Cicinelli E, Savino F, Cagnazzo I, et al. Progesterone administration 
by nasal spray in menopausal women: comparison between 
two different spray formulations. Gynecol Endocrinol 1992; 6(4): 
247–251. 
4 Christen P, Kloeti F, Gander B. Stability of prednisolone and 
prednisolone acetate in various vehicles used in semi-solid topical 
preparations. J Clin Pharm Ther 1990; 15(5): 325–329. 
5 Evans WC. Trease and Evans’ Pharmacognosy, 14th edn. London: 
WB Saunders, 1996: 184. 
6 Guillet G, Guillet M-H. Percutaneous sensitization to almond in 
infancy and study of ointments in 27 children with food allergy. 
Allerg Immunol 2000; 32(8): 309–311. 
7 Davis PA, Iwahashi CK. Whole almonds and almond fractions 
reduce aberrant crypt foci in a rat model of colon carcinogenesis. 
Cancer Lett 2001; 165(1): 27–33. 
20 General References 
Allen LV. Oleaginous vehicles. Int J Pharm Compound 2000; 4(6): 470– 
472. 
Anonymous. Iodine 2% in oil injection. Int J Pharm Compound 2001; 
5(2): 131. 
Brown JH, Arquette DJ, Kleiman R, et al. Oxidative stability of 
botanical emollients. Cosmet Toilet 1997; 112(Jul): 87–90, 92, 94, 
96–98. 
Shaath NA, Benveniste B. Natural oil of bitter almond. Perfum Flavor 
1991; 16(Nov–Dec): 17, 19–24. 
21 Authors 
SA Shah, D Thassu. 
22 Date of Revision 
15 August 2005. 
Almond Oil 31

Alpha Tocopherol 
1 Nonproprietary Names 
BP: Alpha tocopherol 
JP: Tocopherol 
PhEur: RRR-a-Tocopherolum 
USP: Vitamin E 
See also Sections 3, 9, and 17. 
2 Synonyms 
Copherol F1300; (
)-3,4-dihydro-2,5,7,8-tetramethyl-2- 
(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-ol; E307; Eastman 
Vitamin E TPGS; synthetic alpha tocopherol; all-rac-atocopherol; 
dl-a-tocopherol; 5,7,8-trimethyltocol. 
3 Chemical Name and CAS Registry Number 
(
)-(2RS,40RS,80RS)-2,5,7,8-Tetramethyl-2-(40,80,120-trimethyltridecyl)-
6-chromanol [10191-41-0] 
Note that alpha tocopherol has three chiral centers, giving 
rise to eight isomeric forms. The naturally occurring form is 
known as d-alpha tocopherol or (2R,40R,80R)-alpha-tocopherol. 
The synthetic form, dl-alpha tocopherol or simply 
alpha tocopherol, occurs as a racemic mixture containing 
equimolar quantities of all the isomers. 
Similar considerations apply to beta, delta, and gamma 
tocopherol and tocopherol esters. 
See Section 17 for further information. 
4 Empirical Formula and Molecular Weight 
C29H50O2 430.72 
5 Structural Formula 
Alpha tocopherol: R1 = R2 = R3 = CH3 
Beta tocopherol: R1 = R3 = CH3; R2 = H 
Delta tocopherol: R1 = CH3; R2 = R3 = H 
Gamma tocopherol: R1 = R2 = CH3; R3 = H 
* Indicates chiral centers. 
6 Functional Category 
Antioxidant; therapeutic agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Alpha tocopherol is primarily recognized as a source of vitamin 
E, and the commercially available materials and specifications 
reflect this purpose. While alpha tocopherol also exhibits 
antioxidant properties, the beta, delta, and gamma tocopherols 
are considered to be more effective as antioxidants. 
Alpha-tocopherol is a highly lipophilic compound, and is an 
excellent solvent for many poorly soluble drugs.(1–4) Of 
widespread regulatory acceptability, tocopherols are of value 
in oil- or fat-based pharmaceutical products and are normally 
used in the concentration range 0.001–0.05% v/v. There is 
frequently an optimum concentration; thus the autoxidation of 
linoleic acid and methyl linolenate is reduced at low concentrations 
of alpha tocopherol, and is accelerated by higher 
concentrations. Antioxidant effectiveness can be increased by 
the addition of oil-soluble synergists such as lecithin and 
ascorbyl palmitate.(4) 
D-a-Tocopherol has also been used as a non-ionic surfactant 
in oral and injectable formulations.(3) 
8 Description 
Alpha tocopherol is a natural product. The PhEur 2005 (Suppl. 
5.1) describes a-tocopherol as a clear, colorless or yellowishbrown, 
viscous, oily liquid. See also Section 17. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for alpha tocopherol. 
Test JP 2001 PhEur 2005 
(Suppl. 5.1) 
USP 28 
Identification . . . 
Characters — . — 
Acidity — — . 
Acid value — 42 — 
Optical rotation — –0.018 to .0.018 . 
Heavy metals 420 ppm 420 ppm — 
Sulfated ash — 40.1% — 
Organic volatile 
impurities 
— — . 
Absorbance . . — 
at 255 nm — 5.5–8.0 — 
at 292 nm 71.0–76.0 72.0–76.0 — 
Refractive index 1.503–1.507 — — 
Specific gravity 0.947–0.955 — — 
Clarity and color 
of solution 
. — — 
Assay 96.0–102.0% 96.0–101.5% 96.0– 
102.0% 
Note that the USP 28 describes vitamin E as comprising d- or 
dl-alpha tocopherol, d- or dl-alpha tocopheryl acetate, or d- or 
dl-alpha tocopheryl acid succinate. However, the PhEur 2005 
describes alpha tocopherol and alpha tocopheryl acetate in 
separate monographs. 
The diversity of the tocopherols described in the various 
pharmacopeial monographs makes the comparison of specifications 
more complicated; see Section 17.

10 Typical Properties 
Boiling point: 2358C 
Density: 0.947–0.951 g/cm3 
Flash point: 2408C 
Ignition point: 3408C 
Refractive index: nD
20 = 1.503–1.507 
Solubility: practically insoluble in water; freely soluble in 
acetone, ethanol, ether, and vegetable oils. 
11 Stability and Storage Conditions 
Tocopherols are oxidized slowly by atmospheric oxygen and 
rapidly by ferric and silver salts. Oxidation products include 
tocopheroxide, tocopherylquinone, and tocopherylhydroquinone, 
as well as dimers and trimers. Tocopherol esters are more 
stable to oxidation than the free tocopherols but are in 
consequence less effective antioxidants. See also Section 17. 
Tocopherols should be stored under an inert gas, in an 
airtight container in a cool, dry place and protected from light. 
12 Incompatibilities 
Tocopherols are incompatible with peroxides and metal ions, 
especially iron, copper, and silver. Tocopherols may be 
absorbed into plastic.(5) 
13 Method of Manufacture 
Naturally occurring tocopherols are obtained by the extraction 
or molecular distillation of steam distillates of vegetable oils; 
for example, alpha tocopherol occurs in concentrations of 
0.1–0.3% in corn, rapeseed, soybean, sunflower, and wheat 
germ oils.(6) Beta and gamma tocopherol are usually found in 
natural sources along with alpha tocopherol. Racemic synthetic 
tocopherols may be prepared by the condensation of the 
appropriate methylated hydroquinone with racemic isophytol.(
7) 
14 Safety 
Tocopherols (vitamin E) occur in many food substances that are 
consumed as part of the normal diet. The daily nutritional 
requirement has not been clearly defined but is estimated to be 
3.0–20.0 mg. Absorption from the gastrointestinal tract is 
dependent upon normal pancreatic function and the presence of 
bile. Tocopherols are widely distributed throughout the body, 
with some ingested tocopherol metabolized in the liver; 
excretion of metabolites is via the urine or bile. Individuals 
with vitamin E deficiency are usually treated by oral administration 
of tocopherols, although intramuscular and intravenous 
administration may sometimes be used. 
Tocopherols are well tolerated, although excessive oral 
intake may cause headache, fatigue, weakness, digestive 
disturbance, and nausea. Prolonged and intensive skin contact 
may lead to erythema and contact dermatitis. 
The use of tocopherols as antioxidants in pharmaceuticals 
and food products is unlikely to pose any hazard to human 
health since the daily intake from such uses is small compared 
to the intake of naturally occurring tocopherols in the diet. 
The WHO has set an acceptable daily intake of tocopherol 
used as an antioxidant at 0.15–2.0 mg/kg body-weight.(8) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Gloves and eye protection are 
recommended. 
16 Regulatory Status 
GRAS listed. Accepted in Europe as a food additive. Included in 
the FDA Inactive Ingredients Guide (IV injections, powder, 
lyophilized powder for liposomal suspension; oral capsules, 
tablets, and topical preparations). Included in the Canadian 
List of Acceptable Non-medicinal Ingredients. Included in 
nonparenteral medicines licensed in the UK. 
17 Related Substances 
d-Alpha tocopherol; d-Alpha tocopheryl acetate; dl-Alpha 
tocopheryl acetate; d-Alpha tocopheryl acid succinate; dl- 
Alpha tocopheryl acid succinate; beta tocopherol; delta 
tocopherol; gamma tocopherol; tocopherols excipient. 
d-Alpha tocopherol 
Empirical formula: C29H50O2 
Molecular weight: 430.72 
CAS number: [59-02-9] 
Synonyms: natural alpha tocopherol; (.)-(2R,40R,80R)- 
2,5,7,8-tetramethyl-2-(40,80,120-trimethyltridecyl)-6-chromanol; 
d-a-tocopherol; vitamin E. 
Appearance: a practically odorless, clear, yellow, or greenishyellow 
viscous oil. 
Melting point: 2.5–3.58C 
Solubility: practically insoluble in water; soluble in ethanol 
(95%). Miscible with acetone, chloroform, ether, and 
vegetable oils. 
Specific gravity: 0.95 
Comments: d-alpha tocopherol is the naturally occurring form 
of alpha tocopherol. 
d-Alpha tocopheryl acetate 
Empirical formula: C31H52O3 
Molecular weight: 472.73 
CAS number: [58-95-7] 
Synonyms: (.)-(2R,40R,80R)-2,5,7,8-tetramethyl-2-(40,80,120- 
trimethyltridecyl)-6-chromanyl acetate; d-a-tocopheryl acetate; 
vitamin E. 
Appearance: a practically odorless, clear, yellow, or greenishyellow 
colored viscous oil that may solidify in the cold. 
Melting point: 288C 
Solubility: practically insoluble in water; soluble in ethanol 
(95%). Miscible with acetone, chloroform, ether, and 
vegetable oils. 
Specific rotation [a]D
25: .0.258 (10% w/v solution in chloroform) 
Comments: unstable to alkalis. 
dl-Alpha tocopheryl acetate 
Empirical formula: C31H52O3 
Molecular weight: 472.73 
CAS number: [7695-91-2] 
Synonyms: (
)-3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-
2H-1-benzopyran-6-ol acetate; (
)- 
(2RS,40RS,80RS)-2,5,7,8-tetramethyl-2-(40,80,120-trimethyltridecyl)-
6-chromanyl acetate; (
)-a-tocopherol acetate; atocopheroli 
acetas; all-rac-a-tocopheryl acetate; dl-a-tocopheryl 
acetate; vitamin E. 
Alpha Tocopherol 33

Appearance: a practically odorless, clear, yellow, or greenishyellow 
viscous oil. 
Density: 0.953 g/cm3 
Melting point: –27.58C 
Refractive index: nD
20 = 1.4950–1.4972 
Solubility: practically insoluble in water; freely soluble in 
acetone, chloroform, ethanol, ether, and vegetable oils; 
soluble in ethanol (95%). 
Comments: unstable to alkali. However, unlike alpha tocopherol, 
the acetate is much less susceptible to the effects of 
air, light, or ultraviolet light. Alpha tocopherol acetate 
concentrate, a powdered form of alpha tocopherol acetate, 
is described in the PhEur 2005. The concentrate may be 
prepared by either dispersing alpha tocopherol acetate in a 
suitable carrier such as acacia or gelatin, or by adsorbing 
alpha tocopherol acetate on silicic acid. 
d-Alpha tocopheryl acid succinate 
Empirical formula: C33H54O5 
Molecular weight: 530.8 
CAS number: [4345-03-3] 
Synonyms: (.)-a-tocopherol hydrogen succinate; d-a-tocopheryl 
acid succinate; vitamin E. 
Appearance: a practically odorless white powder. 
Melting point: 76–778C 
Solubility: practically insoluble in water; slightly soluble in 
alkaline solutions; soluble in acetone, ethanol (95%), ether, 
and vegetable oils; very soluble in chloroform. 
Comments: unstable to alkalis. 
dl-Alpha tocopheryl acid succinate 
Empirical formula: C33H54O5 
Molecular weight: 530.8 
CAS number: [17407-37-3] 
Synonyms: (
)-a-tocopherol hydrogen succinate; dl-a-tocopheryl 
acid succinate; dl-a-tocopherol succinate; vitamin E. 
Appearance: a practically odorless, white crystalline powder. 
Solubility: practically insoluble in water; slightly soluble in 
alkaline solutions; soluble in acetone, ethanol (95%), ether, 
and vegetable oils; very soluble in chloroform. 
Comments: unstable to alkalis. 
Beta tocopherol 
Empirical formula: C28H48O2 
Molecular weight: 416.66 
CAS number: [148-03-8] 
Synonyms: cumotocopherol; (
)-3,4-dihydro-2,5,8-trimethyl- 

2-(4,8,12-trimethyltridecyl)-2H-1-b-benzopyran-6-ol; 5,8- 
dimethyltocol; neotocopherol; dl-b-tocopherol; vitamin E; 
p-xylotocopherol. 
Appearance: a pale yellow-colored viscous oil. 
Solubility: practically insoluble in water; freely soluble in 
acetone, chloroform, ethanol (95%), ether, and vegetable 
oils. 
Specific rotation [a]D
20: .6.378 
Comments: less active biologically than alpha tocopherol. 
Obtained along with alpha tocopherol and gamma tocopherol 
from natural sources. Beta tocopherol is very stable 
to heat and alkalis and is slowly oxidized by atmospheric 
oxygen. 
Delta tocopherol 
Empirical formula: C27H46O2 
Molecular weight: 402.64 
CAS number: [119-13-1] 
Synonyms: (
)-3,4-dihydro-2,8-dimethyl-2-(4,8,12-trimethyltridecyl)-
2H-1-benzopyran-6-ol; E309; 8-methyltocol; dl-dtocopherol; 
vitamin E. 
Appearance: a pale yellow-colored viscous oil. 
Solubility: practically insoluble in water; freely soluble in 
acetone, chloroform, ethanol (95%), ether, and vegetable 
oils. 
Comments: occurs naturally as 30% of the tocopherol content 
of soybean oil. Delta tocopherol is said to be the most potent 
antioxidant of the tocopherols. 
Gamma tocopherol 
Empirical formula: C28H48O2 
Molecular weight: 416.66 
CAS number: [7616-22-0] 
Synonyms: (
)-3,4-dihydro-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)-
2H-1-benzopyran-6-ol; 7,8-dimethyltocol; 
E308; dl-g-tocopherol; vitamin E; o-xylotocopherol. 
Appearance: a pale yellow-colored viscous oil. 
Melting point: –308C 
Solubility: practically insoluble in water; freely soluble in 
acetone, chloroform, ethanol (95%), ether, and vegetable 
oils. 
Specific rotation [a]D
20: –2.48 (in ethanol (95%)) 
Comments: occurs in natural sources along with alpha and beta 
tocopherol. Gamma tocopherol is biologically less active 
than alpha tocopherol. Very stable to heat and alkalis; 
slowly oxidized by atmospheric oxygen and gradually 
darkens on exposure to light. 
Tocopherols excipient 
Synonyms: Embanox tocopherol. 
Appearance: a pale yellow-colored viscous oil. 
Comments: tocopherols excipient is described in the USPNF 23 
as a vegetable oil solution containing not less than 50.0% of 
total tocopherols, of which not less than 80.0% consists of 
varying amounts of beta, delta, and gamma tocopherols. 
18 Comments 
Note that most commercially available tocopherols are used as 
sources of vitamin E, rather than as antioxidants in pharmaceutical 
formulations. 
Various mixtures of tocopherols, and mixtures of tocopherols 
with other excipients, are commercially available and 
individual manufacturers should be consulted for specific 
information on their products. The EINECS number for atocopherol 
is 215-798-8. The EINECs number for d-atocopherol 
is 200-412-2; and the EINECS number for dl-atocopherol 
is 233-466-0. 
19 Specific References 
1 Nielsen PB, Mu. llertz A, Norling T, Kristensen HG. The effect of atocopherol 
on the in vitro solubilisation of lipophilic drugs. Int J 
Pharm 2001; 222: 217–224. 
2 Constantinides PP, Tustian A, Kessler DR. Tocol emulsions for 
drug solubilization and parenteral delivery. Adv Drug Delivery 
2004; 56(9): 1243–1255. 
3 Strickley RG. Solubilizing excipients in oral and injectable 
formulations. Pharm Res 2004; 21(2): 201–230. 
34 Alpha Tocopherol

4 Johnson DM, Gu LC. Autoxidation and antioxidants. In: 
Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical 
Technology, volume 1. New York: Marcel Dekker, 1988: 415–450. 
5 Allwood MC. Compatibility and stability of TPN mixtures in big 
bags. J Clin Hosp Pharm 1984; 9: 181–198. 
6 Buck DF. Antioxidants. In: Smith J, ed. Food Additive User’s 
Handbook. Glasgow: Blackie, 1991: 1–46. 
7 Rudy BC, Senkowski BZ. dl-Alpha-tocopheryl acetate. In: Florey 
K, ed. Analytical Profiles of Drug Substances, volume 3. New 
York: Academic Press, 1974: 111–126. 
8 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirtieth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1987; No. 
751. 
20 General References 
US National Research Council Food and Nutrition Board. Recommended 
Dietary Allowances, 10th edn. Washington DC: National 
Academy Press, 1989: 99–105. 
21 Authors 
SC Owen. 
22 Date of Revision 
4 August 2005. 
Alpha Tocopherol 35

Aluminum Hydroxide Adjuvant 
1 Nonproprietary Names 
PhEur: Aluminii hydroxidum hydricum ad adsorptionem 
2 Synonyms 
Alhydrogel; aluminium hydroxide adjuvant; aluminium oxyhydroxide; 
poorly crystalline boehmite; pseudoboehmite; 
Rehydragel. 
3 Chemical Name and CAS Registry Number 
Aluminum oxyhydroxide [21645-51-2] 
4 Empirical Formula and Molecular Weight 
AlO(OH) 59.99 
5 Structural Formula 
Structural hydroxyl groups form hydrogen bonds between 
AlO(OH) octahedral sheets, where hydroxyl groups are 
exposed at the surface. The surface hydroxyl groups produce 
a pH-dependent surface charge by accepting a proton to 
produce a positive site, or donating a proton to produce a 
negative site. The pH-dependent surface charge is characterized 
by the point of zero charge, which is equivalent to the isoelectric 
point in protein chemistry. The surface hydroxyl groups may 
also undergo ligand exchange with fluoride, phosphate, 
carbonate, sulfate, or borate anions. 
6 Functional Category 
Adsorbent; vaccine adjuvant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Aluminum hydroxide adjuvant is used in parenteral human and 
veterinary vaccines.(1) It activates TH2 immune responses, 
including IgG and IgE antibody responses. It is also used for the 
isolation of certain serum components such as blood clotting 
factors.(2) 
8 Description 
Aluminum hydroxide adjuvant is a white hydrogel that 
sediments slowly and forms a clear supernatant. 
9 Pharmacopeial Specifications 
See Table I. Note that the USP 28 includes a monograph for 
aluminum hydroxide gel, which is a form of aluminum 
hydroxide that is used as an antacid, in which there is a partial 
substitution of carbonate for hydroxide. 
See Section 17. 
Table I: Pharmacopeial specifications for aluminum hydroxide 
adjuvant. 
Test PhEur 2005 
Identification . 
Characters . 
Solution . 
pH 5.5–8.5 
Adsorption power . 
Sedimentation . 
Chlorides 40.33% 
Nitrates 4100 ppm 
Sulfates 40.5% 
Ammonium 450 ppm 
Arsenic 41 ppm 
Iron 410 ppm 
Heavy metals 420 ppm 
Bacterial endotoxins . 
Assay 90.0–110.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 5.5–8.5 
Particle size distribution: primary particles are fibrous with 
average dimensions of 4.5  2.2  10 nm. The primary 
particles form aggregates of 1–10 mm. 
Point of zero charge: pH = 11.4 
Protein binding capacity: >0.5 mg BSA/mg equivalent Al2O3 
Solubility: soluble in alkali hydroxides and mineral acids. Heat 
may be required to dissolve the aluminum hydroxide 
adjuvant. 
Specific surface area: 500m2/g.(3) 
X-ray diffractogram: exhibits characteristic x-ray diffraction 
pattern having diffraction bands at 6.46, 3.18, 2.35, 1.86, 
1.44 and 1.31A .
. 
11 Stability and Storage Conditions 
Aluminum hydroxide adjuvant is stable for at least two years 
when stored at 4–308C in well-sealed inert containers. It must 
not be allowed to freeze as the hydrated colloid structure will be 
irreversibly damaged. 
12 Incompatibilities 
When exposed to phosphate, carbonate, sulfate, or borate 
anions, the point of zero charge for aluminum hydroxide 
adjuvant decreases. 
13 Method of Manufacture 
Aluminum hydroxide adjuvant is prepared by the precipitation 
of a soluble aluminum salt by an alkali hydroxide, or the 
precipitation of an alkali aluminate by acid.

14 Safety 
Aluminum hydroxide adjuvant is intended for use in parenteral 
vaccines and is generally regarded as nontoxic. It may cause 
mild irritation, dryness, and dermatitis on skin contact. On eye 
contact, aluminum hydroxide adjuvant may also cause redness, 
conjunctivitis, and short-term mild irritation. Ingestion of large 
amounts may cause gastrointestinal irritation with nausea, 
vomiting, and constipation. Inhalation of the dried product 
may cause respiratory irritation and cough. Type I hypersensitivity 
reactions following parenteral administration have been 
reported.(4) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use in human and veterinary 
parenteral vaccines in Europe and the USA. The limits for use 
in human vaccines are 0.85 mg aluminum/dose (FDA) and 
1.25 mg aluminum/dose (WHO). There are no established 
limits for use in veterinary vaccines. Reported in the EPATSCA 
Inventory. 
17 Related Substances 
Aluminum phosphate adjuvant. 
18 Comments 
Different grades of aluminum hydroxide adjuvant with various 
concentrations, protein binding capacities, and points of zero 
charge are available. 
The impurity limits at 2% equivalent Al2O3 are Cl < 0.5%; 
SO4 < 0.5%; PO4 < 0.1%; NO3 < 0.1%; NH4 < 0.1%; Fe < 
20 ppm; As < 0.6 ppm; and heavy metals < 20 ppm. 
The aluminum hydroxide gel referred to in the USP 28 is 
used in cosmetics as an emollient, filler, humectant, a mild 
astringent, and viscosity controlling agent. In pharmaceutical 
preparations it is used as an adsorbent, and as a protein 
binder.(5) It is also used therapeutically as an antacid, and as an 
abrasive in dentrifrices. It is not, however, used as a vaccine 
adjuvant. 
19 Specific References 
1 Shirodkar S, Hutchinson RL, Perry DL, et al. Aluminum 
compounds used as adjuvants in vaccines. Pharm Res 1990; 7: 
1282–1288. 
2 Prowse CV, Griffin B, Pepper DS, et al. Changes in factor VIII 
complex activities during the production of a clinical intermediate 
purity factor VIII concentrate. Thromb Haemost 1981; 46: 597– 
601. 
3 Johnston CT, Wang JL, Hem SL. Measuring the surface area of 
aluminum hydroxide adjuvant. J Pharm Sci 2002; 91: 1702–1706. 
4 Goldenthal KL, Cavagnaro JA, Alving G, Vogel FR. Safety 
evaluation of vaccine adjuvants. AIDS Res Hum Retroviruses 
1993: 9 (Suppl. 1): 547–551. 
5 Ash M, Ash I. Handbook of Pharmaceutical Additives, 2nd edn. 
Endicott, NY: Synapse Information Resources, 2002: 298. 
20 General References 
Gupta RK, Rost BE, Relyveld E, Siber GR. Adjuvant properties of 
aluminum and calcium compounds. In: Powell MF, Newman MJ, 
eds. Vaccine Design. New York: Plenum, 1995: 229–248. 
Hem SL, White JL. Structure and properties of aluminum-containing 
adjuvants. In: Powel MF, Newman MJ, eds. Vaccine Design. New 
York: Plenum, 1995: 249–276. 
Lindblad EB. Aluminum adjuvants – in retrospect and prospect. 
Vaccine 2004; 22: 3658–3668. 
Lindblad EB. Aluminum adjuvants. In: Stewart-Tull DES, ed. The 
Theory and Practical Application of Adjuvants. New York: Wiley, 
1995: 21–35. 
Vogel FR, Powell MF. A compendium of vaccine adjuvants and 
excipients. In: Powell MF, Newman MJ, eds. Vaccine Design. New 
York: Plenum, 1995: 229–248. 
Vogel FR, Hem SL. Immunogenic adjuvants. In: Plotkin SA, Orestein 
WA, eds. Vaccines, 4th edn. New York: W.B. Saunders, 2004: 72– 
76. 
White JL, Hem SL. Characterization of aluminum-containing adjuvants. 
In: Brown F, Corbel M, Griffiths E, eds. Physico-Chemical 
Procedures for the Characterization of Vaccines, IABS Symposia 
Series, Development in Biologicals. New York: Karger, 2000; 103: 
217–228. 
21 Authors 
SL Hem, PB Klepak, EB Lindblad. 
22 Date of Revision 
2 September 2005. 
Aluminum Hydroxide Adjuvant 37

Aluminum Oxide 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Activated alumina; activated aluminum oxide; alpha aluminum 
oxide; alumina; alumina, activated; alumina, calcined; alumina, 
tabular; aluminum oxide alumite; aluminum trioxide. 
3 Chemical Name and CAS Registry Number 
Aluminum oxide [1344-28-1] 
4 Empirical Formula and Molecular Weight 
Al2O3 101.96 
5 Structural Formula 
Aluminum oxide occurs naturally as the minerals bauxite, 
bayerite, boehmite, corundum, diaspore, and gibbsite. 
6 Functional Category 
Adsorbent; dispersing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Aluminum oxide is used mainly in tablet formulations.(1) It is 
used for decoloring powders and is particularly widely used in 
antibiotic formulations. It is also used in suppositories, 
pessaries, and urethral inserts. Hydrated aluminum oxide (see 
Section 18) is used in mordant dyeing to make lake pigments, in 
cosmetics, and therapeutically as an antacid. 
8 Description 
Aluminum oxide occurs as a white crystalline powder. 
Aluminum oxide occurs as two crystalline forms. a-aluminum 
oxide is composed of colorless hexagonal crystals, and galuminum 
oxide is composed of minute colorless cubic crystals 
that are transformed to the a-form at high temperatures. 
9 Pharmacopeial Specifications 
See Section 18. 
10 Typical Properties 
Boiling point: 29778C 
Density (bulk): 0.91.1 g/cm3 
Flammability: nonflammable. 
Hardness (Mohs): 8.8 
Hygroscopicity: very hygroscopic. 
Melting point: 20508C 
Solubility: slowly soluble in aqueous alkaline solutions; 
practically insoluble in nonpolar organic solvents, diethyl 
ether, ethanol (95%), and water. 
Specific gravity: 2.8 (becomes 4.0 at 8008C) 
Vapor pressure: 133.3 Pa at 21588C 
11 Stability and Storage Conditions 
Aluminum oxide should be stored in a well-closed container in 
a cool, dry, place. It is very hygroscopic. 
12 Incompatibilities 
Aluminum oxide should be kept well away from water. It is 
incompatible with strong oxidizers and chlorinated rubber. 
Aluminum oxide also reacts with chlorine trifluoride, ethylene 
oxide, sodium nitrate, and vinyl acetate. Exothermic reactions 
above 2008C with halocarbon vapors produce toxic hydrogen 
chloride and phosgene fumes. 
13 Method of Manufacture 
Most of the aluminum oxide produced commercially is 
obtained by the calcination of aluminum hydroxide. 
14 Safety 
Aluminum oxide is generally regarded as relatively nontoxic 
and nonirritant when used as an excipient. Inhalation of finely 
divided particles may cause lung damage (Shaver’s disease). 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of the material handled.(2) In the UK, the 
occupational exposure limits for aluminum oxide are 
10 mg/m3 long-term (8-hour TWA) for total inhalable dust 
and 4 mg/m3 for respirable dust.(3) 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral tablets 
and topical sponge). Included in nonparenteral medicines 
licensed in the UK. 
17 Related Substances 
—
18 Comments 
A specification for aluminum oxide is included in Japanese 
Pharmaceutical Excipients 2004 (JPE), see Table I. A specification 
for light aluminum oxide is also included. The PhEur 2005 
includes a specification for hydrated aluminum oxide that 
contains the equivalent of 47.0–60.0% of Al2O3. The EINECS 
number for aluminum oxide is 215-691-6.

Table I: JPE specification for aluminum oxide.(4) 
Test JPE 2004 
Identification . 
Water-soluble substances . 
Heavy metals 430 ppm 
Lead 430 ppm 
Arsenic 45 ppm 
Loss on drying 41.5% 
Loss on ignition 42.5% 
Assay 596.0% 
19 Specific References 
1 Rupprecht H. Processing of potent substances with inorganic 
supports by imbedding and coating. Acta Pharm Technol 1980; 
26: 13–27. 
2 National Poisons Information Service (1997). Aluminium oxide. 
http://www.intox.org/databank/documents/chemical/alumoxde/ 
ukpid33.htm (accessed 25 April 2005). 
3 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
4 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004: 67–68. 
20 General References 
—
21 Authors 
LY Galichet. 
22 Date of Revision 
17 August 2005. 
Aluminum Oxide 39

Aluminum Phosphate Adjuvant 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Aluminum hydroxyphosphate; aluminium hydroxyphosphate; 
Adju-Phos; Rehydraphos. 
3 Chemical Name and CAS Registry Number 
Aluminum phosphate [7784-30-7] 
4 Empirical Formula and Molecular Weight 
Al(OH)x(PO4)y 
The molecular weight is dependent on the degree of 
substitution of phosphate groups for hydroxyl groups. 
5 Structural Formula 
Aluminum phosphate adjuvant occurs as a precipitate of 
amorphous aluminum hydroxide in which some sites contain 
phosphate groups instead of hydroxyl. Both hydroxyl and 
phosphate groups are exposed at the surface. The hydroxyl 
groups produce a pH-dependent surface charge by accepting a 
proton to produce a positive site, or donating a proton to 
produce a negative site. The pH-dependent surface charge is 
characterized by the point of zero charge, which is equivalent to 
the isoelectric point in protein chemistry. The surface hydroxyl 
groups may also undergo ligand exchange with fluoride, 
phosphate, carbonate, sulfate, or borate groups. 
Aluminum phosphate adjuvant is not a stoichiometric 
compound. Rather, the degree of phosphate group substitution 
for hydroxyl groups depends on the precipitation recipe and 
conditions. 
6 Functional Category 
Adsorbent; vaccine adjuvant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Aluminum phosphate adjuvant is used in parenteral human and 
veterinary vaccines.(1) It activates TH2 immune responses, 
including IgG and IgE antibody responses. 
8 Description 
Aluminum phosphate adjuvant is a white hydrogel that 
sediments slowly and forms a clear supernatant. 
9 Pharmacopeial Specifications 
— 
10 Typical Properties 
Acidity/alkalinity: 6.0–8.0 
Al : P atomic ratio: 1.1–1.15 : 1.0 
Aluminum (%): 0.5–0.75 
Particle size distribution: primary particles are platy with an 
average diameter of 50 nm. The primary particles form 
aggregates of 1–10 mm. 
Point of zero charge: pH = 4.6–5.6, depending on the Al : P 
atomic ratio. 
Protein binding capacity: >0.6 mg lysozyme/mg equivalent 
Al2O3 
Solubility: soluble in mineral acids and alkali hydroxides. 
X-ray diffractogram: amorphous to x-rays. 
11 Stability and Storage Conditions 
Aluminum phosphate adjuvant is stable for at least six months 
when stored at 4–308C in well-sealed inert containers. It must 
not be allowed to freeze as the hydrated colloid structure will be 
irreversibly damaged. 
12 Incompatibilities 
The point of zero charge is related directly to the Al : P atomic 
ratio. Therefore, the substitution of additional phosphate 
groups for hydroxyl groups will lower the point of zero charge. 
Substitution of carbonate, sulfate, or borate ions for hydroxyl 
groups will also affect the point of zero charge. 
13 Method of Manufacture 
Aluminum phosphate adjuvant is formed by the reaction of a 
solution of aluminum chloride and phosphoric acid with alkali 
hydroxide. 
14 Safety 
Aluminum phosphate adjuvant is intended for use in parenteral 
vaccines and is generally regarded as safe. It may cause mild 
irritation, dryness, and dermatitis on skin contact. It may also 
cause redness, conjunctivitis, and short-term mild irritation on 
eye contact. Ingestion of large amounts of aluminum phosphate 
adjuvant may cause respiratory irritation with nausea, vomiting, 
and constipation. Inhalation is unlikely, although the dried 
product may cause respiratory irritation and cough. Type I 
hypersensitivity reactions following parenteral administration 
have also been reported.(2) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use in human and veterinary 
vaccines in Europe and the USA. The limits for use in human

vaccines are 0.85 mg aluminum/dose (FDA) and 1.25 mg 
aluminum/dose (WHO). There are no established limits for 
use in veterinary vaccines. Reported in the EPA TSCA 
Inventory. 
17 Related Substances 
Aluminum hydroxide adjuvant. 
18 Comments 
The USP 28 monograph for aluminum phosphate (ALPO4) gel 
describes aluminum phosphate, which is used as an antacid, not 
as a vaccine adjuvant. 
19 Specific References 
1 Shirodkar S, Hutchinson RL, Perry DL, et al. Aluminum 
compounds used as adjuvants in vaccines. Pharm Res 1990; 7: 
1282–1288. 
2 Goldenthal KL, Cavagnaro JA, Alving G, Vogel FR. Safety 
evaluation of vaccine adjuvants. AIDS Res Hum Retroviruses 
1993: 9 (Suppl. 1): 547–551. 
20 General References 
Hem SL, White JL. Structure and properties of aluminum-containing 
adjuvants. In: Powell MF, Newman MJ, eds. Vaccine Design. New 
York: Plenum, 1995: 249–276. 
Gupta RK, Rost BE, Relyveld E, Siber GR. Adjuvant properties of 
aluminum and calcium compounds. In: Powell MF, Newman MJ, 
eds. Vaccine Design. New York: Plenum, 1995: 229–248. 
Lindblad EB. Aluminum adjuvants – in retrospect and prospect. 
Vaccine 2004; 22: 3658–3668. 
Lindblad EB. Aluminum adjuvants. In: Stewart-Tull DES, ed. The 
Theory and Practical Application of Adjuvants. New York: Wiley, 
1995: 21–35. 
Vogel FR, Hem SL. Immunogenic adjuvants. In: Plotkin SA, Orenstein 
WA, eds. Vaccines, 4th edn. New York: W.B. Saunders, 2003. 
Vogel FR, Powell MF. A compendium of vaccine adjuvants and 
excipients. In: Powell MF, Newman MJ, eds. Vaccine Design. New 
York: Plenum, 1995: 142. 
White JL, Hem SL. Characterization of aluminum-containing adjuvants. 
In: Brown F, Corbel M, Griffiths E, eds. Physico-Chemical 
Procedures for the Characterization of Vaccines, IABS Symposia 
Series, Developments in Biologicals. New York: Karger, 2000, 103: 
217–228. 
21 Authors 
SL Hem, PB Klepak, EB Lindblad. 
22 Date of Revision 
2 September 2005. 
Aluminum Phosphate Adjuvant 41

Aluminum Stearate 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Octadecanoic acid aluminum salt; stearic acid aluminum salt. 
3 Chemical Name and CAS Registry Number 
Aluminum tristearate [637-12-7] 
4 Empirical Formula and Molecular Weight 
C54H105AlO6 877.39 
5 Structural Formula 
[CH3(CH2)16COO]3Al 
6 Functional Category 
Emollient; emulsion stabilizer; gelling agent; opacifier; stabilizing 
agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Aluminum stearate is mainly used in microencapsulation(1–3) 
and in the manufacture of ointments. It is also used in cosmetics 
such as mascara, moisturizers, and sunscreens. 
It should be noted that aluminum stearate can also refer to 
the distearate (CAS number [300-92-5]) and the monostearate 
(CAS number [7047-84-9]) in addition to the tristearate. The 
distearate exhibits the same excipient properties as the 
tristearate and is used in similar pharmaceutical applications. 
However, the monostearate is more widely used in cosmetics as 
a colorant. 
8 Description 
Aluminum stearate occurs as a white, fine, bulky powder with a 
slight odor of fatty acid. It is a hard material. 
9 Pharmacopeial Specifications 
See Section 18. 
10 Typical Properties 
Melting point: 117–1208C 
Solubility: practically insoluble in water. Soluble in ethanol 
(95%), benzene, turpentine oil, and mineral oils when 
freshly prepared. 
Specific gravity: 1.01 
11 Stability and Storage Conditions 
Aluminum stearate should be stored in a well-closed container 
in a cool, dry, place. It is stable under ordinary conditions of use 
and storage. 
12 Incompatibilities 
—
13 Method of Manufacture 
Aluminum stearate is prepared by reacting aluminum with 
stearic acid. 
14 Safety 
Aluminum stearate is generally regarded as relatively nontoxic 
and nonirritant when used as an excipient. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of the material handled. When heated to 
decomposition, aluminum stearate emits acrid smoke and 
irritating vapors. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral capsules 
and tablets, topical creams and ointments). Included in 
nonparenteral medicines licensed in the UK. 
17 Related Substances 
Aluminum distearate; aluminum monostearate. 
Aluminum distearate 
Empirical formula: C36H71O5Al 
Molecular weight: 610.9 
CAS number: [300-92-5] 
Synonyms: hydroxyaluminum distearate; aluminum stearate; 
aluminum monobasic stearate 
Description: aluminum distearate occurs as a fine white to offwhite 
colored powder with a slight odor of fatty acid. 
Melting point: 150–165 8C 
Specific gravity: 1.01 
Solubility: soluble in benzene, and in ethanol (95%); practically 
insoluble in water. 
Comments: the EINECS number for aluminum distearate is 
206-101-8. 
Aluminum monostearate 
Empirical formula: C18H37O4Al 
Molecular weight: 344.5 
CAS number: [7047-84-9] 
Synonyms: dihydroxyaluminum monostearate; aluminum stearate; 
aluminum, dihydroxy (octadecanoato-O-); stearic acid 
aluminum dihydroxide salt.

Melting point: 220–2258C 
Specific gravity: 1.14 
Solubility: soluble in benzene, and in ethanol (95%); practically 
insoluble in water. 
Comments: the EINECS number for aluminum monostearate is 
230-325-5. 
18 Comments 
A specification for aluminum stearate, described as consisting 
mainly of the distearate, is included in the Japanese Pharmaceutical 
Excipients 2004 (JPE), see Table I. The EINECS 
number for aluminum tristearate is 211-279-5. 
Table I: JPE specifications for aluminum stearate.(4) 
Test JPE 2004 
Identification . 
Acid value of fatty acid . 
Free fatty acid . 
Soluble salt . 
Heavy metals 420 ppm 
Lead 420 ppm 
Arsenic 42 ppm 
Loss on drying 42.0% 
Assay (of Al) 4.0–6.0% 
19 Specific References 
1 Horoz BB, Kilicarslan M, Yuksel N, et al. Effect of different 
dispersing agents on the characteristics of Eudragit microspheres 
prepared by a solvent evaporation method. J Microencapsul 2004; 
21: 191–202. 
2 Wu PC, Huang YB, Chang JI, et al. Preparation and evaluation of 
sustained release microspheres of potassium chloride prepared 
with ethylcellulose. Int J Pharm 2003; 260: 115–121. 
3 Wu PC, Huang YB, Chang JS, et al. Design and evaluation of 
sustained release microspheres of potassium chloride prepared by 
Eudragit. Eur J Pharm Sci 2003; 19: 115–122. 
4 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004: 74–75. 
20 General References 
—
21 Authors 
LY Galichet. 
22 Date of Revision 
17 August 2005. 
Aluminum Stearate 43

Ammonia Solution 
1 Nonproprietary Names 
BP: Ammonia solution, concentrated 
PhEur: Ammoniae solution concentrata 
USPNF: Strong ammonia solution 
2 Synonyms 
Ammoniaca; ammoniacum; aqua ammonia; concentrated 
ammonia solution; spirit of hartshorn; stronger ammonia 
water. 
3 Chemical Name and CAS Registry Number 
Ammonia [7664-41-7] 
4 Empirical Formula and Molecular Weight 
NH3 17.03 
5 Structural Formula 
NH3 
6 Functional Category 
Alkalizing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ammonia solution is typically not used undiluted in pharmaceutical 
applications. Generally, it is used as a buffering agent 
or to adjust the pH of solutions. Most commonly, ammonia 
solution (the concentrated form) is used to produce more dilute 
ammonia solutions. 
Therapeutically, dilute ammonia solution is used as a reflex 
stimulant in ‘smelling salts’, as a rubefacient, and as a 
counterirritant to neutralize insect bites or stings.(1) 
8 Description 
Strong ammonia solution occurs as a clear, colorless liquid 
having an exceedingly pungent, characteristic odor. The PhEur 
2005 states that concentrated ammonia solution contains not 
less than 25.0% and not more than 30.0% w/w of ammonia 
(NH3). The USPNF 23 states that strong ammonia solution 
contains not less than 27.0% and not more than 31.0% w/w of 
ammonia (NH3). 
See also Section 17. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for ammonia solution. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Appearance of solution . — 
Oxidizable substances . . 
Pyridine and related substances 42 ppm — 
Carbonates 460 ppm — 
Chlorides 41 ppm — 
Sulfates 45 ppm — 
Iron 40.25 ppm — 
Heavy metals 41 ppm 40.0013% 
Residue on evaporation 40.02 g/L — 
Limit of nonvolatile residue — 40.05% 
Assay (of NH3) 25.0–30.0% 27.0–31.0% 
10 Typical Properties 
Solubility: miscible with ethanol (95%) and water. 
Specific gravity: 0.892–0.910 
11 Stability and Storage Conditions 
On exposure to the air, ammonia solution rapidly loses 
ammonia. Ammonia solution should be stored in a well-closed 
container, protected from the air, in a cool, dry place. The 
storage temperature should not exceed 208C. 
12 Incompatibilities 
Ammonia solution reacts vigorously with sulfuric acid or other 
strong mineral acids and the reaction generates considerable 
heat; the mixture boils. 
13 Method of Manufacture 
Ammonia is obtained commercially chiefly by synthesis from its 
constituent elements, nitrogen and hydrogen, which are 
combined under high pressure and temperature in the presence 
of a catalyst. Ammonia solution is produced by dissolving 
ammonia gas in water. 
14 Safety 
Ingestion of strong solutions of ammonia is very harmful and 
causes severe pain in the mouth, throat, and gastrointestinal 
tract as well as severe local edema with cough, vomiting, and 
shock. Burns to the esophagus and stomach may result in 
perforation. Inhalation of the vapor causes sneezing, coughing, 
and, in high concentration, pulmonary edema. Asphyxia has 
been reported. The vapor is irritant to the eyes. Strong solutions 
are harmful when applied to the conjunctiva and mucous 
membranes. Topical application of even dilute ammonia 
solutions, used to treat insect bites, has caused burns, 
particularly when used with a subsequent dressing.(2–4)

When used as an excipient, ammonia solution is generally 
present in a formulation in a highly diluted form. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Care should be used in 
handling strong or concentrated ammonia solutions because of 
the caustic nature of the solution and the irritating properties of 
its vapor. Before containers are opened, they should be well 
cooled. The closure should be covered with a cloth or similar 
material while opening. Ammonia solution should not be tasted 
and inhalation of the vapor should be avoided. Ammonia 
solution should be handled in a fume cupboard. Eye protection, 
gloves, and a respirator are recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral suspensions, 
topical preparations). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Dilute ammonia solution. 
Dilute ammonia solution 
Synonyms: ammonia water. 
Specific gravity: 0.95–0.96 
Comments: several pharmacopeias include monographs for 
dilute ammonia solution. The JP 2001, for example, states 
that ammonia water contains not less than 9.5% and not 
more than 10.5% w/v of ammonia (NH3). 
18 Comments 
Where ‘ammonia solution’ is prescribed therapeutically, dilute 
ammonia solution should be dispensed or supplied. 
The EINECS number for ammonia solution is 231-635-3. 
19 Specific References 
1 Frohman IG. Treatment of physalia stings. J Am Med Assoc 1996; 
197: 733. 
2 Beare JD, Wilson RS, Marsh RJ. Ammonia burns of the eye: an old 
weapon in new hands. Br Med J 1988; 296: 590. 
3 Payne MP, Delic JI. Ammonia. In: Toxicity Review 24. London: 
HMSO, 1991: 1–12. 
4 Leduc D, Gris P, Lheureux P, et al. Acute and long term respiratory 
damage following inhalation of ammonia. Thorax 1992; 47: 755– 
757. 
20 General References 
—
21 Authors 
PJ Sheskey. 
22 Date of Revision 
12 August 2005. 
Ammonia Solution 45

Ammonium Alginate 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Alginic acid, ammonium salt; ammonium polymannuronate; 
E404; Keltose. 
3 Chemical Name and CAS Registry Number 
Ammonium alginate [9005-34-9] 
4 Empirical Formula and Molecular Weight 
(C6H11NO6)n 193.16 (calculated) 
217 (actual, average) 
Ammonium alginate is the ammonium salt of alginic acid. 
5 Structural Formula 
The number and sequence of the mannuronate and 
glucuronate residues shown above vary in the naturally 
occurring alginate. The associated water molecules are not 
shown. 
6 Functional Category 
Diluent; emulsifier; film-former; humectant; stabilizer; thickener; 
thickening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ammonium alginate is widely used in foods as a stabilizer, 
thickener and emulsifier. It is also used in pharmaceutical 
preparations as a color-diluent, emulsifier, film-former, and 
humectant. 
8 Description 
Ammonium alginate occurs as white to yellowish brown 
filamentous, grainy, granular, or powdered forms. 
9 Pharmacopeial Specifications 
See Section 18. 
10 Typical Properties 
Solubility: dissolves slowly in water to form a viscous solution; 
insoluble in ethanol and in ether. 
Moisture content: not more than 15% at 1058C for 4 hours. 
11 Stability and Storage Conditions 
Ammonium alginate is a hygroscopic material, although it is 
stable if stored at low relative humidities and cool temperatures. 
12 Incompatibilities 
Incompatible with oxidizing agents and strong acids and 
alkalis. 
13 Method of Manufacture 
—
14 Safety 
Ammonium alginate is widely used in cosmetics and food 
products, and also in pharmaceutical formulations such as 
tablets. It is generally regarded as a nontoxic and nonirritant 
material, although excessive oral consumption may be harmful. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of the material handled. Eye protection, gloves, 
and a dust respirator are recommended. 
16 Regulatory Status 
GRAS listed. Accepted in Europe for use as a food additive. 
Included in the FDA Inactive Ingredients Guide (oral, tablets). 
17 Related Substances 
Alginic acid; calcium alginate; potassium alginate; propylene 
glycol alginate; sodium alginate. 
18 Comments 
Alginates are commonly used in wound dressings.(1) Chitosan 
and alginates have been used together to produce sponges for 
use as wound dressings, or matrices for tissue engineering.(2) 
Alginate microspheres have been produced by internal gelation 
using emulsification methods.(3) 
Although not included in any pharmacopeias, a specification 
for ammonium alginate is contained in the Food Chemicals 
Codex (FCC), see Table I.

Table I: FCC specification for ammonium alginate.(4) 
Test FCC 1996(4) 
Identification . 
Arsenic 43 mg/kg 
Ash 44.0% after drying 
Heavy metals (as Pb) 40.002% 
Lead 45 mg/kg 
Loss on drying 415.0% 
Assay 18.0–21.0% of CO2, corresponding to 
88.7–103.6% ammonium alginate 
19 Specific References 
1 Morgan D. Wounds—what should a dressing formulary include? 
Hosp Pharm 2002; 9(9): 261–266. 
2 Lai HL, Abu’ Khalil A, Craig DQ. The preparation and 
characterization of drug-loaded alginate and chitosan sponges. 
Int J Pharm 2003; 251(1–2): 175–181. 
3 Chan LW, Lee HY, Heng PW. Production of alginate microspheres 
by internal gelation using an emulsification method. Int J Pharm 
2002; 242(1–2): 259–262. 
4 Food Chemicals Codex, 4th edn. Washington, DC: National 
Academy Press, 1996: 24. 
20 General References 
—
21 Authors 
D Thassu, S Shah. 
22 Date of Revision 
15 August 2005. 
Ammonium Alginate 47

Ascorbic Acid 
1 Nonproprietary Names 
BP: Ascorbic acid 
JP: Ascorbic acid 
PhEur: Acidum ascorbicum 
USP: Ascorbic acid 
2 Synonyms 
C-97; cevitamic acid; 2,3-didehydro-L-threo-hexono-1,4-lactone; 
E300; 3-oxo-L-gulofuranolactone, enol form; vitamin C. 
3 Chemical Name and CAS Registry Number 
L-(.)-Ascorbic acid [50-81-7] 
4 Empirical Formula and Molecular Weight 
C6H8O6 176.13 
5 Structural Formula 
6 Functional Category 
Antioxidant; therapeutic agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ascorbic acid is used as an antioxidant in aqueous pharmaceutical 
formulations at a concentration of 0.01–0.1% w/v. 
Ascorbic acid has been used to adjust the pH of solutions for 
injection, and as an adjunct for oral liquids. It is also widely 
used in foods as an antioxidant. Ascorbic acid has also proven 
useful as a stabilizing agent in mixed micelles containing 
tetrazepam.(1) 
8 Description 
Ascorbic acid occurs as a white to light-yellow-colored, 
nonhygroscopic, odorless, crystalline powder or colorless 
crystals with a sharp, acidic taste. It gradually darkens in color 
upon exposure to light. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for ascorbic acid. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters — . — 
Specific rotation . 20.58 to . 20.58 to . 20.58 to 
(10% w/v solution) . 21.58 . 21.58 . 21.58 
Residue on ignition 40.10% — 40.1% 
pH 2.2–2.5 2.1–2.6 — 
Sulfated ash — 40.1% — 
Copper — 45 ppm — 
Heavy metals 420 ppm 410 ppm 40.002% 
Loss on drying 40.20% — — 
Iron — 42 ppm — 
Oxalic acid — . — 
Appearance of 
solution 
. . — 
Organic volatile 
impurities 
— — . 
Assay 599.0% 99.0–100.5% 99.0–100.5% 
10 Typical Properties 
Acidity/alkalinity: pH = 2.1–2.6 (5% w/v aqueous solution) 
Density (bulk): 
0.7–0.9 g/cm3 for crystalline material; 
0.5–0.7 g/cm3 for powder. 
Density (particle): 1.65 g/cm3 
Density (tapped): 
1.0–1.2 g/cm3 for crystalline material; 
0.9–1.1 g/cm3 for powder. 
Density (true): 1.688 g/cm3 
Dissociation constant: 
pKa1 = 4.17; 
pKa2 = 11.57. 
Melting point: 1908C (with decomposition) 
Moisture content: 0.1% w/w 
Solubility: see Table II. 
Table II: Solubility of ascorbic acid. 
Solvent Solubility at 208C 
Chloroform Practically insoluble 
Ethanol 1 in 50 
Ethanol (95%) 1 in 25 
Ether Practically insoluble 
Fixed oils Practically insoluble 
Glycerin 1 in 1000 
Propylene glycol 1 in 20 
Water 1 in 3.5

SEM: 1 
Excipient: Ascorbic acid USP (fine powder) 
Manufacturer: Pfizer Ltd 
Lot No.: 9A-3/G92040-CO 146 
Magnification: 120 Voltage: 20 kV 
SEM: 2 
Excipient: Ascorbic acid USP (fine powder) 
Manufacturer: Pfizer Ltd 
Lot No.: 9A-3/G92040-CO 146 
Magnification: 600 Voltage: 20 kV 
SEM: 3 
Excipient: Ascorbic acid USP (fine granular) 
Manufacturer: Pfizer Ltd 
Lot No.: 9A-2/G01280-CO 148 
Magnification: 120 Voltage: 20 kV 
11 Stability and Storage Conditions 
In powder form, ascorbic acid is relatively stable in air. In the 
absence of oxygen and other oxidizing agents it is also heat 
stable. Ascorbic acid is unstable in solution, especially alkaline 
solution, readily undergoing oxidation on exposure to the 
air.(2,3) The oxidation process is accelerated by light and heat 
and is catalyzed by traces of copper and iron. Ascorbic acid 
solutions exhibit maximum stability at about pH 5.4. Solutions 
may be sterilized by filtration. 
The bulk material should be stored in a well-closed 
nonmetallic container, protected from light, in a cool, dry place. 
12 Incompatibilities 
Incompatible with alkalis, heavy metal ions, especially copper 
and iron, oxidizing materials, methenamine, phenylephrine 
hydrochloride, pyrilamine maleate, salicylamide, sodium 
nitrite, sodium salicylate, theobromine salicylate, and picotamide.(
4,5) Additionally, ascorbic acid has been found to 
interfere with certain colorimetric assays by reducing the 
intensity of the color produced.(6) 
13 Method of Manufacture 
Ascorbic acid is prepared synthetically or extracted from 
various vegetable sources in which it occurs naturally, such as 
rose hips, blackcurrants, the juice of citrus fruits, and the ripe 
fruit of Capsicum annuum L. A common synthetic procedure 
involves the hydrogenation of D-glucose to D-sorbitol, followed 
by oxidation using Acetobacter suboxydans to form L-sorbose. 
A carboxyl group is then added at C1 by air oxidation of the 
diacetone derivative of L-sorbose and the resulting diacetone-2- 
keto-L-gulonic acid is converted to L-ascorbic acid by heating 
with hydrochloric acid. 
Ascorbic Acid 49

14 Safety 
Ascorbic acid is an essential part of the human diet, with 40 mg 
being the recommended daily dose in the UK(7) and 60 mg in the 
US.(8) However, these figures are controversial, with some 
advocating doses of 150 or 250 mg daily. Megadoses of 10 g 
daily have also been suggested to prevent illness although such 
large doses are now generally considered to be potentially 
harmful.(9–11) 
The body can absorb about 500 mg of ascorbic acid daily 
with any excess immediately excreted by the kidneys. Large 
doses may cause diarrhea or other gastrointestinal disturbances. 
Damage to the teeth has also been reported.(12) 
However, no adverse effects have been reported at the levels 
employed as an antioxidant in foods and pharmaceuticals. The 
WHO has set an acceptable daily intake of ascorbic acid, 
potassium ascorbate, and sodium ascorbate, as antioxidants in 
food, at up to 15 mg/kg body-weight in addition to that 
naturally present in food.(13) 
LD50 (mouse, IV): 0.52 g/kg(14) 
LD50 (mouse, oral): 3.37 g/kg 
LD50 (rat, oral): 11.9 g/kg 
15 Handling Precautions 
Ascorbic acid may be harmful if ingested in large quantities and 
may be irritating to the eyes. Observe normal precautions 
appropriate to the circumstances and quantity of material 
handled. Eye protection and rubber or plastic gloves are 
recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (inhalations, 
injections, oral capsules, suspensions, tablets, topical preparations, 
and suppositories). Included in medicines licensed in the 
UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Ascorbyl palmitate; erythorbic acid; sodium ascorbate. 
18 Comments 
Many dosage forms for ascorbic acid have been developed for 
its administration to patients, including microencapsulation.(15) 
A specification for ascorbic acid is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for ascorbic acid is 200-066-2. 
19 Specific References 
1 Hammad MA, Muller BW. Solubility and stability of tetrazepam in 
mixed micelles. Eur J Pharm Sci 1998; 7: 49–55. 
2 Hajratwala BR. Stability of ascorbic acid. STP Pharma 1985; 1: 
281–286. 
3 Touitou E, Gilhar D, Alhaique F, et al. Ascorbic acid in aqueous 
solution: bathochromic shift in dilution and degradation. Int J 
Pharm 1992; 78: 85–87. 
4 Botha SA, Lo. tter AP, du Preez JFL. DSC screening for drug–drug 
interactions in polypharmaceuticals intended for the alleviation of 
the symptoms of colds and flu. Drug Dev Ind Pharm 1987; 13: 
345–354. 
5 Mura P, Bettinetti GP, Faucci MT, et al. Differential scanning 
calorimetry in compatibility testing of picotamide with pharmaceutical 
excipients. Thermochim Acta 1998; 321: 59–65. 
6 Krishnan G, Talwar SK, Sharma SC, Sharma RG. Estimation of 
phenylephrine hydrochloride in multi-component pharmaceutical 
preparations. Eastern Pharmacist 1990; 33: 143–145. 
7 Department of Health. Dietary reference values for food energy 
and nutrients for the United Kingdom: report of the panel on 
dietary reference values of the committee on medical aspects of 
food policy. Report on Health and Social Subjects 41. London: 
HMSO, 1991. 
8 Subcommittee on the tenth edition of the RDAs, Food and 
Nutrition Board, Commission on Life Sciences. National Research 
Council. Recommended Dietary Allowances, 10th edn. Washington, 
DC: National Academy Press, 1989. 
9 Ovesen L. Vitamin therapy in the absence of obvious deficiency: 
what is the evidence? Drugs 1984; 27: 148–170. 
10 Bates CJ. Is there a maximum safe dose of vitamin C (ascorbic 
acid)? Br Med J 1992; 305: 32. 
11 Mason P. Vitamin C. Dietary Supplements, 2nd edn. London: 
Pharmaceutical Press, 2001: 227–233. 
12 Giunta JL. Dental erosion resulting from chewable vitamin C 
tablets. J Am Dent Assoc 1983; 107: 253–256. 
13 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications. 
Seventeenth report of the joint FAO/WHO expert committee on 
food additives.World Health Organ Tech Rep Ser 1974; No. 539. 
14 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 309–310. 
15 Esposito E, Cervellayi F, Menegatti E, et al. Spray-dried Eudragit 
microparticles as encapsulation devices for vitamin C. Int J Pharm 
2002; 242: 329–334. 
20 General References 
Abramovici B, Molard F, Seguin B, Gromenil JC. Comparative study of 
the tabletability of different grades of vitamin C [in French]. STP 
Pharma 1987; 3: 16–22. 
Allwood MC. Factors influencing the stability of ascorbic acid in total 
parenteral nutrition infusions. J Clin Hosp Pharm 1984; 9: 75–85. 
Bhagavan HN,Wolkoff BI. Correlation between the disintegration time 
and the bioavailability of vitamin C tablets. Pharm Res 1993; 10: 
239–242. 
Davies MB, Austin J, Partridge DA. Vitamin C—Its Chemistry and 
Biochemistry. London: Royal Society of Chemistry, 1991. 
Hu F, Wang H, Wu X. Effects of different adhesives on the stability of 
vitamin C buccal tablets. Zhejiang Yike Daxue Xuebao 1997; 26: 
108–110. 
Krishna G, Mao J, Almassian B. Development of a parenteral 
formulation of an investigational anticancer drug, 3-aminopyridine-
2-carboxaldehyde thiosemicarbazone. Pharm Dev Technol 
1999; 4: 71–80. 
Nebuloni M, Pifferi G, Munna E. Thermal analysis in preformulation 
studies of a lyophilized form of an antibiotic. Boll Chim Farm 1996; 
135: 94–100. 
Pinsuwan S, Alvarez-Nunez FA, et al. Degradation kinetics of 4- 
dedimethylamino sancycline, a new anti-tumor agent, in aqueous 
solutions. Int J Pharm 1999; 181: 31–40. 
Saleh SI, Stamm A. Evaluation of some directly compressible L-ascorbic 
acid forms. STP Pharma 1988; 4: 10–14. 
Saleh SI, Stamm A. Contribution to the preparation of a directly 
compressible L-ascorbic acid granular form: comparison of granules 
prepared by three granulation methods and evaluation of their 
corresponding tablets. STP Pharma 1988; 4: 182–187. 
Seta Y, Higuchi F, Otsuka T, et al. Preparation and pharmacological 
evaluation of Captopril sustained-release dosage forms using oily 
semisolid matrix. Int J Pharm 1988; 41: 255–262. 
21 Authors 
AH Kibbe. 
22 Date of Revision 
12 August 2005. 
50 Ascorbic Acid

Ascorbyl Palmitate 
1 Nonproprietary Names 
BP: Ascorbyl palmitate 
PhEur: Ascorbylis palmitas 
USPNF: Ascorbyl palmitate 
2 Synonyms 
L-Ascorbic acid 6-palmitate; E304; 3-oxo-L-gulofuranolactone 
6-palmitate; vitamin C palmitate. 
3 Chemical Name and CAS Registry Number 
L-Ascorbic acid 6-hexadecanoate [137-66-6] 
4 Empirical Formula and Molecular Weight 
C22H38O7 414.54 
5 Structural Formula 
6 Functional Category 
Antioxidant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ascorbyl palmitate is primarily used either alone or in 
combination with alpha tocopherol as a stabilizer for oils in 
oral pharmaceutical formulations and food products; generally 
0.05% w/v is used. It may also be used in oral and topical 
preparations as an antioxidant for drugs unstable to oxygen. 
The combination of ascorbyl palmitate with alpha tocopherol 
shows marked synergism, which increases the effect of the 
components and allows the amount used to be reduced. 
The solubility of ascorbyl palmitate in alcohol permits it to 
be used in nonaqueous and aqueous systems and emulsions. 
8 Description 
Ascorbyl palmitate is a practically odorless, white to yellowish 
powder. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for ascorbyl palmitate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Appearance of solution . — 
Melting range — 107–1178C 
Specific rotation (10% w/v in 
methanol) 
.218 to .248 .218 to .248 
Loss on drying 41.0% 42.0% 
Residue on ignition — 40.1% 
Sulfated ash 40.1% — 
Heavy metals 410 ppm 40.001% 
Organic volatile impurities — . 
Assay (dried basis) 98.0–100.5% 95.0–100.5% 
10 Typical Properties 
Solubility: see Table II. 
Table II: Solubility of ascorbyl palmitate. 
Solvent Solubility at 208C unless otherwise stated(1) 
Acetone 1 in 15 
Chloroform 1 in 3300 
1 in 11 at 608C 
Cottonseed oil 1 in 1670 
Ethanol 1 in 8 
1 in 1.7 at 708C 
Ethanol (95%) 1 in 9.3 
Ethanol (50%) 1 in 2500 
Ether 1 in 132 
Methanol 1 in 5.5 
1 in 1.7 at 608C 
Olive oil 1 in 3300 
Peanut oil 1 in 3300 
Propan-2-ol 1 in 20 
1 in 5 at 708C 
Sunflower oil 1 in 3300 
Water Practically insoluble 
1 in 500 at 708C 
1 in 100 at 1008C 
11 Stability and Storage Conditions 
Ascorbyl palmitate is stable in the dry state, but is gradually 
oxidized and becomes discolored when exposed to light and 
high humidity. In an unopened container, stored in a cool place, 
it has a shelf life of at least 12 months. During processing, 
temperatures greater than 658C should be avoided. 
The bulk material should be stored in an airtight container 
at 8–158C, protected from light.

12 Incompatibilities 
Incompatibilities are known with oxidizing agents, e.g., in 
solution oxidation is catalyzed by trace metal ions such as Cu2. 
and Fe3.. 
13 Method of Manufacture 
Ascorbyl palmitate is prepared synthetically by the reaction of 
ascorbic acid with sulfuric acid followed by reesterification 
with palmitic acid. 
14 Safety 
Ascorbyl palmitate is used in oral pharmaceutical formulations 
and food products and is generally regarded as an essentially 
nontoxic and nonirritant material. The WHO has set an 
estimated acceptable daily intake for ascorbyl palmitate at up 
to 1.25 mg/kg body-weight.(2) 
LD50 (mouse, oral): 25 g/kg(3) 
LD50 (rat, oral): 10 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Ascorbyl palmitate dust may 
cause irritation to the eyes and respiratory tract. Eye protection 
is recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral, rectal, 
topical preparations). Included in nonparenteral medicines 
licensed in the UK. 
17 Related Substances 
Ascorbic acid; sodium ascorbate. 
18 Comments 
The EINECS number for ascorbyl palmitate is 205-305-4. 
In order to maximize the stability and efficacy of ascorbyl 
palmitate the following precautions are recommended: stainless 
steel, enamel, or glass should be used; deaeration (vacuum) 
procedures and inert gas treatment are recommended where 
feasible; protect from light and radiant energy. 
The formation of ascorbyl palmitate vesicles (Aspasomes) 
and their pharmaceutical applications has recently been 
investigated.(4) 
19 Specific References 
1 Kla. ui H. Tocopherol, carotene and ascorbyl palmitate. Int 
Flavours Food Addit 1976; 7(4): 165–172. 
2 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications. 
Seventeenth report of the joint FAO/WHO expert committee on 
food additives.World Health Organ Tech Rep Ser 1974; No. 539. 
3 Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. 
Cincinnati: US Department of Health, 1987. 
4 Gopinath D, Ravi D, Rao BR, et al. Ascorbyl palmitate vesicles 
(Aspasomes): formation, characterization and applications. Int J 
Pharm 2004; 271: 95–113. 
20 General References 
Austria R, Semenzato A, Bettero A. Stability of vitamin C derivatives in 
solution and topical formulations. J Pharm Biomed Anal 1997; 15: 
795–801. 
Daniel JW. Metabolic aspects of antioxidants and preservatives. 
Xenobiotica 1986; 16(10–11): 1073–1078. 
Johnson DM, Gu LC. Autoxidation and antioxidants. In: Swarbrick J, 
Boylan JC, eds. Encyclopedia of Pharmaceutical Technology, vol. 1. 
New York: Marcel Dekker, 1988: 415–449. 
Pongracz G. Antioxidant mixtures for use in food. Int J Vitam Nutr Res 
1973; 43: 517–525. 
S.
piclin P, Gas.perlin M, Kmetec V. Stability of ascorbyl palmitate in 
topical microemulsions. Int J Pharm 2001; 222: 271–279. 
Weller PJ, Newman CM, Middleton KR, Wicker SM. Stability of a 
novel dithranol ointment formulation, containing ascorbyl palmitate 
as an anti-oxidant. J Clin Pharm Ther 1990; 15: 419–423. 
21 Authors 
PJ Weller. 
22 Date of Revision 
4 August 2005. 
52 Ascorbyl Palmitate

Aspartame 
1 Nonproprietary Names 
BP: Aspartame 
PhEur: Aspartamum 
USPNF: Aspartame 
2 Synonyms 
3-Amino-N-(a-carboxyphenethyl)succinamic acid N-methyl 
ester; 3-amino-N-(a-methoxycarbonylphenethyl)succinamic 
acid; APM; aspartyl phenylamine methyl ester; Canderel; 
E951; Equal; methyl N-a-L-aspartyl-L-phenylalaninate; 
NutraSweet; Pal Sweet; Pal Sweet Diet; Sanecta; SC-18862; 
Tri-Sweet. 
3 Chemical Name and CAS Registry Number 
N-a-L-Aspartyl-L-phenylalanine 1-methyl ester [22839-47-0] 
4 Empirical Formula and Molecular Weight 
C14H18N2O5 294.31 
5 Structural Formula 
6 Functional Category 
Sweetening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Aspartame is used as an intense sweetening agent in beverage 
products, food products, and table-top sweeteners, and in 
pharmaceutical preparations including tablets,(1,2) powder 
mixes, and vitamin preparations. It enhances flavor systems 
and can be used to mask some unpleasant taste characteristics; 
the approximate sweetening power is 180–200 times that of 
sucrose. 
Unlike some other intense sweeteners, aspartame is metabolized 
in the body and consequently has some nutritive value: 
1 g provides approximately 17 kJ (4 kcal). However, in practice, 
the small quantity of aspartame consumed provides a minimal 
nutritive effect. 
Therapeutically, aspartame has also been used in the 
treatment of sickle cell anemia.(3) 
8 Description 
Aspartame occurs as an off white, almost odorless crystalline 
powder with an intensely sweet taste. 
SEM: 1 
Excipient: Aspartame 
Magnification: 70 Voltage: 3kV 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for aspartame. 
Test PhEur 2005 USPNF 23 
Characters . — 
Identification . . 
Appearance of solution . — 
Conductivity 430 mS/cm — 
Specific optical rotation .14.58 to .16.58 .14.58 to .16.58 
Related substances . — 
Heavy metals 410 ppm 40.001% 
Loss on drying 44.5% 44.5% 
Sulfated ash 40.2% 40.2% 
Impurities . — 
Transmittance — . 
Limit of 5-benzyl-3,6-dioxo- 
2-piperazineacetic acid 
— 41.5% 
Organic volatile impurities — . 
Assay 98.0–102.0% 98.0–102.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 4.5–6.0 (0.8% w/v aqueous solution). 
Brittle fracture index: 1.05(4)

Bonding index: 
0.8102 (worst case)(4) 
2.3102 (best case)(4) 
Flowability: 44% (Carr compressibility index)(4) 
Density (bulk): 
0.5–0.7 g/cm3 for granular grade; 
0.2–0.4 g/cm3 for powder grade; 
0.17 g/cm3 (Spectrum Quality Products).(4) 
Density (tapped): 0.29 g/cm3 (Spectrum Quality Products)(4) 
Density (true): 1.347 g/cm3 
Effective angle of internal friction: 43.08(4) 
Melting point: 246–2478C 
Solubility: slightly soluble in ethanol (95%); sparingly soluble 
in water. At 208C the solubility is 1% w/v at the isoelectric 
point (pH 5.2). Solubility increases at higher temperature 
and at more acidic pH, e.g., at pH 2 and 208C solubility is 
10% w/v. 
Specific rotation [a]D
22: 2.38 in 1N HCl 
11 Stability and Storage Conditions 
Aspartame is stable in dry conditions. In the presence of 
moisture, hydrolysis occurs to form the degradation products 
L-aspartyl-L-phenylalanine and 3-benzyl-6-carboxymethyl-2,5- 
diketopiperazine. A third-degradation product is also known, 
b-L-aspartyl-L-phenylalanine methyl ester. For the stability 
profile at 258C in aqueous buffers, see Figure 1. 
Stability in aqueous solutions has been enhanced by the 
addition of cyclodextrins,(5,6) and by the addition of polyethylene 
glycol 400 at pH 2.(7) However, at pH 3.5–4.5 stability 
is not enhanced by the replacement of water with organic 
solvents.(8) 
Aspartame degradation also occurs during prolonged heat 
treatment; losses of aspartame may be minimized by using 
processes that employ high temperatures for a short time 
followed by rapid cooling. 
The bulk material should be stored in a well-closed 
container, in a cool, dry place. 
Figure 1: Stability profile of aspartame in aqueous buffers at 258C.(9) 
12 Incompatibilities 
Differential scanning calorimetry experiments with some 
directly compressible tablet excipients suggests that aspartame 
is incompatible with dibasic calcium phosphate and also with 
the lubricant magnesium stearate.(10) Reactions between 
aspartame and sugar alcohols are also known. 
13 Method of Manufacture 
Aspartame is produced by coupling together L-phenylalanine 
(or L-phenylalanine methyl ester) and L-aspartic acid, either 
chemically or enzymatically. The former procedure yields both 
the sweet a-aspartame and nonsweet b-aspartame from which 
the a-aspartame has to be separated and purified. The 
enzymatic process yields only a-aspartame. 
14 Safety 
Aspartame is widely used in oral pharmaceutical formulations, 
beverages, and food products as an intense sweetener and is 
generally regarded as a nontoxic material. However, the use of 
aspartame has been of some concern owing to the formation of 
the potentially toxic metabolites methanol, aspartic acid, and 
phenylalanine. Of these materials, only phenylalanine is 
produced in sufficient quantities, at normal aspartame intake 
levels, to cause concern. In the normal healthy individual any 
phenylalanine produced is harmless, however it is recommended 
that aspartame be avoided or its intake restricted by 
those persons with phenylketonuria.(11) 
The WHO has set an acceptable daily intake for aspartame 
at up to 40 mg/kg body-weight.(12) Additionally, the acceptable 
daily intake of diketopiperazine (an impurity found in 
aspartame) has been set by the WHO at up to 7.5 mg/kg 
body-weight.(13) 
A number of adverse effects have been reported following 
the consumption of aspartame,(11,13) particularly in individuals 
who drink large quantities (up to 8 liters per day in one case) of 
aspartame-sweetened beverages. Reported adverse effects 
include: headaches;(14) grand mal seizure;(15) memory loss;(16) 
gastrointestinal symptoms; and dermatological symptoms. 
Although aspartame has been reported to cause hyperactivity 
and behavioral problems in children, a double-blind 
controlled trial of 48 preschool-age children fed diets containing 
a daily intake of 38 
 13 mg/kg body-weight of aspartame 
for 3 weeks showed no adverse effects attributable to 
aspartame, or dietary sucrose, on children’s behavior or 
cognitive function.(17) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Measures should be taken to 
minimize the potential for dust explosion. Eye protection is 
recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral powder 
for reconstitution, buccal patch, granules, film-coated, and 
tablets). Included in nonparenteral medicines licensed in the 
UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
54 Aspartame

17 Related Substances 
Alitame. 
18 Comments 
The intensity of sweeteners relative to sucrose depends upon 
their concentration, temperature of tasting, and pH, and on the 
flavor and texture of the product concerned. 
Intense sweetening agents will not replace the bulk, textural, 
or preservative characteristics of sugar, if sugar is removed from 
a formulation. 
Synergistic effects for combinations of sweeteners have been 
reported, e.g., aspartame with acesulfame potassium. 
Aspartame can cause browning when used at high 
temperatures. 
A specification for aspartame is contained in the Food 
Chemicals Codex (FCC). 
19 Specific References 
1 Joachim J, Kalantzis G, Delonca H, et al. The compression of 
effervescent aspartame tablets: the influence of particle size on the 
strain applied on the punches during compression [in French]. J 
Pharm Belg 1987; 42: 17–28. 
2 Joachim J, Kalantzis G, Delonca H, et al. The compression of 
effervescent aspartame tablets: the influence of particle size and 
temperature on the effervescence time and carbon dioxide 
liberation kinetics [in French]. J Pharm Belg 1987; 42: 303–314. 
3 Manion CV, Howard J, Ogle B, et al. Aspartame effect in sickle cell 
anemia. Clin Pharmacol Ther 2001; 69: 346–355. 
4 Mullarney MP, Hancock BC, Carlson GT, et al. The powder flow 
and compact mechanical properties of sucrose and three highintensity 
sweeteners used in chewable tablets. Int J Pharm 2003; 
257(1–2): 227–236. 
5 Brewster ME, Loftsson T, Baldvinsdo. ttir J, Bodor N. Stabilization 
of aspartame by cyclodextrins. Int J Pharm 1991; 75: R5–R8. 
6 Prankerd RJ, Stone HW, Sloan KB, Perrin JH. Degradation of 
aspartame in acidic aqueous media and its stabilization by 
complexation with cyclodextrins or modified cyclodextrins. Int J 
Pharm 1992; 88: 189–199. 
7 Yalkowsky SH, Davis E, Clark T. Stabilization of aspartame by 
polyethylene glycol 400. J Pharm Sci 1993; 82: 978. 
8 Sanyude S, Locock RA, Pagliaro LA. Stability of aspartame in 
water: organic solvent mixtures with different dielectric constants. 
J Pharm Sci 1991; 80: 674–676. 
9 The NutraSweet Company. Technical literature: NutraSweet 
technical bulletin, 1991. 
10 El-Shattawy HE, Peck GE, Kildsig DO. Aspartame-direct compression 
excipients: preformulation stability screening using 
differential scanning calorimetry. Drug Dev Ind Pharm 1981; 7: 
605–619. 
11 Golightly LK, Smolinske SS, Bennett ML, et al. Pharmaceutical 
excipients: adverse effects associated with inactive ingredients in 
drug products (part II). Med Toxicol 1988; 3: 209–240. 
12 FAO/WHO. Evaluation of certain food additives and contaminants. 
Twenty-fifth report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1981; No. 669. 
13 Butchko HH, Kotsonis FN. Aspartame: review of recent research. 
Comments Toxicol 1989; 3(4): 253–278. 
14 Schiffman SS, Buckley E, Sampson HA, et al. Aspartame and 
susceptibility to headache. N Engl J Med 1987; 317: 1181–1185. 
15 Wurtman RJ. Aspartame: possible effect on seizure susceptibility 
[letter]. Lancet 1985; ii: 1060. 
16 Anonymous. Sweetener blamed for mental illnesses. New Scientist 
1988; February 18: 33. 
17 Wolraich ML, Lindgreen SD, Stumbo PJ, et al. Effects of diets high 
in sucrose or aspartame on the behavior and cognitive performance 
of children. N Engl J Med 1994; 330: 301–307. 
20 General References 
Marie S. Sweeteners. In: Smith J, ed. Food Additives User’s Handbook. 
Glasgow: Blackie, 1991: 47–74. 
Roy GM. Taste masking in oral pharmaceuticals. Pharm Technol Eur 
1994; 6(6): 24, 26–28, 30–32, 34, 35. 
Stegink LD, Filer LJ, eds. Aspartame, Physiology and Biochemistry. 
New York: Marcel Dekker, 1984. 
21 Authors 
H Wang. 
22 Date of Revision 
12 August 2005. 
Aspartame 55

Attapulgite 
1 Nonproprietary Names 
BP: Attapulgite 
2 Synonyms 
Actapulgite; Attaclay; Attacote; Attagel; attapulgus; palygorscite; 
palygorskite; Pharmsorb Regular. 
3 Chemical Name and CAS Registry Number 
Attapulgite [12174-11-7] 
4 Empirical Formula and Molecular Weight 
Attapulgite is a purified native hydrated magnesium aluminum 
silicate consisting of the clay mineral palygorskite, with the 
empirical formula Mg(Al0.5–1Fe0–0.5)Si4O10(OH)4H2O. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Adsorbent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Attapulgite is widely used as an adsorbent in solid dosage 
forms. Colloidal clays (such as attapulgite) absorb considerable 
amounts of water to form gels and in concentrations of 2–5% 
w/v usually form oil-in-water emulsions. Activated attapulgite, 
which is attapulgite that has been carefully heated to increase its 
absorptive capacity, is used therapeutically as an adjunct in the 
management of diarrhea. 
8 Description 
Attapulgite occurs as a light cream colored, very fine powder. 
Particle size ranges depend on the grade and manufacturer. 
9 Pharmacopeial Specifications 
See Table I. See also Section 17. 
10 Typical Properties 
Acidity/alkalinity: pH = 9.5 (5% w/v aqueous suspension) 
Angle of repose: 37.2–45.28(1) 
Density: 2.2 g/cm3 
Density (tapped): 0.33 g/cm3(1) 
Flowability: 20.9–29.6% (Carr compressibility index)(1) 
Particle size distribution: 
<2 mm in size for powder; 
2–5 mm in size for aggregate.(1) 
Table I: Pharmacopeial specifications for attapulgite. 
Test BP 2004 
Identification . 
Characters . 
Acidity or alkalinity (5% w/v aqueous 
suspension) 
7.0–9.5 
Adsorptive capacity 5–14% 
Arsenic 48 ppm 
Heavy metals 420 ppm 
Acid-insoluble matter 412.5% 
Water-soluble matter 40.5% 
Loss on drying 417.0% 
Loss on ignition 15.0–27.0% 
11 Stability and Storage Conditions 
Attapulgite can adsorb water. It should be stored in an airtight 
container in a cool, dry, location. 
12 Incompatibilities 
Attapulgite may decrease the bioavailability of some drugs 
such as loperamide(2) and riboflavin.(3) Oxidation of hydrocortisone 
is increased in the presence of attapulgite.(4) 
13 Method of Manufacture 
Attapulgite occurs naturally as the mineral palygorskite. 
14 Safety 
Attapulgite is widely used in pharmaceutical formulations and 
is generally regarded as an essentially nontoxic and nonirritant 
material. It is not absorbed following oral administration. In 
oral preparations, activated attapulgite up to 9 g is used in daily 
divided doses as an adjunct in the management of diarrhea.(5) 
LD50 (rat, IP): 0.34 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection, gloves, and a 
dust mask are recommended. Attapulgite should be handled in 
a well-ventilated environment and dust generation should be 
minimized. When heated to decomposition, attapulgite emits 
acrid smoke and irritating fumes. 
16 Regulatory Status 
Included in nonparenteral medicines licensed in a number of 
countries worldwide including the UK and US. 
17 Related Substances 
Activated attapulgite; magnesium aluminum silicate.

Activated attapulgite 
Comments: activated attapulgite is a processed native magnesium 
aluminum silicate that has been carefully heated to 
increase its adsorptive capacity. Monographs for activated 
attapulgite are included in the BP 2004, USP 28, and other 
pharmacopeias. The USP 28 also includes a monograph for 
colloidal activated attapulgite. 
18 Comments 
The EINECS number for attapulgite is 302-243-0. 
19 Specific References 
1 Viseras C, Lo. pez-Galindo A. Characteristics of pharmaceutical 
grade phyllosilicate powders. Pharm Dev Technol 2000; 5(1): 47– 
52. 
2 Mboya SA, Bhargava HN. Adsorption and desorption of 
loperamide hydrochloride by activated attapulgites. Am J Health 
Syst Pharm 1995; 52: 2816–2818. 
3 Khalil SAH, Mortada LM, Shams-Eldeen MA, El-Khawas MM. 
Effect of attapulgite on the bioavailability of a model low dose 
drug (riboflavine) in humans. Drug Dev Ind Pharm 1987; 13: 
369–382. 
4 Cornejo J, Hernosin MC, White JL, et al. Oxidative degradation of 
hydrocortisone in the presence of attapulgite. J Pharm Sci 1980; 
69: 945–948. 
5 Sweetman SC, ed. Martindale: the Complete Drug Reference, 34th 
edn. London: Pharmaceutical Press, 2005: 1251. 
20 General References 
Anonymous. The silicates: attapulgite, kaolin, kieselguhr, magnesium 
trisilicate, pumice, talc. Int J Pharm Compound 1998; 2(2): 162– 
163. 
Viseras C, Yebra A, Lo. pez-Galindo A. Characteristics of pharmaceutical 
grade phyllosilicate compacts. Pharm Dev Technol 2000; 5(1): 
53–58. 
21 Authors 
A Palmieri. 
22 Date of Revision 
8 August 2005. 
Attapulgite 57

Bentonite 
1 Nonproprietary Names 
BP: Bentonite 
JP: Bentonite 
PhEur: Bentonitum 
USPNF: Bentonite 
2 Synonyms 
Albagel; E558; Magnabrite; mineral soap; Polargel; soap clay; 
taylorite; Veegum HS; wilkinite. 
3 Chemical Name and CAS Registry Number 
Bentonite [1302-78-9] 
4 Empirical Formula and Molecular Weight 
Al2O34SiO2H2O 359.16 
Bentonite is a native colloidal hydrated aluminum silicate 
consisting mainly of montmorillonite, Al2O34SiO2H2O; it 
may also contain calcium, magnesium, and iron. The average 
chemical analysis is expressed as oxides, see Table I, in 
comparison with magnesium aluminum silicate. 
Table I: Average chemical analysis of bentonite expressed as oxides 
in comparison with magnesium aluminum silicate. 
Bentonite Magnesium aluminum silicate 
Silicon dioxide 59.92% 61.1% 
Aluminum oxide 19.78% 9.3% 
Magnesium oxide 1.53% 13.7% 
Ferric oxide 2.96% 0.9% 
Calcium oxide 0.64% 2.7% 
Sodium oxide 2.06% 2.9% 
Potassium oxide 0.57% 0.3% 
5 Structural Formula 
The PhEur 2005 describes bentonite as a natural clay containing 
a high proportion of montmorillonite, a native hydrated 
aluminum silicate in which some aluminum and silicon atoms 
may be replaced by other atoms such as magnesium and iron. 
The USPNF 23 describes bentonite, purified benonite, and 
bentonite magma in three separate monographs. Bentonite is 
described as a native, colloidal, hydrated aluminum silicate; 
and purified bentonite is described as a colloidal montmorillonite 
that has been processed to remove grit and nonswellable 
ore compounds. 
See also Section 4. 
6 Functional Category 
Adsorbent; stabilizing agent; suspending agent; viscosityincreasing 
agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Bentonite is a naturally occurring hydrated aluminum silicate 
used primarily in the formulation of suspensions, gels, and sols, 
for topical pharmaceutical applications. It is also used to 
suspend powders in aqueous preparations and to prepare 
cream bases containing oil-in-water emulsifying agents. 
Bentonite may also be used in oral pharmaceutical preparations, 
cosmetics, and food products, see Section 18. In oral 
preparations, bentonite, and other similar silicate clays, can be 
used to adsorb cationic drugs and so retard their release.(1–3) 
Adsorbents are also used to mask the taste of certain drugs. See 
Table II. 
Bentonite has been investigated as a diagnostic agent for 
magnetic resonance imaging.(4) 
Therapeutically, bentonite has been investigated as an 
adsorbent for lithium poisoning.(5) 
8 Description 
Bentonite is a crystalline, claylike mineral, and is available as an 
odorless, pale buff, or cream to grayish-colored fine powder, 
which is free from grit. It consists of particles about 50–150 mm 
in size along with numerous particles about 1–2 mm. Microscopic 
examination of samples stained with alcoholic methylene 
blue solution reveals strongly stained blue particles. 
Bentonite may have a slight earthy taste. 
SEM: 1 
Excipient: Bentonite 
Manufacturer: American Colloid Co. 
Lot No.: NMD 11780 
Magnification: 600 Voltage: 10 kV

SEM: 2 
Excipient: Bentonite 
Manufacturer: American Colloid Co. 
Lot No: NMD 11780 
Magnification: 2400 Voltage: 20 kV 
9 Pharmacopeial Specifications 
See Table III. 
Table III: Pharmacopeial specifications for bentonite. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters . . — 
Alkalinity — . — 
Microbial limit — 4103/g . 
Coarse particles — 40.5% — 
pH (2% w/v suspension) 9.0–10.5 — 9.5–10.5 
Loss on drying 5.0–10.0% 415% 5.0–8.0% 
Arsenic 42 ppm — 45 ppm 
Lead — — 40.004% 
Heavy metals 450 ppm 450 ppm — 
Organic volatile impurities — — . 
Gel formation . — . 
Sedimentation volume — 42mL — 
Swelling power 520 mL 522 mL 524 mL 
Fineness of powder . — . 
The USPNF 23 also contains specifications for bentonite 
magma and purified bentonite. See Section 17. 
10 Typical Properties 
Acidity/alkalinity: pH = 9.5–10.5 for a 2% w/v aqueous 
suspension. 
Flowability: no flow. 
Hygroscopicity: bentonite is hygroscopic.(6) See also Figure 1. 
Moisture content: 5–12%. 
Solubility: practically insoluble in ethanol, fixed oils, glycerin, 
propan-2-ol, and water. Bentonite swells to about 12 times 
its original volume in water, to form viscous homogeneous 
suspensions, sols, or gels depending upon the concentration. 
Bentonite does not swell in organic solvents. Sols and gels 
may be conveniently prepared by sprinkling the bentonite 
on the surface of hot water and allowing to stand for 24 
hours, stirring occasionally when the bentonite has become 
thoroughly wetted. Water should not be added to bentonite 
alone, but bentonite may be satisfactorily dispersed in water 
if it is first triturated with glycerin or mixed with a powder 
such as zinc oxide. A 7% w/v aqueous suspension of 
bentonite is just pourable. See also Section 12. 
Viscosity (dynamic): 75–225 mPa s (75–225 cP) for a 5.5% w/v 
aqueous suspension at 258C. Viscosity increases with 
increasing concentration. 
11 Stability and Storage Conditions 
Bentonite is hygroscopic, and sorption of atmospheric water 
should be avoided. 
Aqueous bentonite suspensions may be sterilized by autoclaving. 
The solid material may be sterilized by maintaining it at 
1708C for 1 hour after drying at 1008C. 
Bentonite should be stored in an airtight container in a cool, 
dry place. 
Figure 1: Equilibrium, moisture content of bentonite USPNF. 
12 Incompatibilities 
Aqueous bentonite suspensions retain their viscosity above 
pH 6, but are precipitated by acids. Acid-washed bentonite 
Table II: Uses of bentonite. 
Use Concentration (%) 
Adsorbent (clarifying agent) 1.0–2.0 
Emulsion stabilizer 1.0 
Suspending agent 0.5–5.0 
Bentonite 59

does not have suspending properties. The addition of alkaline 
materials, such as magnesium oxide, increases gel formation. 
Addition of significant amounts of alcohol to aqueous 
preparations will precipitate bentonite, primarily by dehydration 
of the lattice structure; see also Section 18. 
Bentonite particles are negatively charged and flocculation 
occurs when electrolytes or positively charged suspensions are 
added. Bentonite is thus said to be incompatible with strong 
electrolytes, although this effect is sometimes used beneficially 
to clarify turbid liquids. 
The antimicrobial efficacy of cationic preservatives may be 
reduced in aqueous bentonite suspensions, but nonionic and 
anionic preservatives are unaffected.(7) 
Bentonite is incompatible with acriflavine hydrochloride. 
13 Method of Manufacture 
Bentonite is a native, colloidal, hydrated aluminum silicate, 
found in regions of Canada and the USA. The mined ore is 
processed to remove grit and nonswelling materials so that it is 
suitable for pharmaceutical applications. 
14 Safety 
Bentonite is mainly used in topical pharmaceutical formulations 
but has also been used in oral pharmaceutical preparations, 
food products, and cosmetics. 
Following oral administration, bentonite is not absorbed 
from the gastrointestinal tract. Bentonite is generally regarded 
as a nontoxic and nonirritant material. 
LD50 (rat, IV): 0.035 g/kg(8) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection, gloves, and a 
dust mask are recommended. Bentonite should be handled in a 
well-ventilated environment and dust generation minimized. 
16 Regulatory Status 
Accepted in Europe as a food additive in certain applications. 
Included in the FDA Inactive Ingredients Guide (oral capsules, 
tablets and suspensions, topical suspensions, controlled release 
transdermal films and vaginal suppositories). Included in 
nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Bentonite magma; kaolin; magnesium aluminum silicate; 
magnesium trisilicate; purified bentonite; talc. 
Bentonite magma 
Comments: a 5%w/w suspension of bentonite in purified water 
appears in some pharmacopeias, such as the USPNF 23. 
Purified bentonite 
Acidity/alkalinity: pH = 9.0–10.0 for a 5% w/w aqueous 
suspension. 
Viscosity (dynamic): 40–200 mPa s (40–200 cP) for a 5% w/w 
aqueous suspension. 
Comments: specifications for purified bentonite occur in some 
pharmacopeias such as the USPNF 23. Purified bentonite is 
bentonite that has been processed to remove grit and 
nonswellable ore components. 
18 Comments 
Bentonite may be used with concentrations of up to 30% 
ethanol or propan-2-ol; 50% glycerin; 30% propylene glycol; 
or high molecular weight polyethylene glycols. The EINECS 
number for bentonite is 215-108-5. 
Bentonite is used in the food industry as a processing aid as a 
clarifying or filter agent. A specification for bentonite is 
contained in the Food Chemicals Codex (FCC). 
19 Specific References 
1 Stul MS, Vliers DP, Uytterhoven JB. In vitro adsorption-desorption 
of phenethylamines and phenylimidazoles by a bentonite and a 
resin. J Pharm Sci 1984; 73: 1372–1375. 
2 Shrivastava R, Jain SR, Frank SG. Dissolution dialysis studies of 
metronidazole–montmorillonite adsorbates. J Pharm Sci 1985; 74: 
214–216. 
3 Forni F, Iannuccelli V, Coppi G, Bernabei MT. Effect of 
montmorillonite on drug release from polymeric matrices. Arch 
Pharm 1989; 322: 789–793. 
4 Listinsky JJ, Bryant RG. Gastrointestinal contrast agents: a 
diamagnetic approach. Magn Reson Med 1988; 8(3): 285–292. 
5 Ponampalam R, Otten EJ. In vitro adsorption of lithium by 
bentonite. Singapore Med J 2002; 43(2): 86–89. 
6 Callahan JC, Cleary GW, Elefant M, et al. Equilibrium moisture 
content of pharmaceutical excipients. Drug Dev Ind Pharm 1982; 
8: 355–369. 
7 Harris WA. The inactivation of cationic antiseptics by bentonite 
suspensions. Aust J Pharm 1961; 42: 583–588. 
8 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 351. 
20 General References 
Altagracia M, Ford I, Garzon ML, Kravzov J. A comparative 
mineralogical and physico-chemical study of some crude Mexican 
and pharmaceutical grade montmorillonites. Drug Dev Ind Pharm 
1987; 13: 2249–2262. 
Sadik F, Fincher JH, Hartman CW. X-Ray diffraction analysis for 
identification of kaolin NF and bentonite USP. J Pharm Sci 1971; 
60: 916–918. 
21 Authors 
A Palmieri. 
22 Date of Revision 
8 August 2005. 
60 Bentonite

Benzalkonium Chloride 
1 Nonproprietary Names 
BP: Benzalkonium chloride 
JP: Benzalkonium chloride 
PhEur: Benzalkonii chloridum 
USPNF: Benzalkonium chloride 
2 Synonyms 
Alkylbenzyldimethylammonium chloride; alkyl dimethyl benzyl 
ammonium chloride; BKC; Hyamine 3500; Pentonium; 
Zephiran. 
3 Chemical Name and CAS Registry Number 
Alkyldimethyl(phenylmethyl)ammonium chloride [8001-54-5] 
4 Empirical Formula and Molecular Weight 
The USPNF 23 describes benzalkonium chloride as a mixture of 
alkylbenzyldimethylammonium chlorides of the general formula 
[C6H5CH2N(CH3)2R]Cl, where R represents a mixture 
of alkyls, including all or some of the group beginning with 
n-C8H17 and extending through higher homologs, with 
n-C12H25, n-C14H29, and n-C16H33 comprising the major 
portion. 
The average molecular weight of benzalkonium chloride is 
360. 
5 Structural Formula 
R = mixture of alkyls: n-C8H17 to n-C18H37; mainly 
n-C12H25 (dodecyl), n-C14H29 (tetradecyl), and n-C16H33 
(hexadecyl). 
6 Functional Category 
Antimicrobial preservative; antiseptic; disinfectant; solubilizing 
agent; wetting agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Benzalkonium chloride is a quaternary ammonium compound 
used in pharmaceutical formulations as an antimicrobial 
preservative in applications similar to other cationic surfactants, 
such as cetrimide. 
In ophthalmic preparations, benzalkonium chloride is one 
of the most widely used preservatives,(1) at a concentration of 
0.01–0.02% w/v. Often it is used in combination with other 
preservatives or excipients, particularly 0.1% w/v disodium 
edetate, to enhance its antimicrobial activity against strains of 
Pseudomonas. 
In nasal,(2) and otic formulations a concentration of 
0.002–0.02% w/v is used, sometimes in combination with 
0.002–0.005% w/v thimerosal. Benzalkonium chloride 0.01% 
w/v is also employed as a preservative in small-volume 
parenteral products. Benzalkonium chloride was also shown 
to enhance the topical penetration of lorazepam.(3) 
Benzalkonium chloride is additionally used as a preservative 
in cosmetics. 
8 Description 
Benzalkonium chloride occurs as a white or yellowish-white 
amorphous powder, a thick gel, or gelatinous flakes. It is 
hygroscopic, soapy to the touch, and has a mild aromatic odor 
and very bitter taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for benzalkonium chloride. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters . . — 
Acidity or alkalinity — . — 
Appearance of 
solution 
. . — 
Water 415.0% 410.0% 415.0% 
Residue on ignition 40.2% — 42.0% 
Sulfated ash — 40.1% — 
Water-insoluble 
matter 
— — . 
Foreign amines — . . 
Ratio of alkyl 
components 
— — . 
Petroleum ethersoluble 
substances 
41.0% — — 
Assay (dried basis) 
of n-C12H25 — — 540.0% 
of n-C14H29 — — 520.0% 
of n-C12H25 and 
n-C14H29 
— — 570.0% 
for total alkyl 
content 
95.0–105.0% 95.0–104.0% 97.0–103.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 5–8 for a 10% w/v aqueous solution.

Antimicrobial activity: benzalkonium chloride solutions are 
active against a wide range of bacteria, yeasts, and fungi. 
Activity is more marked against Gram-positive than Gramnegative 
bacteria and minimal against bacterial endospores 
and acid-fast bacteria, see Table II. The antimicrobial 
activity of benzalkonium chloride is significantly dependent 
upon the alkyl composition of the homolog mixture.(4) 
Benzalkonium chloride is ineffective against some Pseudomonas 
aeruginosa strains, Mycobacterium tuberculosis, 
Trichophyton interdigitale, and T. rubrum. However, 
combined with disodium edetate (0.01–0.1% w/v), benzyl 
alcohol, phenylethanol, or phenylpropanol, the activity 
against Pseudomonas aeruginosa is increased.(5) Antimicrobial 
activity may also be enhanced by the addition of 
phenylmercuric acetate, phenylmercuric borate, chlorhexidine, 
cetrimide, or m-cresol.(6,7) In the presence of citrate 
and phosphate buffers (but not borate), activity against 
Pseudomonas can be reduced. See also Sections 11 and 12. 
Benzalkonium chloride is relatively inactive against spores 
and molds, but is active against some viruses, including 
HIV.(8) Inhibitory activity increases with pH, although 
antimicrobial activity occurs at pH 4–10. 
Table II: Minimum inhibitory concentrations (MICs) of benzalkonium 
chloride. 
Microorganism MIC (mg/mL) 
Aerobacter aerogenes 64 
Clostridium histolyticum 5 
Clostridium oedematiens 5 
Clostridium tetani 5 
Clostridium welchii 5 
Escherichia coli 16 
Pneumococcus II 5 
Proteus vulgaris 64 
Pseudomonas aeruginosa 30 
Salmonella enteritidis 30 
Salmonella paratyphi 16 
Salmonella typhosa 4 
Shigella dysenteriae 2 
Staphylococcus aureus 1.25 
Streptococcus pyrogenes 1.25 
Vibrio cholerae 2 
Density: 0.98 g/cm3 at 208C 
Melting point: 408C 
Partition coefficients: the octanol : water partition coefficient 
varies with the alkyl chain length of the homolog; 9.98 for 
C12, 32.9 for C14, and 82.5 for C16. 
Solubility: practically insoluble in ether; very soluble in acetone, 
ethanol (95%), methanol, propanol, and water. Aqueous 
solutions of benzalkonium chloride foam when shaken, 
have a low surface tension and possess detergent and 
emulsifying properties. 
11 Stability and Storage Conditions 
Benzalkonium chloride is hygroscopic and may be affected by 
light, air, and metals. 
Solutions are stable over a wide pH and temperature range 
and may be sterilized by autoclaving without loss of effectiveness. 
Solutions may be stored for prolonged periods at room 
temperature. Dilute solutions stored in polyvinyl chloride or 
polyurethane foam containers may lose antimicrobial activity. 
The bulk material should be stored in an airtight container, 
protected from light and contact with metals, in a cool, dry 
place. 
12 Incompatibilities 
Incompatible with aluminum, anionic surfactants, citrates, 
cotton, fluorescein, hydrogen peroxide, hypromellose,(9) 
iodides, kaolin, lanolin, nitrates, nonionic surfactants in high 
concentration, permanganates, protein, salicylates, silver salts, 
soaps, sulfonamides, tartrates, zinc oxide, zinc sulfate, some 
rubber mixes, and some plastic mixes. 
Benzalkonium chloride has been shown to be adsorbed to 
various filtering membranes, especially those that are hydrophobic 
or anionic.(10) 
13 Method of Manufacture 
Benzalkonium chloride is formed by the reaction of a solution 
of N-alkyl-N-methylbenzamine with methyl chloride in an 
organic solvent suitable for precipitating the quaternary 
compound as it is formed. 
14 Safety 
Benzalkonium chloride is usually nonirritating, nonsensitizing, 
and is well tolerated in the dilutions normally employed on the 
skin and mucous membranes. However, benzalkonium chloride 
has been associated with adverse effects when used in some 
pharmaceutical formulations.(11) 
Ototoxicity can occur when benzalkonium chloride is 
applied to the ear(12) and prolonged contact with the skin can 
occasionally cause irritation and hypersensitivity. Benzalkonium 
chloride is also known to cause bronchoconstriction 
in some asthmatics when used in nebulizer solutions.(13–17) 
Toxicity experiments with rabbits have shown benzalkonium 
chloride to be harmful to the eye in concentrations 
higher than that normally used as a preservative. However, the 
human eye appears to be less affected than the rabbit eye and 
many ophthalmic products have been formulated with benzalkonium 
chloride 0.01% w/v as the preservative. 
Benzalkonium chloride is not suitable for use as a 
preservative in solutions used for storing and washing 
hydrophilic soft contact lenses, as the benzalkonium chloride 
can bind to the lenses and may later produce ocular toxicity 
when the lenses are worn.(18) Solutions stronger than 0.03% 
w/v concentration entering the eye require prompt medical 
attention. 
Local irritation of the throat, esophagus, stomach, and 
intestine can occur following contact with strong solutions 
(>0.1% w/v). The fatal oral dose of benzalkonium chloride in 
humans is estimated to be 1–3 g. Adverse effects following oral 
ingestion include vomiting, collapse, and coma. Toxic doses 
lead to paralysis of the respiratory muscles, dyspnea, and 
cyanosis. 
LD50 (mouse, oral): 150 mg/kg(19) 
LD50 (rat, IP): 14.5 mg/kg 
LD50 (rat, IV): 13.9 mg/kg 
LD50 (rat, oral): 300 mg/kg 
LD50 (rat, skin): 1.42 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Benzalkonium chloride is 
62 Benzalkonium Chloride

irritant to the skin and eyes and repeated exposure to the skin 
may cause hypersensitivity. Concentrated benzalkonium chloride 
solutions accidentally spilled on the skin may produce 
corrosive skin lesions with deep necrosis and scarring, and 
should be washed immediately with water, followed by soap 
solutions applied freely. Gloves, eye protection, and suitable 
protective clothing should be worn. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (inhalations, 
IM injections, nasal, ophthalmic, otic, and topical preparations). 
Included in nonparenteral medicines licensed in the UK. 
It is also included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Benzethonium chloride; cetrimide. 
18 Comments 
Benzalkonium chloride has been used in antiseptic wipes and 
has been shown to produce significantly less stinging or burning 
than isopropyl alcohol and hydrogen peroxide.(20) The 
EINECS numbers for benzalkonium chloride are 264-151-6; 
260-080-8; 269-919-4; 270-325-2; 287-089-1. 
19 Specific References 
1 Sklubalova Z. Antimicrobial substances in ophthalmic drops. 
Ceska Slov Form 2004; 53(3): 107–116. 
2 Pisal SS, Poradkar AR, Mahadik KR, Kadam SS. Pluronic gels for 
nasal delivery of vitamin B. Int J Pharm 2004; 270(1–2): 37–45. 
3 Nokodchi A, Shokri J, Dashbolaphi A, et al. The enhancement 
effect of surfactants in the penetration of lorazepam through rat 
skin. Int J Pharm 2003; 250(2): 359–369. 
4 Euerby MR. High performance liquid chromatography of 
benzalkonium chlorides – variation in commercial preparations. 
J Clin Hosp Pharm 1985; 10: 73–77. 
5 Richards RME, McBride RJ. Enhancement of benzalkonium 
chloride and chlorhexidine acetate activity against Pseudomonas 
aeruginosa by aromatic alcohols. J Pharm Sci 1973; 62: 2035– 
2037. 
6 Hugbo PG. Additivity and synergism in vitro as displayed by 
mixtures of some commonly employed antibacterial preservatives. 
Can J Pharm Sci 1976; 11: 17–20. 
7 McCarthy TJ, Myburgh JA, Butler N. Further studies on the 
influence of formulation on preservative activity. Cosmet Toilet 
1977; 92(3): 33–36. 
8 Chermann JC, Barre-Sinoussi F, Henin Y, Marechal V. HIV 
inactivation by a spermicide containing benzalkonium. AIDS 
Forsch 1987; 2: 85–86. 
9 Richards RME. Effect of hypromellose on the antibacterial activity 
of benzalkonium chloride. J Pharm Pharmacol 1976; 28: 264. 
10 Bin T, Kulshreshtha AK, Al-Shakhshir R, Hem SL. Adsorption of 
benzalkonium chloride by filter membranes: mechanisms and 
effect of formulation and processing parameters. Pharm Dev 
Technol 1999; 4(2): 151–165. 
11 Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 31–39. 
12 Honigman JL. Disinfectant ototoxicity [letter]. Pharm J 1975; 215: 
523. 
13 Beasley CRW, Rafferty P, Holgate ST. Bronchoconstrictor properties 
of preservatives in ipratropium bromide (Atrovent) nebuliser 
solution. Br Med J 1987; 294: 1197–1198. 
14 Miszkiel KA, Beasley R, Rafferty P, Holgate ST. The contribution 
of histamine release to bronchoconstriction provoked by inhaled 
benzalkonium chloride in asthma. Br J Clin Pharmacol 1988; 25: 
157–163. 
15 Miszkiel KA, Beasley R, Holgate ST. The influence of ipratropium 
bromide and sodium cromoglycate on benzalkonium chlorideinduced 
bronchoconstriction in asthma. Br J Clin Pharmacol 
1988; 26: 295–301. 
16 Worthington I. Bronchoconstriction due to benzalkonium chloride 
in nebulizer solutions. Can J Hosp Pharm 1989; 42: 165–166. 
17 Boucher M, Roy MT, Henderson J. Possible association of 
benzalkonium chloride in nebulizer solutions with respiratory 
arrest. Ann Pharmacother 1992; 26: 772–774. 
18 Gasset AR. Benzalkonium chloride toxicity to the human cornea. 
Am J Ophthalmol 1977; 84: 169–171. 
19 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 104. 
20 Pagnoni A, Spinelli G, Berger RS, et al. Lack of burning and 
stinging from a novel first-aid formulation applied to experimental 
wounds. J Cosmet Sci 2004; 55(2): 157–162. 
20 General References 
Cowen RA, Steiger B. Why a preservative system must be tailored to a 
specific product. Cosmet Toilet 1977; 92(3): 15–20. 
El-Falaha BMA, Rogers DT, Furr JR, Russell AD. Surface changes in 
Pseudomonas aeruginosa exposed to chlorhexidine diacetate and 
benzalkonium chloride. Int J Pharm 1985; 23: 239–243. 
El-Falaha BMA, Russell AD, Furr JR, Rogers DT. Activity of 
benzalkonium chloride and chlorhexidine diacetate against wildtype 
and envelope mutants of Escherichia coli and Pseudomonas 
aeruginosa. Int J Pharm 1985; 25: 329–337. 
Karabit MS, Juneskans OT, Lundgren P. Studies on the evaluation of 
preservative efficacy III: the determination of antimicrobial characteristics 
of benzalkonium chloride. Int J Pharm 1988; 46: 141– 
147. 
Lien EJ, Perrin JH. Effect of chain length on critical micelle formation 
and protein binding of quaternary ammonium compounds. J Med 
Chem 1976; 19: 849–850. 
Martin AR. Anti-infective agents. In: Doerge RF, ed. Wilson and 
Gisvold’s Textbook of Organic, Medicinal and Pharmaceutical 
Chemistry. Philadelphia: JB Lippincott, 1982: 141–142. 
Pense. AM, Vauthier C, Puisieux F, Benoit JP. Microencapsulation of 
benzalkonium chloride. Int J Pharm 1992; 81: 111–117. 
Prince HN, Nonemaker WS, Norgard RC, Prince DL. Drug resistance 
studies with topical antiseptics. J Pharm Sci 1978; 67: 1629–1631. 
Wallha. usser KH. Benzalkonium chloride. In: Kabara JJ, ed. Cosmetic 
and Drug Preservation Principles and Practice. New York: Marcel 
Dekker, 1984: 731–734. 
21 Authors 
AH Kibbe. 
22 Date of Revision 
12 August 2005. 
Benzalkonium Chloride 63

Benzethonium Chloride 
1 Nonproprietary Names 
BP: Benzethonium chloride 
JP: Benzethonium chloride 
PhEur: Benzethonii chloridum 
USP: Benzethonium chloride 
2 Synonyms 
Benzyldimethyl-[2-[2-(p-1,1,3,3-tetramethylbutylphenoxy) 
ethoxy]ethyl]ammonium chloride; BZT; diisobutylphenoxyethoxyethyl 
dimethyl benzyl ammonium chloride; Hyamine 
1622. 
3 Chemical Name and CAS Registry Number 
N,N-Dimethyl-N-[2-[2-[4-(1,1,3,3-tetramethylbutyl)phenoxy] 
ethoxy]ethyl]benzene-methanaminium chloride [121-54-0] 
4 Empirical Formula and Molecular Weight 
C27H42ClNO2 448.10 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; antiseptic; disinfectant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Benzethonium chloride is a quaternary ammonium compound 
used in pharmaceutical formulations as an antimicrobial 
preservative. Typically, it is used for this purpose in injections, 
ophthalmic and otic preparations at concentrations 
0.01–0.02% w/v. Benzethonium chloride may also be used as 
a wetting and solubilizing agent, and as a topical disinfectant. 
In cosmetics such as deodorants, benzethonium chloride 
may be used as an antimicrobial preservative in concentrations 
up to 0.5% w/v. 
The physical properties and applications of benzethonium 
chloride are similar to those of other cationic surfactants such 
as cetrimide. 
8 Description 
Benzethonium chloride occurs as a white crystalline material 
with a mild odor and very bitter taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for benzethonium chloride. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters — . — 
Appearance of 
solution 
— . — 
Acidity or alkalinity — . — 
Melting range 158–1648C 158–1648C 158–1638C 
Loss on drying 45.0% 45.0% 45.0% 
Residue on ignition 40.1% — 40.1% 
Sulfated ash — 40.1% — 
Ammonium 
compounds 
. 450 ppm . 
Assay (dried basis) 597.0% 97.0–103.0% 97.0–103.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 4.8–5.5 for a 1% w/v aqueous 
solution. 
Antimicrobial activity: optimum antimicrobial activity occurs 
between pH 4–10. Preservative efficacy is enhanced by 
ethanol and reduced by soaps and other anionic surfactants. 
For typical minimum inhibitory concentrations (MICs) see 
Table II.(1) 
Table II: Minimum inhibitory concentration (MIC) for benzethonium 
chloride. 
Microorganism MIC (mg/mL) 
Aspergillus niger 128 
Candida albicans 64 
Escherichia coli 32 
Penicillium notatum 64 
Proteus vulgaris 64 
Pseudomonas aeruginosa 250 
Pseudomonas cepacia 250 
Pseudomonas fluorescens 250 
Staphylococcus aureus 0.5 
Streptococcus pyogenes 0.5 
Solubility: soluble 1 in less than 1 of acetone, chloroform, 
ethanol (95%), and water; soluble 1 in 6000 of ether. 
Dissolves in water to produce a foamy, soapy solution. 
11 Stability and Storage Conditions 
Benzethonium chloride is stable. Aqueous solutions may be 
sterilized by autoclaving. 
The bulk material should be stored in an airtight container 
protected from light, in a cool, dry place.

12 Incompatibilities 
Benzethonium chloride is incompatible with soaps and other 
anionic surfactants and may be precipitated from solutions 
greater than 2% w/v concentration by the addition of mineral 
acids and some salt solutions. 
13 Method of Manufacture 
p-Diisobutylphenol is condensed in the presence of a basic 
catalyst with b,b0-dichlorodiethyl ether to yield 2-[2-[4- 
(1,1,3,3-tetramethylbutyl)phenoxy]ethoxy]ethyl chloride. 
Alkaline dimethylamination then produces the corresponding 
tertiary amine which, after purification by distillation, is 
dissolved in a suitable organic solvent and treated with benzyl 
chloride to precipitate benzethonium chloride.(2) 
14 Safety 
Benzethonium chloride is readily absorbed and is generally 
regarded as a toxic substance when administered orally. 
Ingestion may cause vomiting, collapse, convulsions, and 
coma. The probable lethal human oral dose is estimated to be 
50–500 mg/kg body-weight. 
The topical use of solutions containing greater than 5% w/v 
benzethonium chloride can cause irritation although benzethonium 
chloride is not regarded as a sensitizer. The use of 0.5% 
w/v benzethonium chloride in cosmetics is associated with few 
adverse effects. A maximum concentration of 0.02% w/v 
benzethonium chloride is recommended for use in cosmetics 
used in the eye area and this is also the maximum concentration 
generally used in pharmaceutical formulations such as injections 
and ophthalmic preparations.(3) 
See also Benzalkonium Chloride. 
LD50 (mouse, IP): 15.5 mg/kg(4) 
LD50 (mouse, IV): 30 mg/kg 
LD50 (mouse, oral): 338 mg/kg 
LD50 (rat, IP): 16.5 mg/kg 
LD50 (rat, IV): 19 mg/kg 
LD50 (rat, oral): 368 mg/kg 
LD50 (rat, SC): 119 mg/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IM and IV 
injections, ophthalmic and otic preparations). Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Benzalkonium chloride; cetrimide. 
18 Comments 
Benzethonium chloride has been used therapeutically as a 
disinfectant and topical anti-infective agent. However, its use in 
these applications has largely been superseded by other more 
effective antimicrobials and it is now largely used solely as a 
preservative in a limited number of pharmaceutical and 
cosmetic formulations. 
The EINECS number for benzethonium chloride is 204- 
479-9. 
19 Specific References 
1 Wallha. usser KH. Benzethonium chloride. In: Kabara JJ, ed. 
Cosmetic and Drug Preservation Principles and Practice. New 
York: Marcel Dekker, 1984: 734–735. 
2 Gennaro AR, ed. Remington: The Science and Practice of 
Pharmacy, 20th edn. Baltimore: Lippincott Williams and Wilkins, 
2000: 1508. 
3 The Expert Panel of the American College of Toxicology. Final 
report on the safety assessment of benzethonium chloride and 
methylbenzethonium chloride. J AmColl Toxicol 1985; 4: 65–106. 
4 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 407. 
20 General References 
—
21 Authors 
LME McIndoe. 
22 Date of Revision 
12 August 2005. 
Benzethonium Chloride 65

Benzoic Acid 
1 Nonproprietary Names 
BP: Benzoic acid 
JP: Benzoic acid 
PhEur: Acidum benzoicum 
USP: Benzoic acid 
2 Synonyms 
Benzenecarboxylic acid; benzeneformic acid; carboxybenzene; 
dracylic acid; E210; phenylcarboxylic acid; phenylformic acid. 
3 Chemical Name and CAS Registry Number 
Benzoic acid [65-85-0] 
4 Empirical Formula and Molecular Weight 
C7H6O2 122.12 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; therapeutic agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Benzoic acid is widely used in cosmetics, foods, and pharmaceuticals 
(see Table I), as an antimicrobial preservative.(1–3) 
Greatest activity is seen at pH values between 2.5–4.5; see 
Section 10. 
Benzoic acid also has a long history of use as an antifungal 
agent(4) in topical therapeutic preparations such as Whitfield’s 
ointment (benzoic acid 6% and salicylic acid 3%). 
Table I: Uses of benzoic acid. 
Use Concentration (%) 
IM and IV injections 0.17 
Oral solutions 0.01–0.1 
Oral suspensions 0.1 
Oral syrups 0.15 
Topical preparations 0.1–0.2 
Vaginal preparations 0.1–0.2 
8 Description 
Benzoic acid occurs as feathery, light, white or colorless crystals 
or powder. It is essentially tasteless and odorless or with a slight 
characteristic odor suggestive of benzoin. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for benzoic acid. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters — . — 
Congealing range 121–1248C 121–1248C 121–1238C 
Water 40.5% — 40.7% 
Residue on ignition 40.05% 40.1% 40.05% 
Readily carbonizable 
substances 
. . . 
Readily oxidizable 
substances 
. . . 
Heavy metals 420 ppm 410 ppm 410 ppm 
Halogenated 
compounds and 
halides 
. 4300 ppm — 
Appearance of solution — . — 
Assay 599.5% 99.0–100.5% 99.5–100.5% 
10 Typical Properties 
Acidity/alkalinity: pH = 2.8 (saturated aqueous solution at 
258C) 
Antimicrobial activity: only the undissociated acid shows 
antimicrobial properties, the activity therefore depends on 
the pH of the medium. Optimum activity occurs at pH 
values below 4.5; at values above pH 5, benzoic acid is 
almost inactive.(5) It has been reported that antimicrobial 
activity is enhanced by the addition of protamine, a basic 
protein.(6) 
Bacteria: moderate bacteriostatic activity against most 
species of Gram-positive bacteria. Typical MIC is 
100 mg/mL. Activity is less, in general, against Gramnegative 
bacteria. MIC for Gram-negative bacteria may be 
up to 1600 mg/mL. 
Molds: moderate activity. Typical MICs are 
400–1000 mg/mL at pH 3; 1000–2000 mg/mL at pH 5. 
Spores: inactive against spores. 
Yeasts: moderate activity. Typical MIC is 1200 mg/mL. The 
addition of propylene glycol may enhance the fungistatic 
activity of benzoic acid. 
Autoignition temperature: 5708C 
Boiling point: 249.28C 
Density: 
1.311 g/cm3 for solid at 248C; 
1.075 g/cm3 for liquid at 1308C. 
Dissociation constant: the dissociation of benzoic acid in mixed 
solvents is dictated by specific solute–solvent interactions as

well as by relative solvent basicity. Increasing the organic 
solvent fraction favors the free acid form.(7) 
pKa = 4.19 at 258C; 
pKa = 5.54 in methanol 60%. 
Flash point: 121–1318C 
Melting point: 1228C (begins to sublime at 1008C). 
Moisture content: 0.17–0.42% w/w 
Partition coefficients: 
Benzene : water = 0.0044;(8) 
Cyclohexane : water = 0.30;(9) 
Octanol : water = 1.87.(10) 
Refractive index: 
nD
15 = 1.5397 for solid; 
nD
132 = 1.504 for liquid. 
Solubility: apparent aqueous solubility of benzoic acid may be 
enhanced by the addition of citric acid or sodium acetate to 
the solution; see Table III. 
Table III: Solubility of benzoic acid. 
Solvent Solubility at 258C unless otherwise stated 
Acetone 1 in 2.3 
Benzene 1 in 9.4 
Carbon disulfide 1 in 30 
Carbon tetrachloride 1 in 15.2 
Chloroform 1 in 4.5 
Cyclohexane 1 in 14.6(9) 
Ethanol 1 in 2.7 at 158C 
1 in 2.2 
Ethanol (76%) 1 in 3.72(11) 
Ethanol (54%) 1 in 6.27(11) 
Ethanol (25%) 1 in 68(11) 
Ether 1 in 3 
Fixed oils Freely soluble 
Methanol 1 in 1.8 
Toluene 1 in 11 
Water 1 in 300 
11 Stability and Storage Conditions 
Aqueous solutions of benzoic acid may be sterilized by 
autoclaving or by filtration. 
A 0.1% w/v aqueous solution of benzoic acid has been 
reported to be stable for at least 8 weeks when stored in 
polyvinyl chloride bottles, at room temperature.(12) 
When added to a suspension, benzoic acid dissociates, with 
the benzoate anion adsorbing onto the suspended drug 
particles. This adsorption alters the charge at the surface of 
the particles, which may in turn affect the physical stability of 
the suspension.(13) 
The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Undergoes typical reactions of an organic acid, e.g. with alkalis 
or heavy metals. Preservative activity may be reduced by 
interaction with kaolin.(14) 
13 Method of Manufacture 
Although benzoic acid occurs naturally, it is produced 
commercially by several synthetic methods. One process 
involves the continuous liquid-phase oxidation of toluene in 
the presence of a cobalt catalyst at 150–2008C and 
0.5–5.0MPa (5.0–50.0 atm) pressure to give a yield of 
approximately 90% benzoic acid. 
Benzoic acid can also be produced commercially from 
benzotrichloride or phthalic anhydride. Benzotrichloride, 
produced by chlorination of toluene, is reacted with 1 mole 
of benzoic acid to yield 2 moles of benzoyl chloride. The 
benzoyl chloride is then converted to 2 moles of benzoic acid by 
hydrolysis. Yield is 75–80%. 
In another commercial process, phthalic anhydride is 
converted to benzoic acid, in about an 85% yield, by hydrolysis 
in the presence of heat and chromium and disodium phthalates. 
Crude benzoic acid is purified by sublimation or recrystallization. 
14 Safety 
Ingested benzoic acid is conjugated with glycine in the liver to 
yield hippuric acid, which is then excreted in the urine;(15) care 
should be taken when administering benzoic acid to patients 
with chronic liver disease.(16) Benzoic acid is a gastric irritant, 
and a mild irritant to the skin.(17–19) It is also a mild irritant to 
the eyes and mucous membranes.(20) Allergic reactions to 
benzoic acid have been reported, although a controlled study 
indicated that the incidence of urticaria in patients given 
benzoic acid is no greater than in those given a lactose 
placebo.(21) 
The WHO acceptable daily intake of benzoic acid and other 
benzoates, calculated as benzoic acid, has been set at up to 
5 mg/kg body-weight.(22,23) The minimum lethal human oral 
dose of benzoic acid is 500 mg/kg body-weight.(24) 
LD50 (cat, oral): 2 g/kg(24) 
LD50 (dog, oral): 2 g/kg 
LD50 (mouse, IP): 1.46 g/kg 
LD50 (mouse, oral): 1.94 g/kg 
LD50 (rat, oral): 1.7 g/kg 
See also Sodium benzoate. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Benzoic acid may be harmful 
by inhalation, ingestion, or skin absorption and may be irritant 
to the eyes, skin, and mucous membranes. Benzoic acid should 
be handled in a well-ventilated environment; eye protection, 
gloves, and a dust mask or respirator are recommended. 
Benzoic acid is flammable. 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (IM and IV injections, 
irrigation solutions, oral solutions, suspensions, syrups and 
tablets, rectal, topical, and vaginal preparations). Included in 
nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Potassium benzoate; sodium benzoate. 
18 Comments 
Benzoic acid is known to dimerize in many nonpolar solvents. 
This property, coupled with pH-dependent dissociation in 
Benzoic Acid 67

aqueous media, comprises a classic textbook example of the 
effects of dissociation and molecular association on apparent 
partitioning behavior. The principles involved may be practically 
applied in determination of the total concentration of 
benzoate necessary to provide a bacteriostatic level of benzoic 
acid in the aqueous phase of an oil-in-water emulsion. 
A specification for benzoic acid is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for benzoic acid is 200-618-2. 
19 Specific References 
1 Buzzi MM, Marth EH. Characteristics of sodium benzoate injury 
of Listeria monocytogenes. Microbios 1992; 700: 199–207. 
2 Elder DJ, Kelly DJ. The bacterial degradation of benzoic acid and 
benzenoid compounds under anaerobic conditions: unifying trends 
and new perspectives. FEMS Microbiol Rev 1994; 13(4): 441–468. 
3 Hwang CA, Beuchat LR. Efficacy of a lactic acid/sodium benzoate 
wash solution in reducing bacterial contamination in raw chicken. 
Int J Food Microbiol 1995; 27(1): 91–98. 
4 Burlini N, Pellegrine R, Facheris P, et al. Metabolic effects of 
benzoate and sorbate in the yeast Saccharomyes cerevisiae at 
neutral pH. Arch Microbiol 1993; 159(3): 220–224. 
5 Hurwitz SJ, McCarthy TJ. The effect of pH and concentration on 
the rates of kill of benzoic acid solutions against E. coli. J Clin 
Pharm Ther 1987; 12: 107–115. 
6 Boussard P, Devleeschouwer MJ, Dony J. In vitro modification of 
antimicrobial efficacy by protamine. Int J Pharm 1991; 72: 51–55. 
7 Ghosh SK, Hazra DK. Solvent effects on the dissociation of 
benzoic acid in aqueous mixtures of 2-methoxyethanol and 1,2- 
dimethoxyethane at 258C. J Chem Soc Perkin Trans 1989; 2: 
1021–1024. 
8 Pawlowski W, Wieckowska E. Hydration of benzoic acid in 
benzene solution II: calculation of hydration constant. Z Phys 
Chem 1990; 168: 205–215. 
9 Dearden JC, Roberts MJ. Cyclohexane–water partition coefficients 
of some pharmaceuticals. J Pharm Pharmacol 1989; 41: 
102P. 
10 Yalkowsky SH, Valvani SC, Roseman TJ. Solubility and partitioning 
VI: octanol solubility and octanol–water partition coefficients. 
J Pharm Sci 1983; 72: 866–870. 
11 Pal A, Lahiri SC. Solubility and the thermodynamics of transfer of 
benzoic acid in mixed solvents. Indian J Chem 1989; 28A: 276– 
279. 
12 The Pharmaceutical Society of Great Britain, Department of 
Pharmaceutical Sciences. Plastic medicine bottles of rigid PVC. 
Pharm J 1973; 210: 100. 
13 Gallardo V, Salcedo J, Parera A, Delgado A. Effect of the 
preservatives antipyrin, benzoic acid and sodium metabisulfite 
on properties of the nitrofurantoin/solution interface. Int J Pharm 
1991; 71: 223–227. 
14 Clarke CD, Armstrong NA. Influence of pH on the adsorption of 
benzoic acid by kaolin. Pharm J 1972; 209: 44–45. 
15 Tremblay GC, Qureshi IA. The biochemistry and toxicology of 
benzoic acid metabolism and its relationship to the elimination of 
waste nitrogen. Pharmacol Ther 1993; 60(1): 63–90. 
16 Yamada S, Yamamota T, Suou T, et al. Clinical significance of 
benzoate-metabolizing capacity in patients with chronic liver 
disease: pharmacokinetic analysis. Res Commun Chem Pathol 
Pharmacol 1992; 76(1): 53–62. 
17 Downward CE, Roberts LJ, Morrow JD. Topical benzoic acid 
induces the increased biosynthesis of PGD2 in human skin in vivo. 
Clin Pharmacol Ther 1995; 57(4): 441–445. 
18 Lahti A, Pylvanen V, Hannuksels M. Immediate irritant reactions 
to benzoic acid are enhanced in washed skin areas. Contact 
Dermatitis 1996; 35(1): 51. 
19 Munoz FJ, Bellido J, Moyano JC, et al. Perioral contact urticaria 
from sodium benzoate in a toothpaste. Contact Dermatitis 1996; 
35(1): 51. 
20 Takeichi Y, Kimura T. Improvement of aqueous solubility and 
rectal absorption of 6-mercaptopurine by addition of sodium 
benzoate. Biol Pharm Bull 1994; 17(10): 1391–1394. 
21 Lahti A, Hannuksela M. Is benzoic acid really harmful in cases of 
atopy and urticaria? Lancet 1981; ii: 1055. 
22 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications. 
Seventeenth report of the joint FAO/WHO expert committee on 
food additives.World Health Organ Tech Rep Ser 1974; No. 539. 
23 FAO/WHO. Evaluation of certain food additives and contaminants. 
Twenty-seventh report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1983; No. 696. 
24 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 379. 
20 General References 
Garrett ER, Woods OR. The optimum use of acid preservatives in oil– 
water systems: benzoic acid in peanut oil–water. J Am Pharm Assoc 
(Sci) 1953; 42: 736–739. 
21 Authors 
PJ Weller. 
22 Date of Revision 
14 August 2005. 
68 Benzoic Acid

Benzyl Alcohol 
1 Nonproprietary Names 
BP: Benzyl alcohol 
JP: Benzyl alcohol 
PhEur: Alcohol benzylicus 
USPNF: Benzyl alcohol 
2 Synonyms 
Benzenemethanol; a-hydroxytoluene; phenylcarbinol; phenylmethanol; 
a-toluenol. 
3 Chemical Name and CAS Registry Number 
Benzenemethanol [100-51-6] 
4 Empirical Formula and Molecular Weight 
C7H8O 108.14 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; disinfectant; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Benzyl alcohol is an antimicrobial preservative used in 
cosmetics, foods, and a wide range of pharmaceutical 
formulations,(1–4) including oral and parenteral preparations, 
at concentrations up to 2.0% v/v. In cosmetics, concentrations 
up to 3.0% v/v may be used as a preservative. Concentrations 
of 5% v/v or more are employed as a solubilizer, while a 10% 
v/v solution is used as a disinfectant. 
Benzyl alcohol 10% v/v solutions also have some local 
anesthetic properties, which are exploited in some parenterals, 
cough products, ophthalmic solutions, ointments, and dermatological 
aerosol sprays. 
Although widely used as an antimicrobial preservative, 
benzyl alcohol has been associated with some fatal adverse 
reactions when administered to neonates. It is now recommended 
that parenteral products preserved with benzyl 
alcohol, or other antimicrobial preservatives, should not be 
used in newborn infants if at all possible; see Section 14. 
8 Description 
A clear, colorless, oily liquid with a faint aromatic odor and a 
sharp, burning taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for benzyl alcohol. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters . . — 
Solubility — . — 
Acidity . . . 
Clarity of solution . . — 
Specific gravity 1.043–1.053 1.043–1.049 1.042–1.047 
Distilling range 202.5–206.58C— — 
Refractive index 1.538–1.541 1.538–1.541 1.539–1.541 
Residue on ignition 40.005% — 40.005% 
Nonvolatile matter — 40.05% 41mg 
Chlorinated 
compounds 
. — 40.03% 
Benzaldehyde . . 40.2% 
Peroxide value — 45 — 
Organic volatile 
impurities 
— — . 
Assay 598.0% 98.0–100.5% 97.0–100.5% 
10 Typical Properties 
Acidity/alkalinity: aqueous solutions are neutral to litmus. 
Antimicrobial activity: benzyl alcohol is bacteriostatic and is 
used as an antimicrobial preservative against Gram-positive 
bacteria, molds, fungi, and yeasts, although it possesses only 
modest bactericidal properties. Optimum activity occurs at 
pH below 5; little activity is shown above pH 8. 
Antimicrobial activity is reduced in the presence of nonionic 
surfactants, such as polysorbate 80. However, the reduction 
in activity is less than is the case with either hydroxybenzoate 
esters or quaternary ammonium compounds. The 
activity of benzyl alcohol may also be reduced by 
incompatibilities with some packaging materials, particularly 
polyethylene; see Section 12. 
See Table II for reported minimum inhibitory concentrations 
(MICs). 
Table II: Minimum inhibitory concentrations (MICs) of benzyl 
alcohol.(4) 
Microorganism MIC (mg/mL) 
Aspergillus niger 5000 
Candida albicans 2500 
Escherichia coli 2000 
Pseudomonas aeruginosa 2000 
Staphylococcus aureus 25 
Bacteria: benzyl alcohol is moderately active against most 
Gram-positive organisms (typical MICs are 3–5 mg/mL), 
although some Gram-positive bacteria are very sensitive

(MICs 0.025–0.05 mg/mL). In general, benzyl alcohol is less 
active against Gram-negative organisms. 
Fungi: benzyl alcohol is effective against molds and yeasts; 
typical MICs are 3–5 mg/mL. 
Spores: benzyl alcohol is inactive against spores, but activity 
may be enhanced by heating. Benzyl alcohol 1% v/v, at pH 
5–6, has been claimed to be as effective as phenylmercuric 
nitrate 0.002% w/v against Bacillus stearothermophilus at 
1008C for 30 min. 
Autoignition temperature: 436.58C 
Boiling point: 204.78C 
Flammability: flammable. Limits in air 1.7–15.0% v/v. 
Flash point: 
100.68C (closed cup); 
104.58C (open cup). 
Freezing point: 158C 
Partition coefficients: 
Liquid paraffin : water = 0.2; 
Peanut oil : water = 1.3. 
Solubility: see Table III. 
Table III: Solubility of benzyl alcohol. 
Solvent Solubility at 208C unless otherwise stated 
Chloroform Miscible in all proportions 
Ethanol Miscible in all proportions 
Ethanol (50%) 1 in 2.5 
Ether Miscible in all proportions 
Fixed and volatile oils Miscible in all proportions 
Water 1 in 25 at 258C 
1 in 14 at 908C 
Surface tension: 38.8mN/m (38.8 dynes/cm) 
Vapor density (relative): 3.72 (air = 1) 
Vapor pressure: 
13.3 Pa (0.1 mmHg) at 308C; 
1.769 kPa (13.3 mmHg) at 1008C. 
Viscosity (dynamic): 6 mPa s (6 cP) at 208C 
11 Stability and Storage Conditions 
Benzyl alcohol oxidizes slowly in air to benzaldehyde and 
benzoic acid; it does not react with water. Aqueous solutions 
may be sterilized by filtration or autoclaving; some solutions 
may generate benzaldehyde during autoclaving. 
Benzyl alcohol may be stored in metal or glass containers. 
Plastic containers should not be used; exceptions to this include 
polypropylene containers or vessels coated with inert fluorinated 
polymers such as Teflon; see Section 12. 
Benzyl alcohol should be stored in an airtight container, 
protected from light, in a cool, dry place. 
12 Incompatibilities 
Benzyl alcohol is incompatible with oxidizing agents and strong 
acids. It can also accelerate the autoxidation of fats. 
Although antimicrobial activity is reduced in the presence of 
nonionic surfactants, such as polysorbate 80, the reduction is 
less than is the case with hydroxybenzoate esters or quaternary 
ammonium compounds. 
Benzyl alcohol is incompatible with methylcellulose and is 
only slowly sorbed by closures composed of natural rubber, 
neoprene, and butyl rubber closures, the resistance of which 
can be enhanced by coating with fluorinated polymers.(5) 
However, a 2% v/v aqueous solution in a polyethylene 
container, stored at 208C, may lose up to 15% of its benzyl 
alcohol content in 13 weeks.(6) Losses to polyvinyl chloride and 
polypropylene containers under similar conditions are usually 
negligible. Benzyl alcohol can damage polystyrene syringes by 
extracting some soluble components.(7) 
13 Method of Manufacture 
Benzyl alcohol is prepared commercially by the distillation of 
benzyl chloride with potassium or sodium carbonate. It may 
also be prepared by the Cannizzaro reaction of benzaldehyde 
and potassium hydroxide. 
14 Safety 
Benzyl alcohol is used in a wide variety of pharmaceutical 
formulations. It is metabolized to benzoic acid, which is further 
metabolized in the liver by conjugation with glycine to form 
hippuric acid, which is excreted in the urine. 
Ingestion or inhalation of benzyl alcohol may cause headache, 
vertigo, nausea, vomiting, and diarrhea. Overexposure 
may result in CNS depression and respiratory failure. However, 
the concentrations of benzyl alcohol normally employed as a 
preservative are not associated with such adverse effects. 
Reports of adverse reactions to benzyl alcohol(8,9) used as an 
excipient include toxicity following intravenous administration;(
10,11) neurotoxicity in patients administered benzyl 
alcohol in intrathecal preparations;(12) hypersensitivity,(13,14) 
although relatively rare; and a fatal toxic syndrome in 
premature infants.(15–17) 
The fatal toxic syndrome in low-birth-weight neonates, 
which includes symptoms of metabolic acidosis and respiratory 
depression, was attributed to the use of benzyl alcohol as a 
preservative in solutions used to flush umbilical catheters. As a 
result of this, the FDA has recommended that benzyl alcohol 
should not be used in such flushing solutions and has advised 
against the use of medicines containing preservatives in the 
newborn.(18,19) 
The WHO has set the estimated acceptable daily intake of 
the benzyl/benzoic moiety at up to 5 mg/kg body-weight 
daily.(20) 
LD50 (mouse, IV): 0.32 g/kg(21) 
LD50 (mouse, oral): 1.36 g/kg 
LD50 (rat, IP): 0.4 g/kg 
LD50 (rat, IV): 0.05 g/kg 
LD50 (rat, oral): 1.23 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Benzyl alcohol (liquid and 
vapor) is irritant to the skin, eyes, and mucous membranes. Eye 
protection, gloves, and protective clothing are recommended. 
Benzyl alcohol should be handled in a well-ventilated environment; 
a self-contained breathing apparatus is recommended in 
areas of poor ventilation. Benzyl alcohol is flammable. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (dental 
injections, oral capsules, solutions and tablets, topical, and 
vaginal preparations). Included in parenteral and nonparenteral 
medicines licensed in the UK. Included in the Canadian List 
of Acceptable Non-medicinal Ingredients. 
70 Benzyl Alcohol

17 Related Substances 
—
18 Comments 
The EINECS number for benzyl alcohol is 202-859-9. 
19 Specific References 
1 Croshaw B. Preservatives for cosmetics and toiletries. J Soc Cosmet 
Chem 1977; 28: 3–16. 
2 Karabit MS, Juneskans OT, Lundgren P. Studies on the evaluation 
of preservative efficacy II: the determination of antimicrobial 
characteristics of benzyl alcohol. J Clin Hosp Pharm 1986; 11: 
281–289. 
3 Shah AK, Simons KJ, Briggs CJ. Physical, chemical, and 
bioavailability studies of parenteral diazepam formulations containing 
propylene glycol and polyethylene glycol 400. Drug Dev 
Ind Pharm 1991; 17: 1635–1654. 
4 Wallha. usser KH. Benzyl alcohol. In: Kabara JJ, ed. Cosmetic and 
Drug Preservation Principles and Practice. New York: Marcel 
Dekker, 1984: 627–628. 
5 Royce A, Sykes G. Losses of bacteriostats from injections in 
rubber-closed containers. J Pharm Pharmacol 1957; 9: 814–823. 
6 Roberts MS, Polack AE, Martin G, Blackburn HD. The storage of 
selected substances in aqueous solution in polyethylene containers: 
the effect of some physicochemical factors on the disappearance 
kinetics of the substances. Int J Pharm 1979; 2: 295–306. 
7 Doull J, Klaassen CD, Amdur MO, eds. Casarett and Doull’s 
Toxicology: The Basic Science of Poisons. New York: Macmillan, 
1980. 
8 Reynolds RD. Nebulizer bronchitis induced by bacteriostatic 
saline [letter]. J Am Med Assoc 1990; 264: 35. 
9 Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 47–54. 
10 Evens RP. Toxicity of intravenous benzyl alcohol [letter]. Drug 
Intell Clin Pharm 1975; 9: 154–155. 
11 Lo. pez-Herce J, Bonet C, Meana A, Albajara L. Benzyl alcohol 
poisoning following diazepam intravenous infusion [letter]. Ann 
Pharmacother 1995; 29: 632. 
12 Hahn AF, Feasby TE, Gilbert JJ. Paraparesis following intrathecal 
chemotherapy. Neurology 1983; 33: 1032–1038. 
13 Grant JA, Bilodeau PA, Guernsey BG, Gardner FH. Unsuspected 
benzyl alcohol hypersensitivity [letter]. N Engl J Med 1982; 306: 
108. 
14 Wilson JP, Solimando DA, Edwards MS. Parenteral benzyl 
alcohol-induced hypersensitivity reaction. Drug Intell Clin Pharm 
1986; 20: 689–691. 
15 Brown WJ, Buist NRM, Cory Gipson HT, et al. Fatal benzyl 
alcohol poisoning in a neonatal intensive care unit [letter]. Lancet 
1982; i: 1250. 
16 Gershanik J, Boecler B, Ensley H, et al. The gasping syndrome and 
benzyl alcohol poisoning. N Engl J Med 1982; 307: 1384–1388. 
17 McCloskey SE, Gershanik JJ, Lertora JJL, et al. Toxicity of benzyl 
alcohol in adult and neonatal mice. J Pharm Sci 1986; 75: 702– 
705. 
18 Anonymous. Benzyl alcohol may be toxic to newborns. FDA Drug 
Bull 1982; 12: 10–11. 
19 Belson JJ. Benzyl alcohol questionnaire. Am J Hosp Pharm 1982; 
39: 1850, 1852. 
20 FAO/WHO. Evaluation of certain food additives. Twenty-third 
report of the joint FAO/WHO expert committee on food additives. 
World Health Organ Tech Rep Ser 1980; No. 648. 
21 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 398–399. 
20 General References 
Akers MJ. Considerations in selecting antimicrobial preservative agents 
for parenteral product development. Pharm Technol 1984; 8(5): 
36–40, 43, 44, 46. 
Bloomfield SF. Control of microbial contamination part 2: current 
problems in preservation. Br J Pharm Pract 1986; 8: 72, 74–76, 78, 
80. 
Carter DV, Charlton PT, Fenton AH, et al. The preparation and the 
antibacterial and antifungal properties of some substituted benzyl 
alcohols. J Pharm Pharmacol 1958; 10 (Suppl.): 149T–159T. 
Harrison SM, Barry BW, Dugard PH. Benzyl alcohol vapour diffusion 
through human skin: dependence on thermodynamic activity in the 
vehicle. J Pharm Pharmacol 1982; 34 (Suppl.): 36P. 
Russell AD, Jenkins J, Harrison IH. The inclusion of antimicrobial 
agents in pharmaceutical products. Adv Appl Microbiol 1967; 9: 1– 
38. 
Sklubalova Z. Antimicrobial substances in ophthalmic drops. Ceska 
Slov Form 2004; 53(3): 107–116. 
21 Authors 
E Cahill. 
22 Date of Revision 
15 August 2005. 
Benzyl Alcohol 71

Benzyl Benzoate 
1 Nonproprietary Names 
BP: Benzyl benzoate 
JP: Benzyl benzoate 
PhEur: Benzylis benzoas 
USP: Benzyl benzoate 
2 Synonyms 
Benzoic acid benzyl ester; benzylbenzenecarboxylate; benzyl 
phenylformate. 
3 Chemical Name and CAS Registry Number 
Benzoic acid phenylmethyl ester [120-51-4] 
4 Empirical Formula and Molecular Weight 
C14H12O2 212.24 
5 Structural Formula 
6 Functional Category 
Plasticizer; solubilizing agent; solvent; therapeutic agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Benzyl benzoate is used as a solubilizing agent and nonaqueous 
solvent in intramuscular injections at concentrations of 
0.01–46.0% v/v,(1) and as a solvent and plasticizer for cellulose 
and nitrocellulose. It is also used in the preparation of spraydried 
powders using nanocapsules.(2) 
However, the most widespread pharmaceutical use of benzyl 
benzoate is as a topical therapeutic agent in the treatment of 
scabies.(3) Benzyl benzoate is also used therapeutically as a 
parasiticide in veterinary medicine.(4) 
Other applications of benzyl benzoate include its use as a 
pediculicide and as a solvent and fixative for flavors and 
perfumes in cosmetics and food products. 
8 Description 
Benzyl benzoate is a clear, colorless, oily liquid with a slightly 
aromatic odor. It produces a sharp, burning sensation on the 
tongue. At temperatures below 178C it exists as clear, colorless 
crystals. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for benzyl benzoate. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters . . — 
Specific gravity 1.123 1.118–1.122 1.116–1.120 
Congealing 
temperature 
178C 517.08C 518.08C 
Boiling point 3238C 3208C — 
Refractive index 1.568–1.570 1.568–1.570 1.568–1.570 
Aldehyde — — 40.05% 
Acidity . . . 
Sulfated ash 40.05% 40.1% — 
Organic volatile 
impurities 
— — . 
Assay 599.0% 99.0–100.5% 99.0–100.5% 
10 Typical Properties 
Autoignition temperature: 4818C 
Boiling point: 3238C 
Flash point: 1488C 
Freezing point: 178C 
Refractive index: nD
21 = 1.5681 
Solubility: practically insoluble in glycerin and water; miscible 
with chloroform, ethanol (95%), ether, and with fatty acids 
and essential oils. 
Specific gravity: 1.12 
Vapor density (relative): 7.3 (air = 1) 
11 Stability and Storage Conditions 
Benzyl benzoate is stable when stored in tight, well-filled, lightresistant 
containers. Exposure to excessive heat (above 408C) 
should be avoided. 
12 Incompatibilities 
Benzyl benzoate is incompatible with alkalis and oxidizing 
agents. 
13 Method of Manufacture 
Benzyl benzoate is a constituent of Peru balsam and occurs 
naturally in certain plant species. Commercially, benzyl 
benzoate is produced synthetically by the dry esterification of 
sodium benzoate and benzoyl chloride in the presence of 
triethylamine or by the reaction of sodium benzylate with 
benzaldehyde.

14 Safety 
Benzyl benzoate is metabolized by rapid hydrolysis to benzoic 
acid and benzyl alcohol. Benzyl alcohol is then further 
metabolized to hippuric acid, which is excreted in the urine. 
Benzyl benzoate is widely used as a 25% v/v topical 
application in the treatment of scabies and as an excipient in 
intramuscular injections and oral products. Adverse reactions 
to benzyl benzoate include skin irritation and hypersensitivity 
reactions. Oral ingestion may cause harmful stimulation of the 
CNS and convulsions. 
LD50 (cat, oral): 2.24 g/kg(5–7) 
LD50 (guinea pig, oral): 1.0 g/kg 
LD50 (mouse, oral): 1.4 g/kg 
LD50 (rabbit, oral): 1.68 g/kg 
LD50 (rabbit, skin): 4.0 g/kg 
LD50 (rat, oral): 0.5 g/kg 
LD50 (rat, skin): 4.0 g/kg 
15 Handling Precautions 
Benzyl benzoate may be harmful if ingested and is irritating to 
the skin, eyes, and mucous membranes. Observe normal 
precautions appropriate to the circumstances and quantity of 
material handled. Eye protection, gloves, and a respirator are 
recommended. It is recommended that benzyl benzoate is 
handled in a fume cupboard. Benzyl benzoate is flammable. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IM injections 
and oral capsules). Included, as an active ingredient, in 
nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
— 
18 Comments 
The EINECS number for benzyl benzoate is 204-402-9. 
19 Specific References 
1 Spiegel AJ, Noseworthy MM. Use of nonaqueous solvents in 
parenteral products. J Pharm Sci 1963; 52: 917–927. 
2 Guterres SS, Weiss V, de Lucca Freitas L, Pohlmann AR. Influence 
of benzyl benzoate as oil core on the physicochemical properties of 
spray-dried powders from polymeric nanocapsules containing 
indomethacin. Drug Deliv 2000; 7(4): 195–199. 
3 Gilman AG, Rall TW, Nies AS, et al, eds. Goodman and Gilman’s 
The Pharmacological Basis of Therapeutics, 8th edn. New York: 
Pergamon Press, 1990: 1630. 
4 Bishop Y, ed. The Veterinary Formulary, 6th edn. London: 
Pharmaceutical Press, 2005: 56. 
5 Graham BE, Kuizenga MH. Toxicity studies on benzyl benzoate 
and related benzyl compounds. J Pharmacol Exp Ther 1945; 84: 
358–362. 
6 Draize JH, Alvarez E, Whitesell MF, et al. Toxicological investigations 
of compounds proposed for use as insect repellents. J 
Pharmacol Exp Ther 1948; 93: 26–39. 
7 Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. 
Cincinnati: US Department of Health, 1987: 965. 
20 General References 
Gupta VD, Ho HW. Quantitative determination of benzyl benzoate in 
benzyl benzoate lotion NF. Am J Hosp Pharm 1976; 33: 665–666. 
Hassan MMA, Mossa JS. Benzyl benzoate. In: Florey K, ed. Analytical 
Profiles of Drug Substances, volume 10. New York: Academic 
Press, 1981: 55–74. 
21 Authors 
E Cahill. 
22 Date of Revision 
15 August 2005. 
Benzyl Benzoate 73

Boric Acid 
1 Nonproprietary Names 
BP: Boric acid 
JP: Boric acid 
PhEur: Acidum boricum 
USPNF: Boric acid 
2 Synonyms 
Boracic acid; boraic acid; Borofax; boron trihydroxide; E284; 
orthoboric acid; trihydroxyborene. 
3 Chemical Name and CAS Registry Number 
Orthoboric acid [10043-35-3] 
Metaboric acid [13460-50-9] 
4 Empirical Formula and Molecular Weight 
H3BO3 61.83 (for trihydrate) 
HBO2 43.82 (for monohydrate) 
5 Structural Formula 
H3BO3 
6 Functional Category 
Antimicrobial preservative. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Boric acid is used as an antimicrobial preservative in eye 
drops,(1,2) cosmetic products,(3) ointments,(4,5) and topical 
creams.(6) It is also used as an antimicrobial preservative in 
foods. 
Boric acid has also been used therapeutically in the form of 
suppositories to treat yeast infections,(7–9) and in dilute 
concentrations as a mild antiseptic, although it has been 
superseded by more effective and less toxic disinfectants.(10) See 
Section 14. 
Boric acid and borate have good buffering capacity and are 
used to control pH; they have been used for this purpose in 
external preparations such as eye drops.(11) 
8 Description 
Boric acid occurs as a hygroscopic, white crystalline powder, 
colorless shiny plates, or white crystals. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for boric acid. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Appearance of 
solution 
. . — 
Loss on drying 40.50% — 40.50% 
Sulfate — 4450 ppm — 
Heavy metals 410 ppm 415 ppm 40.002% 
Organic matter — . — 
Arsenic 45 ppm — — 
pH — 3.8–4.8 — 
Solubility in alcohol — . . 
Assay 499.5% 99.5–100.5% 99.5–100.5% 
10 Typical Properties 
Acidity/alkalinity: pH = 3.5–4.1 (5% w/v aqueous solution) 
Density: 1.435 
Melting point: 170.98C. When heated slowly to 181.08C, boric 
acid loses water to form metaboric acid (HBO2); at 1408C, 
tetraboric acid (H2B4O7) is formed; and at higher temperatures, 
boron trioxide (B2O3) is formed.(12) 
Solubility: miscible with ethanol, ether, glycerin, water, and 
other fixed and volatile oils. Solubility in water is increased 
by addition of hydrochloric, citric, or tartaric acids. 
Specific gravity: 1.517 
11 Stability and Storage Conditions 
Boric acid is hygroscopic and should therefore be stored in an 
air-tight, sealed container. The container must be labeled ‘Not 
for Internal Use’. 
12 Incompatibilities 
Boric acid is incompatible with water, strong bases and alkali 
metals. It reacts violently with potassium and acid anhydrides. 
It also forms a complex with glycerin, which is a stronger acid 
than boric acid. 
13 Method of Manufacture 
Boric acid occurs naturally as the mineral sassolite. However, 
the majority of boric acid is produced by reacting inorganic 
borates with sulfuric acid in an aqueous medium. Sodium 
borate and partially refined calcium borate (colemanite) are the 
principal raw materials. When boric acid is made from 
colemanite, the fine-ground ore is vigorously stirred with 
mother liquor and sulfuric acid at about 908C. The by-product 
calcium sulfate is removed by filtration, and the boric acid is 
crystallized by cooling the filtrate. 
14 Safety 
Boric acid is a weak bacteriostatic and antimicrobial agent, and 
has been used in topical preparations such as eye lotions,

mouthwashes and gargles. It has also been used in US- and 
Japanese-approved intravenous products. Solutions of boric 
acid were formerly used to wash out body cavities, and as 
applications to wounds and ulcers, although the use of boric 
acid for these purposes is now regarded as inadvisable owing to 
the possibility of absorption.(13) Boric acid is not used internally 
owing to its toxicity. It is poisonous by ingestion and 
moderately toxic by skin contact. Experimentally it has proved 
to be toxic by inhalation and subcutaneous routes, and 
moderately toxic by intraperitoneal and intravenous routes. 
Boric acid is absorbed from the gastrointestinal tract and 
from damaged skin, wounds, and mucous membranes, 
although it does not readily permeate intact skin. The main 
symptoms of boric acid poisoning are abdominal pain, 
diarrhea, erythematous rash involving both skin and mucous 
membrane, and vomiting. These symptoms may be followed by 
desquamation, and stimulation or depression of the central 
nervous system. Convulsions, hyperpyrexia, and renal tubular 
damage have been known to occur. 
Death has occurred from ingestion of less than 5 g in young 
children, and of 5–20 g in adults. Fatalities have occurred most 
frequently in young children after the accidental ingestion of 
solutions of boric acid, or after the application of boric acid 
powder to abraded skin. 
The permissible exposure limit (PEL) of boric acid is 
15 mg/m3 total dust, and 5 mg/m3 respirable fraction for 
nuisance dusts.(14) 
LD50 (mouse, oral): 3.45 g/kg(15) 
LD50 (mouse, IV): 1.24 g/kg 
LD50 (mouse, SC): 1.74 g/kg 
LD50 (rat, oral): 2.660 g/kg 
LD50 (rat, IV): 1.33 g/kg 
LD50 (rat, SC): 1.4 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Boric acid is irritating to the 
skin and is potentially toxic by inhalation. Gloves, eye 
protection, protective clothing, and a respirator are recommended. 
16 Regulatory Status 
Accepted for use as a food additive in Europe. Included in the 
FDA Inactive Ingredients Guide (IV injections; ophthalmic 
preparations; otic solutions; topical preparations). Reported in 
the EPA TSCA Inventory. In the UK, the use of boric acid in 
cosmetics and toiletries is restricted. Included in the Canadian 
List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Sodium borate. 
18 Comments 
Boric acid has been used experimentally as a model oxo-acid to 
retard mannitol crystallization in the solid state.(16) 
The EINECS number for boric acid is 233-139-2. 
19 Specific References 
1 Kodym A, Marcinkowski A, Kukula H. Technology of eye drops 
containing aloe (Aloe arborescens M–Liliaceae) and eye drops 
containing both aloe and neomycin sulphate. Acta Pol Pharm 
2003; 60(1): 31–39. 
2 Tromp TFJ, Nusman-Schoterman Z, et al. Preservation of eye 
drops. Pharm Weekbl 1975; 110(465–472): 485–492. 
3 Seller R, Caldini O, Orzalesi G, et al. Preservation of cosmetic 
products: protection of the talc powders. Boul Chim Farm 1974; 
113(Dec): 617–627. 
4 Allen LV, Stiles ML. Compound’s corner: diaper rash paste. 
Maryland Pharm 1986: 62(Dec): 30. 
5 Dawson CR, Daghfous T, Whitcher J, et al. Intermittent trachoma 
chemotherapy: controlled trial of tetracycline or erythromycin. 
Bull World Health Organ 1981; 59: 91–97. 
6 Shaw K. Vaginal yeast infections. Pharm Times 1998; 64(Dec): 57– 
58, 60. 
7 Allen LV. Boric acid suppositories. US Pharm 1996; 21(Jan): 92– 
93. 
8 Van Slyke KK, Michel VP, Rein MF. Treatment of vulvovaginal 
candidaisis with boric acid powder. Am J Obstet Gynecol 1981; 
141: 145. 
9 Allen ES. Multiple-ingredient drug for use in the treatment of 
vaginitis. Clin Med 1971; 78: 31–32. 
10 Sweetman SC, ed. Martindale: The Complete Drug Reference, 
34th edn. London: Pharmaceutical Press, 2005: 1662. 
11 LundW, ed. The Pharmaceutical Codex: Principles and Practice of 
Pharmaceutics, 12th edn. London: Pharmaceutical Press, 1994: 67. 
12 LundW, ed. The Pharmaceutical Codex: Principles and Practice of 
Pharmaceutics, 12th edn. London: Pharmaceutical Press, 1994: 
109. 
13 Zabka M, Vitkova Z, Burelova A, Mandak M. Formulation and 
local anesthetic activity of carbizocaine in collyria. Cesk Farm 
1988; 37(10): 457–460. 
14 Dean JA, ed. Lang’s Handbook of Chemistry, 13th edn. New York: 
McGraw-Hill, 1985: 4–57. 
15 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 536. 
16 Yoshinari T, Forbes RT, York P, et al. Crystallisation of amorphous 
mannitol is retarded using boric acid. Int J Pharm 2003; 258: 109– 
120. 
20 General References 
—
21 Authors 
M Yelvigi. 
22 Date of Revision 
15 August 2005. 
Boric Acid 75

Bronopol 
1 Nonproprietary Names 
BP: Bronopol 
2 Synonyms 
2-Bromo-2-nitro-1,3-propanediol; b-bromo-b-nitrotrimethyleneglycol; 
Myacide. 
3 Chemical Name and CAS Registry Number 
2-Bromo-2-nitropropane-1,3-diol [52-51-7] 
4 Empirical Formula and Molecular Weight 
C3H6BrNO4 200.00 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; antiseptic. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Bronopol 0.01–0.1% w/v is used as an antimicrobial preservative 
either alone or in combination with other preservatives 
in topical pharmaceutical formulations, cosmetics, and 
toiletries; the usual concentration is 0.02% w/v. 
8 Description 
Bronopol is a white or almost white crystalline powder; 
odorless or with a faint characteristic odor. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for bronopol. 
Test BP 2004 
Identification . 
Characters . 
Acidity or alkalinity (1% w/v solution) 5.0–7.0 
Related substances . 
Sulfated ash 40.1% 
Water 40.5% 
Assay (anhydrous basis) 99.0–101.0% 
10 Typical Properties 
Antimicrobial activity: bronopol is active against both Grampositive 
and Gram-negative bacteria including Pseudomonas 
aeruginosa, with typical minimum inhibitory concentrations 
(MICs) between 10–50 mg/mL;(1–8) see also Table II. 
At room temperature, a 0.08% w/v aqueous solution may 
reduce the viability of culture collection strains of Escherichia 
coli and Pseudomonas aeruginosa by 100-fold or more 
in 15 minutes. Antimicrobial activity is not markedly 
influenced by pH in the range 5.0–8.0, nor by common 
anionic and nonionic surfactants, lecithin, or proteins.(2,5,6) 
Bronopol is less active against yeasts and molds, with typical 
MICs of 50–400 mg/mL or more, and has little or no useful 
activity against bacterial spores. See also Section 12. 
Table II: Minimum inhibitory concentrations (MICs) of bronopol.(2,9) 
Microorganism MIC (mg/mL) 
Aspergillus niger 3200 
Bacillus subtilis 12.5 
Burkholderia (Pseudomonas) cepacia 25 
Candida albicans 1600 
Escherichia coli 12.5–50 
Klebsiella aerogenes 25 
Legionella pneumophilia 50 
Penicillium roqueforti 400 
Penicillium funiculosum 1600 
Pityrosporum ovale 125 
Proteus mirabilis 25–50 
Proteus vulgaris 12.5–50 
Pseudomonas aeruginosa 12.5–50 
Saccharomyces cerevisiae 3200 
Salmonella gallinarum 25 
Staphylococcus aureus 12.5–50 
Staphylococcus epidermidis 50 
Streptococcus faecalis 50 
Trichophyton mentagrophytes 200 
Trichoderma viride 6400 
Melting point: 128–1328C 
Partition coefficients: 
Mineral oil : water = 0.043 at 22–248C; 
Peanut oil : water = 0.11 at 22–248C. 
Solubility: see Table III. 
Table III: Solubility of bronopol. 
Solvent Solubility at 208C 
Cottonseed oil Slightly soluble 
Ethanol (95%) 1 in 2 
Glycerol 1 in 100 
Isopropyl myristate 1 in 200 
Mineral oil Slightly soluble 
Propan-2-ol 1 in 4 
Propylene glycol 1 in 2 
Water 1 in 4

11 Stability and Storage Conditions 
Bronopol is stable and its antimicrobial activity is practically 
unaffected when stored as a solid at room temperature and 
ambient relative humidity for up to 2 years.(3) 
The pH of a 1.0% w/v aqueous solution is 5.0–6.0 and falls 
slowly during storage; solutions are more stable in acid 
conditions. Half-lives of bronopol in buffered aqueous solutions 
at 0.03% w/v are shown in Table IV.(9) 
Microbiological assay results indicate longer half-lives than 
those obtained by HPLC and thus suggest that degradation 
products may contribute to antimicrobial activity. Formaldehyde 
and nitrites are among the decomposition products, but 
formaldehyde arises in such low concentrations that its 
antimicrobial effect is not likely to be significant. On exposure 
to light, especially under alkaline conditions, solutions become 
yellow or brown-colored but the degree of discoloration does 
not directly correlate with loss of antimicrobial activity. 
The bulk material should be stored in a well-closed, nonaluminum 
container protected from light, in a cool, dry place. 
Table IV: Half-lives of bronopol under different storage conditions. 
Temperature (8C) pH 4 pH 6 pH 8 
5 >5 years >5 years 6 months 
25 >5 years >5 years 4 months 
40 2 years 4 months 8 days 
60 2 weeks <2 days <1 day 
12 Incompatibilities 
Sulfhydryl compounds cause significant reductions in the 
activity of bronopol, and cysteine hydrochloride may be used 
as the deactivating agent in preservative efficacy tests; lecithin/ 
polysorbate combinations are unsuitable for this purpose.(5) 
Bronopol is incompatible with sodium thiosulfate, with sodium 
metabisulfite, and with amine oxide or protein hydrolysate 
surfactants. Owing to an incompatibility with aluminum, the 
use of aluminum in the packaging of products that contain 
bronopol should be avoided. 
13 Method of Manufacture 
Bronopol is synthesized by the reaction of nitromethane with 
paraformaldehyde in an alkaline environment, followed by 
bromination. After crystallization, bronopol powder may be 
milled to produce a powder of the required fineness. 
14 Safety 
Bronopol is used widely in topical pharmaceutical formulations 
and cosmetics as an antimicrobial preservative. 
Although bronopol has been reported to cause both irritant 
and hypersensitivity adverse reactions following topical 
use,(10–13) it is generally regarded as a nonirritant and 
nonsensitizing material at concentrations up to 0.1% w/v. At 
a concentration of 0.02% w/v, bronopol is frequently used as a 
preservative in ‘hypoallergenic’ formulations. 
Animal toxicity studies have shown no evidence of 
phototoxicity or tumor occurrence when bronopol is applied 
to rodents topically or administered orally; and there is no in 
vitro or in vivo evidence of mutagenicity;(1) this is despite the 
demonstrated potential of bronopol to liberate nitrite on 
decomposition, which in the presence of certain amines may 
generate nitrosamines. Formation of nitrosamines in formulations 
containing amines may be reduced by limiting the 
concentration of bronopol to 0.01% w/v and including an 
antioxidant such as 0.2% w/v alpha tocopherol or 0.05% w/v 
butylated hydroxytoluene;(14) other inhibitor systems may also 
be appropriate.(15) 
LD50 (dog, oral): 250 mg/kg (16) 
LD50 (mouse, IP): 15.5 mg/kg 
LD50 (mouse, IV): 48 mg/kg 
LD50 (mouse, oral): 270 mg/kg 
LD50 (mouse, SC): 116 mg/kg 
LD50 (mouse, skin): 4.75 g/kg 
LD50 (rat, IP): 26 mg/kg 
LD50 (rat, IV): 37.4 mg/kg 
LD50 (rat, oral): 180 mg/kg 
LD50 (rat, SC): 170 mg/kg 
LD50 (rat, skin): 1.6 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Bronopol may be harmful 
upon inhalation and the solid or concentrated solutions can be 
irritant to the skin and eyes. Eye protection, gloves, and dust 
respirator are recommended. Bronopol burns to produce toxic 
fumes. 
16 Regulatory Status 
Included in topical pharmaceutical formulations licensed in 
Europe. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
—
18 Comments 
Bronopol owes its usefulness as a preservative largely to its 
activity against Pseudomonas aeruginosa, and its affinity for 
polar solvents, which prevents the loss of preservative into the 
oil phase of emulsions that is seen with some other preservatives. 
Other advantages include a low incidence of microbial 
resistance; low concentration exponent;(17) and good compatibility 
with most surfactants, other excipients, and preservatives, 
with which it can therefore be used in combination. 
The major disadvantages of bronopol are relatively poor 
activity against yeasts and molds, instability at alkaline pH, and 
the production of formaldehyde and nitrite on decomposition, 
although there is no evidence of serious toxicity problems 
associated with bronopol that are attributable to these 
compounds. 
The EINECS number for bronopol is 200-143-0. 
19 Specific References 
1 Croshaw B, Groves MJ, Lessel B. Some properties of bronopol, a 
new antimicrobial agent active against Pseudomonas aeruginosa. J 
Pharm Pharmacol 1964; 16 (Suppl.): 127T–130T. 
2 Anonymous. Preservative properties of bronopol. Cosmet Toilet 
1977; 92(3): 87–88. 
3 Bryce DM, Croshaw B, Hall JE, et al. The activity and safety of the 
antimicrobial agent bronopol (2-bromo-2-nitropropane-1,3-diol). 
J Soc Cosmet Chem 1978; 29: 3–24. 
Bronopol 77

4 Moore KE, Stretton RJ. A method for studying the activity of 
preservatives and its application to bronopol. J Appl Bacteriol 
1978; 45: 137–141. 
5 Myburgh JA, McCarthy TJ. Effect of certain formulation factors 
on the activity of bronopol. Cosmet Toilet 1978; 93(2): 47–48. 
6 Moore KE, Stretton RJ. The effect of pH, temperature and certain 
media constituents on the stability and activity of the preservative 
bronopol. J Appl Bacteriol 1981; 51: 483–494. 
7 Sondossi M. The effect of fifteen biocides on formaldehyde 
resistant strains of Pseudomonas aeruginosa. J Ind Microbiol 
1986; 1: 87–96. 
8 Kumanova R, Vassileva M, Dobreva S, et al. Evaluating bronopol. 
Manuf Chem 1989; 60(9): 36–38. 
9 BASF Corp. Technical literature: Bronopol products, 2000. 
10 Maibach HI. Dermal sensitization potential of 2-bromo-2- 
nitropropane-1,3-diol (bronopol). Contact Dermatitis 1977; 3: 99. 
11 Elder RL. Final report on the safety assessment for 2-bromo-2- 
nitropropane-1,3-diol. J Environ Pathol Toxicol 1980; 4: 47–61. 
12 Storrs FJ, Bell DE. Allergic contact dermatitis to 2-bromo-2- 
nitropropane-1,3-diol in a hydrophilic ointment. J Am Acad 
Dermatol 1983; 8: 157–170. 
13 Grattan CEH, Harman RRM. Bronopol contact dermatitis in a 
milk recorder. Br J Dermatol 1985; 113 (Suppl. 29): 43. 
14 Dunnett PC, Telling GM. Study of the fate of bronopol and the 
effects of antioxidants on N-nitrosamine formation in shampoos 
and skin creams. Int J Cosmet Sci 1984; 6: 241–247. 
15 Challis BC, Trew DF, Guthrie WG, Roper DV. Reduction of 
nitrosamines in cosmetic products. Int J Cosmet Sci 1995; 17: 119– 
131. 
16 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 566. 
17 Denyer SP, Wallha. usser KH. Antimicrobial preservatives and their 
properties. In: Denyer SP, Baird RM, eds. Guide to Microbiological 
Control in Pharmaceuticals. London: Ellis Horwood, 1990: 251– 
273. 
20 General References 
Croshaw B. Preservatives for cosmetics and toiletries. J Soc Cosmet 
Chem 1977; 28: 3–16. 
Rossmore HW, Sondossi M. Applications and mode of action of 
formaldehyde condensate biocides. Adv Appl Microbiol 1988; 33: 
223–273. 
Shaw S. Patch testing bronopol. Cosmet Toilet 1997; 112(4): 67, 68, 
71–73. 
Toler JC. Preservative stability and preservative systems. Int J Cosmet 
Sci 1985; 7: 157–164. 
Wallha. usser KH. Bronopol. In: Kabara JJ, ed. Cosmetic and Drug 
Preservation Principles and Practice. New York: Marcel Dekker, 
1984: 635–638. 
21 Authors 
SP Denyer, NA Hodges. 
22 Date of Revision 
15 August 2005. 
78 Bronopol

Butylated Hydroxyanisole 
1 Nonproprietary Names 
BP: Butylated hydroxyanisole 
PhEur: Butylhydroxyanisolum 
USPNF: Butylated hydroxyanisole 
2 Synonyms 
BHA; tert-butyl-4-methoxyphenol; 1,1-dimethylethyl-4-methoxyphenol; 
E320; Nipanox BHA; Nipantiox 1-F; Tenox BHA. 
3 Chemical Name and CAS Registry Number 
2-tert-Butyl-4-methoxyphenol [25013-16-5] 
4 Empirical Formula and Molecular Weight 
C11H16O2 180.25 
The PhEur 2005 describes butylated hydroxyanisole as 2-(1,1- 
dimethylethyl)-4-methoxyphenol containing not more than 
10% of 3-(1,1-dimethylethyl)-4-methoxyphenol. 
5 Structural Formula 
6 Functional Category 
Antioxidant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Butylated hydroxyanisole is an antioxidant (see Table I) with 
some antimicrobial properties.(1) It is used in a wide range of 
cosmetics, foods, and pharmaceuticals. When used in foods, it 
is used to delay or prevent oxidative rancidity of fats and oils 
and to prevent loss of activity of oil-soluble vitamins. 
Butylated hydroxyanisole is frequently used in combination 
with other antioxidants, particularly butylated hydroxytoluene 
and alkyl gallates, and with sequestrants or synergists such as 
citric acid. 
FDA regulations direct that the total content of antioxidant 
in vegetable oils and direct food additives shall not exceed 
0.02% w/w (200 ppm) of fat or oil content or essential (volatile) 
oil content of food. 
USDA regulations require that the total content of 
antioxidant shall not exceed 0.01% w/w (100 ppm) of any 
one antioxidant or 0.02% w/w combined total of any 
antioxidant combination in animal fats. 
Japanese regulations allow up to 1 g/kg in animal fats. 
Table I: Antioxidant uses of butylated hydroxyanisole. 
Antioxidant use Concentration (%) 
b-Carotene 0.01 
Essential oils and flavoring agents 0.02–0.5 
IM injections 0.03 
IV injections 0.0002–0.0005 
Oils and fats 0.02 
Topical formulations 0.005–0.02 
Vitamin A 10mg per million units 
8 Description 
Butylated hydroxyanisole occurs as a white or almost white 
crystalline powder or a yellowish-white waxy solid with a faint, 
characteristic aromatic odor. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for butylated hydroxyanisole. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Appearance of solution . — 
Residue on ignition — 40.01% 
Sulfated ash 40.1% — 
Related substances . — 
Heavy metals 410 ppm 40.001% 
Organic volatile impurities — . 
Assay — 598.5% 
10 Typical Properties 
Antimicrobial activity: activity is similar to that of the 
p-hydroxybenzoate esters (parabens). The greatest activity 
is against molds and Gram-positive bacteria, with less 
activity against Gram-negative bacteria. 
Boiling point: 2648C at 745mmHg 
Density (true): 1.117 g/cm3 
Flash point: 1308C 
Melting point: 478C (for pure 2-tert-butyl-4-methoxyphenol); 
see also Section 18. 
Solubility: practically insoluble in water; soluble in methanol; 
freely soluble in 550% aqueous ethanol, propylene glycol, 
chloroform, ether, hexane, cottonseed oil, peanut oil, 
soybean oil, glyceryl monooleate, and lard, and in solutions 
of alkali hydroxides. 
Viscosity (kinematic): 3.3mm2/s (3.3 cSt) at 998C.

11 Stability and Storage Conditions 
Exposure to light causes discoloration and loss of activity. 
Butylated hydroxyanisole should be stored in a well-closed 
container, protected from light, in a cool, dry place. 
12 Incompatibilities 
Butylated hydroxyanisole is phenolic and undergoes reactions 
characteristic of phenols. It is incompatible with oxidizing 
agents and ferric salts. Trace quantities of metals and exposure 
to light cause discoloration and loss of activity. 
13 Method of Manufacture 
Prepared by the reaction of p-methoxyphenol with isobutene. 
14 Safety 
Butylated hydroxyanisole is absorbed from the gastrointestinal 
tract and is metabolized and excreted in the urine with less than 
1% unchanged within 24 hours of ingestion.(2) Although there 
have been some isolated reports of adverse skin reactions to 
butylated hydroxyanisole,(3,4) it is generally regarded as 
nonirritant and nonsensitizing at the levels employed as an 
antioxidant. 
Concern over the use of butylated hydroxyanisole has 
occurred following long-term animal feeding studies. Although 
previous studies in rats and mice fed butylated hydroxyanisole 
at several hundred times the US-permitted level in the human 
diet showed no adverse effects, a study in which rats, hamsters, 
and mice were fed butylated hydroxyanisole at 1–2% of the 
diet produced benign and malignant tumors of the forestomach, 
but in no other sites. However, humans do not have any 
region of the stomach comparable to the rodent forestomach 
and studies in animals that also do not have a comparable 
organ (dogs, monkeys, and guinea pigs) showed no adverse 
effects. Thus, the weight of evidence does not support any 
relevance to the human diet where butylated hydroxyanisole is 
ingested at much lower levels.(5) The WHO acceptable daily 
intake of butylated hydroxyanisole has been set at 500 mg/kg 
body-weight.(5) 
LD50 (mouse, oral): 1.1–2.0 g/kg(6) 
LD50 (rabbit, oral): 2.1 g/kg 
LD50 (rat, IP): 0.88 g/kg 
LD50 (rat, oral): 2.0 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Butylated hydroxyanisole 
may be irritant to the eyes and skin and on inhalation. It should 
be handled in a well-ventilated environment; gloves and eye 
protection are recommended. On combustion, toxic fumes may 
be given off. 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (IM and IV injections, nasal 
sprays, oral capsules and tablets, and sublingual, rectal, topical, 
and vaginal preparations). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Butylated hydroxytoluene. 
18 Comments 
The commercially available material can have a wide melting 
point range (47–578C) owing to the presence of varying 
amounts of 3-tert-butyl-4-methoxyphenol. 
Tenox brands contain 0.1% w/w citric acid as a stabilizer. 
A specification for butylated hydroxyanisole is contained in 
the Food Chemicals Codex (FCC). 
The EINECS number for butylated hydroxyanisole is 246- 
563-8. 
19 Specific References 
1 Lamikanra A, Ogunbayo TA. A study of the antibacterial activity 
of butyl hydroxy anisole (BHA). Cosmet Toilet 1985; 100(10): 69– 
74. 
2 El-Rashidy R, Niazi S. A new metabolite of butylated hydroxyanisole 
in man. Biopharm Drug Dispos 1983; 4: 389–396. 
3 Roed-Peterson J, Hjorth N. Contact dermatitis from antioxidants: 
hidden sensitizers in topical medications and foods. Br J Dermatol 
1976; 94: 233–241. 
4 Juhlin L. Recurrent urticaria: clinical investigation of 330 patients. 
Br J Dermatol 1981; 104: 369–381. 
5 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirty-third report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1989; 
No. 776. 
6 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 609. 
20 General References 
Babich H, Borenfreund E. Cytotoxic effects of food additives and 
pharmaceuticals on cells in culture as determined with the neutral 
red assay. J Pharm Sci 1990; 79: 592–594. 
Verhagen H. Toxicology of the food additives BHA and BHT. Pharm 
Weekbl Sci 1990; 12: 164–166. 
21 Authors 
RT Guest. 
22 Date of Revision 
23 August 2005. 
80 Butylated Hydroxyanisole

Butylated Hydroxytoluene 
1 Nonproprietary Names 
BP: Butylated hydroxytoluene 
PhEur: Butylhydroxytoluenum 
USPNF: Butylated hydroxytoluene 
2 Synonyms 
Agidol; BHT; 2,6-bis(1,1-dimethylethyl)-4-methylphenol; 
butylhydroxytoluene; Dalpac; dibutylated hydroxytoluene; 
2,6-di-tert-butyl-p-cresol; 3,5-di-tert-butyl-4-hydroxytoluene; 
E321; Embanox BHT; Impruvol; Ionol CP; Nipanox BHT; 
OHS28890; Sustane; Tenox BHT; Topanol; Vianol. 
3 Chemical Name and CAS Registry Number 
2,6-Di-tert-butyl-4-methylphenol [128-37-0] 
4 Empirical Formula and Molecular Weight 
C15H24O 220.35 
5 Structural Formula 
6 Functional Category 
Antioxidant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Butylated hydroxytoluene is used as an antioxidant (see Table I) 
in cosmetics, foods, and pharmaceuticals. It is mainly used to 
delay or prevent the oxidative rancidity of fats and oils and to 
prevent loss of activity of oil-soluble vitamins. 
Butylated hydroxytoluene is also used at 0.5–1.0% w/w 
concentration in natural or synthetic rubber to provide 
enhanced color stability. 
Butylated hydroxytoluene has some antiviral activity(1) and 
has been used therapeutically to treat herpes simplex labialis.(2) 
8 Description 
Butylated hydroxytoluene occurs as a white or pale yellow 
crystalline solid or powder with a faint characteristic odor. 
Table I: Antioxidant uses of butylated hydroxytoluene. 
Antioxidant use Concentration (%) 
b-Carotene 0.01 
Edible vegetable oils 0.01 
Essential oils and flavoring agents 0.02–0.5 
Fats and oils 0.02 
Fish oils 0.01–0.1 
Inhalations 0.01 
IM injections 0.03 
IV injections 0.0009–0.002 
Topical formulations 0.0075–0.1 
Vitamin A 10mg per million units 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for butylated hydroxytoluene. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Appearance of solution . — 
Congealing temperature — 569.28C 
Freezing point 69–708C — 
Residue on ignition — 40.002% 
Sulfated ash 40.1% — 
Heavy metals — 40.001% 
Organic volatile impurities — . 
Related substances . — 
Assay — 599.0% 
10 Typical Properties 
Boiling point: 2658C 
Density (bulk): 0.48–0.60 g/cm3 
Density (true): 1.031 g/cm3 
Flash point: 1278C (open cup) 
Melting point: 708C 
Moisture content: 40.05% 
Partition coefficient: Octanol : water = 4.17–5.80 
Refractive index: nD
75 = 1.4859 
Solubility: practically insoluble in water, glycerin, propylene 
glycol, solutions of alkali hydroxides, and dilute aqueous 
mineral acids. Freely soluble in acetone, benzene, ethanol 
(95%), ether, methanol, toluene, fixed oils, and mineral oil. 
More soluble than butylated hydroxyanisole in food oils 
and fats. 
Specific gravity: 
1.006 at 208C; 
0.890 at 808C; 
0.883 at 908C; 
0.800 at 1008C. 
Specific heat: 
1.63 J/g/8C (0.39 cal/g/8C) for solid;

2.05 J/g/8C (0.49 cal/g/8C) for liquid. 
Vapor density (relative): 7.6 (air = 1) 
Vapor pressure: 
1.33 Pa (0.01 mmHg) at 208C; 
266.6 Pa (2 mmHg) at 1008C. 
Viscosity (kinematic): 3.47mm2/s (3.47 cSt) at 808C. 
11 Stability and Storage Conditions 
Exposure to light, moisture, and heat causes discoloration and 
a loss of activity. Butylated hydroxytoluene should be stored in 
a well-closed container, protected from light, in a cool, dry 
place. 
12 Incompatibilities 
Butylated hydroxytoluene is phenolic and undergoes reactions 
characteristic of phenols. It is incompatible with strong 
oxidizing agents such as peroxides and permanganates. 
Contact with oxidizing agents may cause spontaneous combustion. 
Iron salts cause discoloration with loss of activity. Heating 
with catalytic amounts of acids causes rapid decomposition 
with the release of the flammable gas isobutene. 
13 Method of Manufacture 
Prepared by the reaction of p-cresol with isobutene. 
14 Safety 
Butylated hydroxytoluene is readily absorbed from the gastrointestinal 
tract and is metabolized and excreted in the urine 
mainly as glucuronide conjugates of oxidation products. 
Although there have been some isolated reports of adverse 
skin reactions, butylated hydroxytoluene is generally regarded 
as nonirritant and nonsensitizing at the levels employed as an 
antioxidant.(3,4) 
The WHO has set a temporary estimated acceptable daily 
intake for butylated hydroxytoluene at up to 125 mg/kg bodyweight.(
5) 
Ingestion of 4 g of butylated hydroxytoluene, although 
causing severe nausea and vomiting, has been reported to be 
nonfatal.(6) 
LD50 (guinea pig, oral): 10.7 g/kg(7) 
LD50 (mouse, IP): 0.14 g/kg 
LD50 (mouse, IV): 0.18 g/kg 
LD50 (mouse, oral): 0.65 g/kg 
LD50 (rat, oral): 0.89 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Butylated hydroxytoluene 
may be irritant to the eyes and skin and on inhalation. It should 
be handled in a well-ventilated environment; gloves and eye 
protection are recommended. Closed containers may explode 
owing to pressure build-up when exposed to extreme heat. 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (IM and IV injections, nasal 
sprays, oral capsules and tablets, rectal, topical, and vaginal 
preparations). Included in nonparenteral medicines licensed in 
the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Butylated hydroxyanisole. 
18 Comments 
A specification for butylated hydroxytoluene is contained in the 
Food Chemicals Codex (FCC). 
The EINECS number for butylated hydroxytoluene is 204- 
881-4. 
19 Specific References 
1 Snipes W, Person S, Keith A, Cupp J. Butylated hydroxytoluene 
inactivates lipid-containing viruses. Science 1975; 188: 64–66. 
2 Freeman DJ, Wenerstrom G, Spruance SL. Treatment of recurrent 
herpes simplex labialis with topical butylated hydroxytoluene. 
Clin Pharmacol Ther 1985; 38: 56–59. 
3 Roed-Peterson J, Hjorth N. Contact dermatitis from antioxidants: 
hidden sensitizers in topical medications and foods. Br J Dermatol 
1976; 94: 233–241. 
4 Juhlin L. Recurrent urticaria: clinical investigation of 330 patients. 
Br J Dermatol 1981; 104: 369–381. 
5 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirty-seventh report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1991; No. 806. 
6 Shlian DM, Goldstone J. Toxicity of butylated hydroxytoluene. N 
Engl J Med 1986; 314: 648–649. 
7 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 430. 
20 General References 
Verhagen H. Toxicology of the food additives BHA and BHT. Pharm 
Weekbl (Sci) 1990; 12: 164–166. 
21 Authors 
RT Guest. 
22 Date of Revision 
23 August 2005. 
82 Butylated Hydroxytoluene

Butylparaben 
1 Nonproprietary Names 
BP: Butyl hydroxybenzoate 
JP: Butyl parahydroxybenzoate 
PhEur: Butylis parahydroxybenzoas 
USPNF: Butylparaben 
2 Synonyms 
4-Hydroxybenzoic acid butyl ester; Lexgard B; Nipabutyl; 
Tegosept B; Trisept B; Uniphen P-23; Unisept B. 
3 Chemical Name and CAS Registry Number 
Butyl-4-hydroxybenzoate [94-26-8] 
4 Empirical Formula and Molecular Weight 
C11H14O3 194.23 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Butylparaben is widely used as an antimicrobial preservative in 
cosmetics and pharmaceutical formulations; see Table I. 
It may be used either alone or in combination with other 
paraben esters or with other antimicrobial agents. In cosmetics, 
it is the fourth most frequently used preservative.(1) 
As a group, the parabens are effective over a wide pH range 
and have a broad spectrum of antimicrobial activity, although 
they are most effective against yeasts and molds; see Section 10. 
Owing to the poor solubility of the parabens, paraben salts, 
particularly the sodium salt, are frequently used in formulations. 
However, this may raise the pH of poorly buffered 
formulations. 
See Methylparaben for further information. 
Table I: Uses of butylparaben. 
Use Concentration (%) 
Oral suspensions 0.006–0.05 
Topical preparations 0.02–0.4 
SEM: 1 
Excipient: Butylparaben 
Magnification: 240 
SEM: 2 
Excipient: Butylparaben 
Magnification: 2400 
8 Description 
Butylparaben occurs as colorless crystals or a white, crystalline, 
odorless or almost odorless, tasteless powder. 
9 Pharmacopeial Specifications 
See Table II.

Table II: Pharmacopeial specifications for butylparaben. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters . . — 
Appearance of solution — . — 
Melting range 69–728C 68–718C 68–728C 
Acidity — . . 
Loss on drying 40.5% — 40.5% 
Residue on ignition 40.1% — 40.05% 
Sulfated ash — 40.1% — 
Related substances — . — 
Chloride 40.035% — — 
Sulfate 40.024% — — 
Heavy metals 420 ppm — — 
Readily carbonizable 
substances 
. — — 
Parahydroxybenzoic 
acid and salicylic 
acid 
. — — 
Organic volatile 
impurities 
— — . 
Assay (dried basis) 599.0% 98.0–102.0% 99.0–100.5% 
10 Typical Properties 
Antimicrobial activity: butylparaben exhibits antimicrobial 
activity between pH 4–8. Preservative efficacy decreases 
with increasing pH owing to the formation of the phenolate 
anion. Parabens are more active against yeasts and molds 
than against bacteria. They are also more active against 
Gram-positive than against Gram-negative bacteria; see 
Table III.(2) 
The activity of the parabens increases with increasing 
chain length of the alkyl moiety, but solubility decreases. 
Butylparaben is thus more active than methylparaben. 
Activity may be improved by using combinations of 
parabens since synergistic effects occur. Activity has also 
been reported to be improved by the addition of other 
excipients; see Methylparaben for further information. 
Density (bulk): 0.731 g/cm3 
Density (tapped): 0.819 g/cm3 
Melting point: 68–728C 
Partition coefficients: values for different vegetable oils vary 
considerably and are affected by the purity of the oil; see 
Table IV.(3) 
Solubility: see Table V. 
Table IV: Partition coefficients for butylparaben between oils and 
water.(3) 
Solvent Partition coefficient oil : water 
Mineral oil 3.0 
Peanut oil 280 
Soybean oil 280 
Table V: Solubility of butylparaben. 
Solvent Solubility at 208C unless otherwise stated 
Acetone Freely soluble 
Ethanol 1 in 0.5 
Ethanol (95%) 1 in 1 
Ether Freely soluble 
Glycerin 1 in 330 
Methanol 1 in 0.5 
Mineral oil 1 in 1000 
Peanut oil 1 in 20 
Propylene glycol 1 in 1 
Water 1 in >5000 
1 in 670 at 808C 
11 Stability and Storage Conditions 
Aqueous butylparaben solutions at pH 3–6 can be sterilized by 
autoclaving, without decomposition.(4) At pH 3–6, aqueous 
solutions are stable (less than 10% decomposition) for up to 
about 4 years at room temperature, while solutions at pH 8 or 
above are subject to rapid hydrolysis (10% or more after about 
60 days at room temperature).(5) 
Butylparaben should be stored in a well-closed container, in 
a cool, dry place. 
12 Incompatibilities 
The antimicrobial activity of butylparaben is considerably 
reduced in the presence of nonionic surfactants as a result of 
micellization.(6) Absorption of butylparaben by plastics has not 
been reported but appears probable given the behavior of other 
parabens. Some pigments, e.g., ultramarine blue and yellow 
iron oxide, absorb butylparaben and thus reduce its preservative 
properties.(7) 
Butylparaben is discolored in the presence of iron and is 
subject to hydrolysis by weak alkalis and strong acids. 
See also Methylparaben. 
Table III: Minimum inhibitory concentrations (MICs) for butylparaben 
in aqueous solution.(2) 
Microorganism MIC (mg/mL) 
Aerobacter aerogenes ATCC 8308 400 
Aspergillus niger ATCC 9642 125 
Aspergillus niger ATCC 10254 200 
Bacillus cereus var. mycoides ATCC 6462 63 
Bacillus subtilis ATCC 6633 250 
Candida albicans ATCC 10231 125 
Enterobacter cloacae ATCC 23355 250 
Escherichia coli ATCC 8739 5000 
Escherichia coli ATCC 9637 5000 
Klebsiella pneumoniae ATCC 8308 250 
Penicillium chrysogenum ATCC 9480 70 
Penicillium digitatum ATCC 10030 32 
Proteus vulgaris ATCC 13315 125 
Pseudomonas aeruginosa ATCC 9027 >1000 
Pseudomonas aeruginosa ATCC 15442 >1000 
Pseudomonas stutzeri 500 
Rhizopus nigricans ATCC 6227A 63 
Saccharomyces cerevisiae ATCC 9763 35 
Salmonella typhosa ATCC 6539 500 
Serratia marcescens ATCC 8100 500 
Staphylococcus aureus ATCC 6538P 125 
Staphylococcus epidermidis ATCC 12228 250 
Trichophyton mentagrophytes 35 
84 Butylparaben

13 Method of Manufacture 
Butylparaben is prepared by esterification of p-hydroxybenzoic 
acid with n-butanol. 
14 Safety 
Butylparaben and other parabens are widely used as antimicrobial 
preservatives in cosmetics and oral and topical 
pharmaceutical formulations. 
Systemically, no adverse reactions to parabens have been 
reported, although they have been associated with hypersensitivity 
reactions. See Methylparaben for further information. 
LD50 (mouse, IP): 0.23 g/kg(8) 
LD50 (mouse, oral): 13.2 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Butylparaben may be irritant 
to the skin, eyes, and mucous membranes and should be 
handled in a well-ventilated environment. Eye protection, 
gloves, and a dust mask or respirator are recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (injections, oral 
capsules, solutions, suspensions, syrups and tablets, rectal, and 
topical preparations). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Butylparaben sodium; ethylparaben; methylparaben; propylparaben. 
Butylparaben sodium 
Empirical formula: C11H13NaO3 
Molecular weight: 216.23 
CAS number: [36457-20-2] 
Synonyms: butyl-4-hydroxybenzoate sodium salt; sodium butyl 
hydroxybenzoate. 
Appearance: white, odorless or almost odorless, hygroscopic 
powder. 
Acidity/alkalinity: pH = 9.5–10.5 (0.1% w/v aqueous solution) 
Solubility: 1 in 10 of ethanol (95%); 1 in 1 of water. 
Comments: butylparaben sodium may be used instead of 
butylparaben because of its greater aqueous solubility. In 
unbuffered formulations, pH adjustment may be required. 
18 Comments 
See Methylparaben for further information and references. 
The EINECS number for butylparaben is 202-318-7. 
19 Specific References 
1 Decker RL, Wenninger JA. Frequency of preservative use in 
cosmetic formulas as disclosed to FDA—1987. Cosmet Toilet 
1987; 102(12): 21–24. 
2 Haag TE, Loncrini DF. Esters of para-hydroxybenzoic acid. In: 
Kabara JJ, ed. Cosmetic and Drug Preservation. New York: 
Marcel Dekker, 1984: 63–77. 
3 Wan LSC, Kurup TRR, Chan LW. Partition of preservatives in oil/ 
water systems. Pharm Acta Helv 1986; 61: 308–313. 
4 Aalto TR, Firman MC, Rigler NE. p-Hydroxybenzoic acid esters 
as preservatives I: uses, antibacterial and antifungal studies, 
properties and determination. J Am Pharm Assoc (Sci) 1953; 42: 
449–457. 
5 Kamada A, Yata N, Kubo K, Arakawa M. Stability of phydroxybenzoic 
acid esters in acidic medium. Chem Pharm Bull 
1973; 21: 2073–2076. 
6 Aoki M, Kameta A, Yoshioka I, Matsuzaki T. Application of 
surface active agents to pharmaceutical preparations I: effect of 
Tween 20 upon the antifungal activities of p-hydroxybenzoic acid 
esters in solubilized preparations [in Japanese]. J Pharm Soc Jpn 
1956; 76: 939–943. 
7 Sakamoto T, Yanagi M, Fukushima S, Mitsui T. Effects of some 
cosmetic pigments on the bactericidal activities of preservatives. J 
Soc Cosmet Chem 1987; 38: 83–98. 
8 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 637. 
See also Methylparaben. 
20 General References 
Golightly LK, Smolinske SS, Bennett ML, et al. Pharmaceutical 
excipients associated with inactive ingredients in drug products 
(part I). Med Toxicol 1988; 3: 128–165. 
See also Methylparaben. 
21 Authors 
R Johnson, R Steer. 
22 Date of Revision 
23 August 2005. 
Butylparaben 85

Calcium Alginate 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Alginic acid; calcium salt; Algin; CA33; calc algin; calcium 
polymannuronate; Calginate; E404; Kaltostat. 
3 Chemical Name and CAS Registry Number 
Calcium alginate [9005-35-0] 
4 Empirical Formula and Molecular Weight 
[(C6H7O6)2Ca]n 195.16 (calculated) 
219.00 (actual, average) 
Each calcium ion binds with two alginate molecules. The 
molecular weight of 195.16 relates to one alginate molecule, 
and the equivalent of half a calcium ion, therefore n = 1=2. 
Calcium alginate is a polyuronide made up of a sequence of 
two hexuronic acid residues, namely D-mannuronic acid and Lguluronic 
acid. The two sugars form blocks of up to 20 units 
along the chain, with the proportion of the blocks dependent on 
the species of seaweed and also the part of the seaweed used. 
The number and length of the blocks are important in 
determining the physical properties of the alginate produced; 
the number and sequence of the mannuronate and guluronate 
residues varies in the naturally occurring alginate. 
It has a typical macromolecular weight between 10 000 and 
600 000. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Emulsifiying agent; stabilizing agent; tablet disintegrant; 
thickener. 
7 Applications in Pharmaceutical Formulation 
or Technology 
In pharmaceutical formulations, calcium alginate and calciumsodium 
alginate have been used as tablet disintegrants.(1) The 
use of a high concentration (10%) of calcium-sodium alginate 
has been reported to cause slight speckling of tablets.(1) 
A range of different types of delivery systems intended for 
oral administration have been investigated. These exploit the 
gelling properties of calcium alginate.(2) Calcium alginate beads 
have been used to prepare floating dosage systems(3,4) containing 
amoxicillin,(5) frusemide,(6) and barium sulfate;(7) and as a 
means of providing a sustained or controlled-release action for 
sulindac,(8) diclofenac,(9,10) tiaramide,(11) insulin,(12) and ampicillin.(
13) The use of calcium alginate beads, reinforced with 
chitosan, may be useful for the controlled release of protein 
drugs to the gastro-intestinal tract.(14) The bioadhesive properties 
of calcium alginate beads have also been investigated.(15) 
A series of studies investigating the production,(16) formulation,(
17) and drug release(18) from calcium alginate matrices for 
oral administration have been published. The release of 
diltiazem hydrochloride from a polyvinyl alcohol matrix was 
shown to be controlled by coating with a calcium alginate 
membrane; the drug release profile could be modified by 
increasing the coating thickness of the calcium alginate layer.(19) 
The microencapsulation of live attenuated Bacillus Calmette– 
Gue.rin (BCG) cells within a calcium alginate matrix has also 
been reported.(20) 
It has been shown that a modified drug release can be 
obtained from calcium alginate microcapsules,(21) pellets,(22,23) 
and microspheres.(24) When biodegradable bone implants 
composed of calcium alginate spheres and containing gentamicin 
were introduced into the femur of rats, effective drug 
levels in bone and soft tissue were obtained for 30 days and 7 
days, respectively.(25) 
Therapeutically, the gelling properties of calcium alginate 
are utilized in wound dressings in the treatment of leg ulcers, 
pressure sores, and other exuding wounds. These dressings are 
highly absorbent and are suitable for moderately or heavily 
exuding wounds. Calcium alginate dressings also have hemostatic 
properties, with calcium ions being exchanged for sodium 
ions in the blood; this stimulates both platelet activation and 
whole blood coagulation. A mixed calcium–sodium salt of 
alginic acid is used as fibers in dressings or wound packing 
material. 
Sterile powder consisting of a mixture of calcium and 
sodium alginates has been used in place of talc in glove 
powders. 
In foods, calcium alginate is used as an emulsifier, thickener, 
and stabilizer. 
8 Description 
Calcium alginate is an odorless or almost odorless, tasteless, 
white to pale yellowish-brown powder or fibers. 
9 Pharmacopeial Specifications 
See Section 18. 
10 Typical Properties 
Moisture content: loses not more than 22% of its weight on 
drying. 
Solubility: practically insoluble in chloroform, ethanol, ether, 
water, and other organic solvents. Soluble in dilute solutions 
of sodium citrate and of sodium bicarbonate and in sodium 
chloride solution. Soluble in alkaline solutions or in 
solutions of substances that combine with calcium. 
11 Stability and Storage Conditions 
Calcium alginate can be sterilized by autoclaving at 1158C for 
30 minutes or by dry heat at 1508C for 1 hour. Calcium alginate 
should be stored in airtight containers.

12 Incompatibilities 
Calcium alginate is incompatible with alkalis and alkali salts. 
Propranolol hydrochloride has been shown to bind to alginate 
molecules, suggesting that propranolol and calcium ions share 
common binding sites in the alginate chains; the formation of 
the calcium alginate gel structure was impeded in the presence 
of propranolol molecules.(26) 
13 Method of Manufacture 
Calcium alginate can be obtained from seaweed, mainly species 
of Laminaria. 
Solutions of sodium alginate interact with an ionized 
calcium salt, resulting in the instantaneous precipitation of 
insoluble calcium alginate, which can then be further processed. 
Introducing varying proportions of sodium ions during 
manufacture can produce products having different absorption 
rates. 
14 Safety 
Calcium alginate is widely used in oral and topical formulations, 
and in foods. 
In 1974, the WHO set an estimated acceptable daily intake 
of calcium alginate of up to 25 mg, as alginic acid, per kilogram 
body-weight.(27) 
When heated to decomposition, it emits acrid smoke and 
irritating fumes. 
LD50 (rat, IP): 1.41 g/kg(28) 
LD50 (rat, IV): 0.06 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of the material handled. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral tablets). 
Included in nonparenteral medicines licensed in the UK. 
17 Related Substances 
Alginic acid; potassium alginate; sodium alginate; propylene 
glycol alginate. 
18 Comments 
Although not included in any pharmacopeias, a specification 
for calcium alginate is contained in the Food Chemicals Codex 
(FCC),(29) and has been included in the British Pharmaceutical 
Codex (BPC);(30) see Table I. 
Table I: FCC(29) and BPC(30) specifications for calcium alginate. 
Test FCC 1996 BPC 1973 
Arsenic 43 ppm 43ppm 
Ash 12–18% — 
Heavy metals 40.004% (as lead) — 
Iron — 4530 ppm 
Lead 410 ppm 410 ppm 
Loss on drying 415% 22.00% 
Sulfated ash — 31.0–34.0% 
Assay 89.6–104.5% — 
19 Specific References 
1 Khan KA, Rhodes CT. A comparative evaluation of some alginates 
as tablet disintegrants. Pharm Acta Helv 1972; 47: 41–50. 
2 Tonnesen HH, Karlsen J. Alginate in drug delivery systems. Drug 
Dev Ind Pharm 2002; 28(6): 621–630. 
3 Iannuccelli V, Coppi G, Bernabei MT, Cameroni R. Air compartment 
multiple-unit system for prolonged gastric residence. Part 1 
Formulation study. Int J Pharm 1998; 174: 47–54. 
4 Whitehead L, Fell JT, Collett JH, Sharma HL, Smith AM. Floating 
dosage forms: in vivo study demonstrating prolonged gastric 
retention. J Control Release 1998; 55: 3–12. 
5 Whitehead L, Collett JH, Fell JT. Amoxicillin release from a 
floating dosage form based on alginates. Int J Pharm 2000; 210: 
45–49. 
6 Iannuccelli V, Coppi G, Leo E. PVP solid dispersions for the 
controlled release of frusemide from a floating multiple-unit 
system. Drug Dev Ind Pharm 2000; 26(6): 595–603. 
7 Iannuccelli V, Coppi G, Sansone R, Ferolla G. Air compartment 
multiple-unit system for prolonged gastric residence. Part 2. In 
vivo evaluation. Int J Pharm 1998; 174: 55–62. 
8 Abd-Elmageed A. Preparation and evaluation of sulindac alginate 
beads. Bull Pharm Sci Assiut Univ 1999; 22(1): 73–80. 
9 Mirghani A, Idkaidek NM, Salem MS, Najib NM. Formulation 
and release behavior of diclofenac sodium in Compritol 888 
matrix beads encapsulated in alginate. Drug Dev Ind Pharm 2000; 
26(7): 791–795. 
10 Turkoglu M, Gursoy A, Eroglu L, Okar I. Effect of aqueous 
polymer dispersions on properties of diclofenac/alginate beads and 
in vivo evaluation in rats. STP Pharm Sci 1997; 7(2): 135–140. 
11 Fathy M, Safwat SM, El-Shanawany SM, Tous SS, Otagiri M. 
Preparation and evaluation of beads made of different calcium 
alginate compositions for oral sustained release of tiaramide. 
Pharm Dev Tech 1998; 3(3): 355–364. 
12 Rasmussen MR, Snabe T, Pedersen LH. Numerical modelling of 
insulin and amyloglucosidase release from swelling Ca-alginate 
beads. J Controlled Release 2003; 91(3): 395–405. 
13 Torre ML, Giunchedi P, Maggi L, et al. Formulation and 
characterization of calcium alginate beads containing ampicillin. 
Pharm Dev Tech 1998; 3(2): 193–198. 
14 Anal AK, Bhopatkar D, Tokura S, Tamura H, Stevens WF. 
Chitosan-alginate multilayer beads for gastric passage and 
controlled intestinal release of protein. Drug Dev Ind Pharm 
2003; 29(6): 713–724. 
15 Gaserod O, Jolliffe IG, Hampson FC, Dettmar PW, Skjak-Braek G. 
Enhancement of the bioadhesive properties of calcium alginate gel 
beads by coating with chitosan. Int J Pharm 1998; 175: 237–246. 
16 Ostberg T, Graffner C. Calcium alginate matrices for oral multiple 
unit administration. Part 1. Pilot investigations of production 
method. Acta Pharm Nord 1992; 4(4): 201–208. 
17 Ostberg T, Vesterhus L, Graffner C. Calcium alginate matrices for 
oral multiple unit administration. Part 2. Effect of process and 
formulation factors on matrix properties. Int J Pharm 1993; 97: 
183–193. 
18 Ostberg T, Lund EM, Graffner C. Calcium alginate matrices for 
oral multiple unit administration. Part 4. Release characteristics in 
different media. Int J Pharm 1994; 112: 241–248. 
Calcium Alginate 87

19 Coppi G, Iannuccelli V, Cameroni R. Polysaccharide film-coating 
for freely swellable hydrogels. Pharm Dev Tech 1998; 3(3): 347– 
353. 
20 Esquisabel A, Hernandez RM, Igartua M, et al. Production of BCG 
alginate-PLL microcapsules by emulsification/internal gelation. J 
Microencapsul 1997; 14(5): 627–638. 
21 El-Gibaly I, Anwar MM. Development, characterization and in 
vivo evaluation of polyelectrolyte complex membrane gel microcapsules 
containing melatonin-resin complex for oral use. Bull 
Pharm Sci Assiut Univ 1998; 21(2): 117–139. 
22 Pillay V, Fassihi R. In vitro modulation from cross-linked pellets 
for site-specific drug delivery to the gastrointestinal tract. Part 1. 
Comparison of pH-responsive drug release and associated kinetics. 
J Control Release 1999; 59: 229–242. 
23 Pillay V, Fassihi R. In vitro release modulation from cross-linked 
pellets for site-specific drug delivery to the gastrointestinal tract. 
Part 2. Physicochemical characterization of calcium-alginate, 
calcium-pectinate and calcium-alginate-pectinate pellets. J Control 
Release 1999; 59: 243–256. 
24 Chickering DE, Jacob JS, Desai TA, et al. Bioadhesive microspheres. 
Part 3. In vivo transit and bioavailability study of drug 
loaded alginate and poly (fumaric–co-sebacic anhydride) microspheres. 
J Control Release 1997; 48: 35–46. 
25 Iannuccelli V, Coppi G, Bondi M, et al. Biodegradable intraoperative 
system for bone infection treatment. Part 2. In vivo evaluation. 
Int J Pharm 1996; 143: 187–194. 
26 Lim LY, Wan LSC. Propranolol hydrochloride binding in calcium 
alginate beads. Drug Dev Ind Pharm 1997; 23(10): 973–980. 
27 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications. 
Seventeenth report of the joint FAO/WHO expert committee on 
food additives.World Health Organ Tech Rep Ser 1974; No. 539. 
28 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 668. 
29 Food Chemicals Codex, 4th edn. Washington, DC: National 
Academy Press, 1996: 54. 
30 British Pharmaceutical Codex. London: Pharmaceutical Press, 
1973: 66. 
20 General References 
—
21 Authors 
CG Cable. 
22 Date of Revision 
22 August 2005. 
88 Calcium Alginate

Calcium Carbonate 
1 Nonproprietary Names 
BP: Calcium carbonate 
JP: Precipitated calcium carbonate 
PhEur: Calcii carbonas 
USP: Calcium carbonate 
2 Synonyms 
Calcium carbonate (1 : 1); carbonic acid calcium salt 1:1; creta 
preparada; Destab; E170; MagGran CC; Micromite; Pharma- 
Carb; precipitated carbonate of lime; precipitated chalk; 
Vivapress Ca; Witcarb. 
3 Chemical Name and CAS Registry Number 
Carbonic acid, calcium salt (1 : 1) [471-34-1] 
4 Empirical Formula and Molecular Weight 
CaCO3 100.09 
5 Structural Formula 
CaCO3 
6 Functional Category 
Buffering agent; coating agent; opacifier; tablet and capsule 
diluent; therapeutic agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Calcium carbonate, employed as a pharmaceutical excipient, is 
mainly used in solid-dosage forms as a diluent.(1–6) It is also 
used as a base for medicated dental preparations, as a buffering 
agent, and as a dissolution aid in dispersible tablets. Calcium 
carbonate is used as a bulking agent in tablet sugar-coating 
processes and as an opacifier in tablet film-coating. 
Calcium carbonate is also used as a food additive and 
therapeutically as an antacid and calcium supplement. 
8 Description 
Calcium carbonate occurs as an odorless and tasteless white 
powder or crystals. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for calcium carbonate. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters — . — 
Loss on drying 41.0% 42.0% 42.0% 
Substances 
insoluble in 
acetic acid 
40.2% 40.2% 40.2% 
Fluoride — — 40.005% 
Arsenic 45 ppm 44 ppm 43 ppm 
Barium . . . 
Chlorides — 4330 ppm — 
Lead — — 43 ppm 
Iron — 4200 ppm 40.1% 
Heavy metals 420 ppm 420 ppm 40.002% 
Magnesium and 
alkali (metals) 
salts 
40.5% 41.5% 41.0% 
Sulfates — 40.25% — 
Mercury — — 40.5 mg/g 
Organic volatile 
impurities 
— — . 
Assay (dried basis) 5 98.5% 98.5%–100.5% 98.0%–100.5% 
SEM: 1 
Excipient: Calcium carbonate 
Manufacturer: Whittaker, Clark & Daniels 
Lot No.: 15A-3 
Magnification: 600 Voltage: 20 kV

SEM: 2 
Excipient: Calcium carbonate 
Manufacturer: Whittaker, Clark & Daniels 
Lot No.: 15A-3 
Magnification: 2400 Voltage: 20 kV 
SEM: 3 
Excipient: Calcium carbonate 
Manufacturer: Whittaker, Clark & Daniels 
Lot No.: 15A-4 
Magnification: 600 Voltage: 20 kV 
SEM: 4 
Excipient: Calcium carbonate 
Manufacturer: Whittaker, Clark & Daniels 
Lot No.: 15A-4 
Magnification: 2400 Voltage: 20 kV 
SEM: 5 
Excipient: Calcium carbonate 
Manufacturer: Whittaker, Clark & Daniels 
Lot No.: 15A-2 
Magnification: 600 Voltage: 20 kV 
90 Calcium Carbonate

SEM: 6 
Excipient: Calcium carbonate 
Manufacturer: Whittaker, Clark & Daniels 
Lot No.: 15A-2 
Magnification: 2400 Voltage: 20 kV 
10 Typical Properties 
Acidity/alkalinity: pH = 9.0 (10% w/v aqueous dispersion) 
Density (bulk): 0.8 g/cm3 
Density (tapped): 1.2 g/cm3 
Flowability: cohesive. 
Hardness (Mohs): 3.0 for Millicarb. 
Melting point: decomposes at 8258C. 
Moisture content: see Figure 1. 
Particle size: see Figure 2. 
Refractive index: 1.59 
Solubility: practically insoluble in ethanol (95%) and water. 
Solubility in water is increased by the presence of 
ammonium salts or carbon dioxide. The presence of alkali 
hydroxides reduces solubility. 
Specific gravity: 2.7 
Specific surface area: 6.21–6.47m2/g 
11 Stability and Storage Conditions 
Calcium carbonate is stable and should be stored in a wellclosed 
container in a cool, dry place. 
12 Incompatibilities 
Incompatible with acids and ammonium salts (see also Sections 
10 and 18). 
13 Method of Manufacture 
Calcium carbonate is prepared by double decomposition of 
calcium chloride and sodium bicarbonate in aqueous solution. 
Density and fineness are governed by the concentrations of the 
solutions. Calcium carbonate is also obtained from the 
naturally occurring minerals aragonite, calcite, and vaterite. 
14 Safety 
Calcium carbonate is mainly used in oral pharmaceutical 
formulations and is generally regarded as a nontoxic material. 
However, calcium carbonate administered orally may cause 
constipation and flatulence. Consumption of large quantities 
(4–60 g daily) may also result in hypercalcemia or renal 
impairment.(7) Therapeutically, oral doses of up to about 
1.5 g are employed as an antacid. In the treatment of 
hyperphosphatemia in patients with chronic renal failure, oral 
daily doses of 2.5–17 g have been used. Calcium carbonate may 
interfere with the absorption of other drugs from the 
gastrointestinal tract if administered concomitantly. 
LD50 (rat, oral): 6.45 g/kg 
Figure 1: Moisture sorption–desorption isotherm of calcium carbonate. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Calcium carbonate may be 
irritant to the eyes and on inhalation. Eye protection, gloves, 
and a dust mask are recommended. Calcium carbonate should 
be handled in a well-ventilated environment. In the UK, the 
long-term (8-hour TWA) occupational exposure limit for 
calcium carbonate is 10 mg/m3 for total inhalable dust and 
4 mg/m3 for respirable dust.(8) 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral capsules 
and tablets; otic solutions). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
— 
Calcium Carbonate 91

Figure 2: Particle-size distribution of calcium carbonate (Sturcal, 
Rhodia). 
*: Sturcal F 
&: Sturcal H 
~: Sturcal L 
18 Comments 
When calcium carbonate is used in tablets containing aspirin 
and related substances, traces of iron may cause discoloration. 
This may be overcome by inclusion of a suitable chelating 
agent. Grades with reduced lead levels are commercially 
available for use in antacids and calcium supplements. 
Directly compressible tablet diluents containing calcium 
carbonate and other excipients are commercially available. 
Examples of such grades are Barcroft CS90 (containing 10% 
starch), Barcroft CX50 (containing 50% sorbitol), and 
Barcroft CZ50 (containing 50% sucrose) available from SPI 
Pharma. Available from DMV International, are Cal-Carb 
4450 PG (containing maltodextrin), and Cal-Carb 4457 and 
Cal-Carb 4462 (both containing pregelatinized corn starch). 
Two directly compressible grades containing only calcium 
carbonate are commercially available (Vivapress Ca 740 and 
Vivapress Ca 800, J. Rettenmaier and So. hne). 
A specification for calcium carbonate is contained in the 
Food Chemicals Codex (FCC). 
The EINECS number for calcium carbonate is 207-439-9. 
19 Specific References 
1 Haines-Nutt RF. The compression properties of magnesium and 
calcium carbonates. J Pharm Pharmacol 1976; 28: 468–470. 
2 Ejiofor O, Esezebo S, Pilpel N. The plasto-elasticity and 
compressibility of coated powders and the tensile strength of their 
tablets. J Pharm Pharmacol 1986; 38: 1–7. 
3 Gorecki DKJ, Richardson CJ, Pavlakidis P, Wallace SM. Dissolution 
rates in calcium carbonate tablets: a consideration in product 
selection. Can J Pharm 1989; 122: 484–487, 508. 
4 Allen LV. Featured excipient: capsule and tablet diluents. Int J 
Pharm Compound 2000; 4(4): 306–310, 324–325. 
5 Mattsson S, Nystrom C. Evaluation of strength-enhancing factors 
of a ductile binder in direct compression of sodium bicarbonate 
and calcium carbonate powders. Eur J Pharm Sci 2000; 10(1): 53– 
66. 
6 Serra MD, Robles LV. Compaction of agglomerated mixtures of 
calcium carbonate and microcrystalline cellulose. Int J Pharm 
2003; 258(1–2): 153–164. 
7 Orwoll ES. The milk-alkali syndrome: current concepts. Ann 
Intern Med 1982; 97: 242–248. 
8 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
Armstrong NA. Tablet manufacture. In: Swarbrick J, Boylan JC, eds. 
Encyclopedia of Pharmaceutical Technology, 2nd edn, vol. 3. New 
York: Marcel Dekker, 2002: 2713–2732. 
Ciancio SG. Dental products. In: Swarbrick J, Boylan JC, eds. 
Encyclopedia of Pharmaceutical Technology, 2nd edn, vol. 3. 
New York: Marcel Dekker, 2002: 691–701. 
Roberts DE, Rogers CM, Richards CE, Lee MG. Calcium carbonate 
mixture. Pharm J 1986; 236: 577. 
21 Authors 
NA Armstrong. 
22 Date of Revision 
16 August 2005. 
92 Calcium Carbonate

Calcium Phosphate, Dibasic Anhydrous 
1 Nonproprietary Names 
BP: Anhydrous calcium hydrogen phosphate 
JP: Anhydrous dibasic calcium phosphate 
PhEur: Calcii hydrogenophosphas anhydricus 
USP: Dibasic calcium phosphate 
2 Synonyms 
A-TAB; calcium monohydrogen phosphate; calcium orthophosphate; 
Di-Cafos AN; dicalcium orthophosphate; E341; 
Emcompress Anhydrous; Fujicalin; phosphoric acid calcium 
salt (1 : 1); secondary calcium phosphate. 
3 Chemical Name and CAS Registry Number 
Dibasic calcium phosphate [7757-93-9] 
4 Empirical Formula and Molecular Weight 
CaHPO4 136.06 
5 Structural Formula 
CaHPO4 
6 Functional Category 
Tablet and capsule diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Anhydrous dibasic calcium phosphate is used both as an 
excipient and as a source of calcium in nutritional supplements. 
It is used particularly in the nutritional/health food sectors. It is 
also used in pharmaceutical products because of its compaction 
properties, and the good flow properties of the coarse-grade 
material.(1–5) The predominant deformation mechanism of 
anhydrous dibasic calcium phosphate coarse-grade is brittle 
fracture and this reduces the strain-rate sensitivity of the 
material, thus allowing easier transition from the laboratory to 
production scale. However, unlike the dihydrate, anhydrous 
dibasic calcium phosphate when compacted at higher pressures 
can exhibit lamination and capping. This phenomenon can be 
observed when the material represents a substantial proportion 
of the formulation and is exacerbated by the use of deep 
concave tooling. This phenomenon also appears to be 
independent of rate of compaction. 
Anhydrous dibasic calcium phosphate is abrasive and a 
lubricant is required for tableting, for example 1% w/w 
magnesium stearate or 1% w/w sodium stearyl fumarate. 
Two particle-size grades of anhydrous dibasic calcium 
phosphate are used in the pharmaceutical industry. Milled 
material is typically used in wet-granulated or roller-compacted 
formulations. The ‘unmilled’ or coarse-grade material is 
typically used in direct-compression formulations. 
Anhydrous dibasic calcium phosphate is nonhygroscopic 
and stable at room temperature. It does not hydrate to form the 
dihydrate. 
Anhydrous dibasic calcium phosphate is used in toothpaste 
and dentifrice formulations for its abrasive properties. 
8 Description 
Anhydrous dibasic calcium phosphate is a white, odorless, 
tasteless powder or crystalline solid. It occurs as triclinic 
crystals. 
SEM: 1 
Excipient: Emcompress Anhydrous 
Manufacturer: JRS Pharma LP 
Magnification: 50 Voltage: 5kV 
SEM: 2 
Excipient: Emcompress Anhydrous 
Manufacturer: JRS Pharma LP 
Magnification: 200 Voltage: 5kV

9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for calcium phosphate, dibasic 
anhydrous. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters . . — 
Loss on ignition — — 6.6–8.5% 
Loss on drying 41.0% 42.0% — 
Acid insoluble substance 40.05% — 40.2% 
Heavy metals 431 ppm 440 ppm 40.003% 
Chloride 40.248% 4330 ppm 40.25% 
Fluoride — 4100 ppm 40.005% 
Sulfate 40.200% 40.5% 40.5% 
Carbonate . . . 
Barium . . . 
Arsenic 42 ppm 410 ppm 43 mg/g 
Organic volatile impurities — — . 
Iron — 4400 ppm — 
Assay (dried basis) 598.0% 98.0–101.0% 98.0–105.0% 
10 Typical properties 
Acidity/alkalinity: 
pH = 7.3 (20% slurry); 
pH = 5.1 (20% slurry of A-TAB); 
pH = 6.1–7.2 (5% slurry of Fujicalin). 
Angle of repose: 328 (for Fujicalin) 
Density: 2.89 g/cm3 
Density (bulk): 
0.78 g/cm3 for A-TAB; 
0.45 g/cm3 for Fujicalin. 
Density (tapped): 
0.82 g/cm3 for A-TAB; 
0.46 g/cm3 for Fujicalin. 
Melting point: does not melt; decomposes at 4258C to form 
calcium pyrophosphate. 
Moisture content: 0.1–0.2%. The anhydrous material contains 
only surface-adsorbed moisture and cannot be rehydrated to 
form the dihydrate. 
Particle size distribution: 
A-TAB: average particle diameter 180 mm; 
Encompress Anhydrous: average particle diameter 136 mm; 
Fujicalin: average particle diameter 94 mm; 
Powder: average particle diameter: 15 mm. 
Solubility: practically insoluble in ether, ethanol, and water; 
soluble in dilute acids. 
Specific surface area: 
20–30m2/g for A-TAB; 
35m2/g for Fujicalin. 
11 Stability and Storage Conditions 
Dibasic calcium phosphate anhydrous is a nonhygroscopic, 
relatively stable material. Under conditions of high humidity it 
does not hydrate to form the dihydrate. 
The bulk material should be stored in a well-closed 
container in a dry place. 
12 Incompatibilities 
Dibasic calcium phosphate should not be used to formulate 
tetracyline antibiotics.(6) 
The surface of milled anhydrous dibasic calcium phosphate 
is alkaline(2) and consequently it should not be used with drugs 
that are sensitive to alkaline pH. However, reports(7,8) suggest 
there are differences in the surface alkalinity/acidity between 
the milled and unmilled grades of anhydrous dibasic calcium 
phosphate; the unmilled form has an acidic surface environment. 
This difference has important implications for drug 
stability, particularly when reformulating from, e.g. roller 
compaction to direct compression, when the particle size of 
the anhydrous dibasic calcium phosphate might be expected to 
change. 
Dibasic calcium phosphate dihydrate has been reported to 
be incompatible with a number of drugs and excipients and 
many of these incompatibilities are expected to occur with 
dibasic calcium phosphate, anhydrous; see Calcium phosphate, 
dibasic dihydrate. 
13 Method of Manufacture 
Calcium phosphates are usually prepared by reacting very pure 
phosphoric acid with calcium hydroxide, Ca(OH)2 obtained 
from limestone, in stoichiometric ratio in aqueous suspension(2) 
followed by drying at a temperature that will allow the correct 
hydration state to be achieved. After drying, the coarse-grade 
material is obtained by means of a classification unit; the fine 
particle-size material is obtained by milling. Dibasic calcium 
phosphate, anhydrous, may also be prepared by spraydrying.(
9,10) 
14 Safety 
Dibasic calcium phosphate anhydrous is widely used in oral 
pharmaceutical products, food products, and toothpastes and 
is generally regarded as a relatively nontoxic and nonirritant 
material. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. The fine-milled grades can 
generate nuisance dusts and the use of a respirator or dust mask 
may be necessary. 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (oral capsules and tablets). 
Included in nonparenteral medicines licensed in Europe. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Calcium phosphate, dibasic dihydrate; calcium phosphate, 
tribasic; calcium sulfate. 
18 Comments 
Grades of anhydrous dibasic calcium phosphate available for 
direct compression include A-TAB (Rhodia), Di-Cafos AN 
(Chemische Fabrik Budenheim), Emcompress Anhydrous (JRS 
Pharma LP), and Fujicalin (Fuji Chemical Industry Co. Ltd.). 
The EINECS number for calcium phosphate is 231-837-1. 
94 Calcium Phosphate, Dibasic Anhydrous

19 Specific References 
1 Fischer E. Calcium phosphate as a pharmaceutical excipient. 
Manuf Chem 1992; 64(6): 25–27. 
2 Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical 
tableting 1: physico-pharmaceutical properties. Pharm World Sci 
1993; 15(3): 105–115. 
3 Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical 
tableting 2: comparison of tableting properties. Pharm World Sci 
1993; 15(3): 116–122. 
4 Hwang R-C, Peck GR. A systematic evaluation of the compression 
and tablet characteristics of various types of lactose and dibasic 
calcium phosphate. Pharm Technol 2001; 25(6): 54, 56, 58, 60, 
62, 64, 66, 68. 
5 Schlack H, Bauer-Brandl A, Schubert R, Becker D. Properties of 
Fujicalin, a new modified anhydrous dibasic calcium phosphate for 
direct compression: comparison with dicalcium phosphate dihydrate. 
Drug Dev Ind Pharm 2001; 27(8): 789–801. 
6 Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation 
Agents: A Handbook of Excipients. New York: Marcel Dekker. 
1989: 93–94. 
7 Dulin WA. Degradation of bisoprolol fumarate in tablets 
formulated with dicalcium phosphate. Drug Dev Ind Pharm 
1995; 21(4): 393–409. 
8 Glombitza BW, Oelkrug D, Schmidt PC. Surface acidity of solid 
pharmaceutical excipients I. Determination of the surface acidity. 
Eur J Pharm Biopharm 1994; 40(5): 289–293. 
9 Takami K, Machimura H, Takado K, Inagaki M, Kawashima Y. 
Novel preparation of free-flowing spherically granulated dibasic 
calcium phosphate anhydrous for direct tabletting. Chem Pharm 
Bull 1996; 44(4): 868–870. 
10 Schlack H, Bauer-Brandl A, Schubert R, Becker D. Properties of 
Fujicalin, a new modified anhydrous dibasic calcium phosphate 
dihydrate. Drug Dev Ind Pharm 2001; 27(9): 789–801. 
20 General References 
Bryan JW, McCallister JD. Matrix forming capabilities of three calcium 
diluents. Drug Dev Ind Pharm 1992; 18(19): 2029–2047. 
Carstensen JT, Ertell C. Physical and chemical properties of calcium 
phosphates for solid state pharmaceutical formulations. Drug Dev 
Ind Pharm 1990; 16(7): 1121–1133. 
Fuji Chemical Industry Co. Ltd. Technical literature: Fujicalin, 1998. 
Rhodia. Technical literature: Calcium phosphate excipients, 1999. 
21 Authors 
RC Moreton. 
22 Date of Revision 
30 August 2005. 
Calcium Phosphate, Dibasic Anhydrous 95

Calcium Phosphate, Dibasic Dihydrate 
1 Nonproprietary Names 
BP: Calcium hydrogen phosphate 
JP: Dibasic calcium phosphate 
PhEur: Calcii hydrogenophosphas dihydricus 
USP: Dibasic calcium phosphate 
2 Synonyms 
Calcium hydrogen orthophosphate dihydrate; calcium monohydrogen 
phosphate dihydrate; Di-Cafos; dicalcium orthophosphate; 
DI-TAB; E341; Emcompress; phosphoric acid 
calcium salt (1 : 1) dihydrate; secondary calcium phosphate. 
3 Chemical Name and CAS Registry Number 
Dibasic calcium phosphate dihydrate [7789-77-7] 
4 Empirical Formula and Molecular Weight 
CaHPO42H2O 172.09 
5 Structural Formula 
CaHPO42H2O 
6 Functional Category 
Tablet and capsule diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dibasic calcium phosphate dihydrate is widely used in tablet 
formulations both as an excipient and as a source of calcium 
and phosphorus in nutritional supplements.(1–8) It is one of the 
more widely used materials, particularly in the nutritional/ 
health food sectors. It is also used in pharmaceutical products 
because of its compaction properties, and the good flow 
properties of the coarse-grade material. The predominant 
deformation mechanism of dibasic calcium phosphate coarsegrade 
is brittle fracture and this reduces the strain-rate 
sensitivity of the material, thus allowing easier transition 
from the laboratory to production scale. However, dibasic 
calcium phosphate dihydrate is abrasive and a lubricant is 
required for tableting, for example about 1% w/w of 
magnesium stearate or about 1% w/w of sodium stearyl 
fumarate is commonly used. 
Two main particle-size grades of dibasic calcium phosphate 
dihydrate are used in the pharmaceutical industry. The milled 
material is typically used in wet-granulated, roller-compacted 
or slugged formulations. The ‘unmilled’ or coarse-grade 
material is typically used in direct-compression formulations. 
Dibasic calcium phosphate dihydrate is nonhygroscopic and 
stable at room temperature. However, under certain conditions 
of temperature and humidity, it can lose water of crystallization 
below 1008C. This has implications for certain types of 
packaging and aqueous film coating since the loss of water of 
crystallization appears to be initiated by high humidity and by 
implication high moisture vapor concentrations in the vicinity 
of the dibasic calcium phosphate dihydrate particles.(8) 
Dibasic calcium phosphate dihydrate is also used in toothpaste 
and dentifrice formulations for its abrasive properties. 
8 Description 
Dibasic calcium phosphate dihydrate is a white, odorless, 
tasteless powder or crystalline solid. It occurs as monoclinic 
crystals. 
SEM: 1 
Excipient: Dibasic calcium phosphate dihydrate, coarse grade 
Manufacturer: JRS Pharma LP. 
Lot No.: W28C 
Magnification: 100

SEM: 2 
Excipient: Dibasic calcium phosphate dihydrate, coarse grade 
Manufacturer: JRS Pharma LP. 
Lot No.: W28C 
Magnification: 300 
SEM: 3 
Excipient: Dibasic calcium phosphate dihydrate 
Manufacturer: Rhodia. 
Lot No.: 16A-1 (89) 
Magnification: 120 
SEM: 4 
Excipient: Dibasic calcium phosphate dihydrate, coarse grade 
Manufacturer: Rhodia. 
Lot No.: 16A-1 (89) 
Magnification: 600 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for calcium phosphate, dibasic 
dihydrate. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters . . — 
Loss on ignition — — 24.5–26.5% 
Loss on drying 19.5–22.0% — — 
Acid insoluble 
substances 
40.05% — 40.2% 
Heavy metals 431 ppm 440 ppm 40.003% 
Chloride 40.248% 4330 ppm 40.25% 
Fluoride — 4100 ppm 40.005% 
Sulfate 40.160% 40.5% 40.5% 
Carbonate . . . 
Barium . . . 
Arsenic 42 ppm 410 ppm 43 mg/g 
Organic volatile 
impurities 
— — . 
Iron — 4400 ppm — 
Assay 598.0% 98.0–105.0% 98.0–105.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 7.4 (20% slurry of DI-TAB) 
Angle of repose: 28.38 for Emcompress.(9) 
Density (bulk): 0.915 g/cm3 
Density (tapped): 1.17 g/cm3 
Density (true): 2.389 g/cm3 
Calcium Phosphate, Dibasic Dihydrate 97

Flowability: 
27.3 g/s for DI-TAB; 
11.4 g/s for Emcompress.(9) 
Melting point: dehydrates below 1008C. 
Moisture content: dibasic calcium phosphate dihydrate contains 
two molecules of water of crystallization, which can be 
lost at temperatures well below 1008C. 
Particle size distribution: DI-TAB: average particle diameter 
180 mm 
Fine powder: average particle diameter 9 mm 
Solubility: practically insoluble in ethanol, ether, and water; 
soluble in dilute acids. 
Specific surface area: 0.44–0.46m2/g for Emcompress 
11 Stability and Storage Conditions 
Dibasic calcium phosphate dihydrate is a nonhygroscopic, 
relatively stable material. However, under certain conditions 
the dihydrate can lose water of crystallization. This has 
implications for both storage of the bulk material and coating 
and packaging of tablets containing dibasic calcium phosphate 
dihydrate. 
The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Dibasic calcium phosphate dihydrate should not be used to 
formulate tetracycline antibiotics.(10) Dibasic calcium phosphate 
dihydrate has been reported to be incompatible with 
indomethacin,(11) aspirin,(12) aspartame,(13) ampicillin,(14) 
cephalexin,(15) and erythromycin.(16) The surface of dibasic 
calcium phosphate dihydrate is alkaline(16) and consequently it 
should not be used with drugs that are sensitive to alkaline pH. 
13 Method of Manufacture 
Calcium phosphates are usually manufactured by reacting very 
pure phosphoric acid with calcium hydroxide, Ca(OH)2 
obtained from limestone, in stoichiometric ratio in aqueous 
suspension followed by drying at a temperature that will allow 
the correct hydration state to be achieved. After drying, the 
coarse-grade material is obtained by means of a classification 
unit; the fine particle-size material is obtained by milling. 
14 Safety 
Dibasic calcium phosphate dihydrate is widely used in oral 
pharmaceutical products, food products, and toothpastes and 
is generally regarded as a nontoxic and nonirritant material. 
However, oral ingestion of large quantities may cause 
abdominal discomfort. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. The fine-milled grades can 
generate nuisance dusts and the use of a respirator or dust mask 
may be necessary. 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (oral capsules and tablets). 
Included in nonparenteral medicines licensed in Europe. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Calcium phosphate, dibasic anhydrous; calcium phosphate, 
tribasic. 
18 Comments 
Grades of dibasic calcium phosphate dihydrate available for 
direct compression include Calstar (FMC Biopolymer), Di- 
Cafos (Chemische Fabrik Budenheim), DI-TAB (Rhodia), and 
Emcompress (JRS Pharma LP). 
Accelerated stability studies carried out at elevated temperatures 
on formulations containing significant proportions of 
dibasic calcium phosphate dihydrate can give erroneous results 
owing to irreversible dehydration of the dihydrate to the 
anhydrous form. Depending on the type of packaging and 
whether or not the tablet is coated, the phenomenon can be 
observed at temperatures as low as 408C after 6 weeks of 
storage. As the amount of dibasic calcium phosphate dihydrate 
in the tablet is reduced, the effect is less easy to observe. 
The EINECS number for calcium phosphate is 231-837-1. 
19 Specific References 
1 Lausier JM, Chiang C-W, Zompa HA, Rhodes CT. Aging of tablets 
made with dibasic calcium phosphate dihydrate as matrix. J Pharm 
Sci 1977; 66(11): 1636–1637. 
2 Carstensen JT, Ertell C. Physical and chemical properties of 
calcium phosphates for solid state pharmaceutical formulations. 
Drug Dev Ind Pharm 1990; 16(7): 1121–1133. 
3 Bryan JW, McCallister JD. Matrix forming capabilities of three 
calcium diluents. Drug Dev Ind Pharm 1992; 18(19): 2029–2047. 
4 Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical 
tableting I: physico-pharmaceutical properties. Pharm World Sci 
1993; 15(3): 105–115. 
5 Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical 
tableting II: comparison of tableting properties. Pharm World Sci 
1993; 15(3): 116–122. 
6 Land..n M, Mart..nez-Pacheco R, Go.mez-Amoza JL, et al. The 
effect of country of origin on the properties of dicalcium phosphate 
dihydrate powder. Int J Pharm 1994; 103: 9–18. 
7 Land..n M, Mart..nez-Pacheco R, Go.mez-Amoza JL, et al. 
Dicalcium phosphate dihydrate for direct compression: characterization 
and intermanufacturer variability. Int J Pharm 1994; 109: 
1–8. 
8 Land..n M, Rowe RC, York P. Structural changes during the 
dehydration of dicalcium phosphate dihydrate. Eur J Pharm Sci 
1994; 2: 245–252. 
9 C. elik M, Okutgen E. A feasibility study for the development of a 
prospective compaction functionality test and the establishment of 
a compaction data bank. Drug Dev Ind Pharm 1993; 19(17–18): 
2309–2334. 
10 Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation 
Agents: A Handbook of Excipients. New York: Marcel Dekker, 
1989: 93–94. 
11 Eerika. inen S, Yliruusi J, Laakso R. The behaviour of the sodium 
salt of indomethacin in the cores of film-coated granules containing 
various fillers. Int J Pharm 1991; 71: 201–211. 
12 Land..n M, Perez-Marcos B, Casalderrey M, et al. Chemical 
stability of acetyl salicylic acid in tablets prepared with different 
commercial brands of dicalcium phosphate dihydrate. Int J Pharm 
1994; 107: 247–249. 
98 Calcium Phosphate, Dibasic Dihydrate

13 El-Shattawy HH, Peck GE, Kildsig DO. Aspartame direct 
compression excipients: preformulation stability screening using 
differential scanning calorimetry. Drug Dev Ind Pharm 1981; 7(5): 
605–619. 
14 El-Shattaway HH. Ampicillin direct compression excipients: 
preformulation stability screening using differential scanning 
calorimetry. Drug Dev Ind Pharm 1982; 8(6): 819–831. 
15 El-Shattaway HH, Kildsig DO, Peck GE. Cephalexin I direct 
compression excipients: preformulation stability screening using 
differential scanning calorimetry. Drug Dev Ind Pharm 1982; 8(6): 
897–909. 
16 El-Shattaway HH, Kildsig DO, Peck GE. Erythromycin direct 
compression excipients: preformulation stability screening using 
differential scanning calorimetry. Drug Dev Ind Pharm 1982; 8(6): 
937–947. 
20 General References 
Green CE, Makhija RG, Carstensen JT. R-P trials calcium excipient. 
Manuf Chem 1996; 67(8): 55, 57. 
Rhodia. Technical literature: Calcium phosphate excipients, 1999. 
21 Authors 
RC Moreton. 
22 Date of Revision 
22 August 2005. 
Calcium Phosphate, Dibasic Dihydrate 99

Calcium Phosphate, Tribasic 
1 Nonproprietary Names 
BP: Calcium phosphate 
PhEur: Tricalcii phosphas 
USPNF: Tribasic calcium phosphate 
2 Synonyms 
Calcium orthophosphate; E341; hydroxylapatite; phosphoric 
acid calcium salt (2 : 3); precipitated calcium phosphate; 
tertiary calcium phosphate; Tri-Cafos; tricalcium diorthophosphate; 
tricalcium orthophosphate; tricalcium phosphate; 
TRI-CALWG; TRI-TAB. 
3 Chemical Name and CAS Registry Number 
Tribasic calcium phosphate is not a clearly defined chemical 
entity but is a mixture of calcium phosphates. Several chemical 
names, CAS Registry Numbers, and molecular formulas have 
therefore been used to describe this material. Those most 
frequently cited are shown below. 
Calcium hydroxide phosphate [12167-74-7] 
Tricalcium orthophosphate [7758-87-4] 
See also Sections 4 and 8. 
4 Empirical Formula and Molecular Weight 
Ca3(PO4)2 310.20 
Ca5(OH)(PO4)3 502.32 
5 Structural Formula 
See Sections 3 and 4. 
6 Functional Category 
Anticaking agent; buffer; dietary supplement; glidant; tablet 
and capsule diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Tribasic calcium phosphate is widely used as a capsule diluent 
and tablet filler/binder in either direct-compression or wetgranulation 
processes. The primary bonding mechanism in 
compaction is plastic deformation. As with dibasic calcium 
phosphate, a lubricant and a disintegrant should usually be 
incorporated in capsule or tablet formulations that include 
tribasic calcium phosphate. In some cases tribasic calcium 
phosphate has been used as a disintegrant.(1) It is most widely 
used in vitamin and mineral preparations(2) as a filler and as a 
binder. It is a source of both calcium and phosphorus, the two 
main osteogenic minerals for bone health. The bioavailability 
of the calcium is well known to be improved by the presence of 
cholecalciferol. Recent research reports that combinations of 
tribasic calcium phosphate and vitamin D3 are a cost-effective 
advance in bone fracture prevention.(3) 
In food applications, tribasic calcium phosphate powder is 
widely used as an anticaking agent. See Section 18. 
See also Calcium phosphate, dibasic dihydrate. 
8 Description 
The PhEur 2005 states that tribasic calcium phosphate consists 
of a mixture of calcium phosphates. It contains not less than 
35.0% and not more than the equivalent of 40.0% of calcium. 
The USPNF 23 specifies that tribasic calcium phosphate 
consists of variable mixtures of calcium phosphates having 
the approximate composition 10CaO3P2O5H2O. This corresponds 
to a molecular formula of Ca5(OH)(PO4)3 or 
Ca10(OH)2(PO4)6. 
Tribasic calcium phosphate is a white, odorless and tasteless 
powder. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for tribasic calcium phosphate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Loss on ignition 48.0% 48.0% 
Water-soluble substances — 40.5% 
Acid-insoluble substances 40.2% 40.2% 
Carbonate — . 
Chloride 40.15% 40.14% 
Fluoride 475 ppm 40.0075% 
Nitrate — . 
Sulfate 40.5% 40.8% 
Arsenic 44 ppm 43 ppm 
Barium — . 
Iron 4400 ppm — 
Dibasic salt and calcium oxide — . 
Heavy metals 430 ppm 40.003% 
Assay (as Ca) 35.0–40.0% 34.0–40.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 6.8 (20% slurry in water) 
Density: 3.14 g/cm3 
Density (bulk): 
0.3–0.4 g/cm3 for powder form; 
0.80 g/cm3 for granular TRI-TAB.(4) 
Density (tapped): 0.95 g/cm3 for granular TRI-TAB.(4) 
Flowability: 25.0 g/s for granular TRI-TAB(4) 
Melting point: 16708C 
Moisture content: slightly hygroscopic. A well-defined crystalline 
hydrate is not formed although surface moisture may be 
picked up or contained within small pores in the crystal 
structure. At relative humidities between about 15% and 
65%, the equilibrium moisture content at 258C is about 
2.0%. At relative humidities above about 75%, tribasic 
calcium phosphate may absorb small amounts of moisture. 
Particle size distribution: Tribasic calcium phosphate powder: 
typical particle diameter 5–10 mm; 98% of particles <44 mm. 
TRI-CALWG: average particle diameter 180 mm;99%of 
particles<420 mm, 46%<149 mm, and 15%<44 mmin size.

TRI-TAB: average particle diameter 350 mm; 97% of 
particles <420 mm, and 2% <149 mm. 
Solubility: soluble in dilute mineral acids; very slightly soluble 
in water; practically insoluble in acetic acid and alcohols. 
Specific surface area: 70–80m2/g(4) 
11 Stability and Storage Conditions 
Tribasic calcium phosphate is a chemically stable material, and 
is also not liable to cake during storage. 
The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
All calcium salts are incompatible with tetracycline antibiotics. 
Tribasic calcium phosphate is incompatible with tocopheryl 
acetate (but not tocopheryl succinate). Tribasic calcium 
phosphate may form sparingly soluble phosphates with 
hormones. 
13 Method of Manufacture 
Tribasic calcium phosphate occurs naturally as the minerals 
hydroxylapatite, voelicherite, and whitlockite. Commercially, it 
is prepared by treating phosphate-containing rock with sulfuric 
acid. Tribasic calcium phosphate powder is then precipitated by 
the addition of calcium hydroxide. Tribasic calcium phosphate 
is alternatively prepared by treating calcium hydroxide from 
limestone with purified phosphoric acid. It may also be 
obtained from calcined animal bones.(5) Some tribasic calcium 
phosphate products may be prepared in coarser, directly 
compressible forms by granulating the powder using roller 
compaction or spray drying. 
14 Safety 
Tribasic calcium phosphate is widely used in oral pharmaceutical 
formulations and food products and is generally regarded 
as nontoxic and nonirritant at the levels employed as a 
pharmaceutical excipient. 
Ingestion or inhalation of excessive quantities may result in 
the deposition of tribasic calcium phosphate crystals in tissues. 
These crystals may lead to inflammation and cause tissue 
lesions in the areas of deposition. 
Oral ingestion of very large quantities of tribasic calcium 
phosphate may cause abdominal discomfort such as nausea and 
vomiting. 
No teratogenic effects were found in chicken embryos 
exposed to a dose of 2.5 mg of tribasic calcium phosphate.(6) 
LD50 (rat, oral): >1 g/kg(4) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. Handle in a well-ventilated environment since 
dust inhalation may be an irritant. For processes generating 
large amounts of dust, the use of a respirator is recommended. 
16 Regulatory Acceptance 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral capsules 
and tablets). Included in nonparenteral medicines licensed in 
the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Calcium phosphate, dibasic anhydrous; calcium phosphate, 
dibasic dihydrate. 
18 Comments 
One gram of tribasic calcium phosphate represents approximately 
10.9 mmol of calcium and 6.4 mmol of phosphate; 38% 
calcium and 17.3% phosphorus by weight.(4) Tribasic calcium 
phosphate provides a higher calcium load than dibasic calcium 
phosphate and a higher Ca/P ratio. Granular and fine powder 
forms of tribasic calcium phosphate are available from various 
manufacturers. 
A specification for calcium phosphate tribasic is contained 
in the Food Chemicals Codex (FCC). 
The EINECS number for calcium phosphate is 231-837-1. 
19 Specific References 
1 Delonca H, Puech A, Segura G, Youakim J. Effect of excipients and 
storage conditions on drug stability I: acetylsalicylic acid-based 
tablets [in French]. J Pharm Belg 1969; 24: 243–252. 
2 Magid L. Stable multivitamin tablets containing tricalcium 
phosphate. United States Patent No. 3,564,097; 1971. 
3 Lilliu H, Chapuy MC, Meunier PJ, et al. Calcium-vitamin D3 
supplementation is cost-effective in hip fractures prevention. 
Muturitas 2003; 44(4): 299–305. 
4 Rhodia. Technical literature: Calcium phosphate pharmaceutical 
ingredients, 1995. 
5 Magami A. Basic pentacalcium triphosphate production. Japanese 
Patent 56 022 614; 1981. 
6 Verrett MJ, Scott WF, Reynaldo EF, et al. Toxicity and 
teratogenicity of food additive chemicals in the developing chicken 
embryo. Toxicol Appl Pharmacol 1980; 56: 265–273. 
20 General References 
Bryan JW, McCallister JD. Matrix forming capabilities of three calcium 
diluents. Drug Dev Ind Pharm 1992; 18: 2029–2047. 
Chowhan ZT, Amaro AA. The effect of low- and high-humidity aging 
on the hardness, disintegration time and dissolution rate of tribasic 
calcium phosphate-based tablets. Drug Dev Ind Pharm 1979; 5: 
545–562. 
Fischer E. Calcium phosphate as a pharmaceutical excipient. Manuf 
Chem 1992; 64(6): 25–27. 
Kutty TRN. Thermal decomposition of hydroxylapatite. Indian J Chem 
1973; 11: 695–697. 
Molokhia AM, Moustafa MA, Gouda MW. Effect of storage 
conditions on the hardness, disintegration and drug release from 
some tablet bases. Drug Dev Ind Pharm 1982; 8: 283–292. 
Pontier C, Viana M. Energetic yields in apatitic calcium phosphate 
compression: influence of the Ca/P molar ratio. Polymer International 
2003; 52(4): 625–628. 
Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical 
tableting 1: physico-pharmaceutical properties. Pharm World Sci 
1993; 15(3): 105–115. 
Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical 
tableting 2: comparison of tableting properties. Pharm World Sci 
1993; 15(3): 116–122. 
21 Authors 
V King, L Hendricks, W Camarco. 
22 Date of Revision 
15 August 2005. 
Calcium Phosphate, Tribasic 101

Calcium Stearate 
1 Nonproprietary Names 
BP: Calcium stearate 
JP: Calcium stearate 
PhEur: Calcii stearas 
USPNF: Calcium stearate 
2 Synonyms 
Calcium distearate; HyQual; stearic acid, calcium salt; calcium 
octadecanoate; octadecanoic acid, calcium salt. 
3 Chemical Name and CAS Registry Number 
Octadecanoic acid calcium salt [1592-23-0] 
4 Empirical Formula and Molecular Weight 
C36H70CaO4 607.03 (for pure material) 
The PhEur 2005 describes calcium stearate as a mixture of 
calcium salts of different fatty acids consisting mainly of stearic 
acid [(C17H35COO)2Ca] and palmitic acid [(C15H31COO)2Ca] 
with minor proportions of other fatty acids. It contains the 
equivalent of 9.0–10.5% of calcium oxide. 
5 Structural Formula 
6 Functional Category 
Tablet and capsule lubricant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Calcium stearate is primarily used in pharmaceutical formulations 
as a lubricant in tablet and capsule manufacture at 
concentrations up to 1.0% w/w. Although it has good 
antiadherent and lubricant properties, calcium stearate has 
poor glidant properties. 
Calcium stearate is also employed as an emulsifier, stabilizing 
agent, and suspending agent, and is also used in cosmetics 
and food products. 
8 Description 
Calcium stearate occurs as a fine, white to yellowish-white, 
bulky powder having a slight, characteristic odor. It is unctuous 
and free from grittiness. 
SEM: 1 
Excipient: Calcium stearate (Standard) 
Manufacturer: Durham Chemicals 
Lot No.: 0364 
Voltage: 20 kV 
SEM: 2 
Excipient: Calcium stearate (Precipitated) 
Manufacturer: Witco Corporation 
Lot No.: 0438 
Voltage: 12 kV

SEM: 3 
Excipient: Calcium stearate (Fused) 
Manufacturer: Witco Corporation 
Voltage: 15 kV 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for calcium stearate. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters . . — 
Microbial limit — 103/g — 
Acidity or alkalinity — . — 
Loss on drying 44.0% 46.0% 44.0% 
Arsenic 42 ppm — — 
Heavy metals 420 ppm — 410 mg/g 
Chlorides — 40.1% — 
Sulfates — 40.3% — 
Cadmium — 43 ppm — 
Lead — 410 ppm — 
Nickel — 45 ppm — 
Organic volatile impurities — — . 
Assay (as CaO) — — 9.0–10.5% 
Assay (as Ca) 6.4–7.1% 6.4–7.4% — 
10 Typical Properties 
Acid value: 191–203 
Ash: 9.9–10.3% 
Chloride: <200 ppm 
Density (bulk and tapped): see Table II. 
Density (true): 1.064–1.096 g/cm3 
Flowability: 21.2–22.6% (Carr compressibility index) 
Free fatty acid: 0.3–0.5% 
Melting point: 149–1608C 
Moisture content: 2.96% 
Particle size distribution: 1.7–60 mm; 100% through a 73.7 mm 
(#200 mesh); 99.5% through a 44.5 mm (#325 mesh). 
Table II: Density (bulk and tapped) of calcium stearate. 
Bulk density (g/cm3) Tapped density (g/cm3) 
Durham Chemicals 
Standard — 0.26 
A — 0.45 
AM — 0.33 
Witco Corporation 
EA 0.21 0.27 
Fused 0.38 0.48 
Precipitated 0.16 0.20 
Shear strength: 14.71MPa 
Solubility: practically insoluble or insoluble in ethanol (95%), 
ether, chloroform, acetone and water. Slightly soluble in hot 
alcohol, and hot vegetable and mineral oils. Soluble in hot 
pyridine. 
Specific surface area: 4.73–8.03m2/g 
Sulfate: <0.25% 
11 Stability and Storage Conditions 
Calcium stearate is stable and should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
—
13 Method of Manufacture 
Calcium stearate is prepared by the reaction of calcium chloride 
with a mixture of the sodium salts of stearic and palmitic acids. 
The calcium stearate formed is collected and washed with water 
to remove any sodium chloride. 
14 Safety 
Calcium stearate is used in oral pharmaceutical formulations 
and is generally regarded as a relatively nontoxic and 
nonirritant material. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Calcium stearate should be 
used in a well-ventilated environment; eye protection, gloves, 
and a respirator are recommended. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(oral capsules and tablets). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Magnesium stearate; stearic acid; zinc stearate. 
18 Comments 
Calcium stearate exhibits interesting properties when heated; 
softening between 120–1308C, and exhibiting a viscous 
Calcium Stearate 103

consistency at approximately 1608C. At approximately 1008C, 
it loses about 3% of its weight, corresponding to one mole of 
water of crystallization. The crystalline structure changes at this 
point, leading to the collapse of the crystal lattice at a 
temperature of about 1258C.(1) 
See Magnesium stearate for further information and 
references. 
A specification for calcium stearate is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for calcium stearate is 216-472-8. 
19 Specific References 
1 SpecialChem (2005). Metallic stearates center. 
http://www.specialchem4polymers.com/tc/metallic-stearates/ 
index.aspx?id-2404 (accessed 9 August 2005). 
20 General References 
Bu. sch G, Neuwald F. Metallic soaps as water-in-oil emulsifiers [in 
German]. J Soc Cosmet Chem 1973; 24: 763–769. 
Phadke DS, Sack MJ. Evaluation of batch-to-batch and manufacturerto-
manufacturer variability in the physical and lubricant properties 
of calcium stearate. Pharm Technol 1996; 20(Mar): 126–140. 
21 Authors 
LV Allen. 
22 Date of Revision 
9 August 2005. 
104 Calcium Stearate

Calcium Sulfate 
1 Nonproprietary Names 
BP: Calcium sulphate dihydrate 
PhEur: Calcii sulfas dihydricus 
USPNF: Calcium sulfate 
2 Synonyms 
Calcium sulfate anhydrous: anhydrite; anhydrous gypsum; 
anhydrous sulfate of lime; Destab; Drierite; E516; karstenite; 
muriacite; Snow White. 
Calcium sulfate dihydrate: alabaster; Cal-Tab; Compactrol; 
Destab; E516; gypsum; light spar; mineral white; native 
calcium sulfate; precipitated calcium sulfate; satinite; satin 
spar; selenite; terra alba; USG Terra Alba. 
3 Chemical Name and CAS Registry Number 
Calcium sulfate [7778-18-9] 
Calcium sulfate dihydrate [10101-41-4] 
4 Empirical Formula and Molecular Weight 
CaSO4 136.14 
CaSO42H2O 172.17 
5 Structural Formula 
CaSO4 
CaSO42H2O 
6 Functional Category 
Tablet and capsule diluent. The anhydrous form is used as a 
desiccant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Calcium sulfate dihydrate is used in the formulation of tablets 
and capsules. In granular form it has good compaction 
properties and moderate disintegration properties.(1,2) 
Calcium sulfate hemihydrate (see Section 17), is used in the 
preparation of plaster of Paris bandage, which is used for the 
immobilization of limbs and fractures; it should not be used in 
the formulation of tablets or capsules. 
Anhydrous calcium sulfate is hygroscopic and uptake of 
water can cause the tablets to become very hard and to fail to 
disintegrate on storage. It is not recommended for the 
formulation of tablets, capsules, or powders for oral administration. 
Therapeutically, calcium sulfate is used in dental and 
craniofacial surgical procedures.(3,4) 
8 Description 
A white or off-white, fine, odorless, and tasteless powder or 
granules. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for calcium sulfate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Acidity or alkalinity . — 
Arsenic 410 ppm — 
Chlorides 4300 ppm — 
Heavy metals 420 ppm 40.001% 
Iron 4100 ppm 40.01% 
Loss on drying 
Anhydrous — 41.5% 
Dihydrate — 19.0–23.0% 
Loss on ignition 18.0–22.0% — 
Assay 98.0–102.0% 98.0–101.0% 
10 Typical properties 
Acidity/alkalinity: 
pH = 7.3 (10% slurry) for dihydrate; 
pH = 10.4 (10% slurry) for anhydrous material. 
Angle of repose: 37.68 for Compactrol.(2) 
Compressibility: see Figure 1. 
Figure 1: Compression characteristics of calcium sulfate dihydrate. 
Tablet weight: 700 mg.

Density (bulk): 
0.94 g/cm3 for Compactrol;(2) 
0.67 g/cm3 for dihydrate; 
0.70 g/cm3 for anhydrous material. 
Density (tapped): 
1.10 g/cm3 for Compactrol;(2) 
1.12 g/cm3 for dihydrate; 
1.28 g/cm3 for anhydrous material. 
Density (true): 2.308 g/cm3 
Flowability: 48.4% (Carr compressibility index); 5.2 g/s for 
Compactrol.(2) 
Melting point: 14508C for anhydrous material. 
Particle size distribution: 93% less than 45 mm in size for the 
dihydrate (USG Terra Alba); 97% less than 45 mm in size for 
the anhydrous material (Snow White). Average particle size 
is 17 mm for the dihydrate and 8 mm for the anhydrous 
material. For Compactrol, not less than 98% passes through 
a #40 screen (425 mm), and not less than 85% is retained in a 
#140 screen (100 mm). 
Solubility: see Table II. 
Table II: Solubility of calcium sulfate dihydrate. 
Solvent Solubility at 208C unless otherwise stated 
Ethanol (95%) Practically insoluble 
Water 1 in 375 
1 in 485 at 1008C 
Specific gravity: 
2.32 for dihydrate; 
2.96 for anhydrous material. 
Specific surface area: 3.15m2/g (Strohlein apparatus) 
11 Stability and Storage Conditions 
Calcium sulfate is chemically stable. Anhydrous calcium sulfate 
is hygroscopic and may cake on storage. Store in a well-closed 
container in a dry place, avoiding heat. 
12 Incompatibilities 
In the presence of moisture, calcium salts may be incompatible 
with amines, amino acids, peptides, and proteins, which may 
form complexes. Calcium salts will interfere with the bioavailability 
of tetracycline antibiotics.(5) It is also anticipated that 
calcium sulfate would be incompatible with indomethacin,(6) 
aspirin,(7) aspartame,(8) ampicillin,(9) cephalexin,(10) and erythromycin(
11) since these materials are incompatible with other 
calcium salts. 
Calcium sulfate may react violently, at high temperatures, 
with phosphorus and aluminum powder; it can react violently 
with diazomethane. 
13 Method of Manufacture 
Anhydrous calcium sulfate occurs naturally as the mineral 
anhydrite. The naturally occurring rock gypsum may be 
crushed and ground for use as the dihydrate or calcined at 
1508C to produce the hemihydrate. A purer variety of calcium 
sulfate may also be obtained chemically by reacting calcium 
carbonate with sulfuric acid or by precipitation from calcium 
chloride and a soluble sulfate. 
14 Safety 
Calcium sulfate dihydrate is used as an excipient in oral capsule 
and tablet formulations. At the levels at which it is used as an 
excipient, it is generally regarded as nontoxic. However, 
ingestion of a sufficiently large quantity can result in obstruction 
of the upper intestinal tract after absorption of moisture. 
Owing to the limited intestinal absorption of calcium from 
its salts, hypercalcemia cannot be induced even after the 
ingestion of massive oral doses. 
Calcium salts are soluble in bronchial fluid. Pure salts do not 
induce pneumoconiosis. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. The fine-milled grades can 
generate nuisance dusts that may be irritant to the eyes or on 
inhalation. The use of a respirator or dust mask is recommended 
to prevent excessive powder inhalation since excessive 
inhalation may saturate the bronchial fluid, leading to 
precipitation and thus blockage of the air passages. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral capsules, 
sustained release, tablets). Included in nonparenteral medicines 
licensed in the UK and Europe. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Calcium phosphate, dibasic anhydrous; calcium phosphate, 
dibasic dihydrate; calcium phosphate, tribasic; calcium sulfate 
hemihydrate. 
Calcium sulfate hemihydrate 
Empirical formula: CaSO41=2H2O 
Molecular weight: 145.14 
CAS number: [26499-65-0] 
Synonyms: annalin; calcii sulfas hemihydricus; calcined gypsum; 
dried calcium sulfate; dried gypsum; E516; exsiccated 
calcium sulfate; plaster of Paris; sulfate of lime; yeso blanco. 
Appearance: a white or almost white, odorless, crystalline, 
hygroscopic powder. 
Solubility: practically insoluble in ethanol (95%); slightly 
soluble in water; more soluble in dilute mineral acids. 
Comments: the BP 2004 defines dried calcium sulfate as 
predominantly the hemihydrate, produced by drying powdered 
gypsum (CaSO42H2O) at about 1508C, in a 
controlled manner, such that minimum quantities of the 
anhydrous material are produced. Dried calcium sulfate 
may also contain suitable setting accelerators or decelerators. 
18 Comments 
Calcium sulfate will absorb moisture and therefore should be 
used with caution in the formulation of products containing 
drugs that easily decompose in the presence of moisture. A 
specification for calcium sulfate is contained in the Food 
Chemicals Codex (FCC). The EINECS number for calcium 
sulfate is 231-900-3. 
106 Calcium Sulfate

19 Specific References 
1 Bergman LA, Bandelin FJ. Effects of concentration, ageing and 
temperature on tablet disintegrants in a soluble direct compression 
system. J Pharm Sci 1965; 54: 445–447. 
2 C. elik M, Okutgen E. A feasibility study for the development of a 
prospective compaction functionality test and the establishment of 
a compaction data bank. Drug Dev Ind Pharm 1993; 19: 2309– 
2334. 
3 Cho BC, Park JW, Baik BS, Kim IS. Clinical application of 
injectable calcium sulfate on early bone consolidation in distraction 
osteogenesis for the treatment of craniofacial microsomia. J 
Craniofac Surg 2002; 13(3): 465–474. 
4 Deporter DA, Todescan R. A possible ‘rescue’ procedure for dental 
implants with a textured surface geometry: a case report. J 
Periodontol 2001; 72(10): 1420–1423. 
5 Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation 
Agents: A Handbook of Excipients. New York: Marcel Dekker, 
1989: 93–94. 
6 Eerika. inen S, Yliruusi J, Laakso R. The behaviour of the sodium 
salt of indomethacin in the cores of film-coated granules containing 
various fillers. Int J Pharm 1991; 71: 201–211. 
7 Land..n M, Pe.rez-Marcos B, Casalderrey M, et al. Chemical 
stability of acetylsalicylic acid in tablets prepared with different 
commercial brands of dicalcium phosphate dihydrate. Int J Pharm 
1994; 107: 247–249. 
8 El-Shattawy HH, Peck GE, Kildsig DO. Aspartame – direct 
compression excipients: preformulation stability screening using 
differential scanning calorimetry. Drug Dev Ind Pharm 1981; 7(5): 
605–619. 
9 El-Shattawy HH. Ampicillin – direct compression excipients: 
preformulation stability screening using differential scanning 
calorimetry. Drug Dev Ind Pharm 1982; 8(6): 819–831. 
10 El-Shattawy HH, Kildsig DO, Peck GE. Cephalexin 1 – direct 
compression excipients: preformulation stability screening using 
differential scanning calorimetry. Drug Dev Ind Pharm 1982; 8(6): 
897–909. 
11 El-Shattawy HH, Kildsig DO, Peck GE. Erythromycin – direct 
compression excipients: preformulation stability screening using 
differential scanning calorimetry. Drug Dev Ind Pharm 1982; 8(6): 
937–947. 
20 General References 
Bryan JW, McCallister JD. Matrix forming capabilities of three calcium 
diluents. Drug Dev Ind Pharm 1992; 18: 2029–2047. 
21 Authors 
RC Moreton. 
22 Date of Revision 
26 August 2005. 
Calcium Sulfate 107

Canola Oil 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Canbra oil; Colzao CT; Lipex 108; Lipex 204; Lipovol CAN; 
low erucic acid colza oil; low erucic acid rapeseed oil. 
3 Chemical Name and CAS Registry Number 
Canola oil [120962-03-0] 
4 Empirical Formula and Molecular Weight 
Canola oil contains approximately 6% saturated acids, 2% 
monounsaturated acids, and 32% polyunsaturated acids; see 
Table I. Additionally, sulfur-containing fatty acids may also be 
present as minor constituents. 
Table I: Typical composition of glycerides present in canola oil. 
Glyceride Amount present (%) 
Erucic acid 0.2–1.8 
Palmitic acid 3.0–4.5 
Palmitoleic acid 0.2–0.3 
Stearic acid 1.3–1.7 
Linoleic acid 19.0–24.0 
Oleic acid 56.0–62.0 
The sulfur-containing compounds have been held responsible 
for the unpleasant odors from heated rapeseed oil. It has 
been suggested that the sulfur compounds in rapeseed oil are of 
three types: volatile, thermolabile, and nonvolatile.(1) 
Unrefined canola oil is said to contain low levels of sulfurcontaining 
fatty acids, resulting in the presence of sulfur in the 
oil in the stable form of triglycerides. These triglycerides resist 
refining procedures.(2) See Table II for the sulfur content of 
crude, refined, and deodorized canola oils.(3) 
Table II: Total sulfur content in crude, refined and bleached and 
deodorized canola oil.(a) 
Oil sample Range (mg/kg) Mean Standard 
deviation 
Crude 23.6–24.1 23.8 1.0 
Refined 19.1–20.2 19.7 2.85 
Bleached and deodorized 15.6–16.5 16.2 2.7 
(a) Determined using five replicates of each sample analyzed by ion chromatography. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Lubricant; oleaginous vehicle. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Canola oil is a refined rapeseed oil obtained from particular 
species of rapeseed that have been genetically selected for their 
low erucic acid content.(4) In pharmaceutical formulations, 
canola oil is used mainly in topical preparations such as soft 
soaps and liniments. It is also used in cosmetics. 
8 Description 
A clear, light yellow-colored oily liquid with a bland taste. 
9 Pharmacopeial Specifications 
—
10 Typical Properties 
Acid value: 40.5 
Density: 0.913–0.917 g/cm3 
Erucic acid: 42.0% 
Flash point: 290–3308C 
Free fatty acid: 40.05% as oleic acid 
Freezing point: 10 to 28C 
Iodine number: 94–126 
Refractive index: nD
40 = 1.465–1.469 
Saponification value: 186–198 
Solubility: soluble in chloroform and ether; practically insoluble 
in ethanol (95%); miscible with fixed oils. 
Viscosity (dynamic): 77.3–78.3 mPa s (77.3–78.3 cP) at 208C 
11 Stability and Storage Conditions 
Canola oil is stable and should be stored in an airtight, lightresistant 
container in a cool, dry place. During storage, grassy, 
paintlike, or rancid off-flavors can develop. 
Flavor deterioration has been attributed mainly to secondary 
oxidation products of linolenic acid, which normally makes 
up 9–15% of the fatty acids in canola oil. Storage tests of 
canola oil showed sensory changes after 2–4 days at 60–658C 
in comparison to 16 weeks at room temperature. Canola oil 
seems to be more stable to storage in light than cottonseed oil 
and soybean oils, but is less stable than sunflower oil.(5) In 
addition, the effects of various factors on sediment formation in 
canola oil have been reported.(6) 
It has been reported that oils stored at 28C showed the 
highest rate of sediment formation, followed by those stored at 
68C.(5) All samples showed little sediment formation, as 
measured by turbidity, during storage at 128C. Removal of 
sediment from canola oil prior to storage by cold precipitation 
and filtration did not eliminate this phenomenon, which still 
developed rapidly at 28C. 
A study on the effect of heating on the oxidation of low 
linolenic acid canola oil at frying temperatures under nitrogen 
and air clearly showed that a significantly lower development 
of oxidation was evident for the low linolenic acid canola oil. 
Reduction in the linolenic acid content of canola oil reduced the 
development of room odor at frying temperatures.

12 Incompatibilities 
—
13 Method of Manufacture 
Canola oil is obtained by mechanical expression or n-hexane 
extraction from the seeds of Brassica napus (Brassica campestris) 
var. oleifera and certain other species of Brassica 
(Cruciferae). The crude oil thus obtained is refined, bleached, 
and deodorized to substantially remove free fatty acids, 
phospholipids, color, odor and flavor components, and 
miscellaneous nonoil materials. 
14 Safety 
Canola oil is generally regarded as an essentially nontoxic and 
nonirritant material and has been accepted by the FDA for use 
in cosmetics, foods, and pharmaceuticals. 
Rapeseed oil has been used for a number of years in food 
applications as a cheap alternative to olive oil. However, there 
are large amounts of erucic acid and glucosinolates in 
conventional rapeseed oil, both substances being toxic to 
humans and animals.(7) Canola oil derived from genetically 
selected rapeseed plants that are low in erucic acid content has 
been developed to overcome this problem. 
Feeding studies in rats have suggested that canola oil is 
nontoxic to the heart, although it has also been suggested that 
the toxicological data may be unclear.(8) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Spillages of this material are 
very slippery and should be covered with an inert absorbent 
material prior to disposal. Canola oil poses a slight fire hazard. 
16 Regulatory Status 
Accepted for use by the FDA in cosmetics and foods. Included 
in the FDA Inactive Ingredients Guide (oral capsules). Included 
in the Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Almond oil; corn oil; cottonseed oil; peanut oil; rapeseed oil; 
sesame oil; soybean oil. 
Rapeseed oil 
CAS number: [8002-13-9] 
Synonyms: Calchem H-102; colza oil; rape oil. 
Appearance: a clear, yellow to dark yellow-colored oily liquid. 
Iodine number: 94–120 
Peroxide value: <5 
Saponification value: 168–181 
Comments: rapeseed oil contains 40–55% erucic acid. It is an 
edible oil and has been primarily used as an alternative, in 
foods and some pharmaceutical applications, to the more 
expensive olive oil. However, the safety of rapeseed oil as 
part of the diet has been questioned; see Section 14. 
18 Comments 
Canola oil has the lowest level of saturated fat compared to all 
other oils on the market at present. It has both a high protein 
(28%) and a high oil content (40%). When the oil is extracted, 
a high-quality and highly palatable feed concentrate of 37% 
protein remains. Canola oil is also high in the monounsaturated 
fatty acid oleic acid; see Table III. 
The content of tocopherol, a natural antioxidant in canola, 
is comparable to those of peanut and palm oil. This is an 
important factor for oils with high linolenic acid content, which 
can reduce the shelf-life of the product, while the natural 
antioxidant, if present, can prevent oxidation during storage 
and processing. 
Suggested specifications for refined, bleached, and deodorized 
canola oil are shown in Table IV. A specification for canola 
oil is contained in the Food Chemicals Codex (FCC). 
The EINECS number for canola oil is 232-313-5. 
Table III: Comparison of the composition of crude soybean, canola, 
palm, and peanut oils. 
Components Canola Palm Peanut Soybean 
Fatty acid (%) 0.4–1.0 4.6 0.5–1.0 0.3–0.7 
Phosphatides (gum) 
(%) 
3.6 0.05–0.1 0.3–0.4 1.2–1.5 
Sterols/triterpene 
alcohol (%) 
0.53 0.1–0.5 0.2 0.33 
Tocopherols (%) 0.06 0.003–0.1 0.02–0.06 0.15–0.21 
Carotenoids (mg/kg) 25–50 500–1600 >1 40–50 
Chlorophyll/ 
pheophytins (ppm) 
5–25 — — 1–2 
Sulfur (ppm) — — — 12–17 
Iodine value 112–131 44–60 84–100 123–139 
Table IV: Suggested specifications for canola oil. 
Test Minimum Maximum 
Acid value — 6 
Iodine value 110 126 
Heavy metal (as lead) — 5 mg/kg 
Refractive index nD
40 1.465 1.467 
Free fatty acid (as oleic) — 0.05% 
Erucic acid — 2% 
Moisture and impurities — 0.05% 
Saponification value (mg KOH/g oil) 182 193 
Unsaponifiable matter — 15 g/kg 
19 Specific References 
1 Devinat G, Biasini S, Naudet M. Sulfur-compounds in the rapeseed 
oils. Rev Fr Corps Gras 1980; 27: 229–236. 
2 Wijesundera RC, Ackman RG. Evidence for the probable presence 
of sulfur-containing fatty-acids as minor constituents in canola oil. 
J Am Oil Chem Soc 1988; 65: 959–963. 
3 Abraham V, de Man JM. Determination of total sulfur in canola 
oil. J Am Oil Chem Soc 1987; 64: 384–387. 
4 Hiltunen R, Huhtikangas A, Hovinen S. Breeding of a zero erucic 
spring turnip-rape cultivar, Brassica campestris L. adapted to 
Finnish climatic conditions. Acta Pharm Fenn 1979; 88: 31–34. 
5 Przybylski R, Billiaderis CG, Eskin NAM. Formation and partial 
characterization of canola. J Am Oil Chem Soc 1993; 70: 1009– 
1016. 
6 Liu H, Billiaderis CG, Przybylski R. Effects of crystalization 
conditions on sediment. J Am Oil Chem Soc 1994; 71: 409–418. 
Canola Oil 109

7 Anonymous. Rapeseed oil revisited. Lancet 1974; ii: 1359–1360. 
8 Anonymous. Rapeseed oil and the heart. Lancet 1973; ii: 193. 
20 General References 
Koseoglu SS, Iusas EW. Recent advances in canola oil hydrogenations. J 
Am Oil Chem Soc 1990; 67: 3947. 
Malcolmson LJ, Vaisey-Genser M, Przybylski R, Eskin NAM. Sensory 
stability of canola oil: present status. J Am Oil Chem Soc 1994; 71: 
435–440. 
21 Authors 
KS Alexander. 
22 Date of Revision 
22 August 2005. 
110 Canola Oil

Carbomer 
1 Nonproprietary Names 
BP: Carbomers 
PhEur: Carbomera 
USPNF: Carbomer 
Note that the USPNF 23 contains several individual carbomer 
monographs; see Sections 4 and 9. 
2 Synonyms 
Acritamer; acrylic acid polymer; Carbopol; carboxy polymethylene, 
polyacrylic acid; carboxyvinyl polymer; Pemulen; 
Ultrez. 
3 Chemical Name and CAS Registry Number 
Carbomer [9003-01-4] 
Note that carbomer 910, 934, 934P, 940, 941, 971P and 
974P resins share the common CAS registry number 9003-01- 
4. Carbomer 1342 is a copolymer and has a different CAS 
registry number. 
4 Empirical Formula and Molecular Weight 
Carbomers are synthetic high-molecular-weight polymers of 
acrylic acid that are crosslinked with either allyl sucrose or allyl 
ethers of pentaerythritol. They contain between 56% and 68% 
of carboxylic acid (COOH) groups calculated on the dry basis. 
The BP 2004 and PhEur 2005 have a single monograph 
describing carbomer; the USPNF 23 contains several monographs 
describing individual carbomer grades that vary in 
aqueous viscosity and in labeling for oral or non-oral use. The 
molecular weight of carbomer resins is theoretically estimated 
at 7  105 to 4  109. In an effort to measure the molecular 
weight between crosslinks, MC, researchers have extended the 
network theory of elasticity to swollen gels and have utilized the 
inverse relationship between the elastic modulus and MC.(1–3) 
EstimatedMC values of 237 600 g/mol for Carbopol 941 and of 
104 400 g/mol for Carbopol 940 have been reported.(4) In 
general, carbomer resins with lower viscosity and lower rigidity 
will have higher MC values. Conversely, higher-viscosity, more 
rigid carbomer resins will have lower MC values. 
5 Structural Formula 
Carbomer polymers are formed from repeating units of acrylic 
acid. The monomer unit is shown above. The polymer chains 
are crosslinked with allyl sucrose or allyl pentaerythritol. See 
also Section 4. 
6 Functional Category 
Bioadhesive; emulsifying agent; release-modifying agent; suspending 
agent; tablet binder; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Carbomers are mainly used in liquid or semisolid pharmaceutical 
formulations as suspending or viscosity-increasing agents. 
Formulations include creams, gels, and ointments for use in 
ophthalmic,(5–7) rectal,(8–10) and topical preparations.(11–17) 
Carbomer grades, even with a low residual benzene content, 
such as carbomer 934P, are no longer included in the PhEur 
2005. However, carbomer having low residuals only of other 
solvents than the ICH-defined ‘Class I OVI solvents’ may be 
used in Europe. Carbomer having low residuals only of ethyl 
acetate, such as carbomer 971P or 974P, may be used in oral 
preparations, in suspensions, tablets, or sustained release tablet 
formulations.(18–22) In tablet formulations, carbomers are used 
as dry or wet binders and as a rate controlling excipient. In wet 
granulation processes, water or an alcohol–water blend is used 
as the granulating fluid. Anhydrous organic solvents have also 
been used, with the inclusion of a polymeric binder. The 
tackiness of the wet mass can be reduced with the addition of 
certain cationic species to the granulating fluid(23) or, in the case 
of water, with talc in the formulation. Carbomer resins have 
also been investigated in the preparation of sustained-release 
matrix beads,(23) as enzyme inhibitors of intestinal proteases in 
peptide-containing dosage forms,(24,25) as a bioadhesive for a 
cervical patch(26) and for intranasally administered microspheres,(
27) in magnetic granules for site-specific drug delivery 
to the esophagus(28) and in oral mucoadhesive controlled drug 
delivery systems.(29,30) Carbomers are also employed as 
emulsifying agents in the preparation of oil-in-water emulsions 
for external use. For this purpose, the carbomer is neutralized 
partly with sodium hydroxide and partly with a long-chain 
amine such as stearylamine. Carbomer 951 has been investigated 
as a viscosity-increasing aid in the preparation of multiple 
emulsion microspheres.(31) Carbomers are also used in cosmetics. 
Therapeutically, carbomer gel formulations have 
proved efficacious in improving symptoms of moderate-tosevere 
dry eye syndrome.(32,33) See Table I. 
Table I: Uses of carbomers. 
Use Concentration (%) 
Emulsifying agent 0.1–0.5 
Gelling agent 0.5–2.0 
Suspending agent 0.5–1.0 
Tablet binder 5.0–10.0

SEM: 1 
Excipient: Carbomer 971P (Carbopol 971P) 
Manufacturer: BF Goodrich 
Magnification: 2000 Voltage: 25 kV 
8 Description 
Carbomers are white-colored, ‘fluffy’, acidic, hygroscopic 
powders with a slight characteristic odor. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for carbomers. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Aqueous viscosity (mPa s) 300–115 000 — 
Carbomer 934 (0.5% w/v) — 30 500–39 400 
Carbomer 934P (0.5% w/v) — 29 400–39 400 
Carbomer 940 (0.5 w/v) — 40 000–60 000(a) 
Carbomer 941 (0.5 w/v) — 4 000–11 000 
Carbomer 1342 (1.0% w/v) — 9 500–26 500 
Loss on drying 43.0% 42.0% 
Sulfated ash 44.0% — 
Heavy metals 420 ppm 40.002% 
Benzene 42 ppm — 
Carbomer 910 — 40.5% 
Carbomer 934 — 40.5% 
Carbomer 934P — 40.01% 
Carbomer 940 — 40.5% 
Carbomer 941 — 40.5% 
Carbomer 1342 — 40.2% 
Free acrylic acid 40.25% — 
Organic volatile impurities — . 
Assay (COOH content) 56.0–68.0% 56.0–68.0% 
(a) See USPNF 23 Suppl. 1.0 for new method. 
Note that the USPNF 23 has several monographs for 
different carbomer grades, while the BP 2004 and the PhEur 
2005 have only a single monograph. Other grades of carbomer 
SEM: 2 
Excipient: Carbomer 971P (Carbopol 971P) 
Manufacturer: BF Goodrich 
Magnification: 6000 Voltage: 25 kV 
meet the existing USPNF 23 standards as indicated above. 
Carbomer 974P is covered by the monograph for carbomer 
934P in the USPNF 23. Likewise, carbomer 980 meets the 
specifications for carbomer 940; carbomers 971P and 981 meet 
the monograph limits for carbomer 941. Carbomer resins are 
also covered either individually or together in other pharmacopeias. 
Unless otherwise indicated, the test limits shown above 
apply to all grades of carbomer. 
10 Typical Properties 
Acidity/alkalinity: 
pH = 2.7–3.5 for a 0.5% w/v aqueous dispersion; 
pH = 2.5–3.0 for a 1% w/v aqueous dispersion. 
Density (bulk): 1.76–2.08 g/cm3 
Density (tapped): 1.4 g/cm3 
Glass transition temperature: 100–1058C 
Melting point: decomposition occurs within 30 minutes at 
2608C. See Section 11. 
Moisture content: normal water content is up to 2% w/w. 
However, carbomers are hygroscopic and a typical equilibrium 
moisture content at 258C and 50% relative humidity 
is 8–10% w/w. The moisture content of a carbomer does not 
affect its thickening efficiency, but an increase in the 
moisture content makes the carbomer more difficult to 
handle because it is less readily dispersed. 
Particle size distribution: primary particles average about 
0.2 mm in diameter. The flocculated powder particles 
average 2–7 mm in diameter and cannot be broken down 
into the primary particles. Recently, a granular carbomer 
having a particle size in the range 180–425 mm has been 
introduced. Its bulk and tap densities are also higher than 
those of other carbomers. 
Solubility: soluble in water and, after neutralization, in ethanol 
(95%) and glycerin. 
Although they are described as ‘soluble’, carbomers do 
not dissolve but merely swell to a remarkable extent, since 
they are three-dimensionally crosslinked microgels. Furthermore, 
the pharmacopeial specifications are unclear, in that 
neutralization with long-chain aliphatic amines or ethoxy- 
112 Carbomer

lated long-chain amines is required for swellability in 
ethanol, and with water-soluble amines for swellability in 
glycerin. 
Specific gravity: 1.41 
Viscosity (dynamic): carbomers disperse in water to form acidic 
colloidal dispersions of low viscosity that, when neutralized, 
produce highly viscous gels. Carbomer powders should first 
be dispersed into vigorously stirred water, taking care to 
avoid the formation of indispersible lumps, then neutralized 
by the addition of a base. The Carbopol ETD and Ultrez 10 
series of carbomers was introduced to overcome some of the 
problems of dispersing the powder into aqueous solvents. 
These carbomer resins wet quickly yet hydrate slowly, while 
possessing a lower unneutralized dispersion viscosity. 
Agents that may be used to neutralize carbomer polymers 
include amino acids, borax, potassium hydroxide, sodium 
bicarbonate, sodium hydroxide, and polar organic amines 
such as triethanolamine. Lauryl and stearyl amines may be 
used as gelling agents in nonpolar systems. One gram of 
carbomer is neutralized by approximately 0.4 g of sodium 
hydroxide. During preparation of the gel, the solution 
should be agitated slowly with a broad, paddlelike stirrer to 
avoid introducing air bubbles. Neutralized aqueous gels are 
more viscous at pH 6–11. The viscosity is considerably 
reduced at pH values less than 3 or greater than 12 or in the 
presence of strong electrolytes.(23,34) Gels rapidly lose 
viscosity on exposure to ultraviolet light, but this can be 
minimized by the addition of a suitable antioxidant. See also 
Section 11. 
11 Stability and Storage Conditions 
Carbomers are stable, hygroscopic materials that may be 
heated at temperatures below 1048C for up to 2 hours without 
affecting their thickening efficiency. However, exposure to 
excessive temperatures can result in discoloration and reduced 
stability. Complete decomposition occurs with heating for 30 
minutes at 2608C. Dry powder forms of carbomer do not 
support the growth of molds and fungi. In contrast, microorganisms 
grow well in unpreserved aqueous dispersions and 
therefore an antimicrobial preservative such as 0.1% w/v 
chlorocresol, 0.18% w/v methylparaben–0.02% w/v propylparaben, 
or 0.1% w/v thimerosal should be added. The 
addition of certain antimicrobials, such as benzalkonium 
chloride or sodium benzoate, in high concentrations (0.1% 
w/v) can cause cloudiness and a reduction in viscosity of 
carbomer dispersions. Aqueous gels may be sterilized by 
autoclaving(7) with minimal changes in viscosity or pH, 
provided care is taken to exclude oxygen from the system, or 
by gamma irradiation, although this technique may increase the 
viscosity of the formulation.(35,36) At room temperature, 
carbomer dispersions maintain their viscosity during storage 
for prolonged periods. Similarly, dispersion viscosity is maintained, 
or only slightly reduced, at elevated storage temperatures 
if an antioxidant is included in the formulation or if the 
dispersion is stored protected from light. Exposure to light 
causes oxidation that is reflected in a decrease in dispersion 
viscosity. Stability to light may be improved by the addition of 
0.05–0.1% w/v of a water-soluble UV absorber such as 
benzophenone-2 or benzophenone-4 in combination with 
0.05–0.1% w/v edetic acid. The UV stability of carbomer gels 
may also be improved by using triethanolamine as the 
neutralizing base; see Section 10. 
Carbomer powder should be stored in an airtight, corrosion-
resistant container in a cool, dry place. The use of glass, 
plastic, or resin-lined containers is recommended for the 
storage of formulations containing carbomer. Packaging in 
aluminum tubes usually requires the formulation to have a pH 
less than 6.5, and packaging in other metallic tubes or 
containers necessitates a pH greater than 7.7 to prolong 
carbomer stability. 
12 Incompatibilities 
Carbomers are discolored by resorcinol and are incompatible 
with phenol, cationic polymers, strong acids, and high levels of 
electrolytes. Certain antimicrobial adjuvants should also be 
avoided or used at low levels, see Section 11. Trace levels of iron 
and other transition metals can catalytically degrade carbomer 
dispersions. Intense heat may be generated if a carbomer is in 
contact with a strong basic material such as ammonia, 
potassium or sodium hydroxide, or strongly basic amines. 
Certain amino-functional actives form water-insoluble 
complexes with carbomer; often this can be prevented by 
adjusting the solubility parameter of the fluid phase using 
appropriate alcohols and polyols. 
Carbomers also form pH-dependent complexes with certain 
polymeric excipients. Adjustment of solubility parameter can 
also work in this situation. 
13 Method of Manufacture 
Carbomers are synthetic, high-molecular-weight, crosslinked 
polymers of acrylic acid. These poly(acrylic acid) polymers are 
crosslinked with allyl sucrose or allyl pentaerythritol. The 
polymerization solvent used most commonly was benzene; 
however, some of the newer commercially available grades of 
carbomer are manufactured using either ethyl acetate or a 
cyclohexane–ethyl acetate cosolvent mixture. The Carbopol 
ETD resins are produced in the cosolvent mixture with a 
proprietary polymerization aid, and these resins are crosslinked 
with a polyalkenyl polyether. 
14 Safety 
Carbomers are used extensively in nonparenteral products, 
particularly topical liquid and semisolid preparations. They 
may also be used in oral formulations, although only certain 
grades can be used; see Section 18. Acute oral toxicity studies in 
animals indicate that carbomer 934P has a low oral toxicity, 
with doses up to 8 g/kg being administered to dogs without 
fatalities occurring. Carbomers are generally regarded as 
essentially nontoxic and nonirritant materials; there is no 
evidence in humans of hypersensitivity reactions to carbomers 
used topically. In humans, oral doses of 1–3 g of carbomer have 
been used as a bulk laxative. 
LD50 (guinea pig, oral): 2.5 g/kg for carbomer 934(37) 
LD50 (guinea pig, oral): 2.5 g/kg for carbomer 934P 
LD50 (guinea pig, oral): 2.5 g/kg for carbomer 940 
LD50 (mouse, IP): 0.04 g/kg for carbomer 934P 
LD50 (mouse, IP): 0.04 g/kg for carbomer 940 
LD50 (mouse, IV): 0.07 g/kg for carbomer 934P 
LD50 (mouse, IV): 0.07 g/kg for carbomer 940 
LD50 (mouse, oral): 4.6 g/kg for carbomer 934P 
LD50 (mouse, oral): 4.6 g/kg for carbomer 934 
LD50 (mouse, oral): 4.6 g/kg for carbomer 940 
LD50 (rat, oral): 10.25 g/kg for carbomer 910 
LD50 (rat, oral): 2.5 g/kg for carbomer 934P 
LD50 (rat, oral): 4.1 g/kg for carbomer 934 
LD50 (rat, oral): 2.5 g/kg for carbomer 940 
LD50 (rat, oral): > 1g/kg for carbomer 941 
Carbomer 113

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Excessive dust generation 
should be minimized to avoid the risk of explosion (lowest 
explosive concentration is 100 g/m3). Carbomer dust is irritating 
to the eyes, mucous membranes, and respiratory tract. In 
contact with the eye, carbomer dust is difficult to remove with 
water owing to the gelatinous film that forms; saline should 
therefore be used for irrigation purposes. Gloves, eye protection, 
and a dust respirator are recommended during handling. 
16 Regulatory Acceptance 
Included in the FDA Inactive Ingredients Guide (oral suspensions, 
tablets; ophthalmic, rectal, and topical preparations 
transdermal preparations, vaginal suppositories). Included in 
nonparenteral medicines licensed in Europe. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Polycarbophil. 
18 Comments 
A number of different carbomer grades are commercially 
available that vary in their molecular weight, degree of 
crosslinking, polymer structure, and residual components. 
These differences account for the specific rheological, handling, 
and use characteristics of each grade. Carbomer grades that 
have the polymer backbone modified with long-chain alkyl 
acrylates are used as polymeric emulsifiers or in formulations 
requiring increased resistance to ions. 
Polycarbophil, poly(acrylic acid) polymers crosslinked with 
divinyl glycol, is available for bioadhesive or medicinal 
applications. Carbomers designated with the letter ‘P’, e.g. 
carbomer 971P, are the only pharmaceutical grades of polymer 
accepted for oral or mucosal contact products. These resins are 
particularly useful in the production of clear gels. 
19 Specific References 
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3 Nae HN, Reichert WW. Rheological properties of lightly crosslinked 
carboxy copolymers in aqueous solutions. Rheol Acta 1992; 
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6 U. nlu. N, Ludwig A, van Ooteghem M, et al. Formulation of 
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properties. Pharmazie 1991; 46: 784–788. 
7 Deshpande SG, Shirolkar S. Sustained release ophthalmic formulations 
of pilocarpine. J Pharm Pharmacol 1989; 41: 197–200. 
8 Dal Zotto M, Realdon N, Ragazzi E, et al. Effect of hydrophilic 
macromolecular substances on the drug release rate from 
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11 Tamburic S, Craig DQM. Investigation into the rheological, 
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12 Ferrari F, Bertoni M, Caramella C, et al. Description and validation 
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13 Chu JS, Yu DM, Amidon GL, et al. Viscoelastic properties of 
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14 Amsellem E, Derrien F, Lanquetin M, Paris J, et al. In vitro studies 
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1402–1408. 
114 Carbomer

33 Marner K, Mooller PM, Dillon M, Rask-Pedersen E. Viscous 
carbomer eye drops in patients with dry eyes. Efficacy and safety. A 
randomized, open, cross-over, multicentre study. Acta Ophthalmol 
Scand 1996; 74: 249–252. 
34 Charman WN, Christy DP, Geunin EP, Monkhouse DC. Interaction 
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Ind Pharm 1991; 17(2): 271–280. 
35 Adams I, Davis SS. Formulation and sterilization of an original 
lubricant gel base in carboxypolymethylene. J Pharm Pharmacol 
1973; 25: 640–646. 
36 Adams I, Davis SS, Kershaw R. Formulation of a sterile surgical 
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37 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
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20 General References 
Alexander P. Organic rheological additives. Manuf Chem 1986; 57: 81, 
83–84. 
BF Goodrich Company. Technical literature: Carbopol, Noveon, 
Pemulen resins handbook, 1995. 
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drug-polyelectrolyte matrices (SDPM). Characterization and delivery 
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Secard DL. Carbopol pharmaceuticals. Drug Cosmet Ind 1962; 90: 28– 
30, 113, 115–116. 
21 Authors 
JJ Koleng, JW McGinity. 
22 Date of Revision 
25 August 2005. 
Carbomer 115

Carbon Dioxide 
1 Nonproprietary Names 
BP: Carbon dioxide 
JP: Carbon dioxide 
PhEur: Carbonei dioxidum 
USP: Carbon dioxide 
2 Synonyms 
Carbonic acid gas; carbonic anhydride; E290. 
3 Chemical Name and CAS Registry Number 
Carbon dioxide [124-38-9] 
4 Empirical Formula and Molecular Weight 
CO2 44.01 
5 Structural Formula 
CO2 
6 Functional Category 
Aerosol propellant; air displacement. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Carbon dioxide and other compressed gases such as nitrogen 
and nitrous oxide are used as propellants for topical 
pharmaceutical aerosols. They are also used in other aerosol 
products that work satisfactorily with the coarse aerosol spray 
that is produced with compressed gases, e.g., cosmetics, 
furniture polish, and window cleaners.(1–3) 
The advantages of compressed gases as aerosol propellants 
are that they are inexpensive; are of low toxicity; and are 
practically odorless and tasteless. Also, in comparison to 
liquefied gases, their pressures change relatively little with 
temperature. However, the disadvantages of compressed gases 
are that there is no reservoir of propellant in the aerosol and 
pressure consequently decreases as the product is used. This 
results in a change in spray characteristics. Additionally, if a 
product that contains a compressed gas as a propellant is 
actuated in an inverted position, the vapor phase, rather than 
the liquid phase, is discharged. Most of the propellant is 
contained in the vapor phase and therefore some of the 
propellant will be lost and the spray characteristics will be 
altered. Also, sprays produced using compressed gases are very 
wet. Valves, such as the vapor tap or double dip tube, are 
currently available and will overcome these problems. 
Carbon dioxide is also used to displace air from pharmaceutical 
products by sparging and hence to inhibit oxidation. As 
a food additive it is used to carbonate beverages and to preserve 
foods such as bread from spoilage by mold formation, the gas 
being injected into the space between the product and its 
packaging.(4,5) 
Solid carbon dioxide is also widely used to refrigerate 
products temporarily, while liquid carbon dioxide, which can 
be handled at temperatures up to 318C under high pressure, is 
used as a solvent for flavors and fragrances primarily in the 
perfumery and food manufacturing industries. 
8 Description 
Carbon dioxide occurs naturally as approximately 0.03% v/v 
of the atmosphere. It is a colorless, odorless, noncombustible 
gas with a faint acid taste. Solid carbon dioxide, also known as 
dry ice, is usually encountered as white-colored pellets or 
blocks. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for carbon dioxide. 
Test JP 2001 PhEur 2005 USP 28 
Characters . . — 
Production — . — 
Total sulfur — 41 ppm — 
Water — 467 ppm 4150mg/m2 
Identification . . . 
Carbon monoxide . 45 ppm 40.001% 
Sulfur dioxide — 42 ppm 45 ppm 
Nitrogen monoxide and 
nitrogen dioxide 
— 42 ppm 42.5 ppm 
Impurities — . — 
Limit of ammonia — — 40.0025% 
Limit of nitric oxide — — 42.5 ppm 
Acid . — — 
Hydrogen phosphide, 
hydrogen sulfide or 
reducing organic 
substances 
. 41 ppm 41 ppm 
Oxygen and nitrogen . — — 
Assay 499.50% 499.50% 499.00% 
10 Typical Properties 
Boiling point: 56.68C 
Critical pressure: 7.39MPa (72.9 atm) 
Critical temperature: 31.38C 
Density: 
0.714 g/cm3 for liquid at 258C; 
0.742 g/cm3 for vapor at 258C. 
Flammability: nonflammable 
Melting point: sublimes at 78.58C 
Solubility: 1 in about 1 of water by volume at normal 
temperature and pressure. 
Vapor density (absolute): 1.964 g/m3 
Vapor density (relative): 1.53 (air = 1) 
Vapor pressure: 6.436 MPa at 258C 
Viscosity (kinematic): 0.14mm2/s (0.14 cSt) at 17.88C

11 Stability and Storage Conditions 
Extremely stable and chemically nonreactive. Store in a tightly 
sealed cylinder. Avoid exposure to excessive heat. 
12 Incompatibilities 
Carbon dioxide is generally compatible with most materials 
although it may react violently with various metal oxides or 
reducing metals such as aluminum, magnesium, titanium, and 
zirconium. Mixtures with sodium and potassium will explode if 
shocked. 
13 Method of Manufacture 
Carbon dioxide is obtained industrially in large quantities as a 
by-product in the manufacture of lime; by the incineration of 
coke or other carbonaceous material; and by the fermentation 
of glucose by yeast. In the laboratory it may be prepared by 
dropping acid on a carbonate. 
14 Safety 
In formulations, carbon dioxide is generally regarded as an 
essentially nontoxic material. 
See also Section 15. 
15 Handling Precautions 
Handle in accordance with standard procedures for handling 
metal cylinders containing liquefied or compressed gases. 
Carbon dioxide is an asphyxiant and inhalation in large 
quantities is hazardous. It should therefore be handled in a wellventilated 
environment equipped with suitable safety devices 
for monitoring vapor concentration. 
It should be noted that carbon dioxide is classified as a 
greenhouse gas responsible for global warming. At the present 
time there are no restrictions on its use for aerosols and other 
applications. 
In the UK, the occupational exposure limits for carbon 
dioxide are 9150 mg/m3 (5000 ppm) long-term (8-hour TWA) 
and 27 400 mg/m3 (15 000 ppm) short-term (15-minute).(6) In 
the USA, the permissible exposure limits are 9000 mg/m3 
(5000 ppm) long-term and the recommended exposure limits 
are 18 000 mg/m3 (10 000 ppm) short-term and 54 000 mg/m3 
(30 000 ppm) maximum, short-term.(7) 
Solid carbon dioxide can produce severe burns in contact 
with the skin and appropriate precautions, depending on the 
circumstances and quantity of material handled, should be 
taken. A face shield and protective clothing, including thick 
gloves, are recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use in Europe as a food additive. 
Included in the FDA Inactive Ingredients Guide (aerosol 
formulation for nasal preparations; IM and IV injections). 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Nitrogen; nitrous oxide. 
18 Comments 
Supercritical carbon dioxide has been used in the formation of 
fine powders of stable protein formulations.(8,9) 
Carbon dioxide has also been investigated for its suitability 
in Aerosol Solvent Extraction Systems (ASES), to generate 
microparticles of proteins suitable for aerosol delivery from 
aqueous based solutions.(10) 
A specification for carbon dioxide is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for carbon dioxide is 204-696-9. 
19 Specific References 
1 Haase LW. Application of carbon dioxide in cosmetic aerosols. 
Cosmet Perfum 1975; 90(8): 31–32. 
2 Sanders PA. Aerosol packaging of pharmaceuticals. In: Banker GS, 
Rhodes CT, eds. Modern Pharmaceutics. New York: Marcel 
Dekker, 1979; 591–626. 
3 Anonymous. CO2/acetone propellant kinder to ozone layer. Manuf 
Chem 1992; 63(1): 14. 
4 King JS, Mabbitt LA. The use of carbon dioxide for the 
preservation of milk. In: Board RG, Allwood MC, Banks JG, 
eds. Preservatives in the Food, Pharmaceutical and Environmental 
Industries. Oxford: Blackwell Scientific, 1987; 35–43. 
5 Anonymous. Carbon dioxide breaks the mould. Chem Br 1992; 
28: 506. 
6 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
7 National Institute for Occupational Safety and Health. Recommendations 
for occupational safety and health. MMWR 1988; 
37(Suppl S-7): 1–29. 
8 Bettini R, Bonassi L, Castoro V, et al. Solubility and conversion of 
carbamazepine polymorphs in supercritical carbon dioxide. Eur J 
Pharm Sci 2001; 13(3): 281–286. 
9 Sellers SP, Clark GS, Sievers RE, Carpenter JF. Dry powders of 
stable protein formulations from aqueous solutions prepared using 
supercritical CO2-assisted aerosolization. J Pharm Sci 2001; 90: 
785–797. 
10 Bustami RT, Chan HK, Dehghani F, Foster NR. Generation of 
microparticles of proteins for aerosol delivery using high pressure 
modified carbon dioxide. Pharm Res 2000; 17: 1360–1366. 
20 General References 
Johnson MA. The Aerosol Handbook, 2nd edn. Mendham, NJ: WE 
Dorland Co., 1982: 361–372. 
Sanders PA. Handbook of Aerosol Technology, 2nd edn. New York: 
Van Nostrand Reinhold Company, 1979: 44–54. 
Sciarra JJ, Sciarra CJ. Pharmaceutical and cosmetic aerosols. J Pharm 
Sci 1974; 63: 1815–1837. 
Sciarra JJ. Aerosols. In: Gennaro AR, ed. Remington: The Science and 
Practice of Pharmacy, 20th edn. Baltimore, MD: Lippincott, 
Williams and Wilkins, 2000: 963–979. 
Sciarra JJ. Pharmaceutical aerosols. In: Banker GS, Rhoes CT, eds: 
Modern Pharmaceutics, 3rd edn. New York: Marcel Dekker, 1996: 
547–574. 
Sciarra JJ, Stoller L. The Science and Technology of Aerosol Packaging. 
New York: Wiley, 1974: 137–145. 
21 Authors 
CJ Sciarra, JJ Sciarra. 
22 Date of Revision 
23 August 2005. 
Carbon Dioxide 117

Carboxymethylcellulose Calcium 
1 Nonproprietary Names 
BP: Carmellose calcium 
JP: Carmellose calcium 
PhEur: Carmellosum calcicum 
USPNF: Carboxymethylcellulose calcium 
2 Synonyms 
Calcium carboxymethylcellulose; calcium CMC; ECG 505; 
Nymcel ZSC. 
3 Chemical Name and CAS Registry Number 
Cellulose, carboxymethyl ether, calcium salt [9050-04-8] 
4 Empirical Formula and Molecular Weight 
The USPNF 23 describes carboxymethylcellulose calcium as the 
calcium salt of a polycarboxymethyl ether of cellulose. 
5 Structural Formula 
Structure shown with a degree of substitution (DS) of 1.0. 
6 Functional Category 
Stabilizing agent; suspending agent; tablet and capsule disintegrant; 
viscosity-increasing agent; water-absorbing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
The main use of carboxymethylcellulose calcium is in tablet 
formulations (see Table I), where it is used as a binder, diluent, 
and disintegrant.(1–4) Although carboxymethylcellulose calcium 
is insoluble in water, it is an effective tablet disintegrant as 
it swells to several times its original bulk on contact with water. 
Concentrations up to 15% w/w may be used in tablet 
formulations; above this concentration, tablet hardness is 
reduced. 
Carboxymethylcellulose calcium is also used in other 
applications similarly to carboxymethylcellulose sodium; for 
example, as a suspending or viscosity-increasing agent in oral 
and topical pharmaceutical formulations. Carboxymethylcellulose 
calcium is also used in modern wound dressings for 
its water absorption, retention and hemostatic properties. 
Table I: Uses of carboxymethylcellulose calcium. 
Use Concentration (%) 
Tablet binder 5–15 
Tablet disintegrant 1–15 
8 Description 
Carboxymethylcellulose calcium occurs as a white to yellowishwhite, 
hygroscopic, fine powder. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for carboxymethylcellulose 
calcium. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters — . — 
Alkalinity . . . 
pH 4.5–6.0 — — 
Loss on drying 410.0% 410.0% 410.0% 
Residue on ignition 10.0–20.0% 10.0–20.0% 10.0–20.0% 
Chloride 40.360% 40.36% 40.36% 
Silicate 40.5% 40.60% 41.5% 
Sulfate 40.960% 41.0% 40.96% 
Arsenic 410 ppm — — 
Heavy metals 420 ppm 420 ppm 40.002% 
Starch . — . 
Organic volatile 
impurities 
— — . 
10 Typical Properties 
Acidity/alkalinity: pH = 4.5–6.0 for a 1% w/v aqueous 
dispersion. 
Particle size distribution: 95% through a 73.7 mm sieve (#200 
mesh). 
Solubility: practically insoluble in acetone, chloroform, ethanol 
(95%), and ether. Insoluble in water, but swells to twice its 
volume to form a suspension. Insoluble in 0.1 mol/L 
hydrochloric acid, but slightly soluble in 0.1 mol/L sodium 
hydroxide. 
11 Stability and Storage Conditions 
Carboxymethylcellulose calcium is a stable, though hygroscopic 
material. It should be stored in a well-closed container in 
a cool, dry place. 
See also Carboxymethylcellulose sodium.

12 Incompatibilities 
See Carboxymethylcellulose sodium. 
13 Method of Manufacture 
Cellulose, obtained from wood pulp or cotton fibers, is 
carboxymethylated, followed by conversion to the calcium 
salt. It is then graded on the basis of its degree of 
carboxymethylation and pulverized. 
14 Safety 
Carboxymethylcellulose calcium is used in oral and topical 
pharmaceutical formulations, similarly to carboxymethylcellulose 
sodium, and is generally regarded as a nontoxic and 
nonirritant material. However, as with other cellulose derivatives, 
oral consumption of large amounts of carboxymethylcellulose 
calcium may have a laxative effect. 
See also Carboxymethylcellulose sodium. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Carboxymethylcellulose 
calcium may be irritant to the eyes; eye protection is 
recommended. 
16 Regulatory Status 
Accepted for use as a food additive in Japan at concentrations 
up to 2% w/w. Included in the FDA Inactive Ingredients Guide 
(oral, capsules and tablets). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Carboxymethylcellulose sodium; croscarmellose sodium. 
18 Comments 
—
19 Specific References 
1 Khan KA, Rooke DJ. Effect of disintegrant type upon the 
relationship between compressional pressure and dissolution 
efficiency. J Pharm Pharmacol 1976; 28(8): 633–636. 
2 Kitamori N, Makino T. Improvement in pressure-dependent 
dissolution of trepibutone tablets by using intragranular disintegrants. 
Drug Dev Ind Pharm 1982; 8(1): 125–139. 
3 Roe TS, Chang KY. The study of Key-Jo clay as a tablet 
disintegrator. Drug Dev Ind Pharm 1986; 12(11–13): 1567–1585. 
4 Ozeki T, Yasuzawa Y, Katsuyama H, et al. Design of rapidly 
disintegrating oral tablets using acid-treated yeast cell wall: a 
technical note. AAPS Pharm Tech Sci 2003; 4(4): E70. 
20 General References 
Doelker E. Cellulose derivatives. Adv Polym Sci 1993 107: 199–265. 
21 Authors 
D Parsons. 
22 Date of Revision 
17 August 2005. 
Carboxymethylcellulose Calcium 119

Carboxymethylcellulose Sodium 
1 Nonproprietary Names 
BP: Carmellose sodium 
JP: Carmellose sodium 
PhEur: Carmellosum natricum 
USP: Carboxymethylcellulose sodium 
2 Synonyms 
Akucell; Aquasorb; Blanose; cellulose gum; CMC sodium; 
E466; Finnfix; Nymcel; SCMC; sodium carboxymethylcellulose; 
sodium cellulose glycolate; sodium CMC; Tylose CB. 
3 Chemical Name and CAS Registry Number 
Cellulose, carboxymethyl ether, sodium salt [9004-32-4] 
4 Empirical Formula and Molecular Weight 
The USP 28 describes carboxymethylcellulose sodium as the 
sodium salt of a polycarboxymethyl ether of cellulose. Typical 
molecular weight is 90 000–700 000. 
5 Structural Formula 
Structure shown with a degree of substitution (DS) of 1.0. 
6 Functional Category 
Coating agent; stabilizing agent; suspending agent; tablet and 
capsule disintegrant; tablet binder; viscosity-increasing agent; 
water-absorbing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Carboxymethylcellulose sodium is widely used in oral and 
topical pharmaceutical formulations, primarily for its viscosityincreasing 
properties. Viscous aqueous solutions are used to 
suspend powders intended for either topical application or oral 
and parenteral administration.(1,2) Carboxymethylcellulose 
sodium may also be used as a tablet binder and disintegrant,(
3–6) and to stabilize emulsions.(7,8) 
Higher concentrations, usually 3–6%, of the mediumviscosity 
grade are used to produce gels that can be used as 
the base for applications and pastes; glycols are often included 
in such gels to prevent them drying out. Carboxymethylcellulose 
sodium is additionally one of the main ingredients of selfadhesive 
ostomy, wound care,(9) and dermatological patches, 
where it is used as a muco-adhesive and to absorb wound 
exudate or transepidermal water and sweat. This mucoadhesive 
property is used in products designed to prevent 
post-surgical tissue adhesions;(10–12) and to localize and modify 
the release kinetics of active ingredients applied to mucous 
membranes; and for bone repair. Encapsulation with carboxymethylcellulose 
sodium can affect drug protection and delivery.(
6,13) There have also been reports of its use as a cytoprotective 
agent.(14,15) 
Carboxymethylcellulose sodium is also used in cosmetics, 
toiletries,(16) surgical prosthetics,(17) and incontinence, personal 
hygiene, and food products. 
See Table I. 
Table I: Uses of carboxymethylcellulose sodium. 
Use Concentration (%) 
Emulsifying agent 0.25–1.0 
Gel-forming agent 3.0–6.0 
Injections 0.05–0.75 
Oral solutions 0.1–1.0 
Tablet binder 1.0–6.0 
8 Description 
Carboxymethylcellulose sodium occurs as a white to almost 
white, odorless, granular powder. See also Section 18. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for carboxymethylcellulose 
sodium. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters . . — 
pH (1% w/v solution) 6.0–8.0 6.0–8.0 6.5–8.5 
Appearance of solution . . — 
Viscosity . . . 
Loss on drying 410.0% 410.0% 410.0% 
Heavy metals 420 ppm 420 ppm 420 mg/g 
Chloride 40.640% 40.25% — 
Arsenic 410 ppm — — 
Sulfate 40.960% — — 
Silicate 40.5% — — 
Sodium glycolate — 40.4% — 
Starch . — — 
Sulfated ash — 20.0–33.3% — 
Organic volatile impurities — — . 
Assay (of sodium) 6.5–8.5% 6.5–10.8% 6.5–9.5%

SEM: 1 
Excipient: Carboxymethylcellulose sodium 
Manufacturer: Buckeye Cellulose Corp. 
Lot No.: 9247 AP 
Magnification: 120 Voltage: 10 kV 
10 Typical Properties 
Density (bulk): 0.52 g/cm3 
Density (tapped): 0.78 g/cm3 
Dissociation constant: pKa = 4.30 
Melting point: browns at approximately 2278C, and chars at 
approximately 2528C. 
Moisture content: typically contains less than 10% water. 
However, carboxymethylcellulose sodium is hygroscopic 
and absorbs significant amounts of water at temperatures 
up to 378C at relative humidities of about 80%. See Section 
11. See also Figure 1. 
Solubility: practically insoluble in acetone, ethanol (95%), ether, 
and toluene. Easily dispersed in water at all temperatures, 
forming clear, colloidal solutions. The aqueous solubility 
varies with the degree of substitution (DS). See Section 18. 
Viscosity: various grades of carboxymethylcellulose sodium are 
commercially available that have differing aqueous viscosities; 
see Table III. Aqueous 1% w/v solutions with 
viscosities of 5–13 000 mPa s (5–13 000 cP) may be 
obtained. An increase in concentration results in an increase 
in aqueous solution viscosity.(16) Prolonged heating at high 
temperatures will depolymerize the gum and permanently 
decrease the viscosity. The viscosity of sodium carboxymethylcellulose 
solutions is fairly stable over a pH range of 
4–10. The optimum pH range is neutral. See Section 11. 
Table III: Viscosity of aqueous carboxymethylcellulose sodium 1% 
w/v solutions. (Measurements made with a Brookfield LVT viscometer at 
258C.) 
Grade Viscosity 
(mPa s) 
Spindle Speed 
Low viscosity Akucell AF 0305 10–15 #1 60 rpm 
Medium viscosity Akucell AF 2785 1500–2500 #3 30 rpm 
High viscosity Akucell AF 3085 8000–12000 #4 30 rpm 
SEM: 2 
Excipient: Carboxymethylcellulose sodium 
Manufacturer: Hercules Ltd. 
Lot No.: 21 A-1 (44390) 
Magnification: 600 Voltage: 10 kV 
Figure 1: Sorption–desorption isotherm of carboxymethylcellulose 
sodium. 
*: Sorption 
&: Desorption 
11 Stability and Storage Conditions 
Carboxymethylcellulose sodium is a stable, though hygroscopic 
material. Under high-humidity conditions, carboxymethylcellulose 
sodium can absorb a large quantity (>50%) of water. 
Carboxymethylcellulose Sodium 121

In tablets, this has been associated with a decrease in tablet 
hardness and an increase in disintegration time.(18) 
Aqueous solutions are stable at pH 2–10; precipitation can 
occur below pH 2, and solution viscosity decreases rapidly 
above pH 10. Generally, solutions exhibit maximum viscosity 
and stability at pH 7–9. 
Carboxymethylcellulose sodium may be sterilized in the dry 
state by maintaining it at a temperature of 1608C for 1 hour. 
However, this process results in a significant decrease in 
viscosity and some deterioration in the properties of solutions 
prepared from the sterilized material. 
Aqueous solutions may similarly be sterilized by heating, 
although this also results in some reduction in viscosity. After 
autoclaving, viscosity is reduced by about 25%, but this 
reduction is less marked than for solutions prepared from 
material sterilized in the dry state. The extent of the reduction is 
dependent on the molecular weight and degree of substitution; 
higher molecular weight grades generally undergo a greater 
percentage reduction in viscosity.(19) Sterilization of solutions 
by gamma irradiation also results in a reduction in viscosity. 
Aqueous solutions stored for prolonged periods should 
contain an antimicrobial preservative.(20) 
The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Carboxymethylcellulose sodium is incompatible with strongly 
acidic solutions and with the soluble salts of iron and some 
other metals, such as aluminum, mercury, and zinc. Precipitation 
may occur at pH <2, and also when it is mixed with 
ethanol (95%). 
Carboxymethylcellulose sodium forms complex coacervates 
with gelatin and pectin. It also forms a complex with collagen 
and is capable of precipitating certain positively charged 
proteins. 
13 Method of Manufacture 
Alkali cellulose is prepared by steeping cellulose obtained from 
wood pulp or cotton fibers in sodium hydroxide solution. The 
alkaline cellulose is then reacted with sodium monochloroacetate 
to produce carboxymethylcellulose sodium. Sodium 
chloride and sodium glycolate are obtained as by-products of 
this etherification. 
14 Safety 
Carboxymethylcellulose sodium is used in oral, topical, and 
some parenteral formulations. It is also widely used in 
cosmetics, toiletries, and food products, and is generally 
regarded as a nontoxic and nonirritant material. However, 
oral consumption of large amounts of carboxymethylcellulose 
sodium can have a laxative effect; therapeutically, 4–10 g in 
daily divided doses of the medium- and high-viscosity grades of 
carboxymethylcellulose sodium have been used as bulk 
laxatives.(21) 
The WHO has not specified an acceptable daily intake for 
carboxymethylcellulose sodium as a food additive since the 
levels necessary to achieve a desired effect were not considered 
to be a hazard to health.(22–25) However, in animal studies, 
subcutaneous administration of carboxymethylcellulose 
sodium has been found to cause inflammation, and in some 
cases of repeated injection fibrosarcomas have been found at 
the site of injection.(26) 
Hypersensitivity and anaphylactic reactions have occurred 
in cattle and horses, which have been attributed to carboxymethylcellulose 
sodium in parenteral formulations such as 
vaccines and penicillins.(27–30) 
LD50 (guinea pig, oral): 16 g/kg(31) 
LD50 (rat, oral): 27 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Carboxymethylcellulose 
sodium may be irritant to the eyes. Eye protection is 
recommended. 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (dental preparations; 
inhalations; intra-articular, intrabursal, intradermal, intralesional, 
IM, intrasynovial and SC injections; oral capsules, 
drops, solutions, suspensions, syrups and tablets; topical and 
vaginal preparations). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Carboxymethylcellulose calcium. 
18 Comments 
A number of grades of carboxymethylcellulose sodium are 
commercially available, such as Accelerate. These have a degree 
of substitution (DS) in the range 0.7–1.2. The DS is defined as 
the average number of hydroxyl groups substituted per 
anhydroglucose unit and it is this that determines the aqueous 
solubility of the polymer. Thermal crosslinking reduces 
solubility while retaining water absorption, therefore producing 
materials suitable for water absorption. 
Grades are typically classified as being of low, medium, or 
high viscosity. The degree of substitution and the maximum 
viscosity of an aqueous solution of stated concentration should 
be indicated on any carboxymethylcellulose sodium labeling. 
Carboxymethylcellulose sodium has been reported to give 
false positive results in the LAL test for endotoxins.(32) 
19 Specific References 
1 Hussain MA, Aungst BJ, Maurin MB, Wu LS. Injectable 
suspensions for prolonged release nalbuphine. Drug Dev Ind 
Pharm 1991; 17(1): 67–76. 
2 Chang JH, Lee KC, Choi HJ, et al. Radiographic contrast study of 
the upper gastrointestinal tract of eight dogs using carboxymethylcellulose 
mixed with a low concentration of barium sulphate. Vet 
Rec 2004; 154(7): 201–204. 
3 Khan KA, Rhodes CT. Evaluation of different viscosity grades of 
sodium carboxymethylcellulose as tablet disintegrants. Pharm 
Acta Helv 1975; 50: 99–102. 
4 Shah NH, Lazarus JH, Sheth PR, Jarowski CI. Carboxymethylcellulose: 
effect of degree of polymerization and substitution on 
tablet disintegration and dissolution. J Pharm Sci 1981; 70(6): 
611–613. 
5 Singh J. Effect of sodium carboxymethylcelluloses on the disintegration, 
dissolution and bioavailability of lorazepam from 
tablets. Drug Dev Ind Pharm 1992; 18(3): 375–383. 
6 Dabbagh MA, Ford JL, Rubinstein MH, et al. Release of 
propanolol hydrochloride from matrix tablets containing sodium 
122 Carboxymethylcellulose Sodium

carboxymethylcellulose and hydroxypropylmethylcellulose. 
Pharm Dev Technol 1999; 4(3): 313–324. 
7 Oza KP, Frank SG. Microcrystalline cellulose stabilized emulsions. 
J Disper Sci Technol 1986; 7(5): 543–561. 
8 Adeyeye MC, Jain AC, Ghorab MK, Reilly WJ Jr. Viscoelastic 
evaluation of topical creams containing microcrystalline cellulose/ 
sodium carboxymethylcellulose as stabilizer. AAPS PharmSciTech 
2002; 3(2): E8. 
9 Fletcher J. The benefits if using hydrocolloids. Nurs Times 2003; 
99(21): 57. 
10 Yelimlies B, Alponat A, Cubukcu A, et al. Carboxymethylcellulose 
coated on visceral face of polypropylene mesh prevents adhesion 
without impairing wound healing in incisional hernia model in 
rats. Hernia 2003; 7(3): 130–133. 
11 Hay WP, Mueller PO, Harmon B, Amoroso L. One percent sodium 
carboxymethylcellulose prevents experimentally induced adhesions 
in horses. Vet Surg 2001; 673(3): 223–227. 
12 Liu LS, Berg RA. Adhesion barriers of carboxymethylcellulose and 
polyethylene oxide composite gels. J Biomed Mater Res 2002; 
63(3): 326–332. 
13 Marschutz MK, Caliceti P, Bernkop-Schnurch A. Design and in 
vivo evaluation of an oral delivery system for insulin. Pharm Res 
2000; 17(12): 1468–1474. 
14 Ahee JA, Kaufman SC, Samuel MA, et al. Decreased incidence of 
epithelial defects during laser in situ keratomileusis using 
intraoperative nonpreserved carboxymethylcellulose sodium 
0.5% solution. J Cateract Refract Surg 2002; 28(9): 1651–1654. 
15 Vehige JG, Simmons PA, Anger C, et al. Cytoprotective properties 
of carboxymethylcellulose (CMC) when used prior to wearing 
contact lenses treated with cationic disinfecting agents. Eye 
Contact Lens 2003; 29(3): 177–180. 
16 Mombellet H, Bale P. Sodium carboxymethylcellulose toothpaste. 
Manuf Chem 1988; 59(11): 47, 49, 52. 
17 Valeriani M, Mezzana P, Madonna Terracina FS. Carboxymethylcellulose 
hydrogel mammary implants: our experience. Acta Chir 
Plast 2002; 44(3): 77–79. 
18 Khan KA, Rhodes CT. Water-sorption properties of tablet 
disintegrants. J Pharm Sci 1975; 64(6): 447–451. 
19 Chu PI, Doyle D. Development and evaluation of a laboratoryscale 
apparatus to simulate the scale-up of a sterile semisolid and 
effects of manufacturing parameters on product viscosity. Pharm 
Dev Technol 1999; 4(4): 553–559. 
20 Banker G, Peck G, Williams E, et al. Microbiological considerations 
of polymer solutions used in aqueous film coating. Drug Dev 
Ind Pharm 1982; 8(1): 41–51. 
21 Wapnir RA, Wingertzahn MA, Teichberg S. Cellulose derivatives 
and intestinal absorption of water and electrolytes: potential role 
in oral rehydration solutions. Proc Soc Exp Biol Med 1997; 
215(3): 275–280. 
22 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirty-fifth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1990: No. 
789. 
23 Til HP, Bar A. Subchronic (13-week) oral toxicity study of gammacyclodextrin 
in dogs. Regul Toxicol Pharmacol 1998; 27(2): 159– 
165. 
24 Diebold Y, Herreras JM, , Callejo S, et al. Carbomer- versus 
cellulose-based artificial-tear formulations: morphological and 
toxicologic effects on a corneal cell line. Cornea 1998; 17(4): 
433–440. 
25 Ugwoke MI, Agu RU, Jorissen M, et al. Toxicological investigations 
of the effects of carboxymethylcellulose on ciliary beat 
frequency of human nasal epithelial cells in primary suspension 
culture and in vivo on rabbit nasal mucosa. Int J Pharm 2000; 
205(1–2): 43–51. 
26 Teller MN, Brown GB. Carcinogenicity of carboxymethylcellulose 
in rats. Proc Am Assoc Cancer Res 1977; 18: 225. 
27 Schneider CH, de Weck AL, Sta. uble E. Carboxymethylcellulose 
additives in penicillins and the elucidation of anaphylactic 
reactions. Experentia 1971; 27: 167–168. 
28 Aitken MM. Induction of hypersensitivity to carboxymethylcellulose 
in cattle. Res Vet Sci 1975; 19: 110–113. 
29 Bigliardi PL, Izakovic J,Weber JM, Bircher AJ. Anaphylaxis to the 
carbohydrate carboxymethylcellulose in parenteral corticosteroid 
preparations. Dermatology 2003; 207(1): 100–103. 
30 Montoro J, Valero A, Elices A, et al. Anaphylactic shock after 
intra-articular injection of carboxymethylcellulose. Allergol 
Immunopathol 2000; 28(6): 332–333. 
31 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3236. 
32 Tanaka S, Aketagawa J, Takahashi S, et al. Activation of a limulus 
coagulation factor G by (1!3)-b-D-glucans. Carbohydr Res 1991; 
218: 167–174. 
20 General References 
Doelker E. Cellulose derivatives. Adv Polym Sci 1993; 107: 199–265. 
21 Authors 
D Parsons. 
22 Date of Revision 
17 August 2005. 
Carboxymethylcellulose Sodium 123

Carrageenan 
1 Nonproprietary Names 
USPNF: Carrageenan 
2 Synonyms 
Chondrus extract; E407; Gelcarin; Genu; Hygum TP-1; Irish 
moss extract; Marine Colloids; SeaSpen PF; Viscarin. 
3 Chemical Name and CAS Registry Number 
Carrageenan [9000-07-1] 
k-Carrageenan [11114-20-8] 
l-Carrageenan [9064-57-7] 
4 Empirical Formula and Molecular Weight 
The USPNF 23 describes carrageenan as the hydrocolloid 
obtained by extraction with water or aqueous alkali from some 
members of the class Rhodophyceae (red seaweed). It consists 
chiefly of potassium, sodium, calcium, magnesium, and 
ammonium sulfate esters of galactose and 3,6-anhydrogalactose 
copolymers. These hexoses are alternately linked at the 
a-1,3 and b-1,4 sites in the polymer. 
5 Structural Formula 
The carrageenans are divided into three families according to 
the position of sulfate groups and the presence or absence of 
anhydrogalactose. 
l-Carrageenan (lambda-carrageenan) is a nongelling polymer 
containing about 35% ester sulfate by weight and no 3,6- 
anhydrogalactose. 
i-Carrageenan (iota-carrageenan) is a gelling polymer 
containing about 32% ester sulfate by weight and approximately 
30% 3,6-anhydrogalactose. 
k-Carrageenan (kappa-carrageenan) is a strongly gelling 
polymer which has a helical tertiary structure that allows 
gelling.(1) It contains 25% ester sulfate by weight and 
approximately 34% 3,6-anhydrogalactose. 
6 Functional Category 
Emulsifying agent; gel base; stabilizing agent; suspending agent; 
sustained release tablet matrix; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Carrageenan is used in a variety of nonparenteral dosage forms, 
including suspensions (wet and reconstitutable), emulsions, 
gels, creams, lotions, eye drops, suppositories, and tablets and 
capsules. In suspension formulations, usually only the icarrageenen 
and l-carrageenan fractions are used. l-Carrageenan 
is generally used at levels of 0.7% w/v or less, and provides 
viscosity to the liquid. Carrageenan has been shown to mask 
the chalkiness of antacid suspensions when used as a 
suspending agent in these preparations.(2) When used in 
concentrations of 0.1–0.5%, carrageenan gives stable emulsions. 
Carrageenan is used in hand lotions and creams to 
provide slip and improved ’rub out’. 
i-Carrageenan develops a shear-thinning thixotropic gel, 
which can be easily poured after shaking. When i-carrageenan 
is used, the presence of calcium ions is required for the gel 
network to become established. With pure i-carrageenan, 
about 0.4% w/v is required for most suspensions plus the 
addition of calcium. However, if SeaSpen PF is used, it must be 
at about 0.75% w/v level, although no additional calcium is 
required as this is already present in the product to control the 
rate of gelation. 
Studies on the effect of carrageenan and other colloids on 
muco-adhesion of drugs to the oropharyngeal areas(3,4) have 
shown that carrageenan had the greatest propensity for 
adhesion and can be used in formulations for oral and buccal 
drug delivery. 
The application of carrageenan in both topical gel bases and 
suppository bases has been examined,(5,6) and the findings 
indicate that the use of carrageenan in these dosage forms is 
most likely to be dependent on the active drug, owing to the 
potential for ionic interactions. 
In the case of topical gels, a combination of i, k-, and lcarrageenans 
produces a spreadable gel with acceptable tactile 
sensation, resulting in drug release that is more likely to follow 
diffusion kinetics.

In the case of suppository dosage forms, a greater amount of 
k-carrageenan is required in the presence of potassium to form 
a more rigid structure. 
Incorporation of carrageenan into tablet matrices with 
various drugs and other excipients to alter release profiles has 
been studied, illustrating that the carrageenans have good 
tablet-binding properties.(7–10) Furthermore, the inclusion of 
calcium or potassium salts into the tablet creates a microenvironment 
for gelation to occur, which further controls drug 
release. 
There have also been several references to the use of 
carrageenan in chewable tablets having a confectionary 
texture.(11,12) This approach to creating a novel dosage form 
requires the use of both i-carrageenan and k-carrageenan, to 
prevent moisture loss and texture changes that occur over time. 
See also Section 10. Carrageenan has been used for the 
microencapsulation of proteins(13) and probiotic bacteria.(14) It 
has also been used as beads in the preparation of controlled 
release systems.(15,16) Studies have shown that carrageenan 
compounds block infections by the herpes simplex virus;(17) 
human cytomegalovirus; human papilloma virus; Sindbis virus; 
vesicular stomatitis virus; and HIV.(18) A combined k- and lcarrageenan 
formulation is currently being investigated as the 
active ingredient in a topical microbicide used to prevent the 
sexual transmission of HIV.(19–21) In combination with 
chitosan, agar and polyvinyl pyrrolidone, carrageenan forms 
a water-insoluble complex which is able to absorb large 
amounts of body fluids, and is used as an effective wound 
dressing.(22–24) Carrageenan is used in the preparation of hard 
and soft capsule shells.(25) It is also used in toothpastes and 
cosmetic preparations such as conditioners and shampoos.(
26,27) 
8 Description 
Carrageenan, when extracted from the appropriate seaweed 
source, is a yellow-brown to white colored, coarse to fine 
powder that is odorless and tasteless. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for carrageenan. 
Test USPNF 23 
Identification . 
Acid insoluble matter 42.0% 
Arsenic 43 ppm 
Heavy metals 40.004% 
Lead 40.001% 
Loss on drying 412.5% 
Total ash 435.0% 
Viscosity (at 758C) 45 mPa s 
Microbial limits 4200 /g 
10 Typical Properties 
Because of the vast differences in the material that can be 
referred to as carrageenan, it is difficult to give descriptions of 
typical properties. See Table II. 
Solubility: soluble in water at 808C. See Tables II and III. 
Viscosity (dynamic): 5 mPa s (5 cP) at 758C. See Table II. 
11 Stability and Storage Conditions 
Carrageenan is a stable, though hygroscopic, polysaccharide 
and should be stored in a cool, dry place. 
12 Incompatibilities 
Carrageenan can react with cationic materials. If complexation 
of cationic materials, with associated modification of the active 
compound’s solubility, is undesirable, the use of carrageenan is 
not recommended. 
Table III: Solubililty and gelation properties of i-, k-, and lcarrageenans. 
Kappa Iota Lambda 
Solubility in water 
208C Na salt only Na salt only Yes 
808C Yes Yes Yes 
Gelation 
Ions necessary K. Ca2. No gel 
Texture Brittle Elastic No gel 
Re-gelation after shear No Yes — 
Acid stability >pH 3.8 >pH 3.8 — 
Table II: Typical properties of different grades of carrageenan (FMC Biopolymer). 
Trade name Carrageenan 
type 
Gel type Solubility in water Viscosity Use concentration 
(%) 
Use examples 
Gelcarin GP-379 Iota Elastic, medium 
strength 
Hot High, 
thixotropic 
0.3–1.0 Creams, suspensions 
Gelcarin GP-812 Kappa Brittle, strong Hot Low 0.3–1.0 Gels 
Gelcarin GP-911 Kappa Brittle, firm Hot, partial in cold Low 0.25–2.0 Encapsulation 
SeaSpen PF Iota Elastic, weak Cold, delayed gel 
formation 
Medium, 
thixotropic 
0.5–1.0 Creams, suspensions, 
lotions 
Viscarin GP-109 Lambda Non-gelling Partial cold, full in hot Medium 0.1–1.0 Creams, lotions 
Viscarin GP-209 Lambda Non-gelling Partial cold, full in hot High 0.1–1.0 Creams, lotions 
Viscarin GP-328 Kappa/lambda Weak Hot Medium–high 0.7–1.2 Creams, emulsions, 
lotions 
Carrageenan 125

13 Method of Manufacture 
The main species of seaweed from which carrageenan is 
manufactured are Eucheuma, Chondrus, and Gigartina. The 
weed is dried quickly to prevent degradation, and is then baled 
for shipment to processing facilities. The seaweed is repeatedly 
washed to remove gross impurities such as sand, salt and 
marine life. The weed undergoes a hot alkali extraction process, 
releasing the carrageenan from the cell. Once it is in a hot 
solution, carrageenan undergoes clarification and concentration 
in solution and is converted to powder. 
Three processes can be used to remove the carrageenan from 
solution. The first is a ‘freeze–thaw’ technique. The solution is 
gelled with various salts, then the gels are frozen. Upon 
thawing, the water is removed and the resultant mass, primarily 
carrageenan and salt, is ground to the desired particle size. 
The second method, referred to as the ‘alcohol precipitation 
method’ takes the concentrated solution of carrageenan and 
places it in alcohol. This causes the carrageenan to precipitate 
out of solution. The cosolvents are evaporated and the 
precipitated carrageenan is dried and ground to the desired 
particle size. 
The third method is the ‘KCl precipitation’ process, where 
after hot extraction, the filtrate is evaporated to reduce the 
filtrate volume. The filtrate is then extruded through spinnerets 
into a cold 1.0–1.5% solution of potassium chloride. The 
resulting gel threads are washed with KCl solution and are 
pressed, dried and milled to carrageenan powder.(2) Commercial 
carrageenan is usually standardized by blending different 
batches of carrageenan and adding sugar or salt to obtain the 
desired gelling or thickening properties.(28) 
14 Safety 
Carrageenan is widely used in numerous food applications and 
is increasingly being used in pharmaceutical formulations. 
Carrageenan is generally regarded as a relatively nontoxic and 
nonirritating material when used in nonparenteral pharmaceutical 
formulations. 
However, carrageenan is known to induce inflammatory 
responses in laboratory animals, and for this reason it is 
frequently used in experiments for the investigation of antiinflammatory 
drugs.(29,30) Animal studies suggest that 
degraded carrageenan (which is not approved for use in food 
products) may be associated with cancer in the intestinal tract, 
although comparable evidence does not exist in humans.(31) 
The WHO has set an acceptable daily intake of carrageenan 
of ‘not specified’ as the total daily intake was not considered to 
represent a hazard to health.(32) In the UK, the Food Advisory 
Committee has recommended that carrageenan should not be 
used as an additive for infant formulas.(33) 
LD50 (rat, oral): >5 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (dental; oral granules, 
powders and syrups, topical; and transdermal preparations). 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
—
18 Comments 
The EINECS number for carrageenan is 232-524-2. 
19 Specific References 
1 The Merck Index: an Encyclopedia of Chemicals, Drugs and 
Biologicals, 13th edn. Whitehouse Station, NJ: Merck, 2001: 316. 
2 Chaoyuan W, ed. Training Manual on Gracilaria Culture and 
Seaweed Processing in China. China: Depratment of Aquatic 
Products, Ministry of Agriculture, 1990. 
3 Brannon-Peppas L, Reilly W. In vitro testing of bioadhesion of 
solutions for buccal administration and drug delivery. Proceedings 
of the 23rd International Symposium on Controlled Release of 
Bioactive Materials, 1996: 513. 
4 Hanawa T, Masuda N, Mohri K, et al. Development of patientfriendly 
preparations: preparation of a new allopurinol 
mouthwash containing polyethylene(oxide) and carrageenan. 
Drug Dev Ind Pharm 2004; 30(2): 151–161. 
5 Lev R, Long R, Mallonga L, et al. Evaluation of carrageenan as a 
base for topical gels. Pharm Res 1997; 14(11): 42. 
6 Lui Y, Schnaare R, Reilly W. Evaluation of carrageenan as a 
suppository base. Pharm Res 1997; 14(11): 41. 
7 Hariharan M, Wheatley TA, Price JC. Controlled-release tablet 
matrices from carrageenans: compression and dissolution studies. 
Pharm Dev Technol 1997; 2(4): 383–393. 
8 Picker KM. Matrix tablets of carrageenans I: a compaction study. 
Drug Dev Ind Pharm 1999; 25(3): 329–337. 
9 Picker KM. Matrix tablets of carrageenans II: release behavior and 
effect of added cations. Drug Dev Ind Pharm 1999; 25(3): 339– 
346. 
10 Gursoy A, Cevik S. Sustained release properties of alginate 
microspheres and tabletted microspheres of diclofenac sodium. J 
Microencapsul 2000; 17(5): 565–575. 
11 Bubnis W, O’Hare K, Reilly W. A novel soft chewable gel delivery 
system. Proceedings of the 24th International Symposium on 
Controlled Release of Bioactive Materials, 1997: 653. 
12 Bubnis W, O’Hare K, Reilly W. A low moisture hydrocolloid soft 
chewable gel delivery system. Pharm Res 1997; 14(11): 525. 
13 Patil RT, Speaker TJ.Water-based microsphere delivery system for 
proteins. J Pharm Sci 2000; 89(1): 9–15. 
14 Kailasapathy K. Microencapsulation of probiotic bacteria: technology 
and potential applications. Curr Issues Intest Microbiol 
2002; 3(2): 39–48. 
15 Ozsoy Y, Bergisadi N. Preparation of mefenamic acid sustained 
release beads based om kappa-carrageenan. Boll Chim Farm 2000; 
139(3): 120–123. 
16 Sipahigil O, Dortunc B. Preparation and in vitro evaluation of 
verapamil hydrochloride and ibuprofen containing carrageenan 
beads. Int J Pharm 2001; 228(1–2): 119–128. 
17 Carlucci MJ, Scolaro LA, Damonte EB. Inhibitory action of 
natural carrageenans on herpes simplex virus infection of mouse 
astrocytes. Chemotherapy 1999; 45(6): 429–436. 
18 Gonzalez ME, Alarcon B, Carrasco L. Polysaccharides as antiviral 
agents: antiviral activity of carrageenan. Antimicrob Agents 
Chemother 1987; 31(9): 1388–1393. 
19 Population Council. Biomedicine: Population Council Microbicide 
Programme. The Population Council’s Head Candidate Microbicide: 
Carraguard. http://www.popcouncil.org/biomed/ 
carraguard.html (accessed 29 December 2004). 
20 Pearce-Pratt R, Phillips DM. Sulfated polysaccharides inhibit 
lymphocyte-to-epithelial transmission of human immunodeficiency 
virus-1. Biol Reprod 1996; 53(1): 173–182. 
21 Perotti ME, Pirovano A, Phillips DM. Carrageenan formulation 
prevents macrophage trafficking from vagina: implications for 
microbicide development. Biol Reprod 2003; 69(3): 933–939. 
126 Carrageenan

22 Varshney L. Hydrogel: A new radiation processed surgical 
dressing. Nuclear Medicine. India: Press Information Bureau, 
2003. 
23 Wu M, Bao B, Yoshii F, Makuuchi K. Irradiation of cross-linked 
polyvinyl alcohol blended hydrogel for wound dressing. J Radioanal 
Nuclear Chem 2001; 250(2): 391–395. 
24 Radiation studies of carrageenan. Manila, Phillipines: Food and 
Nutrition Research Institute, 2003. 
25 Briones AV. Carrageenan capsules (hard type). Manila, Phillipines: 
Industrial Technology Development Institute, Department of 
Science and Technology, 2003. 
26 Stanley N. In: McHugh DJ, ed. Production, Properties and Uses of 
Carrageenan in Production and Utilization of Products from 
Commercial Seaweeds. Rome: Food and Agriculture Organisation 
of United Nations, 1987. 
27 Profile of Key Industries: Seaweeds/Carrageenan Industry Profile. 
Manila, Philippines: Department of Trade and Industry, 1998. 
28 Marcel Trading Corporation. Technical Literature: Marcel Carrageenan, 
1999. 
29 Cuzzocrea S, Mazzon E, Sautebin L, et al. Protective effects of 
Celecoxib on lung injury and red blood cells modification induced 
by carrageenan in the rat. Biochem Pharmacol 2002; 63(4): 785– 
795. 
30 Manni L, Lundeberg T, Tirassa P, Aloe L. Role of cholecystokinin- 
8 in nerve growth factor and nerve growth factor in mRNA 
expression in carrageenan-induced joint inflammation in adult 
rats. Rheumatology (Oxford) 2002; 41(7): 787–792. 
31 Tobacman JK. Review of harmful gastrointestinal effects of 
carrageenan in animal experiments. Environ Health Perspect 
2001; 109(10): 983–994. 
32 FAO/WHO. Evaluation of certain food additives and contaminants. 
Twenty-eighth report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1984; No 710. 
33 MAFF. Food Advisory Committee: report on the review of the use 
of additives in foods specially prepared for infants and young 
children. FdAC/REP/12. London: HMSO, 1992. 
20 General References 
FMC Biopolymer. Technical literature: Marine colloids, carrageenan 
application bulletins, 2004. 
Whistler RL, BeMiller JN, eds. Industrial Gums, Polysaccharides and 
Their Derivatives, 3rd edn. San Diego: Academic Press, 1993. 
21 Authors 
KK Singh. 
22 Date of Revision 
26 August 2005. 
Carrageenan 127

Castor Oil 
1 Nonproprietary Names 
BP: Virgin castor oil 
JP: Castor oil 
PhEur: Ricini oleum virginale 
USP: Castor oil 
2 Synonyms 
EmCon CO; Lipovol CO; oleum ricini; ricinoleum; ricinus 
communis; ricinus oil; tangantangan. 
3 Chemical Name and CAS Registry Number 
Castor oil [8001-79-4] 
4 Empirical Formula and Molecular Weight 
Castor oil is a triglyceride of fatty acids. The fatty acid 
composition is approximately ricinoleic acid (87%); oleic acid 
(7%); linoleic acid (3%); palmitic acid (2%); stearic acid (1%) 
and trace amounts of dihydroxystearic acid. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Emollient; oleaginous vehicle; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Castor oil is widely used in cosmetics, food products, and 
pharmaceutical formulations. In pharmaceutical formulations, 
castor oil is most commonly used in topical creams and 
ointments at concentrations of 5–12.5%. However, it is also 
used in oral tablet and capsule formulations and as a solvent in 
intramuscular injections.(1,2) 
Therapeutically, castor oil has been administered orally for 
its laxative action, but such use is now obsolete. 
8 Description 
Castor oil is a clear, almost colorless or pale yellow-colored 
viscous oil. It has a slight odor and a taste that is initially bland 
but afterwards slightly acrid. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for castor oil. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . — 
Characters . . — 
Specific gravity 0.953–0.965 0.958 0.957–0.961 
Heavy metals — — 40.001% 
Iodine value 80–90 82–90 83–88 
Saponification value 176–187 — 176–182 
Hydroxyl value 155–177 5150 160–168 
Acid value 41.5 42.0 — 
Peroxide value — 410.0 — 
Refractive index — 1.479 — 
Optical rotation — .3.58 to .6.08 — 
Water — 40.3% — 
Absorbance . 41.5 — 
Composition of fatty 
acids 
— . — 
Purity . — — 
Distinction from most 
other fixed oils 
— — . 
Free fatty acids — — . 
Unsaponifiable 
matter 
— 40.8% — 
10 Typical Properties 
Autoignition temperature: 4498C 
Boiling point: 3138C 
Density: 0.955–0.968 g/cm3 at 258C 
Flash point: 2298C 
Melting point: 128C 
Moisture content: 40.25% 
Refractive index: 
nD
25 = 1.473–1.477; 
nD
40 = 1.466–1.473. 
Solubility: miscible with chloroform, diethyl ether, ethanol, 
glacial acetic acid, and methanol; freely soluble in ethanol 
(95%) and petroleum ether; practically insoluble in water; 
practically insoluble in mineral oil unless mixed with 
another vegetable oil. See also Section 11. 
Surface tension: 
39.0mN/m at 208C; 
35.2mN/m at 808C. 
Viscosity (dynamic): 
1000 mPa s (1000 cP) at 208C; 
200 mPa s (200 cP) at 408C. 
11 Stability and Storage Conditions 
Castor oil is stable and does not turn rancid unless subjected to 
excessive heat. On heating at 3008C for several hours, castor oil 
polymerizes and becomes soluble in mineral oil. When cooled 
to 08C, it becomes more viscous. 
Castor oil should be stored at a temperature not exceeding 
258C in well-filled airtight containers protected from light.

12 Incompatibilities 
Castor oil is incompatible with strong oxidizing agents. 
13 Method of Manufacture 
Castor oil is the fixed oil obtained by cold-expression of the 
seeds of Ricinus communis Linne. (Fam. Euphorbiaceae). No 
other substances are added to the oil. 
14 Safety 
Castor oil is used in cosmetics and foods and orally, 
parenterally, and topically in pharmaceutical formulations. It 
is generally regarded as a relatively nontoxic and nonirritant 
material when used as an excipient.(3) 
Castor oil has been used therapeutically as a laxative and 
oral administration of large quantities may cause nausea, 
vomiting, colic, and severe purgation. It should not be given 
when intestinal obstruction is present. 
Although widely used in topical preparations, including 
ophthalmic formulations, castor oil has been associated with 
some reports of allergic contact dermatitis, mainly to cosmetics 
such as lipsticks.(4–7) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Castor oil may cause mild 
irritation to the skin and eyes. Castor oil is flammable when 
exposed to heat. Spillages are slippery and should be covered 
with an inert absorbant before collection and disposal. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(IM injections; oral capsules and tablets; topical creams, 
emulsions, ointments, and solutions). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian List 
of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Castor oil, hydrogenated. 
18 Comments 
A specification for castor oil is contained in the Food Chemicals 
Codex (FCC). 
The EINECS number for castor oil is 232-293-8. 
19 Specific References 
1 Rifkin C, Huber R, Keysser CH. Castor oil as a vehicle for 
parenteral administration of steroid hormones. J Pharm Sci 1964; 
53: 891–895. 
2 Jumaa M, Mu. ller BW. Development of a novel parenteral 
formulation for tetrazepam using a lipid emulsion. Drug Dev 
Ind Pharm 2001; 27(10): 1115–1121. 
3 Irwin R. NTP technical report on the toxicity studies of castor oil 
(CAS no 8001-79-4) in F344/N rats and B6C3F1 mice (dosed feed 
studies). Toxic Rep Ser 1982; 12: 1–B5. 
4 Fisher LB, Berman B. Contact allergy to sulfonated castor oil. 
Contact Dermatitis 1981; 7(6): 339–340. 
5 Sai S. Lipstick dermatitis caused by castor oil. Contact Dermatitis 
1983; 9(1): 75. 
6 Andersen KE, Nielsen R. Lipstick dermatitis related to castor oil. 
Contact Dermatitis 1984; 11(4): 253–254. 
7 Smolinske SC. CRC Handbook of Food, Drug and Cosmetic 
Excipients. Boca Raton, FL: CRC Press, 1992: 69–70. 
20 General References 
—
21 Authors 
LME McIndoe. 
22 Date of Revision 
7 August 2005. 
Castor Oil 129

Castor Oil, Hydrogenated 
1 Nonproprietary Names 
BP: Hydrogenated castor oil 
PhEur: Ricini oleum hydrogenatum 
USPNF: Hydrogenated castor oil 
2 Synonyms 
Castorwax; Castorwax MP 70; Castorwax MP 80; Croduret; 
Cutina HR; Fancol; Simulsol 1293. 
3 Chemical Name and CAS Registry Number 
Glyceryl-tri-(12-hydroxystearate) [8001-78-3] 
4 Empirical Formula and Molecular Weight 
C57O9H110 939.50 
The USPNF 23 describes hydrogenated castor oil as the 
refined, bleached, hydrogenated, and deodorized castor oil, 
consisting mainly of the triglyceride of hydroxystearic acid. 
5 Structural Formula 
6 Functional Category 
Extended release agent; stiffening agent; tablet and capsule 
lubricant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Hydrogenated castor oil is a hard wax with a high melting 
point used in oral and topical pharmaceutical formulations; see 
Table I. 
In topical formulations, hydrogenated castor oil is used to 
provide stiffness to creams and emulsions.(1) In oral formulations, 
hydrogenated castor oil is used to prepare sustainedrelease 
tablet and capsule preparations;(2–5) the hydrogenated 
castor oil may be used as a coat or to form a solid matrix. 
Hydrogenated castor oil is additionally used to lubricate the 
die walls of tablet presses;(6,7) and is similarly used as a 
lubricant in food processing. 
Hydrogenated castor oil is also used in cosmetics. 
Table I: Uses of hydrogenated castor oil. 
Use Concentration (%) 
Coating agent (delayed release) 5.0–20.0 
Delayed release drug matrix 5.0–10.0 
Tablet die lubricant 0.1–2.0 
8 Description 
Hydrogenated castor oil occurs as a fine, almost white or pale 
yellow powder or flakes. The PhEur 2005 describes hydrogenated 
castor oil as the oil obtained by hydrogenation of virgin 
castor oil. It consists mainly of the triglyceride of 12- 
hydroxystearic acid. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for hydrogenated castor oil. 
Test PhEur 2005 USPNF 23 
Characters . — 
Identification . — 
Acid value 44.0 — 
Hydroxyl value 145–165 154–162 
Iodine value 45.0 45.0 
Saponification value — 176–182 
Alkaline impurities . — 
Composition of fatty acids . . 
Palmitic acid 42.0% — 
Stearic acid 7.0–14% — 
Arachidic acid 41.0% — 
12-Oxostearic acid 45.0% — 
12-Hydroxystearic acid 78.0–91.0% — 
Any other fatty acid 43.0% — 
Nickel 41 ppm — 
Heavy metals — 40.001% 
Melting range 83–888C 85–888C 
10 Typical Properties 
Acid value: 45 
Density: 0.98–1.10 g/cm3 
Flash point: 3168C (open cup) 
Moisture content: 40.1% 
Particle size distribution: 97.7% 51000 mm in size for flakes. 
Solubility: practically insoluble in water; soluble in acetone, 
chloroform, and methylene chloride. 
11 Stability and Storage Conditions 
Hydrogenated castor oil is stable at temperatures up to 1508C. 
Clear, stable, chloroform solutions containing up to 15% 
w/v of hydrogenated castor oil may be produced. Hydrogenated 
castor oil may also be dissolved at temperatures greater

than 908C in polar solvents and mixtures of aromatic and polar 
solvents, although the hydrogenated castor oil precipitates out 
on cooling below 908C. 
Hydrogenated castor oil should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Hydrogenated castor oil is compatible with most natural 
vegetable and animal waxes. 
13 Method of Manufacture 
Hydrogenated castor oil is prepared by the hydrogenation of 
castor oil using a catalyst. 
14 Safety 
Hydrogenated castor oil is used in oral and topical pharmaceutical 
formulations and is generally regarded as an essentially 
nontoxic and nonirritant material. 
Acute oral toxicity studies in animals have shown that 
hydrogenated castor oil is a relatively nontoxic material. 
Irritation tests with rabbits show that hydrogenated castor oil 
causes mild, transient irritation to the eye. 
LD50 (rat, oral): >10 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
Accepted in the USA as an indirect food additive. Included in 
the FDA Inactive Ingredients Guide (oral capsules, tablets, and 
sublingual tablets). 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Castor oil; vegetable oil, hydrogenated. 
18 Comments 
Various different grades of hydrogenated castor oil are 
commercially available, the composition of which may vary 
considerably. Sterotex K (Karlshamns Lipid Specialities), for 
example, is a mixture of hydrogenated castor oil and 
hydrogenated cottonseed oil. See Vegetable Oil, hydrogenated 
for further information. The EINECS number for hydrogenated 
castor oil is 232-292-2. 
19 Specific References 
1 Kline CH. Thixcin R-thixotrope. Drug Cosmet Ind 1964; 95(6): 
895–897, 960, 963, 973, 976. 
2 Yonezawa Y, Ishida S, Suzuki S, Sunada H. Release from or 
through a wax matrix system. III: basic properties of release 
through the wax matrix layer. Chem Pharm Bull (Tokyo) 2002; 
50(6): 814–817. 
3 Pommier AM, Brossard C, Ser J, Duche.ne D. Optimization of a 
prolonged release tablet formulation of diphylline by retention in a 
lipid matrix [in French]. STP Pharma 1988; 4: 384–391. 
4 Boles MG, Deasy PB, Donnellan MF. Design and evaluation of a 
sustained-release aminophylline tablet. Drug Dev Ind Pharm 
1993; 19: 349–370. 
5 Vergote GJ, Verraet C, Van-Driessche I, et al. Oral controlled 
release matrix pellet formulation containing microcrystalline 
ketoprofen. Int J Pharm 2002; 219: 81–87. 
6 Danish FQ, Parrott EL. Effect of concentration and size of 
lubricant on flow rate of granules. J Pharm Sci 1971; 60: 752–754. 
7 Ho. lzer AW, Sjo. gren J. Evaluation of some lubricants by the 
comparison of friction coefficients and tablet properties. Acta 
Pharm Suec 1981; 18: 139–148. 
20 General References 
—
21 Authors 
RT Guest. 
22 Date of Revision 
21 August 2005. 
Castor Oil, Hydrogenated 131

Cellulose, Microcrystalline 
1 Nonproprietary Names 
BP: Microcrystalline cellulose 
JP: Microcrystalline cellulose 
PhEur: Cellulosum microcristallinum 
USPNF: Microcrystalline cellulose 
2 Synonyms 
Avicel PH; Celex; cellulose gel; Celphere; Ceolus KG; crystalline 
cellulose; E460; Emcocel; Ethispheres; Fibrocel; Pharmacel; 
Tabulose; Vivapur. 
3 Chemical Name and CAS Registry Number 
Cellulose [9004-34-6] 
4 Empirical Formula and Molecular Weight 
(C6H10O5)n 36 000 
where n  220. 
5 Structural Formula 
6 Functional Category 
Adsorbent; suspending agent; tablet and capsule diluent; tablet 
disintegrant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Microcrystalline cellulose is widely used in pharmaceuticals, 
primarily as a binder/diluent in oral tablet and capsule 
formulations where it is used in both wet-granulation and 
direct-compression processes.(1–7) In addition to its use as a 
binder/diluent, microcrystalline cellulose also has some lubricant(
8) and disintegrant properties that make it useful in 
tableting. 
Microcrystalline cellulose is also used in cosmetics and food 
products; see Table I. 
8 Description 
Microcrystalline cellulose is a purified, partially depolymerized 
cellulose that occurs as a white, odorless, tasteless, crystalline 
powder composed of porous particles. It is commercially 
available in different particle sizes and moisture grades that 
have different properties and applications. 
Table I: Uses of microcrystalline cellulose. 
Use Concentration (%) 
Adsorbent 20–90 
Antiadherent 5–20 
Capsule binder/diluent 20–90 
Tablet disintegrant 5–15 
Tablet binder/diluent 20–90 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for microcrystalline cellulose. 
Test JP 2001 PhEur 2005 
(Suppl 5.1) 
USPNF 23 
Identification . . . 
Characters . . — 
pH 5.0–7.0 5.0–7.5 5.0–7.5 
Bulk density . — . 
Loss on drying 47.0% 47.0% 47.0% 
Residue on ignition 40.05% — 40.1% 
Conductivity . . . 
Sulfated ash — 40.1% — 
Ether-soluble substances 40.05% 40.05% 40.05% 
Water-soluble substances . 40.25% 40.25% 
Heavy metals 410 ppm 410 ppm 40.001% 
Organic volatile impurities — — . 
Microbial limits . . . 
Aerobic — 4103/g 41000 cfu/g 
Molds and yeasts — 4102/g 4100 cfu/g 
Solubility — . — 
Particle size distribution — — . 
10 Typical Properties 
Angle of repose: 
498 for Ceolus KG; 
34.48 for Emcocel 90M.(9) 
Density (bulk): 
0.337 g/cm3; 
0.32 g/cm3 for Avicel PH-101;(10) 
0.29 g/cm3 for Emcocel 90M;(9) 
0.29 g/cm3 for VivaPur 101. 
Density (tapped): 
0.478 g/cm3; 
0.45 g/cm3 for Avicel PH-101; 
0.35 g/cm3 for Emcocel 90M.(9) 
Density (true): 1.512–1.668 g/cm3 
Flowability: 1.41 g/s for Emcocel 90M.(9) 
Melting point: chars at 260–2708C. 
Moisture content: typically less than 5% w/w. However, 
different grades may contain varying amounts of water. 
Microcrystalline cellulose is hygroscopic.(11) See Table III.

SEM: 1 
Excipient: Microcrystalline cellulose 
Manufacturer: JRS Pharma LP. 
Lot No.: 98662 
Magnification: 100 
SEM: 2 
Excipient: Microcrystalline cellulose 
Manufacturer: JRS Pharma LP. 
Lot No.: 98662 
Magnification: 300 
Particle size distribution: typical mean particle size is 
20–200 mm. Different grades may have a different nominal 
mean particle size; see Table III. 
SEM: 3 
Excipient: Microcrystalline cellulose 
Manufacturer: FMC Biopolymer 
Magnification: 100 
Solubility: slightly soluble in 5% w/v sodium hydroxide 
solution; practically insoluble in water, dilute acids, and 
most organic solvents. 
Specific surface area: 
1.06–1.12m2/g for Avicel PH-101; 
1.21–1.30m2/g for Avicel PH-102; 
0.78–1.18m2/g for Avicel PH-200. 
11 Stability and Storage Conditions 
Microcrystalline cellulose is a stable though hygroscopic 
material. The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Microcrystalline cellulose is incompatible with strong oxidizing 
agents. 
13 Method of Manufacture 
Microcrystalline cellulose is manufactured by controlled 
hydrolysis with dilute mineral acid solutions of a-cellulose, 
obtained as a pulp from fibrous plant materials. Following 
hydrolysis, the hydrocellulose is purified by filtration and the 
aqueous slurry is spray-dried to form dry, porous particles of a 
broad size distribution. 
14 Safety 
Microcrystalline cellulose is widely used in oral pharmaceutical 
formulations and food products and is generally regarded as a 
relatively nontoxic and nonirritant material. 
Microcrystalline cellulose is not absorbed systemically 
following oral administration and thus has little toxic potential. 
Consumption of large quantities of cellulose may have a 
laxative effect, although this is unlikely to be a problem when 
cellulose is used as an excipient in pharmaceutical formulations. 
Cellulose, Microcrystalline 133

Deliberate abuse of formulations containing cellulose, either 
by inhalation or by injection, has resulted in the formation of 
cellulose granulomas.(12) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Microcrystalline cellulose 
may be irritant to the eyes. Gloves, eye protection, and a dust 
mask are recommended. In the UK, the occupational exposure 
limits for cellulose have been set at 10 mg/m3 long-term (8-hour 
TWA) for total inhalable dust and 4 mg/m3 for respirable dust; 
the short-term limit for total inhalable dust has been set at 
20 mg/m3.(13) 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (inhalations; 
oral capsules, powders, suspensions, syrups, and tablets; 
topical and vaginal preparations). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Microcrystalline cellulose and carrageenan; microcrystalline 
cellulose and carboxymethylcellulose sodium; microcrystalline 
cellulose and guar gum; powdered cellulose; silicified microcrystalline 
cellulose. 
Microcrystalline cellulose and carrageenan 
Synonyms: Lustre Clear. 
Comments: Lustre Clear (FMC Biopolymer) is an aqueous film 
coating combining microcrystalline cellulose and carrageenan. 
Microcrystalline cellulose and carboxymethylcellulose sodium 
Synonyms: Avicel CL-611; Avicel RC-581; Avicel RC-591; 
colloidal cellulose; dispersible cellulose. 
Appearance: white, odorless and tasteless, hygroscopic powder. 
Acidity/alkalinity: pH = 6–8 for a 1.2% w/v aqueous 
dispersion. 
Moisture content: not more than 6.0% w/w. 
Particle size distribution: 
Avicel CL-611:40.1% retained on a #60 mesh and450% 
retained on a #325 mesh; 
Avicel RC-581:40.1% retained on a #60 mesh and435% 
retained on a #200 mesh; 
Avicel RC-591:40.1% retained on a #60 mesh and445% 
retained on a #325 mesh. 
Solubility: practically insoluble in dilute acids and organic 
solvents. Partially soluble in dilute alkali and water 
(carboxymethylcellulose sodium fraction). 
Viscosity (dynamic): 
5–20 mPa s (5–20 cP) for a 1.2% w/v aqueous dispersion of 
Avicel CL-611; 
72–168 mPa s (72–168 cP) for Avicel RC-581 at the same 
concentration; 
39–91 mPa s (39–91 cP) for Avicel RC-591 at the same 
concentration. 
Comments: mixtures of microcrystalline cellulose and carboxymethylcellulose 
sodium that are dispersible in water and 
produce thixotropic gels are suitable as suspending vehicles 
in pharmaceutical formulations. The amount of carboxymethylcellulose 
present can vary between 8.3% and 18.8% 
w/w depending upon the grade of material. 
Microcrystalline cellulose and guar gum 
Synonyms: Avicel CE-15. 
Comments: Avicel CE-15 (FMC Biopolymer) is a coprocessed 
mixture of microcrystalline cellulose and guar gum used in 
chewable tablet formulations. 
18 Comments 
Several different grades of microcrystalline cellulose are 
commercially available that differ in their method of manufacture,(
14,15) particle size, moisture, flow, and other physical 
properties.(16–28) The larger-particle-size grades generally provide 
better flow properties in pharmaceutical machinery. Lowmoisture 
grades are used with moisture-sensitive materials. 
Higher-density grades have improved flowability. 
Several coprocessed mixtures of microcrystalline cellulose 
with other excipients such as carrageenan, carboxymethylcellulose 
sodium, and guar gum are commercially available; see 
Section 17. 
Table III: Properties of selected commercially available grades of 
microcrystalline cellulose. 
Grade Nominal mean 
particle size (mm) 
Particle size analysis Moisture 
content (%) 
Mesh 
size 
Amount 
retained (%) 
Avicel PH-101(a) 50 60 41.0 45.0 
200 430.0 
Avicel PH-102(a) 100 60 48.0 45.0 
200 545.0 
Avicel PH-103(a) 50 60 41.0 43.0 
200 430.0 
Avicel PH-105(a) 20 400 41.0 45.0 
Avicel PH-112(a) 100 60 48.0 41.5 
Avicel PH-113(a) 50 60 41.0 41.5 
200 430.0 
Avicel PH-200(a) 180 60 510.0 45.0 
100 550.0 
Avicel PH-301(a) 50 60 41.0 45.0 
200 430.0 
Avicel PH-302(a) 100 60 48.0 45.0 
200 545.0 
Celex 101(b) 75 60 41.0 45.0 
200 530.0 
Ceolus KG-802(c) 50 60 40.5 46.0 
200 430.0 
Emcocel 50M(d) 50 60 40.25 45.0 
200 430.0 
Emcocel 90M(d) 91 60 48.0 45.0 
200 545.0 
Vivapur 101(d) 50 60 41.0 45.0 
200 430.0 
Vivapur 102(d) 90 60 48.0 45.0 
200 545.0 
Vivapur 12(d) 160 38 41.0 45.0 
94 450.0 
Suppliers: 
(a)FMC Biopolymer 
(b) International Specialty Products 
(c) Asahi Kasei Corporation 
(d) J Rettenmaier & So.hne GmbH 
134 Cellulose, Microcrystalline

Celphere (Asahi Kasei Corporation) is a pure spheronized 
microcrystalline cellulose available in several different particle 
size ranges. 
A specification for microcrystalline cellulose is contained in 
the Food Chemicals Codex (FCC). 
19 Specific References 
1 Ene.zian GM. Direct compression of tablets using microcrystalline 
cellulose [in French]. Pharm Acta Helv 1972; 47: 321–363. 
2 Lerk CF, Bolhuis GK. Comparative evaluation of excipients for 
direct compression I. Pharm Weekbl 1973; 108: 469–481. 
3 Lerk CF, Bolhuis GK, de Boer AH. Comparative evaluation of 
excipients for direct compression II. Pharm Weekbl 1974; 109: 
945–955. 
4 Lamberson RF, Raynor GE. Tableting properties of microcrystalline 
cellulose. Manuf Chem Aerosol News 1976; 47(6): 55–61. 
5 Lerk CF, Bolhuis GK, de Boer AH. Effect of microcrystalline 
cellulose on liquid penetration in and disintegration of directly 
compressed tablets. J Pharm Sci 1979; 68: 205–211. 
6 Chilamkurti RN, Rhodes CT, Schwartz JB. Some studies on 
compression properties of tablet matrices using a computerized 
instrumented press. Drug Dev Ind Pharm 1982; 8: 63–86. 
7 Wallace JW, Capozzi JT, Shangraw RF. Performance of pharmaceutical 
filler/binders as related to methods of powder characterization. 
Pharm Technol 1983; 7(9): 94–104. 
8 Omray A, Omray P. Evaluation of microcrystalline cellulose as a 
glidant. Indian J Pharm Sci 1986; 48: 20–22. 
9 Celik M, Okutgen E. A feasibility study for the development of a 
prospective compaction functionality test and the establishment of 
a compaction data bank. Drug Dev Ind Pharm 1993; 19: 2309– 
2334. 
10 Parker MD, York P, Rowe RC. Binder–substrate interactions in 
wet granulation 3: the effect of excipient source variation. Int J 
Pharm 1992; 80: 179–190. 
11 Callahan JC, Cleary GW, Elefant M, et al. Equilibrium moisture 
content of pharmaceutical excipients. Drug Dev Ind Pharm 1982; 
8: 355–369. 
12 Cooper CB, Bai TR, Heyderman E, Corrin B. Cellulose granulomas 
in the lungs of a cocaine sniffer. Br Med J 1983; 286: 2021– 
2022. 
13 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
14 Jain JK, Dixit VK, Varma KC. Preparation of microcrystalline 
cellulose from cereal straw and its evaluation as a tablet excipient. 
Indian J Pharm Sci 1983; 45: 83–85. 
15 Singla AK, Sakhuja A, Malik A. Evaluation of microcrystalline 
cellulose prepared from absorbent cotton as a direct compression 
carrier. Drug Dev Ind Pharm 1988; 14: 1131–1136. 
16 Doelker E, Mordier D, Iten H, Humbert-Droz P. Comparative 
tableting properties of sixteen microcrystalline celluloses. Drug 
Dev Ind Pharm 1987; 13: 1847–1875. 
17 Bassam F, York P, Rowe RC, Roberts RJ. Effect of particle size and 
source on variability of Young’s modulus of microcrystalline 
cellulose powders. J Pharm Pharmacol 1988; 40: 68P. 
18 Dittgen M, Fricke S, Gerecke H. Microcrystalline cellulose in direct 
tabletting. Manuf Chem 1993; 64(7): 17, 19, 21. 
19 Landin M, Martinez-Pacheco R, Go.mez-Amoza JL, et al. Effect of 
country of origin on the properties of microcrystalline cellulose. Int 
J Pharm 1993; 91: 123–131. 
20 Landin M, Martinez-Pacheco R, Go.mez-Amoza JL, et al. Effect of 
batch variation and source of pulp on the properties of 
microcrystalline cellulose. Int J Pharm 1993; 91: 133–141. 
21 Landin M, Martinez-Pacheco R, Go.mez-Amoza JL, et al. Influence 
of microcrystalline cellulose source and batch variation on 
tabletting behavior and stability of prednisone formulations. Int 
J Pharm 1993; 91: 143–149. 
22 Podczeck F, Re.ve.sz P. Evaluation of the properties of microcrystalline 
and microfine cellulose powders. Int J Pharm 1993; 91: 183– 
193. 
23 Rowe RC, McKillop AG, Bray D. The effect of batch and source 
variation on the crystallinity of microcrystalline cellulose. Int J 
Pharm 1994; 101: 169–172. 
24 HasegawaM. Direct compression: microcrystalline cellulose grade 
12 versus classic grade 102. Pharm Technol 2002; 26(5): 50, 52, 
54, 56, 58, 60. 
25 Kothari SH, Kumar V, Banker GS. Comparative evaluations of 
powder and mechanical properties of low crystallinity celluloses, 
microcrystalline celluloses, and powdered celluloses. Int J Pharm 
2002; 232: 69–80. 
26 Levis SR, Deasy PB. Production and evaluation of size-reduced 
grades of microcrystalline cellulose. Int J Pharm 2001; 213: 13–24. 
27 Wu JS, Ho HO, Sheu MT. A statistical design to evaluate the 
influence of manufacturing factors on the material properties and 
functionalities of microcrystalline cellulose. Eur J Pharm Sci 2001; 
12: 417–425. 
28 Suzuki T, Nakagami H. Effect of crystallinity of microcrystalline 
cellulose on the compactability and dissolution of tablets. Eur J 
Pharm Biopharm 1999; 47: 225–230. 
20 General References 
Asahi Kasei Corporation. Technical literature: Ceolus KG microcrystalline 
cellulose, 2001. 
Asahi Kasei Corporation. Technical literature: Celphere microcrystalline 
cellulose spheres, 2001. 
DMV Pharma. Technical literature: Pharmacel microcrystalline cellulose, 
1998. 
Doelker E. Comparative compaction properties of various microcrystalline 
cellulose types and generic products. Drug Dev Ind Pharm 
1993; 19: 2399–2471. 
FMC Biopolymer. Technical literature: Avicel PH microcrystalline 
cellulose, 1998. 
International Specialty Products. Technical literature: Celex 101 
microcrystalline cellulose, 1997. 
JRS Pharma LP. Technical literature: Emcocel microcrystalline cellulose, 
2003. 
Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 71–74. 
Staniforth JN, Baichwal AR, Hart JP, Heng PWS. Effect of addition of 
water on the rheological and mechanical properties of microcrystalline 
celluloses. Int J Pharm 1988; 41: 231–236. 
21 Authors 
LY Galichet. 
22 Date of Revision 
20 August 2005. 
Cellulose, Microcrystalline 135

Cellulose, Powdered 
1 Nonproprietary Names 
BP: Powdered cellulose 
JP: Powdered cellulose 
PhEur: Cellulosi pulvis 
USPNF: Powdered cellulose 
2 Synonyms 
Arbocel; E460; Elcema; Sanacel; Solka-Floc. 
3 Chemical Name and CAS Registry Number 
Cellulose [9004-34-6] 
4 Empirical Formula and Molecular Weight 
(C6H10O5)n 243 000 where n  500. 
Since cellulose is derived from a natural polymer, it has 
variable chain length and thus variable molecular weight. See 
also Sections 8 and 13. 
5 Structural Formula 
6 Functional Category 
Adsorbent; glidant; suspending agent; tablet and capsule 
diluent; tablet disintegrant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Powdered cellulose is used as a tablet diluent and a hard gelatin 
capsule filler; see Table I. In both contexts it acts as a bulking 
agent to increase the physical size of the dosage form for 
formulations containing a small amount of active substance. 
Powdered cellulose has acceptable compression properties, 
although its flow properties are poor. However, low-crystallinity 
powdered cellulose has exhibited properties that are 
different from standard powdered cellulose materials, and has 
shown potential as a direct-compression excipient.(1) 
In soft gelatin capsules, powdered cellulose may be used to 
reduce the sedimentation rate of oily suspension fills. It is also 
used as the powder base material of powder dosage forms, and 
as a suspending agent in aqueous suspensions for peroral 
delivery. It may also be used to reduce sedimentation during the 
manufacture of suppositories. 
Powdered cellulose has been investigated as an alternative to 
microcrystalline cellulose as an agent to assist the manufacture 
of pellets by extrusion/spheronization.(2,3) 
Powdered cellulose is also used widely in cosmetics and food 
products. 
Table I: Uses of powdered cellulose. 
Use Concentration (%) 
Capsule filler 0–100 
Tablet binder 5–25 
Tablet disintegrant 5–15 
Tablet glidant 1–2 
8 Description 
Powdered cellulose occurs as a white or almost white, odorless 
and tasteless powder of various particle sizes, ranging from a 
free-flowing fine or granular dense powder, to a coarse, fluffy, 
nonflowing material. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for powdered cellulose. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters . . — 
Microbial limits 
Aerobic 4103/g 4103/g 4103/g 
Fungi and yeast 4102/g 4102/g 4102/g 
pH (10% w/w suspension) 5.0–7.5 5.0–7.5 5.0–7.5 
Loss on drying 46.0% 46.5% 46.0% 
Residue on ignition 40.3% 40.3% 40.3% 
Solubility — . — 
Ether-soluble substances 415.0mg 40.15% 40.15% 
Water-soluble substances 415.0mg 41.5% 41.5% 
Heavy metals 410 ppm 410 ppm 40.001% 
Organic volatile impurities — — . 
10 Typical Properties 
Angle of repose: 
<628 for Arbocel M80; 
<498 for Arbocel P 290; 
<368 for Arbocel A 300 (J. Rettenmaier and So. hne). 
Density (bulk): 0.139–0.391 g/cm3, depending on the source. 
Density (tapped): 0.210–0.481 g/cm3, depending on the source. 
Density (true): 1.5 g/cm3 
Moisture content: powdered cellulose is slightly hygroscopic;(4) 
see Figures 1 and 2. 
Particle size distribution: powdered cellulose is commercially 
available in several different particle sizes.

Arbocel M80: average particle size 60 mm; 
Arbocel P 290: average particle size 70 mm; 
Arbocel A 300: average particle size 200 mm. 
Solubility: practically insoluble in water, dilute acids, and most 
organic solvents although it disperses in most liquids. 
Slightly soluble in 5% w/v sodium hydroxide solution. 
Powdered cellulose does not swell in water, but does so in 
dilute sodium hypochlorite (bleach). 
11 Stability and Storage Conditions 
Powdered cellulose is a stable, slightly hygroscopic material. 
The bulk material should be stored in a well-closed container in 
a cool, dry place. 
12 Incompatibilities 
Incompatible with strong oxidizing agents. 
13 Method of Manufacture 
Powdered cellulose is manufactured by the purification and 
mechanical size reduction of a-cellulose obtained as a pulp 
from fibrous plant materials. 
14 Safety 
Powdered cellulose is widely used in oral pharmaceutical 
formulations and food products and is generally regarded as a 
nontoxic and nonirritant material. 
Powdered cellulose is not absorbed systemically following 
peroral administration and thus has little toxic potential. 
Figure 1: Equilibrium moisture content of powdered cellulose at 
258C. 
*: Powdered cellulose (Solka-Floc BW-40, Lot no. 8-10- 
30A) 
~: Powdered cellulose (Solka-Floc BW-20, Lot no. 22A- 
19) 
!: Powdered cellulose (Solka-Floc Fine Granular, Lot no. 
9-10-8) 
Consumption of large quantities of cellulose may, however, 
have a laxative effect, although this is unlikely to be a problem 
when cellulose is used as an excipient in pharmaceutical 
formulations. 
Deliberate abuse of formulations containing cellulose, either 
by inhalation or by injection, has resulted in the formation of 
cellulose granulomas.(5) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Powdered cellulose may be 
irritant to the eyes. Gloves, eye protection, and a dust mask are 
recommended. In the UK, the occupational exposure limits for 
cellulose have been set at 10 mg/m3 long-term (8-hour TWA) 
for total inhalable dust and 4 mg/m3 for respirable dust; the 
short-term limit for total inhalable dust has been set at 
20 mg/m3.(6) 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Cellulose, microcrystalline. 
Figure 2: Equilibrium moisture content of powdered cellulose at 
258C. 
*: Powdered cellulose (Solka-Floc BW-100, Lot no. 9-7- 
18B) 
~: Powdered cellulose (Solka-Floc BW-200, Lot no. 22A- 
20) 
!: Powdered cellulose (Solka-Floc Fine BW-2030, Lot no. 
240) 
Cellulose, Powdered 137

18 Comments 
A specification for powdered cellulose is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for powdered cellulose is 232-674-9. 
19 Specific References 
1 Kothari SH, Kumar V, Banker GS. Comparative evaluations of 
powder and mechanical properties of low crystallinity celluloses, 
microcrystalline celluloses, and powdered celluloses. Int J Pharm 
2002; 232(1–2): 69–80. 
2 Alvarez L, Concheiro A, Gomez Amoza JL, et al. Powdered 
cellulose as excipient for extrusion-spheronization pellets of a 
cohesive hydrophobic drug. Eur J Pharm Biopharm 2003; 55(3): 
291–295. 
3 Lindner H, Kleinebudde P. Use of powdered cellulose for the 
production of pellets by extrusion spheronization. J Pharm 
Pharmacol 1994; 46: 2–7. 
4 Callahan JC, Cleary GW, Elefant M, et al. Equilibrium moisture 
content of pharmaceutical excipients. Drug Dev Ind Pharm 1982; 
8: 355–369. 
5 Cooper CB, Bai TR, Heyderman E, Corrin B. Cellulose granulomas 
in the lungs of a cocaine sniffer. Br Med J 1983; 286: 2021– 
2022. 
6 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
See also Cellulose, microcrystalline. 
20 General References 
Allen LV. Featured excipient: capsule and tablet diluents. Int J Pharm 
Compound 2000; 4(4): 306–310, 324–325. 
Belda PM, Mielck JB. The tabletting behavior of cellactose compared 
with mixtures of celluloses with lactoses. Eur J Pharm Biopharm 
1996; 42(5): 325–330. 
Kimura M, Shimada Y, Oshima T, et al. The evaluation of powdered 
cellulose as a pharmaceutical excipient. J Pharm Sci Tech 
Yakuzaigaku 2002; 62(3): 113–123. 
Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 71–74. 
21 Authors 
ME Aulton. 
22 Date of Revision 
21 August 2005. 
138 Cellulose, Powdered

Cellulose, Silicified Microcrystalline 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
ProSolv. 
3 Chemical Name and CAS Registry Number 
See Section 8. 
4 Empirical Formula and Molecular Weight 
See Section 8. 
5 Structural Formula 
See Section 8. 
6 Functional Category 
Tablet and capsule diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Silicified microcrystalline cellulose is used as a filler in the 
formulation of capsules and tablets. It has improved compaction 
properties in both wet granulation and direct compression 
compared to conventional microcrystalline cellulose.(1–5) Silicified 
microcrystalline cellulose was specifically developed to 
address the loss of compaction that occurs with microcrystalline 
cellulose after wet granulation. 
8 Description 
Silicified microcrystalline cellulose is a synergistic, intimate 
physical mixture of two components: microcrystalline cellulose 
and colloidal silicon dioxide (for further information see 
Cellulose, Microcrystalline and Colloidal Silicon Dioxide). 
Silicified microcrystalline cellulose contains 2% w/w colloidal 
silicon dioxide. 
9 Pharmacopeial Specifications 
—
10 Typical properties 
Acidity/alkalinity: pH = 5.0–7.5 (10% w/v suspension) 
Density: 1.58 g/cm(5) 
Density (bulk): 0.31 g/cm3 
Density (tapped): 0.39 g/cm(5) 
Melting point: the microcrystalline cellulose component chars 
at 260–2708C. 
Moisture content: typically less than 6% w/w. 
Particle size distribution: typical particle size is 20–200 mm. 
Different grades may have a different normal mean particle 
size. 
Solubility: practically insoluble in water, dilute acids, and most 
organic solvents. The microcrystalline cellulose component 
is slightly soluble in 5% w/w sodium hydroxide solution. 
SEM: 1 
Excipient: Silicified microcrystalline cellulose 
Manufacturer: JRS Pharma LP 
Lot No.: CSD5866 
Magnification: 100 
SEM: 2 
Excipient: Silicified microcrystalline cellulose 
Manufacturer: JRS Pharma LP 
Lot No.: CSD5866 
Magnification: 300

SEM: 3 
Excipient: Silicified microcrystalline cellulose 
Manufacturer: JRS Pharma LP 
Lot No.: CSD5866 
Magnification: 500 
11 Stability and Storage Conditions 
Silicified microcrystalline cellulose is stable when stored in a 
well-closed container in a cool, dry place. 
12 Incompatibilities 
See Cellulose, Microcrystalline and Colloidal Silicon Dioxide. 
13 Method of Manufacture 
Silicified microcrystalline cellulose is manufactured by codrying 
a suspension of microcrystalline cellulose particles and 
colloidal silicon dioxide so that the dried finished product 
contains 2% w/w colloidal silicon dioxide. 
The colloidal silicon dioxide appears physically bound onto 
the surface and inside the silicified microcrystalline cellulose 
particles. Extensive studies using different spectroscopic 
methods have failed to show any form of chemical interaction.(
4,6,7) 
14 Safety 
See Cellulose, Microcrystalline and Colloidal Silicon Dioxide. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Handling of silicified 
microcrystalline cellulose can generate nuisance dusts and the 
use of a respirator or dust mask may be necessary. 
Microcrystalline cellulose may be irritant to the eyes. 
Gloves, eye protection, and a dust mask are recommended. In 
the UK the long-term occupational exposure limits (8-hour 
TWA) have been set at 10 mg/m3 for total inhalable dust and 
4 mg/m3 for respirable dust; short-term limit for total inhalable 
dust has been set at 20 mg/m3.(8) 
Since the colloidal silicon dioxide is physically bound to the 
microcrystalline cellulose the general recommendations of 
gloves, eye protection, and a dust mask should be followed 
when handling silicified microcrystalline cellulose. 
16 Regulatory Status 
Silicified microcrystalline cellulose is a physical mixture of two 
materials both of which are generally regarded as nontoxic: 
Microcrystalline cellulose: GRAS listed. Included in the FDA 
Inactive Ingredients Guide (inhalations, oral capsules, 
powders, suspensions, syrups, and tablets). Included in 
nonparenteral medicines licensed in Europe and the US. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
Colloidal silicon dioxide: GRAS listed. Included in the FDA 
Inactive Ingredients Guide (oral capsules and tablets). 
Included in nonparenteral medicines licensed in Europe 
and the US. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Cellulose, microcrystalline; colloidal silicon dioxide. 
18 Comments 
Silicified microcrystalline cellulose has greater tensile strength 
and requires lower compression pressures than regular grades 
of microcrystalline cellulose. Furthermore, silicified microcrystalline 
cellulose maintains its compactability when wet granulated; 
the compacts exhibit greater stiffness and they require 
considerably more energy for tensile failure to occur.(4,9) 
19 Specific References 
1 Sherwood BE, Hunter EA, Staniforth JN. Silicified microcrystalline 
cellulose (SMCC): a new class of high functionality binders for 
direct compression. Pharm Res 1996; 13(9): S197. 
2 Staniforth JN, Sherwood BE, Hunter EA. Towards a new class of 
high functionality tablet binders. II: silicified microcrystalline 
cellulose (SMCC). Pharm Res 1996; 13(9): S197. 
3 Tobyn MJ, Staniforth JN, Hunter EA. Compaction studies on a 
new class of high functionality binders: silicified microcrystalline 
cellulose (SMCC). Pharm Res 1996; 13(9): S198. 
4 Habib SY, Abramowitz R, Jerzewski RL, et al. Is silicified wetgranulated 
microcrystalline cellulose better than original wetgranulated 
microcrystalline cellulose? Pharm Dev Technol 1999; 
4(3): 431–437. 
5 Tobyn MJ, McCarthy AP, Staniforth JN, Edge S. Physiochemical 
comparison between microcrystalline cellulose and silicified 
microcrystalline cellulose. Int J Pharm 1998; 169: 183–194. 
6 Edge S, Steele DF, Chen A, et al. The mechanical properties of 
compacts of microcrystalline cellulose and silicified microcrystalline 
cellulose. Int J Pharm 2000; 200: 67–72. 
7 Buckton G, Yoremochi E. Near IR spectroscopy to quantify the 
silica content and differences between silicified miicrocrystalline 
cellulose and physical mixtures of microcrystalline cellulose and 
silica. Int J Pharm 1998; 169: 183–194. 
8 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
9 Buckton G, Yoremochi E, Yoon NL, Moffat AC. Water sorption 
and near IR spectroscopy to study the differences between 
microcrystalline cellulose and silicified miicrocrystalline cellulose 
after wet granulation. Int J Pharm 1999; 181: 41–47. 
140 Cellulose, Silicified Microcrystalline

20 General References 
Li JX, Zhou Y, Wu XY, et al. Characterization of wet masses of 
pharmaceutical powders by triaxial compression test. J Pharm Sci 
2000; 89(2): 178–190. 
Staniforth JN, Hunter EA, Sherwood BE. Pharmaceutical excipient 
having improved compressability. US Patent 5,585,115, 1996. 
21 Authors 
RC Moreton. 
22 Date of Revision 
26 August 2005. 
Cellulose, Silicified Microcrystalline 141

Cellulose Acetate 
1 Nonproprietary Names 
BP: Cellulose acetate 
PhEur: Cellulosi acetas 
USPNF: Cellulose acetate 
2 Synonyms 
Acetyl cellulose; cellulose diacetate; cellulose triacetate. 
3 Chemical Name and CAS Registry Number 
Cellulose acetate [9004-35-7] 
Cellulose diacetate [9035-69-2] 
Cellulose triacetate [9012-09-3] 
4 Empirical Formula and Molecular Weight 
Cellulose acetate is cellulose in which a portion or all of the 
hydroxyl groups are acetylated. Cellulose acetate is available in 
a wide range of acetyl levels and chain lengths and thus 
molecular weights; see Table I. 
5 Structural Formula 
6 Functional Category 
Coating agent; extended release agent; tablet and capsule 
diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Cellulose acetate is widely used in pharmaceutical formulations 
both in sustained-release applications and for taste masking. 
Cellulose acetate is used as a semipermeable coating on 
tablets, especially on osmotic pump-type tablets and implants. 
This allows for controlled, extended release of actives.(1–5) 
Cellulose acetate films, in conjunction with other materials, 
also offer sustained release without the necessity of drilling a 
hole in the coating as is typical with osmotic pump systems. 
Cellulose acetate and other cellulose esters have also been used 
to form drug-loaded microparticles with controlled-release 
characteristics.(6,7) 
Cellulose acetate films are used in transdermal drug delivery 
systems(8,9) and also as film coatings on tablets or granules for 
taste masking. For example, acetaminophen granules have been 
coated with a cellulose acetate-based coating before being 
processed to provide chewable tablets. Extended-release tablets 
can also be formulated with cellulose acetate as a directly 
compressible matrix former.(10) The release profile can be 
modified by changing the ratio of active to cellulose acetate and 
by incorporation of plasticizer, but was shown to be insensitive 
to cellulose acetate molecular weight and particle size distribution. 
Therapeutically, cellulose acetate has been used to treat 
cerebral aneurysms, and also for spinal perimedullary arteriovenous 
fistulas.(11) 
8 Description 
Cellulose acetate occurs as a white to off-white powder, freeflowing 
pellets, or flakes. It is tasteless and odorless, or may 
have a slight odor of acetic acid. 
Table I: Comparison of different types of cellulose acetate.(2) 
Type Acetyl (%) Viscosity (mPa s) Hydroxyl (%) Melting range (8C) Tg
(a) (8C) Density(b) (g/cm3) MWn(c) 
CA-320S 32.0 210.0 8.7 230–250 180 0.4 38 000 
CA-398-3 39.8 11.4 3.5 230–250 180 0.4 30 000 
CA-398-6 39.8 22.8 3.5 230–250 182 0.4 35 000 
CA-398-10NF 39.8 38.0 3.5 230–250 185 0.4 40 000 
CA-398-30 39.7 114.0 3.5 230–250 189 0.4 50 000 
CA-394-60S 39.5 228.0 4.0 240–260 186 — 60 000 
CA-435-75 43.5 — 0.9 280–300 185 0.7 122 000 
(a) Glass transition temperature. 
(b) Tapped. 
(c) Number average molecular weight in polystyrene equivalents. 
Supplier: Eastman Chemical Company.

SEM: 1 
Excipient: Cellulose acetate, CA-398-10NF 
Manufacturer: Eastman Chemical Co. 
Lot No.: AC65280NF 
Magnification: 60 Voltage: 3kV 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for cellulose acetate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Loss on drying 45.0% 45.0% 
Residue on ignition 40.1% 40.1% 
Free acid 40.1% 40.1% 
Heavy metals 410 ppm 40.001% 
Microbial contamination . — 
Aerobic 4103/g — 
Fungi and yeast 4102/g — 
Organic volatile impurities — . 
Assay (of acetyl groups) 29.0–44.8% 29.0–44.8% 
10 Typical Properties 
Density (bulk): typically 0.4 g/cm3 for powders 
Glass transition temperature: 170–1908C 
Melting point: melting range 230–3008C 
Solubility: the solubility of cellulose acetate is greatly influenced 
by the level of acetyl groups present. In general, cellulose 
acetates are soluble in acetone–water blends of varying 
ratios, dichloromethane–ethanol blends, dimethyl formamide, 
and dioxane. The cellulose acetates of higher acetyl 
level are generally more limited in solvent choice than are the 
lower-acetyl materials. 
Viscosity (dynamic): various grades of cellulose acetate are 
commercially available that differ in their acetyl content and 
degree of polymerization. They can be used to produce 10% 
SEM 2 
Excipient: Cellulose acetate, CA-398-10NF 
Manufacturer: Eastman Chemical Co. 
Lot No.: AC65280NF 
Magnification: 600 Voltage: 2kV 
w/v solutions in organic solvents with viscosities of 
10–230 mPa s. Blends of cellulose acetates may also be 
prepared with intermediate viscosity values. See also Table I. 
11 Stability and Storage Conditions 
Cellulose acetate is stable if stored in a well-closed container in 
a cool, dry place. Cellulose acetate hydrolyzes slowly under 
prolonged adverse conditions such as high temperature and 
humidity, with a resultant increase in free acid content and odor 
of acetic acid. 
12 Incompatibilities 
Cellulose acetate is incompatible with strongly acidic or 
alkaline substances. Cellulose acetate is compatible with the 
following plasticizers: diethyl phthalate, polyethylene glycol, 
triacetin, and triethyl citrate. 
13 Method of Manufacture 
Cellulose acetate is prepared from highly purified cellulose by 
treatment with acid catalysis and acetic anhydride. 
14 Safety 
Cellulose acetate is widely used in oral pharmaceutical products 
and is generally regarded as a nontoxic and nonirritant 
material. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Dust may be irritant to the 
eyes and eye protection should be worn. Like most organic 
Cellulose Acetate 143

materials in powder form, these materials are capable of 
creating dust explosions. Cellulose acetate is combustible. 
16 Regulatory Acceptance 
Included in the FDA Inactive Ingredients Guide (oral tablets). 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Cellulose acetate phthalate. 
18 Comments 
When solutions are being prepared, cellulose acetate should 
always be added to the solvent, not the reverse. Various grades 
of cellulose acetate are available with varying physical properties; 
see Table I. 
19 Specific References 
1 Meier MA, Kanis LA, Soldi V. Characterization and drugpermeation 
profiles of microporous and dense cellulose acetate 
membranes: influence of plasticizer and pre-forming agent. Int J 
Pharm 2004; 278(1): 99–110. 
2 Eastman Chemical Company. Technical literature: Cellulose Esters 
for Pharmaceutical Drug Delivery, 1997. 
3 Theeuwes F. Elementary osmotic pump. J Pharm Sci 1975; 64(12): 
1987–1991. 
4 Santus G, Baker RW. Osmotic drug delivery: review of the patent 
literature. J Control Release 1995; 35: 1–21. 
5 Van Savage G, Rhodes CT. The sustained release coating of solid 
dosage forms: a historical review. Drug Dev Ind Pharm 1995; 
21(1): 93–118. 
6 Soppimath KS, Kulkarni AR, Aminabhavi TM. Development of 
hollow microspheres as floating controlled-release systems for 
cardiovascular drugs: preparation and release characteristics. 
Drug Dev Ind Pharm 2001; 27(6): 507–515. 
7 Soppimath KS, Kulkarni AR, Aminabhavi TM, Bhaskar C. 
Cellulose acetate microspheres prepared by o/w emulsification 
and solvent evaporation method. J Microencapsul 2001; 18(6): 
811–817. 
8 Rao PR, Diwan PV. Drug diffusion from cellulose acetatepolyvinyl 
pyrrolidine free films for transdermal administration. 
Indian J Pharm Sci 1996; 58(6): 246–250. 
9 Rao PR, Diwan PV. Permeability studies of cellulose acetate free 
films for transdermal use: influences of plasticizers. Pharm Acta 
Helv 1997; 72: 47–51. 
10 Yuan J,Wu SHW. Sustained-release tablets via direct compression: 
a feasibility study using cellulose acetate and cellulose acetate 
butyrate. Pharm Technol 2000; 24(10): 92, 94, 96, 98, 100, 102, 
104, 106. 
11 Sugiu K, Meguro T, Nakashiama H, Ohmoto T. Successful 
embolization of a spinal perimedullary arteriovenous fistula with 
cellulose acetate polymer solution: technical case report. Neurosurgery 
2001; 49(5): 1257–1260. 
20 General References 
Doelker E. Cellulose derivatives. Adv Polym Sci 1993; 107: 199–265. 
21 Authors 
LA Miller. 
22 Date of Revision 
15 August 2005. 
144 Cellulose Acetate

Cellulose Acetate Phthalate 
1 Nonproprietary Names 
BP: Cellacefate 
JP: Cellulose acetate phthalate 
PhEur: Cellulosi acetas phthalas 
USPNF: Cellacefate 
2 Synonyms 
Acetyl phthalyl cellulose; Aquacoat cPD; CAP; cellacephate; 
cellulose acetate benzene-1,2-dicarboxylate; cellulose acetate 
hydrogen 1,2-benzenedicarboxylate; cellulose acetate hydrogen 
phthalate; cellulose acetate monophthalate; cellulose acetophthalate; 
cellulose acetylphthalate. 
3 Chemical Name and CAS Registry Number 
Cellulose, acetate, 1,2-benzenedicarboxylate [9004-38-0] 
4 Empirical Formula and Molecular Weight 
Cellulose acetate phthalate is a cellulose in which about half the 
hydroxyl groups are acetylated, and about a quarter are 
esterified with one of two acid groups being phthalic acid, 
where the remaining acid group is free. See Section 5. 
5 Structural Formula 
The PhEur 2005 and USPNF 23 describe cellulose acetate 
phthalate as a reaction product of phthalic anhydride and a 
partial acetate ester of cellulose containing 21.5–26.0% of 
acetyl (C2H3O) groups, and 30.0–36.0% of phthalyl(ocarboxybenzoyl, 
C8H5O3) groups. 
6 Functional Category 
Coating agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Cellulose acetate phthalate (CAP) is used as an enteric film 
coating material, or as a matrix binder for tablets and 
capsules.(1–8) Such coatings resist prolonged contact with the 
strongly acidic gastric fluid, but dissolve in the mildly acidic or 
neutral intestinal environment. 
Cellulose acetate phthalate is commonly applied to soliddosage 
forms either by coating from organic or aqueous solvent 
systems or by direct compression. Concentrations generally 
used are 0.5–9.0% of the core weight. The addition of 
plasticizers improves the water resistance of this coating 
material, and formulations using such plasticizers are more 
effective than when cellulose acetate phthalate is used alone. 
Cellulose acetate phthalate is compatible with many 
plasticizers, including acetylated monoglyceride; butyl phthalybutyl 
glycolate; dibutyl tartrate; diethyl phthalate; dimethyl 
phthalate; ethyl phthalylethyl glycolate; glycerin; propylene 
glycol; triacetin; triacetin citrate; and tripropionin. It is also 
used in combination with other coating agents such as ethyl 
cellulose, in drug controlled-release preparations. 
Therapeutically, cellulose acetate phthalate has recently 
been reported to exhibit experimental microbicidal activity 
against sexually transmitted disease pathogens, such as the 
HIV-1 retrovirus.(9,10) 
8 Description 
Cellulose acetate phthalate is a hygroscopic, white to off-white, 
free-flowing powder, granule, or flake. It is tasteless and 
odorless, or might have a slight odor of acetic acid. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for cellulose acetate phthalate. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters . . — 
Free acid 43.0% 43.0% 43.0% 
Heavy metals 410 ppm 410 ppm 40.001% 
Organic volatile 
impurities 
— — . 
Phthaloyl groups — . . 
Residue on ignition 40.1% 40.1% 40.1% 
Viscosity (15% w/v 
solution) 
45–90mPa s 45.0–90.0 mPa s 45.0–90.0 mPa s 
Water 45.0% 45.0% 45.0% 
Assay . . . 
Acetyl groups 21.5–26.0% 21.5–26.0% 21.5–26.0% 
Carboxybenzoyl 
groups 
30.0–40.0% 30.0–36.0% 30.0–36.0% 
10 Typical Properties 
Density (bulk): 0.260 g/cm3 
Density (tapped): 0.266 g/cm3 
Melting point: 1928C. Glass transition temperature is 
160–1708C.(11) 
Moisture content: 2.2%. Cellulose acetate phthalate is hygroscopic 
and precautions are necessary to avoid excessive 
absorption of moisture.(12) See also Figure 1.

Figure 1: Sorption–desorption isotherm of cellulose acetate phthlate. 
Table II: Examples of solvents with which cellulose acetate phthalate 
has 410% w/w solubility. 
Acetone 
Diacetone alcohol 
Dioxane 
Ethoxyethyl acetate 
Ethyl glycol monoacetate 
Ethyl lactate 
Methoxyethyl acetate 
b-Methoxyethylene alcohol 
Methyl acetate 
Methyl ethyl ketone 
Table III: Examples of solvent mixtures with which cellulose acetate 
phthalate has 410% w/w solubility. 
Acetone : ethanol (1 : 1) 
Acetone : water (97 : 3) 
Benzene : methanol (1 : 1) 
Ethyl acetate : ethanol (1 : 1) 
Methylene chloride : ethanol (3 : 1) 
Solubility: practically insoluble in water, alcohols, and chlorinated 
and nonchlorinated hydrocarbons. Soluble in a 
number of ketones, esters, ether alcohols, cyclic ethers, 
and in certain solvent mixtures. It can be soluble in certain 
buffered aqueous solutions as low as pH 6.0. Cellulose 
acetate phthalate has a solubility of 410% w/w in a wide 
range of solvents and solvent mixtures; see Table II and 
Table III. 
Viscosity (dynamic): a 15% w/w solution in acetone with a 
moisture content of 0.4% has a viscosity of 50–90 mPa s 
(50–90 cP). This is a good coating solution with a honey-like 
consistency, but the viscosity is influenced by the purity of 
the solvent. 
11 Stability and Storage Conditions 
Slow hydrolysis of cellulose acetate phthalate will occur under 
prolonged adverse conditions such as high temperatures and 
high humidity, with a resultant increase in free acid content, 
viscosity, and odor of acetic acid. However, cellulose acetate 
phthalate is stable if stored in a well-closed container in a cool, 
dry place. 
12 Incompatibilities 
Cellulose acetate phthalate is incompatible with ferrous sulfate, 
ferric chloride, silver nitrate, sodium citrate, aluminum sulfate, 
calcium chloride, mercuric chloride, barium nitrate, basic lead 
acetate, and strong oxidizing agents such as strong alkalis and 
acids. 
13 Method of Manufacture 
Cellulose acetate phthalate is produced by reacting the partial 
acetate ester of cellulose with phthalic anhydride in the presence 
of a tertiary organic base such as pyridine, or a strong acid such 
as sulfuric acid. 
14 Safety 
Cellulose acetate phthalate is widely used in oral pharmaceutical 
products and is generally regarded as a nontoxic material, 
free of adverse effects. 
Results of long-term feeding in rats and dogs have indicated 
a low oral toxicity. Rats survived daily feedings of up to 30% in 
the diet for up to 1 year without showing a depression in 
growth. Dogs fed 16 g daily in the diet for 1 year remained 
normal. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Cellulose acetate phthalate 
may be irritant to the eyes, mucous membranes, and upper 
respiratory tract. Eye protection and gloves are recommended. 
Cellulose acetate phthalate should be handled in a wellventilated 
environment; use of a respirator is recommended 
when handling large quantities. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral tablets). 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Cellulose acetate; hypromellose phthalate; polyvinyl acetate 
phthalate. 
18 Comments 
Any plasticizers that are used with cellulose acetate phthalate to 
improve performance should be chosen on the basis of 
experimental evidence. The same plasticizer used in a different 
tablet base coating may not yield a satisfactory product. 
In using mixed solvents, it is important to dissolve the 
cellulose acetate phthalate in the solvent with the greater 
dissolving power, and then to add the second solvent. Cellulose 
146 Cellulose Acetate Phthalate

acetate phthalate should always be added to the solvent, not the 
reverse. 
Cellulose acetate phthalate films are permeable to certain 
ionic substances, such as potassium iodide and ammonium 
chloride. In such cases, an appropriate sealer subcoat should be 
used. 
A reconstituted colloidal dispersion of latex particles rather 
than solvent solution coating material of cellulose acetate 
phthalate is also available. This white, water-insoluble powder 
is composed of solid or semisolid submicrometer-sized polymer 
spheres with an average particle size of 0.2 mm. A typical 
coating system made from this latex powder is a 10–30% solidcontent 
aqueous dispersion with a viscosity in the 
50–100 mPa s range. 
19 Specific References 
1 Spitael J, Kinget R, Naessens K. Dissolution rate of cellulose 
acetate phthalate and Bro. nsted catalysis law. Pharm Ind 1980; 42: 
846–849. 
2 Takenaka H, Kawashima Y, Lin SY. Preparation of enteric-coated 
microcapsules for tableting by spray-drying technique and in vitro 
simulation of drug release from the tablet in GI tract. J Pharm Sci 
1980; 69: 1388–1392. 
3 Takenaka H, Kawashima Y, Lin SY. Polymorphism of spray-dried 
microencapsulated sulfamethoxazole with cellulose acetate phthalate 
and colloidal silica, montmorillonite, or talc. J Pharm Sci 
1981; 70: 1256–1260. 
4 Stricker H, Kulke H. Rate of disintegration and passage of entericcoated 
tablets in gastrointestinal tract [in German]. Pharm Ind 
1981; 43: 1018–1021. 
5 Maharaj I, Nairn JG, Campbell JB. Simple rapid method for the 
preparation of enteric-coated microspheres. J Pharm Sci 1984; 73: 
39–42. 
6 Beyger JW, Nairn JG. Some factors affecting the microencapsulation 
of pharmaceuticals with cellulose acetate phthalate. J Pharm 
Sci 1986; 75: 573–578. 
7 Lin SY, Kawashima Y. Drug release from tablets containing 
cellulose acetate phthalate as an additive or enteric-coating 
material. Pharm Res 1987; 4: 70–74. 
8 Thoma K, Heckenmu. ller H. Effect of film formers and plasticizers 
on stability of resistance and disintegration behaviour. Part 4: 
pharmaceutical-technological and analytical studies of gastric juice 
resistant commercial preparations [in German]. Pharmazie 1987; 
42: 837–841. 
9 Neurath AR, Strick N, Li YY, Debnath AK. Cellulose acetate 
phthalate, a common pharmaceutical excipient, inactivates HIV-1 
and blocks the coreceptor binding site on the virus envelope 
glycoprotein gp120. BMC Infect Dis 2001; 1(1): 17. 
10 Neurath AR, Strick N, Jiang S, et al. Anti-HIV-1 activity of 
cellulose acetate phthalate: synergy with soluble CD4 and 
induction of ‘dead-end’ gp41 six-helix bundles. BMC Infect Dis 
2002; 2(1): 6. 
11 Sakellariou P, Rowe RC, White EFT. The thermomechanical 
properties and glass transition temperatures of some cellulose 
derivatives used in film coating. Int J Pharm 1985; 27: 267–277. 
12 Callahan JC, Cleary GW, Elefant M, et al. Equilibrium moisture 
content of pharmaceutical excipients. Drug Dev Ind Pharm 1982; 
8: 355–369. 
20 General References 
Doelker E. Cellulose derivatives. Adv Polym Sci 1993; 107: 199–265. 
Obara S, Mcginty JW. Influence of processing variables on the 
properties of free films prepared from aqueous polymeric dispersions 
by a spray technique. Int J Pharm 1995; 126: 1–10. 
O’Connor RE, Berryman WH. Evaluation of enteric film permeability: 
tablet swelling method and capillary rise method. Drug Dev Ind 
Pharm 1992; 18: 2123–2133. 
Raffin F, Duru C, Jacob M, et al. Physico-chemical characterization of 
the ionic permeability of an enteric coating polymer. Int J Pharm 
1995; 120(2): 205–214. 
Wyatt DM. Cellulose esters as direct compression matrices. Manuf 
Chem 1991; 62(12): 20, 21, 23. 
21 Authors 
LA Miller. 
22 Date of Revision 
15 August 2005. 
Cellulose Acetate Phthalate 147

Ceratonia 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Algaroba; carob bean gum; carob flour; ceratonia gum; 
ceratonia siliqua; ceratonia siliqua gum; Cheshire gum; E410; 
gomme de caroube; locust bean gum; Meyprofleur; St. John’s 
bread. 
3 Chemical Name and CAS Registry Number 
Carob gum [9000-40-2] 
4 Empirical Formula and Molecular Weight 
Ceratonia is a naturally occurring plant material that consists 
chiefly of a high molecular weight hydrocolloidal polysaccharide, 
composed of D-galactose and D-mannose units combined 
through glycosidic linkages, which may be described chemically 
as galactomannan. The molecular weight is approximately 
310 000. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Controlled-release vehicle; stabilizing agent; suspending agent; 
tablet binder; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ceratonia is a naturally occurring material generally used as a 
substitute for tragacanth or other similar gums. A ceratonia 
mucilage that is slightly more viscous than tragacanth mucilage 
may be prepared by boiling 1.0–1.5% of powdered ceratonia 
with water. As a viscosity-increasing agent, ceratonia is said to 
be five times as effective as starch and twice as effective as 
tragacanth. Ceratonia has also been used as a tablet binder(1) 
and is used in oral controlled-release drug delivery systems 
approved in Europe and the USA. 
Ceratonia is widely used as a binder, thickening agent, and 
stabilizing agent in the cosmetics and food industry. In foods, 
0.15–0.75% is used. Therapeutically, ceratonia mucilage is 
used orally in adults and children to regulate intestinal 
function; see Section 14. 
8 Description 
Ceratonia occurs as a yellow-green or white colored powder. 
Although odorless and tasteless in the dry powder form, 
ceratonia acquires a leguminous taste when boiled in water. 
9 Pharmacopeial Specifications 
See Section 18. 
10 Typical Properties 
Acidity/alkalinity: pH = 5.3 (1% w/v aqueous solution) 
Solubility: ceratonia is dispersible in hot water, forming a sol 
having a pH 5.4–7.0 that may be converted to a gel by the 
addition of small amounts of sodium borate. In cold water, 
ceratonia hydrates very slowly and incompletely. Ceratonia 
is practically insoluble in ethanol. 
Viscosity (dynamic): 1200–2500 mPa s (1200–2500 cP) for a 
1% w/v aqueous dispersion at 258C. Viscosity is unaffected 
by pH within the range pH 3–11. Viscosity is increased by 
heating: if heated to 958C then cooled, practically clear 
solutions may be obtained that are more viscous than prior 
to heating. 
11 Stability and Storage Conditions 
The bulk material should be stored in a well-closed container in 
a cool, dry place. Ceratonia loses not more than 15% of its 
weight on drying. 
12 Incompatibilities 
The viscosity of xanthan gum solutions is increased in the 
presence of ceratonia.(2) This interaction is used synergistically 
in controlled-release drug delivery systems. 
13 Method of Manufacture 
Ceratonia is a naturally occurring material obtained from the 
ground endosperms separated from the seeds of the locust bean 
tree, Ceratonia siliqua (Leguminosae). The tree is indigenous to 
southern Europe and the Mediterranean region. 
14 Safety 
Ceratonia is generally regarded as an essentially noncarcinogenic,(
3) nontoxic and nonirritant material. Therapeutically, it 
has been used in oral formulations for the control of vomiting 
and diarrhea in adults and children; 20–40 g daily in adults has 
been used dispersed in liquid.(4) As an excipient, ceratonia is 
used in oral controlled-release formulations approved in 
Europe and the USA. 
Ceratonia is also widely used in food products. The WHO 
has not specified an acceptable total daily intake for ceratonia 
as the total daily intake arising from its use at the levels 
necessary to achieve the desired effect, and from its acceptable 
background in food, was not considered to represent a hazard 
to health.(5) Ceratonia hypersensitivity has been reported, in a 
single case report, in an infant.(6) However, ceratonia is said to 
be nonallergenic in children with known allergy to peanuts.(7) 
LD50 (hamster, oral): 10.0 g/kg(8) 
LD50 (mouse, oral): 13.0 g/kg 
LD50 (rabbit, oral): 9.1 g/kg 
LD50 (rat, oral): 13.0 g/kg

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. When heated to decomposition 
ceratonia emits acrid smoke and irritating fumes. 
16 Regulatory Status 
GRAS listed. Accepted for use in Europe as a food additive. In 
Europe and the USA, ceratonia has been used in oral tablet 
formulations. 
17 Related Substances 
Acacia; ceratonia extract; tragacanth; xanthan gum. 
Ceratonia extract 
Synonyms: ceratonia siliqua extract; extract of carob; locust 
tree extract. 
CAS number: [84961-45-5] 
Comments: ceratonia extract is used as an emollient. The 
EINECS number for ceratonia extract is 284-634-5. 
18 Comments 
The EINECS number for ceratonia is 232-541-5. 
Although not included in any pharmacopeias, a specification 
for ceratonia is contained in the Food Chemicals Codex 
(FCC), see Table I.(9) However, ceratonia (locust bean gum) is 
described under reagent specifications in the USP 28, where the 
reader is directed to the FCC specifications. Ceratonia (carob 
bean gum) is mentioned in the BP 2004 under general reagents 
and is described as a white powder containing 70–80% of a 
water-soluble gum consisting mainly of galactomannoglycone. 
Table I: Food Chemicals Codex specifications for ceratonia.(9) 
Test FCC 1996 
Identification . 
Acid-insoluble matter 44.0% 
Arsenic 43 mg/kg 
Ash 41.2% 
Galactomannans 575% 
Heavy metals (as Pb) 40.002% 
Lead 45 mg/kg 
Loss on drying 414.0% 
Protein 47.0% 
Starch . 
19 Specific References 
1 Georgakopoulos PP, Malamataris S. Locust bean gum as 
granulating and binding agent for tablets. Pharm Ind 1980; 
42(6): 642–646. 
2 Kovacs P. Useful incompatibility of xanthan gum with galactomannans. 
Food Technol 1973; 27(3): 26–30. 
3 National Toxicology Program. Carcinogenesis bioassay of locust 
bean gum (CAS No. 9000-40-2) in F344 rats and B6C3F1 mice 
(feed study). Natl Toxicol Program Tech Rep Ser 1982; 221 (Feb): 
1–99. 
4 Wade A, ed. Martindale: The Extra Pharmacopoeia, 27th edn. 
London: Pharmaceutical Press, 1977: 921. 
5 FAO/WHO. Evaluation of certain food additives. Twenty-fifth 
report of the FAO/WHO expert committee on food additives. 
World Health Organ Tech Rep Ser 1981; No. 669. 
6 Savino F, Muratore MC, Silvestro L, Oggero R, Mostert M. 
Allergy to carob gum in an infant. J Pediatr Gastroenterol Nutr 
1999; 29(4): 475–476. 
7 Fiocchi A, Restaini P, Travaini M, et al. Carob is not allergenic in 
peanut-allergic subjects. Clin Exp Allergy 1999; 29(3): 402–406. 
8 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2247. 
9 Food Chemicals Codex, 4th edn. Washington DC: National 
Academy of Sciences, 1996: 228. 
20 General References 
Bhardwaj TR, Kanwar M, Lal R. Natural gums and modified gums as 
sustained-release carriers. Drug Dev Ind Pharm 2000; 26(10): 
1025–1038. 
Griffiths C. Locust bean gum: a modern thickening agent from a 
biblical fruit. Manuf Chem 1949; 20: 321–324. 
Hoepfner E, Reng A, Schmidt PC, eds. Fiedler Encyclopedia of 
Excipients for Pharmaceuticals, Cosmetics and Related Areas, 5th 
edn. Aulendorf: Editio Cantor Verlag, 2002: 358–359. 
Knight WA, Dowsett MM. Ceratoniae gummi: carob gum. An 
inexpensive substitute for gum tragacanth. Pharm J 1936; 82: 35– 
36. 
Sujja-areevath J, Munday DL, Cox PJ, Khan KA. Release characteristics 
of diclofenac sodium from encapsulated natural gum minimatrix 
formulations. Int J Pharm 1996; 139: 53–62. 
Woodruff J. Ingredients for success in thickening. Manuf Chem 1998; 
69(9): 49, 50, 52. 
Yousif AK, Alghzawi HM. Processing and characterization of carob 
powder. Food Chem 2000; 69: 283–287. 
21 Authors 
PJ Weller. 
22 Date of Revision 
14 August 2005. 
Ceratonia 149

Cetostearyl Alcohol 
1 Nonproprietary Names 
BP: Cetostearyl alcohol 
PhEur: Alcohol cetylicus et stearylicus 
USPNF: Cetostearyl alcohol 
2 Synonyms 
Cetearyl alcohol; Crodacol CS90; Lanette O; Tego Alkanol 
1618; Tego Alkanol 6855. 
3 Chemical Name and CAS Registry Number 
Cetostearyl alcohol [67762-27-0] and [8005-44-5] 
4 Empirical Formula and Molecular Weight 
Cetostearyl alcohol is a mixture of solid aliphatic alcohols 
consisting mainly of stearyl (C18H38O) and cetyl (C16H34O) 
alcohols. The proportion of stearyl to cetyl alcohol varies 
considerably, but the material usually consists of about 
50–70% stearyl alcohol and 20–35% cetyl alcohol, with limits 
specified in pharmacopeias. The combined stearyl alcohol and 
cetyl alcohol comprise at least 90% of the material. Small 
quantities of other alcohols, chiefly myristyl alcohol, make up 
the remainder of the material. Two emulsifying grades of 
ceteostearyl alcohol are recognized by the PhEur 2005 and 
contain at least 7% surfactant, with Type A containing sodium 
cetostearyl sulfate and Type B containing sodium lauryl sulfate. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Emollient; emulsifying agent; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Cetostearyl alcohol is used in cosmetics and topical pharmaceutical 
preparations. In topical pharmaceutical formulations, 
cetostearyl alcohol will increase the viscosity and impart body 
in both water-in-oil and oil-in-water emulsions. Cetostearyl 
alcohol will stablize an emulsion and also act as a co-emulsifier, 
thus decreasing the amount of surfactant required to form a 
stable emulsion. Cetostearyl alcohol is also used in the 
preparation of nonaqueous creams and sticks. Research articles 
have been published in which cetostearyl alcohol has been used 
to slow the dissolution of water-soluble drugs.(1–4) In combination 
with surfactants, cetostearyl alcohol forms emulsions with 
very complex microstructures. These microstructures can 
include liquid crystals, lamellar structures, and gel phases.(5–16) 
8 Description 
Cetostearyl alcohol occurs as white or cream-colored unctuous 
masses, or almost white flakes or granules. It has a faint, 
characteristic sweet odor. On heating, cetostearyl alcohol melts 
to a clear, colorless or pale yellow-colored liquid free of 
suspended matter. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for cetostearyl alcohol. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Appearance of solution . — 
Melting range 49–568C 48–558C 
Acid value 41.0 42.0 
Iodine value 42.0 44 
Hydroxyl value 208–228 208–228 
Saponification value 42.0 — 
Assay 
of C18H38O 540.0% 540.0% 
of C16H34O and C18H38O 590.0% 590.0% 
10 Typical Properties 
Solubility: soluble in ethanol (95%), ether, and oil; practically 
insoluble in water. 
11 Stability and Storage Conditions 
Cetostearyl alcohol is stable under normal storage conditions. 
Cetostearyl alcohol should be stored in a well-closed container 
in a cool, dry place. 
12 Incompatibilities 
Incompatible with strong oxidizing agents and metal salts. 
13 Method of Manufacture 
Cetostearyl alcohol is prepared by the reduction of the 
appropriate fatty acids from vegetable and animal sources. 
Cetostearyl alcohol can also be prepared directly from 
hydrocarbon sources. 
14 Safety 
Cetostearyl alcohol is mainly used in topical pharmaceutical 
formulations and topical cosmetic formulations. 
Cetostearyl alcohol is generally regarded as a nontoxic 
material.(17) Although it is essentially nonirritating, sensitization 
reactions to cetostearyl, cetyl, and stearyl alcohols(18–23) 
have been reported.

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. Cetostearyl alcohol is flammable and on 
combustion may produce fumes containing carbon monoxide. 
16 Regulatory Status 
Accepted as an indirect food additive and as an adhesive and a 
component of packaging coatings in the USA. Included in the 
FDA Inactive Ingredients Guide (oral tablets and topical 
emulsions, lotions, ointments, vaginal suppositories). Included 
in nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Anionic emulsifying wax; cetyl alcohol; sodium lauryl sulfate; 
stearyl alcohol. 
18 Comments 
The composition of cetostearyl alcohol from different sources 
may vary considerably. The composition of the minor 
components, typically straight-chain and branched-chain alcohols, 
varies greatly depending upon the source, which may be 
animal, vegetable, or synthetic. This has been reported in the 
literature to impart differences in emulsification behavior, 
particularly with respect to emulsion consistency or stability.(
14–16) 
The PhEur 2005 also contains specifications for cetostearyl 
alcohol, emulsifying Type A, and Type B, respectively. 
19 Specific References 
1 Al-Kassas RS, Gilligan CA, Li Wan Po A. Processing factors 
affecting particle size and in vitro drug release of sustained-release 
ibuprofen microspheres. Int J Pharm 1993; 94: 59–67. 
2 Lashmar UT, Beesley J. Correlation of rheological properties of an 
oil-in-water emulsion with manufacturing procedures and stability. 
Int J Pharm 1993; 91: 59–67. 
3 Wong LP, Gilligan CA, Li Wan Po A. Preparation and characterization 
of sustained-release ibuprofen-cetostearyl alcohol spheres. 
Int J Pharm 1992; 83: 95–114. 
4 Ahmed M, Enever RP. Formulation and evaluation of sustained 
release paracetamol tablets. J Clin Hosp Pharm 1981; 6: 27–38. 
5 Forster T, Schambil F, von RybinskiW. Production of fine disperse 
and long-term stable oil-in-water emulsions by the phase inversion 
temperature method. Disper Sci Technol 1992; 13(2): 183–193. 
6 Niemi L, Laine E. Effect of water content on the microstructure of 
an O/W cream. Int J Pharm 1991; 68: 205–214. 
7 Eccleston GM, Beattie L. Microstructural changes during the 
storage of systems containing cetostearyl alcohol; polyoxyethylene 
alkyl ether surfactants. In: Rubinstein MH, ed. Pharmaceutical 
Technology: Drug Stability. Chichester: Ellis Horwood, 1989: 76– 
87. 
8 Schambil F, Jost F, Schwuger MJ. Interfacial and colloidal 
properties of cosmetic emulsions containing fatty alcohol and 
fatty alcohol polygylcol ethers. Progr Colloid Polym Sci 1987; 73: 

37–47. 
9 Rowe RC, Bray D. Water distribution in creams prepared using 
cetostearyl alcohol and cetrimide. J Pharm Pharmacol 1987; 39: 
642–643. 
10 Eros I, Kedvessy G. Applied rheological research on ointment 
bases. Acta Chim Hung 1984; 115(4): 363–375. 
11 Tsugita A, Nishijima Y, Sasaki T. Stable emulsion regions of 
surfactant-oil-water and surfactant-oil-water-long chain alcohol 
systems. Yukagaku 1980; 29(4): 227–234. 
12 Eccleston GM. Structure and rheology of cetomacrogol creams: 
The influence of alcohol chain length and homologue composition. 
J Pharm Pharmacol 1997; 29: 157–162. 
13 Fukushima S, Yamaguchi M, Harusawa F. Effect of cetostearyl 
alcohol on stabilization of oil-in-water emulsion, II. Relation 
between crystal form of the alcohol and stability of the emulsion. J 
Colloid Interface Sci 1977; 59(1): 159–165. 
14 Rowe RC, McMahon J. The stability of oil-in-water emulsions 
containing cetrimide and cetostearyl alcohol. Int J Pharm 1986; 
31: 281–282. 
15 Patel HK, Rowe RC, McMahon J, Stewart RF. A comparison of 
the structure and properties of ternary gels containing cetrimide 
and cetostearyl alcohol obtained from both natural and synthethic 
sources. Acta Pharm Technol 1985; 31(4): 243–247. 
16 Fukushim S, Yamaguchi M. The effect of cetostearyl alcohol in 
cosmetic emulsions. Cosmet Toilet 1983; 98: 89–102. 
17 Anonymous. Final report on the safety assessment of ceteryl 
alcohol, cetyl alcohol, isostearyl alcohol, myristyl alcohol, and 
behenyl alcohol. J Am Coll Toxicol 1988; 7(3): 359–413. 
18 Tosti A, Guerra L, Morelli R, Bardazzi F. Prevalence and sources of 
sensitization to emulsifiers: A clinical study. Contact Dermatitis 
1990; 23: 68–72. 
19 Pasche-Koo F, Piletta PA, Hunziker N, Hauser C. High sensitization 
rate to emulsifiers in patients with chronic leg ulcers. Contact 
Dermatitis 1994; 31: 226–228. 
20 Wilson CL, Cameron J, Powell SM, et al. High incidence of contact 
dermatitis in leg-ulcer patients – implications for management. 
Clin Exp Dermatol 1991; 16: 250–253. 
21 Pecegueiro M, Brandao M, Pinto J, Concal S. Contact dermatitis to 
hirudoid cream. Contact Dermatitis 1987; 17: 290–293. 
22 Hannuksela M. Skin contact allergy to emulsifiers. Int J Cosmet Sci 
1988; 10: 9–14. 
23 Hannuksela M. Skin reactions to emulsifiers. Cosmet Toilet 1988; 
10: 81–86. 
20 General References 
—
21 Authors 
G Frunzi, B Sarsfield. 
22 Date of Revision 
12 August 2005. 
Cetostearyl Alcohol 151

Cetrimide 
1 Nonproprietary Names 
BP: Cetrimide 
PhEur: Cetrimidum 
2 Synonyms 
Bromat; Cetab; Cetavlon; Cetraol; Lissolamine V; Micol; 
Morpan CHSA; Morphans; Quammonium; Sucticide. 
3 Chemical Name and CAS Registry Number 
Cetrimide [8044-71-1] 
Note that the above name, CAS Registry Number, and 
synonyms refer to the PhEur 2005 material which, although it 
consists predominantly of trimethyltetradecylammonium bromide, 
may also contain other bromides; see Section 4. 
There is some confusion in the literature regarding the 
synonyms, CAS Registry Number, and molecular weight 
applied to cetrimide. It is most common to find the molecular 
weight and CAS Registry Number of trimethyltetradecylammonium 
bromide used, as this is the principal component 
of cetrimide. It should be noted however, that in the original BP 
1953 material the principal component of cetrimide was 
hexadecyltrimethylammonium bromide. 
The CAS Registry Number for hexadecyltrimethylammonium 
hydroxide [505-86-2] has also been widely applied to 
cetrimide. 
See Section 17 for further information. 
4 Empirical Formula and Molecular Weight 
Cetrimide consists mainly of trimethyltetradecylammonium 
bromide (C17H38BrN), and may contain smaller amounts of 
dodecyltrimethylammonium bromide (C15H34BrN) and hexadecyltrimethylammonium 
bromide (C19H42BrN). 
C17H38BrN 336.40 
See also Section 17. 
5 Structural Formula 
where 
n = 11 for dodecyltrimethylammonium bromide 
n = 13 for trimethyltetradecylammonium bromide 
n = 15 for hexadecyltrimethylammonium bromide 
6 Functional Category 
Antimicrobial preservative; antiseptic; cationic surfactant; 
disinfectant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Cetrimide is a quaternary ammonium compound that is used in 
cosmetics and pharmaceutical formulations as an antimicrobial 
preservative; see Section 10. It may also be used as a cationic 
surfactant. In eye-drops, it is used as a preservative at a 
concentration of 0.005% w/v. 
Therapeutically, cetrimide is used in relatively high concentrations, 
generally as 0.1–1.0% w/v aqueous solutions, as a 
topical antiseptic for skin, burns, and wounds. Solutions 
containing 1–3% w/v cetrimide are used as shampoos to 
remove the scales in seborrhea. 
Cetrimide is also used as a cleanser and disinfectant for hard 
contact lenses, although it should not be used on soft lenses; as 
an ingredient of cetrimide emulsifying wax, and in o/w creams 
(e.g. cetrimide cream). 
8 Description 
Cetrimide is a white to creamy white, free-flowing powder, with 
a faint but characteristic odor and a bitter, soapy taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for cetrimide. 
Test PhEur 2005 
Identification . 
Characters . 
Acidity or alkalinity . 
Appearance of solution . 
Amines and amine salts . 
Loss on drying 42.0% 
Sulfated ash 40.5% 
Assay (as C17H38BrN, dried basis) 96.0–101.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 5.0–7.5 (1% w/v aqueous solution) 
Antimicrobial activity: cetrimide has good bactericidal activity 
against Gram-positive species but is less active against 
Gram-negative species. Pseudomonas species, particularly 
Pseudomonas aeruginosa, may exhibit resistance. Cetrimide 
is most effective at neutral or slightly alkaline pH values, 
with activity appreciably reduced in acidic media and in the 
presence of organic matter. The activity of cetrimide is 
enhanced in the presence of alcohols. Cetrimide has variable 
antifungal activity, is effective against some viruses, and is 
inactive against bacterial spores. Typical minimum inhibitory 
concentrations (MICs) are shown in Table II.

Table II: Minimum inhibitory concentrations (MIC) of cetrimide. 
Microorganism MIC (mg/mL) 
Escherichia coli 30 
Pseudomonas aeruginosa 300 
Staphylococcus aureus 10 
Critical micelle concentration: 0.01% 
Melting point: 232–2478C 
Moisture content: at 40–50% relative humidity and 208C, 
cetrimide absorbs sufficient moisture to cause caking and 
retard flow properties. 
Partition coefficients: 
Liquid paraffin : water = <1; 
Vegetable oil : water = <1. 
Solubility: freely soluble in chloroform, ethanol (95%), and 
water; practically insoluble in ether. A 2% w/v aqueous 
solution foams strongly on shaking. 
11 Stability and Storage Conditions 
Cetrimide is chemically stable in the dry state, and also in 
aqueous solution at ambient temperatures. Aqueous solutions 
may be sterilized by autoclaving. Water containing metal ions 
and organic matter may reduce the antimicrobial activity of 
cetrimide. 
The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Incompatible with soaps, anionic surfactants, high concentrations 
of nonionic surfactants, bentonite, iodine, phenylmercuric 
nitrate, alkali hydroxides, and acid dyes. Aqueous solutions 
react with metals. 
13 Method of Manufacture 
Cetrimide is prepared by the condensation of suitable alkyl 
bromides and trimethylamine. 
14 Safety 
Most adverse effects reported relate to the therapeutic use of 
cetrimide. If ingested orally, cetrimide and other quaternary 
ammonium compounds can cause nausea, vomiting, muscle 
paralysis, CNS depression, and hypotension; concentrated 
solutions may cause esophageal damage and necrosis. The 
fatal oral human dose is estimated to be 1.0–3.0 g.(1) 
At the concentrations used topically, solutions do not 
generally cause irritation, although concentrated solutions 
have occasionally been reported to cause burns. Cases of 
hypersensitivity have been reported following repeated application.(
2) 
Adverse effects that have been reported following irrigation 
of hydatid cysts with cetrimide solution include chemical 
peritonitis,(3) methemoglobinemia with cyanosis,(4) and metabolic 
disorders.(5) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Cetrimide powder and 
concentrated cetrimide solutions are irritant; avoid inhalation, 
ingestion, and skin and eye contact. Eye protection, gloves, and 
a respirator are recommended.(6) 
16 Regulatory Status 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Benzalkonium chloride; benzethonium chloride; dodecyltrimethylammonium 
bromide; hexadecyltrimethylammonium 
bromide; trimethyltetradecylammonium bromide. 
Dodecyltrimethylammonium bromide 
Empirical formula: C15H34BrN 
Molecular weight: 308.35 
CAS number: [1119-94-4] 
Synonyms: DTAB; N-lauryl-N,N,N-trimethylammonium bromide; 
N,N,N-trimethyldodecylammonium bromide. 
Safety:
LD50 (mouse, IV): 5.2 mg/kg(7) 
LD50 (rat, IV): 6.8 mg/kg 
Hexadecyltrimethylammonium bromide 
Empirical formula: C19H42BrN 
Molecular weight: 364.48 
CAS number: [57-09-0] 
Synonyms: cetrimide BP 1953; cetrimonium bromide; cetyltrimethylammonium 
bromide; CTAB; N,N,N-trimethylhexadecylammonium 
bromide. 
Appearance: a white to creamy-white, voluminous, freeflowing 
powder, with a characteristic faint odor and bitter, 
soapy taste. 
Melting point: 237–2438C 
Safety:
LD50 (guinea pig, SC): 100 mg/kg(8) 
LD50 (mouse, IP): 106 mg/kg 
LD50 (mouse, IV): 32 mg/kg 
LD50 (rabbit, IP): 125 mg/kg 
LD50 (rabbit, SC): 125 mg/kg 
LD50 (rat, IV): 44 mg/kg 
LD50 (rat, oral): 410 mg/kg 
Solubility: freely soluble in ethanol (95%); soluble 1 in 10 parts 
of water. 
Comments: the original cetrimide BP 1953 consisted largely of 
hexadecyltrimethylammonium bromide, with smaller 
amounts of analogous alkyltrimethylammonium bromides. 
It contained a considerable proportion of inorganic salts, 
chiefly sodium bromide, and was less soluble than the 
present product. 
Trimethyltetradecylammonium bromide 
Empirical formula: C17H38BrN 
Molecular weight: 336.40 
CAS number: [1119-97-7] 
Synonyms: myristyltrimethylammonium bromide; tetradecyltrimethylammonium 
bromide; N,N,N-trimethyl-1-tetradecanaminium 
bromide. 
Safety:
LD50 (mouse, IV): 12 mg/kg(9) 
LD50 (rat, IV): 15 mg/kg 
Cetrimide 153

18 Comments 
As a precaution against contamination with Pseudomonas 
species resistant to cetrimide, stock solutions may be further 
protected by adding at least 7% v/v ethanol or 4% v/v propan- 
2-ol. 
The EINECS number for cetrimide is 214-291-9. 
19 Specific References 
1 Arena JM. Poisonings and other health hazards associated with the 
use of detergents. J Am Med Assoc 1964; 190: 56–58. 
2 Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation 
Agents: A Handbook of Excipients. New York: Marcel Dekker, 
1989. 
3 Gilchrist DS. Chemical peritonitis after cetrimide washout in 
hydatid-cyst surgery [letter]. Lancet 1979; ii: 1374. 
4 Baraka A, Yamut F, Wakid N. Cetrimide-induced methaemoglobinaemia 
after surgical excision of hydatid cyst [letter]. Lancet 
1980; ii: 88–89. 
5 Momblano P, Pradere B, Jarrige N, et al. Metabolic acidosis 
induced by cetrimonium bromide [letter]. Lancet 1984; ii: 1045. 
6 Jacobs JY. Work hazards from drug handling. Pharm J 1984; 233: 
195–196. 
7 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1550. 
8 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1925. 
9 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3385–3386. 
20 General References 
August PJ. Cutaneous necrosis due to cetrimide application. Br Med J 
1975; 1: 70. 
Eccleston GM. Phase transitions in ternary systems and oil-in-water 
emulsions containing cetrimide and fatty alcohols. Int J Pharm 
1985; 27: 311–323. 
Evans BK, Harding KG, Marks J, Ribeiro CD. The disinfection of 
silicone-foam dressings. J Clin Hosp Pharm 1985; 10: 289–295. 
Louden JD, Rowe RC. A quantitative examination of the structure of 
emulsions prepared using cetostearyl alcohol and cetrimide using 
Fourier transform infrared microscopy. Int J Pharm 1990; 63: 219– 
225. 
Rowe RC, Patel HK. The effect of temperature on the conductivity of 
gels and emulsions prepared from cetrimide and cetostearyl alcohol. 
J Pharm Pharmacol 1985; 37: 564–567. 
Rowe RC, McMahon J, Stewart RF. The stability of oil-in-water 
emulsions containing cetrimide and cetostearyl alcohol. Int J Pharm 
1986; 31: 281–282. 
Smith ARW, Lambert PA, Hammond SM, Jessup C. The differing 
effects of cetyltrimethylammonium bromide and cetrimide BP upon 
growing cultures of Escherichia coli NCIB 8277. J Appl Bacteriol 
1975; 38: 143–149. 
21 Authors 
SC Owen. 
22 Date of Revision 
15 August 2005. 
154 Cetrimide

Cetyl Alcohol 
1 Nonproprietary Names 
BP: Cetyl alcohol 
JP: Cetanol 
PhEur: Alcohol cetylicus 
USPNF: Cetyl alcohol 
2 Synonyms 
Avol; Cachalot; Crodacol C70; Crodacol C90; Crodacol C95; 
ethal; ethol; 1-hexadecanol; n-hexadecyl alcohol; Hyfatol 16- 
95; Hyfatol 16-98; Kessco CA; Lanette 16; Lipocol C; palmityl 
alcohol; Rita CA; Tego Alkanol 16. 
3 Chemical Name and CAS Registry Number 
Hexadecan-1-ol [36653-82-4] 
4 Empirical Formula and Molecular Weight 
C16H34O 242.44 (for pure material) 
Cetyl alcohol, used in pharmaceutical preparations, is a 
mixture of solid aliphatic alcohols comprising mainly 
1-hexadecanol (C16H34O). The USPNF 23 specifies not less 
than 90.0% of cetyl alcohol, the remainder consisting chiefly of 
related alcohols. 
Commercially, many grades of cetyl alcohol are available as 
mixtures of cetyl alcohol (60–70%) and stearyl alcohol 
(20–30%), the remainder being related alcohols. 
5 Structural Formula 
6 Functional Category 
Coating agent; emulsifying agent; stiffening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Cetyl alcohol is widely used in cosmetics and pharmaceutical 
formulations such as suppositories, modified-release solid 
dosage forms, emulsions, lotions, creams, and ointments. 
In suppositories cetyl alcohol is used to raise the melting 
point of the base, and in modified-release dosage forms it may 
be used to form a permeable barrier coating. In lotions, creams, 
and ointments cetyl alcohol is used because of its emollient, 
water-absorptive, and emulsifying properties. It enhances 
stability, improves texture, and increases consistency. The 
emollient properties are due to absorption and retention of 
cetyl alcohol in the epidermis, where it lubricates and softens 
the skin while imparting a characteristic ‘velvety’ texture. 
Cetyl alcohol is also used for its water absorption properties 
in water-in-oil emulsions. For example, a mixture of petrolatum 
and cetyl alcohol (19:1) will absorb 40–50% of its weight of 
water. Cetyl alcohol acts as a weak emulsifier of the water-in-oil 
type, thus allowing a reduction of the quantity of other 
emulsifying agents used in a formulation. Cetyl alcohol has also 
been reported to increase the consistency of water-in-oil 
emulsions. 
In oil-in-water emulsions, cetyl alcohol is reported to 
improve stability by combining with the water-soluble emulsifying 
agent. The combined mixed emulsifier produces a close 
packed, monomolecular barrier at the oil–water interface 
which forms a mechanical barrier against droplet coalescence. 
In semisolid emulsions, excess cetyl alcohol combines with 
the aqueous emulsifier solution to form a viscoelastic continuous 
phase that imparts semisolid properties to the emulsion 
and also prevents droplet coalescence. Therefore, cetyl alcohol 
is sometimes referred to as a ‘consistency improver’ or a 
‘bodying agent’, although it may be necessary to mix cetyl 

alcohol with a hydrophilic emulsifier to impart this property. 
It should be noted that pure or pharmacopeial grades of 
cetyl alcohol may not form stable semisolid emulsions and may 
not show the same physical properties as grades of cetyl alcohol 
that contain significant amounts of other similar alcohols. See 
Section 4. 
See Table I. 
Table I: Uses of cetyl alcohol. 
Use Concentration (%) 
Emollient 2–5 
Emulsifying agent 2–5 
Stiffening agent 2–10 
Water absorption 5 
8 Description 
Cetyl alcohol occurs as waxy, white flakes, granules, cubes, or 
castings. It has a faint characteristic odor and bland taste. 
9 Pharmacopeial Specifications 
See Table II. 
10 Typical Properties 
Boiling point: 
316–3448C; 
3448C for pure material. 
Density: 0.908 g/cm3 
Flash point: 1658C 
Melting point: 
45–528C; 
498C for pure material. 
Refractive index: nD
79 = 1.4283 for pure material. 
Solubility: freely soluble in ethanol (95%) and ether, solubility 
increasing with increasing temperature; practically insoluble

in water. Miscible when melted with fats, liquid and solid 
paraffins, and isopropyl myristate. 
Specific gravity:  0.81 g/cm3 at 508C 
Viscosity (dynamic):  7 mPa s (7 cP) at 508C 
11 Stability and Storage Conditions 
Cetyl alcohol is stable in the presence of acids, alkalis, light, and 
air; it does not become rancid. It should be stored in a wellclosed 
container in a cool, dry place. 
12 Incompatibilities 
Incompatible with strong oxidizing agents. Cetyl alcohol is 
responsible for lowering the melting point of ibuprofen, which 
results in sticking tendencies during the process of film coating 
ibuprofen crystals.(1) 
13 Method of Manufacture 
Cetyl alcohol may be manufactured by a number of methods 
such as esterification and hydrogenolysis of fatty acids or by 
catalytic hydrogenation of the triglycerides obtained from 
coconut oil or tallow. Cetyl alcohol may be purified by 
crystallization and distillation. 
14 Safety 
Cetyl alcohol is mainly used in topical formulations, although it 
has also been used in oral and rectal preparations. 
Cetyl alcohol has been associated with allergic delayed-type 
hypersensitivity reactions in patients with stasis dermatitis.(2) 
Cross-sensitization with cetostearyl alcohol, lanolin, and 
stearyl alcohol has also been reported.(3,4) It has been suggested 
that hypersensitivity may be caused by impurities in commercial 
grades of cetyl alcohol since highly refined cetyl alcohol 
(99.5%) has not been associated with hypersensitivity reactions.(
5) 
LD50 (mouse, IP): 1.6 g/kg(6) 
LD50 (mouse, oral): 3.2 g/kg 
LD50 (rat, IP): 1.6 g/kg 
LD50 (rat, oral): 5 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (ophthalmic 
preparations, oral capsules and tablets, otic and rectal 
preparations, topical aerosols, creams, emulsions, ointments 
and solutions, and vaginal preparations). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian 
List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Cetostearyl alcohol; stearyl alcohol. 
18 Comments 
The EINECS number for cetyl alcohol is 253-149-0. 
19 Specific References 
1 Schmid S, Mu. ller-Goymann CC, Schmidt PC. Interactions during 
aqueous film coating of ibuprofen with Aquacoat ECD. Int J 
Pharm 2000; 197: 35–39. 
2 Smolinske SC. Handbook of Food, Drug and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 75–77. 
3 van Ketel WG, Wemer J. Allergy to lanolin and ‘lanolin-free’ 
creams. Contact Dermatitis 1983; 9(5): 420. 
4 Degreef H, Dooms-Goossens A. Patch testing with silver sulfadiazine 
cream. Contact Dermatitis 1985; 12: 33–37. 
5 Hannuksela M, Salo H. The repeated open application test 
(ROAT). Contact Dermatitis 1986; 14(4): 221–227. 
6 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1923. 
20 General References 
Eccleston GM. Properties of fatty alcohol mixed emulsifiers and 
emulsifying waxes. In: Florence AT, ed. Materials Used in 
Pharmaceutical Formulation: Critical Reports on Applied Chemistry, 
volume 6. Oxford: Blackwell Scientific, 1984: 124–156. 
Mapstone GE. Crystallization of cetyl alcohol from cosmetic emulsions. 
Cosmet Perfum 1974; 89(11): 31–33. 
21 Authors 
HM Unvala. 
22 Date of Revision 
12 April 2005. 
Table II: Pharmacopeial specifications for cetyl alcohol. 
Test JP 2001 PhEur 2005 USPNF 
23 
Identification — . . 
Characters — . — 
Melting range 47–538C 46–528C — 
Residue on ignition 40.05% — — 
Ester value 42.0 — — 
Alkali . — — 
Acid value 41.0 41.0 42 
Iodine value 42.0 42.0 45 
Hydroxyl value 210–232 218–238 
218–238 
Saponification value — 42.0 — 
Clarity and color of 
solution 
. . — 
Assay — — 590.0% 
156 Cetyl Alcohol

Cetylpyridinium Chloride 
1 Nonproprietary Names 
BP: Cetylpyridinium chloride 
PhEur: Cetylpridinii chloridum 
USP: Cetylpyridinium chloride 
2 Synonyms 
C16-alkylpyridinium chloride; Cepacol; Cepacol chloride; 
Cetamiun; cetyl pyridium chloride; Dobendan; hexadecylpyridinium 
chloride; 1-hexadecylpyridinium chloride; Medilave; 
Pristacin; Pyrisept. 
3 Chemical Name and CAS Registry Number 
1-Hexadecylpyridinium chloride [123-03-5] 
1-Hexadecylpyridinium chloride monohydrate [6004-24-6] 
4 Empirical Formula and Molecular Weight 
C21H38ClN 339.9 (for anhydrous) 
C21H38ClNH2O 358.1 (for monohydrate) 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; antiseptic; cationic surfactant; 
disinfectant; solubilizing agent; wetting agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Cetylpyridinium chloride is a quaternary ammonium cationic 
surfactant, used in pharmaceutical and cosmetic formulations 
as an antimicrobial preservative; see Section 10. It is used 
therapeutically as an antiseptic agent; used alone or in 
combination with other drugs for oral and throat care; used 
in nonparenteral formulations licensed in the UK; and used in 
oral and inhalation preparations at concentrations of 
0.02–1.5mg (see Section 16). 
Mouthwashes containing cetylpyridinium chloride have 
been shown to inhibit plaque formation,(1–3) although efficacy 
is variable owing to limited published data.(4,5) 
8 Description 
Cetylypyridinium chloride is a white powder with a characteristic 
odor. It is slightly soapy to the touch. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for cetylpyridinium chloride. 
Test PhEur 2005 USP 28 
Absorbance . . 
Acidity . . 
Amines and amine salts . — 
Appearance of solution . — 
Characters . — 
Heavy metals — 40.002% 
Identification . . 
Melting range — 80.0–84.08C 
Organic volatile impurities — . 
Pyridine — . 
Residue on ignition 40.2% 40.2% 
Water 4.5–5.5% 4.5–5.5% 
Assay 96.0–101.0% 99.0–102.0% 
10 Typical Properties 
Antibacterial activity: bactericidal to Gram-positive bacteria; 
relatively ineffective against some Gram-negative bacteria.(6) 
Cetylpyridinium chloride is also antibacterial against a 
number of oral bacteria;(7) see Table II.(8) 
Melting point: 80–838C 
Solubility: freely soluble in water; very soluble in chloroform; 
very slightly soluble in ether; insoluble in acetone, acetic 
acid, and ethanol. 
Table II: Minimum inhibitory concentrations (MICs) for 
cetylpyridinium chloride.(8) 
Microorganism MIC (mg/mL) 
Staphylococcus aureus <2.0 
Bacillus subtilis <2.0 
Salmonella typhimurium 8.0 
Pseudomonas aeruginosa 16.0 
Streptococcus pyogenes <2.0 
Critical micelle concentration: 0.34 g/L (water, 258C).(9,10) 
11 Stability and Storage Conditions 
Cetylpyridinium chloride is stable under normal conditions. It 
should be stored in well-closed containers. 
12 Incompatibilities 
Incompatible with strong oxidizing agents and bases. It is also 
incompatible with methylcellulose. 
Magnesium stearate suspensions in cetylpyridinium chloride 
have been shown to significantly reduce its antimicrobial 
activity. This is due to the absorption of cetylpyridinium chloride 
on magnesium stearate.(11) The cetylpyridinium chloride ion 
also interacts with gelatin, resulting in reduced bioavailability.(
12)

13 Method of Manufacture 
Cetylpyridinium chloride is prepared from cetyl chloride by 
treatment with pyridine. 
14 Safety 
Cetylpyridinium chloride is used widely in mouthwashes as a 
bactericidal antiseptic. It is generally regarded as a relatively 
nontoxic material when used at a concentration of 0.05% w/v, 
although minor side effects such as mild burning sensations on 
the tongue have been reported.(13) 
At higher concentrations, cetylpyridinium chloride may 
damage the mucous membranes in the mouth. It is harmful 
when ingested or inhaled. It can cause eye irritation, and is 
irritant to the respiratory system and the skin. 
LD50 (rat, IP): 0.006 g/kg(14) 
LD50 (rat, IV): 0.03 g/kg 
LD50 (rat, oral): 0.2 g/kg 
LD50 (rat, SC): 0.25 g/kg 
LD50 (mouse, IP): 0.01 g/kg 
LD50 (mouse, oral): 0.108 g/kg 
LD50 (rabbit, oral): 0.4 g/kg 
LD50 (rabbit, IV): 0.036 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of the material handled. When significant 
quantities are being handled, the use of a respirator with an 
appropriate gas filter is advised. When heated to decomposition, 
cetylpyridinium chloride emits very toxic fumes of NOx 
and Cl–. Eye protection, gloves and adequate ventilation are 
recommended. 
16 Regulatory Status 
Included in nonparenteral formulations licensed in the UK. 
Included in the FDA Inactive Ingredients Guide, for use in 
inhalation and oral preparations. Reported in the EPA TSCA 
Inventory. It is not approved for use in Japan. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Cetylpyridinium bromide. 
Cetylpyridinium bromide 
Empirical formula: C21H38BrN 
Molecular weight: 384.45 
CAS number: [140-72-7] 
Synonyms: Aceloquat CPB; Bromocet; Cetapharm; Cetasol; 
N-cetylpyridinium bromide; hexadexylpyridinium bromide; 
Nitrogenol; Seprison; Sterogenol. 
18 Comments 
Cetylpyridinium chloride has also been studied for use as an 
antimicrobial preservative for meat(15) and vegetables.(16) 
However, the residual levels after treatment are considered 
excessive for human consumption; see Section 14. 
The EINECS number for cetylpyridinium chloride is 204- 
593-9. 
19 Specific References 
1 Volpe AR, Kupczak LJ, Brant JH, et al. Antimicrobial control of 
bacterial plaque and calculus, and the effects of these agents on 
oral flora. J Dent Res 1969; 48: 832–841. 
2 Holbeche JD, Ruljancich MK, Reade PC. A clinical trial of the 
efficacy of a cetylpyridinium chloride-based mouth-wash. 1. Effect 
on plaque accumulation and gingival condition. Aust Dent J 1975; 
20: 397–404. 
3 Ashley FP, Skinner A, Jackson P, Woods A, Wilson RF. The effects 
of a 0.1% cetylpyridinium chloride mouth-rinse on plaque and 
gingivitis in adult subjects. Br Dent J 1984; 157: 191–196. 
4 Bonosvoll P, Gjermo P. A comparison between chlorhexedine and 
some quaternary ammonium compounds with regard to retention, 
salivary concentration and plaque-inhibiting effect in the human 
mouth after mouth rinses. Arch Oral Biol 1978; 23: 289–294. 
5 Sheen S, Addy M. An in vitro evaluation of the availability of 
cetylpyridinium chloride and chlorhexidine in some commercially 
available mouthrinse products. Br Dent J 2003; 194(4): 207–210. 
6 Baker Z, Harrison RW, Miller BF. The bacterial action of synthetic 
detergents. J Exp Med 1941; 74: 611–620. 
7 Smith RN, Anderson RN, Kolenbrander PE. Inhibition of 
intergeneric coaggregation among oral bacteria by cetylpyridinium 
chloride, chlorhexidine digluconate and octenidine dihydrochloride. 
J Periodontal Res 1991; 26(5): 422–428. 
8 Bodor N, Kaminski JJ, Selk S. Soft drugs. 1. Labile quaternary 
ammonium salts as soft antimicrobials. J Med Chem 1980; 23: 
469–474. 
9 Harada T, Nishikido N, Moroi Y, Matuura R. Effect of surfactant 
micelles on the rate of reaction of tetranitromethane with 
hydroxide ion. Bull Chem Soc Jpn 1981; 54: 2592–2597. 
10 Wang K, Karlson G, Almgren M, Asakawa T. Aggregation 
behaviour of cationic fluorosurfactants in water and salt solutions. 
A cryoTEM survey. J Phys Chem B 1999; 103(43): 9237–9246. 
11 Richards RM, Xing JZ, Mackay KM. Excipient interaction with 
cetylpyridinium chloride activity in tablet based lozenges. Pharm 
Res 2003: 13(8): 1258–1264. 
12 Ofner CM3d, Schott H. Swelling studies of gelatin. II: Effect of 
additives. J Pharm Sci 1987; 76(9): 715–723. 
13 Ciano SG, Mather ML, Bunnell HL. Clinical evaluation of a 
quaternary ammonium containing mouthrinse. J Periodontol 
1975; 46: 397–401. 
14 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 737. 
15 Cutter CN, Dorsa WJ, Handie A, et al. Antimicrobial activity of 
cetylpyridinium chloride washes against pathogenic bacteria on 
beef surfaces. J Food Prot 2000; 63(5): 593–600. 
16 Wang H, Li Y, Slavik MF. Efficacy of cetylpyridinium chloride in 
immersion treatment reducing populations of pathogenic bacteria 
on fresh-cut vegetables. J Food Prot 2001; 64(12): 2071–2074. 
20 General References 
Huyck CL. Cetylpyridinium chloride. Am J Pharm 1944; 116: 50–59. 
Radford JR, Beighton D, Nugent Z, Jackson RJ. Effect of use of 
0.005% cetylpyridinium chloride mouthwash on normal oral flora. 
J Dent 1997; 25(1): 35–40. 
21 Authors 
JL Gray, CP McCoy. 
22 Date of Revision 
1 September 2005. 
158 Cetylpyridinium Chloride

Chitosan 
1 Nonproprietary Names 
BP: Chitosan hydrochloride 
PhEur: Chitosani hydrochloridum 
2 Synonyms 
2-Amino-2-deoxy-(1,4)-b-D-glucopyranan; deacetylated chitin; 
deacetylchitin; b-1,4-poly-D-glucosamine; poly-D-glucosamine; 
poly-(1,4-b-D-glucopyranosamine). 
3 Chemical Name and CAS Registry Number 
Poly-b-(1,4)-2-Amino-2-deoxy-D-glucose [9012-76-4] 
4 Empirical Formula and Molecular Weight 
Partial deacetylation of chitin results in the production of 
chitosan, which is a polysaccharide comprising copolymers of 
glucosamine and N-acetylglucosamine. Chitosan is the term 
applied to deacetylated chitins in various stages of deacetylation 
and depolymerization and it is therefore not easily defined 
in terms of its exact chemical composition. A clear nomenclature 
with respect to the different degrees of N-deacetylation 
between chitin and chitosan has not been defined,(1–3) and as 
such chitosan is not one chemical entity but varies in 
composition depending on the manufacturer. In essence, 
chitosan is chitin sufficiently deacetylated to form soluble 
amine salts. The degree of deacetylation necessary to obtain a 
soluble product must be greater than 80–85%. Chitosan is 
commercially available in several types and grades that vary in 
molecular weight by 10 000–1 000 000, and vary in degree of 
deacetylation and viscosity.(4) 
5 Structural Formula 
6 Functional Category 
Coating agent; disintegrant; film-forming agent; mucoadhesive; 
tablet binder; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Chitosan is used in cosmetics and is under investigation for use 
in a number of pharmaceutical formulations. The suitability 
and performance of chitosan as a component of pharmaceutical 
formulations for drug delivery applications has been investigated 
in numerous studies.(3,5–8) These include controlled drug 
delivery applications,(9–14) use as a component of mucoadhesive 
dosage forms,(15,16) rapid release dosage forms,(17,18) 
improved peptide delivery,(19,20) colonic drug delivery systems,(
21,22) and use for gene delivery.(23) Chitosan has been 
processed into several pharmaceutical forms including 
gels,(24,25) films,(11,12,26,27) beads,(28,29) microspheres,(30,31) 
tablets,(32,33) and coatings for liposomes.(34) Furthermore, 
chitosan may be processed into drug delivery systems using 
several techniques including spray-drying,(15,16) coacervation,(
35) direct compression,(32) and conventional granulation 
processes.(36) 
8 Description 
Chitosan occurs as odorless, white or creamy-white powder or 
flakes. Fiber formation is quite common during precipitation 
and the chitosan may look ’cottonlike’. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for chitosan. 
Test PhEur 2005 
Identification . 
Characters . 
Appearance of solution . 
Matter insoluble in water 40.5% 
pH (1% w/v solution) 4.0–6.0 
Viscosity . 
Degree of deacetylation . 
Chlorides 10.0–20.0% 
Heavy metals 440 ppm 
Loss on drying 410% 
Sulfated ash 41.0% 
10 Typical Properties 
Chitosan is a cationic polyamine with a high charge density at 
pH <6.5; and so adheres to negatively charged surfaces and 
chelates metal ions. It is a linear polyelectrolyte with reactive 
hydroxyl and amino groups (available for chemical reaction 
and salt formation).(7) The properties of chitosan relate to its 
polyelectrolyte and polymeric carbohydrate character. The 
presence of a number of amino groups allows chitosan to react 
chemically with anionic systems, which results in alteration of 
physicochemical characteristics of such combinations. The 
nitrogen in chitosan is mostly in the form of primary aliphatic 
amino groups. Chitosan therefore undergoes reactions typical

of amines: for example, N-acylation and Schiff reactions.(3) 
Almost all functional properties of chitosan depend on the 
chain length, charge density, and charge distribution.(8) 
Numerous studies have demonstrated that the salt form, 
molecular weight, and degree of deacetylation as well as pH 
at which the chitosan is used all influence how this polymer is 
utilized in pharmaceutical applications.(7) 
Acidity/alkalinity: pH = 4.0–6.0 (1% w/v aqueous solution) 
Density: 1.35–1.40 g/cm3 
Glass transition temperature: 2038C(37) 
Moisture content: chitosan adsorbs moisture from the atmosphere, 
the amount of water adsorbed depending upon the 
initial moisture content and the temperature and relative 
humidity of the surrounding air.(38) 
Particle size distribution: <30 mm 
Solubility: sparingly soluble in water; practically insoluble in 
ethanol (95%), other organic solvents, and neutral or alkali 
solutions at pH above approximately 6.5. Chitosan 
dissolves readily in dilute and concentrated solutions of 
most organic acids and to some extent in mineral inorganic 
acids (except phosphoric and sulfuric acids). Upon dissolution, 
amine groups of the polymer become protonated, 
resulting in a positively charged polysaccharide (RNH3.) 
and chitosan salts (chloride, glutamate, etc.) that are soluble 
in water; the solubility is affected by the degree of 
deacetylation.(7) Solubility is also greatly influenced by the 
addition of salt to the solution. The higher the ionic strength, 
the lower the solubility as a result of a salting-out effect, 
which leads to the precipitation of chitosan in solution.(39) 
When chitosan is in solution, the repulsions between the 
deacetylated units and their neighboring glucosamine units 
cause it to exist in an extended conformation. Addition of an 
electrolyte reduces this effect and the molecule possesses a 
more random, coil-like conformation.(40) 
Viscosity (dynamic): a wide range of viscosity types is 
commercially available. Owing to its high molecular weight 
and linear, unbranched structure, chitosan is an excellent 
viscosity-enhancing agent in an acidic environment. It acts 
as a pseudo-plastic material, exhibiting a decrease in 
viscosity with increasing rates of shear.(7) The viscosity of 
chitosan solutions increases with increasing chitosan concentration, 
decreasing temperature, and increasing degree of 
deacetylation; see Table II.(40) 
Table II: Typical viscosity (dynamic) values for chitosan 1% w/v 
solutions in different acids.(40) 
Acid 1% acid 
concentration 
5% acid 
concentration 
10% acid 
concentration 
Viscosity 
(mPa s) 
pH Viscosity 
(mPa s) 
pH Viscosity 
(mPa s) 
pH 
Acetic 260 4.1 260 3.3 260 2.9 
Adipic 190 4.1 — — — — 
Citric 35 3.0 195 2.3 215 2.0 
Formic 240 2.6 185 2.0 185 1.7 
Lactic 235 3.3 235 2.7 270 2.1 
Malic 180 3.3 205 2.3 220 2.1 
Malonic 195 2.5 — — — — 
Oxalic 12 1.8 100 1.1 100 0.8 
Tartaric 52 2.8 135 2.0 160 1.7 
11 Stability and Storage Conditions 
Chitosan powder is a stable material at room temperature, 
although it is hygroscopic after drying. Chitosan should be 
stored in a tightly closed container in a cool, dry place. The 
PhEur 2005 specifies that chitosan should be stored at a 
temperature of 2–88C. 
12 Incompatibilities 
Chitosan is incompatible with strong oxidizing agents. 
13 Method of Manufacture 
Chitosan is manufactured commercially by chemically treating 
the shells of crustaceans such as shrimps and crabs. The basic 
manufacturing process involves the removal of proteins by 
treatment with alkali and of minerals such as calcium carbonate 
and calcium phosphate by treatment with acid.(3,40) Before 
these treatments, the shells are ground to make them more 
accessible. The shells are initially deproteinized by treatment 
with an aqueous sodium hydroxide 3–5% solution. The 
resulting product is neutralized and calcium is removed by 
treatment with an aqueous hydrochloric acid 3–5% solution at 
room temperature to precipitate chitin. The chitin is dried so 
that it can be stored as a stable intermediate for deacetylation to 
chitosan at a later stage. N-deacetylation of chitin is achieved 
by treatment with an aqueous sodium hydroxide 40–45% 
solution at elevated temperature (1108C), and the precipitate is 
washed with water. The crude sample is dissolved in acetic acid 
2% and the insoluble material is removed. The resulting clear 
supernatant solution is neutralized with aqueous sodium 
hydroxide solution to give a purified white precipitate of 
chitosan. The product can then be further purified and ground 
to a fine uniform powder or granules.(1) The animals from 
which chitosan is derived must fulfil the requirements for the 
health of animals suitable for human consumption to the 
satisfaction of the competent authority. The method of 
production must consider inactivation or removal of any 
contamination by viruses or other infectious agents. 
14 Safety 
Chitosan is being investigated widely for use as an excipient in 
oral and other pharmaceutical formulations. It is also used in 
cosmetics. Chitosan is generally regarded as a nontoxic and 
nonirritant material. It is biocompatible(41) with both healthy 
and infected skin.(42) Chitosan has been shown to be 
biodegradable.(3,41) 
LD50 (mouse, oral): >16 g/kg(43) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Chitosan is combustible; 
open flames should be avoided. Chitosan is temperaturesensitive 
and should not be heated above 2008C. Airborne 
chitosan dust may explode in the presence of a source of 
ignition, depending on its moisture content and particle size. 
Water, dry chemicals, carbon dioxide, sand, or foam firefighting 
media should be used. 
160 Chitosan

Chitosan may cause skin or eye irritation. It may be harmful 
if absorbed through the skin or if inhaled and may be irritating 
to mucous membranes and the upper respiratory tract. Eye and 
skin protection and protective clothing are recommended; wash 
thoroughly after handling. Prolonged or repeated exposure 
(inhalation) should be avoided by handling in a well-ventilated 
area and wearing a respirator. 
16 Regulatory Status 
Chitosan is registered as a food supplement in some countries. 
17 Related Substances 
See Section 18. 
18 Comments 
Chitosan derivatives are easily obtained under mild conditions 
and can be considered as substituted glucens.(3) 
19 Specific References 
1 Muzzarelli RAA, ed. Natural Chelating Polymers. New York: 
Pergamon Press, 1973: 83–227. 
2 Zikakis JP, ed. Chitin, Chitosan and Related Enzymes. New York: 
Academic Press, 1974. 
3 Kumar MNVR. A review of chitin and chitosan applications. 
React Funct Polym 2000; 46: 1–27. 
4 Genta I, Perugini P, Pavanetto F. Different molecular weight 
chitosan microspheres: influence on drug loading and drug release. 
Drug Dev Ind Pharm 1998; 24: 779–784. 
5 Illum L. Chitosan and its use as a pharmaceutical excipient. Pharm 
Res 1998; 15: 1326–1331. 
6 PaulW, Sharma CP. Chitosan, a drug carrier for the 21st century: a 
review. STP Pharma Sci 2000; 10: 5–22. 
7 Singla AK, Chawla M. Chitosan: some pharmaceutical and 
biological aspects – an update. J Pharm Pharmacol 2001; 53: 
1047–1067. 
8 Dodane V, Vilivalam VD. Pharmaceutical applications of chitosan. 
PSTT1998; 1: 246–253. 
9 Muzzarelli RAA, ed. Chitin. London: Pergamon Press, 1977: 69. 
10 Nakatsuka S, Andrady LA. Permeability of vitamin-B-12 in 
chitosan membranes: effect of crosslinking and blending with 
poly(vinyl alcohol) on permeability. J Appl Polym Sci 1992; 44: 7– 
28. 
11 Kubota N, Ohga K, Moriguchi M. Permeability properties of 
glycol chitosan membrane modified with thiol groups. J Appl 
Polym Sci 1991; 42: 495–501. 
12 Li Q, Dunn ET, Grandmaison EW, Goosen MFA. Application and 
properties of chitosan. J Bioact Compat Polym 1992; 7: 370–397. 
13 Miyazaki S, Yamaguchi H, Yokouchi C, et al. Sustained release 
and intragastric floating granules of indomethacin using chitosan 
in rabbits. Chem Pharm Bull 1988; 36: 4033–4038. 
14 Sawayangi Y, Nambu N, Nagai T. Use of chitosan for sustainedrelease 
preparations of water soluble drugs. Chem Pharm Bull 
1982; 30: 4213–4215. 
15 He P, Davis SS, Illum L. In vitro evaluation of the mucoadhesive 
properties of chitosan microspheres. Int J Pharm 1998; 166: 75– 
88. 
16 He P, Davis SS, Illum L. Sustained release chitosan microsphere 
produced by novel spray drying methods. J Microencapsul 1999; 
16: 343–355. 
17 Sawayangi Y, Nambu N, Nagai T. Enhancement of dissolution 
properties of griseofulvin from ground mixtures with chitin or 
chitosan. Chem Pharm Bull 1982; 30: 4464–4467. 
18 Shirashi S, Arahira M, Imai T, Otagiri M. Enhancement of 
dissolution rates of several drugs by low molecular weight chitosan 
and alginate. Chem Pharm Bull 1990; 38: 185–187. 
19 Leussen HL, Lehr CM, Rentel CO, et al. Bioadhesive polymers for 
the peroral delivery of drugs. J Control Release 1994; 29: 329– 
338. 
20 Leussen HL, Rentel CO, Kotze AF, et al. Mucoadhesive polymers 
in peroral peptide drug delivery, IV: polycarbophil and chitosan are 
potent enhancers of peptide transport across intestinal mucosae in 
vitro. J Control Release 1997; 45: 15–23. 
21 Tozaki H, Fujita T, Odoriba T, et al. Validation of a pharmacokinetic 
model of colon-specific drug delivery and the therapeutic 
effects of chitosan capsules containing 5-aminosalicylic acid on 
2,4,6-trinitrobenzene sulphonic acid-induced ulcerative colitis in 
rats. J Pharm Pharmacol 1999; 51: 1107–1112. 
22 Tozaki H, Fujita T, Odoriba T, et al. Colon specific delivery of R 
68070, a new thromboxane synthase inhibitor using chitosan 
capsules: therapeutic effects against 2,4,6-trinitrobenzene sulphonic 
acid-induced ulcerative colitis in rats. Life Sci 1999; 64: 1155– 
1162. 
23 Leong KW, Mao HQ, Truong-Le VL, et al. DNA-polycation 
nanospheres as non-viral gene delivery vehicles. J Control Release 
1998; 53: 183–193. 
24 Kristl J, Smid-Korbar J, Struc E, et al. Hydrocolloids and gels of 
chitosan as drug carriers. Int J Pharm 1993; 99: 13–19. 
25 Tasker RA, Ross SJ, Dohoo SE, Elson CM. Pharmacokinetics of an 
injectable sustained-release formulation of morphine for use in 
dogs. J Vet Pharmacol Ther 1997; 20: 362–367. 
26 Remunan-Lopez C, Portero A, Vila-Jato JL, Alonso MJ. Design 
and evaluation of chitosan/ethylcellulose mucoadhesive bilayered 
devices for buccal drug delivery. J Control Release 1998; 55: 143– 
152. 
27 Senel S, Ikinci G, Kas S, et al. Chitosan films and hydrogels of 
chlorhexidine gluconate for oral mucosal delivery. Int J Pharm 
2000; 193: 197–203. 
28 Kofuji K, Shibata K, Murata Y, et al. Preparation and drug 
retention of biodegradable chitosan gel beads. Chem Pharm Bull 
1999; 47: 1494–1496. 
29 Sezer AD, Akbuga J. Release characteristics of chitosan-treated 
alginate beads, 1: sustained release of a macromolecular drug from 
chitosan treated alginate beads. J Microencapsul 1999; 193: 197– 
203. 
30 Ganza-Gonzalez A, Anguiano-Igea S, Otero-Espinar FJ, Mendez 
JB. Chitosan and chondroitin microspheres for oral administration 
controlled release of metoclopromide. Eur J Pharm Biopharm 
1999; 48: 149–155. 
31 Huang RG, Schwartz JB, Offner CM. Microencapsulation of 
chlorpheniramine maleate-resin particles with crosslinked chitosan 
for sustained release. Pharm Dev Technol 1999; 4: 107–115. 
32 Yomota C, Miyazaki T, Okada S. Sustained-release effect of the 
direct compressed tablet based on chitosan and Na alginate. 
Yakugaku Zasshi 1994; 114: 257–263. 
33 Sabnis S, Rege P, Block LH. Use of chitosan in compressed tablets 
of diclofenac sodium: inhibition of drug release in an acidic 
environment. Pharm Dev Technol 1997; 2: 243–255. 
34 Takeuchi H, Yamamoto H, Niwa T, et al. Enteral absorption of 
insulin in rats from mucoadhesive chitosan-coated liposomes. 
Pharm Res 1996; 13: 896–901. 
35 Bayomi MA, al-Suwayeh SA, el-Helw AM, Mesnad AF. Preparation 
of casein-chitosan microspheres containing diltiazem hydrochloride 
by an aqueous coacervation technique. Pharma Acta Helv 
1998; 73: 187–192. 
36 Miyazaki S, Nakayama A, Oda M, et al. Drug release from oral 
mucosal adhesive tablets of chitosan and sodium alginate. Int J 
Pharm 1995; 118: 257–263. 
37 Sakurai K, Maegawa T, Takahashi T. Glass transition temperature 
of chitosan and miscibility of chitosan/poly(N-vinyl pyrrolidone) 
blends. Polymer 2000; 41: 7051–7056. 
38 Gocho H, Shimizu H, Tanioka A, et al. Effect of polymer chain end 
on sorption isotherm of water by chitosan. Carbohydr Polym 
2000; 41: 87–90. 
39 Errington N, Harding SE, Varum KM, Illum L. Hydrodynamic 
characterization of chitosans varying in degree of acetylation. Int J 
Biol Macromol 1993; 15: 113–117. 
40 Skaugrud O. Chitosan – new biopolymer for cosmetics and drugs. 
Drug Cosmet Ind 1991; 148: 24–29. 
Chitosan 161

41 Gebelein CG, Dunn RL, eds. Progress in Biomedical Polymers. 
New York: Plenum Press, 1990: 283. 
42 Gooday GW, Jeuniaux C, Muzzarelli RAA, eds. Chitin in Nature 
and Technology. New York: Plenum Press, 1986: 435. 
43 Arai K, Kinumaki T, Fujita T. Toxicity of chitosan. Bull Tokai Reg 
Fish Res Lab 1968; 43: 89–94. 
20 General References 
Brine CJ, Sandford PA, Zikakis JP, eds. Advances in Chitin and 
Chitosan. London: Elsevier Applied Science, 1992. 
Skjak-Braek G, Anthonsen T, Sandford P, eds. Chitin and Chitosan: 
Sources, Chemistry, Biochemistry, Physical Properties and Applications. 
Amsterdam: Elsevier, 1992. 
21 Authors 
DS Jones, HJ Mawhinney. 
22 Date of Revision 
28 August 2005. 
162 Chitosan

Chlorhexidine 
1 Nonproprietary Names 
BP: Chlorhexidine acetate 
Chlorhexidine gluconate solution 
Chlorhexidine hydrochloride 
JP: Chlorhexidine gluconate solution 
Chlorhexidine hydrochloride 
PhEur: Chlorhexidini diacetas 
Chlorhexidini digluconatis solutio 
Chlorhexidini dihydrochloridum 
Chlorhexidine gluconate solution 
Chlorhexidine is usually encountered as the acetate, gluconate, 
or hydrochloride salt, and a number of pharmacopeias contain 
monographs for such materials. See Sections 9 and 17. 
2 Synonyms 
1,6-bis[N0-(p-Chlorophenyl)-N5-biguanido]hexane; N,N00-bis 
(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediimidamide; 
1,6-di(40-chlorophenyldiguanido)hexane. 
3 Chemical Name and CAS Registry Number 
N,N00-Bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediimidamide 
[55-56-1] 
4 Empirical Formula and Molecular Weight 
C22H30Cl2N10 505.48 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; antiseptic. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Chlorhexidine salts are widely used in pharmaceutical formulations 
in Europe and Japan for their antimicrobial properties.(
1,2) Although mainly used as disinfectants, chlorhexidine 
salts are also used as antimicrobial preservatives. 
As excipients, chlorhexidine salts are mainly used for the 
preservation of eye-drops at a concentration of 0.01% w/v; 
generally the acetate or gluconate salt is used for this purpose. 
Solutions containing 0.002–0.006% w/v chlorhexidine gluconate 
have also been used for the disinfection of hydrophilic 
contact lenses. 
For skin disinfection, chlorhexidine has been formulated as 
a 0.5% w/v solution in 70% v/v ethanol and, in conjunction 
with detergents, as a 4%w/v surgical scrub. Chlorhexidine salts 
may also be used in topical antiseptic creams, mouthwashes, 
dental gels, and in urology for catheter sterilization and bladder 
irrigation.(1–4) 
Chlorhexidine salts have additionally been used as constituents 
of medicated dressings, dusting powders, sprays, and 
creams. 
8 Description 
Chlorhexidine occurs as an odorless, bitter tasting, white 
crystalline powder. See Section 17 for information on chlorhexidine 
salts. 
9 Pharmacopeial Specifications 
See Table I. 
See also Section 17. 
10 Typical Properties 
Antimicrobial activity: chlorhexidine and its salts exhibit 
antimicrobial activity against Gram-positive and Gramnegative 
microorganisms.(5) At the low concentrations 
normally used for preservation and antisepsis, chlorhexidine 
salts are rapidly bactericidal. However, species of Proteus 
and Pseudomonas are less susceptible to chlorhexidine, 
which is also inactive against acid-fast bacilli, bacterial 
spores, and some fungi. Chlorhexidine salts are effective 
against some lipophilic viruses such as adenovirus, herpes 
virus, and influenza virus. Optimum antimicrobial activity 
occurs at pH 5–7. Above pH 8, the chlorhexidine base may 
precipitate from aqueous solutions. 
Bacteria (Gram-positive): chlorhexidine salts are active 
against most species; the minimum inhibitory concentration 
(MIC) is normally in the range 1–10 mg/mL, although much 
higher concentrations are necessary for Streptococcus 
faecalis. Typical MIC values are shown in Table II. 
Bacteria (Gram-negative): chlorhexidine salts are less active 
against Gram-negative species than against Gram-positive 
species. Typical MICs are 1–15 mg/mL, but pseudomonads, 
particularly Pseudomonas aeruginosa, may be more resistant. 
Serratia marcescens may also be resistant. Combinations 
of chlorhexidine acetate with the following substances 
have shown enhanced or more than additive activity 
towards Pseudomonas aeruginosa: benzalkonium chloride; 
benzyl alcohol; bronopol; edetic acid; phenylethanol, and 
phenylpropanol.(6,7) Typical MIC values are shown in Table 
III.

Table II: Typical minimum inhibitory concentrations (MIC) of 
chlorhexidine against Gram-positive bacteria. 
Microorganism MIC (mg/mL) 
Bacillus spp. 1.0–3.0 
Clostridium spp. 1.8–70.0 
Corynebacterium spp. 5.0–10.0 
Staphylococcus spp. 0.5–6.0 
Streptococcus faecalis 2000–5000 
Streptococcus spp. 0.1–7.0 
Fungi: chlorhexidine salts are slowly active against molds 
and yeasts, although they are generally less potent in their 
inhibitory activity against fungi than against bacteria. 
Typical MIC values are shown in Table IV. 
Table III: Typical MIC values of chlorhexidine against Gram-negative 
bacteria. 
Microorganism MIC (mg/mL) 
Escherichia coli 2.5–7.5 
Klebsiella spp. 1.5–12.5 
Proteus spp. 3–100 
Pseudomonas spp. 3–60 
Serratia marcescens 3–75 
Salmonella spp. 1.6–15 
Table IV: Typical MIC values of chlorhexidine against fungi. 
Microorganism MIC (mg/mL) 
Aspergillus spp. 75.0–500.0 
Candida albicans 7.0–15.0 
Microsporum spp. 12.0–18.0 
Penicillium spp. 150.0–200.0 
Saccharomyces spp. 50.0–125.0 
Trichophyton spp. 2.5–14.0 
Spores: chlorhexidine salts are inactive against spores at 
normal room temperature.(8) At 98–1008C there is some 
activity against mesophilic spores. 
Critical micelle concentration: 0.6% w/v (depends on other 
ions in solution).(9) 
Melting point: 132–1348C 
See also Section 17 for additional information. 
SEM: 1 
Excipient: Chlorhexidine 
Manufacturer: SST Corp. 
Magnification: 600 
Table I: Pharmacopeial specifications for chlorhexidine. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
pH 
Chlorhexidine 
gluconate solution 
5.5–7.0 5.5–7.0 5.5–7.0 
Relative density 
Chlorhexidine 
gluconate solution 
1.06–1.07 1.06–1.07 1.06–1.07 
4-Chloroaniline 
Chlorhexidine acetate — 40.25% — 
Chlorhexidine 
gluconate solution 
. . 4500 mg/mL 
Chlorhexidine 
hydrochloride 
. 4500 ppm — 
Related substances — . . 
Loss on drying 
Chlorhexidine acetate — 43.5% — 
Chlorhexidine 
hydrochloride 
42.0% 41.0% — 
Sulfated ash 
Chlorhexidine acetate — 40.15% — 
Chlorhexidine 
gluconate solution 
40.10% — — 
Chlorhexidine 
hydrochloride 
40.10% 40.1% — 
Heavy metals 410 ppm — — 
Arsenic 
Chlorhexidine acetate 42 ppm — — 
Chlorhexidine 
hydrochloride 
42 ppm — — 
Assay 
Chlorhexidine acetate — 98.0–101.0% — 
Chlorhexidine 
gluconate solution 
19.0–21.0% 19.0–21.0% 19.0–21.0% 
Chlorhexidine 
hydrochloride 
598.0% 98.0–101.0% — 
164 Chlorhexidine

SEM: 2 
Excipient: Chlorhexidine 
Manufacturer: SST Corp. 
Magnification: 2400 
11 Stability and Storage Conditions 
Chlorhexidine and its salts are stable at normal storage 
temperatures when in the powdered form. However, chlorhexidine 
hydrochloride is hygroscopic, absorbing significant 
amounts of moisture at temperatures up to 378C and relative 
humidities up to 80%. 
Heating to 1508C causes decomposition of chlorhexidine 
and its salts, yielding trace amounts of 4-chloroaniline. 
However, chlorhexidine hydrochloride is more thermostable 
than the acetate and can be heated at 1158C for 1 hour without 
appreciable formation of 4-chloroaniline. 
In aqueous solution, chlorhexidine salts may undergo 
hydrolysis to form 4-chloroaniline. Following autoclaving of 
a 0.02% w/v chlorhexidine gluconate solution at pH 9 for 30 
minutes at 1208C, it was found that 1.56% w/w of the original 
chlorhexidine content had been converted into 4-chloroaniline; 
for solutions at pH 6.3 and 4.7 the 4-chloroaniline content was 
0.27% w/w and 0.13% w/w, respectively, of the original 
gluconate content.(10) In buffered 0.05% w/v chlorhexidine 
acetate solutions, maximum stability occurs at pH 5.6. 
When chlorhexidine solutions were autoclaved at various 
time and temperature combinations, the rate of hydrolysis 
increased markedly above 1008C, and as pH increased or 
decreased from pH 5.6. At a given pH, chlorhexidine gluconate 
produced more 4-chloroaniline than the acetate. 
It was predicted that in an autoclaved solution containing 
0.01% w/v chlorhexidine, the amount of 4-chloroaniline 
formed would be about 0.00003%. At these low concentrations 
there would be little likelihood of any toxic hazard as a 
result of the increase in 4-chloroaniline content in the 
autoclaved solution. 
Chlorhexidine solutions and aqueous-based products may 
be packaged in glass and high-density polyethylene or 
polypropylene bottles provided that they are protected from 
light. If not protected from light, chlorhexidine solutions 
containing 4-chloroaniline discolor owing to polymerization 
of the 4-chloroaniline.(11–13) 
Cork-based closures or liners should not be used in 
packaging in contact with chlorhexidine solutions. 
As a precaution against contamination with Pseudomonas 
species resistant to chlorhexidine, stock solutions may be 
protected by the inclusion of 7% w/v ethanol or 4% w/v 
propan-2-ol. 
Chlorhexidine salts, and their solutions, should be stored in 
well-closed containers, protected from light, in a cool, dry 
place. 
12 Incompatibilities 
Chlorhexidine salts are cationic in solution and are therefore 
incompatible with soaps and other anionic materials. Chlorhexidine 
salts are compatible with most cationic and nonionic 
surfactants, but in high concentrations of surfactant chlorhexidine 
activity can be substantially reduced owing to micellar 
binding. 
Chlorhexidine salts of low aqueous solubility are formed 
and may precipitate from chlorhexidine solutions of concentration 
greater than 0.05% w/v, when in the presence of inorganic 
acids, certain organic acids, and salts (e.g. benzoates, bicarbonates, 
borates, carbonates, chlorides, citrates, iodides, nitrates, 
phosphates, and sulfates).(14) At chlorhexidine concentrations 
below 0.01% w/v precipitation is less likely to occur. 
In hard water, insoluble salts may form owing to interaction 
with calcium and magnesium cations. Solubility may be 
enhanced by the inclusion of surfactants such as cetrimide. 
Other substances incompatible with chlorhexidine salts 
include viscous materials such as acacia, sodium alginate, 
sodium carboxymethylcellulose, starch, and tragacanth.(15,16) 
Also incompatible are brilliant green, chloramphenicol, copper 
sulfate, fluorescein sodium, formaldehyde, silver nitrate, and 
zinc sulfate. 
Interaction has been reported between chlorhexidine gluconate 
and the hydrogel poly(2-hydroxyethyl methacrylate), 
which is a component of some hydrophilic contact lenses.(17,18) 
13 Method of Manufacture 
Chlorhexidine may be prepared either by condensation of 
polymethylene bisdicyandiamide with 4-chloroaniline hydrochloride 
or by condensation of 4-chlorophenyl dicyandiamine 
with hexamethylenediamine dihydrochloride. Chlorhexidine 
may also be synthesized from a series of biguanides.(19) 
14 Safety 
Chlorhexidine and its salts are widely used, primarily as topical 
disinfectants. As excipients, chlorhexidine salts are mainly used 
as antimicrobial preservatives in ophthalmic formulations. 
Animal studies suggest that the acute oral toxicity of 
chlorhexidine is low, with little or no absorption from the 
gastrointestinal tract. However, although humans have consumed 
up to 2 g of chlorhexidine daily for 1 week, without 
untoward symptoms, chlorhexidine is not generally used as an 
excipient in orally ingested formulations. 
Reports have suggested that there may be some systemic 
effects in humans following oral consumption of chlorhexidine.(
20–22) Similarly, the topical application of chlorhexidine 
or its salts produced evidence of very slight percutaneous 
absorption of chlorhexidine, although the concentrations 
absorbed were insufficient to produce systemic adverse 
effects.(23) 
Chlorhexidine 165

Severe hypersensitivity reactions, including anaphylactic 
shock, have been reported following the topical administration 
of chlorhexidine,(24–28) although such instances are rare given 
the extensive use of chlorhexidine and it salts. 
In ophthalmic preparations, irritation of the conjunctiva 
occurs with chlorhexidine solutions of concentration stronger 
than 0.1% w/v. Accidental eye contact with 4% w/v 
chlorhexidine gluconate solution may result in corneal 
damage.(29) 
The aqueous concentration of chlorhexidine normally 
recommended for contact with mucous surfaces is 0.05% 
w/v. At this concentration, there is no irritant effect on soft 
tissues, nor is healing delayed. The gluconate salt (1% w/v) is 
frequently used in creams, lotions, and disinfectant solutions. 
Direct instillation of chlorhexidine into the middle ear can 
result in ototoxicity;(30) when used in dental preparations, 
staining of teeth and oral lesions may occur.(31,32) 
Use of chlorhexidine on the brain or meninges is extremely 
dangerous. 
LD50 (mouse, IP): 0.04 g/kg(33) 
LD50 (mouse, oral): 2.52 g/kg 
LD50 (rat, IP): 0.06 g/kg 
LD50 (rat, IV): 0.02 g/kg 
LD50 (rat, oral): 9.2 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. The dust of chlorhexidine 
and its salts may be irritant to the skin, eyes, and respiratory 
tract. Gloves, eye protection, and a respirator are recommended. 
16 Regulatory Status 
Chlorhexidine salts are included in nonparenteral and parenteral 
medicines licensed in the UK. Included in the Canadian 
List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Chlorhexidine acetate; chlorhexidine gluconate; chlorhexidine 
hydrochloride. 
Chlorhexidine acetate 
Empirical formula: C22H30Cl2N102C2H4O2 
Molecular weight: 625.64 
CAS number: [56-95-1] 
Synonyms: chlorhexidini acetas; chlorhexidine diacetate; 1,10- 
hexamethylenebis[5-(4-chlorophenyl)biguanide] diacetate; 
Hibitane diacetate. 
Appearance: a white or almost white, microcrystalline powder. 
Melting point: 1548C 
Moisture content: chlorhexidine acetate is hygroscopic, absorbing 
significant amounts of moisture at relative humidities up 
to about 80% and temperatures up to 378C. 
Partition coefficients: 
Mineral oil : water = 0.075; 
Peanut oil : water = 0.04. 
Solubility: soluble 1 in 15 of ethanol (95%), 1 in 55 of water; 
slightly soluble in glycerin and propylene glycol. 
Safety:
LD50 (mouse, IP): 0.04 g/kg(33) 
LD50 (mouse, IV): 0.03 g/kg 
LD50 (mouse, oral): 2 g/kg 
LD50 (mouse, SC): 0.33 g/kg 
Comments: aqueous solutions may be sterilized by autoclaving; 
the solutions should not be alkaline or contain other 
ingredients that affect the stability of chlorhexidine. See 
Sections 11 and 12. 
The EINECS number for chlorhexidine acetate is 200- 
302-4. 
Chlorhexidine gluconate 
Empirical formula: C22H30Cl2N102C6H12O7 
Molecular weight: 897.88 
CAS number: [18472-51-0] 
Synonyms: chlorhexidine digluconate; chlorhexidini digluconatis; 
1,10-hexamethylenebis[5-(4-chlorophenyl)biguanide] 
digluconate; Hibiclens; Hibiscrub; Hibitane; Unisept. 
Appearance: chlorhexidine gluconate is usually used as an 
almost colorless or pale yellow-colored aqueous solution. 
Acidity/alkalinity: pH = 5.5–7.0 for a 5% w/v aqueous 
dilution. 
Solubility: miscible with water; soluble in acetone and ethanol 
(95%). 
Safety:
LD50 (mouse, IV): 0.02 g/kg(33) 
LD50 (mouse, oral): 1.8 g/kg 
LD50 (mouse, SC): 1.14 g/kg 
LD50 (rat, IV): 0.02 g/kg 
LD50 (rat, oral): 2 g/kg 
LD50 (rat, SC): 3.32 g/kg 
Comments: the commercially available 5% w/v chlorhexidine 
gluconate solution contains a nonionic surfactant to prevent 
precipitation and is not suitable for use in body cavities or 
for the disinfection of surgical instruments containing 
cemented glass components. Aqueous dilutions of commercially 
available chlorhexidine gluconate solutions may be 
sterilized by autoclaving. See Sections 11 and 12. 
The EINECS number for chlorhexidine gluconate is 242- 
354-0. 
Chlorhexidine hydrochloride 
Empirical formula: C22H30Cl2N102HCl 
Molecular weight: 578.44 
CAS number: [3697-42-5] 
Synonyms: chlorhexidine dihydrochloride; chlorhexidini 
hydrochloridum; 1,10-hexamethylenebis[5-(4-chlorophenyl)
biguanide]dihydrochloride. 
Appearance: a white or almost white, crystalline powder. 
Melting point: 2618C, with decomposition. 
Solubility: sparingly soluble in water; very slightly soluble in 
ethanol (95%); soluble 1 in 50 of propylene glycol. 
Safety: LD50 (mouse, SC): >5 g/kg(33) 
Comments: chlorhexidine hydrochloride may be sterilized by 
dry heat. See Sections 11 and 12. 
The EINECS number for chlorhexidine hydrochloride is 
223-026-6. 
18 Comments 
The EINECS number for chlorhexidine is 200-238-7. 
19 Specific References 
1 Juliano C, Gavini E, Cossu M, et al. Mucoadhesive alginate 
matrices containing sodium carboxymethyl starch for buccal drug 
delivery in in vitro and in vivo studies. STP Pharma Sci 2004; 
14(2): 159–163. 
166 Chlorhexidine

2 Lupuleasa D, Hirajau V, Mititelu M, et al. Bucoadhesive dosage 
form with chlorhexidine dichlorhydrate. Farmacia 2003; 51(5): 
49–55. 
3 Leyes Borrajo JL, Garcia VL, Lopez CG, et al. Efficacy of 
chlorhexidine mouthrinses with and without alcohol: a clinical 
study. J Peridontol 2002; 73(3): 317–321. 
4 Alaki SM, Loesche WJ, da Fonesca MA, et al. Preventing the 
transfer of Streptococcus mutans from primary molars to 
permanent first molars using chlorhexidine. Pediatr Dent 2002; 
24(2): 103–108. 
5 Prince HN, Nonemaker WS, Norgard RC, Prince DL. Drug 
resistance studies with topical antiseptics. J Pharm Sci 1978; 67: 
1629–1631. 
6 Richards RME, McBride RJ. Enhancement of benzalkonium 
chloride and chlorhexidine activity against Pseudomonas aeruginosa 
by aromatic alcohols. J Pharm Sci 1973; 62: 2035–2037. 
7 Russell AD, Furr JR. Comparitive sensitivity of smooth, rough and 
deep rough strains of Escherichia coli to chlorhexidine, quaternary 
ammonium compounds and dibromopropamidine isethionate. Int 
J Pharm 1987; 36: 191–197. 
8 Shaker LA, Russell AD, Furr JR. Aspects of the action of 
chlorhexidine on bacterial spores. Int J Pharm 1986; 34: 51–56. 
9 Heard DD, Ashworth RW. The colloidal properties of chlorhexidine 
and its interaction with some macromolecules. J Pharm 
Pharmacol 1968; 20: 505–512. 
10 Jaminet F, Delattre L, Delporte JP, Moes A. Influence of 
sterilization temperature and pH on the stability of chlorhexidine 
solutions [in French]. Pharm Acta Helv 1970; 45: 60–63. 
11 Goodall RR, Goldman J, Woods J. Stability of chlorhexidine in 
solutions. Pharm J 1968; 200: 33–34. 
12 Dolby J, Gunnarsson B, Kronberg L, Wikner H. Stability of 
chlorhexidine when autoclaving. Pharm Acta Helv 1972; 47: 615– 
620. 
13 Myers JA. Hospital infections caused by contaminated fluids 
[letter]. Lancet 1972; ii: 282. 
14 Oelschla. ger H, Canenbley R. Clear indication of chlorhexidine 
dihydrochloride precipitate in isotonic eye-drops: report based on 
experience on the use of chlorhexidine as a preservative. Pharm 
Ztg 1983; 128: 1166–1168. 
15 Yousef RT, El-Nakeeb MA, Salama S. Effect of some pharmaceutical 
materials on the bactericidal activities of preservatives. Can J 
Pharm Sci 1973; 8: 54–56. 
16 McCarthy TJ, Myburgh JA. The effect of tragacanth gel on 
preservative activity. Pharm Weekbl 1974; 109: 265–268. 
17 Plaut BS, Davies DJG, Meakin BJ, Richardson NE. The mechanism 
of interaction between chlorhexidine digluconate and poly(2- 
hydroxyethyl methacrylate). J Pharm Pharmacol 1981; 33: 82–88. 
18 Stevens LE, Durrwachter JR, Helton DO. Analysis of chlorhexidine 
sorption in soft contact lenses by catalytic oxidation of 
[14C]chlorhexidine and by liquid chromatography. J Pharm Sci 
1986; 75: 83–86. 
19 Rose FL, Swain G. Bisguanides having antibacterial activity. J 
Chem Soc 1956; 4422–4425. 
20 Massano G, Ciocatto E, Rosabianca C, et al. Striking aminotransferase 
rise after chlorhexidine self-poisoning [letter]. Lancet 
1982; i: 289. 
21 Emerson D, Pierce C. A case of a single ingestion of 4% Hibiclens. 
Vet Hum Toxicol 1988; 30: 583. 
22 Quinn MW, Bini RM. Bradycardia associated with chlorhexidine 
spray [letter]. Arch Dis Child 1989; 64: 892–893. 
23 Alder VG, Burman D, Simpson RA, et al. Comparison of 
hexachlorophane and chlorhexidine powders in prevention of 
neonatal infection. Arch Dis Child 1980; 55: 277–280. 
24 Lockhart AS, Harle CC. Anaphylactic reactions due to chlorhexidine 
allergy [letter]. Br J Anaesth 2001; 87(6): 940–941. 
25 Wahlberg JE,Wennersten G. Hypersensitivity and photosensitivity 
to chlorhexidine. Dermatologica 1971; 143: 376–379. 
26 Okano M, Nomura M, Hata S, et al. Anaphylactic symptoms due 
to chlorhexidine gluconate. Arch Dermatol 1989; 125: 50–52. 
27 Evans RJ. Acute anaphylaxis due to topical chlorhexidine acetate. 
Br Med J 1992; 304: 686. 
28 Chisholm DG, Calder I, Peterson D, Powell M. Intranasal 
chlorhexidine resulting in an anaphylactic circulatory arrest. Br 
Med J 1997; 315: 785. 
29 Tabor E, Bostwick DC, Evans CC. Corneal damage due to eye 
contact with chlorhexidine gluconate [letter]. J Am Med Assoc 
1989; 261: 557–558. 
30 Honigman JL. Disinfectant ototoxicity [letter]. Pharm J 1975; 215: 
523. 
31 Addy M, Moran J, Griffiths AA, Wills-Wood NJ. Extrinsic tooth 
discoloration by metals and chlorhexidine I: surface protein 
denaturation or dietary precipitation? Br Dent J 1985; 159: 
281–285. 
32 Addy M, Moran J. Extrinsic tooth discoloration by metals and 
chlorhexidine II: clinical staining produced by chlorhexidine, iron 
and tea. Br Dent J 1985; 159: 331–334. 
33 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 471. 
20 General References 
Davies GE, Francis J, Martin AR, et al. 1,6-Di-40-chlorophenyldiguanidohexane 
(Hibitane): laboratory investigation of a new antibacterial 
agent of high potency. Br J Pharmacol Chemother 1954; 9: 
192–196. 
McCarthy TJ. The influence of insoluble powders on preservatives in 
solution. J Mond Pharm 1969; 12: 321–328. 
Senior N. Some observations on the formulation and properties of 
chlorhexidine. J Soc Cosmet Chem 1973; 24: 259–278. 
21 Authors 
SC Owen. 
22 Date of Revision 
25 August 2005. 
Chlorhexidine 167

Chlorobutanol 
1 Nonproprietary Names 
BP: Chlorobutanol 
JP: Chlorobutanol 
PhEur: Chlorobutanolum anhydricum 
USPNF: Chlorobutanol 
2 Synonyms 
Acetone chloroform; chlorbutanol; chlorbutol; trichloro-tertbutanol; 
b,b,b-trichloro-tert-butyl alcohol. 
3 Chemical Name and CAS Registry Number 
1,1,1-Trichloro-2-methyl-2-propanol [57-15-8] 
4 Empirical Formula and Molecular Weight 
C4H7Cl3O 177.46 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; plasticizer. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Chlorobutanol is primarily used in ophthalmic or parenteral 
dosage forms as an antimicrobial preservative at concentrations 
up to 0.5% w/v; see Section 10. It is commonly used as an 
antibacterial agent for epinephrine solutions, posterior pituitary 
extract solutions, and ophthalmic preparations intended 
for the treatment of miosis. It is especially useful as an 
antibacterial agent in nonaqueous formulations. Chlorobutanol 
is also used as a preservative in cosmetics (see Section 16); 
as a plasticizer for cellulose esters and ethers; and has been used 
therapeutically as a mild sedative and local analgesic. 
8 Description 
Volatile, colorless or white crystals with a musty, camphoraceous 
odor. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for chlorobutanol. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters . . — 
Melting point 5768C . — 
Anhydrous — 958C — 
Hemihydrate — 788C — 
Acidity . . . 
Water (anhydrous form) 46.0% 41.0% 41.0% 
Hemihydrate — 4.5–5.5% 46.0% 
Chloride 40.071% . 40.07% 
Anhydrous — 4300 ppm — 
Hemihydrate — 4100 ppm — 
Residue on ignition 40.10% — — 
Sulfated ash — 40.1% — 
Organic volatile 
impurities 
— — . 
Assay (anhydrous 
basis) 
598.0% 98.0–101.0% 98.0–100.5% 
Note: the JP 2001 and USPNF 23 allow either the anhydrous form or the hemihydrate; the PhEur 
2005 includes them as separate monographs. 
10 Typical Properties 
Antimicrobial activity: chlorobutanol has both antibacterial 
and antifungal properties. It is effective against Grampositive 
and Gram-negative bacteria and some fungi, e.g., 
Candida albicans, Pseudomonas aeruginosa, and Staphylococcus 
albus. Antimicrobial activity is bacteriostatic, rather 
than bactericidal, and is considerably reduced above pH 5.5. 
In addition, activity may also be reduced by increasing heat 
and by incompatibilities between chlorobutanol and other 
excipients or packaging materials; see Sections 11 and 12. 
However, activity may be increased by combination with 
other antimicrobial preservatives; see Section 18. Typical 
minimum inhibitory concentrations (MICs) are: Grampositive 
bacteria 650 mg/mL; Gram-negative bacteria 
1000 mg/mL; yeasts 2500 mg/mL; fungi 5000 mg/mL. 
Boiling point: 1678C 
Melting point: 
76–788C for the hemihydrate; 
95–978C for the anhydrous form. 
Refractive index: nD
25 = 1.4339 
Solubility: see Table II. 
Table II: Solubility of chlorobutanol. 
Solvent Solubility at 208C 
Chloroform Freely soluble 
Ethanol (95%) 1 in 1 
Ether Freely soluble 
Glycerin 1 in 10 
Methanol Freely soluble 
Volatile oils Freely soluble 
Water 1 in 125

11 Stability and Storage Conditions 
Chlorobutanol is volatile and readily sublimes. In aqueous 
solution degradation is catalyzed by hydroxide ions. Stability is 
good at pH 3 but becomes progressively worse with increasing 
pH.(1) The half-life at pH 7.5 for a chlorobutanol solution 
stored at 258C was determined to be approximately 3 
months.(2) In a 0.5% w/v aqueous chlorobutanol solution at 
room temperature, chlorobutanol is almost saturated and may 
crystallize out of solution if the temperature is reduced. 
Losses of chlorobutanol also occur owing to its volatility, 
with appreciable amounts being lost during autoclaving; at pH 
5 about 30% of chlorobutanol is lost.(3) Porous containers 
result in losses from solutions, and polyethylene containers 
result in rapid loss. Losses of chlorobutanol during autoclaving 
in polyethylene containers may be reduced by pre-autoclaving 
the containers in a solution of chlorobutanol; the containers 
should then be used immediately.(4) There is also appreciable 
loss of chlorobutanol through stoppers in parenteral vials. 
The bulk material should be stored in a well-closed 
container at a temperature of 8–158C. 
12 Incompatibilities 
Owing to problems associated with sorption, chlorobutanol is 
incompatible with plastic vials,(4–8) rubber stoppers, bentonite,(
9) magnesium trisilicate,(9) polyethylene, and polyhydroxyethylmethacrylate, 
which has been used in soft contact 
lenses.(10) To a lesser extent, carboxymethylcellulose and 
polysorbate 80 reduce antimicrobial activity by sorption or 
complex formation. 
13 Method of Manufacture 
Chlorobutanol is prepared by condensing acetone and chloroform 
in the presence of solid potassium hydroxide. 
14 Safety 
Chlorobutanol is widely used as a preservative in a number of 
pharmaceutical formulations, particularly ophthalmic preparations. 
Although animal studies have suggested that chlorobutanol 
may be harmful to the eye, in practice the widespread use 
of chlorobutanol as a preservative in ophthalmic preparations 
has been associated with few reports of adverse reactions. A 
study of the irritation potential of a local anesthetic on the 
murine cornea indicated significant corneal surface damage in 
the presence of 0.5% w/v chlorobutanol, which may be related 
to the preservative’s effective concentration.(11) Reported 
adverse reactions to chlorobutanol include: cardiovascular 
effects following intravenous administration of heparin sodium 
injection preserved with chlorobutanol;(12) neurological effects 
following administration of a large dose of morphine infusion 
preserved with chlorobutanol;(13) and hypersensitivity reactions, 
although these are regarded as rare.(14–16) 
The lethal human dose of chlorobutanol is estimated to be 
50–500 mg/kg.(17) 
LD50 (dog, oral): 0.24 g/kg(18,19) 
LD50 (mouse, oral): 0.99 g/kg 
LD50 (rabbit, oral): 0.21 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Chlorobutanol may be 
irritant to the skin, eyes, and mucous membranes. Eye 
protection and gloves are recommended along with a respirator 
in poorly ventilated environments. There is a slight fire hazard 
on exposure to heat or flame. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IM, IV, and SC 
injections, inhalations, nasal, otic, ophthalmic, and topical 
preparations). Labeling must state ‘contains chlorobutanol up 
to 0.5%’. Included in nonparenteral and parenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
In the UK, the maximum concentration of chlorobutanol 
permitted for use in cosmetics, other than foams, is 0.5%. It is 
not suitable for use in aerosols. 
17 Related Substances 
Phenoxyethanol; phenylethyl alcohol. 
18 Comments 
It has been reported that a combination of chlorobutanol and 
phenylethanol, both at 0.5% w/v concentration, has shown 
greater antibacterial activity than either compound alone. An 
advantage of the use of this combination is that chlorobutanol 
dissolves in the alcohol; the resulting liquid can then be 
dissolved in an aqueous pharmaceutical preparation without 
the application of heat. 
The EINECS number for chlorobutanol is 200-317-6. 
19 Specific References 
1 Patwa NV, Huyck CL. Stability of chlorobutanol. J Am Pharm 
Assoc 1966; NS6: 372–373. 
2 Nair AD, Lach JL. The kinetics of degradation of chlorobutanol. J 
Am Pharm Assoc (Sci) 1959; 48: 390–395. 
3 Lang JC, Roehrs RE, Rodeheaver DP, et al. Design and evaluation 
of ophthalmic pharmaceutical products. In: Banker GS, Rhodes 
CT, eds. Modern Pharmaceutics, 4th edn. New York: Marcel 
Dekker, 2002: 415–478. 
4 Blackburn HD, Polack AE, Roberts MS. The effect of container 
pre-treatment on the interaction between chlorbutol and polyethylene 
during autoclaving. Aust J Hosp Pharm 1983; 13: 153– 
156. 
5 Lachman L,Weinstein S, Hopkins G, et al. Stability of antibacterial 
preservatives in parenteral solutions I: factors influencing the loss 
of antimicrobial agents from solutions in rubber-stoppered 
containers. J Pharm Sci 1962; 51: 224–232. 
6 Friesen WT, Plein EM. The antibacterial stability of chlorobutanol 
stored in polyethylene bottles. Am J Hosp Pharm 1971; 28: 507– 
512. 
7 Blackburn HD, Polack AE, Roberts MS. Preservation of ophthalmic 
solutions: some observations on the use of chlorbutol in plastic 
containers [letter]. J Pharm Pharmacol 1978; 30: 666. 
8 Holdsworth DG, Roberts MS, Polack AE. Fate of chlorbutol 
during storage in polyethylene dropper containers and simulated 
patient use. J Clin Hosp Pharm 1984; 9: 29–39. 
9 Yousef RT, El-Nakeeb MA, Salama S. Effect of some pharmaceutical 
materials on the bactericidal activities of preservatives. Can J 
Pharm Sci 1973; 8: 54–56. 
10 Richardson NE, Davies DJG, Meakin BJ, Norton DA. The 
interaction of preservatives with polyhydroxyethylmethacrylate 
(polyHEMA). J Pharm Pharmacol 1978; 30: 469–475. 
11 Kalin P, Mayer JM, Etter JC. Influence of preservatives on the 
irritation potential of a local anaesthetic on murine cornea. Eur J 
Pharm Biopharm 1996; 42: 402. 
Chlorobutanol 169

12 Bowler GMR, Galloway DW, Meiklejohn BH, Macintyre CCA. 
Sharp fall in blood pressure after injection of heparin containing 
chlorbutol [letter]. Lancet 1986; i: 848–849. 
13 DeChristoforo R, Corden BJ, Hood JC, et al. High-dose morphine 
infusion complicated by chlorobutanol-induced somnolence. Ann 
Intern Med 1983; 98: 335–336. 
14 Dux S, Pitlik S, Perry G, Rosenfeld JB. Hypersensitivity reaction to 
chlorobutanol-preserved heparin [letter]. Lancet 1981; i: 149. 
15 Itabashi A, Katayama S, Yamaji T. Hypersensitivity to chlorobutanol 
in DDAVP solution [letter]. Lancet 1982; i: 108. 
16 Hofmann H, Goerz G, Plewig G. Anaphylactic shock from 
chlorobutanol-preserved oxytocin. Contact Dermatitis 1986; 15: 
241. 
17 Gosselin RE, Hodge HC, Smith RP, Gleason MN. Clinical 
Toxicology of Commercial Products, 4th edn. Baltimore: Williams 
& Wilkins, 1976: II-119. 
18 Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. 
Cincinnati: US Department of Health, 1987: 3838. 
19 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 784. 
20 General References 
Summers QA, Nesbit MR, Levin R, Holgate ST. A non-bronchoconstrictor, 
bacteriostatic preservative for nebuliser solutions. Br J Clin 
Pharmacol 1991; 31: 204–206. 
21 Authors 
RA Nash. 
22 Date of Revision 
22 August 2005. 
170 Chlorobutanol

Chlorocresol 
1 Nonproprietary Names 
BP: Chlorocresol 
PhEur: Chlorocresolum 
USPNF: Chlorocresol 
2 Synonyms 
Aptal; Baktol; 4-chloro-m-cresol; p-chloro-m-cresol; 1-chloro- 
4-hydroxy-2-methylbenzene; 2-chloro-5-hydroxytoluene; 6- 
chloro-3-hydroxytoluene; 4-chloro-3-methylphenol; 3-methyl- 
4-chlorophenol; Nipacide PC; parachlorometacresol; PCMC. 
3 Chemical Name and CAS Registry Number 
4-Chloro-3-methylphenol [59-50-7] 
4 Empirical Formula and Molecular Weight 
C7H7ClO 142.58 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; disinfectant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Chlorocresol is used as an antimicrobial preservative in 
cosmetics and pharmaceutical formulations. It is generally 
used in concentrations up to 0.2% in a variety of preparations 
except those intended for oral administration or that contact 
mucous membrane. Chlorocresol is effective against bacteria, 
spores, molds, and yeasts; it is most active in acidic media. 
Preservative efficacy may be reduced in the presence of some 
other excipients, particularly nonionic surfactants, see Sections 
10 and 12. 
In higher concentrations, chlorocresol is an effective 
disinfectant. See Table I. 
Table I: Uses of chlorocresol. 
Use Concentration (%) 
Eye drops 0.05 
Injections 0.1 
Shampoos and other cosmetics 0.1–0.2 
Topical creams and emulsions 0.075–0.12 
8 Description 
Colorless or almost colorless, dimorphous crystals or crystalline 
powder with a characteristic phenolic odor. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for chlorocresol. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Appearance of solution . . 
Melting range 64–678C 63–668C 
Nonvolatile matter 40.1% 40.1% 
Acidity or alkalinity . — 
Related substances . — 
Assay 98.0–101.0% 99.0–101.0% 
10 Typical Properties 
Antimicrobial activity: chlorocresol has bactericidal activity 
against both Gram-positive and Gram-negative organisms 
(including Pseudomonas aeruginosa), spores, molds, and 
yeasts. It is most active in acidic solutions, with antimicrobial 
effectiveness decreasing with increasing pH; it is inactive 
above pH 9. Antimicrobial activity may also be reduced by 
loss of chlorocresol from a formulation due to incompatibilities 
with packaging materials or other excipients, such as 
nonionic surfactants, see Section 12. Synergistic antimicrobial 
effects between chlorocresol and other antimicrobial preservatives, 
such as 2-phenylethanol, have been reported.(1,2) 
Reported minimum inhibitory concentrations (MICs) for 
chlorocresol are shown in Table III.(3) Like most antimicrobials, 
chlorocresol has a non-linear dose response.(4,5) 
Bacteria: concentrations of approximately 0.08%, with a 
contact time of 10 minutes, are bactericidal. A typical MIC 
is 0.02%. 
Fungi: chlorocresol is active against molds and yeasts. 
Fungicidal concentrations (after 24 hours of contact) are in 
the range 0.01–0.04%.

Table III: Minimum inhibitory concentrations (MICs) for 
chlorocresol.(3) 
Microorganism MIC (mg/mL) 
Aspergillus niger 2500 
Candida albicans 2500 
Escherichia coli 1250 
Klebsiella pneumoniae 625 
Pseudomonas aeruginosa 1250 
Pseudomonas fluorescens 1250 
Staphylococcus aureus 625 
Spores: at temperatures of 808C or above and in concentrations 
greater than 0.012%, chlorocresol is active against 
spores. It is much less active at room temperature. Heating 
at 98–1008C for 30 minutes in the presence of 0.2% 
chlorocresol has previously been used as a compendial 
method for the sterilization of solutions of substances that 
would not withstand autoclaving. 
Boiling point: 2358C 
Dissociation constant: pKa = 9.2 
Flash point: 1188C 
Melting point: dimorphous crystals with a melting point of 
55.58C and 658C. 
Partition coefficients: at 258C 
Liquid paraffin : water = 1.53; 
Octanol : water = 3; 
Peanut oil : water = 117. 
Solubility: see Table IV. 
Table IV: Solubility of chlorocresol. 
Solvent Solubility at 208C unless otherwise stated 
Acetone Soluble 
Alkali hydroxide solutions Soluble 
Chloroform Soluble 
Ethanol 1 in 0.4 
Ether Soluble 
Fixed oils Soluble 
Glycerin Soluble 
Terpenes Soluble 
Water 1 in 260(a) 
1 in 50 at 1008C(a) 
(a) Aqueous solubility is decreased in the presence of electrolytes, particularly sodium chloride, 
potassium chloride, and potassium sulfonate.(6) 
Vapor pressure: 0.008 kPa at 208C; 
0.67 kPa at 1008C. 
11 Stability and Storage Conditions 
Chlorocresol is stable at room temperature but is volatile in 
steam. Aqueous solutions may be sterilized by autoclaving. On 
exposure to air and light, aqueous solutions may become 
yellow colored. Solutions in oil or glycerin may be sterilized by 
heating at 1608C for 1 hour. The bulk material should be stored 
in a well-closed container, protected from light, in a cool, dry 
place. 
12 Incompatibilities 
Chlorocresol can decompose on contact with strong alkalis, 
evolving heat and fumes that ignite explosively. It is also 
incompatible with oxidizing agents, copper, and with solutions 
of calcium chloride, codeine phosphate, diamorphine hydrochloride, 
papaveretum, and quinine hydrochloride.(7) Discoloration 
also occurs with iron salts. Chlorocresol additionally 
exhibits strong sorption or binding tendencies to organic 
materials such as rubber, certain plastics, and nonionic 
surfactants.(8–11) 
Chlorocresol may be lost from solutions to rubber closures, 
and in contact with polyethylene may initially be rapidly 
removed by sorption and then by permeation, the uptake being 
temperature dependent. Presoaking of components may reduce 
losses due to sorption, but not those by permeation.(12,13) 
Chlorocresol may also be taken up by polymethylmethacrylate 
and by cellulose acetate. Losses to polypropylene or rigid 
polyvinyl chloride are usually small.(14) 
At a concentration of 0.1%, chlorocresol may be completely 
inactivated in the presence of nonionic surfactants, such as 
polysorbate 80.(9) However, other studies have suggested an 
enhancement of antimicrobial properties in the presence of 
surfactants.(15)(16) Bactericidal activity is also reduced, due to 
binding, by cetomacrogol, methylcellulose, pectin, or cellulose 
derivatives.(9,11) In emulsified or solubilized systems, chlorocresol 
readily partitions into the oil phase, particularly into 
vegetable oils and higher concentrations will be required for 
efficient preservation.(10,17) 
13 Method of Manufacture 
Chlorocresol is prepared by the chlorination of m-cresol. 
14 Safety 
Chlorocresol is used primarily as a preservative in topical 
pharmaceutical formulations but has also been used in 
nebulized solutions(18) and ophthalmic and parenteral preparations. 
It should not, however, be used in formulations for 
intrathecal, intracisternal, or peridural injection. 
Chlorocresol is metabolized by conjugation with glucuronic 
acid and sulfate and is excreted in the urine, mainly as the 
conjugate, with little chlorocresol being excreted unchanged. 
Although less toxic than phenol, chlorocresol may be 
irritant to the skin, eyes, and mucous membranes and has 
been reported to cause some adverse reactions when used as an 
excipient.(19,20) 
Sensitization reactions may follow the prolonged application 
of strong solutions to the skin, although patch tests have 
shown that chlorocresol is not a primary irritant at concentrations 
up to 0.2%. Cross sensitization with the related 
preservative chloroxylenol has also been reported.(21)(22) At 
concentrations of 0.005% w/v, chlorocresol has been shown to 
produce a reversible reduction in the ciliary movement of 
human nasal epithelial cells in vitro; and at concentrations of 
0.1% chlorocresol produces irreversible ciliostasis; therefore it 
should be used with caution in nasal preparations.(23) However, 
a clinical study in asthma patients challenged with chlorocresol 
or saline concluded that preservative might be used safely in 
nebulizer solution.(18) 
Chlorocresol at a concentration as low as 0.05% produces 
ocular irritation in rabbits.(20) Despite such reports, chlorocresol 
has been tested in ophthalmic preparations.(24,25) 
When used systemically, notably in a heparin injection 
preserved with chlorocresol 0.15%, delayed irritant and 
hypersensitivity reactions attributed to chlorocresol have been 
reported.(26,27) See also Section 19. 
LD50 (mouse, IV): 0.07 g/kg(28) 
LD50 (mouse, oral): 0.6 g/kg 
172 Chlorocresol

LD50 (mouse, SC): 0.36 g/kg 
LD50 (rabbit, dermal): >5 g/kg 
LD50 (rat, dermal): >2 g/kg 
LD50 (rat, oral): 1.83 g/kg 
LD50 (rat, SC): 0.4 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Chlorocresol can be irritant 
to the skin, eyes, and mucous membranes. Eye protection, 
gloves, and protective clothing are recommended. Chlorocresol 
presents a slight fire hazard when exposed to heat or flame. It 
burns to produce highly toxic fumes containing phosgene and 
hydrogen chloride. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (topical creams 
and emulsions). Included in nonparenteral and parenteral 
medicines licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Cresol; chloroxylenol. 
18 Comments 
Chlorocresol has a characteristic odor which is difficult to mask 
in formulations, even at concentrations of 0.05–0.1%. 
Although used in Europe, chlorocresol is not used in the 
USA in parenteral formulations. Chlorocresol has also been 
used as an experimental in vitro diagnostic agent for the 
diagnosis of hyperthermia.(29) 
The EINECS number for chlorocresol is 200-431-6. 
19 Specific References 
1 Denyer SP, Hugo WB, Harding VD. The biochemical basis of 
synergy between the antibacterial agents, chlorocresol and 2- 
phenylethanol. Int J Pharm 1986; 29: 29–36. 
2 Abdelaziz AA, El-Nakeeb MA. Sporicidal activity of local 
anaesthetics and their binary combinations with preservatives. J 
Clin Pharm Ther 1988; 13: 249–256. 
3 Wallha. usser KH. p-Chloro-m-cresol. In: Kabara JJ, ed. Cosmetic 
and Drug Preservation Principles and Practice. New York: Marcel 
Dekker, 1984: 683–684. 
4 Lambert RJW, Johnston MD, Hanlon GW, Denyer SP. Membrane 
damage to bacteria caused by single and combined biocides. J Appl 
Microbiol 2003; 94: 1015–1023. 
5 Lambert RJW, Johnston MD, Hanlon GW, Denyer SP. Theory of 
antimicrobial combinations: biocide mixtures—synergy or additions? 
J Appl Microbiol 2003; 94: 747–759. 
6 Gadalla MAF, Saleh AM, Motawi MM. Effect of electrolytes on 
the solubility and solubilization of chlorocresol. Pharmazie 1974; 
29: 105–107. 
7 McEwan JS, Macmorran GH. The compatibility of some 
bactericides. Pharm J 1947; 158: 260–262. 
8 Yousef RT, El-Nakeeb MA, Salama S. Effect of some pharmaceutical 
materials on the bactericidal activities of preservatives. Can J 
Pharm Sci 1973; 8: 54–56. 
9 McCarthy TJ. Dissolution of chlorocresol from various pharmaceutical 
formulations. Pharm Weekbl 1975; 110: 101–106. 
10 Kazmi SJA, Mitchell AG. Preservation of solubilized and 
emulsified systems I: correlation of mathematically predicted 
preservative availability with antimicrobial activity. J Pharm Sci 
1978; 67: 1260–1266. 
11 Kazmi SJA, Mitchell AG. Preservation of solubilized and 
emulsified systems II: theoretical development of capacity and its 
role in antimicrobial activity of chlorocresol in cetomacrogolstabilized 
systems. J Pharm Sci 1978; 67: 1266–1271. 
12 McCarthy TJ. Interaction between aqueous preservative solutions 
and their plastic containers III. Pharm Weekbl 1972; 107: 1–7. 
13 Roberts MS, Polack AE, Martin G, Blackburn HD. The storage of 
selected substances in aqueous solution in polyethylene containers: 
the effect of some physicochemical factors on the disappearance 
kinetics of the substances. Int J Pharm 1979; 2: 295–306. 
14 McCarthy TJ. Interaction between aqueous preservative solutions 
and their plastic containers. Pharm Weekbl 1970; 105: 557–563. 
15 Kurup TRR, Wan LSC, Chan LW. Preservative requirements in 
emulsions. Pharma Acta Helv 1992; 67: 204–208. 
16 Kurup TRR, Wan LSC, Chan LW. Effect of surfactants on the 
antimicrobial activity of preservatives. Pharma Acta Helv 1991; 
66: 274–280. 
17 Sznitowska M, Janicki S, Dabrowska EA, Gajewksa M. Physicochemical 
screening of antimicrobial agents as potential preservatives 
for submicron emulsions. Eur J Pharm Sci 2002; 15: 489– 
495. 
18 Summers QA, Nesbit MR, Levin R, Holgate ST. A nonbronchoconstrictor, 
bacteriostatic preservative for nebuliser solutions. 
Br J Clin Pharmacol 1991; 31: 204–206. 
19 Smolinske SC. Handbook of Food, Drug and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 87–90. 
20 Zondlo M. Final report on the safety assessment of p-chloro-mcresol. 
J Toxicol 1997; 16: 235–268. 
21 Burry JN, Kirk J, Reid JG, Turner T. Chlorocresol sensitivity. 
Contact Dermatitis 1975; 1: 41–42. 
22 Andersen KE, Hamann K. How sensitizing is chlorocresol? Allergy 
tests in guinea pigs vs. the clinical experience. Contact Dermatitis 
1984; 11: 11–20. 
23 Agu RU, Jorissen M, Willems T, et al. Effects of pharmaceutical 
compounds on ciliary beating in human nasal epithelial cells: a 
comparative study of cell culture models. Pharm Res 1999; 16: 
1380–1385. 
24 Palanichamy S, Ramakrishnan PN, Balasubramanian S, et al. 
Preservation of sodium chloride eye lotion BPC against contamination 
with Pseudomonas aeruginosa. Indian Drugs 1982; 19: 
153–155. 
25 Palanichamy S, Ramakrishnan PN, Murugesh N, et al. Preservation 
of compound zinc sulfate eye lotion BPC 1963 against 
contamination with Pseudomonas aeruginosa. Indian J Hosp 
Pharm 1982; 19: 64–65. 
26 Hancock BW, Naysmith A. Hypersensitivity to chlorocresolpreserved 
heparin. Br Med J 1975; 3: 746–747. 
27 Ainley EJ, Mackie IG, Macarthur D. Adverse reaction to 
chlorocresol-preserved heparin [letter]. Lancet 1977; i: 705. 
28 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 790. 
29 Wappler F, Anetseder M, Baur CP, et al. Multicenter evaluation of 
in vitro contracture testing with bolus administration of 4-chlorom-
cresol for diagnosis of malignant hyperthermia susceptibility. 
Eur J Anaesth 2003; 20: 528–536. 
20 General References 
Denyer SP, Wallha. usser KH. Antimicrobial preservatives and their 
properties. In: Denyer SP, Baird R, eds. Guide to Microbiological 
Control in Pharmaceuticals. Chichester: Ellis Horwood, 1990: 251– 
273. 
Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004: 171. 
21 Authors 
S Nema. 
22 Date of Revision 
27 August 2005. 
Chlorocresol 173

Chlorodifluoroethane (HCFC) 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
1,1-Difluoro-1-chloroethane; Dymel 142b; Genetron 142b; 
HCFC 142b; P-142b; propellant 142b; refrigerant 142b; 
Solkane 142b. 
3 Chemical Name and CAS Registry Number 
1-Chloro-1,1-difluoroethane [75-68-3] 
4 Empirical Formula and Molecular Weight 
C2H3ClF2 100.50 
5 Structural Formula 
6 Functional Category 
Aerosol propellant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Chlorodifluoroethane is a hydrochlorofluorocarbon (HCFC) 
aerosol propellant previously used in topical pharmaceutical 
formulations. However, it is no longer permitted for use in 
pharmaceutical formulations because its harmful effects on the 
environment. It was also generally used in conjunction with 
difluoroethane to form a propellant blend with a specific 
gravity of 1. Chlorodifluoroethane was also used in combination 
with chlorodifluoromethane and hydrocarbon propellants. 
Chlorodifluoroethane may be used as a vehicle for dispersions 
and emulsions. 
8 Description 
Chlorodifluoroethane is a liquefied gas and exists as a liquid at 
room temperature when contained under its own vapor 
pressure, or as a gas when exposed to room temperature and 
atmospheric pressure. The liquid is practically odorless and 
colorless. Chlorodifluoroethane is noncorrosive and nonirritating. 
9 Pharmacopeial Specifications 
— 
10 Typical Properties 
Autoignition temperature: 6328C 
Boiling point: 9.88C 
Critical temperature: 137.18C 
Density: 
1.11 g/cm3 for liquid at 258C; 
1.03 g/cm3 for liquid at 54.58C. 
Flammability: flammable. Limits of flammability 6.2–17.9% 
v/v in air. 
Melting point: 1318C 
Solubility: soluble 1 in 715 parts of water at 208C. 
Vapor density (absolute): 4.487 g/m3 at standard temperature 
and pressure. 
Vapor density (relative): 3.48 (air = 1) 
Vapor pressure: 
339 kPa (49.2 psia) at 258C (29.1 psig at 21.18C); 
772 kPa (112.0 psia) at 54.58C. 
Viscosity (dynamic): 0.33 mPa s (0.33 cP) for liquid at 218C. 
11 Stability and Storage Conditions 
Chlorodifluoroethane is a nonreactive and stable material. The 
liquefied gas is stable when used as a propellant and should be 
stored in a metal cylinder in a cool, dry place. 
12 Incompatibilities 
Compatible with the usual ingredients used in the formulation 
of pharmaceutical aerosols. Chlorodifluoroethane can react 
vigorously with oxidizing materials. 
13 Method of Manufacture 
Chlorodifluoroethane is prepared by the chlorination of 
difluoroethane in the presence of a suitable catalyst; hydrochloric 
acid is also formed. The chlorodifluoroethane is purified 
to remove all traces of water and hydrochloric acid, as well as 
traces of the starting and intermediate materials. 
14 Safety 
Chlorodifluoroethane is no longer permitted for use as an 
aerosol propellant in topical pharmaceutical formulations. It is 
generally regarded as an essentially nontoxic and nonirritant 
material. 
Deliberate inhalation of excessive quantities of chlorofluorocarbon 
propellant may result in death, and the following 
‘warning’ statements must appear on the label of all aerosols: 
WARNING: Avoid inhalation. Keep away from eyes or 
other mucous membranes. 
(Aerosols designed specifically for oral and nasal inhalation 
need not contain this statement.) 
WARNING: Do not inhale directly; deliberate inhalation of 
contents can cause death.

or 
WARNING: Use only as directed; intentional misuse by 
deliberately concentrating and inhaling the contents can be 
harmful or fatal. 
Additionally, the label should contain the following information: 
WARNING: Contents under pressure. Do not puncture or 
incinerate container. Do not expose to heat or store at room 
temperature above 1208F (498C). Keep out of the reach of 
children. 
In the USA, the Environmental Protection Agency (EPA) 
additionally requires the following information on all aerosols 
containing chlorofluorocarbons as the propellant: 
WARNING: Contains a chlorofluorocarbon that may harm 
the public health and environment by reducing ozone in the 
upper atmosphere. 
15 Handling Precautions 
Chlorodifluoroethane is usually encountered as a liquefied gas 
and appropriate precautions for handling such materials should 
be taken. Eye protection, gloves, and protective clothing are 
recommended. Chlorodifluoroethane should be handled in a 
well-ventilated environment. Chlorofluorocarbon vapors are 
heavier than air and do not support life; therefore, when 
cleaning large tanks that have contained chlorofluorocarbons, 
adequate provisions for oxygen supply in the tanks must be 
made in order to protect workers cleaning the tanks. 
Chlorodifluoroethane is flammable; see Section 10. When 
heated to decomposition, chlorodifluoroethane emits toxic 
fumes. 
16 Regulatory Status 
—
17 Related Substances 
Chlorodifluoromethane. 
Chlorodifluoromethane 
Empirical formula: CHClF2 
Molecular weight: 86.47 
CAS number: [75-45-6] 
Synonyms: Arcton 22; difluorochloromethane; Dyriel 22; 
Frigen 22; HCFC 22; Isceon 22; P-22; propellant 22; 
refrigerant 22. 
Boiling point: –40.88C 
Critical temperature: 968C 
Density: 1.19 g/cm3 for liquid at 258C. 
Melting point: –1468C 
Solubility: freely soluble in acetone, chloroform, and ether; 
soluble 1 in 330 parts of water at 258C. 
Vapor density (absolute): 3.860 g/cm3 at standard temperature 
and pressure. 
Vapor density (relative): 2.98 (air = 1) 
Vapor pressure: 
1041 kPa (151 psia) at 258C; 
2137 kPa (310 psia) at 54.58C. 
Handling precautions: the long-term exposure limit (8-hour 
TWA) for chlorodifluoromethane is 3590 mg/m3 
(1000 ppm).(1) 
Comments: chlorodifluoromethane is a hydrochlorofluorocarbon 
(HCFC) aerosol propellant used in topical pharmaceutical 
formulations. 
18 Comments 
For a discussion of the numerical nomenclature applied to this 
aerosol propellant, see Chlorofluorocarbons. 
19 Specific References 
1 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
Johnson MA. The Aerosol Handbook, 2nd edn. Caldwell: WE 
Dorland, 1982: 305–335. 
Johnson MA. Flammability aspects of dimethy ether, p22, p-142b, p- 
1152a. Aerosol Age 1988; 33(8): 32, 34, 36, 38–39. 
Sanders PA. Handbook of Aerosol Technology, 2nd edn. New York: 
Van Nostrand Reinhold, 1979: 19–35. 
Sciarra JJ. Aerosols. In: Gennaro AR, ed. Remington: The Science and 
Practice of Pharmacy, 19th edn. Easton, PA: Mack Publishing Co., 
1995: 1676–1692. 
Sciarra JJ. Aerosol suspensions and emulsions. In: Lieberman H, Rieger 
J, Banker G, eds. Pharmaceutical Dosage Forms: Disperse Systems, 
vol. 2, 2nd edn. New York: Marcel Dekker, 1996: 319–356. 
Sciarra JJ. Pharmaceutical aerosols. In: Banker GS, Rhodes CT, eds. 
Modern Pharmaceutics, 3rd edn. New York: Marcel Dekker, 1996: 
547–574. 
Sciarra JJ, Stoller L. The Science and Technology of Aerosol Packaging. 
New York: Wiley, 1974: 137–145. 
21 Authors 
CJ Sciarra, JJ Sciarra. 
22 Date of Revision 
23 August 2005.
Chlorodifluoroethane (HCFC) 175

Chlorofluorocarbons (CFC) 
(a) Dichlorodifluoromethane (Propellant 12) 
(b) Dichlorotetrafluoroethane (Propellant 114) 
(c) Trichloromonofluoromethane (Propellant 11) 
1 Nonproprietary Names 
(a) USPNF: Dichlorodifluoromethane 
(b) USPNF: Dichlorotetrafluoroethane 
(c) USPNF: Trichloromonofluoromethane 
2 Synonyms 
Arcton; Dymel; Freon; Frigen; Genetron; Halon; Isceon; 
Isotron. 
Commonly also known as propellant-x or refrigerant-x 
(where x is 12, 114, or 11, for (a), (b), or (c), respectively). 
3 Chemical Name and CAS Registry Number 
(a) Dichlorodifluoromethane [75-71-8] 
(b) 1,2-Dichloro-1,1,2,2-tetrafluoroethane [76-14-2] 
(c) Trichlorofluoromethane [75-69-4] 
4 Empirical Formula and Molecular Weight 
(a) CCl2F2 120.91 
(b) C2Cl2F4 170.92 
(c) CCl3F 137.37 
5 Structural Formula 
6 Functional Category 
Aerosol propellants. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dichlorodifluoromethane, dichlorotetrafluoroethane, and trichloromonofluoromethane 
are chlorofluorocarbon (CFC) 
aerosol propellants used in pharmaceutical formulations. 
Dichlorodifluoromethane is used as an aerosol propellant in 
metered-dose inhaler (MDI) formulations, either as the sole 
propellant or in combination with dichlorotetrafluoroethane, 
trichloromonofluoromethane, or mixtures of these chlorofluorocarbons. 
Dichlorodifluoromethane may also be used as 
a propellant in an aerosolized sterile talc used for intrapleural 
administration and is also used alone in some MDIs containing 
a steroid. 
Dichlorotetrafluoroethane is used in combination with 
dichlorodifluoromethane, and in several cases with dichlorodifluoromethane 
and trichloromonofluoromethane, as the 
propellant in metered-dose oral and nasal aerosols. 
Trichloromonofluoromethane is used in combination with 
dichlorodifluoromethane as the propellant in metered-dose 
inhaler aerosols. It is also used in combination with dichlorotetrafluoroethane 
and dichlorodifluoromethane. 
These three propellants may be blended to obtain suitable 
solubility characteristics for MDIs when formulated as solutions. 
They will produce suitable vapor pressures so that 
optimum particle-size distribution as well as suitable respiratory 
fractions may be achieved. 
Blends of trichloromonofluoromethane and dichlorodifluoromethane 
(propellant 11/12) or propellant 11/114/12 
produce vapor pressures of 103–484 kPa (15–70 psig) at 218C, 
which adequately cover the range of pressures required to 
produce the proper particle-size distribution for satisfactory 
aerosol products. Trichloromonofluoromethane is unique 
among the chlorofluorocarbon propellants in that it is a liquid 
at room temperature and atmospheric pressure and can be used 
to prepare a slurry with insoluble medicinal agents. 
8 Description 
Dichlorodifluoromethane is a liquefied gas and exists as a 
liquid at room temperature when contained under its own 
vapor pressure, or as a gas when exposed to room temperature 
and atmospheric pressure. The liquid is practically odorless and 
colorless. The gas in high concentrations has a faint etherlike 
odor. Dichlorodifluoromethane is noncorrosive, nonirritating, 
and nonflammable. 
Dichlorotetrafluoroethane is a colorless, nonflammable 
liquefied gas with a faint, ethereal odor. 
Trichloromonofluoromethane is a clear, volatile liquid at 
room temperature and atmospheric pressure. It has a characteristic 
carbon tetrachloride-like odor and is nonirritating 
and nonflammable. 
9 Pharmacopeial Specifications 
See Table I.

Table I: Pharmacopeial specifications from USPNF 23. 
Test Propellant 12 Propellant 114 Propellant 11 
Identification . . . 
Boiling temperature –308C 48C 248C 
Water 40.001% 40.001% 40.001% 
High-boiling 
residues 
40.01% 40.01% 40.01% 
Inorganic chlorides . . . 
Chromatographic 
purity 
. . . 
Assay 99.6–100.0% 99.6–100.0% 99.6–100.0% 
10 Typical Properties 
See Table II for selected typical properties. 
11 Stability and Storage Conditions 
Chlorofluorocarbon propellants are nonreactive and stable at 
temperatures up to 5508C. The liquefied gas is stable when used 
as a propellant and should be stored in a metal cylinder in a 
cool, dry place. 
12 Incompatibilities 
The presence of greater than 5% water in solutions that contain 
trichloromonofluoromethane may lead to hydrolysis of the 
propellant and the formation of traces of hydrochloric acid, 
which may be irritant to the skin or cause corrosion of metallic 
canisters. Trichloromonofluoromethane may also react with 
aluminum, in the presence of ethanol, to cause corrosion within 
a cylinder with the formation of hydrogen gas. Similarly, 
alcohols in the presence of trace amounts of oxygen, peroxides, 
or other free-radical catalysts may react with trichloromonofluoromethane 
to form trace quantities of hydrochloric acid. 
Both dichlorodifluoromethane and dichlorotetrafluoroethane 
are compatible with most ingredients used in pharmaceutical 
aerosols. Because of their poor miscibility with water, 
most MDIs are formulated as suspensions. However, solution 
MDIs can be prepared through the use of ethanol as a cosolvent 
for water and propellant, resulting in a clear solution (provided 
the water content is less than 5%). 
13 Method of Manufacture 
Dichlorodifluoromethane is prepared by the reaction of 
hydrogen fluoride with carbon tetrachloride in the presence 
of a suitable catalyst, such as polyvalent antimony. The 
dichlorodifluoromethane formed is further purified to remove 
all traces of water and hydrochloric acid as well as traces of the 
starting and intermediate materials. 
Trichloromonofluoromethane is also obtained by this 
process. 
Dichlorotetrafluoroethane is prepared by the reaction of 
hydrogen fluoride with chlorine and perchloroethylene in the 
presence of a suitable catalyst such as polyvalent antimony. 
14 Safety 
Dichlorodifluoromethane, dichlorotetrafluoroethane, and trichloromonofluoromethane 
have been used for over 40 years as 
propellants in topical, oral, and nasal aerosol formulations and 
are generally regarded as nontoxic and nonirritant materials 
when used as directed. 
The propellants used for metered-dose inhalant aerosol 
products generally vaporize quickly and most of the vapors 
escape and are not inhaled. However, a small amount of the 
propellant may be inhaled with the active ingredient and be 
carried to the respiratory system. These amounts of propellant 
Table II: Selected typical properties for chlorofluorocarbon propellants. 
Test Propellant 12 Propellant 114 Propellant 11 
Boiling point 29.88C 4.18C 23.78C 
Critical pressure 4.01MPa (39.6 atm) 3268 kPa (474 psia) 4.38MPa (43.2 atm) 
Critical temperature 111.58C 145.78C 1988C 
Density 
Liquid at 218C 1.325 g/cm3 1.468 g/cm3 1.485 g/cm3 
Liquid at 54.58C 1.191 g/cm3 1.360 g/cm3 1.403 g/cm3 
Flammability Nonflammable Nonflammable Nonflammable 
Freezing point 1588C 948C 1118C 
Kauri-butanol value 18 12 60 
Solubility at 208C (unless otherwise stated) 
Ethanol (95%) Soluble Soluble Soluble 
Ether Soluble Soluble Soluble 
Water 1 in 3570 at 258C 1 in 7690 at 258C 1 in 909 at 258C 
Surface tension at 258C 9mN/m (9 dynes/cm) 13mN/m (13 dynes/cm) 19mN/m (19 dynes/cm) 
Vapor density 
Absolute 5.398 g/m3 7.63 g/m3 6.133 g/m3 
Relative 4.19 (air = 1) 5.92 (air = 1) 5.04 (air = 1) 
Vapor pressure 
At 218C 585.4 kPa (84.9 psia) 190.3 kPa (27.6 psia) 92.4 kPa (13.4 psia) 
At 54.58C 1351.4 kPa (196.0 psia) 506.8 kPa (73.5 psia) 268.9 kPa (39.0 psia) 
Viscosity (dynamic) 
Liquid at 218C 0.262 mPa s (0.262 cP) 0.386 mPa s (0.386 cP) 0.439 mPa s (0.439 cP) 
Liquid at 54.58C 0.227 mPa s (0.227 cP) 0.296 mPa s (0.296 cP) 0.336 mPa s (0.336 cP) 
Chlorofluorocarbons (CFC) 177

do not present a toxicological problem and are quickly cleared 
from the lungs. Deliberate inhalation of excessive quantities of 
fluorocarbon propellant may result in death, and the following 
‘warning’ statements must appear on the label of all aerosols: 
WARNING: Avoid inhalation. Keep away from eyes or 
other mucous membranes. 
(Aerosols designed specifically for oral inhalation need not 
contain this statement). 
WARNING: Do not inhale directly; deliberate inhalation of 
contents can cause death. 
or 
WARNING: Use only as directed; intentional misuse by 
deliberately concentrating and inhaling the contents can be 
harmful or fatal. 
Additionally, the label should contain the following information: 
WARNING: Contents under pressure. Do not puncture or 
incinerate container. Do not expose to heat or store at room 
temperature above 1208F (498C). Keep out of the reach of 
children. 
In the USA, the Environmental Protection Agency (EPA) 
additionally requires the following information on all aerosols 
containing chlorofluorocarbons as the propellant: 
WARNING: Contains a chlorofluorocarbon that may harm 
the public health and environment by reducing ozone in the 
upper atmosphere. 
(Metered-dose inhalers are exempt from this regulation.) 
15 Handling Precautions 
Dichlorodifluoromethane and dichlorotetrafluoroethane are 
usually encountered as a liquefied gas and appropriate 
precautions for handling such materials should be taken. Eye 
protection, gloves, and protective clothing are recommended. 
These propellants should be handled in a well-ventilated 
environment. Chlorofluorocarbon vapors are heavier than air 
and do not support life; therefore, when cleaning large tanks 
that have contained chlorofluorocarbons, adequate provisions 
for supply of oxygen in the tanks must be made in order to 
protect workers cleaning the tanks. 
Although nonflammable, when heated to decomposition 
chlorofluorocarbons emit toxic fumes containing phosgene and 
fluorides. Although not as volatile as dichlorodifluoroethane 
or dichlorotetrafluoroethane, trichloromonofluoromethane 
should be handled as indicated above. Since it is a liquid at 
room temperature, caution should be exercised in handling this 
material to prevent spillage onto the skin. It is an irritant to the 
eyes. 
The long-term exposure limit (8-hour TWA) for dichlorodifluoromethane 
is 5030 mg/m3 (1000 ppm). The short-term 
exposure limit (15-minute) is 6280 mg/m3 (1250 ppm).(1) 
The long-term exposure limit (8-hour TWA) for dichlorotetrafluoroathane 
is 7110 mg/m3 (1000 ppm). The short-term 
exposure limit (15-minute) is 8890 mg/m3 (1250 ppm).(1) 
The long-term exposure limit (8-hour TWA) for trichlorofluoromethane 
is 5710 mg/m3 (1000 ppm). The short-term 
exposure limit (15-minute) is 7140 mg/m3 (1250 ppm).(1) 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (aerosol 
formulations for inhalation, nasal, oral, and topical applications). 
Included in nonparenteral medicines licensed in the UK. 
17 Related Substances 
—
18 Comments 
Fluorocarbon (FC) aerosol propellants may be identified by a 
standardized numbering nomenclature; for example, dichlorodifluoromethane 
is known as propellant 12, while dichlorotetrafluoroethane 
is known as propellant 114. 
Usually, three digits are used to describe the propellant, 
except when the first digit would be zero, in which case only 
two digits are used. The first digit is one less than the number of 
carbon atoms in the molecule. Thus, if the molecule is a 
methane derivative the first digit would be zero (1 – 1) and is 
ignored, so that only two digits are used in the propellant 
description; e.g. propellant 12. For an ethane derivative, the 
first digit would be a one (2 – 1); e.g. propellant 114. 
The second digit is one more than the number of hydrogen 
atoms in the molecule, while the third digit represents the 
number of fluorine atoms in the molecule. The difference 
between the sum of the fluorine and hydrogen atoms and the 
number of atoms required to saturate the carbon chain is the 
number of chlorine atoms in the molecule. Isomers of a 
compound have the same identifying number and an additional 
letter; a, b, c, and so on. Cyclic derivatives are indicated by the 
letter C before the identifying number. With unsaturated 
propellants, the number 1 is used as the fourth digit from the 
right to indicate an unsaturated double bond. 
Thus for dichlorodifluoromethane (propellant 12): 
First digit = 0 signifies number of C atoms = 1 
Second digit = 1 signifies number of H atoms = 0 
Third digit = 2 signifies number of F atoms = 2 
Number of Cl atoms = 4 – (2 – 0) = 2 
Under the terms of the Montreal Protocol, aimed at reducing 
damage to the ozone layer, the use of chlorofluorocarbons, 
including dichlorodifluoromethane, dichlorotetrafluoroethane, 
and trichloromonofluoromethane, has been prohibited from 
January 1996.(2–6) However, this prohibition does not apply to 
essential uses such as existing pharmaceutical formulations for 
which no alternative chlorofluorocarbon-free product is available. 
New pharmaceutical formulations containing chlorofluorocarbons 
may also be exempted provided they 
demonstrate that there is no technically feasible alternative to 
their use, that the product is of a substantial health benefit, and 
that its use would not involve release of significant quantities of 
chlorofluorocarbon into the atmosphere. The EPA and FDA 
approved essential-use status for dichlorodifluoromethane for a 
sterile aerosol talc used in the treatment of malignant pleural 
effusion in patients with lung cancer. Regulatory bodies in 
individual countries should be consulted for advice on 
chlorofluorocarbon use in MDI formulations. 
Essential-use allowances are allocated in the USA by the 
Environmental Protection Agency following approval of the 
‘Parties to the Montreal Protocol on Substances that Deplete 
178 Chlorofluorocarbons (CFC)

the Ozone Layer’. These allocations are made for a specified 
essential use and cannot be used for other essential uses, traded, 
or sold. This allows for the continued sale of existing exempted 
MDIs and other products designated as an essential use. These 
allocations are granted on an annual basis. Both the EPA and 
the FDA have proposed rules for the eventual elimination of 
CFC-containing MDIs. The development of CFC-free MDIs 
has been slow and time-consuming. Albuterol-containing CFCfree 
MDIs are available in the USA, the UK, and Germany, as 
well as most other countries of the world. A CFC-free MDI 
containing beclomethasone dipropionate has also been 
approved for sale in the UK and USA. In June 2004 the FDA 
proposed the near-term elimination of the essential use 
designation for albuterol MDI. The eventual elimination of 
the essential use exemption is required as part of the United 
States’ general obligations under the Montreal Protocol. 
Additionally, there is a more immediate requirement for an 
action plan that includes a specific end-date for essential use 
exemptions for CFCs for albuterol MDIs. A phase-out date has 
been proposed for 2010.(7) See Tetrafluoroethane and Heptafluoropropane 
for further details. 
19 Specific References 
1 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
2 Fischer FX, Hess H, Sucker H, Byron PR. CFC propellant 
substitution: international perspectives. Pharm Technol 1989; 
13(9): 44, 48, 50, 52. 
3 Kempner N. Metered dose inhaler CFC’s under pressure. Pharm J 
1990; 245: 428–429. 
4 Dalby RN. Possible replacements for CFC-propelled metered-dose 
inhalers. Med Device Technol 1991; 2(4): 21–25. 
5 CFC-free aerosols; the final hurdle. Manuf Chem 1992; 63(7): 22– 
23. 
6 Mackenzie D. Large hole in the ozone agreement. New Scientist 
1992; Nov 28: 5. 
7 Spray Technology and Marketing (June 2003). Sciarra C, Sciarra J. 
CFC-free MDIs. http://www.spraytechnology.com/ 
prev2003.htm#June (accessed 4 January 2005). 
20 General References 
Amin YM, Thompson EB, Shiou WL. Fluorocarbon aerosol propellants 
XII: correlation of blood levels of trichloromonofluormethane to 
cardiovascular and respiratory responses in anesthetized dogs. J 
Pharm Sci 1979; 68: 160–163. 
Byron PR, ed. Respiratory Drug Delivery. Boca Raton, FL: CRC Press, 
1990. 
Johnson MA. The Aerosol Handbook, 2nd edn. Caldwell: WE 
Dorland, 1982: 305–335. 
Niazi S, Chiou WL. Fluorocarbon aerosol propellants XI: pharmacokinetics 
of dichlorodifluoromethane in dogs following single dose 
and multiple dosing. J Pharm Sci 1977; 66: 49–53. 
Sanders PA. Handbook of Aerosol Technology, 2nd edn. New York: 
Van Nostrand Reinhold, 1979: 19–35. 
Sawyer E, Green B, Colton HM. Microorganism survival in non-CFC 
propellant P134a and a combination of CFC propellants P11 and 
P12. Pharm Technol 2001; 25(3): 90–96. 
Sciarra JJ. Pharmaceutical aerosols. In: Lachman L, Lieberman HA, 
Kanig JL, eds. The Theory and Practice of Industrial Pharmacy, 3rd 
edn. Philadelphia: Lea and Febiger, 1986: 589–618. 
Sciarra JJ. Aerosols. In: Gennaro AR, ed. Remington: The Science and 
Practice of Pharmacy, 19th edn. Easton, PA: Mack Publishing Co., 
1995: 1676–1692. 
Sciarra JJ. In: Banker GS, Rhodes C, eds. Modern Pharmaceutics, 3rd 
edn. New York: Marcel Dekker, 1996: 547–574. 
Sciarra JJ, Stoller L. The Science and Technology of Aerosol Packaging. 
New York: Wiley, 1974: 97–130. 
Strobach DR. Alternatives to CFCs. Aerosol Age 1988; 32–33, 42–43. 
21 Authors 
CJ Sciarra, JJ Sciarra. 
22 Date of Revision 
23 August 2005. 
Chlorofluorocarbons (CFC) 179

Chloroxylenol 
1 Nonproprietary Names 
BP: Chloroxylenol 
USP: Chloroxylenol 
2 Synonyms 
4-Chloro-3,5-dimethylphenol; Nipacide PX; parachlorometaxylenol; 
p-chloro-m-xylenol; PCMX. 
3 Chemical Name and CAS Registry Number 
4-Chloro-3,5-xylenol [88-04-0] 
4 Empirical Formula and Molecular Weight 
C8H9ClO 156.61 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; antiseptic; disinfectant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Chloroxylenol is a common constituent of many proprietary 
disinfectants used for skin and wound disinfection; see Table I. 
As a pharmaceutical excipient, chloroxylenol is commonly 
used in low concentrations as an antimicrobial preservative in 
topical formulations such as creams and ointments. Chloroxylenol 
is also used in a number of cosmetic formulations. 
Therapeutically, chloroxylenol has been investigated as a 
treatment for acne vulgaris,(1) and also for treating infected root 
canals.(2) 
Table I: Uses of chloroxylenol. 
Use Concentration (%) 
Antiseptic powder 0.5 
Antimicrobial preservative for otic and topical 
preparations 
0.1–0.8 
Disinfectant 2.5–5.0 
8 Description 
White or cream-colored crystals or crystalline powder with a 
characteristic phenolic odor. Volatile in steam. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for chloroxylenol. 
Test BP 2004 USP 28 
Identification . . 
Characters . — 
Residue on ignition — 40.1% 
Water — 40.5% 
Iron — 40.01% 
Melting range 114–1168C 114–1168C 
Related substances . . 
Assay 98.0–103.0% 598.5% 
10 Typical Properties 
Antimicrobial activity: chloroxylenol is effective against Grampositive 
bacteria but less active against Gram-negative 
bacteria. The activity of chloroxylenol against Gramnegative 
bacilli can be increased by the addition of a 
chelating agent such as edetic acid.(3) Chloroxylenol is 
inactive against bacterial spores. Antimicrobial activity may 
be reduced by loss of chloroxylenol from a formulation due 
to incompatibilities with packaging materials or other 
excipients, such as nonionic surfactants.(4) Solution pH 
does not have a marked effect on the activity of chloroxylenol.(
5) 
Boiling point: 2468C 
Melting point: 115.58C 
Solubility: freely soluble in ethanol (95%); soluble in ether, 
terpenes, and fixed oils; very slightly soluble in water. 
Dissolves in solutions of alkali hydroxides. 
11 Stability and Storage Conditions 
Chloroxylenol is stable at normal room temperature, but is 
volatile in steam. Contact with natural rubber should be 
avoided. Aqueous solutions of chloroxylenol are susceptible to 
microbial contamination and appropriate measures should be 
taken to prevent contamination during storage or dilution. 
Chloroxylenol should be stored in polyethylene, mild steel or 
stainless steel containers, which should be well-closed and kept 
in a cool, dry place. 
12 Incompatibilities 
Chloroxylenol has been reported to be incompatible with 
nonionic surfactants and methylcellulose.

13 Method of Manufacture 
Chloroxylenol is prepared by treating 3,5-dimethylphenol with 
chlorine or sulfuryl chloride (SO2Cl2). 
14 Safety 
Chloroxylenol is generally regarded as a relatively nontoxic 
and nonirritant material when used as an excipient. However, 
allergic skin reactions have been reported.(6,7) Taken orally, 
chloroxylenol is mildly toxic and has been associated with 
isolated reports of fatal(8) or severe instances of self-poisoning.(
9,10) 
LD50 (mouse, IP): 0.115 g/kg(11) 
LD50 (rat, oral): 3.83 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Chloroxylenol is an eye 
irritant and eye protection is recommended. When heated to 
decomposition, chloroxylenol emits toxic fumes. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (otic preparations; 
topical creams and emulsions). Included in nonparenteral 
medicines licensed in the UK. 
17 Related Substances 
Chlorocresol. 
18 Comments 
The EINECS number for chloroxylenol is 201-793-8. 
19 Specific References 
1 Papageorgiou PP, Chu AC. Chloroxylenol and zinc oxide containing 
cream (Nels cream) vs. 5% benzoyl peroxide cream in the 
treatment of acne vulgaris. A double-blind, randomized, controlled 
trial. Clin Exp Dermatol 2000; 25(1): 16–20. 
2 Schafer E, Bossmann K. Antimicrobial efficacy of chloroxylenol 
and chlorhexidine in the treatment of infected root canals. Am J 
Dent 2001; 14(4): 233–237. 
3 Ayliffe GAJ, Fraise AP, Geddes AM, Mitchell K, eds. Control of 
Hospital Infection, 4th edn. London: Arnold, 2000: 78. 
4 Kazmi SJA, Mitchell AG. Interaction of preservatives with 
cetomacrogol. J Pharm Pharmacol 1971; 23: 482–489. 
5 Judis J. Studies on the mechanism of action of phenolic 
disinfectants I. J Pharm Sci 1962; 51: 261–265. 
6 Mowad C. Chloroxylenol causing hand dermatitis in a plumber. 
Am J Contact Dermatitis 1998; 9(2): 128–129. 
7 Malakar S, Panda S. Post-inflammatory depigmentation following 
allergic contact dermatitis to chloroxylenol [letter]. Br J Dermatol 
2001; 144(6): 1275–1276. 
8 Meek D, Gabriel R, Piercy DM. Fatal self-poisoning with Dettol. 
Postgrad Med J 1977; 53: 229–231. 
9 Joubert P, Hundt H, Du Toit P. Severe Dettol (chloroxylenol and 
terpineol) poisoning. Br Med J 1978; 1: 890. 
10 Chan TYK, Sung JJY, Critchley JAJH. Chemical gastro-oesophagitis, 
upper gastrointestinal haemorrhage and gastroscopic findings 
following Dettol poisoning. Hum Exp Toxicol 1995; 14: 18– 
19. 
11 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 906–907. 
20 General References 
Chapman DG. Preservatives available for use. In: Board RG, Allwood 
MC, Banks JG, eds. Preservatives in the Food, Pharmaceutical and 
Environmental Industries. Oxford: Blackwell Scientific, 1987. 
Gatti R, Roveri P, Bonazzi D, Cavrini V. HPLC-fluorescence 
determination of chlorocresol and chloroxylenol in pharmaceuticals. 
J Pharm Biomed Anal 1997; 16: 405–412. 
21 Authors 
LME McIndoe. 
22 Date of Revision 
24 August 2005. 
Chloroxylenol 181

Cholesterol 
1 Nonproprietary Names 
BP: Cholesterol 
JP: Cholesterol 
PhEur: Cholesterolum 
USPNF: Cholesterol 
2 Synonyms 
Cholesterin; cholesterolum. 
3 Chemical Name and CAS Registry Number 
Cholest-5-en-3b-ol [57-88-5] 
4 Empirical Formula and Molecular Weight 
C27H46O 386.67 
5 Structural Formula 
6 Functional Category 
Emollient; emulsifying agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Cholesterol is used in cosmetics and topical pharmaceutical 
formulations at concentrations of 0.3–5.0% w/w as an 
emulsifying agent. It imparts water-absorbing power to an 
ointment and has emollient activity. 
Cholesterol also has a physiological role. It is the major 
sterol of the higher animals, and it is found in all body tissues, 
especially in the brain and spinal cord. It is also the main 
constituent of gallstones. 
8 Description 
Cholesterol occurs as white or faintly yellow, almost odorless, 
pearly leaflets, needles, powder, or granules. On prolonged 
exposure to light and air, cholesterol acquires a yellow to tan 
color. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for cholesterol. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Acidity . . . 
Characters — . — 
Clarity of solution . — — 
Loss on drying 40.3% 40.3% 40.3% 
Melting range 147–1508C 147–1508C 147–1508C 
Organic volatile 
impurities 
— — . 
Residue on ignition 40.10% — 40.1% 
Solubility in alcohol — . . 
Specific rotation –348 to –388 — –348 to –388 
Sulfated ash — 40.1% — 
Assay — 95.0–97.0% — 
10 Typical Properties 
Boiling point: 3608C 
Density: 1.052 g/cm3 for anhydrous form. 
Dielectric constant D20: 5.41 
Melting point: 147–1508C 
Solubility: see Table II.(1–3) 
Specific rotation [a]D
20: 
39.58 (2% w/v solution in chloroform); 
31.58 (2% w/v solution in ether). 
Table II: Solubility of cholesterol. 
Solvent Solubility at 208C(1–3) 
unless otherwise stated 
Acetone Soluble 
Benzene 1 in 7 
Chloroform 1 in 4.5 
Ethanol 1 in 147 at 08C 
1 in 78 at 208C 
1 in 29 at 408C 
1 in 19 at 508C 
1 in 13 at 608C 
Ethanol (95%) 1 in 78 (slowly) 
1 in 3.6 at 808C 
Ether 1 in 2.8 
Hexane 1 in 52 
Isopropyl myristate 1 in 19 
Methanol 1 in 294 at 08C 
1 in 153 at 208C 
1 in 53 at 408C 
1 in 34 at 508C 
1 in 23 at 608C 
Vegetable oils Soluble 
Water Practically insoluble

SEM: 1 
Excipient: Cholesterol 
Manufacturer: Pflatz & Bauer, Inc. 
Magnification: 240 
SEM: 2 
Excipient: Cholesterol 
Manufacturer: Pfaltz & Bauer, Inc. 
Magnification: 2400 
11 Stability and Storage Conditions 
Cholesterol is stable and should be stored in a well-closed 
container, protected from light. 
12 Incompatibilities 
Cholesterol is precipitated by digitonin. 
13 Method of Manufacture 
The commercial material is normally obtained from the spinal 
cord of cattle by extraction with petroleum ethers, but it may 
also be obtained from wool fat. Purification is normally 
accomplished by repeated bromination. Cholesterol may also 
be produced by entirely synthetic means.(4) 
Cholesterol produced from animal organs will always 
contain cholestanol and other saturated sterols. 
See also Section 14. 
14 Safety 
Cholesterol is generally regarded as an essentially nontoxic and 
nonirritant material at the levels employed as an excipient.(3) It 
has, however, exhibited experimental teratogenic and reproductive 
effects, and mutation data have been reported.(5) 
Cholesterol is often derived from animal sources and this 
must be done in accordance with the regulations for human 
consumption. The risk of bovine spongiform encephalopathy 
(BSE) contamination has caused some concern over the use of 
animal-derived cholesterol in pharmaceutical products.(6) 
However, synthetic methods of cholesterol manufacture have 
been developed.(4) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Rubber or plastic gloves, eye 
protection, and a respirator are recommended. 
May be harmful following inhalation or ingestion of large 
quantities, or over prolonged periods of time, owing to the 
possible involvement of cholesterol in atherosclerosis and 
gallstones. May be irritant to the eyes. When heated to 
decomposition, cholesterol emits acrid smoke and irritating 
fumes. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (injections, 
ophthalmic, topical, and vaginal preparations). 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Lanolin; lanolin alcohols; lanolin hydrous. 
18 Comments 
A novel cholesterol-based cationic lipid has been developed that 
promotes DNA transfer in cells.(7,8) Cholesterol monohydrate 
becomes anhydrous at 70–808C. 
The EINECS number for cholesterol is 200-353-2. 
19 Specific References 
1 Harwood RJ, Cohen EM. Solubility of cholesterol in isopropyl 
myristate. J Soc Cosmet Chem 1977; 28: 79–82. 
2 Flynn GL, Shah Y, Prakongpan S, et al. Cholesterol solubility in 
organic solvents. J Pharm Sci 1979; 68: 1090–1097. 
3 Cosmetic, Toiletry and Fragrance Association. Final report on the 
safety assessment of cholesterol. J Am Coll Toxicol 1986; 5(5): 
491–516. 
4 Carmichael H. Safer by synthesis? Chem Br 2001; 37(2): 40–42. 
Cholesterol 183

5 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 912. 
6 Anonymous. Beefing about contamination. Pharm Dev Technol 
Eur 1997; 9(11): 12, 14. 
7 Percot A, Briane D, Coudert R, et al. Hydroxyethylated 
cholesterol-based cationic lipid for DNA delivery: effect of 
conditioning. Int J Pharm 2004; 278(1): 143–163. 
8 Reynier P, Briane D, Coudert R, et al. Modifications in the head 
group and in the spacer of cholesterol-based cationic lipids 
promote transfection in melanoma B16-F10 cells and tumours. J 
Drug Target 2004; 12(1): 25–38. 
20 General References 
Bogardus JB. Unusual cholesterol solubility in water/glyceryl-1-monooctanoate 
solutions. J Pharm Sci 1982; 71: 370–372. 
Cadwallader DE, Madan DK. Effect of macromolecules on aqueous 
solubility of cholesterol and hormone drugs. J Pharm Sci 1981; 70: 
442–446. 
Feld KM, Higuchi WI, Su C-C. Influence of benzalkonium chloride on 
the dissolution behavior of several solid-phase preparations of 
cholesterol in bile acid solutions. J Pharm Sci 1982; 71: 182–188. 
Singh VS, Gaur RC. Dispersion of cholesterol in aqueous surfactant 
solutions: interpretation of viscosity data. J Disper Sci Technol 
1983; 4: 347–359. 
Udupa N, Chandraprakash KS, Umadevi P, Pillai GK. Formulation and 
evaluation of methotrexate niosomes. Drug Dev Ind Pharm 1993; 
19: 1331–1342. 
21 Authors 
SC Owen. 
22 Date of Revision 
12 August 2005. 
184 Cholesterol

Citric Acid Monohydrate 
1 Nonproprietary Names 
BP: Citric acid monohydrate 
JP: Citric acid 
PhEur: Acidum citricum monohydricum 
USP: Citric acid 
2 Synonyms 
E330; 2-hydroxypropane-1,2,3-tricarboxylic acid monohydrate. 
3 Chemical Name and CAS Registry Number 
2-Hydroxy-1,2,3-propanetricarboxylic acid monohydrate 
[5949-29-1] 
4 Empirical Formula and Molecular Weight 
C6H8O7H2O 210.14 
5 Structural Formula 
6 Functional Category 
Acidifying agent; antioxidant; buffering agent; chelating agent; 
flavor enhancer. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Citric acid (as either the monohydrate or anhydrous material) is 
widely used in pharmaceutical formulations and food products, 
primarily to adjust the pH of solutions. It has also been used 
experimentally to adjust the pH of tablet matrices in entericcoated 
formulations for colon-specific drug delivery.(1) Citric 
acid monohydrate is used in the preparation of effervescent 
granules, while anhydrous citric acid is widely used in the 
preparation of effervescent tablets.(2–4) Citric acid has also been 
shown to improve the stability of spray-dried insulin powder in 
inhalation formulations.(5) 
In food products, citric acid is used as a flavor enhancer for 
its tart, acidic taste. Citric acid monohydrate is used as a 
sequestering agent and antioxidant synergist; see Table I. It is 
also a component of anticoagulant citrate solutions. Therapeutically, 
preparations containing citric acid have been used to 
dissolve renal calculi. 
Table I: Uses of citric acid monohydrate. 
Use Concentration (%) 
Buffer solutions 0.1–2.0 
Flavor enhancer for liquid formulations 0.3–2.0 
Sequestering agent 0.3–2.0 
8 Description 
Citric acid monohydrate occurs as colorless or translucent 
crystals, or as a white crystalline, efflorescent powder. It is 
odorless and has a strong acidic taste. The crystal structure is 
orthorhombic. 
SEM: 1 
Excipient: Citric acid monohydrate 
Manufacturer: Pfizer Ltd. 
Magnification: 60

SEM: 2 
Excipient: Citric acid monohydrate 
Manufacturer: Pfizer Ltd. 
Magnification: 600 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for citric acid monohydrate 
(and anhydrous). 
Test JP 2001 PhEur 2005 USP 28(a) 
Identification . . . 
Characters — . — 
Appearance of solution — . — 
Water 
(hydrous form) — 7.5–9.0% 48.8% 
(anhydrous form) 40.5% 41.0% 40.5% 
Bacterial endotoxins — . — 
Residue on ignition 40.1% — 40.05% 
Sulfated ash — 40.1% — 
Calcium . — — 
Aluminum — 40.2 ppm — 
Oxalate . — . 
Oxalic acid — 4350 ppm — 
Sulfate 40.048% 4150 ppm . 
Arsenic 41 ppm — 43 ppm 
Heavy metals 410 ppm 410 ppm 40.001% 
Related substances . — — 
Readily carbonizable 
substances 
. . . 
Polycyclic aromatic 
hydrocarbon 
. — — 
Organic volatile 
impurities 
— — . 
Assay (anhydrous 
basis) 
599.5% 99.5–101.0% 99.5–100.5% 
(a) Note that the JP 2001 and PhEur 2005 have separate monographs for the monohydrate and 
anhydrous material; the USP 28 has a single monograph for both materials. 
10 Typical Properties 
Acidity/alkalinity: pH = 2.2 (1% w/v aqueous solution) 
Dissociation constant: 
pKa1: 3.128 at 258C; 
pKa2: 4.761 at 258C; 
pKa3: 6.396 at 258C. 
Density: 1.542 g/cm3 
Heat of combustion: 1972 kJ/mol (471.4 kcal/mol) 
Heat of solution: 16.3 kJ/mol (3.9 kcal/mol) at 258C 
Hygroscopicity: at relative humidities less than about 65%, 
citric acid monohydrate effloresces at 258C, the anhydrous 
acid being formed at relative humidities less than about 
40%. At relative humidities between about 65% and 75%, 
citric acid monohydrate absorbs insignificant amounts of 
moisture, but under more humid conditions substantial 
amounts of water are absorbed. 
Melting point: 1008C (softens at 758C) 
Particle size distribution: various grades of citric acid monohydrate 
with different particle sizes are commercially 
available. 
Solubility: soluble 1 in 1.5 parts of ethanol (95%) and 1 in less 
than 1 part of water; sparingly soluble in ether. 
Viscosity (dynamic): 6.5 mPa s (6.5 cP) for a 50% w/v aqueous 
solution at 258C. 
See also Section 17. 
11 Stability and Storage Conditions 
Citric acid monohydrate loses water of crystallization in dry air 
or when heated to about 408C. It is slightly deliquescent in 
moist air. Dilute aqueous solutions of citric acid may ferment on 
standing. 
The bulk monohydrate or anhydrous material should be 
stored in airtight containers in a cool, dry place. 
12 Incompatibilities 
Citric acid is incompatible with potassium tartrate, alkali and 
alkaline earth carbonates and bicarbonates, acetates, and 
sulfides. Incompatibilities also include oxidizing agents, bases, 
reducing agents, and nitrates. It is potentially explosive in 
combination with metal nitrates. On storage, sucrose may 
crystallize from syrups in the presence of citric acid. 
13 Method of Manufacture 
Citric acid occurs naturally in a number of plant species and 
may be extracted from lemon juice, which contains 5–8% citric 
acid, or pineapple waste. Anhydrous citric acid may also be 
produced industrially by mycological fermentation of crude 
sugar solutions such as molasses, using strains of Aspergillus 
niger. Citric acid is purified by recrystallization; the anhydrous 
form is obtained from a hot concentrated aqueous solution and 
the monohydrate from a cold concentrated aqueous solution. 
14 Safety 
Citric acid is found naturally in the body, mainly in the bones, 
and is commonly consumed as part of a normal diet. Orally 
ingested citric acid is absorbed and is generally regarded as a 
nontoxic material when used as an excipient. However, 
excessive or frequent consumption of citric acid has been 
associated with erosion of the teeth.(6) 
Citric acid and citrates also enhance intestinal aluminum 
absorption in renal patients, which may lead to increased, 
186 Citric Acid Monohydrate

harmful serum aluminum levels. It has therefore been suggested 
that patients with renal failure taking aluminum compounds to 
control phosphate absorption should not be prescribed citric 
acid or citrate-containing products.(7) 
See Section 17 for anhydrous citric acid animal toxicity data. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. Direct contact with eyes can cause serious 
damage. Citric acid should be handled in a well-ventilated 
environment or a dust mask should be worn. 
16 Regulatory Status 
GRAS listed. The anhydrous form is accepted for use as a food 
additive in Europe. Included in the FDA Inactive Ingredients 
Guide (inhalations; IM, IV, and other injections; ophthalmic 
preparations; oral capsules, solutions, suspensions and tablets; 
topical and vaginal preparations). Included in nonparenteral 
and parenteral medicines licensed in Japan and the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Anhydrous citric acid; fumaric acid; malic acid; sodium citrate 
dihydrate; tartaric acid. 
Anhydrous citric acid 
Empirical formula: C6H8O7 
Molecular weight: 192.12 
CAS number: [77-92-9] 
Synonyms: acidum citricum anhydricum; citric acid; E330; 2- 
hydroxy-b-1,2,3-propanetricarboxylic acid; 2-hydroxypropane 
1,2,3-tricarboxylic acid. 
Appearance: odorless or almost odorless, colorless crystals or a 
white crystalline powder. Crystal structure is monoclinic 
holohedral. 
Dissociation constants: 
pKa1: 3.128 at 258C; 
pKa2: 4.761 at 258C; 
pKa3: 6.396 at 258C. 
Density: 1.665 g/cm3 
Heat of combustion: –1985 kJ/mol (–474.5 kcal/mol) 
Hygroscopicity: at relative humidities between about 25–50%, 
anhydrous citric acid absorbs insignificant amounts of water 
at 258C. However, at relative humidities between 50% and 
75%, it absorbs significant amounts, with the monohydrate 
being formed at relative humidities approaching 75%. At 
relative humidities greater than 75% substantial amounts of 
water are absorbed by the monohydrate. 
Melting point: 1538C 
Solubility: soluble 1 in 1 part of ethanol (95%) and 1 in 1 of 
water; sparingly soluble in ether. 
Safety:
LD50 (mouse, IP): 0.9 g/kg(8) 
LD50 (mouse, IV): 0.04 g/kg 
LD50 (mouse, oral): 5.04 g/kg 
LD50 (mouse, SC): 2.7 g/kg 
LD50 (rabbit, IV): 0.33 g/kg 
LD50 (rat, IP): 0.88 g/kg 
LD50 (rat, oral): 3.0 g/kg 
LD50 (rat, SC): 5.5 g/kg 
Comments: the EINECS number for anhydrous citric acid is 
201-069-1. 
18 Comments 
A specification for citric acid monohydrate is contained in the 
Food Chemicals Codex (FCC). 
The EINECS number for citric acid monohydrate is 201- 
069-1. 
19 Specific References 
1 Nykaenen P, Sten T, Juerjenson H, Veski P, Marvola M. Citric acid 
as a pH-regulating additive in granules and the tablet matrix in 
enteric-coated formulations for colon-specific drug delivery. 
Pharmazie 2004; 59(4): 268–273. 
2 Anderson NR, Banker GS, Peck GE. Quantitative evaluation of 
pharmaceutical effervescent systems II: stability monitoring by 
reactivity and porosity measurements. J Pharm Sci 1982; 71(1): 7– 
13. 
3 Yanze FM, Duru C, Jacob M. A process to produce effervescent 
tablets: fluidized bed dryer melt granulation. Drug Dev Ind Pharm 
2000; 26(11): 1167–1176. 
4 Nyka.nen P, Lempa.a. S, Aaltonen M-L, et al. Citric acid as excipient 
in multiple-unit enteric-coated tablets for targeting drugs on the 
colon. Int J Pharm 2001; 229(1–2): 155–162. 
5 Todo H, Okamoto H, Iida K, Danjo K. Improvement of stability 
and absorbability of dry insulin powder for inhalation by powdercombination 
technique. Int J Pharm 2004; 271(1–2): 41–52. 
6 Anonymous. Citric acid: tooth enamel destruction. Clin Alert 
1971; No. 151. 
7 Main I, Ward MK. Potentiation of aluminium absorption by 
effervescent analgesic tablets in a haemodialysis patient. Br Med J 
1992; 304: 1686. 
8 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 955. 
20 General References 
Cho MJ, Scieszka JF, Burton PS. Citric acid as an adjuvant for 
transepithelial transport. Int J Pharm 1989; 52: 79–81. 
Timko RJ, Lordi NG. Thermal characterization of citric acid solid 
dispersions with benzoic acid and phenobarbital. J Pharm Sci 1979; 
68: 601–605. 
21 Authors 
GE Amidon. 
22 Date of Revision 
8 August 2005. 
Citric Acid Monohydrate 187

Colloidal Silicon Dioxide 
1 Nonproprietary Names 
BP: Colloidal anhydrous silica 
PhEur: Silica colloidalis anhydrica 
USPNF: Colloidal silicon dioxide 
2 Synonyms 
Aerosil; Cab-O-Sil; Cab-O-Sil M-5P; colloidal silica; fumed 
silica; light anhydrous silicic acid; silicic anhydride; silicon 
dioxide fumed; Wacker HDK. 
3 Chemical Name and CAS Registry Number 
Silica [7631-86-9] 
4 Empirical Formula and Molecular Weight 
SiO2 60.08 
5 Structural Formula 
SiO2 
6 Functional Category 
Adsorbent; anticaking agent; emulsion stabilizer; glidant; 
suspending agent; tablet disintegrant; thermal stabilizer; 
viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Colloidal silicon dioxide is widely used in pharmaceuticals, 
cosmetics, and food products; see Table I. Its small particle size 
and large specific surface area give it desirable flow characteristics 
that are exploited to improve the flow properties of dry 
powders in a number of processes such as tableting.(1–3) 
Colloidal silicon dioxide is also used to stabilize emulsions 
and as a thixotropic thickening and suspending agent in gels 
and semisolid preparations.(4)With other ingredients of similar 
refractive index, transparent gels may be formed. The degree of 
viscosity increase depends on the polarity of the liquid (polar 
liquids generally require a greater concentration of colloidal 
silicon dioxide than nonpolar liquids). Viscosity is largely 
independent of temperature. However, changes to the pH of a 
system may affect the viscosity; see Section 11. 
In aerosols, other than those for inhalation, colloidal silicon 
dioxide is used to promote particulate suspension, eliminate 
hard settling, and minimize the clogging of spray nozzles. 
Colloidal silicon dioxide is also used as a tablet disintegrant and 
as an adsorbent dispersing agent for liquids in powders.(5) 
Colloidal silicon dioxide is frequently added to suppository 
formulations containing lipophilic excipients to increase 
viscosity, prevent sedimentation during molding, and decrease 
the release rate.(6,7) Colloidal silicone dioxide is also used as an 
adsorbent during the preparation of wax microspheres;(8) as a 
thickening agent for topical preparations;(9) and has been used 
to aid the freeze-drying of nanocapsules and nanosphere 
suspensions.(10) 
Table I: Uses of colloidal silicon dioxide. 
Use Concentration (%) 
Aerosols 0.5–2.0 
Emulsion stabilizer 1.0–5.0 
Glidant 0.1–0.5 
Suspending and thickening agent 2.0–10.0 
8 Description 
Colloidal silicon dioxide is a submicroscopic fumed silica with 
a particle size of about 15 nm. It is a light, loose, bluish-whitecolored, 
odorless, tasteless, nongritty amorphous powder. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for colloidal silicon dioxide. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
pH (4% w/v dispersion) 3.5–5.5 3.5–5.5 
Arsenic — 48 mg/g 
Chloride 4250 ppm — 
Heavy metals 425 ppm — 
Loss on drying — 42.5% 
Loss on ignition 45.0% 42.0% 
Organic volatile impurities — . 
Assay (on ignited sample) 99.0–100.5% 99.0–100.5% 
10 Typical Properties 
Acidity/alkalinity: pH = 3.5–4.4 (4% w/v aqueous dispersion) 
Density (bulk): 0.029–0.042 g/cm3 
Density (tapped): See Tables III, IV and V. 
Flowability: 35.52% (Carr compressibility index) 
Moisture content: See Figure 1.(11,12) 
Particle size distribution: 7–16 nm. See also Figure 2. 
Refractive index: 1.46 
Solubility: practically insoluble in organic solvents, water, and 
acids, except hydrofluoric acid; soluble in hot solutions of 
alkali hydroxide. Forms a colloidal dispersion with water. 
Specific gravity: 2.2

Specific surface area: 200–400m2/g (Stroehlein apparatus, 
single point); 50–380m2/g (BET method). See also Tables 
III, IV and V. 
Several grades of colloidal silicon dioxide are commercially 
available, which are produced by modifying the manufacturing 
process. The modifications do not affect the silica content, 
specific gravity, refractive index, color, or amorphous form. 
However, particle size, surface areas, and densities are affected. 
The physical properties of three commercially available 
colloidal silicon dioxides, Aerosil (Degussa), Cab-O-Sil (Cabot 
Corporation), and Wacker HDK (Wacker-Chemie GmbH) are 
shown in Tables III, IV and V, respectively. 
Table III: Physical properties of Aerosil. 
Grade Specific surface area(a) 
(m2/g) 
Density (tapped) 
(g/cm3) 
130 130 
 25 0.05 
130vs 130 
 25 0.12 
200 200 
 25 0.05 
200vs 200 
 25 0.12 
300 300 
 30 0.05 
380 380 
 30 0.05 
(a) BET method. 
Table IV: Physical properties of Cab-O-Sil.(13) 
Grade Specific surface area(a) 
(m2/g) 
Density (tapped) 
(g/cm3) 
LM-5 130 
 25 0.04 
LM-50 150 
 25 0.04 
M-5 200 
 25 0.04 
H-5 325 
 25 0.04 
EH-5 390 
 40 0.04 
M-7D 200 
 25 0.10 
(a) BET method. 
Table V: Physical properties of Wacker HDK.(14) 
Grade Specific surface area(a) 
(m2/g) 
Density (tapped) 
(g/cm3) 
S13 125 
 15 0.05 
V15 150 
 20 0.05 
N20 200 
 30 0.04 
T30 300 
 30 0.04 
T40 400 
 40 0.04 
H15 120 
 20 0.04 
H20 170 
 30 0.04 
H30 250 
 30 0.04 
H2000 140 
 30 0.22 
H3004 210 
 30 0.08 
H2015 110 
 30 0.20 
H2050 110 
 30 0.20 
(a) BET method. 
SEM: 1 
Excipient: Colloidal silicon dioxide (Aerosil A-200) 
Manufacturer: Degussa 
Lot No.: 87A-1 (04169C) 
Magnification: 600 Voltage: 20 kV 
SEM: 2 
Excipient: Colloidal silicon dioxide (Aerosil A-200) 
Manufacturer: Degussa 
Lot No.: 87A-1 (04169C) 
Magnification: 2400 Voltage: 20 kV 
11 Stability and Storage Conditions 
Colloidal silicon dioxide is hygroscopic but adsorbs large 
quantities of water without liquefying. When used in aqueous 
systems at a pH 0–7.5, colloidal silicon dioxide is effective in 
Colloidal Silicon Dioxide 189

increasing the viscosity of a system. However, at a pH greater 
than 7.5 the viscosity-increasing properties of colloidal silicon 
dioxide are reduced; and at a pH greater than 10.7 this ability is 
lost entirely since the silicon dioxide dissolves to form 
silicates.(13) Colloidal silicon dioxide powder should be stored 
in a well-closed container. 
Some grades of colloidal silicon dioxide have hydrophobic 
surface treatments that greatly minimize their hygroscopicity. 
Figure 1: Sorption–desorption isotherm for colloidal silicon dioxide. 
*: Sorption 
&: Desorption 
Figure 2: Particle size distribution of colloidal silicon dioxide (Aerosil 
A-200). 
12 Incompatibilities 
Incompatible with diethylstilbestrol preparations.(15) 
13 Method of Manufacture 
Colloidal silicon dioxide is prepared by the vapor hydrolysis of 
chlorosilanes, such as silicon tetrachloride, at 18008C using a 
hydrogen–oxygen flame. 
14 Safety 
Colloidal silicon dioxide is widely used in oral and topical 
pharmaceutical products and is generally regarded as an 
essentially nontoxic and nonirritant excipient. However, 
intraperitoneal and subcutaneous injection may produce local 
tissue reactions and/or granulomas. Colloidal silicon dioxide 
should therefore not be administered parenterally. 
LD50 (rat, IV): 15 mg/kg(16) 
LD50 (rat, oral): 3.16 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. Precautions should be taken to avoid inhalation 
of colloidal silicon dioxide. In the absence of suitable containment 
facilities, a dust mask should be worn when handling 
small quantities of material. For larger quantities, a dust 
respirator is recommended. 
Inhalation of colloidal silicon dioxide dust may cause 
irritation to the respiratory tract but it is not associated with 
fibrosis of the lungs (silicosis), which can occur upon exposure 
to crystalline silica. 
16 Regulatory Acceptance 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(oral capsules, suspensions, and tablets; transdermal and 
vaginal preparations). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
—
18 Comments 
The PhEur 2005 also contains a specification for hydrated 
colloidal silicone dioxide. The incidence of microbial contamination 
of colloidal silicon dioxide is low. 
The EINECS number for colloidal silicon dioxide is 231- 
545-4. 
19 Specific References 
1 Lerk CF, Bolhuis GK, Smedema SS. Interaction of lubricants and 
colloidal silica during mixing with excipients I: its effect on 
tabletting. Pharm Acta Helv 1977; 52: 33–39. 
2 Lerk CF, Bolhuis GK. Interaction of lubricants and colloidal silica 
during mixing with excipients II: its effect on wettability and 
dissolution velocity. Pharm Acta Helv 1977; 52: 39–44. 
3 Gore AY, Banker GS. Surface chemistry of colloidal silica and a 
possible application to stabilize aspirin in solid matrixes. J Pharm 
Sci 1979; 68: 197–202. 
190 Colloidal Silicon Dioxide

4 Daniels R, Kerstiens B, Tishinger-Wagner H, Rupprecht H. The 
stability of drug absorbates on silica. Drug Dev Ind Pharm 1986; 
12: 2127–2156. 
5 Sherriff M, Enever RP. Rheological and drug release properties of 
oil gels containing colloidal silicon dioxide. J Pharm Sci 1979; 68: 
842–845. 
6 Tukker JJ, De Blaey CJ. The addition of colloidal silicon dioxide to 
suspension suppositories II. The impact on in vitro release and 
bioavailability. Acta Pharm Technol 1984; 30: 155–160. 
7 Realdon N, Ragazzi E, Zotto MD, Fini GD. Effects of silicium 
dioxide on drug release from suppositories. Drug Dev Ind Pharm 
1997; 23: 1025–1041. 
8 Mani N, Suh HR, Jun HW. Microencapsulation of a hydrophilic 
drug into a hydrophobic matrix using a salting-out procedure. II. 
Effects of adsorbents on microsphere properties. Drug Dev Ind 
Pharm 2004; 30(1): 83–93. 
9 Gallagher SJ, Trollet L, Carter TP, Heard CM. Effects of membrane 
type and liquid/liquid phase boundary on in vitro release of 
ketoprofen from gel formulations. J Drug Target 2003; 11(6): 
373–379. 
10 Schaffazick SR, Pohlman AR, Dalla-Costa T, Guterres SS. Freezedrying 
polymeric colloidal suspensions: nanocapsules, nanospheres 
and nanodispersion. A comparative study. Eur J Pharm 
Biopharm 2003; 56(3): 501–505. 
11 Ettlinger M, Ferch H, Mathias J. Adsorption at the surface of 
fumed silica [in German]. Arch Pharm 1987; 320: 1–15. 
12 Callahan JC, Cleary GW, Elefant M, et al. Equilibrium moisture 
content of pharmaceutical excipients. Drug Dev Ind Pharm 1982; 
8: 355–369. 
13 Cabot Corporation. Technical literature: Cab-O-Sil fumed silicas, 
the performance additives, 1995. 
14 Wacker-Chemie GmbH. Technical literature: Wacker HDK fumed 
silica, 1998. 
15 Johansen H, Moller N. Solvent deposition of drugs on excipients 
II: interpretation of dissolution, adsorption and absorption 
characteristics of drugs. Arch Pharm Chem (Sci) 1977; 5: 33–42. 
16 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3205. 
20 General References 
Yang KY, Glemza R, Jarowski CI. Effects of amorphous silicon dioxides 
on drug dissolution. J Pharm Sci 1979; 68: 560–565. 
21 Authors 
SC Owen. 
22 Date of Revision 
22 August 2005. 
Colloidal Silicon Dioxide 191

Coloring Agents 
1 Nonproprietary Names 
See Section 17 and Tables I, II, III, and IV. 
2 Synonyms 
See Section 17 for specific, selected coloring agents. 
3 Chemical Name and CAS Registry Number 
See Tables I, II, III, and IV. 
4 Empirical Formula and Molecular Weight 
See Section 17 for specific selected coloring agents. 
Table I: European Union list of coloring materials authorized for coloring medicinal products up to January 2002. See also Section 16. 
E number Common name CAS number Alternate name 
E100 Curcumin [458-37-7] Turmeric 
E101 Riboflavin [83-88-5] Lactoflavin 
E102 Tartrazine [1934-21-0] 
E104 Quinoline yellow [8004-92-0] 
E110 Sunset yellow FCF [2783-94-0] 
E120 Carmine [1260-17-9] Cochineal, carminic acid 
E122 Carmoisine [3567-69-9] 
E123 Amaranth [915-67-3] 
E124 Ponceau 4R [2611-82-7] 
E127 Erythrosine [16423-68-0] 
E129 Allura red AC [25956-17-6] 
E131 Patent blue V [3536-49-0] 
E132 Indigo carmine [860-22-0] Indigotine 
E133 Brilliant blue FCF [2650-18-2] 
E140 Chlorophylls [479-61-8] for (i) Magnesium chlorophyll 
[519-62-0] for (ii) 
E141 Copper complexes of chlorophylls and chlorophyllins — 
E142 Green S [3087-16-9] Brilliant green BS 
E150 Caramel [8028-89-5] 
E151 Brilliant black BN [2519-30-4] Black PN 
E153 Vegetable carbon [7440-44-0] Carbo medicinalis vegetabilis 
E160 Carotenoids 
(a) Alpha-, beta-, gamma-carotene [7235-40-7] 
(b) Capsanthin [465-42-9] Paprika oleoresin 
(c) Capsorubin [470-38-2] Paprika oleoresin 
(d) Lycopene [502-65-8] 
(e) Beta-apo-80 carotenal [1107-26-2] 
(f) Ethyl ester of beta-apo-80 carotenoic acid — 
E161 Xanthophylls 
(b) Lutein [127-40-2] 
(g) Canthaxanthin [514-78-3] 
E162 Beetroot red [7659-95-2] Betanin 
E163 Anthocyanins 
Cyanidin [528-58-5] 
Delphidin [528-53-0] 
Malvidin [643-84-5] 
Pelargonidin [134-04-3] 
Peonidin [134-01-0] 
Petunidin [1429-30-7] 
E170(a) Calcium carbonate [471-34-1] 
E171 Titanium dioxide [13463-67-7] 
E172 Iron oxides and hydroxides [977053-38-5] 
E173 Aluminum [7429-90-5] 
(a) For surface coloring only. 
Note: List of colors taken from Directive 94/34/EC, Annex I and IV. (Official Journal EC 1994; L237/13).

5 Structural Formula 
See Section 17 for specific selected coloring agents. 
6 Functional Category 
Colorants; opacifiers. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Coloring agents are used mainly to impart a distinctive 
appearance to a pharmaceutical dosage form. The main 
categories of dosage form that are colored are: 
. Tablets: either the core itself or the coating. 
. Hard or soft gelatin capsules: the capsule shell or coated 
beads. 
. Oral liquids. 
. Topical creams and ointments. 
Color is a useful tool to help identify a product in its 
manufacturing and distribution stages. Patients, especially 
those using multiple products, often rely on color to be able 
to recognize the prescribed medication.(1) The use of different 
colors for different strengths of the same drug can also help 
eliminate errors. 
Many drug products look similar; hence color in combination 
with shape and/or an embossed or printed logo can help 
with identification. Also, this combination can assist in the 
prevention of counterfeiting. 
Unattractive medication can be made more acceptable to 
the patient by the use of color, and color can also be used to 
make a preparation more uniform when an ingredient in the 
formulation has itself a variable appearance from batch to 
batch.(2) 
Some of the insoluble colors or pigments have the additional 
benefit when used in tablet coatings or gelatin shells of 
providing useful opacity, which can contribute to the stability 
of light-sensitive active materials in the tablet or capsule 
formulation. Pigments such as the iron oxides, titanium 
Table II: Permanently listed color additives subject to US certification in 2002, excluding those approved exclusively for use in medical devices. 
Color Common name CAS number 21 CFR references to drug use 
FD&C blue #1 Brilliant blue FCF [2650-18-2] 74.1101 
FD&C blue #2 Indigotine [860-22-0] 74.1102 
D&C blue #4 Alphazurine FG [6371-85-3] 74.1104 
D&C blue #9 Indanthrene blue [130-20-1] 74.1109 
FD&C green #3 Fast green FCF [2353-45-9] 74.1203 
D&C green #5 Alizarin cyanine green F [4403-90-1] 74.1205 
D&C green #6 Quinizarine green SS [128-80-3] 74.1206 
D&C green #8 Pyranine concentrated [6358-69-6] 74.1208 
D&C orange #4 Orange II [633-96-5] 74.1254 
D&C orange #5 Dibromofluorescein [596-03-2] 74.1255 
D&C orange #10 Diiodofluorescein [38577-97-8] 74.1260 
D&C orange #11 Erythrosine yellowish Na [38577-97-8] 74.1261 
FD&C red #3(a) Erythrosine [16423-68-0] 74.1303 
FD&C red #4 Ponceau SX [4548-53-2] 74.1304 
D&C red #6 Lithol rubin B [5858-81-1] 74.1306 
D&C red #7 Lithol rubin B Ca [5281-04-9] 74.1307 
D&C red #17 Toney red [85-86-9] 74.1317 
D&C red #21 Tetrabromofluorescein [15086-94-9] 74.1321 
D&C red #22 Eosine [17372-87-1] 74.1322 
D&C red #27 Tetrachlorotetrabromofluorescein [13473-26-2] 74.1327 
D&C red #28 Phloxine B [18472-87-2] 74.1328 
D&C red #30 Helindone pink CN [2379-74-0] 74.1330 
D&C red #31 Brilliant lake red R [6371-76-2] 74.1331 
D&C red #33 Acid fuchsine [3567-66-6] 74.1333 
D&C red #34 Lake bordeaux B [6417-83-0] 74.1334 
D&C red #36 Flaming red [2814-77-9] 74.1336 
D&C red #39 Alba red [6371-55-7] 74.1339 
FD&C red #40 Allura red AC [25956-17-6] 74.1340 
FD&C red #40 lake Allura Red AC [68583-95-9] 74.1340 
D&C violet #2 Alizurol purple SS [81-48-1] 74.1602 
FD&C yellow #5 Tartrazine [1934-21-0] 74.1705 
FD&C yellow #6 Sunset yellow FCF [2783-94-0] 74.1706 
D&C yellow #7 Fluorescein [2321-07-5] 74.1707 
Ext. D&C yellow #7 Naphthol yellow S [846-70-8] 74.1707(a) 
D&C yellow #8 Uranine [518-47-8] 74.1708 
D&C yellow #10 Quinoline yellow WS [8004-92-0] 74.1710 
D&C yellow #11 Quinoline yellow SS [8003-22-3] 74.1711 
(a) Dye is permanently listed. The lake is not permitted in medicinal products (see Table III). 
Coloring Agents 193

dioxide, and some of the aluminum lakes are especially useful 
for this purpose.(3) 
Of the many classifications possible for pharmaceutical 
coloring agents, one of the most useful is to simply divide the 
colors into those that are soluble in water (dyes) and those that 
are insoluble in water (pigments). 
Colors for clear liquid preparations are limited to the dyes;(4) 
e.g. see Section 17. 
For surface coloration, which includes coated tablets, the 
choice of color is usually restricted to insoluble pigments. The 
reasons for this include their lack of color migration, greater 
opacity, and enhanced color stability over water-soluble 
colors.(5) 
Lakes are largely water-insoluble forms of the common 
synthetic water-soluble dyes. They are prepared by adsorbing a 
sodium or potassium salt of a dye onto a very fine substrate of 
hydrated alumina, followed by treatment with a further soluble 
aluminum salt. The lake is then purified and dried.(6) 
Lakes are frequently used in coloring tablet coatings since, 
for this purpose, they have the general advantages of pigments 
over water-soluble colors. See Table V. 
8 Description 
The physical appearances of coloring agents vary widely. See 
Section 17 for specific selected coloring agents. 
9 Pharmacopeial Specifications 
Some materials used as pharmaceutical coloring agents are 
included in various pharmacopeias; for example, titanium 
dioxide is included in the PhEur 2005. However, if titanium 
dioxide is being used exclusively as a colorant, then the specific 
purity criteria from Directive 95/45/EC apply.(7) 
10 Typical Properties 
Typical properties of specific selected coloring agents are shown 
in Section 17. Selected properties are shown in Tables V, VI, and 
VII. 
11 Stability and Storage Conditions 
Pharmaceutical coloring agents form a chemically diverse 
group of materials that have widely varying stability properties. 
Specific information for selected colors is shown in Table VII 
and can be found inWoznicki and Schoneker.(4) See also Section 
17.
While some colors, notably the inorganic pigments, show 
excellent stability, other coloring agents, such as some organic 
colors, have poor stability properties but are used in formulations 
because of their low toxicity.(8) 
Table III: Provisionally listed color additives subject to US certification in 2002. 
Color Common name CAS number 21 CFR references to drug use 
FD&C lakes General See individual color 82.51 
D&C lakes General See individual color 82.1051 
Ext. D&C lakes General See individual color 82.2051 
FD&C blue #1 lake Brilliant blue FCF [53026-57-6] 82.101 
FD&C blue #2 lake Indigotine [16521-38-3] 82.102 
D&C blue #4 lake Alphazurine FG [6371-85-3] 82.1104 
FD&C green #3 lake Fast green FCF [2353-45-9] 82.1203 
D&C green #5 lake Alizarin cyanine green F [4403-90-1] 82.1205 
D&C green #6 lake Quinizarine green SS [128-80-3] 82.1206 
D&C orange #4 lake Orange II [633-56-5] 82.1254 
D&C orange #5 lake Dibromofluorescein [596-03-2] 74.1255 
D&C orange #10 lake Diiodofluorescein [38577-97-8] 82.1260 
D&C orange #11 lake Erythosine yellowish Na [38577-97-8] 82.1261 
FD&C red #4 lake Ponceau SX [4548-53-2] 82.1304 
D&C red #6 lake Lithol rubin B [17852-98-1] 82.1306 
D&C red #7 lake Lithol rubin B Ca [5281-04-9] 82.1307 
D&C red #17 lake Toney red [85-86-9] 82.1317 
D&C red #21 lake Tetrabromofluorescein [15086-94-9] 82.1321 
D&C red #22 lake Eosine [17372-87-1] 82.1322 
D&C red #27 lake Tetrachlorotetrabromo 
fluorescein 
[13473-26-2] 82.1327 
D&C red #28 lake Phloxine B [18472-87-2] 82.1328 
D&C red #30 lake Helindone pink CN [2379-74-0] 82.1330 
D&C red #31 lake Brilliant lake red R [6371-76-2] 82.1331 
D&C red #33 lake Acid fuchsine [3567-66-6] 82.1333 
D&C red #34 lake Lake bordeaux B [6417-83-0] 82.1334 
D&C red #36 lake Flaming red [2814-77-9] 82.1336 
D&C violet #2 lake Alizurol purple SS [81-48-1] 82.1602 
FD&C yellow #5 lake Tartrazine [12225-21-7] 82.1705 
FD&C yellow #6 lake Sunset yellow FCF [15790-07-5] 82.1706 
D&C yellow #7 lake Fluorescein [2321-07-5] 82.1707 
Ext. D&C yellow #7 lake Naphthol yellow S [846-70-8] 82.2707 
D&C yellow #8 lake Uranine [518-47-8] 82.1708 
D&C yellow #10 lake Quinoline yellow WS [68814-04-0] 82.1710 
194 Coloring Agents

Table V: Typical characteristic properties of aluminum lakes. 
Average particle size 5–10 mm 
Moisture content 12–15% 
Oil absorption 40–45(a) 
Specific gravity 1.7–2.0 g/cm3 
pH stability range 4.0–8.0 
(a) ASTM D281-31, expressed as grams of oil per 100 g of color. 
Some natural and synthetic organic colors are particularly 
unstable in light. However, with appropriate manufacturing 
procedures, combined with effective product packaging, these 
colors may be used successfully in formulations, thus making a 
wide choice of colors practically available. 
Lakes, inorganic dyes, and synthetic dyes should be stored in 
well-closed, light-resistant containers at a temperature below 
308C. 
For most natural and nature-identical colors, the storage 
conditions are more stringent and a manufacturer’s recommendations 
for a particular coloring agent should be followed. 
To extend their shelf-life, some natural colors are supplied as 
gelatin-encapsulated or similarly encapsulated powders and 
may be sealed in containers under nitrogen. 
Table VI: Approximate solubilities for selected colors at 258C (g/ 
100 mL)(a) 
Color Water Glycerin Propylene 
glycol 
Ethanol 
(95%) 
Ethanol 
(50%) 
Brilliant blue FCF 18 20 20 1.5 20 
Indigo carmine 1.5 1 0.1 Trace 0.2 
FD&C green #3 17 15 15 0.2 7 
Erythrosine 12 22 22 2 4 
Allura red AC 20 3 1.5 Trace 1 
Tartrazine 15 18 8 Trace 4 
Sunset yellow 18 15 2 Trace 2 
(a) The solubility of individual batches of commercial product will differ widely depending on the 
amounts of salt, pure dye, moisture and subsidiary dyes present. 
12 Incompatibilities 
See Section 17 for incompatibilities of specific selected coloring 
agents; see also Woznicki and Schoneker,(4) and Walford.(9,10) 
13 Method of Manufacture 
See Section 17 and Walford(9,10) for information on specific 
selected coloring agents. 
14 Safety 
Coloring agents are used in a variety of oral and topical 
pharmaceutical formulations, in addition to their extensive use 
in foodstuffs and cosmetic products. 
Toxicology studies are routinely conducted on an ongoing 
basis by organizations such as the World Health Organization 
(WHO), the US Food and Drug Administration (FDA), and the 
European Commission (EC). The outcome of this continuous 
review is that the various regulatory bodies around the world 
have developed lists of permitted colors that are generally 
regarded as being free from serious adverse toxicological 
effects. However, owing to the widespread and relatively large 
use of colors in food, a number of coloring agents in current use 
have been associated with adverse effects, although in a 
relatively small number of people.(11,12) Restrictions or bans 
on the use of some coloring agents have been imposed in some 
countries, while the same colors may be permitted for use in a 
different country. As a result the same color may have a 
different regulatory status in different territories of the world. 
The lake of erythrosine (FD&C red #3), for example, has 
been delisted (see Section 16) in the USA since 1990, following 
studies in rats that suggested that it was carcinogenic. This 
delisting was as a result of the Delaney Clause, which restricts 
the use of any color shown to induce cancer in humans or 
animals in any amount. However, erythrosine was not regarded 
as being an immediate hazard to health and products containing 
it were permitted to be used until supplies were 
exhausted.(13) 
Tartrazine (FD&C yellow #5) has also been the subject of 
controversy over its safety, and restrictions are imposed on its 
use in some countries; see Section 17. 
In general, concerns over the safety of coloring agents in 
pharmaceuticals and foods are associated with reports of 
hypersensitivity(14–16) and hyperkinetic activity, especially 
among children.(17) 
In the USA, specific labeling requirements are in place for 
prescription drugs that contain tartrazine (see Section 18) as 
this color was found to be the potential cause of hives in fewer 
Table IV: List of color additives exempt from certification permitted for 
drug use in the USA in 2002. 
Color CAS number 21 CFR references 
to drug use 
Alumina [1332-73-6] 73.1010 
Aluminum powder [7429-90-5] 73.1645 
Annatto extract [8015-67-6] 73.1030 
Beta-carotene [7235-40-7] 73.1095 
Bismuth oxychloride [7787-59-9] 73.1162 
Bronze powder [7440-66-6] 73.1646 
Calcium carbonate [471-34-1] 73.1070 
Canthaxanthin [514-78-3] 73.1075 
Caramel [8028-89-5] 73.1085 
Chromium–cobalt–aluminum 
oxide 
[68187-11-1] 73.1015 
Chromium hydroxide green [12182-82-0] 73.1326 
Chromium oxide green [1308-38-9] 73.1327 
Cochineal extract; carmine [1260-17-9] 73.1100 
[1390-65-4] 
Copper powder [7440-50-6] 73.1647 
Dihydroxyacetone [62147-49-3] 73.1150 
Ferric ammonium citrate [1185-57-5] 73.1025 
Ferric ammonium ferrocyanide [25869-00-5] 73.1298 
Ferric ferrocyanide [14038-43-8] 73.1299 
Guanine [68-94-0] 73.1329 
[73-40-5] 
Iron oxides synthetic [977053-38-5] 73.1200 
Logwood extract [8005-33-2] 73.1410 
Mica [12001-26-2] 73.1496 
Potassium sodium copper 
chlorophyllin 
— 73.1125 
Pyrogallol [87-66-1] 73.1375 
Pyrophyllite [8047-76-5] 73.1400 
Talc [14807-96-6] 73.1550 
Titanium dioxide [13463-67-7] 73.1575 
Zinc oxide [1314-13-2] 73.1991 
Coloring Agents 195

than one in 10 000 people. In the EU, medicinal products 
containing tartrazine, sunset yellow, carmoisine, amaranth, 
ponceau 4R or brilliant black BN must carry a warning on the 
label concerning possible allergic reactions. 
15 Handling Precautions 
Pharmaceutical coloring agents form a diverse group of 
materials and manufacturers’ data sheets should be consulted 
for safety and handling data for specific colors. 
In general, inorganic pigments and lakes are of low hazard 
and standard chemical handling precautions should be 
observed depending upon the circumstances and quantity of 
material handled. Special care should be taken to prevent 
excessive dust generation and inhalation of dust. 
The organic dyes, natural colors, and nature-identical colors 
present a greater hazard and appropriate precautions should 
accordingly be taken. 
16 Regulatory Status 
Coloring agents have an almost unique status as pharmaceutical 
excipients in that most regulatory agencies of the world 
hold positive lists of colors that may be used in medicinal 
products. Only colors on these lists may be used and some 
colors may be restricted quantitatively. The legislation also 
defines purity criteria for the individual coloring agents. In 
many regions around the world there is a distinction between 
colors that may be used in drugs and those for food use. 
European Union legislation: 
The primary legislation that governs coloring matters that 
may be added to medicinal products is Council Directive 78/ 
25/EEC of 12 December 1977.(18) This Directive links the 
pharmaceutical requirements with those for foods in the EU. 
Unfortunately, the Directive makes some specific references 
to food legislation from 1962 that has subsequently been 
repealed. However the European Commission has provided 
guidance on cross references to the current food color 
legislation as contained in Council Directive 94/36/EC.(19) 
In addition, the Scientific Committee on Medicinal Products 
and Medical Devices has delivered opinions on the 
suitability and safety of amaranth,(20) erythrosine,(21) 
canthaxanthin,(22) aluminum,(23) and silver(24) as colors 
for medicines. Silver was considered unsuitable. Table I gives 
the current position taking the above information into 
account. Directive 95/45/EC(7) lays down specific purity 
criteria for food colors and essentially replaces the provisions 
of the 1962 Directive. 
United States legislation: 
The 1960 Color Additive Amendment to the Food Drug and 
Cosmetic Act defines the responsibility of the Food and 
Drug Administration in the area of pharmaceutical colorants. 
Tables II, III, and IV provide lists of permitted 
colors.(25) The list is superficially long, but many of the 
coloring agents have restricted use. For the so-called 
certified colors, the FDA operates a scheme whereby each 
batch of color produced is certified as analytically correct by 
the FDA prior to the issuing of a certification number and 
document that will permit sale of the batch in question. 
Colors requiring certification are described as FD&C (Food 
Drug and Cosmetic); D&C (Drug and Cosmetic) or 
External D&C. The remaining colors are described as 
uncertified colors and are mainly of natural origin. The 
USA also operates a system of division of certified colors 
into permanently and provisionally listed colors. Provisionally 
listed colors require the regular intervention of the FDA 
Commissioner to provide continued listing of these colors. 
Should the need arise, the legislative process for removal of 
these colors from use is comparatively easy. 
Licensing authority approval: 
In addition to national approvals and lists, a pharmaceutical 
licensing authority can impose additional restrictions at the 
time of application review. Within the EU this generally 
takes the form of restricting colors, such as tartrazine and 
other azo colors, in medicinal products for chronic 
administration, and especially in medicines for allergic 
conditions. 
17 Related Substances 
Beta-carotene; indigo carmine; iron oxides; sunset yellow FCF; 
tartrazine; titanium dioxide. 
Beta-carotene 
Empirical formula: C40H56 
Molecular weight: 536.85 
CAS number: [7235-40-7] 
Synonyms: betacarotene; b-carotene; b,b-carotene; E160a. 
Structure: 
Appearance: occurs in the pure state as red crystals when 
recrystallized from light petroleum. 
Table VII: Stability properties of selected colors. 
Color Heat Light Acid Base Oxidizing agents Reducing agents 
Brilliant blue FCF Good Moderate Very good Moderate Moderate Poor 
Indigo carmine Good Very poor Moderate Poor Poor Good 
FD&C green #3 Good Fair Good Poor Poor Very poor 
Erythrosine Good Poor Insoluble Good Fair Very poor 
Allura red AC Good Moderate Good Moderate Fair Fair 
Tartrazine Good Good Good Moderate Fair Fair 
Sunset yellow Good Moderate Good Moderate Fair Fair 
D&C yellow #10 Good Fair Good Moderate Poor Good 
196 Coloring Agents

Color Index No.: 
CI 75130 (natural) 
CI 40800 (synthetic) 
Melting point: 1838C 
Purity (EU): 
Arsenic: 43 ppm 
Lead: 410 ppm 
Mercury: 41 ppm 
Cadmium: 41 ppm 
Heavy metals: 440 ppm 
Assay: 596% total coloring matters expressed as betacarotene 
Identification: maximum in cyclohexane at 453–456nm 
Sulfated ash: 40.2% 
Subsidiary coloring matters: carotenoids other than betacarotene, 
43.0% of total coloring matters. 
Purity (US): 
Arsenic: 43 ppm 
Assay: 96–101% 
Lead: 410 ppm 
Residue on ignition: 40.2% 
Loss on drying: 40.2% 
Solubility: soluble 1 in 30 parts of chloroform; practically 
insoluble in ethanol, glycerin, and water. 
Incompatibilities: generally incompatible with oxidizing agents; 
decolorization will take place. 
Stability: beta-carotene is very susceptible to oxidation and 
antioxidants such as ascorbic acid, sodium ascorbate, or 
tocopherols should be added. Store protected from light at a 
low temperature (–208C) in containers sealed under nitrogen. 
Method of manufacture: all industrial processes for preparing 
carotenoids are based on b-ionone. This material can be 
obtained by total synthesis from acetone and acetylene via 
dehydrolinalol. The commercially available material is 
usually ‘extended’ on a matrix such as acacia or maltodextrin. 
These extended forms of beta-carotene are dispersible 
in aqueous systems. Beta-carotene is also available as 
micronized crystals suspended in an edible oil such as 
peanut oil. 
Comments: beta-carotene is capable of producing colors 
varying from pale yellow to dark orange. It can be used as 
a color for sugar-coated tablets prepared by the ladle 
process. However, beta-carotene is very unstable to light and 
air, and products containing this material should be securely 
packaged to minimize degradation. Beta-carotene is particularly 
unstable when used in spray-coating processes, 
probably owing to atmospheric oxygen attacking the finely 
dispersed spray droplets. 
Because of its poor water solubility, beta-carotene cannot 
be used to color clear aqueous systems, and cosolvents such 
as ethanol must be used. 
Suppositories have been successfully colored with betacarotene 
in approximately 0.1% concentration. 
The EINECS number for beta-carotene is 230-636-6. 
Indigo carmine 
Empirical formula: C16H8N2Na2O8S2 
Molecular weight: 466.37 
CAS number: [860-22-0] 
Synonyms: 2-(1,3-dihydro-3-oxo-5-sulfo-2H-indol-2-ylidene)- 
2,3-dihydro-3-oxo-1H-indole-5-sulfonic acid disodium salt; 
disodium 5,50-indigotin disulfonate; E132; FD&C blue #2; 
indigotine; sodium indigotin disulfonate; soluble indigo 
blue. 
Structure: 
Appearance: dark blue powder. Aqueous solutions are blue 
or bluish-purple. 
Absorption maximum: 604nm 
Color Index No.: CI 73015 
Purity (EU): 
Arsenic: 43 ppm 
Lead: 410 ppm 
Mercury: 41 ppm 
Cadmium: 41 ppm 
Heavy metals: 440 ppm 
Ether-extractable matter: 40.2% under neutral conditions 
Accessory colorings: 41.0% 
Isatin-5-sulfonic acid: 41.0% 
Water-insoluble matter: 40.2% 
Assay: 585% total coloring matters, calculated as the 
sodium salt 
Disodium 3,30-dioxo-2,20-biindoylidene-5,70-disulfonate: 
418%. 
Water-insoluble matter: 40.2%. 
Subsidiary coloring matters: excluding provision above, 
41.0% 
Organic compounds other than coloring matters: 40.5% 
Unsulfonated primary aromatic amines:40.01%, as aniline 
Purity (US): 
Arsenic: 43 ppm 
2-(1,3-Dihydro-3-oxo-2H-indol-2-ylidene)-2,3-dihydro-3- 
oxo-1H-indole-5-sulfonic acid sodium salt: 42% 
2-(1,3-Dihydro-3-oxo-7-sulfo-2H-indol-2-ylidene)-2,3- 
dihydro-3-oxo-1H-indole-5-sulfonic acid disodium salt: 
418% 
Isatin-5-sulfonic acid: 40.4% 
Lead: 410 ppm 
Mercury: 41 ppm 
5-Sulfoanthranilic acid: 40.2% 
Total color: 585% 
Volatile matter, chlorides and sulfates (calculated as the 
sodium salts): 415.0% at 1358C 
Water-insoluble matter: 40.4% 
Solubility: see Table VIII. 
Table VIII: Solubility of indigo carmine. 
Solvent Solubility at 208C 
unless otherwise stated 
Acetone Practically insoluble 
Ethanol (75%) 1 in 1430 
Glycerin 1 in 100 
Propylene glycol 1 in 1000 
Propylene glycol (50%) 1 in 167 
Water 1 in 125 at 28C 
1 in 63 at 258C 
1 in 45 at 608C 
Coloring Agents 197

Incompatibilities: poorly compatible with citric acid and 
saccharose solutions. Incompatible with ascorbic acid, 
gelatin, glucose, lactose, oxidizing agents, and saturated 
sodium bicarbonate solution. 
Stability: sensitive to light. 
Method of manufacture: indigo is sulfonated with concentrated 
or fuming sulfuric acid. 
Safety: LD50 (rat, IV): 93 mg/kg 
Comments: Indigo carmine is an indigoid dye used to color oral 
and topical pharmaceutical preparations. It is used with 
yellow colors to produce green colors. Indigo carmine is also 
used to color nylon surgical sutures and is used diagnostically 
as a 0.8% w/v injection. 
Sunset yellow FCF 
Empirical formula: C16H10N2Na2O7S2 
Molecular weight: 452.37 
CAS number: [2783-94-0] 
Synonyms: E110; FD&C yellow #6; 6-hydroxy-5-[(4-sulfophenyl)
azo]-2-naphthalenesulfonic acid disodium salt; 1-psulfophenylazo-
2-naphthol-6-sulfonic acid disodium salt; 
yellow orange S. 
Structure: 
Appearance: reddish yellow powder. Aqueous solutions are 
bright orange colored. 
Absorption maximum: 482nm 
Color Index No.: CI 15985 
Purity (EU): 
Arsenic: 43 ppm 
Lead: 410 ppm 
Mercury: 41 ppm 
Cadmium: 41 ppm 
Heavy metals: 440 ppm 
Ether-extractable matter: 40.2% under neutral conditions 
Assay: 585% total coloring matters as the sodium salt 
Subsidiary colors: 45% 
Water-insoluble matter: 40.2% 
Organic compounds other than coloring matters: 40.5% 
Unsulfonated primary aromatic amines: 40.01% as aniline 
Ether-extractable matter: 40.2% under neutral conditions 
Purity (US): 
Arsenic: 43 ppm 
Lead: 410 ppm 
Mercury: 41 ppm 
4-Aminobenzenesulfonic acid: 40.2% as the sodium salt 
6-Hydroxy-2-naphthalenesulfonic acid: 40.3% as the 
sodium salt 
6,60-Oxybis[2-naphthalenesulfonic acid]: 41% as the disodium 
salt 
4,40-(1-Triazene-1,3-diyl)bis[benzenesulfonic acid]: 40.1% 
as the disodium salt 
4-Aminobenzene: 450 ppb 
4-Aminobiphenyl: 415 ppb 
Aniline: 4250 ppb 
Azobenzene: 4200 ppb 
Benzidine: 41 ppb 
1,3-Diphenyltriazene: 440 ppb 
1-(Phenylazo)-2-naphthalenol: 410 ppm 
Total color: 587% 
Sum of volatile matter at 1358C, chlorides and sulfates: 
413.0% 
Water-insoluble matter: 40.2% 
Solubility: see Table IX. 
Incompatibilities: poorly compatible with citric acid, saccharose 
solutions, and saturated sodium bicarbonate solutions. 
Incompatible with ascorbic acid, gelatin, and glucose. 
Method of manufacture: diazotized sulfanilic acid is coupled 
with Schaeffer’s salt (sodium salt of b-naphthol-6-sulfonic 
acid). 
Safety:
LD50 (mouse, IP): 4.6 g/kg 
LD50 (mouse, oral): >6 g/kg 
LD50 (rat, IP): 3.8 g/kg 
LD50 (rat, oral): >10 g/kg 
Comments: sunset yellow FCF is a monoazo dye. 
The EINECS number for sunset yellow FCF is 220-491-7. 
Table IX: Solubility of Sunset yellow FCF. 
Solvent Solubility at 208C 
unless otherwise stated 
Acetone 1 in 38.5 
Ethanol (75%) 1 in 333 
Glycerin 1 in 5 
Propylene glycol 1 in 45.5 
Propylene glycol (50%) 1 in 5 
Water 1 in 5.3 at 28C 
1 in 5.3 at 258C 
1 in 5 at 608C 
Tartrazine 
Empirical formula: C16H9N4Na3O9S2 
Molecular weight: 534.39 
CAS number: [1934-21-0] 
Synonyms: 4,5-dihydro-5-oxo-1-(4-sulfophenyl)-4-[(4-sulfophenyl)
azo]-1H-pyrazole-3-carboxylic acid trisodium salt; 
E102; FD&C yellow #5; hydrazine yellow. 
Structure: 
Appearance: yellow or orange-yellow powder. Aqueous 
solutions are yellow-colored; the color is retained upon 
addition of hydrochloric acid solution, but with sodium 
hydroxide solution a reddish color is formed. 
Absorption maximum: 425nm 
Color Index No.: CI 19140 
Purity (EU): 
Arsenic: 43 ppm 
Lead: 410 ppm 
198 Coloring Agents

Mercury: 41 ppm 
Cadmium: 41 ppm 
Heavy metals: 440 ppm 
Assay: 585% total coloring matters as the sodium salt 
Organic compounds other than coloring matters: 40.5% 
Unsulfonated primary aromatic amines: 40.01% as aniline 
Ether-extractable matter: 40.2% under neutral conditions 
Accessory colorings: 41.0% 
Water-insoluble matter: 40.2% 
Purity (US): 
Arsenic: 43 ppm 
Lead: 410 ppm 
Mercury: 41 ppm 
Total color: 587.0% 
Volatile matter, chlorides and sulfates (calculated as the 
sodium salts): 413.0% at 1358C 
Water-insoluble matter: 40.2% 
4,40-[4,5-Dihydro-5-oxo-4-[(4-sulfophenyl)hydrazono]-1Hpyrazol-
1,3-diyl]bis[benzenesulfonic acid]: 40.1% as the 
trisodium salt 
4-Aminobenzenesulfonic acid: 40.2% as the sodium salt 
4,5-Dihydro-5-oxo-1-(4-sulfophenyl)-1H-pyrazole-3-carboxylic 
acid: 40.2% as the disodium salt 
Ethyl or methyl 4,5-dihydro-5-oxo-1-(4-sulfophenyl)-1Hpyrazole-
3-carboxylate: 40.1% as the sodium salt 
4,40-(1-Triazene-1,3-diyl)bis[benzenesulfonic acid]: 
40.05% as the disodium salt 
4-Aminobenzene: 475 ppb 
4-Aminobiphenyl: 45 ppb 
Aniline: 4100 ppb 
Azobenzene: 440 ppb 
Benzidine: 41 ppb 
1,3-Diphenyltriazene: 440 ppb 
Solubility: see Table X. 
Table X: Solubility of tartrazine. 
Solvent Solubility at 208C unless otherwise stated 
Acetone Practically insoluble 
Ethanol (75%) 1 in 91 
Glycerin 1 in 5.6 
Propylene glycol 1 in 14.3 
Propylene glycol (50%) 1 in 5 
Water 1 in 26 at 28C 
1 in 5 at 258C 
1 in 5 at 608C 
Incompatibilities: poorly compatible with citric acid solutions. 
Incompatible with ascorbic acid, lactose, 10% glucose 
solution, and saturated aqueous sodium bicarbonate solution. 
Gelatin accelerates the fading of the color. 
Method of manufacture: phenylhydrazine p-sulfonic acid is 
condensed with sodium ethyl oxalacetate; the product 
obtained from this reaction is then coupled with diazotized 
sulfanilic acid. 
Safety:
LD50 (mouse, oral): >6 g/kg 
LD50 (mouse, IP): 4.6 g/kg 
LD50 (rat, oral): 10 g/kg 
LD50 (rat, IP): 3.8 g/kg 
Comments: tartrazine is a monoazo, or pyrazolone, dye. It is 
used to improve the appearance of a product and to impart a 
distinctive coloring for identification purposes. 
US regulations require that prescription drugs for human 
use containing tartrazine bear the warning statement: 
This product contains FD&C yellow #5 (tartrazine) 
which may cause allergic-type reactions (including 
bronchial asthma) in certain susceptible persons. 
Although the overall incidence of sensitivity to FD&C 
yellow #5 (tartrazine) in the general population is low, it is 
frequently seen in patients who are also hypersensitive to 
aspirin. 
18 Comments 
Titanium dioxide is used extensively to impart a white color to 
film-coated tablets, sugar-coated tablets, and gelatin capsules. It 
is also used in lakes as an opacifier, to ‘extend’ the color. See 
Titanium dioxide for further information. 
In the EU, colors used in pharmaceutical formulations and 
colors used in cosmetics are controlled by separate regulations. 
Cosmetic colors are also classified according to their use, e.g. 
those that may be used in external products that are washed off 
after use. 
19 Specific References 
1 Hess H, Schrank J. Coloration of pharmaceuticals: possibilities 
and technical problems. Acta Pharm Technol 1979; 25 (Suppl. 8): 
77–87. 
2 Aulton ME, Abdul-Razzak MH, Hogan JE. The mechanical 
properties of hydroxypropylmethylcellulose films derived from 
aqueous systems part 1: the influence of solid inclusions. Drug Dev 
Ind Pharm 1984; 10: 541–561. 
3 Rowe RC. The opacity of tablet film coatings. J Pharm Pharmacol 
1984; 36: 569–572. 
4 Woznicki EJ, Schoneker DR. Coloring agents for use in 
pharmaceuticals. In: Swarbrick J, Boylan JC, eds. Encyclopedia 
of Pharmaceutical Technology, vol. 3. New York: Marcel Dekker, 
1990: 65–100. 
5 Porter SC. Tablet coating. Drug Cosmet Ind 1981; 128(5): 46, 48, 
50, 53, 86–93. 
6 Marmion DM. Handbook of US Colorants for Foods, Drugs and 
Cosmetics, 3rd edn. New York: Wiley-Interscience, 1991. 
7 European Commission. Official Journal EC. 1995; L226/1. 
8 Delonca H, Laget J-P, Saunal H, Ahmed K. Stability of principal 
tablet coating colors II: effect of adjuvants on color stability [in 
French]. Pharm Acta Helv 1983; 58: 332–337. 
9 Walford J, ed. Developments in Food Colors, vol. 1. New York: 
Elsevier, 1980. 
10 Walford J, ed. Developments in Food Colors, vol. 2. New York: 
Elsevier, 1980. 
11 Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation 
Agents: a Handbook of Excipients. New York: Marcel Dekker, 
1989: 159–165. 
12 Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992. 
13 Blumenthal D. Red No. 3 and other colorful controversies. FDA 
Consumer 1990; 21: 18. 
14 Bell T. Colourants and drug reactions [letter]. Lancet 1991; 338: 
55–56. 
15 Le.vesque H, Moore N, Courtois H. Reporting adverse drug 
reactions by proprietary name [letter]. Lancet 1991; 338: 393. 
16 Dietemann-Molard A, Braun JJ, Sohier B, Pauli G. Extrinsic 
allergic alveolitis secondary to carmine [letter]. Lancet 1991; 338: 
460. 
17 Pollock I, Young E, Stoneham M, et al. Survey of colourings and 
preservatives in drugs. Br Med J 1989; 299: 649–651. 
18 European Commission. Official Journal EC. 1978; L11/18. 
19 European Commission. Official Journal EC. 1994; L237/13. 
Coloring Agents 199

20 European Commission (1998). Opinion on toxicological data on 
colouring agents for medicinal products: amaranth, adopted by the 
Scientific Committee on Medicinal Products and Medical Devices 
on 21 October 1998. http://europa.eu.int/comm/health/ph_risk/ 
committees/scmp/scmp_en.htm (accessed 30 June 2005). 
21 European Commission (1998). Opinion on toxicological data on 
colouring agents for medicinal products: erythrosin, adopted by 
the Scientific Committee on Medicinal Products and Medical 
Devices on 21 October 1998. http://europa.eu.int/comm/health/ 
ph_risk/committees/scmp/docshtml/scmp_out08_en.htm (accessed 
24 January 2005). 
22 European Commission (1998). Opinion on toxicological data 
colouring agents for medicinal products: canthaxanthine, adopted 
by the Scientific Committee on Medicinal Products and Medical 
Devices on 21 October 1998. http://europa.eu.int/comm/health/ 
ph_risk/committees/scmp/docshtml/scmp_out10_en.htm (accessed 
24 January 2005). 
23 European Commission (1999). Opinion on toxicological data on 
colouring agents for medicinal products: aluminum, adopted by 
the Scientific Committee on Medicinal Products and Medical 
Devices on 14 April 1999. http://europa.eu.int/comm/health/ 
ph_risk/committees/scmp/docshtml/scmp_out21_en.htm (accessed 
24 January 2005). 
24 European Commission (2000). Opinion on toxicological data on 
colouring agents for medicinal products: E174 silver, adopted by 
the Scientific Committee on Medicinal Products and Medical 
Devices on 27 June 2000. http://europa.eu.int/comm/health/ 
ph_risk/committees/scmp/documents/out30_en.pdf (accessed 24 
January 2005). 
25 Code of Federal Regulations. Title 21 Parts 74, 81, 82. 
20 General References 
Jones BE. Colours for pharmaceutical products. Pharm Technol Int 
1993; 5(4): 14–16, 18–20. 
21 Authors 
C Mroz. 
22 Date of Revision 
27 August 2005. 
200 Coloring Agents

Copovidone 
1 Nonproprietary Names 
BP: Copovidone 
PhEur: Copovidonum 
USPNF: Copovidone 
2 Synonyms 
Acetic acid vinyl ester, polymer with 1-vinyl-2-pyrrolidinone; 
copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a ratio 
of 3 : 2 by mass; copolyvidone; Kollidon VA 64; Luviskol VA; 
Plasdone S-630; poly(1-vinylpyrrolidone–co-vinyl acetate); 
polyvinylpyrrolidone–vinyl acetate copolymer; PVP/VA; PVP/ 
VA copolymer. 
3 Chemical Name and CAS Registry Number 
Acetic acid ethenyl ester, polymer with 1-ethenyl-2-pyrrolidinone 
[25086-89-9] 
4 Empirical Formula and Molecular Weight 
(C6H9NO)n(C4H6O2)m (111.1)n . (86.1)m 
The ratio of n to m is approximately n = 1.2m. Molecular 
weights of 45 000–70 000 have been determined for Kollidon 
VA 64. The average molecular weight of copovidone is usually 
expressed as a K-value. 
The K-value of Kollidon VA 64 is nominally 28, with a range 
of 25.2–30.8. The K-value of Plasdone S 630 is specified 
between 25.4 and 34.2. K-values are calculated from the 
kinematic viscosity of a 1% aqueous solution. Molecular 
weight can be calculated with the formula: 
M = 22.22 (K . 0.075K2)1.65 
The PhEur 2005 and USPNF 23 (Suppl. 1) describe 
copovidone as a copolymer of 1-ethenylpyrrolidin-2-one and 
ethenyl acetate in the mass proportion of 3 : 2. 
5 Structural Formula 
6 Functional Category 
Film-former; granulating agent; tablet binder. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Copovidone is used as a tablet binder, a film-former, and as part 
of the matrix material used in controlled-release formulations. 
In tableting, copovidone can be used as a binder for direct 
compression(1–3) and as a binder in wet granulation.(4,5) 
Copovidone is often added to coating solutions as a filmforming 
agent. It provides good adhesion, elasticity, and 
hardness, and can be used as a moisture barrier. 
See Table I. 
Table I: Uses of copovidone. 
Use Concentration (%) 
Film-forming agent 0.5–5.0(a) 
Tablet binder, direct 
compression 
2.0–5.0 
Tablet binder, wet 
granulation 
2.0–5.0 
(a) This corresponds to the % w/w copovidone in the film-forming solution formulation, before 
spraying. 
8 Description 
Copovidone is a white to yellowish-white amorphous powder. 
It is typically spray-dried with a relatively fine particle size. It 
has a slight odor and a faint taste. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for copovidone. 
Test PhEur 2005 USPNF 23 (Suppl. 1) 
Aldehydes 4500 ppm 40.05% 
Appearance of solution . . 
Characters . — 
Ethenyl acetate 35.3–42.0% 35.3–41.4% 
Heavy metals 420 ppm — 
Hydrazine 41 ppm 41 ppm 
Identification . . 
K-value 90–110% 90.0–110.0% 
Loss on drying 45.0% 45.0% 
Monomers 40.1% 40.1% 
Nitrogen content 7.0–8.0% 7.0–8.0% 
Peroxides 4400 ppm 40.04% 
2-Pyrrolidone 40.5% — 
Sulfated ash 40.1% 40.1% 
Viscosity, expressed as 
K-value 
. — 
10 Typical Properties 
Density(bulk): 0.24–0.28 g/cm3 
Density (tapped): 0.35–0.45 g/cm3 
Flash point: 2158C 
Flowability: relatively free-flowing powder. 
Glass transition temperature: 1068C for Plasdone S-630.(6) 
Hygroscopicity: at 50% relative humidity, copovidone gains 
less than 10% weight. 
K-value: 25.4–34.2 for Plasdone S-630.(6)

SEM: 1 
Excipient: Copovidone (Kollidon VA 64) 
Manufacturer: BASF 
Magnification: 400 Voltage: 10 kV 
Melting point: 1408C 
Solubility: greater than 10% solubility in 1,4-butanediol, 
glycerol, butanol, chloroform, dichloromethane, ethanol 
(95%), glycerol, methanol, polyethylene glycol 400, propan-
2-ol, propanol, propylene glycol, and water. Less than 
1% solubility in cyclohexane, diethyl ether, liquid paraffin, 
and pentane. 
Viscosity (dynamic): the viscosity of aqueous solutions depends 
on the molecular weight and the concentration. At 
concentrations less than 10%, the viscosity is less than 
10 mPa s (258C). 
11 Stability and Storage Conditions 
Copovidone is stable and should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Copovidone is compatible with most organic and inorganic 
pharmaceutical ingredients. When exposed to high water levels, 
copovidone may form molecular adducts with some materials; 
see Crospovidone and Povidone. 
13 Method of Manufacture 
Copovidone is manufactured by free-radical polymerization of 
vinylpyrrolidone and vinyl acetate in a ratio of 6 : 4. The 
synthesis is conducted in an organic solvent owing to the 
insolubility of vinyl acetate in water. 
14 Safety 
Copovidone is used widely in pharmaceutical formulations and 
is generally regarded as nontoxic. However, it is moderately 
toxic by ingestion, producing gastric disturbances. It has no 
irritating or sensitizing effects on the skin. 
LD50 (rat, oral): >0.63 g/kg(7) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. When heated to decomposition, 
copovidone emits toxic vapors of NOx. Eye protection, 
gloves, and a dust mask are recommended. 
16 Regulatory Status 
Copovidone is included in the FDA Inactive Ingredients Guide 
(oral tablets, oral film-coated tablets, sustained action). 
17 Related Substances 
Crospovidone; povidone. 
18 Comments 
Kollidon VA 64, has a spherical structure, with a high 
proportion of damaged spheres. The shell-like structure reduces 
flowability, but the damaged spheres cover a greater surface 
area of the filler particles, increasing the efficacy of its use as a 
dry binder.(8) Furthermore, when used in transdermal drug 
delivery systems, copovidone has been shown to significantly 
alter the melting behavior, by reducing the heat of fusion and 
the melting point of estradiol and various other sex steroids.(9) 
Plasdone S-630 has been used in direct compression 
experiments with active substances that are difficult to 
compress, such as acetaminophen (paracetamol); and has 
been shown to produce harder tablets than those containing 
the same actives but made with microcrystalline cellulose.(10) 
In general, copovidone has better plasticity than povidone as 
a tablet binder, and is less hygroscopic, more elastic, and less 
tacky in film-forming applications than povidone. 
Up to about 1975, copovidone was marketed by BASF 
under the name Luviskol VA 64. Luviskol is currently used only 
for the technical/cosmetic grade of copovidone. 
19 Specific References 
1 Moroni A. A novel copovidone binder for dry granulation and 
direct-compression tableting. Pharm Tech 2001; 25 (Suppl.): 8–24. 
2 Selmeczi B. The influence of the compressional force on the 
physical properties of tablets made by different technological 
processes. Arch Pharm (Weinheim) 1974; 307(10): 755–760. 
3 Stamm A, Mathis C. The liberation of propyromazine from tablets 
prepared by direct compression. J Pharm Belg 1990; 29(4): 375– 
389. 
4 Vojnovic D, Rubessa F, Bogataj M, Mrhar A. Formulation and 
evaluation of vinylpyrrolidone/vinylacetate copolymer microspheres 
with griseofulvin. J Microencapsul 1993; 10(1): 89–99. 
5 Kristensen HG, Holm P, Jaegerskou A, Schaefer T. Granulation in 
high speed mixers. Part 4: Effect of liquid saturation on the 
agglomeration. Pharm Ind 1984; 46(7): 763–767. 
6 International Specialty Products. Technical Literature: Plasdone S- 
630, 2002. 
7 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 17. 
8 Kolter K, Flick D. Structure and dry binding activity of different 
polymers, including Kollidon VA 64. Drug Dev Ind Pharm 2000; 
26(11): 1159–1165. 
9 Lipp R. Selection and use of crystallization inhibitors for matrixtype 
transdermal drug-delivery systems containing sex steroids. J 
Pharm Pharmacol 1998; 50: 1343–1349. 
202 Copovidone

10 International Specialty Products. Technical literature: Plasdone 
S0630: A binder for direct compression and wet/dry granulation, 
2002. 
20 General References 
BASF. Technical literature: Kollidon VA 64, March 2000. 
21 Authors 
OA AbuBaker, D Pipkorn. 
22 Date of Revision 
1 August 2005. 
Copovidone 203

Corn Oil 
1 Nonproprietary Names 
BP: Refined maize oil 
JP: Corn oil 
PhEur: Maydis oleum raffinatum 
USPNF: Corn oil 
2 Synonyms 
Maize oil; Majsao CT. 
3 Chemical Name and CAS Registry Number 
Corn oil [8001-30-7] 
4 Empirical Formula and Molecular Weight 
Corn oil is composed of fatty acid esters with glycerol, known 
commonly as triglycerides. Typical corn oil produced in the 
USA contains five major fatty acids: linoleic 58.9%; oleic 
25.8%; palmitic 11.0%; stearic 1.7%; and linolenic 1.1%. 
Corn grown outside the USA yields corn oil with lower linoleic, 
higher oleic, and higher saturated fatty acid levels. Corn oil also 
contains small quantities of plant sterols. 
The USPNF 23 describes corn oil as the refined fixed oil 
obtained from the embryo of Zea mays Linne. (Fam. 
Gramineae). 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Oleaginous vehicle; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Corn oil is used primarily in pharmaceutical formulations as a 
solvent for intramuscular injections or as a vehicle for topical 
preparations. Emulsions containing up to 67% corn oil are also 
used as oral nutritional supplements; see also Section 18. When 
combined with surfactants and gel-forming polymers, it is used 
to formulate veterinary vaccines. 
Corn oil has a long history of use as an edible oil and may be 
used in tablets or capsules for oral administration. 
8 Description 
Clear, light yellow-colored, oily liquid with a faint characteristic 
odor and slightly nutty, sweet taste resembling cooked 
sweet corn. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for corn oil. 
Test JP 2001 PhEur 2005 USPNF 23 
Acid value 40.2 40.5 — 
Alkaline impurities — . — 
Characters . . — 
Cottonseed oil — — . 
Composition of fatty 
acids 
— . . 
Fatty acids less than 
C16 
— 40.6% — 
Arachidic acid — 40.8% — 
Behenic acid — 40.5% — 
Oleic acid — 20.0–42.2% — 
Eicosaenoic acid — 40.5% — 
Linoleic acid — 39.4–65.6% — 
Linolenic acid — 0.5–1.5% — 
Palmitic acid — 8.6–16.5% — 
Stearic acid — 43.3% — 
Other fatty acids — 40.5% — 
Sterols — 40.3% — 
Water — 40.1% — 
Free fatty acids — — . 
Heavy metals — — 40.001% 
Iodine value 103–130 — 102–130 
Organic volatile 
impurities 
— — . 
Peroxide value — 410.0 — 
Refractive index — 1.474 — 
Saponification value 187–195 — 187–193 
Specific gravity 0.915–0.921 0.920 0.914–0.921 
Unsaponifiable matter 41.5% 42.8% 41.5% 
10 Typical Properties 
Acid value: 2–6 
Autoignition temperature: 3938C 
Density: 0.915–0.918 g/cm3 
Flash point: 3218C 
Hydroxyl value: 8–12 
Melting point: 18 to 108C 
Refractive index: 
nD
25 = 1.470–1.474; 
nD
40 = 1.464–1.468. 
Solubility: miscible with benzene, chloroform, dichloromethane, 
ether, and hexane; practically insoluble in ethanol 
(95%) and water. 
Viscosity (dynamic): 37–39 mPa s (37–39 cP) 
11 Stability and Storage Conditions 
Corn oil is stable when protected with nitrogen in tightly sealed 
bottles. Prolonged exposure to air leads to thickening and 
rancidity. Corn oil may be sterilized by dry heat, maintaining it 
at 1508C for 1 hour.(1)

Corn oil should be stored in an airtight, light-resistant 
container in a cool, dry place. Exposure to excessive heat 
should be avoided. 
12 Incompatibilities 
The photooxidation of corn oil is sensitized by cosmetic and 
drug-grade samples of coated titanium oxide and zinc oxide.(2) 
13 Method of Manufacture 
Refined corn oil is obtained from the germ or embryo of Zea 
mays Linne. (Fam. Gramineae), which contains nearly 50% of 
the fixed oil compared with 3.0–6.5% in the whole kernel. The 
oil is obtained from the embryo by expression and/or solvent 
extraction. Refining involves the removal of free fatty acids, 
phospholipids, and impurities; decolorizing with solid adsorbents; 
dewaxing by chilling; and deodorization at high 
temperature and under vacuum. 
14 Safety 
Corn oil is generally regarded as a relatively nontoxic and 
nonirritant material with an extensive history of usage in food 
preparation. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Spillages of this material are 
very slippery and should be covered with an inert absorbent 
material prior to disposal. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IM injections, 
oral capsules and tablets). Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Almond oil; canola oil; cottonseed oil; peanut oil; sesame oil; 
soybean oil; sunflower oil. 
18 Comments 
Owing to its high content of unsaturated acids, corn oil has 
been used as a replacement for fats and oils containing a high 
content of saturated acids in the diets of patients with 
hypercholesterolemia. 
A specification for corn oil is contained in the Food 
Chemicals Codex (FCC). The EINECS number for corn oil is 
232-281-2. 
19 Specific References 
1 Pasquale D, Jaconia D, Eisman P, Lachman L. A study of sterilizing 
conditions for injectable oils. Bull Parenter Drug Assoc 1964; 
18(3): 1–11. 
2 Sayre RM, Dowdy JC. Titanium dioxide and zinc oxide induce 
photooxidation of unsaturated lipids. Cosmet Toilet 2000; 115: 
75–80, 82. 
20 General References 
Halbaut L, Barbe. C, Aro. ztegui M, de la Torre C. Oxidative stability of 
semi-solid excipient mixtures with corn oil and its implication in the 
degradation of vitamin A. Int J Pharm 1997; 147: 31–40. 
Mann JI, Carter R, Eaton P. Re-heating corn oil does not saturate its 
double bonds [letter]. Lancet 1977; ii: 401. 
Watson SA, Ramstead PE, eds. Corn Chemistry and Technology. St. 
Paul, MN: American Association of Cereal Chemists Inc., 1987: 53– 
78. 
21 Authors 
KS Alexander 
22 Date of Revision 
22 August 2005. 
Corn Oil 205

Cottonseed Oil 
1 Nonproprietary Names 
USPNF: Cottonseed oil 
2 Synonyms 
Cotton oil; refined cottonseed oil. 
3 Chemical Name and CAS Registry Number 
Cottonseed oil [8001-29-4] 
4 Empirical Formula and Molecular Weight 
A typical analysis of refined cottonseed oil indicates the 
composition of the acids present as glycerides to be as follows: 
linoleic acid 39.3%; oleic acid 33.1%; palmitic acid 19.1%; 
stearic acid 1.9%; arachidic acid 0.6%, and myristic acid 0.3%. 
Also present are small quantities of phospholipid, phytosterols, 
and pigments. The toxic polyphenolic pigment gossypol is 
present in raw cottonseed and in the oil cake remaining after 
expression of oil; it is not found in the refined oil. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Oleaginous vehicle; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Cottonseed oil is used in pharmaceutical formulations primarily 
as a solvent for intramuscular injections. It has been used in 
intravenous emulsions as a fat source in parenteral nutrition 
regimens, although its use for this purpose has been superseded 
by soybean oil emulsions; see Section 14. It has also been used 
as an adjuvant in cholecystography and as a pediculicide and 
acaricide. It has the nutritive and emollient properties of fixed 
vegetable oils. By virtue of its high content of unsaturated acid 
glycerides (especially linoleic acid), it is used for dietary control 
of blood cholesterol levels in the prophylaxis and treatment of 
atherosclerosis. It is used as a solvent and vehicle for injections; 
as an emollient vehicle for other medications; and orally as a 
mild cathartic (in a dose of 30mL or more). It can also retard 
gastric secretion and motility, and increase caloric intake. It has 
been used in the manufacture of soaps, oleomargarine, lard 
substitutes, glycerin, lubricants, and cosmetics. 
Cottonseed oil has been used as a tablet binder for 
acetaminophen; for characterization of the hot-melt fluid bed 
coating process;(1) in the manufacturing of stable oral 
pharmaceutical powders; in encapsulation of enzymes; and as 
an aqueous dispersion in pharmaceutical coating. 
8 Description 
Pale yellow or bright golden yellow-colored, clear oily liquid. It 
is odorless, or nearly so, with a bland, nutty taste. At 
temperatures below 108C particles of solid fat may separate 
from the oil, and at about –5 to 08C the oil becomes solid or 
nearly so. If it solidifies, the oil should be remelted and 
thoroughly mixed before use. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for cottonseed oil. 
Test USPNF 23 
Identification . 
Free fatty acids . 
Heavy metals 40.001% 
Iodine value 109–120 
Organic volatile impurities . 
Specific gravity 0.915–0.921 
10 Typical Properties 
Autoignition temperature: 3448C 
Density: 0.916 g/cm3 
Flash point: 3218C 
Freezing point: 5 to 08C 
Heat of combustion: 37.1 kJ/g 
Refractive index: nD
40 = 1.4645–1.4655 
Solubility: slightly soluble in ethanol (95%); miscible with 
carbon disulfide, chloroform, ether, hexane, and petroleum 
ether. 
Surface tension: 
35.4mN/m (35.4 dynes/cm) at 208C; 
31.3mN/m (31.3 dynes/cm) at 808C. 
Viscosity (dynamic): up to 70.4 mPa s (70.4 cP) at 208C 
11 Stability and Storage Conditions 
Cottonseed oil is stable if stored in a well-filled, airtight, lightresistant 
container in a cool, dry place. 
12 Incompatibilities 
—
13 Method of Manufacture 
Cottonseed oil is the refined fixed oil obtained from the seed of 
cultivated varieties of Gossypium hirsutum Linne. or of other 
species of Gossypium (Fam. Malvaceae). The seeds contain 
about 15% oil. The testae of the seeds are first separated and 
the kernels are then exposed to powerful expression in a 
hydraulic press. The crude oil thus obtained has a bright red or 
blackish-red color and requires purification before it is suitable 
for food or pharmaceutical purposes.

Cottonseed oil is refined by treatment with diluted alkali to 
neutralize acids, decolorized with fuller’s earth or activated 
carbon, deodorized with steam under reduced pressure, and 
chilled to separate glycerides and resinous substances of higher 
melting point. 
14 Safety 
Cottonseed oil emulsions have in the past been used in longterm 
intravenous nutrition regimens.(2,3) A complex of adverse 
reactions, called the ‘overloading syndrome’(4) has been seen 
with chronic administration of cottonseed oil emulsion. This 
consisted of anorexia, nausea, abdominal pain, headache, fever, 
and sore throat. Signs of impaired liver function, anemia, 
hepatosplenomegaly, thrombocytopenia, and spontaneous 
hemorrhage due to delayed blood clotting have been reported. 
For parenteral nutrition purposes, cottonseed oil has been 
replaced by soybean oil,(2,5,6) especially in pregnant women, 
where the use of cottonseed lipid emulsion has been associated 
with adverse effects.(7) 
A notable difference between the cottonseed oil emulsion 
and the soybean oil emulsion is the particle size. The cottonseed 
oil emulsion has much larger particles than the soybean oil 
emulsion. These larger particles may have been handled 
differently by the body, thus perhaps accounting for some of 
the toxic reactions. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Spillages of this material are 
very slippery and should be covered with an inert absorbent 
material prior to disposal. 
Cottonseed oil is a combustible liquid when exposed to heat 
or flame. If it is allowed to impregnate rags or oily waste, there 
is a risk due to spontaneous heating. Dry chemicals such as 
carbon dioxide should be used to fight any fires. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IM injections, 
oral, capsule, tablet and sublingual preparations). Included in 
the Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Almond oil; canola oil; corn oil; hydrogenated vegetable oil; 
peanut oil; sesame oil; soybean oil; sunflower oil. 
18 Comments 
A specification for unhydrogenated cottonseed oil is contained 
in the Food Chemicals Codex (FCC). The EINECS number for 
cottonseed oil is 232-280-7. 
19 Specific References 
1 Jozwiakowski MJ, Jones DM, Franz RM. Characterization of a 
hot-melt fluid bed coating process for fine granules. Pharm Res 
1990; 7: 1119–1126. 
2 McNiff BL. Clinical use of 10% soybean oil emulsion. Am J Hosp 
Pharm 1977; 34: 1080–1086. 
3 Cole WH. Fat emulsion for intravenous use. J Am Med Assoc 
1958; 166: 1042–1043. 
4 Goulon M, Barois A, Grosbuis S, Schortgen G. Fat embolism after 
repeated perfusion of lipid emulsion. Nouv Presse Med 1974; 3: 
13–18. 
5 Davis SS. Pharmaceutical aspects of intravenous fat emulsions. J 
Hosp Pharm 1974; 32: 149–160, 165–171. 
6 Singh M, Ravin LJ. Parenteral emulsions as drug carrier systems. J 
Parenter Sci Technol 1986; 41: 34–41. 
7 Amato P, Quercia RA. Historical perspective and review of the 
safety of lipid emulsion in pregnancy. Nutr Clin Prac 1991; 6(5): 
189–192. 
20 General References 
—
21 Authors 
KS Alexander. 
22 Date of Revision 
22 August 2005. 
Cottonseed Oil 207

Cresol 
1 Nonproprietary Names 
BP: Cresol 
JP: Cresol 
USPNF: Cresol 
2 Synonyms 
Cresylic acid; cresylol; hydroxytoluene; tricresol. 
3 Chemical Name and CAS Registry Number 
Methylphenol [1319-77-3] 
4 Empirical Formula and Molecular Weight 
C7H8O 108.14 
5 Structural Formula 
m-Cresol 
6 Functional Category 
Antimicrobial preservative; disinfectant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Cresol is used at 0.15–0.3% concentration as an antimicrobial 
preservative in intramuscular, intradermal, and subcutaneous 
injectable pharmaceutical formulations. It is also used as a 
preservative in some topical formulations and as a disinfectant. 
Cresol is not suitable as a preservative for preparations that are 
to be freeze-dried.(1) 
8 Description 
Cresol consists of a mixture of cresol isomers, predominantly 
m-cresol, and other phenols obtained from coal tar or 
petroleum. It is a colorless, yellowish to pale brownish-yellow, 
or pink-colored liquid, with a characteristic odor similar to 
phenol but more tarlike. An aqueous solution has a pungent 
taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for cresol. 
Test BP 2004 JP 2001 USPNF 23 
Identification . . . 
Characters . — — 
Specific gravity 1.029–1.044 1.032–1.041 1.030–1.038 
Distilling range . . 195–2058C 
Acidity . — — 
Hydrocarbons 40.15% . . 
Volatile bases 40.15% — — 
Hydrocarbons and 
volatile bases 
combined 
40.25% — — 
Phenol — — 45.0% 
Sulfur compounds . . — 
Nonvolatile matter 40.1% — — 
10 Typical Properties 
Acidity/alkalinity: a saturated aqueous solution is neutral or 
slightly acidic to litmus. 
Antimicrobial activity: cresol is similar to phenol but has 
slightly more antimicrobial activity. It is moderately active 
against Gram-positive bacteria, less active against Gramnegative 
bacteria, yeasts, and molds. Cresol is active below 
pH 9; optimum activity is obtained in acidic conditions. 
Synergistic effects between cresol and other preservatives 
have been reported.(2,3) When used as a disinfectant most 
common pathogens are killed within 10 minutes by 
0.3–0.6% solutions. Cresol has no significant activity 
against bacterial spores. 
Solubility: see Table II. 
Table II: Solubility of cresol. 
Solvent Solubility at 208C 
Benzene Miscible 
Chloroform Freely soluble 
Ethanol (95%) Freely soluble 
Ether Freely soluble 
Fixed alkali hydroxides Freely soluble 
Fixed and volatile oils Freely soluble 
Glycerin Miscible 
Water 1 in 50 
11 Stability and Storage Conditions 
Cresol and aqueous cresol solutions darken in color with age 
and on exposure to air and light. 
Cresol should be stored in a well-closed container, protected 
from light, in a cool, dry place. 
12 Incompatibilities 
Cresol has been reported to be incompatible with chlorpromazine.(
4) Antimicrobial activity is reduced in the presence of 
nonionic surfactants.

13 Method of Manufacture 
Cresol may be obtained from coal tar or prepared synthetically 
by either sulfonation or oxidation of toluene. 
14 Safety 
Reports of adverse reactions to cresol are generally associated 
with the use of either the bulk material or cresol-based 
disinfectants, which may contain up to 50% cresol, rather 
than for its use as a preservative. 
Cresol is similar to phenol although it is less caustic and 
toxic. However, cresol is sufficiently caustic to be unsuitable for 
skin and wound disinfection. In studies in rabbits, cresol was 
found to be metabolized and excreted primarily as the 
glucuronide.(5) 
A patient has survived ingestion of 12 g of cresol though 
with severe adverse effects.(6) 
LD50 (mouse, oral): 0.76 g/kg(7) 
LD50 (rabbit, skin): 2 g/kg 
LD50 (rat, oral): 1.45 g/kg 
See also Sections 17 and 18. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Cresol may be irritant to the 
skin, eyes, and mucous membranes. Eye protection, gloves, and 
a respirator are recommended. In the UK, the occupational 
exposure limit for cresol is 22 mg/m3 (5 ppm) long-term (8-hour 
TWA).(8) In the USA, the permissible and recommended 
exposure limits are 22 mg/m3 long-term and 10 mg/m3 longterm 
respectively.(9) 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IM, IV, 
intradermal, and SC injections). Included in parenteral 
medicines licensed in the UK. Included in the Canadian List 
of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Chlorocresol; m-cresol; o-cresol; p-cresol; phenol. 
m-Cresol 
Empirical formula: C7H8O 
Molecular weight: 108.14 
CAS number: [108-39-4] 
Synonyms: m-cresylic acid; 3-hydroxytoluene; meta-cresol; 3- 
methylphenol. 
Appearance: colorless or yellowish liquid with a characteristic 
phenolic odor. 
Boiling point: 2028C 
Density: 1.034 g/cm3 at 208C 
Flash point: 868C (closed cup) 
Melting point: 11–128C 
Refractive index: nD
20 = 1.5398 
Solubility: soluble in organic solvents; soluble 1 in 40 parts of 
water. 
Safety:
LD50 (cat, SC): 0.15 g/kg(7,10) 
LD50 (mouse, IP): 0.17 g/kg 
LD50 (mouse, oral): 0.83 g/kg 
LD50 (mouse, SC): 0.45 g/kg 
LD50 (rabbit, IV): 0.28 g/kg 
LD50 (rabbit, oral): 1.1 g/kg 
LD50 (rabbit, SC): 0.5 g/kg 
LD50 (rabbit, skin): 2.05 g/kg 
LD50 (rat, oral): 2.02 g/kg 
LD50 (rat, skin): 1.1 g/kg 
o-Cresol 
Empirical formula: C7H8O 
Molecular weight: 108.14 
CAS number: [95-48-7] 
Synonyms: o-cresylic acid; 2-hydroxytoluene; 2-methylphenol; 
ortho-cresol. 
Appearance: colorless deliquescent solid with a characteristic 
odor; it becomes yellow on storage. 
Boiling point: 191–1928C 
Density: 1.047 g/cm3 at 208C 
Flash point: 81–838C (closed cup) 
Melting point: 308C 
Refractive index: nD
20 = 1.553 
Safety:
LD50 (cat, SC): 0.6 g/kg(7,10) 
LD50 (mouse, oral): 0.34 g/kg 
LD50 (mouse, SC): 0.35 g/kg 
LD50 (mouse, skin): 0.62 g/kg 
LD50 (rabbit, IV): 0.2 g/kg 
LD50 (rabbit, oral): 0.8 g/kg 
LD50 (rabbit, SC): 0.45 g/kg 
LD50 (rat, oral): 1.35 g/kg 
LD50 (rat, skin): 0.62 g/kg 
p-Cresol 
Empirical formula: C7H8O 
Molecular weight: 108.14 
CAS number: [106-44-5] 
Synonyms: p-cresylic acid; 4-hydroxytoluene; 4-methylphenol; 
para-cresol. 
Appearance: crystalline solid. 
Boiling point: 201.88C 
Density: 1.0341 g/cm3 at 208C 
Flash point: 868C (closed cup) 
Melting point: 35.58C 
Refractive index: nD
20 = 1.5395 
Solubility: soluble in ethanol (95%) and ether; very slightly 
soluble in water. 
Safety:
LD50 (cat, SC): 0.08 g/kg(7,10) 
LD50 (mouse, IP): 0.03 g/kg 
LD50 (mouse, oral): 0.34 g/kg 
LD50 (mouse, SC): 0.15 g/kg 
LD50 (rabbit, IV): 0.16 g/kg 
LD50 (rabbit, oral): 1.1 g/kg 
LD50 (rabbit, SC): 0.3 g/kg 
LD50 (rabbit, skin): 0.3 g/kg 
LD50 (rat, oral): 1.80 g/kg 
LD50 (rat, skin): 0.75 g/kg 
18 Comments 
m-Cresol is generally considered the least toxic of the three 
cresol isomers.(10) Inhalation of aerosolized m-cresol in 
pulmonary insulin delivery formulations has been shown to 
be safe in animal models.(11) 
The PhEur 2005 contains a specification for cresol, crude. 
The EINECS number for cresol is 203–577–9. 
Cresol 209

19 Specific References 
1 FAO/WHO. WHO expert committee on biological standardization. 
Thirty-seventh report. World Health Organ Tech Rep Ser 
1987; No. 760. 
2 Denyer SP, Baird RM, eds. Guide to Microbiological Control in 
Pharmaceuticals. Chichester: Ellis Horwood, 1990: 261. 
3 Hugbo PG. Additive and synergistic actions of equipotent 
admixtures of some antimicrobial agents. Pharm Acta Helv 
1976; 51: 284–288. 
4 McSherry TJ. Incompatibility between chlorpromazine and 
metacresol [letter]. Am J Hosp Pharm 1987; 44: 1574. 
5 Cresol. In: The Pharmaceutical Codex, 11th edn. London: 
Pharmaceutical Press, 1979: 232. 
6 Co. te. MA, Lyonnais J, Leblond PF. Acute Heinz-body anemia due 
to severe cresol poisoning: successful treatment with erythrocytapheresis. 
Can Med Assoc J 1984; 130: 1319–1322. 
7 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1003. 
8 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: HSE Books, 2002. 
9 NIOSH. Recommendations for occupational safety and health 
standard. MMWR 1988; 37(Suppl S-7): 1–29. 
10 Deichmann WB, Keplinger ML. Phenols and phenolic compounds. 
In: Clayton GD, Clayton FE, eds. Patty’s Industrial Hygiene and 
Toxicology, 3rd edn. New York: Wiley, 1981: 2597–2600. 
11 Gopalakrishnan V, Uster P, Rajendran N, Yoshida M. Inhalation 
safety of phenol and m-cresol in rodents: a fourteen-day repeat 
dose study. Presented at ISAM congress 2001, Interlaken, Switzerland. 
20 General References 
Chapman DG. o-Cresol. In: Board RG, Allwood MC, Banks JG, eds. 
Preservatives in the Food, Pharmaceutical and Environmental 
Industries. Oxford: Blackwell Scientific, 1987: 184. 
Russell AD, Jones BD, Milburn P. Reversal of the inhibition of bacterial 
spore germination and outgrowth by antibacterial agents. Int J 
Pharm 1985; 25: 105–112. 
21 Authors 
LY Galichet. 
22 Date of Revision 
17 August 2005. 
210 Cresol

Croscarmellose Sodium 
1 Nonproprietary Names 
BP: Croscarmellose sodium 
PhEur: Carmellosum natricum conexum 
USPNF: Croscarmellose sodium 
2 Synonyms 
Ac-Di-Sol; crosslinked carboxymethylcellulose sodium; Explocel; 
modified cellulose gum; Nymcel ZSX; Pharmacel XL; 
Primellose; Solutab; Vivasol. 
3 Chemical Name and CAS Registry Number 
Cellulose, carboxymethyl ether, sodium salt, crosslinked 
[74811-65-7] 
4 Empirical Formula and Molecular Weight 
Croscarmellose sodium is a crosslinked polymer of carboxymethylcellulose 
sodium. 
See Carboxymethylcellulose sodium. 
5 Structural Formula 
See Carboxymethylcellulose sodium. 
6 Functional Category 
Tablet and capsule disintegrant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Croscarmellose sodium is used in oral pharmaceutical formulations 
as a disintegrant for capsules,(1,2) tablets,(3–13) and 
granules. 
In tablet formulations, croscarmellose sodium may be used 
in both direct-compression and wet-granulation processes. 
When used in wet granulations, the croscarmellose sodium 
should be added in both the wet and dry stages of the process 
(intra- and extragranularly) so that the wicking and swelling 
ability of the disintegrant is best utilized.(11,12) Croscarmellose 
sodium at concentrations up to 5% w/w may be used as a tablet 
disintegrant, although normally 2% w/w is used in tablets 
prepared by direct compression and 3% w/w in tablets 
prepared by a wet-granulation process. See Table I. 
Table I: Uses of croscarmellose sodium. 
Use Concentration (%) 
Disintegrant in capsules 10–25 
Disintegrant in tablets 0.5–5.0 
SEM: 1 
Excipient: Croscarmellose sodium (Ac-Di-Sol) 
Manufacturer: FMC Biopolymer 
Magnification: 100 
SEM: 2 
Excipient: Croscarmellose sodium (Ac-Di-Sol) 
Manufacturer: FMC Biopolymer 
Magnification: 1000

8 Description 
Croscarmellose sodium occurs as an odorless, white or grayishwhite 
powder. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for croscarmellose sodium. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
pH (1% w/v dispersion) 5.0–7.0 5.0–7.0 
Loss on drying 410.0% 410.0% 
Heavy metals 410 ppm 40.001% 
Sodium chloride and sodium glycolate 40.5% 40.5% 
Sulfated ash 14.0–28.0% — 
Degree of substitution 0.60–0.85 0.60–0.85 
Content of water-soluble material 410.0% 1.0–10.0% 
Settling volume 10.0–30.0 ml 10.0–30.0 ml 
Microbial contamination . — 
Aerobic 103/g 103/g 
Fungi 102/g 102/g 
Organic volatile impurities — . 
10 Typical Properties 
Acidity/alkalinity: pH = 5.0–7.0 in aqueous dispersions. 
Bonding index: 0.0456 
Brittle fracture index: 0.1000 
Density (bulk): 0.529 g/cm3 for Ac-Di-Sol(7) 
Density (tapped): 0.819 g/cm3 for Ac-Di-Sol(7) 
Density (true): 1.543 g/cm3 for Ac-Di-Sol(7) 
Particle size distribution: 
Ac-Di-Sol: not more than 2% retained on a #200 (73.7 mm) 
mesh and not more than 10% retained on a #325 (44.5 mm) 
mesh. 
Pharmacel XL: more than 90% less than 45 mm, and more 
than 98% less than 100 mm in size. 
Solubility: insoluble in water, although croscarmellose sodium 
rapidly swells to 4–8 times its original volume on contact 
with water. Practically insoluble in acetone, ethanol and 
toluene. 
Specific surface area: 0.81–0.83m2/g 
11 Stability and Storage Conditions 
Croscarmellose sodium is a stable though hygroscopic material. 
A model tablet formulation prepared by direct compression, 
with croscarmellose sodium as a disintegrant, showed no 
significant difference in drug dissolution after storage at 308C 
for 14 months.(9) 
Croscarmellose sodium should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
The efficacy of disintegrants, such as croscarmellose sodium, 
may be slightly reduced in tablet formulations prepared by 
either the wet-granulation or direct-compression process that 
contain hygroscopic excipients such as sorbitol.(10) 
Croscarmellose sodium is not compatible with strong acids 
or with soluble salts of iron and some other metals such as 
aluminum, mercury, and zinc. 
13 Method of Manufacture 
Alkali cellulose is prepared by steeping cellulose, obtained from 
wood pulp or cotton fibers, in sodium hydroxide solution. The 
alkali cellulose is then reacted with sodium monochloroacetate 
to obtain carboxymethylcellulose sodium. After the substitution 
reaction is completed and all of the sodium hydroxide has 
been used, the excess sodium monochloroacetate slowly 
hydrolyzes to glycolic acid. The glycolic acid changes a few of 
the sodium carboxymethyl groups to the free acid and catalyzes 
the formation of crosslinks to produce croscarmellose sodium. 
The croscarmellose sodium is then extracted with aqueous 
alcohol and any remaining sodium chloride or sodium glycolate 
is removed. After purification, croscarmellose sodium of purity 
greater than 99.5% is obtained.(4) The croscarmellose sodium 
may be milled to break the polymer fibers into shorter lengths 
and hence improve its flow properties. 
14 Safety 
Croscarmellose sodium is mainly used as a disintegrant in oral 
pharmaceutical formulations and is generally regarded as an 
essentially nontoxic and nonirritant material. However, oral 
consumption of large amounts of croscarmellose sodium may 
have a laxative effect, although the quantities used in solid 
dosage formulations are unlikely to cause such problems. 
In the UK, croscarmellose sodium is accepted for use in 
dietary supplements. 
The WHO has not specified an acceptable daily intake for 
the related substance carboxymethylcellulose sodium, used as a 
food additive, since the levels necessary to achieve a desired 
effect were not considered sufficient to be a hazard to health.(14) 
See also Carboxymethylcellulose sodium. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Croscarmellose sodium may 
be irritant to the eyes; eye protection is recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral capsules, 
granules, sublingual tablets, and tablets). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian 
List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Carboxymethylcellulose calcium; carboxymethylcellulose 
sodium. 
18 Comments 
Typically, the degree of substitution (DS) for croscarmellose 
sodium is 0.7. 
19 Specific References 
1 Botzolakis JE, Augsburger LL. Disintegrating agents in hard 
gelatin capsules. Part I: mechanism of action. Drug Dev Ind Pharm 
1988; 14(1): 29–41. 
212 Croscarmellose Sodium

2 Dahl TC, Sue IT, Yum A. The influence of disintegrant level and 
capsule size on dissolution of hard gelatin capsules stored in high 
humidity conditions. Drug Dev Ind Pharm 1991; 17(7): 1001– 
1016. 
3 Gissinger D, Stamm A. A comparative evaluation of the properties 
of some tablet disintegrants. Drug Dev Ind Pharm 1980; 6(5): 
511–536. 
4 Shangraw R, Mitrevej A, Shah M. A new era of tablet 
disintegrants. Pharm Technol 1980; 4(10): 49–57. 
5 Rudnic EM, Rhodes CT, Bavitz JF, Schwartz JB. Some effects of 
relatively low levels of eight tablet disintegrants on a direct 
compression system. Drug Dev Ind Pharm 1981; 7(3): 347–358. 
6 Gorman EA, Rhodes CT, Rudnic EM. An evaluation of 
croscarmellose as a tablet disintegrant in direct compression 
systems. Drug Dev Ind Pharm 1982; 8: 397–410. 
7 Rudnic EM, Rhodes CT, Welch S, Bernado P. Evaluations of the 
mechanism of disintegrant action. Drug Dev Ind Pharm 1982; 8: 
87–109. 
8 Gordon MS, Chowhan ZT. Effect of tablet solubility and 
hygroscopicity on disintegrant efficiency in direct compression 
tablets in terms of dissolution. J Pharm Sci 1987; 76: 907–909. 
9 Gordon MS, Chowhan ZT. The effect of aging on disintegrant 
efficiency in direct compression tablets with varied solubility and 
hygroscopicity, in terms of dissolution. Drug Dev Ind Pharm 1990; 
16: 437–447. 
10 Johnson JR, Wang L-H, Gordon MS, Chowhan ZT. Effect of 
formulation solubility and hygroscopicity on disintegrant efficiency 
in tablets prepared by wet granulation, in terms of 
dissolution. J Pharm Sci 1991; 80: 469–471. 
11 Gordon MS, Rudraraju VS, Dani K, Chowhan ZT. Effect of the 
mode of super disintegrant incorporation on dissolution in wet 
granulated tablets. J Pharm Sci 1993; 82(2): 220–226. 
12 Khattab I, Menon A, Sakr A. Effect of mode of incorporation of 
disintegrants on the characteristics of fluid-bed wet-granulated 
tablets. J Pharm Pharmacol 1993; 45(8): 687–691. 
13 Ferrero C, Mun. oz N, Velasco MV, et al. Disintegrating efficiency 
of croscarmellose sodium in a direct compression formulation. Int 
J Pharm 1997; 147: 11–21. 
14 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirty-fifth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1990; No. 
789. 
20 General References 
DMV International. Technical literature: Pharmacel XL, 1997. 
DMV International. Primellose and Primojel. 
http://www.dmv-international.com (accessed 26 August 2005). 
FMC Corporation. Technical literature: Ac-Di-Sol, 2003. 
J. Rettenmaier and So.hne GmbH. Technical literature: Vivasol, 2001. 
Metsa. -Serla Chemicals BV. Technical literature: Nymcel ZSX, 1995. 
21 Authors 
RT Guest. 
22 Date of Revision 
23 August 2005. 
Croscarmellose Sodium 213

Crospovidone 
1 Nonproprietary Names 
BP: Crospovidone 
PhEur: Crospovidonum 
USPNF: Crospovidone 
2 Synonyms 
Crosslinked povidone; E1202; Kollidon CL; Kollidon CL-M; 
Polyplasdone XL; Polyplasdone XL-10; polyvinylpolypyrrolidone; 
PVPP; 1-vinyl-2-pyrrolidinone homopolymer. 
3 Chemical Name and CAS Registry Number 
1-Ethenyl-2-pyrrolidinone homopolymer [9003-39-8] 
4 Empirical Formula and Molecular Weight 
(C6H9NO)n >1 000 000 
The USPNF 23 describes crospovidone as a water-insoluble 
synthetic crosslinked homopolymer of N-vinyl-2-pyrrolidinone. 
An exact determination of the molecular weight has 
not been established because of the insolubility of the material. 
5 Structural Formula 
See Povidone. 
6 Functional Category 
Tablet disintegrant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Crospovidone is a water-insoluble tablet disintegrant and 
dissolution agent used at 2–5% concentration in tablets 
prepared by direct-compression or wet- and dry-granulation 
methods.(1–6) It rapidly exhibits high capillary activity and 
pronounced hydration capacity, with little tendency to form 
gels. Studies suggest that the particle size of crospovidone 
strongly influences disintegration of analgesic tablets.(7) Larger 
particles provide a faster disintegration than smaller particles. 
Crospovidone can also be used as a solubility enhancer. With 
the technique of co-evaporation, crospovidone can be used to 
enhance the solubility of poorly soluble drugs. The drug is 
adsorbed on to crospovidone in the presence of a suitable 
solvent and the solvent is then evaporated. This technique 
results in faster dissolution rate. 
8 Description 
Crospovidone is a white to creamy-white, finely divided, freeflowing, 
practically tasteless, odorless or nearly odorless, 
hygroscopic powder. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for crospovidone. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
pH (1% suspension) — 5.0–8.0 
Water — 45.0% 
Residue on ignition 40.1% 40.4% 
Water-soluble 
substances 
41.0% 41.50% 
Peroxides 4400 ppm — 
Heavy metals 410 ppm 40.001% 
Vinylpyrrolidinone — 40.1% 
Loss on drying 45.0% — 
Nitrogen content 
(anhydrous basis) 
11.0–12.8% . 
10 Typical Properties 
Acidity/alkalinity: pH = 5.0–8.0 (1% w/v aqueous slurry) 
Density: 1.22 g/cm3 
Density (bulk): see Table II. 
Density (tapped): see Table II. 
Table II: Density values of commercial grades of crospovidone. 
Commercial grade Density (bulk) 
g/cm3 
Density (tapped) 
g/cm3 
Kollidon CL 0.3–0.4 0.4–0.5 
Kollidon CL-M 0.15–0.25 0.3–0.5 
Polyplasdone XL 0.213 0.273 
Polyplasdone XL-10 0.323 0.461 
Moisture content: maximum moisture sorption is approximately 
60%. 
Particle size distribution: less than 400 mm for Polyplasdone 
XL; less than 74 mm for Polyplasdone XL-10. Approximately 
50% greater than 50 mm and maximum of 3% 
greater than 250 mm in size for Kollidon CL. Minimum of 
90% of particles are below 15 mm for Kollidon CL-M. 
Solubility: practically insoluble in water and most common 
organic solvents. 
Specific surface area: see Table III. 
Table III: Specific surface areas for commercial grades of 
crospovidone. 
Commercial grade Surface area 
(m2/g) 
Kollidon CL 1.0 
Kollidon CL-M 3.0–6.0 
Polyplasdone XL 0.6–0.8 
Polyplasdone XL-10 1.2–1.4

SEM 1 
Excipient: Crospovidone (Polyplasdone XL-10) 
Manufacturer: ISP Corp. 
Lot No.: S81031 
Magnification: 400 Voltage: 10 kV 
11 Stability and Storage Conditions 
Since crospovidone is hygroscopic, it should be stored in an 
airtight container in a cool, dry place. 
12 Incompatibilities 
Crospovidone is compatible with most organic and inorganic 
pharmaceutical ingredients. When exposed to a high water 
level, crospovidone may form molecular adducts with some 
materials; see Povidone. 
13 Method of Manufacture 
Acetylene and formaldehyde are reacted in the presence of a 
highly active catalyst to form butynediol, which is hydrogenated 
to butanediol and then cyclodehydrogenated to form 
butyrolactone. Pyrrolidone is produced by reacting butyrolactone 
with ammonia. This is followed by a vinylation reaction in 
which pyrrolidone and acetylene are reacted under pressure. 
The monomer vinylpyrrolidone is then polymerized in solution, 
using a catalyst. Crospovidone is prepared by a ‘popcorn 
polymerization’ process. 
14 Safety 
Crospovidone is used in oral pharmaceutical formulations and 
is generally regarded as a nontoxic and nonirritant material. 
Short-term animal toxicity studies have shown no adverse 
effects associated with crospovidone.(8) However, owing to the 
lack of available data, an acceptable daily intake in humans has 
not been specified by the WHO.(8) 
LD50 (mouse, IP): 12 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection, gloves, and a 
dust mask are recommended. 
16 Regulatory Status 
Accepted for use as a food additive in Europe. Included in the 
FDA Inactive Ingredients Guide (IM injections, oral capsules 
and tablets; topical, transdermal, and vaginal preparations). 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Copovidone; povidone. 
18 Comments 
Crospovidone has been studied as a superdisintegrant. The 
ability of the compound to swell has been examined directly 
using scanning electron microscopy.(9) The impact of crospovidone 
on percolation has also been examined.(10) The 
impact of crospovidone on dissolution of poorly soluble drugs 
in tablets has also been investigated.(11) 
A specification for crospovidone is contained in the Food 
Chemicals Codex (FCC). 
19 Specific References 
1 Kornblum SS, Stoopak SB. A new tablet disintegrating agent: 
crosslinked polyvinylpyrrolidone. J Pharm Sci 1973; 62: 43–49. 
2 Rudnic EM, Lausier JM, Chilamkurti RN, Rhodes CT. Studies of 
the utility of cross linked polyvinylpolypyrrolidine as a tablet 
disintegrant. Drug Dev Ind Pharm 1980; 6: 291–309. 
3 Gordon MS, Chowhan ZT. Effect of tablet solubility and 
hygroscopicity on disintegrant efficiency in direct compression 
tablets in terms of dissolution. J Pharm Sci 1987; 76: 907–909. 
4 Gordon MS, Rudraraju VS, Dani K, Chowhan ZT. Effect of the 
mode of super disintegrant incorporation on dissolution in wet 
granulated tablets. J Pharm Sci 1993; 82: 220–226. 
5 Tagawa M, Chen R, Chen P, et al. Effect of various disintegrants on 
drug release behavior from tablets. J Pharm Sci Tech Yakuzaigaku 
2003; 63(4): 238–248. 
6 Hipasawa N, Ishise S, Miyata M, Danjo K. Application of 
nilvadipine solid dispersion to tablet formulation and manufacturing 
using crospovidone and methylcellulose on dispersion carriers. 
Chem Pharm Bull 2004; 52(2): 244–247. 
7 Schiermeier S, Schmidt PC. Fast dispersible ibuprofen tablets. Eur J 
Pharm Sci 2002; 15(3): 295–305. 
8 FAO/WHO. Evaluation of certain food additives and contaminants. 
Twenty-seventh report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1983; No. 696. 
9 Thibert R, Hancock BC. Direct visualization of superdisintegrant 
hydration using environmental scanning electron microscopy. J 
Pharm Sci 1996; 85: 1255–1258. 
10 Caraballo I, Fernandez-Arevalo M, Millan M, et al. Influence of 
disintegrant on the drug percolation threshold in tablets. Drug Dev 
Ind Pharm 1997; 23(7): 665–669. 
11 Yen SY, Chen CR, Lee MT, Chen LC. Investigation of dissolution 
enhancement of nifedipine by deposition on superdisintegrants. 
Drug Dev Ind Pharm 1997; 23(3): 313–317. 
Crospovidone 215

20 General References 
Barabas ES, Adeyeye CM. Crospovidone. In: Brittain HG, ed. 
Analytical Profiles of Drug Substances and Excipients, vol. 24. 
London: Academic Press, 1996: 87–163. 
BASF. Technical literature: Insoluble Kollidon grades, 1996. 
ISP. Technical literature: Polyplasdone crospovidone NF, 1999. 
Wan LSC, Prasad KPP. Uptake of water by excipients in tablets. Int J 
Pharm 1989; 50: 147–153. 
21 Authors 
AH Kibbe. 
22 Date of Revision 
25 August 2005. 
216 Crospovidone

Cyclodextrins 
1 Nonproprietary Names 
BP: Betadex 
PhEur: Betadexum 
USPNF: Betadex 
Note: b-cyclodextrin (betadex) is the only cyclodextrin to be 
currently described in a pharmacopeia. Alfadex is the rINN for 
a-cyclodextrin. 
2 Synonyms 
Cyclodextrin: Cavitron; cyclic oligosaccharide; cycloamylose; 
cycloglucan; Encapsin; Schardinger dextrin. 
a-Cyclodextrin: alfadex; alpha-cycloamylose; alpha-cyclodextrin; 
alpha-dextrin; Cavamax W6 Pharma; cyclohexaamylose; 
cyclomaltohexose. 
b-Cyclodextrin: beta-cycloamylose; beta-dextrin; Cavamax 
W7 Pharma; cycloheptaamylose; cycloheptaglucan; cyclomaltoheptose; 
Kleptose. 
g-Cyclodextrin: Cavamax W8 Pharma; cyclooctaamylose; 
gamma cyclodextrin. 
3 Chemical Name and CAS Registry Number 
a-Cyclodextrin [10016-20-3] 
b-Cyclodextrin [7585-39-9] 
g-Cyclodextrin [17465-86-0] 
4 Empirical Formula and Molecular Weight 
a-Cyclodextrin C36H60O30 972 
b-Cyclodextrin C42H70O35 1135 
g-Cyclodextrin C48H80O40 1297 
5 Structural Formula 
Note: the structure of b-cyclodextrin (7 glucose units) is 
shown. 
R0, R00 = H for ‘natural’ a-, b- and g-cyclodextrins 
R0, R00 = CH3 for methyl cyclodextrins 
R0, R00 = CHOHCH3 for 2-hydroxyethyl cyclodextrins 
R0, R00 = CH2CHOHCH3 for 2-hydroxypropyl cyclodextrins 
6 Functional Category 
Solubilizing agent; stabilizing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Cyclodextrins are crystalline, nonhygroscopic, cyclic oligosaccharides 
derived from starch. Among the most commonly used 
forms are a-, b-, and g-cyclodextrin, which have respectively 6, 
7, and 8 glucose units; see Section 5. 
Substituted cyclodextrin derivatives are also available; see 
Section 17. 
Cyclodextrins are ‘bucketlike’ or ‘conelike’ toroid molecules, 
with a rigid structure and a central cavity, the size of 
which varies according to the cyclodextrin type; see Section 8. 
The internal surface of the cavity is hydrophobic and the 
outside of the torus is hydrophilic; this is due to the 
arrangement of hydroxyl groups within the molecule. This 
arrangement permits the cyclodextrin to accommodate a guest 
molecule within the cavity, forming an inclusion complex. 
Cyclodextrins may be used to form inclusion complexes 
with a variety of drug molecules, resulting primarily in 
improvements to dissolution and bioavailability owing to 
enhanced solubility and improved chemical and physical 
stability; see Section 18. 
Cyclodextrin inclusion complexes have also been used to 
mask the unpleasant taste of active materials and to convert a 
liquid substance into a solid material. 
b-Cyclodextrin is the most commonly used cyclodextrin, 
although it is the least soluble; see Section 10. It is the least 
expensive cyclodextrin; is commercially available from a 
number of sources; and is able to form inclusion complexes 
with a number of molecules of pharmaceutical interest. 
However, b-cyclodextrin is nephrotoxic and should not be 
used in parenteral formulations; see Section 14. 
b-Cyclodextrin is considered to be nontoxic when administered 
orally, and is primarily used in tablet and capsule 
formulations. b-Cyclodextrin derivatives tend to be nontoxic 
when used either orally or parenterally, and the derivatives 2- 
hydroxypropyl-b-cyclodextrin and 3-hydroxypropyl-b-cyclodextrin 
are becoming increasingly important in pharmaceutical 
formulations.(1–5) 
a-Cyclodextrin is used mainly in parenteral formulations. 
However, as it has the smallest cavity of the cyclodextrins it can 
form inclusion complexes with only relatively few, small-sized 
molecules. In contrast, g-cyclodextrin has the largest cavity and 
can be used to form inclusion complexes with large molecules; 
it has low toxicity and enhanced water solubility. 
In oral tablet formulations, b-cyclodextrin may be used in 
both wet-granulation and direct-compression processes. The 
physical properties of b-cyclodextrin vary depending on the 
manufacturer. However, b-cyclodextrin tends to possess poor

flow properties and requires a lubricant, such as 0.1% w/w 
magnesium stearate, when it is directly compressed.(6,7) 
In parenteral formulations, cyclodextrins have been used to 
produce stable and soluble preparations of drugs that would 
otherwise have been formulated using a nonaqueous solvent. 
In eye drop formulations, cyclodextrins form water-soluble 
complexes with lipophilic drugs such as corticosteroids. They 
have been shown to increase the water solubility of the drug; to 
enhance drug absorption into the eye; to improve aqueous 
stability; and to reduce local irritation.(8) 
Cyclodextrins have also been used in the formulation of 
solutions,(9,10) suppositories,(11,12) and cosmetics.(13,14) 
8 Description 
Cyclodextrins are cyclic oligosaccharides containing at least six 
D-(.)-glucopyranose units attached by a(1!4) glucoside 
bonds. The three natural cyclodextrins, a, b, and g, differ in 
their ring size and solubility. They contain 6, 7, or 8 glucose 
units, respectively. 
Cyclodextrins occur as white, practically odorless, fine 
crystalline powders, having a slightly sweet taste. Some 
cyclodextrin derivatives occur as amorphous powders. 
The PhEur 2005 lists a-cyclodextrin and g-cyclodextrin as 
potential impurities in b-cyclodextrin. 
See also Table I. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for b-cyclodextrin (betadex). 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Color and clarity of solution . . 
pH 5.0–8.0 — 
Specific rotation .160 to .1648 .160 to .1648 
Microbial limits — 41000/g(a) 
Sulfated ash 40.1% 40.1% 
Heavy metals 410 ppm 45 ppm 
Light-absorbing impurities . — 
Loss on drying 416.0% 414.0% 
Related substances . — 
Residual solvents . — 
Reducing sugars 40.2% 41.0% 
Assay (anhydrous basis) 98.0–101.0% 98.0–101.0% 
(a) Tests for Salmonella and Escherichia coli are negative. 
10 Typical Properties 
Compressibility: 21.0–44.0% for b-cyclodextrin. 
Density (bulk): 
a-cyclodextrin: 0.526 g/cm3; 
b-cyclodextrin: 0.523 g/cm3; 
g-cyclodextrin: 0.568 g/cm3. 
Density (tapped): 
a-cyclodextrin: 0.685 g/cm3; 
b-cyclodextrin: 0.754 g/cm3; 
g-cyclodextrin: 0.684 g/cm3. 
Density (true): 
a-cyclodextrin: 1.521 g/cm3; 
g-cyclodextrin: 1.471 g/cm3. 
Melting point: 
a-cyclodextrin: 250–2608C; 
b-cyclodextrin: 255–2658C; 
g-cyclodextrin: 240–2458C. 
Moisture content: 
a-cyclodextrin: 10.2% w/w; 
b-cyclodextrin: 13.0–15.0% w/w; 
g-cyclodextrin: 8–18% w/w. 
Particle size distribution: 
b-cyclodextrin: 7.0–45.0 mm 
Physical characteristics: see Table II. 
Table II: Physical characteristics of cyclodextrins. 
Characteristic Cyclodextrin 
a b g 
Cavity diameter (A) 4.7–5.3 6.0–6.5 7.5–8.3 
Height of torus (A) 7.9 7.9 7.9 
Diameter of periphery (A) 14.6 15.4 17.5 
Approximate volume of cavity (A3) 174 262 472 
Approximate cavity volume 
Per mol cyclodextrin (mL) 104 157 256 
Per g cyclodextrin (mL) 0.1 0.14 0.20 
Note: 1A = 0.1 nm. 
Solubility: 
a-cyclodextrin: soluble 1 in 7 parts of water at 208C, 1 in 3 
at 508C. 
b-cyclodextrin: soluble 1 in 200 parts of propylene glycol, 1 
in 50 of water at 208C, 1 in 20 at 508C; practically insoluble 
in acetone, ethanol (95%), and methylene chloride. 
g-cyclodextrin: soluble 1 in 4.4 parts of water at 208C, 1 in 2 
at 458C. 
Specific rotation [a]D
25: 
a-cyclodextrin: .150.58; 
b-cyclodextrin: .162.08; 
g-cyclodextrin: .177.48. 
Surface tension (at 258C): 
a-cyclodextrin: 71mN/m (71 dynes/cm); 
b-cyclodextrin: 71mN/m (71 dynes/cm); 
g-cyclodextrin: 71mN/m (71 dynes/cm). 
11 Stability and Storage Conditions 
b-Cyclodextrin and other cyclodextrins are stable in the solid 
state if protected from high humidity. 
Cyclodextrins should be stored in a tightly sealed container, 
in a cool, dry place. 
12 Incompatibilities 
The activity of some antimicrobial preservatives in aqueous 
solution can be reduced in the presence of hydroxypropyl-bcyclodextrin.(
15–17) 
13 Method of Manufacture 
Cyclodextrins are manufactured by the enzymatic degradation 
of starch using specialized bacteria. For example, b-cyclodextrin 
is produced by the action of the enzyme cyclodextrin 
glucosyltransferase upon starch or a starch hydrolysate. An 
organic solvent is used to direct the reaction that produces bcyclodextrin, 
and to prevent the growth of microorganisms 
218 Cyclodextrins

during the enzymatic reaction. The insoluble complex of bcyclodextrin 
and organic solvent is separated from the 
noncyclic starch, and the organic solvent is removed in vacuo 
so that less than 1 ppm of solvent remains in the b-cyclodextrin. 
The b-cyclodextrin is then carbon treated and crystallized from 
water, dried, and collected. 
Hydroxyethyl-b-cyclodextrin is made by reacting b-cyclodextrin 
with ethylene oxide; hydroxypropyl-b-cyclodextrin is 
made by reacting b-cyclodextrin with propylene oxide. 
14 Safety 
Cyclodextrins are starch derivatives and are mainly used in oral 
and parenteral pharmaceutical formulations. They are also 
used in topical and ophthalmic formulations.(8) 
Cyclodextrins are also used in cosmetics and food products, 
and are generally regarded as essentially nontoxic and 
nonirritant materials. However, when administered parenterally, 
b-cyclodextrin is not metabolized but accumulates in the 
kidneys as insoluble cholesterol complexes, resulting in severe 
nephrotoxicity.(18) Other cyclodextrins, such as 2-hydroxypropyl-
b-cyclodextrin, have been the subject of extensive toxicological 
studies. They are not associated with nephrotoxicity and 
are reported to be safe for use in parenteral formulations.(3) 
Cyclodextrin administered orally is metabolized by microflora 
in the colon, forming the metabolites maltodextrin, 
maltose, and glucose; which are themselves further metabolized 
before being finally excreted as carbon dioxide and water. 
Although a study published in 1957 suggested that orally 
administered cyclodextrins were highly toxic,(19) more recent 
animal toxicity studies in rats and dogs have shown this not to 
be the case, and cyclodextrins are now approved for use in food 
products and orally administered pharmaceuticals in a number 
of countries. 
Cyclodextrins are not irritant to the skin and eyes, or upon 
inhalation. There is also no evidence to suggest that cyclodextrins 
are mutagenic or teratogenic. 
a-Cyclodextrin: 
LD50 (rat, IP): 1.0 g/kg(20) 
LD50 (rat, IV): 0.79 g/kg 
b-Cyclodextrin: 
LD50 (mouse, IP): 0.33 g/kg(21) 
LD50 (mouse, SC): 0.41 g/kg 
LD50 (rat, IP): 0.36 g/kg 
LD50 (rat, IV): 1.0 g/kg 
LD50 (rat, oral): 18.8 g/kg 
LD50 (rat, SC): 3.7 g/kg 
g-Cyclodextrin: 
LD50 (rat, IP): 4.6 g/kg(20) 
LD50 (rat ,IV): 4.0 g/kg 
LD50 (rat, oral): 8.0 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Cyclodextrins are fine 
organic powders and should be handled in a well-ventilated 
environment. Efforts should be made to limit the generation of 
dust, which can be explosive. 
16 Regulatory Status 
b-cyclodextrin is included in the FDA Inactive Ingredients guide 
(IM, IV injections, and other injection preparations). 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients (stabilizing agent; solubilizing agent ); and in oral 
and rectal pharmaceutical formulations licensed in Europe, 
Japan, and the USA. 
17 Related Substances 
Dimethyl-b-cyclodextrin; 2-hydroxyethyl-b-cyclodextrin; 
2-hydroxypropyl-b-cyclodextrin; 3-hydroxypropyl-b-cyclodextrin; 
trimethyl-b-cyclodextrin. 
Dimethyl-b-cyclodextrin 
Molecular weight: 1331 
Synonyms: DM-b-CD. 
Appearance: white crystalline powder. 
Cavity diameter: 6 A. 
Melting point: 295.0–300.08C 
Moisture content: 41% w/w 
Solubility: soluble 1 in 135 parts of ethanol (95%), and 1 in 
1.75 of water at 258C. Solubility decreases with increasing 
temperature. 
Surface tension: 62mN/m (62 dynes/cm) at 258C 
Method of manufacture: dimethyl-b-cyclodextrin is prepared 
from b-cyclodextrin by the selective methylation of all C2 
secondary hydroxyl groups and all C6 primary hydroxyl 
groups (C3 secondary hydroxyl groups remain unsubstituted). 
Comments: used in applications similar to those for bcyclodextrin.(
2,3) 
2-Hydroxyethyl-b-cyclodextrin 
CAS number: [98513-20-3] 
Synonyms: 2-HE-b-CD. 
Appearance: white crystalline powder. 
Density (bulk): 0.681 g/cm3 
Density (tapped): 0.916 g/cm3 
Density (true): 1.378 g/cm3 
Solubility: greater than 1 in 2 parts of water at 258C. 
Surface tension: 68.0–71.0mN/m (68–71 dynes/cm) at 258C. 
Comments: used in applications similar to those for 
b-cyclodextrin. The degree of substitution of hydroxyethyl 
groups can vary.(2,3,22) 
2-Hydroxypropyl-b-cyclodextrin 
CAS number: [128446-35-5] 
Synonyms: 2-HP-b-CD; Kleptose HPB. 
Appearance: white crystalline powder. 
Solubility: greater than 1 in 2 parts of water at 258C. 
Surface tension: 52.0–69.0mN/m (52–69 dynes/cm) at 258C. 
Comments: used in applications similar to those for bcyclodextrin. 
However, as it is not nephrotoxic it has been 
suggested for use in parenteral formulations. Included in 
oral and parenteral pharmaceutical formulations licensed in 
Europe and the USA. The degree of substitution of 
hydroxypropyl groups can vary.(1–5) 
3-Hydroxypropyl-b-cyclodextrin 
Synonyms: 3-HP-b-CD. 
Appearance: white crystalline powder. 
Solubility: greater than 1 in 2 parts of water at 258C. 
Surface tension: 70.0–71.0mN/m (70–71 dynes/cm) at 258C. 
Cyclodextrins 219

Comments: used in applications similar to those for bcyclodextrin. 
However, as it is not nephrotoxic it has been 
suggested for use in parenteral formulations. The degree of 
substitution of hydroxypropyl groups can vary.(2,3) 
Trimethyl-b-cyclodextrin 
Molecular weight: 1429 
Synonyms: TM-b-CD. 
Appearance: white crystalline powder. 
Cavity diameter: 4.0–7.0 A .
Melting point: 1578C 
Moisture content: 41% w/w 
Solubility: soluble 1 in 3.2 parts of water at 258C. Solubility 
decreases with increasing temperature. 
Surface tension: 56mN/m (56 dynes/cm) at 258C. 
Method of manufacture: trimethyl-b-cyclodextrin is prepared 
from b-cyclodextrin by the complete methylation of all C2 
and C3 secondary hydroxyl groups along with all C6 
primary hydroxyl groups. 
Comments: used in applications similar to those for bcyclodextrin.(
2,3) 
18 Comments 
In addition to their use in pharmaceutical formulations, 
cyclodextrins have also been investigated for use in various 
industrial applications. Analytically, cyclodextrin polymers are 
used in chromatographic separations, particularly of chiral 
materials. 
b-Cyclodextrin derivatives are more water-soluble than bcyclodextrin, 
and studies have shown that they have greater 
solubilizing action with some drugs such as ibuproxam, a 
poorly water-soluble anti-inflammatory agent.(23,24) 
The EINECS number for cyclodextrin is 231-493-2. 
19 Specific References 
1 Brewster ME, Simpkins JW, Hora MS, et al. The potential use of 
cyclodextrins in parenteral formulations. J Parenter Sci Technol 
1989; 43: 231–240. 
2 Duche.ne D, Wouessidjewe D. Physicochemical characteristics and 
pharmaceutical uses of cyclodextrin derivatives, part I. Pharm 
Technol 1990; 14(6): 26, 28, 34. 
3 Duche.ne D, Wouessidjewe D. Physicochemical characteristics and 
pharmaceutical uses of cyclodextrin derivatives, part II. Pharm 
Technol 1990; 14(8): 14, 22, 24, 26. 
4 Brewster ME, Hora MS, Simpkins JW, Bodor N. Use of 2- 
hydroxypropyl-b-cyclodextrin as a solubilizing and stabilizing 
excipient for protein drugs. Pharm Res 1991; 8(6): 792–795. 
5 Choudhury S, Nelson KF. Improvement of oral bioavailability of 
carbamazepine by inclusion in 2-hydroxypropyl-b-cyclodextrin. 
Int J Pharm 1992; 85: 175–180. 
6 El Shaboury MH. Physical properties and dissolution profiles of 
tablets directly compressed with b-cyclodextrin. Int J Pharm 1990; 
63: 95–100. 
7 Shangraw RF, Pande GS, Gala P. Characterization of the tableting 
properties of b-cyclodextrin and the effects of processing variables 
on inclusion complex formation, compactibility and dissolution. 
Drug Dev Ind Pharm 1992; 18(17): 1831–1851. 
8 Loftsson T, Stefansson E. Cyclodextrins in eye drop formulations: 
enhanced topical delivery of corticosteroids to the eye. Acta 
Ophthamol Scand 2002; 80(2): 144–150. 
9 Prankerd RJ, Stone HW, Sloan KB, Perrin JH. Degradation of 
aspartame in acidic aqueous media and its stabilization by 
complexation with cyclodextrins or modified cyclodextrins. Int J 
Pharm 1992; 88: 189–199. 
10 Palmieri GF, Wehrle. P, Stamm A. Inclusion of vitamin D2 in bcyclodextrin. 
Evaluation of different complexation methods. Drug 
Dev Ind Pharm 1993; 19(8): 875–885. 
11 Szente L, Apostol I, Szejtli J. Suppositories containing bcyclodextrin 
complexes, part 1: stability studies. Pharmazie 
1984; 39: 697–699. 
12 Szente L, Apostol I, Gerloczy A, Szejtli J. Suppositories containing 
b-cyclodextrin complexes, part 2: dissolution and absorption 
studies. Pharmazie 1985; 40: 406–407. 
13 Amann M, Dressnandt G. Solving problems with cyclodextrins in 
cosmetics. Cosmet Toilet 1993; 108(11): 90, 92–95. 
14 Buschmann HJ, Schollmeyer E. Applications of cyclodextrins in 
cosmetic products: a review. J Cosmet Sci 2002; 53(3): 185–191. 
15 Loftsson T, Stefa.nsdo. ttir O.
, Fridriksdo. ttir H, Gudmundsson O.
. 
Interactions between preservatives and 2-hydroxypropyl-b-cyclodextrin. 
Drug Dev Ind Pharm 1992; 18(13): 1477–1484. 
16 Lehner SJ, Mu. ller BW, Seydel JK. Interactions between phydroxybenzoic 
acid esters and hydroxypropyl-b-cyclodextrin 
and their antimicrobial effect against Candida albicans. Int J 
Pharm 1993; 93: 201–208. 
17 Lehner SJ, Mu. ller BW, Seydel JK. Effect of hydroxypropyl-bcyclodextrin 
on the antimicrobial action of preservatives. J Pharm 
Pharmacol 1994; 46: 186–191. 
18 Frank DW, Gray JE, Weaver RN. Cyclodextrin nephrosis in the 
rat. Am J Pathol 1976; 83: 367–382. 
19 French D. The Schardinger dextrins. Adv Carbohydr Chem 1957; 
12: 189–260. 
20 Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. 
Cincinnati: US Department of Health, 1987: 1721. 
21 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1031. 
22 Menard FA, Dedhiya MG, Rhodes CT. Potential pharmaceutical 
applications of a new beta cyclodextrin derivative. Drug Dev Ind 
Pharm 1988; 14(11): 1529–1547. 
23 Mura P, Zerrouk N, Faucci M, et al. Comparative study of 
ibuproxam complexation with amorphous beta-cyclodextrin 
derivatives in solution and in the solid state. Eur J Pharm 
Biopharm 2002; 54(2): 181. 
24 Liu X, Lin HS, Chan SY, Ho PC. Biopharmaceuticals of betacyclodextrin 
derivative-based formulations of acitretin in Sprague- 
Dawley rats. J Pharm Sci 2004; 93(4): 805–815. 
20 General References 
Bekers O, Uijtendaal EV, Beijnen JH, et al. Cyclodextrins in the 
pharmaceutical field. Drug Dev Ind Pharm 1991; 17: 1503–1549. 
Bender ML, Komiyama M. Cyclodextrin Chemistry. New York: 
Springer-Verlag, 1978. 
Carpenter TO, Gerloczy A, Pitha J. Safety of parenteral hydroxypropyl 
b-cyclodextrin. J Pharm Sci 1995; 84: 222–225. 
Chaubal MV. Drug delivery applications of cyclodextrins Part I. Drug 
Dev Technol 2002; 2(7): 34–38. 
Chaubal MV. Drug delivery applications of cyclodextrins Part II. Drug 
Dev Technol 2003; 3(2): 34–36. 
Darrouzet H. Preparing cyclodextrin inclusion compounds. Manuf 
Chem 1993; 64(11): 33–34. 
Fenyvest E.
, Antal B, Zsadon B, Szejtli J. Cyclodextrin polymer, a new 
tablet disintegrating agent. Pharmazie 1984; 39: 473–475. 
Leroy-Lechat F, Wouessidjewe D, Andreux J-P, et al. Evaluation of the 
cytotoxicity of cyclodextrins and hydroxypropylated derivatives. 
Int J Pharm 1994; 101: 97–103. 
Loftsson T, Brewster ME. Pharmaceutical applications of cyclodextrins 
1: drug solubilization and stabilization. J Pharm Sci 1996; 85(10): 
1017–1025. 
Loftsson T, Brewster ME. Cyclodextrins as pharmaceutical excipients. 
Pharm Technol Eur 1997; 9(5): 26–34. 
Loftsson T. Pharmaceutical applications of b-cyclodextrin. Pharm 

Technol 1999; 23(12): 40–50. 
Loftsson T, Masson M. Cyclodextrins in topical drug formulations: 
theory and practice. Int J Pharm 2001; 225: 15–30. 
Loftsson T, Masson M, Brewster ME. Self-association of cyclodextrins 
and cyclodextrin complexes. J Pharm Sci 2004; 93(4): 1091–1099. 
220 Cyclodextrins

Pande GS, Shangraw RF. Characterization of b-cyclodextrin for direct 
compression tableting. Int J Pharm 1994; 101: 71–80. 
Pande GS, Shangraw RF. Characterization of b-cyclodextrin for direct 
compression tableting II: the role of moisture in the compactibility 
of b-cyclodextrin. Int J Pharm 1995; 124: 231–239. 
Pitha J, Szente L, Szejtli J. Molecular encapsulation by cyclodextrin and 
congeners. In: Bruck SD, ed. Controlled Drug Delivery, vol. I. Boca 
Raton, FL: CRC Press, 1983. 
Shao Z, Krishinamoorthy R, Mitra AK. Cyclodextrins as nasal 
absorption promoters of insulin: mechanistic evaluations. Pharm 
Res 1992; 9: 1157–1163. 
Sina VR, Nanda A, Kumria R. Cyclodextrins as sustained-release 
carriers. Pharm Technol 2002; 26(10): 36–46. 
Stella VJ, Rajewski RA. Cyclodextrins: their future in drug formulation. 
Pharm Res 1997; 14(5): 556–567. 
Stoddard F, Zarycki R. Cyclodextrins. Boca Raton, FL: CRC Press, 
1991. 
Strattan CE. 2-Hydroxypropyl-b-cyclodextrin, part II: safety and 
manufacturing issues. Pharm Technol 1992; 16(2): 52, 54, 56, 58. 
Szejtli J. Cyclodextrins in drug formulations: part I. Pharm Technol Int 
1991; 3(2): 15–18, 20–22. 
Szejtli J. Cyclodextrins in drug formulations: part II. Pharm Technol Int 
1991; 3(3): 16, 18, 20, 22, 24. 
Szejtli J. General overview of cyclodextrin. Chem Rev 1998; 98: 1743– 
2076. 
Yamamoto M, Yoshida A, Hirayama F, Uekama K. Some physicochemical 
properties of branched b-cyclodextrins and their inclusion 
characteristics. Int J Pharm 1989; 49: 163–171. 
21 Authors 
RA Nash. 
22 Date of Revision 
23 August 2005. 
Cyclodextrins 221

Cyclomethicone 
1 Nonproprietary Names 
USPNF: Cyclomethicone 
2 Synonyms 
Dimethylcyclopolysiloxane; Dow Corning 245 Fluid; Dow 
Corning 246 Fluid; Dow Corning 345 Fluid. 
3 Chemical Name and CAS Registry Number 
Cyclopolydimethylsiloxane [69430-24-6] 
4 Empirical Formula and Molecular Weight 
The USPNF 23 describes cyclomethicone as a fully methylated 
cyclic siloxane containing repeating units of the formula 
[–(CH3)2SiO–]n in which n is 4, 5, or 6, or a mixture of them. 
5 Structural Formula 
6 Functional Category 
Emollient; humectant; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Cyclomethicone is mainly used in topical pharmaceutical and 
cosmetic formulations such as water-in-oil creams.(1–3) 
Cyclomethicone has been used in cosmetic formulations, at 
concentrations of 0.1–50%, since the late 1970s and is now the 
most widely used silicone in the cosmetics industry. Its high 
volatility, and mild solvent properties, make it ideal for use in 
topical formulations because its low heat of vaporization means 
that when applied to skin it has a ‘dry’ feel. 
See also Dimethicone. 
8 Description 
Cyclomethicone occurs as a clear, colorless and tasteless volatile 
liquid. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for cyclomethicone. 
Test USPNF 23 
Identification . 
Limit of nonvolatile residue 40.15% 
Assay of (C2H6OSi)n calculated as the sum of 
cyclomethicone 4, cyclomethicone 5, and 
cyclomethicone 6 
598.0% 
Assay of individual cyclomethicone components 95.0–105.0% 
10 Typical Properties 
Solubility: soluble in ethanol (95%), isopropyl myristate, 
isopropyl palmitate, mineral oil, and petrolatum at 808C; 
practially insoluble in glycerin, propylene glycol, and water. 
See also Table II. 
11 Stability and Storage Conditions 
Cyclomethicone should be stored in an airtight container in a 
cool, dry, place. 
12 Incompatibilities 
—
13 Method of Manufacture 
Cyclomethicone is manufactured by the distillation of crude 
polydimethylsiloxanes. 
14 Safety 
Cyclomethicone is generally regarded as a relatively nontoxic 
and nonirritant material. Although it has been used in oral 
pharmaceutical applications, cyclomethicone is mainly used in 
topical pharmaceutical formulations. It is also widely used in 
cosmetics. Studies of the animal and human toxicology of 
cyclomethicone suggest that it is nonirritant and not absorbed 
through the skin. Only small amounts are absorbed orally; an 
acute oral dose in rats produced no deaths.(4,5) 
See also Dimethicone. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral powder 
for reconstitution). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients.

17 Related Substances 
Dimethicone; simethicone. 
18 Comments 
–
19 Specific References 
1 Goldenberg RL, Tassof JA, DiSapio AJ. Silicones in clear 
formulations. Drug Cosmet Ind 1986; 138(Feb): 34, 38, 40, 44. 
2 Chandra D, DiSapio A, Frye C, Zellner D. Silicones for cosmetics 
and toiletries: environmental update. Cosmet Toilet 1994; 
109(Mar): 63–66. 
3 Forster AH, Herrington TM. Rheology of siloxane-stabilized 
water in silicone emulsions. Int J Cosmet Sci 1997; 19(4): 173– 
191. 
4 Anonymous. Final report on the safety assessment of cyclomethicone. 
J Am Coll Toxicol 1991; 10(1): 9–19. 
5 Christopher SM, Myers RC, Ballantyne B. Acute toxicologic 
evaluation of cyclomethicone. J Am Coll Toxicol 1994; 12(6): 578. 
20 General References 
—
21 Authors 
RT Guest. 
22 Date of Revision 
22 August 2005. 
Table II: Typical physical properties of selected commercially available cyclomethicones. 
Grade Boiling 
point (8C) 
Flash 
point (8C) 
Freezing 
point (8C) 
Refractive 
index at 258C 
Surface tension 
(mN/m) 
Specific gravity 
at 258C 
Viscosity 
(kinematic) 
(mm2/s) 
Water 
content 
(%) 
Dow Corning 245 Fluid 205 77 <50 1.397 18.0 0.95 4.0 0.025 
Dow Corning 246 Fluid 245 93 <40 1.402 18.8 0.96 6.8 0.025 
Dow Corning 345 Fluid 217 77 <50 1.398 20.8 0.957 6.0 0.025 
Cyclomethicone 223

Denatonium Benzoate 
1 Nonproprietary Names 
USPNF: Denatonium benzoate 
2 Synonyms 
Bitrex; Bitterguard; N-[2-(2,6-dimethylphenyl)amino]-2- 
oxoethyl]-N,N-diethylbenzenemethanaminium benzoate 
monohydrate; lignocaine benzyl benzoate. 
3 Chemical Name and CAS Registry Number 
Benzyldiethyl[(2,6-xylylcarbamolyl)methyl]ammonium benzoate 
anhydrous [3734-33-6] 
Benzyldiethyl[(2,6-xylylcarbamolyl)methyl]ammonium benzoate 
monohydrate [86398-53-0] 
4 Empirical Formula and Molecular Weight 
C28H34N2O3 446.59 (for anhydrous) 
C28H34N2O3H2O 464.60 (for monohydrate) 
5 Structural Formula 
6 Functional Category 
Alcohol denaturant; flavoring agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Denatonium benzoate is among the most bitter of substances 
known and is detectable at concentrations of approximately 
10 ppb. In pharmaceutical and other industrial applications it is 
added to some products as a deterrent to accidental ingestion.(
1–4) It is most commonly used at levels of 5–500 ppm. 
Denatonium benzoate may also be used to replace brucine or 
quassin as a denaturant for ethanol. 
In pharmaceutical formulations, denatonium benzoate has 
been used as a flavoring agent in placebo tablets, and in a 
topical formulation it has been used in an anti-nailbiting 
preparation.(5) 
8 Description 
Denatonium benzoate occurs as an odorless, very bitter tasting, 
white crystalline powder or granules. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for denatonium benzoate. 
Test USPNF 23 
Identification . 
Melting range 163–1708C 
pH (3% aqueous solution) 6.5–7.5 
Loss on drying (monohydrate) 43.5–4.5% 
Loss on drying (anhydrous) 41.0% 
Residue on ignition 40.1% 
Chloride 40.2% 
Assay (dried substance) 99.5–101.0% 
10 Typical Properties 
Density (bulk): 0.3–0.6 g/cm3 
Density (tapped): 0.4–0.7 g/cm3 
Solubility: very soluble in chloroform, and methanol; soluble in 
ethanol (95%), and water; sparingly soluble in acetone; 
practically insoluble in ether. 
11 Stability and Storage Conditions 
Denatonium benzoate is stable up to 1408C and over a wide pH 
range. It should be stored in a well-closed container (such as 
polythene-lined steel) in a cool, dry place. Aqueous or alcoholic 
solutions retain their bitterness for several years even when 
exposed to light. 
12 Incompatibilities 
Denatonium benzoate is incompatible with strong oxidizing 
agents. 
13 Method of Manufacture 
Denatonium benzoate was first synthesized in the 1950s and is 
usually prepared by reacting denatonium chloride with benzyl 
benzoate. 
14 Safety 
Denatonium benzoate is generally regarded as a nonirritant and 
nonmutagenic substance. However, there has been a single 
report of contact urticaria attributed to denatonium benzoate 
occurring in a 30-year-old man who developed asthma and 
pruritus after using an insecticidal spray denatured with 
denatonium benzoate.(6) 
LD50 (rabbit, oral): 0.508 g/kg(7) 
LD50 (rat, oral): 0.584 g/kg

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Containers should be kept 
tightly closed and handled in areas with good ventilation. Eye 
protection, gloves, and a dust mask are recommended. 
Denatonium benzoate is moderately toxic by ingestion and 
when heated to decomposition emits toxic vapors of NOx. 
Denatonium benzoate may also cause hypersensitization. 
16 Regulatory Status 
Denatonium benzoate is used worldwide as a denaturant for 
alcohol. It is included in the FDA Inactive Ingredients Guide 
(topical gel and solution). 
17 Related Substances 
—
18 Comments 
Several HPLC methods of analysis for denatonium benzoate 
have been reported.(8–10) The EINECS number for denatonium 
benzoate is 223-095-2. 
19 Specific References 
1 Klein-Schwartz W. Denatonium benzoate: review of efficacy and 
safety. Vet Hum Toxicol 1991; 33(6): 545–547. 
2 Sibert JR, Frude N. Bittering agents in the prevention of accidental 
poisoning: children’s reactions to denatonium benzoate (Bitrex). 
Arch Emerg Med 1991; 8(1): 1–7. 
3 Hansen SR, Janssen C, Beasley VR. Denatonium benzoate as a 
deterrent to ingestion of toxic substances: toxicity and efficacy. Vet 
Hum Toxicol 1993; 35(3): 234–236. 
4 Rodgers GC, Tenenbein M. Role of aversive bittering agents in the 
prevention of pediatric poisonings. Pediatrics 1994; 93(Jan): 68– 
69. 
5 Anonymous. Relief for warts; none for nail biters. FDA Consum 
1981; 15(Feb): 13. 
6 Bjo. rkner B. Contact urticaria and asthma from denatonium 
benzoate (Bitrex). Contact Dermatitis 1980; 6(7): 466–471. 
7 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1087. 
8 Sugden K, Mayne TG, Loscombe CR. Determination of denaturants 
in alcoholic toilet preparations 1: denatonium benzoate 
(Bitrex) by high performance liquid chromatography. Analyst 
1978; 103(Jun): 653–656. 
9 Faulkner A, DeMontigny P. High-performance liquid chromatographic 
determination of denatonium benzoate in ethanol with 5% 
polyvinylpyrrolidone. J Chromatogr-A 1995; 715(1): 189–194. 
10 Henderson MC, Neumann CM, Buhler DR. Analysis of denatonium 
benzoate in Oregon consumer products by HPLC. Chemosphere 
1998; 36(1): 203–210. 
20 General References 
Payne HAS. Bitrex – a bitter solution to safety. Chem Ind 1988; 22: 
721–723. 
Payne HAS. Bitrex – a bitter solution to product safety. Drug Cosmet 
Ind 1989; 144(May): 30, 32, 34. 
21 Authors 
PJ Weller. 
22 Date of Revision 
14 August 2005. 
Denatonium Benzoate 225

Dextrates 
1 Nonproprietary Names 
USPNF: Dextrates 
2 Synonyms 
Candex; Emdex. 
3 Chemical Name and CAS Registry Number 
Dextrates [39404-33-6] 
4 Empirical Formula and Molecular Weight 
The USPNF 23 describes dextrates as a purified mixture of 
saccharides resulting from the controlled enzymatic hydrolysis 
of starch. It may be either hydrated or anhydrous. Its dextrose 
equivalent is not less than 93.0% and not more than 99.0%, 
calculated on the dried basis. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Tablet binder; tablet and capsule diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dextrates is a directly compressible tablet diluent used in 
chewable, nonchewable, soluble, dispersible, and effervescent 
tablets.(1–3) It is a free-flowing material and glidants are thus 
unnecessary. Lubrication with magnesium stearate (0.5–1.0% 
w/w) is recommended.(4) Dextrates may also be used as a 
binding agent by the addition of water, no further binder being 
required.(4) 
Tablets made from dextrates increase in crushing strength in 
the first few hours after manufacture, but no further increase 
occurs on storage.(5) 
8 Description 
Dextrates is a purified mixture of saccharides resulting from the 
controlled enzymatic hydrolysis of starch. It is either anhydrous 
or hydrated. In addition to dextrose, dextrates contains 3–5% 
w/w maltose and higher polysaccharides. 
Dextrates comprises white spray-crystallized free-flowing 
porous spheres. It is odorless with a sweet taste (about half as 
sweet as sucrose). 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for dextrates. 
Test USPNF 23 
pH (20% aqueous solution) 3.8–5.8 
Loss on drying 
Anhydrous 42.0% 
Hydrated 7.8–9.2% 
Residue on ignition 40.1% 
Heavy metals 45 ppm 
Organic volatile impurities . 
Dextrose equivalent (dried basis) 93.0–99.0% 
10 Typical Properties 
Angle of repose: 26.48 (6) 
Compressibility: see Figure 1.(6) 
Density (bulk): 0.68 g/cm3(6) 
Density (tapped): 0.72 g/cm3(6) 
Density (true): 1.539 g/cm3 
Hausner ratio: 1.05 
Flowability: 9.3 g/s (6) 
Heat of combustion: 16.8–18.8 J/g (4.0–4.5 cal/g) 
Heat of solution: 105 J/g (–25 cal/g) 
Melting point: 1418C. 
Moisture content: 7.8–9.2% w/w (hydrated form). See also 
Figure 2.(7) 
Particle size distribution: not more than 3% retained on a 
840 mm sieve; not more than 25% passes through a 150 mm 
sieve. Mean particle size 190–220 mm. 
Solubility: soluble 1 in 1 part of water; insoluble in ethanol 
(95%), propan-2-ol, and common organic solvents. 
Specific surface area: 0.70m2/g 
11 Stability and Storage Conditions 
Dextrates may be heated to 508C without any appreciable 
darkening of color. Dextrates should be stored in a well-closed 
container in conditions that do not exceed 258C and 60% 
relative humidity. When correctly stored in unopened containers, 
dextrates has a shelf-life of 3 years. 
12 Incompatibilities 
At high temperatures and humidities, dextrates may react with 
substances containing a primary amino group (Maillard 
reaction).(8,9) Also incompatible with oxidizing agents. 
13 Method of Manufacture 
Dextrates is produced by controlled enzymatic hydrolysis of 
starch. The product is spray-crystallized, and may be dried to 
produce an anhydrous form.

Figure 1: Crushing strength for dextrates. 
&: Dextrates, Emdex (Lot # L-53X, Mendell) at V = 
100 mm/s 
~: Dextrates, Emdex (Lot # L-53X, Mendell) at V = 
300 mm/s 
Figure 2: Equilibrium moisture content of dextrates at 258C.(7) 
14 Safety 
Dextrates is used in oral pharmaceutical formulations and is 
generally regarded as a relatively nontoxic and nonirritant 
material. 
15 Handling Precautions 
Observe normal handling precautions appropriate to the 
circumstances and quantity of material handled. Eye protection, 
gloves, and a dust mask are recommended. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredient Guide 
(oral; tablets, sustained action). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Dextrose. 
18 Comments 
Only the hydrated form of dextrates is currently commercially 
available. 
19 Specific References 
1 Henderson NL, Bruno AJ. Lactose USP (Beadlets) and Dextrose 
(PAF 2011): two new agents for direct compression. J Pharm Sci 
1970; 59: 1336–1340. 
2 Shukla AJ, Price JC. Effect of moisture content on compression 
properties of two dextrose-based directly compressible diluents. 
Pharm Res 1991; 8(3): 336–340. 
3 Allen LV. Featured excipient: capsule and tablet diluents. Int J 
Pharm Compound 2000; 4(4): 306–310, 324–325. 
4 Penwest. Technical Literature: Emdex, 2004. 
5 Shangraw RF, Wallace JW, Bowers FM. Morphology and 
functionality in tablet excipients by direct compression: Part I. 
Pharm Technol 1981; 5(9): 69–78. 
6 Celik M, Okutgen E. A feasibility study for the development of a 
prospective compaction functionality test and the establishment of 
a compaction data bank. Drug Dev Ind Pharm 1993; 19: 2309– 
2334. 
7 Callahan JC, Cleary GW, Elefant M, et al. Equilibrium moisture 
content of pharmaceutical excipients. Drug Dev Ind Pharm 1982; 
8(3): 355–369. 
8 Blang SM, Huang WT. Interaction of dexamphetamine sulphate 
with dextrates in solution. J Pharm Sci 1973; 62(4): 652–655. 
9 Blaug SM, Huang WT. Browning of dextrates in solid-solid 
mixtures containing dexamphetamine sulfate. J Pharm Sci 1974; 
63(9): 1415–1418. 
20 General References 
Armstrong NA. Tablet manufacture. In: Swarbrick J, Boylan JC, eds. 
Encyclopedia of Pharmaceutical Technology, 2nd edn, vol. 3. New 
York: Marcel Dekker, 2002: 2713–2732. 
Shangraw RF. Direct compression tabletting. In: Swarbrick J, Boylan 
JC, eds. Encyclopedia of Pharmaceutical Technology, vol. 4. New 
York: Marcel Dekker, 1988: 85–106. 
21 Authors 
NA Armstrong. 
22 Date of Revision 
16 August 2005. 
Dextrates 227

Dextrin 
1 Nonproprietary Names 
BP: Dextrin 
JP: Dextrin 
PhEur: Dextrinum 
USPNF: Dextrin 
2 Synonyms 
Avedex; British gum; Caloreen; canary dextrin; C*Pharm; 
Crystal Gum; dextrinum album; Primogran W; starch gum; 
yellow dextrin; white dextrin. 
3 Chemical Name and CAS Registry Number 
Dextrin [9004-53-9] 
4 Empirical Formula and Molecular Weight 
(C6H10O5)nxH2O (162.14)n 
The molecular weight of dextrin is typically 4500–85 000 
and depends on the number of (C6H10O5) units in the polymer 
chain. 
5 Structural Formula 
6 Functional Category 
Stiffening agent; suspending agent; tablet binder; tablet and 
capsule diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dextrin is a dextrose polymer used as an adhesive and stiffening 
agent for surgical dressings. It is also used as a tablet and 
capsule diluent; as a binder for tablet granulation; as a sugarcoating 
ingredient that serves as a plasticizer and adhesive; and 
as a thickening agent for suspensions. 
Additionally, dextrin has been used as a source of 
carbohydrate by people with special dietary requirements 
because it has a low electrolyte content and is free of lactose 
and sucrose.(1) 
Dextrin is also used in cosmetics. 
8 Description 
Dextrin is partially hydrolyzed maize (corn) or potato starch. It 
is a white, pale yellow or brown-colored powder with a slight 
characteristic odor. 
SEM: 1 
Excipient: Dextrin 
Manufacturer: Matheson Colleman & Bell 
Magnification: 600 
SEM: 2 
Excipient: Dextrin 
Manufacturer: Matheson Colleman & Bell 
Magnification: 2400

9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for dextrin. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters — . — 
Appearance of solution . — — 
Loss on drying 410.0% 413.0% 413.0% 
Acidity . . . 
Residue on ignition 40.5% 40.5% 40.5% 
Chloride 40.013% 40.2% 40.2% 
Sulfate 40.019% — — 
Oxalate . — — 
Calcium . — — 
Heavy metals 450 ppm 420 ppm 420 mg/g 
Protein — — 41.0% 
Organic volatile impurities — — . 
Reducing sugars/substances 
(calculated as C6H12O6) 
— 410.0% 410.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 2.8–8.0 for a 5% w/v aqueous 
solution. 
Density (bulk): 0.80 g/cm3 
Density (tapped): 0.91 g/cm3 
Density (true): 1.495–1.589 g/cm3 
Melting point: 1788C (with decomposition) 
Moisture content: 5% w/w 
Particle size distribution: see Figure 1. 
Solubility: practically insoluble in chloroform, ethanol (95%), 
ether, and propan-2-ol; slowly soluble in cold water; very 
soluble in boiling water, forming a mucilaginous solution. 
Specific surface area: 0.14m2/g 
11 Stability and Storage Conditions 
Physical characteristics of dextrin may vary slightly depending 
on the method of manufacture and on the source material. In 
aqueous solutions, dextrin molecules tend to aggregate as 
density, temperature, pH, or other characteristics change. An 
increase in viscosity is caused by gelation or retrogradation as 
dextrin solutions age, and is particularly noticeable in the lesssoluble 
maize starch dextrins. Dextrin solutions are thixotropic, 
becoming less viscous when sheared but changing to a soft 
paste or gel when allowed to stand. However, acids that are 
present in dextrin as residues from manufacturing can cause 
further hydrolysis, which results in a gradual thinning of 
solutions. Residual acid, often found in less-soluble dextrins 
such as pyrodextrin, will also cause a reduction in viscosity 
during dry storage. To eliminate these problems, dextrin 
manufacturers neutralize dextrins of low solubility with 
ammonia or sodium carbonate in the cooling vessel. 
The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Incompatible with strong oxidizing agents. 
Figure 1: Particle size distribution of dextrin. 
13 Method of Manufacture 
Dextrin is prepared by the incomplete hydrolysis of starch by 
heating in the dry state with or without the aid of suitable acids 
and buffers; moisture may be added during heating. The PhEur 
2005 specifies that dextrin is derived from maize (corn) or 
potato starch. A specification for cassava is included in the 
USPNF 23. 
14 Safety 
Dextrin is generally regarded as a nontoxic and nonirritant 
material at the levels employed as an excipient. Larger 
quantities are used as a dietary supplement without adverse 
effects, although ingestion of very large quantities may be 
harmful. 
LD50 (mouse, IV): 0.35 g/kg(2) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Dextrin may be irritant to the 
eyes. Eye protection, gloves, and a dust mask are recommended. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(IV injections, oral tablets and topical preparations). Included 
in nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Dextrates; dextrose; glucose liquid; maltodextrin. 
See also Section 18. 
Dextrin 229

18 Comments 
Dextrin is available from suppliers in a number of modified 
forms and mixtures such as dextrimaltose, a mixture of maltose 
and dextrin obtained by the enzymatic action of barley malt on 
corn flour. It is a light, amorphous powder, readily soluble in 
milk or water. 
Crystal Gum is a grade of dextrin containing carbohydrate 
not less than 98% of dry weight. Caloreen(1) is a water-soluble 
mixture of dextrins consisting predominantly of polysaccharides 
containing an average of 5 dextrose molecules, with a 
mean molecular weight of 840, that does not change after 
heating. A 22% w/v solution of Caloreen is isoosmotic with 
serum. 
A specification for dextrin is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for dextrin is 232-675-4. 
19 Specific References 
1 Berlyne GM, Booth EM, Brewis RAL, et al. A soluble glucose 
polymer for use in renal failure and calorie-deprivation states. 
Lancet 1969; i: 689–692. 
2 Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. 
Cincinnati: US Department of Health, 1987: 1859. 
20 General References 
French D. Chemical and physical properties of starch. J Animal Sci 
1973; 37: 1048–1061. 
Satterthwaite RW, Iwinski DJ. Starch dextrins. In: Whistler RL, 
Bemiller JN, eds. Industrial Gums. New York: Academic Press, 
1973: 577–599. 
21 Authors 
A Day. 
22 Date of Revision 
17 August 2005. 
230 Dextrin

Dextrose 
1 Nonproprietary Names 
BP: Glucose monohydrate 
JP: Glucose 
PhEur: Glucosum monohydricum 
USP: Dextrose 
2 Synonyms 
Blood sugar; Caridex; corn sugar; C*PharmDex; Dextrofin; 
D-(.)-glucopyranose monohydrate; grape sugar; Lycadex PF; 
Roferose; starch sugar; Tabfine D-100. 
3 Chemical Name and CAS Registry Number 
D-(.)-Glucose monohydrate [5996-10-1] 
See also Section 17. 
4 Empirical Formula and Molecular Weight 
C6H12O6H2O 198.17 (for monohydrate) 
See also Section 17. 
5 Structural Formula 
Anhydrous material shown. 
6 Functional Category 
Tablet and capsule diluent; therapeutic agent; tonicity agent; 
sweetening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dextrose is widely used in solutions to adjust tonicity and as a 
sweetening agent. Dextrose is also used as a wet granulation 
diluent and binder, and as a direct-compression tablet diluent 
and binder, primarily in chewable tablets. Although dextrose is 
comparable as a tablet diluent to lactose, tablets produced with 
dextrose monohydrate require more lubrication, are less 
friable, and have a tendency to harden.(1–3) The mildly reducing 
properties of dextrose may be used when tableting to improve 
the stability of active materials that are sensitive to oxidation. 
Dextrose is also used therapeutically and is the preferred 
source of carbohydrate in parenteral nutrition regimens. 
8 Description 
Dextrose occurs as odorless, sweet-tasting, colorless crystals or 
as a white crystalline or granular powder. The JP 2001 
describes dextrose as dextrose anhydrous; the PhEur 2005 
specifies dextrose as either dextrose anhydrous or dextrose 
monohydrate; and the USP 28 specifies dextrose as dextrose 
monohydrate. 
SEM: 1 
Excipient: Dextrose anhydrous (granular) 
Manufacturer: Mallinckrodt Specialty Chemicals Co. 
Lot No.: KLKZ 
Magnification: 180 
9 Pharmacopeial Specifications 
See Table I. 
10 Typical Properties 
Data are shown for dextrose monohydrate; see Section 17 for 
data for dextrose anhydrous. 
Acidity/alkalinity: pH = 3.5–5.5 (20% w/v aqueous solution) 
Density (bulk): 0.826 g/cm3 
Density (tapped): 1.020 g/cm3 
Density (true): 1.54 g/cm3 
Heat of solution: 105.4 J/g (25.2 cal/g) 
Melting point: 838C 
Moisture content: anhydrous dextrose absorbs significant 
amounts of moisture at 258C and a relative humidity of 
about 85% to form the monohydrate. The monohydrate 
similarly only absorbs moisture at around 85% relative 
humidity and 258C. See Figure 1.

Table II: Solubility of dextrose monohydrate. 
Solvent Solubility at 208C 
Chloroform Practically insoluble 
Ethanol (95%) 1 in 60 
Ether Practically insoluble 
Glycerin Soluble 
Water 1 in 1 
Osmolarity: a 5.51% w/v aqueous solution is isoosmotic with 
serum. However, it is not isotonic since dextrose can pass 
through the membrane of red cells and cause hemolysis. 
Solubility: see Table II. 
11 Stability and Storage Conditions 
Dextrose has good stability under dry storage conditions. 
Aqueous solutions may be sterilized by autoclaving. However, 
excessive heating can cause a reduction in pH and caramelization 
of solutions.(4–7) 
The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Dextrose solutions are incompatible with a number of drugs 
such as cyanocobalamin, kanamycin sulfate, novobiocin 
sodium, and warfarin sodium.(8) Erythromycin gluceptate is 
unstable in dextrose solutions at a pH less than 5.05.(9) 
Decomposition of B-complex vitamins may occur if they are 
warmed with dextrose. 
In the aldehyde form, dextrose can react with amines, 
amides, amino acids, peptides, and proteins. Brown coloration 
and decomposition occur with strong alkalis. 
Dextrose may cause browning of tablets containing amines 
(Maillard reaction). 
13 Method of Manufacture 
Dextrose, a monosaccharide sugar, occurs widely in plants and 
is manufactured on a large scale by the acid or enzymatic 
hydrolysis of starch, usually maize (corn) starch. Below 508C a- 
D-dextrose monohydrate is the stable crystalline form produced; 
above 508C the anhydrous form is obtained; and at still 
higher temperatures b-D-dextrose is formed, which has a 
melting point of 148–1558C. 
14 Safety 
Dextrose is rapidly absorbed from the gastrointestinal tract. It 
is metabolized to carbon dioxide and water with the release of 
energy. 
Concentrated dextrose solutions given by mouth may cause 
nausea and vomiting. Dextrose solutions of concentration 
greater than 5% w/v are hyperosmotic and are liable to cause 
local vein irritation following intravenous administration. 
Thrombophlebitis has been observed following the intravenous 
infusion of isoosmotic dextrose solution with low pH, probably 
owing to the presence of degradation products formed by 
overheating during sterilization. The incidence of phlebitis may 
be reduced by adding sufficient sodium bicarbonate to raise the 
pH of the infusion above pH 7. 
LD50 (mouse, IV): 9 g/kg(10) 
LD50 (rat, oral): 25.8 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. Dust generation should be minimized to reduce 
the risk of explosion. 
Table I: Pharmacopeial specifications for dextrose. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters — . — 
Color of solution . . . 
Specific optical rotation — .52.58 to 
.53.38 
.52.68 to 
.53.28 
Acidity . . . 
Organic volatile impurities — — . 
Water 
for monohydrate — 7.0–9.5% 7.5–9.5% 
for anhydrous 41.0% — 40.5% 
Residue on ignition 40.1% 40.1% 40.1% 
Chloride 40.018% 4125 ppm 40.018% 
Sulfate 40.024% 4200 ppm 40.025% 
Arsenic 41.3 ppm 41 ppm 41 ppm 
Barium — . — 
Calcium — 4200 ppm — 
Heavy metals 44 ppm — 45 ppm 
Lead — 40.5 ppm — 
Dextrin . . . 
Soluble starch, and sulfites . . . 
Pyrogens(a) — . — 
Assay (dried basis) 599.5% — — 
(a) If intended for large volume parenteral use. 
Figure 1: Sorption–desorption isotherm for anhydrous dextrose 
granules. 
^: Sorption 
&: Desorption 
232 Dextrose

16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (capsules; 
inhalations; IM, IV, and SC injections; tablets, oral solutions, 
and syrups). Included in nonparenteral and parenteral medicines 
licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Dextrates; dextrin; dextrose anhydrous; fructose; glucose 
liquid; polydextrose; sucrose. 
Dextrose anhydrous 
Empirical formula: C6H12O6 
Molecular weight: 180.16 
CAS number: [50-99-7] 
Synonyms: anhydrous dextrose; anhydrous D-(.)-glucopyranose; 
anhydrous glucose; dextrosum anhydricum. 
Appearance: white, odorless, crystalline powder with a sweet 
taste. 
Acidity/alkalinity: pH = 5.9 (10% w/v aqueous solution) 
Density (bulk): 1.3–1.4 g/cm3 
Density (tapped): 1.1–1.2 g/cm3 
Melting point: 1468C 
Moisture content: see Section 10. 
Osmolarity: a 5.05% w/v aqueous solution is isoosmotic with 
serum. See also Section 10. 
Refractive index: nD
20 = 1.3479 (10% w/v aqueous solution) 
Solubility: see Table III. 
Specific gravity: see Table IV. 
Specific surface area: 0.22–0.29m2/g 
Table III: Solubility of dextrose anhydrous. 
Solvent Solubility at 208C 
unless otherwise stated 
Ethanol (95%) Sparingly soluble 
Ether Sparingly soluble 
Methanol 1 in 120 
Water 1 in 1.1 at 258C 
1 in 0.8 at 308C 
1 in 0.41 at 508C 
1 in 0.28 at 708C 
1 in 0.18 at 908C 
Table IV: Specific gravity of dextrose anhydrous aqueous solutions. 
Concentration of aqueous dextrose 
solution (% w/v) 
Specific gravity at 17.58C 
5 1.019 
10 1.038 
20 1.076 
30 1.113 
40 1.149 
18 Comments 
The way in which the strengths of dextrose solutions are 
expressed varies from country to country. The JP 2001 requires 
strengths to be expressed in terms of dextrose monohydrate, 
while the BP 2004 and USP 28 require strengths to be expressed 
in terms of anhydrous dextrose. Approximately 1.1 g of 
dextrose monohydrate is equivalent to 1 g of anhydrous 
dextrose. 
A specification for dextrose is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for dextrose is 200-075-1. 
19 Specific References 
1 DuVall RN, Koshy KT, Dashiell RE. Comparative evaluation of 
dextrose and spray-dried lactose in direct compression systems. J 
Pharm Sci 1965; 54: 1196–1200. 
2 Henderson NL, Bruno AJ. Lactose USP (beadlets) and dextrose 
(PAF 2011): two new agents for direct compression. J Pharm Sci 
1970; 59: 1336–1340. 
3 Armstrong NA, Patel A, Jones TM. The compressional properties 
of dextrose monohydrate and anhydrous dextrose of varying 
water contents. In: Rubinstein MH, ed. Pharmaceutical Technology: 
Tableting Technology, vol. 1. Chichester: Ellis Horwood, 
1987: 127–138. 
4 Wing WT. An examination of the decomposition of dextrose 
solution during sterilisation. J Pharm Pharmacol 1960; 12: 191T– 
196T. 
5 Murty BSR, Kapoor JN, Smith FX. Levels of 5-hydroxymethylfurfural 
in dextrose injection. Am J Hosp Pharm 1977; 34: 205– 
206. 
6 Sturgeon RJ, Athanikar NK, Harbison HA, et al. Degradation of 
dextrose during heating under simulated sterilization. J Parenter 
Drug Assoc 1980; 34: 175–182. 
7 Durham DG, Hung CT, Taylor RB. Identification of some acids 
produced during autoclaving of D-glucose solutions using HPLC. 
Int J Pharm 1982; 12: 31–40. 
8 Patel JA, Phillips GL. A guide to physical compatibility of intravenous 
drug admixtures. Am J Hosp Pharm 1966; 23: 409–411. 
9 Edward M. pH – an important factor in the compatibility of 
additives in intravenous therapy. Am J Hosp Pharm 1967; 24: 
440–449. 
10 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1860–1861. 
20 General References 
—
21 Authors 
A Day. 
22 Date of Revision 
9 June 2005. 
Dextrose 233

Dibutyl Phthalate 
1 Nonproprietary Names 
BP: Dibutyl phthalate 
PhEur: Dibutylis phthalas 
2 Synonyms 
Araldite 502; benzenedicarboxylic acid; benzene-o-dicarboxylic 
acid di-n-butyl ester; butyl phthalate; Celluflex DBP; 
DBP; dibutyl 1,2-benzenedicarboxylate; dibutyl benzene 1,2- 
dicarboxylate; dibutyl ester of 1,2-benzenedicarboxylic acid; 
dibutyl-o-phthalate; di-n-butyl phthalate; Elaol; Ergoplast 
FDB; Genoplast B; Hatcol DBP; Hexaplast M/B; Kodaflex 
DBP; Monocizer DBP; Palatinol C; phthalic acid dibutyl ester; 
Polycizer DBP; PX 104; RC Plasticizer DBP; Staflex DBP; 
Unimoll DB; Vestimol C; Witcizer 300. 
3 Chemical Name and CAS Registry Number 
Dibutyl benzene-1,2-dicarboxylate [84-74-2] 
4 Empirical Formula and Molecular Weight 
C16H22O4 278.34 
5 Structural Formula 
6 Functional Category 
Film-former; plasticizer; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dibutyl phthalate is used in pharmaceutical formulations as a 
plasticizer in film-coatings. It is also used extensively as a 
solvent particularly in cosmetic formulations such as antiperspirants, 
hair shampoos and hair sprays. In addition to a 
number of industrial applications, dibutyl phthalate is used as 
an insect repellent, although it is not as effective as dimethyl 
phthalate. 
8 Description 
Dibutyl phthalate occurs as an odorless, oily, colorless, or very 
slightly yellow-colored, viscous liquid. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for dibutyl phthalate. 
Test PhEur 2005 
Identification . 
Characters . 
Appearance . 
Relative density 1.043–1.048 
Refractive index 1.490–1.495 
Acidity . 
Related substances . 
Water 40.2% 
Sulfated ash 40.1% 
Assay 99.0–101.0% 
10 Typical Properties 
Boiling point: 3408C 
Density: see Table II. 
Flash point: 1718C open cup. 
Melting point: 358C 
Partition coefficient: 
Octanol : water log kow = 4.50 
Refractive index: nD
20 = 1.491–1.495 
Solubility: very soluble in acetone, benzene, ethanol (95%), and 
ether; soluble 1 in 2500 of water at 208C. 
Viscosity (dynamic): see Table II. 
Table II: Density and dynamic viscosity of dibutyl phthalate at 
specified temperatures. 
Temperature (8C) Density (g/cm3) Dynamic viscosity (mPa s) 
0 1.0627 59 
10 1.0546 33 
20 1.0465 20 
30 1.0384 13 
40 1.0303 9 
50 1.0222 7 
11 Stability and Storage Conditions 
Dibutyl phthalate should be stored in a well-closed container in 
a cool, dry, location. Containers may be hazardous when empty 
since they can contain product residues such as vapors and 
liquids. 
12 Incompatibilities 
Dibutyl phthalate reacts violently with chlorine. It also reacts 
with oxidizing agents, acids, bases, and nitrates.

13 Method of Manufacture 
Dibutyl phthalate is produced from n-butanol and phthalic 
anhydride in an ester formation reaction. 
14 Safety 
Dibutyl phthalate is generally regarded as a relatively nontoxic 
material, although it has occasionally been reported to cause 
hypersensitivity reactions. It is widely used in topical cosmetic 
and some oral pharmaceutical formulations. 
LD50 (mouse, IV): 0.72 g/kg(1) 
LD50 (mouse, oral): 5.3 g/kg 
LD50 (rat, oral): 8.0 g/kg 
LD50 (rat, IP): 3.05 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Contact with the skin and 
eyes should be avoided. Decomposition produces toxic fumes, 
carbon monoxide and carbon dioxide. 
In the USA, the permitted 8-hour exposure limit for dibutyl 
phthalate is 5 mg/m3. In the UK, the long-term (8-hour TWA) 
exposure limit for dibutyl phthalate is 5 mg/m3. The short-term 
(15-minute) exposure limit is 10 mg/m3.(2) 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral delayed 
action, enteric coated, tablets). Included in nonparenteral 
medicines licensed in the UK (oral capsules, tablets, granules; 
topical creams and solutions). 
17 Related Substances 
Diethyl phthalate; dimethyl phthalate; dioctyl phthalate. 
Dioctyl phthalate 
Empirical formula: C24H38O4 
Molecular weight: 390.55 
CAS number: dioctyl phthalate occurs commercially in two 
isomeric forms: di-n-octyl phthalate [117-84-0] and di(2- 
ethylhexyl) phthalate [117-81-7]. 
Synonyms: 1,2-benzenedicarboxylic acid bis(2-ethylhexyl) 
ester; bis(2-ethylhexyl) phthalate; di(2-ethyl-hexyl)phthalate; 
DEHP; DOP; Octoil. 
Description: clear, colorless, odorless, and anhydrous liquid. 
Boiling point: 3848C 
Flash point: 2068C (closed cup). 
Melting point: 508C 
Refractive index: nD
20 = 1.50 
Solubility: soluble in conventional organic solvents; practically 
insoluble in water. 
Comments: the EINECS number for dioctyl phthalate is 204- 
214-7. 
18 Comments 
The EINECS number for dibutyl phthalate is 201-557-4. 
19 Specific References 
1 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1164. 
2 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
Wilson AS. Plasticisers – Principles and Practice. London: Institute of 
Materials, 1995. 
21 Authors 
RT Guest. 
22 Date of Revision 
21 August 2005. 
Dibutyl Phthalate 235

Dibutyl Sebacate 
1 Nonproprietary Names 
USPNF: Dibutyl sebacate 
2 Synonyms 
Butyl sebacate; decanedioic acid, dibutyl ester; dibutyl decanedioate; 
dibutyl 1,8-octanedicarboxylate; Kodaflex DBS. 
3 Chemical Name and CAS Registry Number 
Decanedioic acid, di-n-butyl ester [109-43-3] 
4 Empirical Formula and Molecular Weight 
C18H34O4 314.47 
The USPNF 23 describes dibutyl sebacate as consisting of 
the esters of n-butyl alcohol and saturated dibasic acids, 
principally sebacic acid. 
5 Structural Formula 
6 Functional Category 
Plasticizer. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dibutyl sebacate is used in oral pharmaceutical formulations as 
a plasticizer for film coatings on tablets, beads, and granules, at 
concentrations of 10–30% by weight of polymer.(1,2) It is also 
used as a plasticizer in controlled-release tablets and microcapsule 
preparations.(3,4) 
Dibutyl sebacate is also used as a synthetic flavor and flavor 
adjuvant in food products; for example, up to 5 ppm is used in 
ice cream and nonalcoholic beverages. 
8 Description 
Dibutyl sebacate is a clear, colorless, oily liquid with a bland to 
slight butyl odor. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for dibutyl sebacate. 
Test USPNF 23 
Specific gravity 0.935–0.939 
Refractive index 1.429–1.441 
Acid value 40.1 
Saponification value 352–357 
Assay (of C18H34O4) 592.0% 
10 Typical Properties 
Acid value: 0.02 
Boiling point: 344–3498C 
Flash point: 1938C 
Melting point: 108C 
Refractive index: nD
25 = 1.4401 
Solubility: soluble in ethanol (95%), isopropanol, and mineral 
oil; practically insoluble in water. 
Specific gravity: 0.937 at 208C 
Vapor density (relative): 10.8 (air = 1) 
Vapor pressure: 0.4 kPa (3 mmHg) at 1808C 
11 Stability and Storage Conditions 
Dibutyl sebacate is stable. It is not reactive with water and 
hazardous polymerization does not occur. Dibutyl sebacate 
should be stored in a closed container in a cool, dry location. 
12 Incompatibilities 
Dibutyl sebacate is incompatible with strong oxidizing 
materials and strong alkalis. 
13 Method of Manufacture 
Dibutyl sebacate is manufactured by the esterification of nbutanol 
and sebacic acid in the presence of a suitable catalyst, 
and by the distillation of sebacic acid with n-butanol in the 
presence of concentrated acid. 
14 Safety 
Dibutyl sebacate is used in cosmetics, foods, and oral 
pharmaceutical formulations, and is generally regarded as a 
nontoxic and nonirritant material. Following oral administration, 
dibutyl sebacate is metabolized in the same way as fats. In 
humans, direct eye contact and prolonged or repeated contact 
with the skin may cause very mild irritation. Acute animal 
toxicity tests and long-term animal feeding studies have shown 
no serious adverse effects to be associated with orally 
administered dibutyl sebacate. 
LD50 (rat, oral): 16 g/kg(5) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. It is recommended that eye

protection be used at all times. When heating this product, it is 
recommended to have a well-ventilated area, and the use of a 
respirator is advised. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral capsules, 
granules, film-coated, sustained action, and tablets). Included 
in the Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
—
18 Comments 
As dibutyl sebacate is an emollient ester, the personal care grade 
is recommended for use in cosmetics, hair products, lotions, 
and creams. 
The EINECS number for dibutyl sebacate is 203-672-5. 
19 Specific References 
1 Goodhart FW, Harris MR, Murthy KS, Nesbitt RU. An evaluation 
of aqueous film-forming dispersions for controlled release. Pharm 
Technol 1984; 8(4): 64, 66, 68, 70, 71. 
2 Iyer U, Hong W-H, Das N, Ghebre-Sellassie I. Comparative 
evaluation of three organic solvent and dispersion-based ethylcellulose 
coating formulations. Pharm Technol 1990; 14(9): 68, 70, 
72, 74, 76, 78, 80, 82, 84, 86. 
3 Lee BJ, Ryn SG, Cui JH. Controlled release of dual drug loaded 
hydroxypropyl methylcellulose matrix tablet using drug containing 
polymeric coatings. Int J Pharm 1999; 188: 71–80. 
4 Zhang ZY, Ping QN, Xiao B. Microencapsulation and characterization 
of tramadol-resin complexes. J Control Release 2000; 66: 
107–113. 
5 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1165. 
20 General References 
Appel LE, Zentner GM. Release from osmotic tablets coated with 
modified Aquacoat lattices. Proc Int Symp Control Rel Bioact 
Mater 1990; 17: 335–336. 
Ozturk AG, Ozturk SS, Palsson BO, et al. Mechanism of release from 
pellets coated with an ethylcellulose-based film. J Control Release 
1990; 14: 203–213. 
Rowe RC. Materials used in the film coating of oral dosage forms. In: 
Florence AT, ed. Materials Used in Pharmaceutical Formulation: 
Critical Reports on Applied Chemistry, vol. 6. Oxford: Blackwell 
Scientific, 1984: 1–36. 
Wheatley TA, Steurnagel CR. Latex emulsions for controlled drug 
delivery. In: McGinity JC, ed. Aqueous Polymeric Coatings for 
Pharmaceutical Dosage Forms, 2nd edn. New York: Marcel 
Dekker, 1996: 13–41. 
21 Authors 
SW Kennedy. 
22 Date of Revision 
15 August 2005. 
Dibutyl Sebacate 237

Diethanolamine 
1 Nonproprietary Names 
USPNF: Diethanolamine 
2 Synonyms 
Bis(hydroxyethyl)amine; DEA; diethylolamine; 2,20-dihydroxydiethylamine; 
diolamine; 2,20-iminodiethanol. 
3 Chemical Name and CAS Registry Number 
2,20-Iminobisethanol [111-42-2] 
4 Empirical Formula and Molecular Weight 
C4H11NO2 105.14 
5 Structural Formula 
6 Functional Category 
Alkalizing agent; emulsifying agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Diethanolamine is primarily used in pharmaceutical formulations 
as a buffering agent, such as in the preparation of 
emulsions with fatty acids. In cosmetics and pharmaceuticals it 
is used as a pH adjuster and dispersant. 
Diethanolamine has also been used to form the soluble salts 
of active compounds, such as iodinated organic acids that are 
used as contrast media. As a stabilizing agent, diethanolamine 
prevents the discoloration of aqueous formulations containing 
hexamethylenetetramine-1,3-dichloropropene salts. 
Diethanolamine is also used in cosmetics. 
8 Description 
The USPNF 23 describes diethanolamine as a mixture of 
ethanolamines consisting largely of diethanolamine. At about 
room temperature it is a white, deliquescent solid. Above room 
temperature diethanolamine is a clear, viscous liquid with a 
mildly ammoniacal odor. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for diethanolamine. 
Test USPNF 23 
Identification . 
Limit of triethanolamine 41.0% 
Organic volatile impurities . 
Refractive index at 308C 1.473–1.476 
Water 40.15% 
Assay (anhydrous basis) 98.5–101.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 11.0 for a 0.1 N aqueous solution. 
Autoignition temperature: 6628C 
Boiling point: 268.88C 
Density: 
1.0881 g/cm3 at 308C; 
1.0693 g/cm3 at 608C. 
Dissociation constant: pKa = 8.88 
Flash point (open cup): 1388C 
Hygroscopicity: very hygroscopic. 
Melting point: 288C 
Refractive index: nD
30 = 1.4753 
Solubility: see Table II. 
Table II: Solubility of diethanolamine. 
Solvent Solubility at 208C 
Acetone Miscible 
Benzene 1 in 24 
Chloroform Miscible 
Ether 1 in 125 
Glycerin Miscible 
Methanol Miscible 
Water 1 in 1 
Surface tension: 49.0mN/m (49.0 dynes/cm) at 208C. 
Vapor density (relative): 3.65 (air = 1) 
Vapor pressure: >1Pa at 208C. 
Viscosity (dynamic): 
351.9 mPa s (351.9 cP) at 308C; 
53.85 mPa s (53.85 cP) at 608C. 
11 Stability and Storage Conditions 
Diethanolamine is hygroscopic and light- and oxygen-sensitive; 
it should be stored in an airtight container, protected from light, 
in a cool, dry place. 
See Monoethanolamine for further information. 
12 Incompatibilities 
Diethanolamine is a secondary amine that contains two 
hydroxy groups. It is capable of undergoing reactions typical 
of secondary amines and alcohols. The amine group usually

exhibits the greater activity whenever it is possible for a 
reaction to take place at either the amine or a hydroxy group. 
Diethanolamine will react with acids, acid anhydrides, acid 
chlorides, and esters to form amide derivatives, and with 
propylene carbonate or other cyclic carbonates to give the 
corresponding carbonates. As a secondary amine, diethanolamine 
reacts with aldehydes and ketones to yield aldimines and 
ketimines. Diethanolamine also reacts with copper to form 
complex salts. Discoloration and precipitation will take place in 
the presence of salts of heavy metals. 
13 Method of Manufacture 
Diethanolamine is prepared commercially by the ammonolysis 
of ethylene oxide. The reaction yields a mixture of monoethanolamine, 
diethanolamine, and triethanolamine which is 
separated to obtain the pure products. 
14 Safety 
Diethanolamine is used in topical and parenteral pharmaceutical 
formulations, with up to 1.5% w/v being used in 
intravenous infusions. Experimental studies in dogs have 
shown that intravenous administration of larger doses of 
diethanolamine results in sedation, coma, and death. 
Animal toxicity studies suggest that diethanolamine is less 
toxic than monoethanolamine, although in rats the oral acute 
and subacute toxicity is greater.(1) Diethanolamine is said to be 
heptacarcinogenic in mice and has also been reported to induce 
hepatic choline deficiency in mice.(2) 
Diethanolamine is an irritant to the skin, eyes, and mucous 
membranes when used undiluted or in high concentration. 
However, in rabbits, aqueous solutions containing 10% w/v 
diethanolamine produce minor irritation. The lethal human 
oral dose of diethanolamine is estimated to be 5–15 g/kg bodyweight. 
The US Cosmetic Ingredient Review Expert Panel evaluated 
diethanolamine and concluded that it is safe for use in cosmetic 
formulations designed for discontinuous, brief use followed by 
thorough rinsing from the surface of the skin. In products 
intended for prolonged contact with the skin, the concentration 
of ethanolamines should not exceed 5%. Diethanolamine 
should not be used in products containing N-nitrosating 
agents.(1) See also Section 18. 
LD50 (guinea pig, oral): 2.0 g/kg(3) 
LD50 (mouse, IP): 2.3 g/kg 
LD50 (mouse, oral): 3.3 g/kg 
LD50 (rabbit, skin): 12.2 g/kg 
LD50 (rat, IM): 1.5 g/kg 
LD50 (rat, IP): 0.12 g/kg 
LD50 (rat, IV): 0.78 g/kg 
LD50 (rat, oral): 0.71 g/kg 
LD50 (rat, SC): 2.2 g/kg 
15 Handling Precautions 
Diethanolamine is irritating to the skin, eyes, and mucous 
membranes. Protective clothing, gloves, eye protection, and a 
respirator are recommended. Ideally, diethanolamine should be 
handled in a fume cupboard. In the UK, the long-term (8-hour 
TWA) exposure limit for diethanolamine is 13 mg/m3 
(3 ppm).(4) Diethanolamine poses a slight fire hazard when 
exposed to heat or flame. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IV infusions, 
ophthalmic solutions, and topical preparations). Included in 
medicines licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Monoethanolamine; triethanolamine. 
18 Comments 
Through a standard battery of rodent studies, diethanolamine 
has been identified by the US National Toxicology Program as a 
potential carcinogen following topical administration. Several 
possible confounding issues have been noted during the review 
of these studies, which may affect the ultimate conclusion made 
regarding the carcinogenicity of diethanolamine and the 
relevance of these findings to humans. Diethanolamine is not 
permitted for use in cosmetics sold within the EU. 
19 Specific References 
1 Neudahl GA. Diethanolamine (DEA) and diethanolamides toxicology. 
Drug Cosmet Ind 1998; 162(4): 26–29. 
2 Lehman-McKeeman LD, Gamsky EA, Hicks SM, et al. Diethanolamine 
induces hepatic choline deficiency in mice. Toxicol Sci 2002; 
67(1): 38–45. 
3 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1235. 
4 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
—
21 Authors 
K Fowler. 
22 Date of Revision 
17 August 2005. 
Diethanolamine 239

Diethyl Phthalate 
1 Nonproprietary Names 
BP: Diethyl phthalate 
PhEur: Diethylis phthalas 
USPNF: Diethyl phthalate 
2 Synonyms 
DEP; ethyl benzene-1,2-dicarboxylate; ethyl phthalate; Kodaflex 
DEP; phthalic acid diethyl ester. 
3 Chemical Name and CAS Registry Number 
1,2-Benzenedicarboxylic acid, diethyl ester [84-66-2] 
4 Empirical Formula and Molecular Weight 
C12H14O4 222.24 
5 Structural Formula 
6 Functional Category 
Film-former; plasticizer; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Diethyl phthalate is used as a plasticizer for film coatings on 
tablets, beads, and granules at concentrations of 10–30% by 
weight of polymer. 
Diethyl phthalate is also used as an alcohol denaturant and 
as a solvent for cellulose acetate in the manufacture of varnishes 
and dopes. In perfumery, diethyl phthalate is used as a perfume 
fixative at a concentration of 0.1–0.5% of the weight of the 
perfume used. 
8 Description 
Diethyl phthalate is a clear, colorless, oily liquid. It is practically 
odorless, or with a very slight aromatic odor and a bitter, 
disagreeable taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for diethyl phthalate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Specific gravity 1.117–1.121 1.118–1.122 
Refractive index 1.500–1.505 1.500–1.505 
Acidity . . 
Related substances . — 
Water 40.2% 40.2% 
Residue on ignition — 40.02% 
Sulfated ash 40.1% — 
Assay (anhydrous basis) 99.0–101.0% 98.0–102.0% 
10 Typical Properties 
Boiling point: 2958C 
Flash point: 1608C (open cup) 
Melting point: 408C 
Refractive index: nD
25 = 1.501 
Solubility: miscible with ethanol (95%), ether, and many other 
organic solvents; practically insoluble in water. 
Specific gravity: 1.120 at 258C 
Vapor density (relative): 7.66 (air = 1) 
Vapor pressure: 1.87 kPa (14 mmHg) at 1638C 
11 Stability and Storage Conditions 
Diethyl phthalate is stable when stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Incompatible with strong oxidizing materials. 
13 Method of Manufacture 
Diethyl phthalate is produced by the reaction of phthalic 
anhydride with ethanol in the presence of sulfuric acid. 
14 Safety 
Diethyl phthalate is used in oral pharmaceutical formulations 
and is generally regarded as a nontoxic and nonirritant material 
at the levels employed as an excipient. However, if consumed in 
large quantities it can act as a narcotic and cause paralysis of 
the central nervous system. 
Although some animal studies have suggested that high 
concentrations of diethyl phthalate may be teratogenic, other 
studies have shown no adverse effects.(1) 
LD50 (guinea pig, oral): 8.6 g/kg(2) 
LD50 (mouse, IP): 2.7 g/kg 
LD50 (mouse, oral): 6.2 g/kg 
LD50 (rat, IP): 5.1 g/kg 
LD50 (rat, oral): 8.6 g/kg

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Diethyl phthalate is irritant 
to the skin, eyes, and mucous membranes. Protective clothing, 
eye protection, and nitrile gloves are recommended. Diethyl 
phthalate should be handled in a fume cupboard or a wellventilated 
environment; a respirator is recommended. In the 
UK, the long-term (8-hour TWA) exposure limit for diethyl 
phthalate is 5 mg/m3. The short-term (15-minute) exposure 
limit is 10 mg/m3.(3) 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral capsules, 
delayed action, enteric coated, and sustained action tablets). 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Dibutyl phthalate; dimethyl phthalate. 
18 Comments 
The EINECS number for diethyl phthalate is 201-550-6. 
19 Specific References 
1 Field EA, Price CJ, Sleet RB, et al. Developmental toxicity 
evaluation of diethyl and dimethyl phthalate in rats. Teratology 
1993; 48(1): 33–44. 
2 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1284–1285. 
3 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
Banker GS. Film coating theory and practice. J Pharm Sci 1966; 55: 81– 
89. 
Berg JA, Mayor GH. Diethyl phthalate not dangerous [letter]. Am J 
Hosp Pharm 1991; 48: 1448–1449. 
Cafmeyer NR, Wolfson BB. Possible leaching of diethyl phthalate into 
levothyroxine sodium tablets. Am J Hosp Pharm 1991; 48: 735– 
739. 
Chambliss WG. The forgotten dosage form: enteric-coated tablets. 
Pharm Technol 1983; 7(9): 124, 126, 128, 130, 132, 138. 
Health and Safety Executive. Review of the toxicity of the esters of 
phthalic acid (phthalate esters). Toxicity Reviews 14. London: 
HMSO, 1986. 
Kamrin MA, Mayor GH. Diethyl phthalate: a perspective. J Clin 
Pharmacol 1991; 31: 484–489. 
Porter SC, Ridgway K. The permeability of enteric coatings and the 
dissolution rates of coated tablets. J Pharm Pharmacol 1982; 34: 5– 
8. 
Rowe RC. Materials used in the film coating of oral dosage forms. In: 
Florence AT, ed. Materials Used in Pharmaceutical Formulation: 
Critical Reports on Applied Chemistry, volume 6. Oxford: Blackwell 
Scientific, 1984: 1–36. 
Wheatley TA, Steurernagel CR. Latex emulsions for controlled drug 
delivery. In: McGinity JW, ed. Aqueous Polymeric Coatings for 
Pharmaceutical Dosage Forms, 2nd edn. New York: Marcel 
Dekker, 1996: 41–59. 
21 Authors 
RT Guest. 
22 Date of Revision 
21 August 2005. 
Diethyl Phthalate 241

Difluoroethane (HFC) 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Dymel 152a; ethylene fluoride; Genetron 152a; halocarbon 
152a; HFC 152a; P-152a; propellant 152a; refrigerant 152a; 
Solkane 152a. 
3 Chemical Name and CAS Registry Number 
1,1-Difluoroethane [75-37-6] 
4 Empirical Formula and Molecular Weight 
C2H4F2 66.05 
5 Structural Formula 
6 Functional Category 
Aerosol propellant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Difluoroethane, a hydrofluorocarbon (HFC), is an aerosol 
propellant used in topical pharmaceutical formulations.(1) 
Difluoroethane may be used as a vehicle for dispersions and 
emulsions. 
Under the terms of the Montreal Protocol, aimed at reducing 
damage to the ozone layer, the use of chlorofluorocarbons has 
been prohibited since January 1996. Since difluoroethane does 
not contain chlorine, there are no environmental controls on 
the use of this material as a propellant, since it does not deplete 
the ozone layer and is not a greenhouse gas. 
8 Description 
Difluoroethane is a liquefied gas and exists as a liquid at room 
temperature when contained under its own vapor pressure, or 
as a gas when exposed to room temperature and atmospheric 
pressure. The liquid is practically odorless and colorless. 
Difluoroethane is noncorrosive and nonirritating. 
9 Pharmacopeial Specifications 
— 
10 Typical Properties 
Boiling point: 24.78C 
Critical temperature: 113.58C 
Density: 
0.90 g/cm3 for liquid at 258C; 
0.81 g/cm3 for liquid at 54.58C. 
Flammability: flammable. Limits of flammability 3.7–18.0% 
v/v in air. 
Melting point: 1178C 
Solubility: soluble 1 in 357 parts of water at 258C. 
Surface tension: 11.25mN/m (11.25 dynes/cm) for liquid at 
208C. 
Vapor density (absolute): 2.949 g/m3 at standard temperature 
and pressure. 
Vapor density (relative): 2.29 (air = 1) 
Vapor pressure: 
600 kPa (61.7 psig) at 21.18C; 
1317 kPa (191 psia) at 54.58C. 
Viscosity (dynamic): 0.243 mPa s (0.243 cP) for liquid at 208C. 
11 Stability and Storage Conditions 
Difluoroethane is a nonreactive and stable material. The 
liquefied gas is stable when used as a propellant and should 
be stored in a metal cylinder in a cool, dry place. 
12 Incompatibilities 
Compatible with the usual ingredients used in the formulation 
of pharmaceutical aerosols. 
13 Method of Manufacture 
Difluoroethane is prepared from ethyne by the addition of 
hydrogen fluoride in the presence of a suitable catalyst. The 
difluoroethane formed is purified to remove all traces of water, 
as well as traces of the starting materials. 
14 Safety 
Difluoroethane may be used as an aerosol propellant in topical 
pharmaceutical formulations. It is generally regarded as an 
essentially nontoxic and nonirritant material. 
Deliberate inhalation of excessive quantities of this propellant 
may result in death, and the following ‘warning’ statements 
must appear on the label of all aerosols: 
WARNING: Avoid inhalation. Keep away from eyes or 
other mucous membranes. 
(Aerosols designed specifically for oral and nasal inhalation 
need not contain this statement.) 
WARNING: Do not inhale directly; deliberate inhalation of 
contents can cause death. 
or

WARNING: Use only as directed; intentional misuse by 
deliberately concentrating and inhaling the contents can be 
harmful or fatal. 
Additionally, the label should contain the following information: 
WARNING: Contents under pressure. Do not puncture or 
incinerate container. Do not expose to heat or store at room 
temperature above 1208F (498C). Keep out of the reach of 
children. 
When propellants are used in topical aerosols they may cause a 
chilling effect on the skin, although this effect has been 
somewhat overcome by the use of vapor-tap valves. The 
propellants quickly vaporize from the skin, and are nonirritating 
when used as directed. 
15 Handling Precautions 
Difluoroethane is usually encountered as a liquefied gas and 
appropriate precautions for handling such materials should be 
taken. Eye protection, gloves, and protective clothing are 
recommended. Difluoroethane should be handled in a wellventilated 
environment. Fluorocarbon vapors are heavier than 
air and do not support life; therefore, when cleaning large tanks 
that have contained these propellants, adequate provision for 
oxygen supply in the tanks must be made in order to protect 
workers cleaning the tanks. 
Difluoroethane is flammable; see Section 10. When it is 
heated to decomposition, toxic fumes of hydrogen fluoride may 
be formed. 
16 Regulatory Status 
Accepted in the USA, by the FDA, for use as a topical aerosol 
propellant. 
17 Related Substances 
Tetrafluoroethane. 
18 Comments 
Difluoroethane is useful as an aerosol propellant in that it 
shows greater miscibility with water than some other fluorocarbons 
and when combined with chlorodifluoroethane will 
produce a mixture with a specific gravity of 1. For a discussion 
of the numerical nomenclature applied to this aerosol 
propellant, see Chlorofluorocarbons. 
19 Specific References 
1 Sheridan V. Propelling VOCs down. Manuf Chem 1995; 66(10): 
57. 
20 General References 
Johnson MA. The Aerosol Handbook, 2nd edn. Caldwell: WE 
Dorland, 1982: 305–335. 
Johnson MA. Flammability aspects of dimethy ether, p-22, p-142b, p- 
152a. Aerosol Age 1988; 33(8): 32, 34, 36, 38–39. 
Sanders PA. Handbook of Aerosol Technology, 2nd edn. New York: 
Van Nostrand Reinhold, 1979: 19–35. 
Sciarra JJ. Aerosols. In: Gennaro AR, ed. Remington: The Science and 
Practice of Pharmacy, 19th edn. Easton, PA: Mack Publishing Co., 
1995: 1676–1692. 
Sciarra JJ. Aerosol suspensions and emulsions. In: Lieberman H, Rieger 
J, Banker G, eds. Pharmaceutical Dosage Forms: Disperse Systems, 
vol. 2, 2nd edn. New York: Marcel Dekker, 1996: 319–356. 
Sciarra JJ. Pharmaceutical aerosols. In: Banker GS, Rhodes CT, eds. 
Modern Pharmaceutics, 3rd edn. New York: Marcel Dekker, 1996: 
547–574. 
Sciarra JJ, Stoller L. The Science and Technology of Aerosol Packaging. 
New York: Wiley, 1974: 137–145. 
21 Authors 
CJ Sciarra, JJ Sciarra. 
22 Date of Revision 
23 August 2005. 
Difluoroethane (HFC) 243

Dimethicone 
1 Nonproprietary Names 
BP: Dimeticone 
PhEur: Dimeticonum 
USPNF: Dimethicone 
2 Synonyms 
ABIL; dimethylpolysiloxane; dimethylsilicone fluid; dimethylsiloxane; 
Dow Corning Q7-9120; E900; methyl polysiloxane; 
poly(dimethylsiloxane); Sentry. 
3 Chemical Name and CAS Registry Number 
a-(Trimethylsilyl)-o-methylpoly[oxy(dimethylsilylene)] [9006- 
65-9] 
4 Empirical Formula and Molecular Weight 
The PhEur 2005 describes dimethicone as a polydimethylsiloxane 
obtained by hydrolysis and polycondensation of dichlorodimethylsilane 
and chlorotrimethylsilane. The degree of 
polymerization (n = 20–400) is such that materials with 
kinematic viscosities nominally 20–1300mm2/s (20–1300 cSt) 
are produced. Dimethicones with a nominal viscosity of 
50mm2/s (50 cSt) or lower are intended for external use only. 
The USPNF 23 describes dimethicone as a mixture of fully 
methylated linear siloxane polymers containing repeating units 
of the formula [–(CH3)2SiO–]n stabilized with trimethylsiloxy 
end-blocking units of the formula [(CH3)3SiO–], where n has 
an average value such that the corresponding nominal viscosity 
is in a discrete range 20–30 000mm2/s (20–30 000 cSt). 
5 Structural Formula 
6 Functional Category 
Antifoaming agent; emollient. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dimethicones of various viscosities are widely used in cosmetic 
and pharmaceutical formulations. In topical oil-in-water 
emulsions dimethicone is added to the oil phase as an 
antifoaming agent. Dimethicone is hydrophobic and is also 
widely used in topical barrier preparations. Therapeutically, 
dimethicone may be used with simethicone in oral pharmaceutical 
formulations used in the treatment of flatulence. Dimethicone 
is also used to form a water-repellent film on glass 
containers. See Table I. 
Table I: Uses of dimethicone. 
Use Concentration (%) 
Creams, lotions and ointments 10–30 
Oil–water emulsions 0.5–5.0 
8 Description 
Dimethicones are clear, colorless liquids available in various 
viscosities; see Section 4. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for dimethicone. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Acidity . . 
Specific gravity — .(a) 
Viscosity (kinematic) of the 
nominal stated value 
90–110% .(a) 
Refractive index — .(a) 
Mineral oils . — 
Phenylated compounds . — 
Heavy metals 45 ppm 45 mg/g 
Volatile matter (for dimethicones 
with a viscosity greater than 
50mm2/s (50 cSt) 
40.3% — 
Loss on heating — .(a) 
Bacterial endotoxins (coating of 
containers for parenteral use) 
— . 
Assay (of polydimethylsiloxane) — 97.0–103.0% 
(a) The USPNF 23 specifies limits for these tests specific to the nominal viscosity of the 
dimethicone. 
10 Typical Properties 
Acid value: <0.01 
Density: 0.94–0.98 g/cm3 at 258C 
Refractive index: nD
25 = 1.401–1.405 
Solubility: miscible with ethyl acetate, methyl ethyl ketone, 
mineral oil, and toluene; soluble in isopropyl myristate, very 
slightly soluble in ethanol (95%); practically insoluble in 
glycerin, propylene glycol, and water. 
Surface tension: 20.5–21.2mN/m at 258C 
11 Stability and Storage Conditions 
Dimethicones should be stored in an airtight container in a 
cool, dry, place; they are stable to heat and are resistant to most 
chemical substances although they are affected by strong acids. 
Thin films of dimethicone may be sterilized by dry heat for at 
least 2 hours at 1608C. Sterilization of large quantities of

dimethicone by steam autoclaving is not recommended since 
excess water diffuses into the fluid causing it to become hazy. 
However, thin films may be sterilized by this method. Gamma 
irradiation may also be used to sterilize dimethicone. Gamma 
irradiation can, however, cause cross-linking with a consequent 
increase in the viscosity of fluids. 
12 Incompatibilities 
—
13 Method of Manufacture 
Dimethicone is a poly(dimethylsiloxane) obtained by hydrolysis 
and polycondensation of dichlorodimethylsilane and 
chlorotrimethylsilane. The hydrolysis products contain active 
silanol groups through which condensation polymerization 
proceeds. By varying the proportions of chlorotrimethylsilane, 
which acts as a chain terminator, silicones of varying molecular 
weight may be prepared. Different grades of dimethicone are 
produced that may be distinguished by a number placed after 
the name indicating the nominal viscosity. For example, ABIL 
20 (Goldschmidt UK Ltd) has a nominal kinematic viscosity of 
18–22mm2/s (18–22 cSt). See also Section 4. 
14 Safety 
Dimethicone is generally regarded as a relatively nontoxic and 
nonirritant material although it can cause temporary irritation 
to the eyes. In pharmaceutical formulations it may be used in 
oral and topical preparations. Dimethicones are also used 
extensively in cosmetic formulations and in certain food 
applications. 
The WHO has set a tentative estimated acceptable daily 
intake of dimethicone with a relative molecular mass in the 
range of 200–300 at up to 1.5 mg/kg body-weight.(1) 
Injection of silicones into tissues may cause granulomatous 
reactions. Accidental intravascular injection has been associated 
with fatalities. 
LD50 (mouse, oral): >20 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Dimethicone is flammable 
and should not be exposed to naked flames or heat. 
16 Regulatory Status 
Accepted for use as a food additive in Europe. Included in the 
FDA Inactive Ingredients Guide (oral capsules and tablets, 
topical creams, emulsions, lotions, and transdermal preparations). 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Cyclomethicone; simethicone. 
18 Comments 
—
19 Specific References 
1 FAO/WHO. Evaluation of certain food additives. Twenty-third 
report of the joint FAO/WHO expert committee on food additives. 
World Health Organ Tech Rep Ser 1980; No. 648. 
20 General References 
Calogero AV. Regulatory review. Cosmet Toilet 2000; 115(May): 24, 
26, 27. 
21 Authors 
RT Guest. 
22 Date of Revision 
21 August 2005. 
Dimethicone 245

Dimethyl Ether 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Dimethyl oxide; DME; Dymel A; methoxymethane; methyl 
ether; oxybismethane; wood ether. 
3 Chemical Name and CAS Registry Number 
Dimethyl ether [115-10-6] 
4 Empirical Formula and Molecular Weight 
C2H6O 46.07 
5 Structural Formula 
6 Functional Category 
Aerosol propellant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dimethyl ether may be used as an aerosol propellant for topical 
aerosol formulations in combination with hydrocarbons and 
other propellants.(1–4) Generally, it cannot be used alone as a 
propellant owing to its high vapor pressure. Dimethyl ether is a 
good solvent and has the unique property of high water 
solubility, compared to other propellants. It has frequently been 
used with aqueous aerosols. A coarse, wet, spray is formed 
when dimethyl ether is used as a propellant. 
Dimethyl ether is also used as a propellant in cosmetics such 
as hair sprays, and in other aerosol products such as air 
fresheners and fly sprays. 
Dimethyl ether is additionally used as a refrigerant. 
8 Description 
Dimethyl ether is a liquefied gas and exists as a liquid at room 
temperature when contained under its own vapor pressure, or 
as a gas when exposed to room temperature and pressure. 
It is a clear, colorless, virtually odorless liquid. In high 
concentrations, the gas has a faint etherlike odor. 
9 Pharmacopeial Specifications 
—
10 Typical Properties 
Autoignition temperature: 3508C 
Boiling point: 23.68C 
Critical temperature: 126.98C 
Density: 0.66 g/cm3 for liquid at 258C. 
Flammability: the pure material is flammable; limit of flammability 
is 3.4–18.2% v/v in air. Aqueous mixtures are 
nonflammable. 
Freezing point: 138.58C 
Flash point: 418C 
Heat of combustion: 28.9 kJ/g (6900 cal/g) 
Kauri-butanol value: 60 
Solubility: soluble in acetone, chloroform, ethanol (95%), 
ether, and 1 in 3 parts of water. Dimethyl ether is generally 
miscible with water, nonpolar materials, and some semipolar 
materials. For pharmaceutical aerosols, ethanol (95%) 
is the most useful cosolvent. Glycols, oils, and other similar 
materials exhibit varying degrees of miscibility with 
dimethyl ether. 
Surface tension: 16mN/m (16 dynes/cm) at –108C 
Vapor density (absolute): 2.058 g/m3 at standard temperature 
and pressure. 
Vapor density (relative): 1.596 (air = 1) 
Vapor pressure: 
592 kPa at 258C (63 psig at 21.18C); 
1301 kPa at 548C. 
11 Stability and Storage Conditions 
The liquefied gas is stable when used as a propellant. However, 
exposure to the air for long periods of time may result in 
explosive peroxides being slowly formed. 
Solutions of liquid dimethyl ether should not be concentrated 
either by distillation or by evaporation. Dimethyl ether 
should be stored in tightly closed metal cylinders in a cool, dry 
place. 
12 Incompatibilities 
Dimethyl ether is an aggressive solvent and may affect the 
gasket materials used in aerosol packaging. Oxidizing agents, 
acetic acid, organic acids, and anhydrides should not be used 
with dimethyl ether. See also Section 10. 
13 Method of Manufacture 
Dimethyl ether is prepared by the reaction of bituminous or 
lignite coals with steam in the presence of a finely divided nickel 
catalyst. This reaction produces formaldehyde, which is then 
reduced to methanol and dimethyl ether. Dimethyl ether may 
also be prepared by the dehydration of methanol. 
14 Safety 
Dimethyl ether may be used as a propellant and solvent in 
topical pharmaceutical aerosols, and is generally regarded as an 
essentially nontoxic and nonirritant material when used in such 
applications. However, inhalation of high concentrations of 
dimethyl ether vapor is harmful. Additionally, skin contact with 
dimethyl ether liquid may result in freezing of the skin and 
severe frostbite. 
When used in topical formulations, dimethyl ether may 
exert a chilling effect on the skin, although if it is used as 
directed the propellant quickly vaporizes and is nonirritating.

LD50 (mouse, inhalation): 386 000 ppm/30 min(5) 
LD50 (rat, inhalation): 308 g/m3 
15 Handling Precautions 
Dimethyl ether is usually encountered as a liquefied gas, and 
appropriate precautions for handling such materials should be 
taken. Eye protection, gloves, and protective clothing are 
recommended. 
Dimethyl ether should be handled in a well-ventilated 
environment. 
Dimethyl ether vapor is heavier than air and does not 
support life; therefore, when cleaning large tanks that have 
contained this material, adequate provisions for oxygen supply 
in the tanks must be made in order to protect workers cleaning 
the tanks. 
In the UK, the long-term (8-hour TWA) exposure limit for 
dimethyl ether is 766 mg/m3 (400 ppm). The short-term (15- 
minute) exposure limit is 958 mg/m3 (500 ppm).(6) 
Dimethyl ether is flammable; see Section 10. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (topical 
aerosols). Included in nonparenteral medicines licensed in the 
UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Hydrocarbons (HC). 
18 Comments 
Since the solubility of dimethyl ether in water is about 35%, it 
can be used to good effect in aqueous aerosol products. It also 
has antimicrobial effects that are organism-dependent.(7) 
The EINECS number for dimethyl ether is 204-065-8. 
19 Specific References 
1 Bohnenn LJM. DME: an alternative propellant? Manuf Chem 
Aerosol News 1977; 48(9): 40. 
2 Bohnenn LJM. DME: further data on this alternative propellant. 
Manuf Chem Aerosol News 1978; 49(8): 39, 63. 
3 Bohnenn LJM. ‘Alternative’ aerosol propellant. Drug Cosmet Ind 
1979; 125(Nov): 58, 60, 62, 66, 68, 70, 72, 74. 
4 Boulden ME. Use of dimethyl ether for reduction of VOC content. 
Spray Technol Market 1992; 2(May): 30, 32, 34, 36. 
5 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2442. 
6 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
7 Ibrahim YK, Sonntag HG. Preservative potentials of some aerosol 
propellants: effectiveness in some pharmaceutical oils. Drugs 
Made Ger 1995; 38(Apr–Jun): 62–65. 
20 General References 
Johnson MA. The Aerosol Handbook, 2nd edn. Mendham, NJ: WE 
Dorland, 1982: 305–335. 
Johnson MA. Flammability aspects of dimethyl ether, p-22, p-142b, p- 
152a. Aerosol Age 1988; 33(8): 32, 34, 36, 38–39. 
Sanders PA. Handbook of Aerosol Technology, 2nd edn. New York: 
Van Nostrand Reinhold, 1979: 44–54. 
Sciarra JJ, Stoller L. The Science and Technology of Aerosol Packaging. 
New York: Wiley, 1974: 137–145. 
Sciarra JJ. Pharmaceutical aerosols. In: Banker GS, Rhodes CT, eds. 
Modern Pharmaceutics, 3rd edn. New York: Marcel Dekker, 1996: 
547–574. 
Sciarra JJ, Sciarra CJ. Aerosols. In: Gennaro AR, ed. Remington: The 
Science and Practice of Pharmacy, 20th edn. Baltimore, MD: 
Lippincott, Williams and Wilkins, 2000: 963–979. 
21 Authors 
CJ Sciarra, JJ Sciarra. 
22 Date of Revision 
23 August 2005. 
Dimethyl Ether 247

Dimethyl Phthalate 
1 Nonproprietary Names 
BP: Dimethyl phthalate 
2 Synonyms 
Avolin; 1,2-benzenedicarboxylate; benzenedicarboxylic acid 
dimethyl ester; dimethyl 1,2-benzenedicarboxylate; dimethyl 
benzene-o-dicarboxylate; dimethyl benzeneorthodicarboxylate; 
dimethyl o-phthalate; o-dimethyl phthalate; DMP; Fermine; 
Kodaflex DMP; methyl benzene-1,2-dicarboxylate; 
Mipax; Palatinol M; phthalic acid dimethyl ester; phthalic 
acid methyl ester; Repeftal; Solvanom; Solvarone; Unimoll 
DM. 
3 Chemical Name and CAS Registry Number 
1,2-Benzene-dicarboxylic acid dimethyl ester [131-11-3] 
4 Empirical Formula and Molecular Weight 
C10H10O4 194.19 
5 Structural Formula 
6 Functional Category 
Film-former; plasticizer; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dimethyl phthalate is used in pharmaceutical applications as a 
solvent and plasticizer for film-coatings such as hydroxypropyl 
methylcellulose, cellulose acetate and cellulose acetate–butyrate 
mixtures.(1,2) 
In addition to a number of industrial applications, dimethyl 
phthalate is also widely used as an insect repellent with topical 
preparations typically applied as a 40% cream or lotion; it has 
also been applied as a tent fabric treatment.(3) 
8 Description 
Dimethyl phthalate occurs as a colorless, or faintly colored, 
odorless, viscous, oily liquid. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for dimethyl phthalate. 
Test BP 2004 
Identification . 
Characters . 
Acidity . 
Refractive index 1.515–1.517 
Weight per mL 1.186–1.192 
Related substances . 
Sulfated ash 40.1% 
Water 40.1% 
Assay (dried basis) 99.0–100.5% 
10 Typical Properties 
Boiling point: 2808C, with decomposition. 
Density: 1.186–1.192 g/cm3 
Flash point: 1468C closed cup. 
Freezing point: the commercial product freezes at 08C. 
Melting point: 2.0–5.58C 
Partition coefficient: 
Octanol : water = 1.56(4) 
Refractive index: nD
20 = 1.515–1.517 
Solubility: see Table II. 
Table II: Solubility of dimethyl phthalate. 
Solvent Solubility at 208C unless otherwise stated 
Benzene Miscible 
Chloroform Miscible 
Ethanol (95%) Miscible 
Ether Miscible 
Mineral oil 1 in 294 
Water 1 in 250 at 208C 
Surface tension: 41.9mN/m at 208C 
Vapor density (relative): 6.69 (air = 1) 
Vapor pressure: 120 Pa at 1008C 
Viscosity: 17.2 mPa s (17.2 cP) at 258C. 
11 Stability and Storage Conditions 
Dimethyl phthalate is sensitive to prolonged exposure to light 
and it should therefore be stored in a cool, dark, dry, wellventilated 
area that is protected from physical damage, and 
isolated from incompatible substances. Containers of dimethyl 
phthalate may be hazardous when empty as they may retain 
product residues such as vapors and liquids. There is a slight 
fire hazard when exposed to heat, and above the flash point (see 
Section 10); explosive vapor–air mixtures may be formed. 
Carbon dioxide and carbon monoxide are released when 
dimethyl phthalate is heated to decomposition. Solutions of 
dimethyl phthalate in acetone, dimethyl sulfoxide, ethanol

(95%), and water are stable for 24 hours under normal 
laboratory conditions. 
12 Incompatibilities 
Dimethyl phthalate is incompatible with strong acids or bases, 
nitrates, and strong oxidizing agents. 
13 Method of Manufacture 
Dimethyl phthalate is produced industrially from phthalic 
anhydride and methanol. 
14 Safety 
In pharmaceutical applications, dimethyl phthalate is used in 
film-coating and as a topically applied insect repellent. Acute 
exposure to the eyes and mucous membranes can cause 
irritation although dimethyl phthalate is considered less irritant 
than diethyl phthalate. Inhalation of dimethyl phthalate can 
cause irritation of the respiratory tract; oral ingestion can cause 
a burning sensation in the mouth, vomiting, and diarrhea. 
Owing to the low water solubility and relatively high lipid 
solubility, dimethyl phthalate may accumulate in body tissues 
after chronic exposure, which may cause central nervous 
system depression. 
Although some animal studies have suggested that high 
concentrations of dimethyl phthalate may be teratogenic or 
cause mutagenic effects with bacteria,(5,6) other studies have 
shown no adverse effects.(7) There are no confirmed reports of 
human reproductive or developmental effects and the compound 
is not generally regarded as a carcinogenic material. 
LD50 (chicken, oral): 8.5 g/kg(8) 
LD50 (guinea pig, oral): 2.4 g/kg 
LD50 (mouse, IP): 1.38 g/kg 
LD50 (mouse, oral): 6.8 g/kg 
LD50 (rabbit, oral): 4.40 g/kg 
LD50 (rat, IP): 3.38 g/kg 
LD50 (rat, oral): 6.80 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Skin and eye contact should 
be avoided; eye goggles or a full face shield should be worn 
where splashing may occur. Respirators should be used if the 
compound is heated to decomposition. In the UK, the long-term 
(8-hour TWA) exposure limit for dimethyl phthalate is 
5 mg/m3. The short-term (15-minute) exposure limit is 
10 mg/m3.(9) 
16 Regulatory Status 
Dimethyl phthalate is included in a number of topical 
pharmaceutical formulations. As from 1992, dimethyl phthalate 
is no longer registered for use as a pesticide in California. 
17 Related Substances 
Dibutyl phthalate; diethyl phthalate. 
18 Comments 
The EINECS number for dimethyl phthalate is 205-011-6. 
19 Specific References 
1 Shah PS, Zatz JL. Plasticization of cellulose esters used in the 
coating of sustained release solid dosage forms. Drug Dev Ind 
Pharm 1992; 18: 1759–1772. 
2 Wolf B. Bead cellulose products with film formers and solubilisers 
for controlled drug release. Int J Pharm 1997; 156: 97–107. 
3 Schreck CE. Permethrin and dimethyl phthalate as tent fabric 
treatments against Aedes aegypti. J Am Mosq Control Assoc 1991; 
7(4): 533–535. 
4 Ellington JJ, Floyd TL. EPA/600/5–96: Octanol/water Partition 
Coefficients for Eight Phthalate Esters. Athens, GA: US Environmental 
Protection Agency, 1996. 
5 Kozumbo WJ, Rubin RJ. Mutagenicity and metabolism of 
dimethyl phthalate and its binding to epidermal and hepatic 
macromolecules. J Toxicol Environ Health 1991; 33(1): 29–46. 
6 Niazi JH, Prasad DT, Karegoudar TB. Initial degradation of 
dimethyl phthalate by esterases from Bacillus species. FEMS 
Microbiol Lett 2001; 196(2): 201–205. 
7 Field EA, Price CJ, Sleet RB, et al. Developmental toxicity 
evaluation of diethyl and dimethyl phthalate in rats. Teratology 
1993; 48(1): 33–44. 
8 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1460. 
9 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
—
21 Authors 
W Cook. 
22 Date of Revision 
4 August 2005. 
Dimethyl Phthalate 249

Dimethyl Sulfoxide 
1 Nonproprietary Names 
BP: Dimethyl sulfoxide 
PhEur: Dimethylis sulfoxidum 
USP: Dimethyl sulfoxide 
2 Synonyms 
Deltan; dimexide; dimethyl sulphoxide; DMSO; Kemsol; 
methylsulfoxide; Rimso-50; sulphinylbismethane 
3 Chemical Name and CAS Registry Number 
Sulfinylbismethane [67-68-5] 
4 Empirical Formula and Molecular Weight 
C2H6OS 78.13 
5 Structural Formula 
6 Functional Category 
Penetration enhancer; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dimethyl sulfoxide is a highly polar substance that is aprotic, 
therefore lacking acidic and basic properties. It has exceptional 
solvent properties for both organic and inorganic components, 
which are derived from its capacity to associate with both ionic 
species and neutral molecules that are either polar or 
polarizable. Dimethyl sulfoxide enhances the topical penetration 
of drugs owing to its ability to displace bound water from 
the stratum corneum; this is accompanied by the extraction of 
lipids and configurational changes of proteins.(1) The molecular 
interactions between dimethyl sulfoxide and the stratum 
corneum, as a function of depth and time, have been 
described.(2) Much of the enhancement capacity is lost if the 
solvent is diluted. Increases in drug penetration have been 
reported with dimethyl sulfoxide concentrations as low as 
15%, but significant increases in permeability generally require 
concentrations higher than 60–80%. Furthermore, while low 
molecular weight substances can penetrate quickly into the 
deep layers of the skin, the appreciable transport of molecules 
with a molecular weight of more than 3000 is difficult. 
The use of dimethyl sulfoxide to improve transdermal 
delivery has been reported for ciclosporin,(3) timolol,(4) and a 
wide range of other drugs.(5,6) Dimethyl sulfoxide has also been 
used in the formulation of an injection containing allopurinol.(
7) It has also been investigated for use in an experimental 
parenteral preparation for the treatment of liver tumors.(8) 
In paint formulations of idoxuridine, dimethyl sulfoxide acts 
both as a solvent to increase drug solubility and a means of 
enabling penetration of the antiviral agent to the deeper levels 
of the epidermis. See Table I. 
Dimethyl sulfoxide has also been investigated as a potential 
therapeutic agent in conditions such as scleroderma, interstitial 
cystitis, rheumatoid arthritis, and acute musculoskeletal 
injuries, and as an analgesic.(9–13) It has also been recommended 
for the treatment of anthracycline extravasation(14,15) 
and has been investigated as a potential cryoprotectant.(16) 
Table I: Uses of dimethyl sulfoxide. 
Use Concentration (%) 
Solvent 4100 
Topical penetration enhancer 580 
8 Description 
Dimethyl sulfoxide occurs as a colorless, viscous liquid, or as 
colorless crystals that are miscible with water, alcohol, and 
ether. The material has a slightly bitter taste with a sweet 
aftertaste and is odorless, or has a slight odor characteristic of 
dimethyl sulfoxide. Dimethyl sulfoxide is extremely hygroscopic, 
absorbing up to 70% of its own weight in water with 
evolution of heat. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for dimethyl sulfoxide. 
Test PhEur 2005 USP 28 
Characters . — 
Identification . . 
Specific gravity 1.100–1.104 1.095–1.101 
Freezing point 518.38C 518.38C 
Refractive index 1.478–1.479 1.4755–1.4775 
Acidity . . 
Water 40.2% 40.1% 
Ultraviolet absorbance . . 
Substances darkened by potassium 
hydroxide 
— . 
Limit of dimethyl sulfone — . 
Limit of nonvolatile residue — 45.0mg 
Related substances . — 
Assay — 599.9% 
10 Typical Properties 
Boiling point: 1898C 
Dielectric constant: 48.9 at 208C 
Dipole moment (D): 4.3 at 208C(17) 
Dissociation constant: pKa = 31.3(17) 
Enthalpy of fusion: 3.43 cal/mol(17)

Enthalpy of vaporization: 12.64 cal/mol at 258C(17) 
Flash point (open cup): 958C 
Specific heat: 0.7 cal/g (liquid) 
Solubility: miscible with water with evolution of heat; also 
miscible with ethanol (95%), ether and most organic 
solvents; immiscible with paraffins, hydrocarbons. Practically 
insoluble in acetone, chloroform, ethanol (95%), and 
ether. 
Vapor pressure: 0.37mm at 208C 
Viscosity (dynamic): 1.1 mPa s (1.1 cP) at 278C 
11 Stability and Storage Conditions 
Dimethyl sulfoxide is reasonably stable to heat but upon 
prolonged reflux it decomposes slightly to methyl mercaptan 
and bismethylthiomethane. This decomposition is aided by 
acids, and is retarded by many bases. When heated to 
decomposition, toxic fumes are emitted. 
At temperatures between 40–608C, it has been reported that 
dimethyl sulfoxide suffers a partial breakdown, which is 
indicated by changes in physical properties such as refractive 
index, density, and viscosity.(18) 
Dimethyl sulfoxide should be stored in airtight, lightresistant 
containers. The PhEur 2005 states that glass containers 
should be used. Contact with plastics should be avoided. 
12 Incompatibilities 
Dimethyl sulfoxide can react with oxidizing materials. 
13 Method of Manufacture 
Dimethyl sulfoxide is prepared by air oxidation of dimethyl 
sulfide in the presence of nitrogen oxides. It can also be 
obtained as a by-product of wood pulp manufacture for the 
paper and allied industries. 
14 Safety 
Dimethyl sulfoxide has low systemic toxicity but causes local 
toxic effects.(19–21) It is readily absorbed after injection or after 
oral or percutaneous administration and is widely distributed 
throughout the body. Dimethyl sulfoxide acts as a primary 
irritant on skin, causing redness, burning, itching, and scaling; 
it also causes urticaria. Systemic symptoms include nausea, 
vomiting, chills, cramps, and lethargy; dimethyl sulfoxide can 
also cause increases in intraocular pressure. Administration of 
dimethyl sulfoxide by any route is followed by a garlic-like 
odor on the breath. 
Intravascular hemolysis and biochemical changes(22) and 
reversible neurological deterioration(23) have been reported 
following intravenous administration; however, it has been 
questioned whether these findings were directly attributable to 
dimethyl sulfoxide rather than to concomitant drug therapy or 
contaminants.(24) Recently, a hypersensitivity reaction attributed 
to dimethyl sulfoxide has been reported.(25) 
In 1965, the FDA banned investigation in humans of 
dimethyl sulfoxide owing to the appearance of changes in the 
refractive index of the lens of the eye in experimental animals. 
However, in 1966, the FDA allowed the study of dimethyl 
sulfoxide in serious conditions such as scleroderma, persistent 
herpes zoster, and severe rheumatoid arthritis, and in 1968 
permitted studies using short-term topical application of the 
solvent. By 1980, the FDA no longer specifically regulated 
investigations of dimethyl sulfoxide.(10) 
Dimethyl sulfoxide enhances the skin penetration of several 
drugs, which may result in producing the adverse effects 
associated with those drugs. 
LD50 (dog, IV): 2.5 g/kg(26) 
LD50 (rat, IP): 8.2 g/kg 
LD50 (rat, IV): 5.3 g/kg 
LD50 (rat, oral): 14.5 g/kg 
LD50 (rat, SC): 12 g/kg 
LD50 (mouse, IP): 2.5 g/kg 
LD50 (mouse, IV): 3.8 g/kg 
LD50 (mouse, oral): 7.9 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Dimethyl sulfoxide may 
cause irritation to the skin. Gloves and eye protection are 
recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IV infusions, 
SC implants, and topical preparations). Available in the USA as 
a 50% solution for irrigation in the treatment of interstitial 
cystitis. Also available in Canada as a 70% solution for use as a 
topical antifibrotic and in Germany as a topical gel containing 
10% dimethyl sulfoxide for the treatment of musculoskeletal 
and joint disorders. Included in topical formulations of 
idoxuridine and diclofenac licensed in the UK. 
17 Related Substances 
—
18 Comments 
A 2.16% dimethyl sulfoxide solution in water is iso-osmotic 
with serum. Dimethyl sulfoxide has been used as a 50% 
aqueous solution for instillation into the bladder in the 
treatment of interstitial cystitis; it has also been tried clinically 
for a wide range of indications, including cutaneous and 
musculoskeletal disorders, but with little evidence of beneficial 
effects. 
Dimethyl sulfoxide has been shown to have bactericidal,(27) 
bacteriostatic,(27,28) and fungistatic(28) activity, although the 
concentration required is dependent on the organism present. 
19 Specific References 
1 Anigbogu ANC, Williams AC, Barry BW, Edwards HGM. Fourier 
transform Raman spectroscopy of interactions between the 
penetration enhancer dimethyl sulfoxide and human stratum 
corneum. Int J Pharm 1995; 125: 265–282. 
2 Caspers PJ, Williams AC, Carter EA, et al. Monitoring the 
penetration enhancer dimethyl sulfoxide in human stratum 
corneum in vivo by confocal Raman spectroscopy. Pharm Res 
2002; 19(10): 1577–1580. 
3 Wang D-P, Lin C-Y, Chu D-L, Chang L-C. Effect of various 
physical/chemical properties on the transdermal delivery of 
ciclosporin through topical application. Drug Dev Ind Pharm 
1997; 23(1): 99–106. 
4 Soni S, Jain SK, Jain NK. Effect of penetration enhancers on 
transdermal delivery of timolol maleate. Drug Dev Ind Pharm 
1992; 18(10): 1127–1135. 
5 Barry BW. Dermatological Formulations. New York: Marcel 
Dekker, 1983: 162–167. 
Dimethyl Sulfoxide 251

6 Motlekar NA, Shah RB, Reddy IK, et al. Permeation of genistein 
through human skin. Pharm Technol 2003; 27(3): 140–148. 
7 Lee DKT, Wang D-P. Formulation development of allopurinol 
suppositories and injectables. Drug Dev Ind Pharm 1999; 25(11): 
1205–1208. 
8 Komemushi A, Tanigawa N, Okuda Y, et al. A new liquid embolic 
material for liver tumors. Acta Radiol 2002; 43(2): 186–191. 
9 Murdoch L-A. Dimethyl sulfoxide (DMSO): an overview. Can J 
Hosp Pharm 1982; 35(3): 79–85. 
10 Fischer JM. DMSO: a review. US Pharm 1981; 6(Sept): 25–28. 
11 Namaka M, Briggs C. DMSO revisited. Can Pharm J 1994; 
127(Jun): 248, 249, 255. 
12 Parker WA, Bailie GR. Current therapeutic status of DMSO. Can 
Pharm J 1982; 115(Jul): 247–251. 
13 Ely A, Lockwood B. What is the evidence for the safety and 
efficiency of dimethyl sulfoxide and methylsulfanylmethane in 
pain relief? Pharm J 2002; 269: 685–687. 
14 Bingham JM, Dooley MJ. EXTRA – Extravasation Treatment 
Record Database: a database to record and review cytotoxic drug 
extravasation events. Aust J Hosp Pharm 1998; 28(2): 89–93. 
15 Bertelli G, Dini D, Forno G, et al. Dimethylsulphoxide and cooling 
after extravasation of antitumour agents [letter]. Lancet 1993; 
341: 1098–1099. 
16 Higgins J, Hodges NA, Olliff CJ, Phillips AJ. A comparative 
investigation of glycinebetaine and dimethylsulphoxide as liposome 
cryoprotectants. J Pharm Pharmacol 1987; 39: 577–582. 
17 MacGregor WS. The chemical and physical properties of DMSO. 
Ann NY Acad Sci 1967; 141: 3–12. 
18 Jacob SW, Rosenbaum EE, Wood DC, eds. Dimethyl Sulfoxide, 
vol. 1. New York: Marcel Dekker, 1971: 81. 
19 Brobyn RD. The human toxicology of dimethyl sulfoxide. Ann NY 
Acad Sci 1975; 243: 497–506. 
20 Willhite CC, Katz PI. Toxicology updates: dimethyl sulfoxide. J 
Appl Toxicol 1984; 4: 155–160. 
21 Mottu F, Laurent A, Rufenacht DA, Doelker E. Organic solvents 
for pharmaceutical parenterals and embolic liquids: a review of 
toxicity data. PDA J Pharm Sci Technol 2000; 54(6): 456–469. 
22 Yellowlees P, Greenfield C, McIntyre N. Dimethylsulphoxideinduced 
toxicity. Lancet 1980; ii: 1004–1006. 
23 Bond GR, Curry SC, Dahl DW. Dimethylsulphoxide-induced 
encephalopathy [letter]. Lancet 1989; i: 1134–1135. 
24 Knott LJ. Safety of intravenous dimethylsulphoxide [letter]. Lancet 
1980; ii: 1299. 
25 Creus N, Mateu J, Masso J, et al. Toxicity to topical dimethyl 
sulfoxide (DMSO) when used as an extravasation antidote. Pharm 
Wld Sci 2002; 24(5): 175–176. 
26 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1466. 
27 Ansel HC, Norred WP, Roth IL. Antimicrobial activity of dimethyl 
sulfoxide against Escherichia coli, Pseudomonas aeruginosa, and 
Bacillus megaterium. J Pharm Sci 1969; 58(7): 836–839. 
28 Placencia AM, Oxborrow GS, Danielson JW. Sterility testing of fat 
emulsions using membrane filtration and dimethyl sulfoxide. J 
Pharm Sci 1982; 71(6): 704–705. 
20 General References 
Mottu F, Stelling M-J, Rufenacht DA. Comparative haemolytic activity 
of undiluted organic water-miscible solvents for intravenous and 
intra-arterial injection. PDA J Pharm Sci Technol 2001; 55(1): 16– 
21. 
21 Authors 
CG Cable. 
22 Date of Revision 
19 August 2005. 
252 Dimethyl Sulfoxide

Dimethylacetamide 
1 Nonproprietary Names 
BP: Dimethylacetamide 
PhEur: Dimethylacetamidum 
2 Synonyms 
Acetdimethylamide; acetic acid dimethylamide; acetyldimethylamine; 
dimethylacetone amide; dimethylamide acetate; DMA; 
DMAC. 
3 Chemical Name and CAS Registry Number 
N,N-Dimethylacetamide [127-19-5] 
4 Empirical Formula and Molecular Weight 
C4H9NO 87.12 
5 Structural Formula 
6 Functional Category 
Solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dimethylacetamide is used as a solvent in oral and injectable 
pharmaceutical formulations.(1) It has been used as a cosolvent 
to solubilize poorly soluble drugs.(2–4) The use of dimethylacetamide 
has also been investigated as a vehicle for the 
parenteral delivery of relatively small peptides.(5) 
The use of solvents such as dimethylacetamide has been 
shown to influence the size and rate of release of norfloxacin 
from nanoparticles.(6) 
Dimethylacetamide has also been used in topical formulations 
and has been evaluated as a permeation enhancer for 
transdermal drug delivery.(1) 
8 Description 
Dimethylacetamide occurs as a clear, colorless, slightly hygroscopic 
liquid. It has a weak ammonia-like or fishlike odor. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for dimethylacetamide. 
Test PhEur 2005 
(Suppl. 5.1) 
Identification . 
Characters . 
Appearance . 
Relative density 0.941–0.944 
Refractive index 1.435–1.439 
Acidity . 
Alkalinity . 
Related substances . 
Heavy metals 410 ppm 
Nonvolatile matter 420 ppm 
Water 40.1% 
10 Typical Properties 
Autoignition temperature: 4908C 
Boiling point: 1658C 
Dielectric constant: D20 = 37.8 
Flash point: 708C 
Refractive index: nD
22.5 = 1.4371 
Solubility: miscible with ethanol (95%), water, and most 
common solvents. 
Specific gravity: 0.943 
Surface tension: 35.7mN/m (35.7 dyne/cm) 
Vapor pressure: 0.33 kPa at 208C 
Viscosity (dynamic): 1.02 mPa s (1.02 cP) at 258C 
11 Stability and Storage Conditions 
Dimethylacetamide should be stored in an airtight container, 
protected from light, in a cool, dry, place. Dimethylacetamide 
has an almost unlimited shelf-life when kept in closed containers 
and under nitrogen. It is combustible. 
12 Incompatibilities 
Dimethylacetamide is incompatible with carbon tetrachloride, 
oxidizing agents, halogenated compounds, and iron. It attacks 
plastic and rubber. Contact with strong oxidizers may cause 
fire. 
13 Method of Manufacture 
Dimethylacetamide is manufactured from acetic acid and 
dimethylamine in a closed system. 
14 Safety 
Dimethylacetamide is used in pharmaceutical preparations as a 
solvent in parenteral formulations and is generally regarded as 
a nontoxic material when used as an excipient. Animal toxicity 
studies indicate that dimethylacetamide is readily absorbed into 
the bloodstream following inhalation or topical application. 
Repeated exposure to dimethylacetamide may be harmful and

can result in liver damage. High intravenous doses 
(>400 mg/kg/day for 3 days) may be hallucinogenic.(7–10) 
LD50 (rabbit, SC): 9.6 g/kg(11) 
LD50 (rat, IP): 2.75 g/kg 
LD50 (rat, IV): 2.64 g/kg 
LD50 (rat, oral): 4.93 g/kg 
LD50 (mouse, inhalation): 7.2 g/kg 
LD50 (mouse, IP): 2.8 g/kg 
LD50 (mouse, IV): 3.02 g/kg 
LD50 (mouse, SC): 9.6 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of the material handled. Dimethylacetamide can 
be absorbed into the bloodstream by inhalation and through 
the skin; it is irritating to the skin and eyes. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IM injections, 
IV injections and infusions). Included in parenteral medicines 
licensed in the UK. 
17 Related Substances 
—
18 Comments 
The EINECS number for dimethylacetamide is 204-826-4. A 
specification for dimethylacetamide is included in the Japanese 
Pharmaceutical Excipients (JPE) 2004.(12) 
19 Specific References 
1 Strickley RG. Solubilizing excipients in oral and injectable 
formulations. Pharm Res 2004; 21(2): 201–230. 
2 Kawakami K, Miyoshi K, Ida Y. Solubilisation behavior of poorly 
soluble drugs with combined use of Gelucire 44/14 and cosolvent. J 
Pharm Sci 2004; 93(6): 1471–1479. 
3 Tesconi MS, Bramer SL, Yalkowsky SH. The preparation of soft 
gelatin capsules for a radioactive tracer study. Pharm Dev Technol 
1999; 4(4): 507–513. 
4 Han SK, Kim GY, Park YH. Solubilization of biphenyl dimethyl 
dicarboxylate by cosolvency. Drug Dev Ind Pharm 1999; 25(11): 
1193–1197. 
5 Larsen SW, Ankersen M, Larsen C. Kinetics of degradation and oil 
solubility of ester prodrugs of a model dipeptide (Gly-Phe). Eur J 
Pharm Sci 2004; 22: 399–408. 
6 Jeon HJ, Jeong YI, Jang MK, et al. Effect of solvent on the 
preparation of surfactant-free poly (DL-lactide-co-glycolide) 
nanoparticles and norfloxacin release characteristics. Int J Pharm 
2000; 207(1–2): 99–108. 
7 Horn HJ. Toxicology of dimethylacetamide. Toxicol Appl 
Pharmacol 1961; 3: 12–24. 
8 Anschel J. Solvents and solubilization in injections [in German]. 
Pharm Ind 1965; 27: 781–787. 
9 Kennedy GL, Sherman H. Acute toxicity of dimethylformamide 
and dimethylacetamide following various routes of administration. 
Drug Chem Toxicol 1986; 9: 147–170. 
10 Kim SN. Preclinical toxicology and pharmacology of dimethylacetamide, 
with clinical notes. Drug Metab Rev 1988; 19: 345– 
368. 
11 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1371. 
12 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004: 244–245. 
20 General References 
Sinha VR, Kaur MP. Permeation enhancers for transdermal drug 
delivery. Drug Dev Ind Pharm 2000; 26(11): 1131–1140. 
21 Authors 
RT Guest. 
22 Date of Revision 
21 August 2005. 
254 Dimethylacetamide

Disodium Edetate 
1 Nonproprietary Names 
BP: Disodium edetate 
JP: Disodium edetate 
PhEur: Dinatrii edetas 
USP: Edetate disodium 
2 Synonyms 
Disodium EDTA; disodium ethylenediaminetetraacetate; 
edathamil disodium; edetate disodium; edetic acid, disodium 
salt. 
3 Chemical Name and CAS Registry Number 
Ethylenediaminetetraacetic acid, disodium salt [139-33-3] 
Disodium ethylenediaminetetraacetate dihydrate [6381-92-6] 
4 Empirical Formula and Molecular Weight 
C10H14N2Na2O8 336.2 (for anhydrous) 
C10H18N2Na2O10 372.2 (for dihydrate) 
5 Structural Formula 
6 Functional Category 
Chelating agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Disodium edetate is used as a chelating agent in a wide range of 
pharmaceutical preparations, including mouthwashes, 
ophthalmic preparations, and topical preparations,(1–3) typically 
at concentrations between 0.005 and 0.1% w/v. 
Disodium edetate forms stable water-soluble complexes 
(chelates) with alkaline earth and heavy-metal ions. The 
chelated form has few of the properties of the free ion, and 
for this reason chelating agents are often described as 
‘removing’ ions from solution, a process known as sequestering. 
The stability of the metal–edetate complex is dependent on 
the metal ion involved and the pH. 
Disodium edetate is also used as a water softener as it will 
chelate calcium and magnesium ions present in hard water. It is 
also used therapeutically as an anticoagulant as it will chelate 
calcium and prevent the coagulation of blood in vitro. 
Concentrations of 0.1% w/v are used in small volumes for 
hematological testing and 0.3% w/v in transfusions. 
See also Edetic acid. 
8 Description 
Disodium edetate occurs as a white crystalline, odorless powder 
with a slightly acidic taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for disodium edetate. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters . . — 
Appearance of 
solution 
. . — 
pH 4.3–4.7 4.0–5.5 4.0–6.0 
Iron — 480 ppm — 
Calcium — — . 
Heavy metals 410 ppm 420 ppm 40.005% 
Cyanide . — — 
Arsenic 42 ppm — — 
Limit of nitrilotriacetic 
acid 
— 40.1% 40.1% 
Residue on ignition 37.0–39.0% — — 
Loss on drying — — 8.7–11.4% 
Assay 98.5–101.0% 98.5–101.0% 99.0–101.0% 
10 Typical Properties 
Acidity/alkalinity: pH 4.3–4.7 (1% w/v solution in carbon 
dioxide-free water) 
Freezing point depression: 0.148C (1% w/v aqueous solution) 
Melting point: decomposition at 2528C for the dihydrate. 
Refractive index: 1.33 (1% w/v aqueous solution) 
Solubility: practically insoluble in chloroform and ether; 
slightly soluble in ethanol (95%); soluble 1 part in 11 parts 
water. 
Specific gravity: 1.004 (1% w/v aqueous solution) 
Viscosity (kinematic): 1.03mm2/s (1.03 cSt) (1% w/v aqueous 
solution). 
11 Stability and Storage Conditions 
Edetate salts are more stable than edetic acid (see also Edetic 
acid). However, disodium edetate dihydrate loses water of 
crystallization when heated to 1208C. Aqueous solutions of 
disodium edetate may be sterilized by autoclaving, and should 
be stored in an alkali-free container. 
Disodium edetate is hygroscopic and is unstable when 
exposed to moisture. It should be stored in a well-closed 
container in a cool, dry place.

12 Incompatibilities 
Disosium edetate behaves as a weak acid, displacing carbon 
dioxide from carbonates and reacting with metals to form 
hydrogen. It is incompatible with strong oxidizing agents, 
strong bases, metal ions, and metal alloys. 
See also Edetic acid. 
13 Method of Manufacture 
Disodium edetate may be prepared by the reaction of edetic 
acid and sodium hydroxide. 
14 Safety 
Disodium edetate is used widely in topical, oral, and parenteral 
pharmaceutical formulations; it is used extensively in cosmetic 
and food products. Disodium edetate and edetate calcium 
disodium are used in a greater number and variety of 
pharmaceutical formulations than is edetic acid. Both disodium 
edetate and edetate calcium disodium are poorly absorbed from 
the gastrointestinal tract and are associated with few adverse 
effects when used as excipients in pharmaceutical formulations. 
Disodium edetate, trisodium edetate, and edetic acid readily 
chelate calcium and can, in large doses, cause calcium depletion 
(hypocalcemia) if used over an extended period of time, or if 
administered too rapidly by intravenous infusion. If used in 
preparations for the mouth, they can also leach calcium from 
the teeth. However, edetate calcium disodium does not chelate 
calcium. 
Disodium edetate should be used with caution in patients 
with renal impairment, tuberculosis, and impaired cardiac 
function. 
Although disodium edetate is generally considered safe, 
there have been reports of disodium edetate toxicity in patients 
receiving chelation therapy.(4) 
Nasal formulations containing benzalkonium chloride and 
disodium edetate, both known to be local irritants, were shown 
to produce an inflammatory reaction, and microscopic 
examination showed an extended infiltration of the mucosa 
by eosinophils, and pronounced atrophy and disorganization 
of the epithelium, although these effects were subsequently 
shown to be reversible.(3) 
The WHO has set an estimated acceptable daily intake for 
disodium EDTA in foodstuffs of up to 2.5 mg/kg bodyweight.(
5) See also Edetic acid. 
LD50 (mouse, IP): 0.26 g/kg(6) 
LD50 (mouse, IV): 0.056 g/kg 
LD50 (mouse, OP): 2.05 g/kg 
LD50 (rabbit, IV): 0.047 g/kg 
LD50 (rabbit, OP): 2.3 g/kg 
LD50 (rat, OP): 2.0 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Disodium edetate and its 
derivatives are mild irritants to the mucous membranes. Eye 
protection, gloves, and dust masks are recommended. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(inhalations; injections; ophthalmic preparations; oral capsules, 
solutions, suspensions, syrups, and tablets; rectal topical, and 
vaginal preparations). Included in nonparenteral and parenteral 
medicines licensed in the UK. Included in the Canadian List 
of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Edetic acid. 
18 Comments 
Disodium edetate has been used experimentally to investigate 
the stability and skin penetration capacity of captopril gel, in 
which disodium edetate was shown to exert a potent stabilizing 
effect, and may be used in the development of a transdermal 
drug delivery system.(7) 
A chitosan–EDTA conjugate has been investigated as a 
novel polymer for use in topical gels. The conjugate was shown 
to be stable, colorless, and transparent, and it also demonstrated 
antimicrobial effects.(8) 
The EINECS number for disodium edetate is 205-358-3. 
19 Specific References 
1 Ungphaiboon S, Maitani Y. In vitro permeation studies of 
triamcinolone acetonide mouthwashes. Int J Pharm 2001; 220: 
111–117. 
2 Kaur IP, Singh M, Kanwar M. Formulation and evaluation of 
ophthalmic preparations of acetazolamide. Int J Pharm 2000; 199: 
119–127. 
3 Bechgaard E, Bindseil E, Bagger M, Nielsen HW. Reversibility and 
clinical relevance of morphological changes after nasal application 
of ephedrine nasal drops 1%. Int J Pharm 1997; 152: 67–73. 
4 Morgan BW, Singleton K, Thomas JD. Adverse effects in 5 patients 
receiving EDTA at an outpatient chelation clinic. Vet Hum Toxicol 
2002; 44(5): 274–276. 
5 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications. 
Seventeenth report of the joint FAO/WHO expert committee on 
food additives.World Health Organ Tech Rep Ser 1974; No. 539. 
6 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1660. 
7 Huang YB, Tsai YH, Chang JS, et al. Effect of antioxidants and 
anti-irritants on the stability, skin irritation and penetration 
capacity of captopril gel. Int J Pharm 2002; 241: 345–351. 
8 Valenta C, Christen B, Bernkop-Schnurch A. Chitosan–EDTA 
conjugate: novel polymer for topical gels. J Pharm Pharmacol 
1998; 50: 445–452. 
20 General References 
—
21 Authors 
S Shah, D Thassu. 
22 Date of Revision 
15 August 2005. 
256 Disodium Edetate

Docusate Sodium 
1 Nonproprietary Names 
BP: Docusate sodium 
PhEur: Docusatum natricum 
USP: Docusate sodium 
2 Synonyms 
Bis(2-ethylhexyl) sodium sulfosuccinate; dioctyl sodium sulfosuccinate; 
DSS; sodium dioctyl sulfosuccinate; sulfo-butanedioic 
acid 1,4-bis(2-ethylhexyl) ester, sodium salt. 
3 Chemical Name and CAS Registry Number 
Sodium 1,4-bis(2-ethylhexyl) sulfosuccinate [577-11-7] 
4 Empirical Formula and Molecular Weight 
C20H37NaO7S 444.56 
5 Structural Formula 
6 Functional Category 
Anionic surfactant; wetting agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Docusate sodium and docusate salts are widely used as anionic 
surfactants in pharmaceutical formulations. Docusate sodium 
is mainly used in capsule and direct-compression tablet 
formulations to assist in wetting and dissolution.(1) Docusate 
salts are also used in oral formulations as laxatives and fecal 
softeners; see Table I. 
Table I: Uses of docusate sodium. 
Use Concentration (%) 
IM injections 0.015 
Surfactant (wetting/dispersing/emulsifying agent) 0.01–1.0 
Tablet coating agent 20(a) 
Tablet disintegrant 0.5 
(a) Formulation of a tablet coating solution: 20% docusate sodium; 2–15% sodium benzoate; 
0.5% propylene glycol; solution made in ethanol (70%). 
8 Description 
Docusate sodium is a white or almost white, waxlike, bitter 
tasting, plastic solid with a characteristic octanol-like odor. It is 
hygroscopic and usually available in the form of pellets, flakes, 
or rolls of tissue-thin material. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for docusate sodium. 
Test PhEur 2005 USP 28 
Identification . . 
Characters . — 
Alkalinity . — 
Bis(2-ethylhexyl) maleate — 40.4% 
Chlorides 4350 ppm — 
Clarity of solution — . 
Heavy metals 410 ppm 40.001% 
Related nonionic 
substances 
. — 
Residue on ignition — 15.5–16.5% 
Sodium sulfate 42.0% — 
Water 43.0% 42.0% 
Assay (dried basis) 98.0–100.5% 99.0–100.5% 
10 Typical Properties 
Acidity/alkalinity: pH = 5.8–6.9 (1% w/v aqueous solution). 
Acid value: 42.5 
Critical micelle concentration: 0.11% w/v aqueous solution at 
258C. 
Density: 1.16 g/cm3 
Hydroxyl value: 6.0–8.0 
Interfacial tension: in water versus mineral oil at 258C, see 
Table III. 
Table III: Interfacial tension of docusate sodium. 
Concentration (% w/v) Interfacial tension (mN/m) 
0.01 20.7 
0.1 5.9 
1.0 1.84 
Iodine number: 40.25 
Melting point: 153–1578C 
Moisture content: 1.51% 
Saponification value: 240–253 
Solubility: see Table IV. 
Surface tension: see Table V.

Table IV: Solubility of docusate sodium. 
Solvent Solubility at 208C 
unless otherwise stated 
Acetone Soluble 
Chloroform 1 in 1 
Ethanol (95%) 1 in 3 
Ether 1 in 1 
Glycerin Freely soluble 
Vegetable oils Soluble 
Water 1 in 70 at 258C(a) 
1 in 56 at 308C 
1 in 44 at 408C 
1 in 33 at 508C 
1 in 25 at 608C 
1 in 18 at 708C 
(a) In water, higher concentrations form a thick gel. 
Table V: Surface tension of docusate sodium. 
Concentration in water at 258C (% w/v) Surface tension (mN/m) 
0.001 62.8 
0.1 28.7 
1.0 26.0 
11 Stability and Storage Conditions 
Docusate sodium is stable in the solid state when stored at room 
temperature. Dilute aqueous solutions of docusate sodium 
between pH 1–10 are stable at room temperature. However, at 
very low pH (<1) and very high pH (>10) docusate sodium 
solutions are subject to hydrolysis. 
The solid material is hygroscopic and should be stored in an 
airtight container in a cool, dry place. 
12 Incompatibilities 
Electrolytes, e.g. 3% sodium chloride, added to aqueous 
solutions of docusate sodium can cause turbidity.(2,3) However, 
docusate sodium possesses greater tolerance to calcium, 
magnesium, and other polyvalent ions than do some other 
surfactants. Docusate sodium is incompatible with acids at pH 
<1 and with alkalis at pH >10. 
13 Method of Manufacture 
Maleic anhydride is treated with 2-ethylhexanol to produce 
dioctyl maleate, which is then reacted with sodium bisulfite. 
14 Safety 
Docusate salts are used in oral formulations as therapeutic 
agents for their fecal softening and laxative properties. As a 
laxative in adults, up to 500 mg of docusate sodium is 
administered daily in divided doses; in children over 6 months 
old, up to 75 mg in divided doses is used. The quantity of 
docusate sodium used as an excipient in oral formulations 
should therefore be controlled to avoid unintended laxative 
effects.(4) Adverse effects associated with docusate sodium 
include diarrhea, nausea, vomiting, abdominal cramps, and 
skin rashes. As with the chronic use of laxatives, the excessive 
use of docusate sodium may produce hypomagnesemia.(5) 
Docusate salts are absorbed from the gastrointestinal tract 
and excreted in bile; they may cause alteration of the 
gastrointestinal epithelium.(6,7) The gastrointestinal or hepatic 
absorption of other drugs may also be affected by docusate 
salts, enhancing activity and possibly toxicity. Docusate sodium 
should not be administered with mineral oil as it may increase 
the absorption of the oil. 
LD50 (mouse, IV): 0.06 g/kg(8) 
LD50 (mouse, oral): 2.64 g/kg 
LD50 (rat, IP): 0.59 g/kg 
LD50 (rat, oral): 1.9 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Docusate sodium may be 
irritant to the eyes and skin, and when inhaled. Eye protection, 
gloves, and a dust mask or respirator are recommended. When 
heated to decomposition, docusate sodium emits toxic fumes. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(IM injections, oral capsules, suspensions, and tablets, also 
topical formulations). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Docusate calcium; docusate potassium. 
Docusate calcium 
Empirical formula: C40H74CaO14S2 
Molecular weight: 883.23 
CAS number: [128-49-4] 
Synonyms: 1,4-bis(2-ethylhexyl) sulfosuccinate, calcium salt; 
dioctyl calcium sulfosuccinate. 
Appearance: white amorphous solid with a characteristic 
octanol-like odor. 
Solubility: soluble 1 in less than 1 of ethanol (95%), chloroform, 
and ether, and 1 in 3300 of water; very soluble in corn 
oil and polyethylene glycol 400. 
Docusate potassium 
Empirical formula: C20H37KO7S 
Molecular weight: 460.67 
CAS number: [7491-09-0] 
Synonyms: dioctyl potassium sulfosuccinate; potassium 1,4- 
bis(2-ethylhexyl) sulfosuccinate. 
Appearance: white amorphous solid with a characteristic 
octanol-like odor. 
Solubility: soluble in ethanol (95%) and glycerin; sparingly 
soluble in water. 
18 Comments 
A convenient way of making a 1% w/v aqueous solution of 
docusate sodium is to add 1 g of solid to about 50mL of water 
and to apply gentle heat. The docusate sodium dissolves in a 
short time and the resulting solution can be made up to 100mL 
with water. Alternatively, 1 g may be soaked overnight in 50mL 
of water and the additional water may then be added with 
gentle heating and stirring. 
258 Docusate Sodium

Docusate sodium may alter the dissolution characteristics of 
certain dosage forms and the bioavailability of some drugs. 
The EINECS number for docusate sodium is 209-406-4. 
19 Specific References 
1 Brown S, Rowley G, Pearson JT. Surface treatment of the 
hydrophobic drug danazol to improve drug dissolution. Int J 
Pharm 1998; 165: 227–237. 
2 Ahuja S, Cohen J. Dioctyl sodium sulfosuccinate. In: Florey K, ed. 
Analytical Profiles of Drug Substances, volume 2. New York: 
Academic Press, 1973: 199–219. 
3 Ahuja S, Cohen J. Dioctyl sodium sulfosuccinate. In: Florey K, ed. 
Analytical Profiles of Drug Substances, volume 12. New York: 
Academic Press, 1983: 713–720. 
4 Guidott JL. Laxative components of a generic drug [letter]. Lancet 
1996; 347: 621. 
5 Rude RK, Siger FR. Magnesium deficiency and excess. Annu Rev 
Med 1981; 323: 245–259. 
6 Chapman RW, Sillery J, Fontana DD, Matthys C. Effect of oral 
dioctyl sodium sulfosuccinate on intake–output studies of human 
small and large intestine. Gastroenterology 1985; 89: 489–493. 
7 Moriarty KJ, Kelly MJ, Beetham R, Clark ML. Studies on the 
mechanism of action of dioctyl sodium sulfosuccinate in the 
human jejunum. Gut 1985; 26: 1008–1013. 
8 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1274. 
20 General References 
Chambliss WG, Cleary RW, Fischer R, et al. Effect of docusate sodium 
on drug release from a controlled release dosage form. J Pharm Sci 
1981; 70: 1248–1251. 
Hogue DR, Zimmardi JA, Shah KA. High-performance liquid 
chromatographic analysis of docusate sodium in soft gelatin 
capsules. J Pharm Sci 1992; 81: 359–361. 
Shah DN, Feldkamp JR, White JL, Hem SL. Effect of the pH-zero point 
of charge relationship on the interaction of ionic compounds and 
polyols with aluminum hydroxide gel. J Pharm Sci 1982; 71: 266– 
268. 
21 Authors 
S Murdande. 
22 Date of Revision 
15 August 2005. 
Docusate Sodium 259

Edetic Acid 
1 Nonproprietary Names 
BP: Edetic acid 
PhEur: Acidum edeticum 
USPNF: Edetic acid 
2 Synonyms 
Dissolvine; edathamil; EDTA; ethylenediaminetetraacetic acid; 
(ethylenedinitrilo)tetraacetic acid; Sequestrene AA; tetracemic 
acid; Versene Acid. 
3 Chemical Name and CAS Registry Number 
N,N-1,2-Ethanediylbis[N-(carboxymethyl)glycine] [60-00-4] 
4 Empirical Formula and Molecular Weight 
C10H16N2O8 292.24 
5 Structural Formula 
6 Functional Category 
Chelating agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Edetic acid and edetate salts are used in pharmaceutical 
formulations, cosmetics, and foods as chelating agents. They 
form stable water-soluble complexes (chelates) with alkaline 
earth and heavy metal ions. The chelated form has few of the 
properties of the free ion, and for this reason chelating agents 
are often described as ‘removing’ ions from solution; this 
process is also called sequestering. The stability of the metal– 
edetate complex depends on the metal ion involved and also on 
the pH. The calcium chelate is relatively weak and will 
preferentially chelate heavy metals, such as iron, copper, and 
lead, with the release of calcium ions. For this reason, edetate 
calcium disodium is used therapeutically in cases of lead 
poisoning; see also Section 18. 
Edetic acid and edetates are primarily used as antioxidant 
synergists, sequestering trace amounts of metal ions, particularly 
copper, iron, and manganese, that might otherwise 
catalyze autoxidation reactions. Edetic acid and edetates may 
be used alone or in combination with true antioxidants; the 
usual concentration employed being in the range 0.005–0.1% 
w/v. Edetates have been used to stabilize ascorbic acid; 
corticosteroids; epinephrine; folic acid; formaldehyde; gums 
and resins; hyaluronidase; hydrogen peroxide; oxytetracycline; 
penicillin; salicylic acid, and unsaturated fatty acids. Essential 
oils may be washed with a 2% w/v solution of edetate to 
remove trace metal impurities. 
Edetic acid and edetates possess some antimicrobial activity 
but are most frequently used in combination with other 
antimicrobial preservatives owing to their synergistic effects. 
Many solutions used for the cleaning, storage, and wetting of 
contact lenses contain disodium edetate. Typically, edetic acid 
and edetates are used in concentrations of 0.01–0.1% w/v as 
antimicrobial preservative synergists; see Section 10. 
Edetic acid and disodium edetate may also be used as water 
softeners since they will chelate the calcium and magnesium 
ions present in hard water; edetate calcium disodium is not 
effective. Many cosmetic and toiletry products, e.g., soaps, 
contain edetic acid as a water softener. 
8 Description 
Edetic acid occurs as a white crystalline powder. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for edetic acid. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Appearance of solution . — 
Residue on ignition — 40.2% 
Sulfated ash 40.2% — 
Heavy metals 420 ppm 40.003% 
Nitrilotriacetic acid 40.1% 40.3% 
Iron 480 ppm 40.005% 
Chloride 4200ppm — 
Assay 98.0–101.0% 98.0–100.5% 
10 Typical Properties 
Acidity/alkalinity: pH = 2.2 for a 0.2% w/v aqueous solution. 
Antimicrobial activity: edetic acid has some antimicrobial 
activity against Gram-negative microorganisms, Pseudomonas 
aeruginosa, some yeasts, and fungi; although this 
activity is insufficient for edetic acid to be used effectively 
as an antimicrobial preservative on its own.(1,2) However, 
when used with other antimicrobial preservatives, edetic 
acid demonstrates a marked synergistic effect in its 
antimicrobial activity. Edetic acid and edetates are therefore 
frequently used in combination with such preservatives as 
benzalkonium chloride; bronopol; cetrimide; imidurea; 
parabens; and phenols, especially chloroxylenol. Typically, 
edetic acid is used at a concentration of 0.1–0.15% w/v. In 
the presence of some divalent metal ions, such as Ca2. or 
Mg2., the synergistic effect may be reduced or lost

altogether. The addition of disodium edetate to phenylmercuric 
nitrate(3) and thimerosal(3,4) has also been reported to 
reduce the antimicrobial efficacy of the preservative. Edetic 
acid and iodine form a colorless addition compound that is 
bactericidal. 
Dissociation constant: 
pKa1 = 2.00; 
pKa2 = 2.67; 
pKa3 = 6.16; 
pKa4 = 10.26. 
Melting point: melts above 2208C, with decomposition. 
Solubility: soluble in solutions of alkali hydroxides; soluble 1 in 
500 of water. 
11 Stability and Storage Conditions 
Although edetic acid is fairly stable in the solid state, edetate 
salts are more stable than the free acid, which decarboxylates if 
heated above 1508C. Disodium edetate dihydrate loses water of 
crystallization when heated to 1208C. Edetate calcium disodium 
is slightly hygroscopic and should be protected from 
moisture. 
Aqueous solutions of edetic acid or edetate salts may be 
sterilized by autoclaving, and should be stored in an alkali-free 
container. 
Edetic acid and edetates should be stored in well-closed 
containers in a cool, dry place. 
12 Incompatibilities 
Edetic acid and edetates are incompatible with strong oxidizing 
agents, strong bases, and polyvalent metal ions such as copper, 
nickel, and copper alloy. 
Edetic acid and disodium edetate behave as weak acids, 
displacing carbon dioxide from carbonates and reacting with 
metals to form hydrogen. 
Other incompatibilities include the inactivation of certain 
types of insulin due to the chelation of zinc, and the chelation of 
trace metals in total parenteral nutrition (TPN) solutions 
following the addition of TPN additives stabilized with 
disodium edetate. Calcium disodium edetate has also been 
reported to be incompatible with amphotericin and with 
hydralazine hydrochloride in infusion fluids. 
13 Method of Manufacture 
Edetic acid may be prepared by the condensation of ethylenediamine 
with sodium monochloroacetate in the presence of 
sodium carbonate. An aqueous solution of the reactants is 
heated to about 908C for 10 hours, then cooled, and 
hydrochloric acid is added to precipitate the edetic acid. 
Edetic acid may also be prepared by the reaction of 
ethylenediamine with hydrogen cyanide and formaldehyde 
with subsequent hydrolysis of the tetranitrile, or under alkaline 
conditions with continuous extraction of ammonia. 
See Section 17 for information on the preparation of edetate 
salts. 
14 Safety 
Edetic acid and edetates are widely used in topical, oral, and 
parenteral pharmaceutical formulations. They are also extensively 
used in cosmetics and food products. 
Edetic acid is generally regarded as an essentially nontoxic 
and nonirritant material, although it has been associated with 
dose-related bronchoconstriction when used as a preservative 
in nebulizer solutions. It has therefore been recommended that 
nebulizer solutions for bronchodilation should not contain 
edetic acid.(5) 
Edetates, particularly disodium edetate and edetate calcium 
disodium, are used in a greater number and variety of 
pharmaceutical formulations than the free acid. 
Disodium edetate, trisodium edetate, and edetic acid readily 
chelate calcium and can, in large doses, cause calcium depletion 
(hypocalcemia) if used over an extended period or if 
administered too rapidly by intravenous infusion. If used in 
preparations for the mouth, they can also leach calcium from 
the teeth. In contrast, edetate calcium disodium does not chelate 
calcium. 
Edetate calcium disodium is nephrotoxic and should be used 
with caution in patients with renal impairment. 
The WHO has set an estimated acceptable daily intake for 
disodium edetate in foodstuffs at up to 2.5 mg/kg bodyweight.(
6) 
See also Section 18. 
LD50 (mouse, IP): 0.25 g/kg(7) 
LD50 (rat, IP): 0.397 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Edetic acid and edetates are 
mildly irritant to the skin, eyes, and mucous membranes. 
Ingestion, inhalation, and contact with the skin and eyes should 
therefore be avoided. Eye protection, gloves, and a dust mask 
are recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (otic, rectal, 
and topical preparations). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
See also Section 17. 
17 Related Substances 
Dipotassium edetate; disodium edetate; edetate calcium disodium; 
sodium edetate; trisodium edetate. 
Dipotassium edetate 
Empirical formula: C10H14K2N2O8 
Molecular weight: 368.46 
CAS number: [2001-94-7] 
Synonyms: dipotassium edathamil; dipotassium ethylenediaminetetraacetate; 
edathamil dipotassium; edetate dipotassium; 
edetic acid dipotassium salt; EDTA dipotassium; 
N,N0-1,2-ethanediylbis[N-(carboxymethyl)glycine] dipotassium 
salt; ethylenebis(iminodiacetic acid) dipotassium salt; 
ethylenediaminetetraacetic acid dipotassium salt; (ethylenedinitrilo)
tetraacetic acid dipotassium salt; tetracemate dipotassium. 
Appearance: white crystalline powder. 
Comments: The EINECS number for dipotassium edetate is 
217-895-0. 
Edetate calcium disodium 
Empirical formula: C10H12CaN2Na2O8 
Molecular weight: 374.28 
CAS number: [62-33-9] for the anhydrous material and 
[23411-34-9] for the dihydrate 
Edetic Acid 261

Synonyms: calcium disodium edetate; calcium disodium 
ethylenediaminetetraacetate; calcium disodium (ethylenedinitrilo)
tetraacetate; E385; edathamil calcium disodium; 
edetic acid calcium disodium salt; EDTA calcium; ethylenediaminetetraacetic 
acid calcium disodium chelate; [(ethylenedinitrilo)
tetraacetato]calciate(2-) disodium; sodium 
calciumedetate; Versene CA. 
Appearance: white or creamy-white colored, slightly hygroscopic, 
crystalline powder or granules; odorless, or with a 
slight odor; tasteless, or with a faint saline taste. 
Acidity/alkalinity: pH = 4–5 for a 1% w/v aqueous solution. 
Density (bulk): 0.69 g/cm3 
Solubility: practically insoluble in chloroform, ether, and other 
organic solvents; very slightly soluble in ethanol (95%); 
soluble 1 in 2 of water. 
Method of manufacture: edetate calcium disodium may be 
prepared by the addition of calcium carbonate to a solution 
of disodium edetate. 
Safety: see also Section 14. 
LD50 (mouse, IP): 4.5 g/kg(7) 
LD50 (rabbit, IP): 6 g/kg 
LD50 (rabbit, oral): 7 g/kg 
LD50 (rat, IP): 3.85 g/kg 
LD50 (rat, IV): 3.0 g/kg 
LD50 (rat, oral): 10 g/kg 
Regulatory status: GRAS listed. Accepted for use as a food 
additive in Europe. Included in the FDA Inactive Ingredients 
Guide (injections, oral capsules, solutions, suspensions, 
syrups, and tablets). 
Comments: used in pharmaceutical formulations as a chelating 
agent in concentrations between 0.01–0.1% w/v. Usually 
edetate calcium disodium is used in pharmaceutical formulations 
in preference to disodium edetate or sodium 
edetate to prevent calcium depletion occurring in the body. 
In food products, edetate calcium disodium may also be 
used in flavors and as a color retention agent. Edetate 
calcium disodium occurs as the dihydrate, trihydrate, and 
anhydrous material. 
Some pharmacopeias specify that edetate calcium disodium 
is the dihydrate, others that it is the anhydrous 
material. The USP 28 specifies that edetate calcium 
disodium is a mixture of the dihydrate and trihydrate but 
that the dihydrate predominates. 
The EINECS number for edetate calcium disodium is 
200-529-9. 
Sodium edetate 
Empirical formula: C10H12N2Na4O8 
Molecular weight: 380.20 
CAS number: [64-02-8] 
Synonyms: edetate sodium; edetic acid tetrasodium salt; EDTA 
tetrasodium; N,N0-1,2-ethanediylbis[N-(carboxymethyl)- 
glycine] tetrasodium salt; ethylenebis(iminodiacetic acid) 
tetrasodium salt; ethylenediaminetetraacetic acid tetrasodium 
salt; (ethylenedinitrilo)tetraacetic acid tetrasodium 
salt; Sequestrene NA4; tetracemate tetrasodium; tetracemin; 
tetrasodium edetate; tetrasodium ethylenebis(iminodiacetate); 
tetrasodium ethylenediaminetetraacetate; Versene. 
Appearance: white crystalline powder. 
Acidity/alkalinity: pH = 11.3 for a 1% w/v aqueous solution. 
Melting point: >3008C 
Solubility: soluble 1 in 1 of water. 
Safety: see also Section 14. 
LD50 (mouse, IP): 0.33 g/kg(7) 
Regulatory status: included in the FDA Inactive Ingredients 
Guide (inhalations, injections, ophthalmic preparations, 
oral capsules and tablets, and topical preparations). 
Comments: sodium edetate reacts with most divalent and 
trivalent metallic ions to form soluble metal chelates and is 
used in pharmaceutical formulations in concentrations 
between 0.01–0.1% w/v. 
Trisodium edetate 
Empirical formula: C10H13N2Na3O8 
Molecular weight: 358.20 
CAS number: [150-38-9] 
Synonyms: edetate trisodium; edetic acid trisodium salt; EDTA 
trisodium; N,N0-1,2-ethanediylbis[N-(carboxymethyl)glycine] 
trisodium salt; ethylenediaminetetraacetic acid trisodium 
salt; (ethylenedinitrilo)tetraacetic acid trisodium 
salt; Sequestrene NA3; trisodium ethylenediaminetetraacetate; 
Versene-9. 
Appearance: white crystalline powder. 
Acidity/alkalinity: pH = 9.3 for a 1% w/v aqueous solution. 
Melting point: >3008C 
Method of manufacture: trisodium edetate may be prepared by 
adding a solution of sodium hydroxide to disodium edetate. 
Safety: see also Section 14. 
LD50 (mouse, IP): 0.3 g/kg(7) 
LD50 (mouse, oral): 2.15 g/kg 
LD50 (rat, oral): 2.15 g/kg 
Regulatory status: included in the FDA Inactive Ingredients 
Guide (topical preparations). 
Comments: more soluble in water than either the disodium salt 
or the free acid. Trisodium edetate also occurs as the 
monohydrate and is used in pharmaceutical formulations as 
a chelating agent. The EINECS number for trisodium 
edetate is 205-758-8. 
18 Comments 
Other salts of edetic acid that are commercially available 
include diammonium, dimagnesium, ferric sodium, and magnesium 
disodium edetates. Therapeutically, a dose of 50 mg/kg 
body-weight of disodium edetate, as a slow infusion over a 24- 
hour period, with a maximum daily dose of 3 g, has been used 
as a treatment for hypercalcemia. For the treatment of lead 
poisoning, a dose of 60–80 mg/kg of edetate calcium disodium, 
as a slow infusion in two daily doses, for 5 days, has been used. 
Chelation therapy using edetic acid has been widely used for 
the treatment of ischemic heart disease. However, it has been 
suggested that the therapeutic benefits of this treatment may be 
due to the changes in lifestyle of the patient rather than the 
administration of edetic acid (40 mg/kg by infusion over a 3- 
hour period).(8) 
The EINECS number for edetic acid is 200-449-4. 
19 Specific References 
1 Richards RME, Cavill RH. Electron microscope study of effect of 
benzalkonium chloride and edetate disodium on cell envelope of 
Pseudomonas aeruginosa. J Pharm Sci 1976; 65: 76–80. 
2 Whalley G. Preservative properties of EDTA. Manuf Chem 1991; 
62(9): 22–23. 
3 Richards RME, Reary JME. Changes in antibacterial activity of 
thiomersal and PMN on autoclaving with certain adjuvants. J 
Pharm Pharmacol 1972; 24 (Suppl.): 84P–89P. 
4 Morton DJ. EDTA reduces antimicrobial efficacy of thiomerosal. 
Int J Pharm 1985; 23: 357–358. 
262 Edetic Acid

5 Beasley CRW, Rafferty P, Holgate ST. Bronchoconstrictor properties 
of preservatives in ipratropium bromide (Atrovent) nebuliser 
solution. Br Med J 1987; 294: 1197–1198. 
6 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications. 
Seventeenth report of the joint FAO/WHO expert committee on 
food additives.World Health Organ Tech Rep Ser 1974; No. 539. 
7 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1660. 
8 Knudtson ML, Wyse DG, Galbraith PD, et al. Chelation therapy 
for ischemic heart disease: a randomized controlled trial. J Am 
Med Assoc 2002; 287(4): 481–486. 
20 General References 
Chalmers L. The uses of EDTA and other chelates in industry. Manuf 
Chem 1978; 49(3): 79–80, 83. 
Hart JR. Chelating agents in cosmetic and toiletry products. Cosmet 
Toilet 1978; 93(12): 28–30. 
Hart JR. EDTA-type chelating agents in personal care products. Cosmet 
Toilet 1983; 98(4): 54–58. 
Lachman L. Antioxidants and chelating agents as stabilizers in liquid 
dosage forms. Drug Cosmet Ind 1968; 102(2): 43–45, 146–149. 
21 Authors 
SC Owen. 
22 Date of Revision 
27 August 2005. 
Edetic Acid 263

Erythorbic Acid 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Araboascorbic acid; d-araboascorbic acid; D-2,3-didehydroerythro-
hexono-1,4-lactone; E315; erycorbin; d-erythorbic 
acid; D-erythro-hex-2-enoic acid; D-erythro-3-ketohexonic 
acid lactone; glucosaccharonic acid; D-isoascorbic acid; isovitamin 
C; g-lactone; saccharosonic acid. 
3 Chemical Name and CAS Registry Number 
Isoascorbic acid [89-65-6] 
4 Empirical Formula and Molecular Weight 
C6H8O6 176.14 
5 Structural Formula 
6 Functional Category 
Antioxidant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Erythorbic acid is a stereoisomer of L-ascorbic acid, and is used 
as an antioxidant in foods and oral pharmaceutical formulations. 
It has approximately 5% of the vitamin C activity of 
L-ascorbic acid. 
8 Description 
Erythorbic acid occurs as a white or slightly yellow-colored 
crystals or powder. It gradually darkens in color upon exposure 
to light. 
9 Pharmacopeial Specifications 
See Section 18. 
10 Typical Properties 
Acidity/alkalinity: pH = 2.1 (10% w/v aqueous solution at 
258C) 
Density (bulk): 0.704 g/cm3 
Melting point: 164–1718C with decomposition at 1848C 
Solubility: see Table I. 
Specific rotation [a]D
20: 16.2 to 18.28 (10% w/v aqueous 
solution) 
Table I: Solubility of erythorbic acid. 
Solvent Solubility at 258C unless otherwise stated 
Acetone 1 in 70 
Ethanol (95%) 1 in 20 
Ether Practically insoluble 
Methanol 1 in 5.5 
Propylene glycol 1 in 6.7 
Water 1 in 2.3 
1 in 1.8 at 388C 
1 in 1.6 at 508C 
11 Stability and Storage Conditions 
Erythorbic acid should be stored in an airtight container, 
protected from light, in a cool, dry place. 
12 Incompatibilities 
Erythorbic acid is incompatible with chemically active metals 
such as aluminum, copper, magnesium, and zinc. It is also 
incompatible with strong bases and strong oxidizing agents. 
13 Method of Manufacture 
Erythorbic acid is synthesized by the reaction between methyl 
2-keto-D-gluconate and sodium methoxide. It can also be 
synthesized from sucrose, and produced from Penicillium spp. 
14 Safety 
Erythorbic acid is widely used in food applications as an 
antioxidant. It is also used in oral pharmaceutical applications 
as an antioxidant. Erythorbic acid is generally regarded as 
nontoxic and nonirritant when used as an excipient. Erythorbic 
acid is readily metabolized and does not affect the urinary 
excretion of ascorbic acid. 
The WHO has set an acceptable daily intake of erythorbic 
acid and its sodium salt in foods at up to 5 mg/kg bodyweight.(
1) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. When heated to decomposition, 
erythorbic acid emits acrid smoke and irritating fumes.

16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral concentrate 
and tablets). 
17 Related Substances 
Ascorbic acid; sodium erythorbate 
Sodium erythorbate 
Empirical formula: C6H7NaO6 
Molecular weight: 198.11 
CAS number: [7378-23-6] 
Synonyms: E316; D-erythro-hex-2-enoic acid sodium salt; 
erythorbic acid sodium salt. 
Acidity/alkalinity: pH = 7.2–7.9 for 10% w/v aqueous 
solution. 
Melting point: 1728C 
Solubility: soluble 1 in 6.5 of water. The sodium salt is less 
soluble in water than the free acid. 
Comments: the EINECS number for sodium erythorbate is 228- 
973-6. 
18 Comments 
Although not currently included in any pharmacopeias, a 
specification for erythorbic acid is included in the Food 
Chemicals Codex and Japanese Pharmaceutical Excipients 
(JPE), see Table II. 
The EINECS number for erythorbic acid is 201-928-0. 
Table II: JPE 2004 specification for erythorbic acid.(2) 
Test JPE 2004 
Identification . 
Clarity and color of solution . 
Melting point 166–1728C 
Heavy metals 420 ppm 
Arsenic 44 ppm 
Loss on drying 40.40% 
Residue on ignition 40.30% 
Optical rotation at 208C (10% w/v 
aqueous solution) 
16.2 to 18.28 
Assay >99.0% 
19 Specific References 
1 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications: 
seventeenth report of the joint FAO/WHO expert committee on 
food additives.World Health Organ Tech Rep Ser 1974; No. 539. 
2 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004: 281–282. 
20 General References 
—
21 Authors 
SC Owen, PJ Weller. 
22 Date of Revision 
25 May 2005. 
Erythorbic Acid 265

Erythritol 
1 Nonproprietary Names 
PhEur: Erythritolum 
2 Synonyms 
(2R,3S)-Butane 1,2,3,4-tetrol; C*Eridex; E968; erythrite; 
erythroglucin; meso-erythritol; phycite; tetrahydroxybutane. 
3 Chemical Name and CAS Registry Number 
Erythritol [149-32-6] 
4 Empirical Formula and Molecular Weight 
C4H10O4 122.12 
5 Structural Formula 
6 Functional Category 
Sweetening agent; tablet and capsule diluent; taste masking 
agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Erythritol is a noncariogenic excipient used in a variety of 
pharmaceutical preparations, including in solid dosage forms as 
a tablet filler,(1) and in coatings.(2) It is also used in sugar-free 
lozenges,(3,4) and medicated chewing gum.(3) 
Erythritol can also be used as a diluent in wet granulation in 
combination with moisture-sensitive drugs.(5) In buccal applications, 
such as medicated chewing gums, it is used because of 
its high negative heat of solution which provides a strong 
cooling effect.(3) 
Erythritol is also used as a noncaloric sweetener in syrups;(6) 
it is used to provide sensorial profile-modifying properties with 
intense sweeteners; and it is also used to mask unwanted 
aftertastes.(7) 
Erythritol is also used as a noncariogenic sweetener in 
toothpastes and mouthwash solutions. 
See Table I. 
Table I: Uses of erythritol. 
Use Concentration (%) 
Tablet filler and binder 30.0–90.0% 
Taste masking in solutions 0.5–3.0% 
Oral care products 5.0–10.0% 
8 Description 
Erythritol is a sugar alcohol (polyol) that occurs as a white or 
almost white powder or granular or crystalline substance. It is 
pleasant tasting with a mild sweetness approximately 60–70% 
that of sucrose. It also has a high negative heat of solution that 
provides a strong cooling effect. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for erythritol. 
Test PhEur 2005 
Identification (melting point) 119–1228C 
Identification (IR) . 
Appearance of solution . 
Conductivity . 
Related substances 42.0% 
Lead 40.5 ppm 
Water 40.5% 
Microbial contamination . 
Bacterial endotoxins . 
Assay (anhydrous basis) 96.0–102.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 5–7 at 258C for a 5% w/v aqueous 
solution. 
Boiling point: 329–3318C 
Caloric value: 0.8 kJ/g 
Density: 1.45 g/cm3 
Heat of solution: 22 kJ/mol 
Hygroscopicity: erythritol is nonhygroscopic; it absorbs 
approximately 1% w/w of water at 95% relative humidity 
(RH). 
Melting point: 121.58C, with decomposition at 1608C. 
Solubility: soluble 1 in 3 of water; slightly soluble in ethanol 
(95%); practically insoluble in ether and fats. 
Viscosity (dynamic): 3 mPa s (3 cP) at 608C for a 30% w/w 
solution. 
11 Stability and Storage Conditions 
Erythritol has very good thermal and chemical stability. It is 
nonhygroscopic, and at 258C does not significantly absorb 
additional water up to a relative humidity (RH) of more than 
80%. Erythritol resists decomposition both in acidic and

alkaline media and remains stable for prolonged periods at pH 
2–10.(8) When stored for up to 4 years in ambient conditions 
(208C, 50% RH) erythritol has been shown to be stable.(5) 
12 Incompatibilities 
Erythritol is incompatible with strong oxidizing agents and 
strong bases. 
13 Method of Manufacture 
Erythritol is a starch-derived product. The starch is enzymatically 
hydrolyzed into glucose which is turned into erythritol via 
a fermentation process, using osmophilic yeasts or fungi (e.g. 
Moniliella, Trigonopsis, or Torulopsis).(9) 
14 Safety 
Erythritol is used in oral pharmaceutical formulations, confectionery, 
and food products. It is generally regarded as a 
nontoxic, nonallergenic, and nonirritant material.(10) 
The low molecular weight of erythritol allows more than 
90% of the ingested molecules to be rapidly absorbed from the 
small intestine;(11) it is not metabolized and is excreted 
unchanged in the urine. Erythritol has a low caloric value 
(0.8 kJ/g). The WHO has set an acceptable daily intake of ‘not 
specified’ for erythritol.(10) 
Erythritol is noncariogenic; preliminary studies suggest that 
it may inhibit the formation of dental plaque.(12) 
In general, erythritol is well-tolerated;(13) furthermore, 
excessive consumption does not cause laxative effects. There 
is no significant increase in the blood glucose level after oral 
intake, and glycemic response is very low, making erythritol 
suitable for diabetics. 
LD50 (mouse, IP): 8–9 g/kg(10) 
LD50 (rat, IV): 6.6 g/kg 
LD50 (rat, oral): >13 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of the material handled. Eye protection and a dust 
mask or respirator are recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
17 Related Substances 
Mannitol; sorbitol; xylitol. 
18 Comments 
Active ingredients can be granulated with erythritol and binders 
such as maltodextrin or carboxymethylcellulose, resulting in 
coarser granules with improved flowability.(3) Coprocessing 
erythritol with a small amount of maltodextrin results in a 
proprietary compound that is ideal for use in direct compression.(
14) 
A specification for erythritol is included in the Japanese 
Pharmaceutical Excipients (JPE).(15) 
The EINECS number for erythritol is 205-737-3. 
19 Specific References 
1 Bi YX, Sunada Y, Yonezawa Y, Danjo K. Evaluation of rapidly 
disintegrating tablets prepared by a direct compression method. 
Drug Dev Ind Pharm 1999; 25(5): 571–581. 
2 Ohmori S, Ohno Y, Makino T, Kashihara T. Characteristics of 
erythritol and formulation of a novel coating with erythritol 
termed thin-layer sugarless coating. Int J Pharm 2004; 278(2): 
447–457. 
3 Goossens J, Gonze M. Erythritol. Manuf Confect 2000; 80(1): 71– 
75. 
4 de Cock P. Chewing gum coating with a healthier crunch thanks to 
erythritol. Confect Prod 2003; 6: 10–11. 
5 Michaud J, Haest G. Erythritol: a new multipurpose excipient. 
Pharmaceut Technol Eur 2003; 15(10): 69–72. 
6 de Cock P. Erythritol: a novel noncaloric sweetener ingredient. In: 
Corti A, ed. Low-Calorie Sweeteners: Present and Future. Basel: 
Karger, 1999: 110–116. 
7 de Cock P, Bechert CL. Erythritol. Functionality in noncaloric 
functional beverages. Pure Appl Chem 2002; 74(7): 1281–1289. 
8 Leutner C, ed. Geigy Scientific Tables, vol. 1. Basel: Ciba Geigy, 
1993: 84–85. 
9 Goossens J, Gonze M. Nutritional and application properties of 
erythritol: a unique combination? Part I: nutritional and functional 
properties. Agro Food Ind Hi-tech 1997; 4(8): 3–10. 
10 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirty-fifth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 2000; No. 
896. 
11 Bornet FRJ, Blayo A, Dauchy F, Slama G. Plasma and urine 
kinetics of erythritol after oral ingestion by healthy humans. Regul 
Toxicol Pharmacol 1996; 24: 280–286. 
12 Gonze M, Goossens J. Nutritional and application properties of 
erythritol: a unique combination? Part II: application properties. 
Agro Food Ind Hi-tech 1997; 8(5): 12–16. 
13 Munro IC, Bernt WO, Borzella JF, et al. Erythritol: an interpretive 
summary of biochemical, metabolic, toxicologic and chemical 
data. Food Chem Toxicol 1998; 36(12): 1139–1174. 
14 De Sadeleer J, Gonze M. Erythritol compositions. European Patent 
No. 0497439; 1992. 
15 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004: 283–284. 
20 General References 
Cerestar. Erythritol: the all-natural non-caloric bulk sweetener. 
http://www.eridex.com/english.html(accessed 24 May 2005). 
Endo K, Amikawa S, Matsumoto A, et al. Erythritol-based dry powder 
of glucagons for pulmonary administration. Int J Pharm 2005; 290: 
63–71. 
O’Brien Nabors L, Gelardi RC, eds. Alternative Sweeteners. New York: 
Marcel Dekker, 2001. 
21 Authors 
G Haest. 
22 Date of Revision 
24 May 2005. 
Erythritol 267

Ethyl Acetate 
1 Nonproprietary Names 
BP: Ethyl acetate 
PhEur: Ethylis acetas 
USPNF: Ethyl acetate 
2 Synonyms 
Acetic acid ethyl ester; acetic ester; acetic ether; acetoxyethane; 
aethylis acetas; aethylium aceticum; ethyl ethanoate; vinegar 
naphtha. 
3 Chemical Name and CAS Registry Number 
Ethyl acetate [141-78-6] 
4 Empirical Formula and Molecular Weight 
C4H8O2 88.1 
5 Structural Formula 
6 Functional Category 
Flavoring agent; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
In pharmaceutical preparations, ethyl acetate is primarily used 
as a solvent, although it has also been used as a flavoring agent. 
As a solvent, it is included in topical solutions and gels, and in 
edible printing inks used for tablets. 
Ethyl acetate has also been shown to increase the solubility 
of chlortalidone(1) and to modify the polymorphic crystal forms 
obtained for piroxicam pivalate(2) and mefenamic acid,(3) and 
has been used in the formulation of microspheres.(4,5) Its use as 
a chemical enhancer for the transdermal iontophoresis of 
insulin has been investigated.(6) 
In food applications, ethyl acetate is mainly used as a 
flavoring agent. It is also used in artificial fruit essence and as an 
extraction solvent in food processing. 
8 Description 
Ethyl acetate is a clear, colorless, volatile liquid with a pleasant 
fruity, fragrant, and slightly acetous odor, and has a pleasant 
taste when diluted. Ethyl acetate is flammable. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for ethyl acetate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Boiling point 76–788C — 
Appearance of solution . — 
Acidity . . 
Specific gravity 0.898–0.902 0.894–0.898 
Refractive index 1.370–1.373 — 
Readily carbonizable substances . . 
Reaction with sulfuric acid . — 
Chromatographic purity .(a) . 
Residue on evaporation 430 ppm 40.02% 
Water 40.1% — 
Limit of methyl compounds — . 
Organic volatile impurities — . 
Related substances . — 
Assay — 99.0–100.5% 
(a) The PhEur 2005 lists impurities in ethyl acetate as methyl acetate, ethanol, and methanol. 
10 Typical Properties 
Autoignition temperature: 486.18C 
Boiling point: 778C 
Dielectric constant: 6.11 
Density: 0.902 g/cm3 at 208C 
Explosive limit: 2.2–11.5% (volume in air) 
Flash point: 
.7.28C (open cup); 
5.08C (closed cup). 
Freezing point: 83.68C 
Partition coefficient: Log P (octanol/water) = 0.7 
Refractive index: nD
20 = 1.3719 
Solubility: soluble 1 in 10 of water at 258C; ethyl acetate is 
more soluble in water at lower temperatures than at higher 
temperatures. Miscible with acetone, chloroform, dichloromethane, 
ethanol (95%), and ether, and with most other 
organic liquids. 
Vapor density: 3.04 (air = 1) 
11 Stability and Storage Conditions 
Ethyl acetate should be stored in an airtight container, 
protected from light and at a temperature not exceeding 
308C. Ethyl acetate is slowly decomposed by moisture and 
becomes acidic; the material can absorb up to 3.3% w/w water. 
Ethyl acetate decomposes on heating to produce ethanol and 
acetic acid, and will emit acrid smoke and irritating fumes. It is 
flammable and its vapor may travel a considerable distance to 
an ignition source and cause a ‘flashback’. 
The alkaline hydrolysis of ethyl acetate has been shown to 
be inhibited by polyethylene glycol and by mixed micelle 
systems.(7)

12 Incompatibilities 
Ethyl acetate can react vigorously with strong oxidizers, strong 
alkalis, strong acids, and nitrates to cause fires or explosions. It 
also reacts vigorously with chlorosulfonic acid, lithium 
aluminum hydride, 2-chloromethylfuran, and potassium tertbutoxide. 
13 Method of Manufacture 
Ethyl acetate can be manufactured by the slow distillation of a 
mixture of ethanol and acetic acid in the presence of 
concentrated sulfuric acid. It has also been prepared from 
ethylene using an aluminum alkoxide catalyst. 
14 Safety 
Ethyl acetate is used in foods and oral and topical pharmaceutical 
formulations. It is generally regarded as a relatively 
nontoxic and nonirritant material when used as an excipient. 
However, ethyl acetate may be irritant to mucous membranes 
and high concentrations may cause central nervous 
system depression. Potential symptoms of overexposure include 
irritation of the eyes, nose, and throat, narcosis, and dermatitis. 
Ethyl acetate has not been shown to be a human carcinogen 
or a reproductive or developmental toxin. 
The WHO has set an estimated acceptable daily intake of 
ethyl acetate at up to 25 mg/kg body-weight.(8) 
In the UK, it has been recommended that ethyl acetate be 
temporarily permitted for use as a solvent in food and that the 
maximum concentration consumed in food should be set at 
1000 ppm.(9) 
LD50 (cat, SC): 3.00 g/kg(10) 
LD50 (guinea-pig, oral): 5.50 g/kg 
LD50 (guinea-pig, SC): 3.00 g/kg 
LD50 (mouse, IP): 0.709 g/kg 
LD50 (mouse, oral): 4.10 g/kg 
LD50 (rabbit, oral): 4.935 g/kg 
LD50 (rat, oral): 5.62 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. In the UK, the occupational exposure limit for 
ethyl acetate is 400 ppm (short-term) and 200 ppm (longterm).(
11) 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral tablets 
and sustained-action tablets; topical and transdermal preparations). 
Included in nonparenteral medicines licensed in the UK 
(tablets, topical solutions, and gels). Ethyl acetate is also 
accepted for use in food applications in a number of countries 
including the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
— 
18 Comments 
The following azeotropic mixtures have been reported: 
Ethyl acetate (93.9% w/w)–water (6.1% w/w), boiling point 
70.48C 
Ethyl acetate (83.2% w/w)–water (7.8% w/w)–ethanol (9.0% 
w/w), boiling point 70.38C 
Ethyl acetate (69.4%)–ethanol (30.6%), boiling point 71.88C 
Ethyl acetate (77%)–propan-2-ol (23%), boiling point 74.88C 
A specification for ethyl acetate is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for ethyl acetate is 205-500-4. 
19 Specific References 
1 Lo. tter J, Kreig HM, Keizer K, Breytenbach JC. The influence of bcyclodextrin 
on the solubility of chlorthalidone and its enantiomers. 
Drug Dev Ind Pharm 1999; 25(8): 879–884. 
2 Giordano F, Gazzaniga A, Moyano JR, et al. Crystal forms of 
piroxicam pivalate: preparation and characterization of two 
polymorphs. J Pharm Sci 1998; 87(3): 333–337. 
3 Romero S, Escalera B, Bustamante P. Solubility behavior of 
polymorphs I and II of mefenamic acid in solvent mixtures. Int J 
Pharm 1999; 178: 193–202. 
4 Abu-Izza K, Garcia-Contreras L, Lu DR. Preparation and 
evaluation of zidovudine-loaded sustained-release microspheres. 
2. Optimization of multiple response variables. J Pharm Sci 1996; 
85(6): 572–576. 
5 Cleland JL, Jones AJS. Stable formulations of recombinant human 
growth hormone and interferon-g for microencapsulation and 
biodegradable microspheres. Pharm Res 1996; 13(10): 1464– 
1475. 
6 Pillai O, Nair V, Panchagnula R. Transdermal iontophoresis of 
insulin: IV. Influence of chemical enhancers. Int J Pharm 2004; 
269(1): 109–120. 
7 Xiancheng Z, Xiaonan C, Ziming Q, Qian W. The alkaline 
hydrolysis of ethyl acetate and ethyl propionate in single and 
mixed micellar solutions. J Disper Sci Technol 1996; 17(3): 339– 
348. 
8 FAO/WHO. Specifications for the identity and purity of food 
additives and their toxicological evaluation: some flavouring 
substances and non-nutritive sweetening agents. Eleventh report 
of the Joint FAO/WHO Expert Committee on Food Additives. 
World Health Organ Tech Rep Ser 1968; No. 383. 
9 Ministry of Agriculture, Fisheries and Food. Report on the Review 
of Solvents in Food, FAC/REP/25. London: HMSO, 1978. 
10 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1625. 
11 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
—
21 Authors 
CG Cable. 
22 Date of Revision 
19 August 2005. 
Ethyl Acetate 269

Ethyl Lactate 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Actylol; Acytol; ethyl a-hydroxypropionate; ethyl-2-hydroxypropanoate; 
ethyl-2-hydroxypropionate; ethyl-S-(–)-2-hydroxypropionate; 
2-hydroxypropanoic acid ethyl ester; lactic 
acid ethyl ester; propanoic acid 2-hydroxy-ethyl ester; Purasolv 
EL; Solactol. 
3 Chemical Name and CAS Registry Number 
2-Hydroxy-propanoic acid ethyl ester [97-64-3] 
4 Empirical Formula and Molecular Weight 
C5H10O3 118.13 
5 Structural Formula 
6 Functional Category 
Film-former; flavoring agent; solvent or co-solvent in liquid 
formulations. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ethyl lactate is used as a solvent or co-solvent in liquid 
formulations(1,2) and recently as a co-solvent in emulsions and 
microemulsion technologies. It has also been used as a solvent 
for nitrocellulose, cellulose acetate, cellulose ethers, polyvinyl 
and other resins.(3) It has been applied topically in the treatment 
of acne vulgaris,(4,5) where it accumulates in the sebaceous 
glands and is hydrolyzed to ethanol and lactic acid, lowering 
the skin pH and exerting a bactericidal effect. 
8 Description 
Ethyl lactate occurs as a clear colorless liquid with a sharp 
characteristic odor. 
9 Pharmacopeial Specifications 
—
10 Typical Properties 
Acidity/alkalinity: pH = 7 (10% w/v aqueous solution) 
Boiling point: 154–1558C 
Density: 1.0328 at 208C 
Explosion limits: 1.5–11.4% 
Flash point: 468C 
Heat of combustion: 6.5 kcal/g 
Melting point: –26.08C 
Refractive index: nD
20 = 1.412–1.414 
Solubility: miscible with water (with partial decomposition), 
ethanol (95%), ether, chloroform, ketones, esters, and 
hydrocarbons. 
Viscosity (dynamic): 0.0261 mPa s at 208C 
Vapor density: 4.07 (air = 1) 
Vapor pressure: 0.732 kPa at 308C 
11 Stability and Storage Conditions 
Stable at normal temperature and pressure. Ethyl lactate is a 
flammable liquid and vapor. Store in a cool, dry, and wellventilated 
location away from any fire hazard area, in a tightly 
closed container. 
12 Incompatibilities 
Incompatible with bases or strong alkalis and may cause fire or 
explosion with strong oxidizing agents. 
13 Method of Manufacture 
Ethyl lactate is produced by the esterification of lactic acid with 
ethanol in the presence of a little mineral oil, or by combination 
of acetaldehyde with hydrocyanic acid to form acetaldehyde 
cyanhydrin. This is followed by treatment with ethanol (95%) 
and hydrochloric or sulfuric acid. Purification is achieved using 
fractional distillation. The commercial product is a racemic 
mixture. 
14 Safety 
Ethyl lactate is used as a flavoring agent in pharmaceutical 
preparations, and is found in food products. The estimated 
acceptable daily intake for lactic acid is 12.5 mg/kg bodyweight. 
In general, lactate esters have an oral LD50 > 2000 mg/kg; 
and the inhalation LC50 is generally above 5000 mg/m3. They 
have the potential of causing eye and skin irritation (on 
prolonged contact), but not sensitization.(6) Ethyl lactate is 
moderately toxic by intraperitoneal, subcutaneous, and intravenous 
routes. There is low oral and skin contact toxicity; 
although ingestion may cause nausea, stomach and throat pain, 
and narcosis. Inhalation of concentrated vapor of ethyl lactate 
may cause irritation of the mucous membranes, drowsiness, 
and narcosis. 
LD50 (rat, oral): >5.0 g/kg(7) 
LD50 (mouse, oral): 2.5 g/kg 
LD50 (mouse, SC): 2.5 g/kg 
LD50 (mouse, IV): 0.6 g/kg 
LD50 (rabbit, skin): >5.0 g/kg

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Avoid skin and eye contact; 
eye goggles should be worn, or a full face shield where 
splashing may occur. 
There is a slight explosion hazard in the form of vapor when 
it is exposed to flame. Avoid ignition sources and use adequate 
ventilation to keep vapor and mist as low as possible. 
When heated to decomposition, it emits acrid smoke and 
irritating fumes. Facial respirators are recommended when 
dealing with excessive amounts or with prolonged exposure to 
the compound. 
16 Regulatory Status 
GRAS listed. Reported in the EPA TSCA Inventory. 
17 Related Substances 
n-Butyl lactate; methyl lactate. 
n-Butyl lactate 
Empirical formula: C7H14O3 
Molecular weight: 146.2 
CAS number: [138-22-7] 
Synonyms: butyl a-hydroxypropionate; propanoic acid 2- 
hydroxy butyl ester; lactic acid butyl ester; Purasolv BL. 
Boiling point: 1888C 
Melting point: –438C 
Solubility: partially miscible with water and most organic 
solvents. 
Comments: n-butyl lactate is used as a flavoring agent in 
pharmaceutical preparations. 
The EINECS number for n-butyl lactate is 205-316-4. 
Methyl lactate 
Empirical formula: C4H8O3 
Molecular weight: 104 
CAS number: [547-64-8] 
Synonyms: methyl hydroxy propionate; Purasolv ML. 
Appearance: methyl lactate occurs as a clear, colorless liquid. 
Boiling point: 143.98C 
Comments: methyl lactate is used as a cellulose acetate solvent. 
18 Comments 
Ethyl lactate is found in food products as a flavoring agent; 
owing to its biodegradability, ethyl lactate is replacing many 
solvents in many household products, including packaging, 
plastics, paints, paint strippers, grease removers, cleansers, 
aerosols, adhesives, and varnishes. 
Ethyl lactate is specified as a flavor chemical in the Food 
Chemicals Codex (FCC).(8) 
The EINECS number for ethyl lactate is 202-598-0. 
19 Specific References 
1 Christensen JM, Suvanakoot U, Ayres JW, Tavipatana W. Ethyl 
lactate–ethanol–water cosolvent for intravenous theophylline. Res 
Commun Chem Pathol Pharmacol 1985; 50(1): 147–150. 
2 Mottu F, Laurent A, Rufenacht DA, Doelker E. Organic solvents 
for pharmaceutical parenterals and embolic liquids: A review of 
toxicity data. PDA J Pharm Sci Tech 2000; 54(6): 456–469. 
3 Siew LF, Basit AW, Newton JM. The properties of amylose– 
ethylcellulose films cast from organic-based solvents as potential 
coatings for colonic drug delivery. Eur J Pharm Sci 2000; 11(2): 
133–139. 
4 George D, Prottery C, Black JG, et al. Ethyl lactate as a treatment 
for acne. Br J Dermatol 1983; 108(2): 228–233. 
5 Prottey C, George D, Leech RW, et al. The mode of action of ethyl 
lactate as a treatment for acne. Br J Dermatol 1984; 110(4): 475– 
485. 
6 Clary JJ, Feron VJ, van Velthuijsen JA. Safety assessment of lactate 
esters. Regul Toxicol Pharmacol 1998; 27(2): 88–97. 
7 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2197. 
8 Food Chemicals Codex, 4th edn. Washington, DC: National 
Academy Press, 1996: 490–491. 
20 General References 
—
21 Authors 
O AbuBaker. 
22 Date of Revision 
15 August 2005. 
Ethyl Lactate 271

Ethyl Maltol 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
2-Ethyl pyromeconic acid; 3-hydroxy-2-ethyl-4-pyrone; Veltol 
Plus. 
3 Chemical Name and CAS Registry Number 
2-Ethyl-3-hydroxy-4H-pyran-4-one [4940-11-8] 
4 Empirical Formula and Molecular Weight 
C7H8O3 140.14 
5 Structural Formula 
6 Functional Category 
Flavor enhancer; flavoring agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ethyl maltol is used in pharmaceutical formulations and food 
products as a flavoring agent or flavor enhancer in applications 
similar to maltol. It has a flavor and odor 4–6 times as intense 
as maltol. Ethyl maltol is used in oral syrups at concentrations 
of about 0.004% w/v and also at low levels in perfumery. 
8 Description 
White crystalline solid with characteristic, very sweet, caramellike 
odor and taste. In dilute solution it possesses a sweet, 
fruitlike flavor and odor. 
9 Pharmacopeial Specifications 
See Section 19. 
10 Typical Properties 
Melting point: 89–938C 
Solubility: see Table I. 
Table I: Solubility of ethyl maltol. 
Solvent Solubility at 208C 
Chloroform 1 in 5 
Ethanol (95%) 1 in 10 
Glycerin 1 in 500 
Propan-2-ol 1 in 11 
Propylene glycol 1 in 17 
Water 1 in 55 
11 Stability and Storage Conditions 
Solutions may be stored in glass or plastic containers. The bulk 
material should be stored in a well-closed container, protected 
from light, in a cool, dry place. 
12 Incompatibilities 
—
13 Method of Manufacture 
Unlike maltol, ethyl maltol does not occur naturally. It may be 
prepared by treating a-ethylfurfuryl alcohol with a halogen to 
produce 4-halo-6-hydroxy-2-ethyl-2H-pyran-3(6H)-one, which 
is converted to ethyl maltol by hydrolysis. 
14 Safety 
In animal feeding studies, ethyl maltol has been shown to be 
well tolerated with no adverse toxic, reproductive, or embryogenic 
effects. It has been reported that while the acute toxicity 
of ethyl maltol, in animal studies, is slightly greater than maltol; 
with repeated dosing the opposite is true.(1) Although an 
acceptable daily intake for ethyl maltol has not been set the 
WHO has set an acceptable daily intake for maltol at up to 
1 mg/kg body-weight.(2) 
LD50 (chicken, oral): 1.27 g/kg (3) 
LD50 (rat, oral): 1.15 g/kg 
LD50 (mouse, oral): 0.78 g/kg 
LD50 (mouse, SC): 0.91 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Ethyl maltol should be used 
in a well-ventilated environment. Dust may be irritant and eye 
protection and gloves are recommended. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(oral syrup). 
17 Related Substances 
Maltol.

18 Comments 
See Maltol for further information. 
Although not included in any pharmacopeias, a specification 
for ethyl maltol is contained in the Food Chemicals Codex 
(FCC), see Table II.(4) 
Table II: Food Chemicals Codex specifications for ethyl maltol. 
Test FCC 1996 
Identification . 
Heavy metals (as lead) 40.002% 
Lead 410 ppm 
Residue on ignition 40.2% 
Water 40.5% 
Assay (dried basis) 599.0% 
19 Specific References 
1 Gralla EJ, Stebbins RB, Coleman GL, Delahunt CS. Toxicity 
studies with ethyl maltol. Toxicol Appl Pharmacol 1969; 15: 604– 
613. 
2 FAO/WHO. Evaluation of certain food additives. Twenty-fifth 
report of the joint FAO/WHO expert committee on food additives. 
World Health Organ Tech Rep Ser 1981; No. 669. 
3 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1692. 
4 Food Chemicals Codex, 4th edn. Washington, DC: National 
Academy Press, 1996: 138. 
20 General References 
Allen LV. Featured excipient: flavor enhancing agents. Int J Pharm 
Compound 2003; 7(1): 48–50. 
21 Authors 
PJ Weller. 
22 Date of Revision 
14 August 2005. 
Ethyl Maltol 273

Ethyl Oleate 
1 Nonproprietary Names 
BP: Ethyl oleate 
PhEur: Ethylis oleas 
USPNF: Ethyl oleate 
2 Synonyms 
Ethyl 9-octadecenoate; Kessco EO; oleic acid, ethyl ester. 
3 Chemical Name and CAS Registry Number 
(Z)-9-Octadecenoic acid, ethyl ester [111-62-6] 
4 Empirical Formula and Molecular Weight 
C20H38O2 310.51 
5 Structural Formula 
6 Functional Category 
Oleaginous vehicle; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ethyl oleate is primarily used as a vehicle in certain parenteral 
preparations intended for intramuscular administration. It has 
also been used as a solvent for drugs formulated as biodegradable 
capsules for subdermal implantation(1) and in the 
preparation of microemulsions containing cyclosporin.(2) 
Ethyl oleate is a suitable solvent for steroids and other 
lipophilic drugs. Its properties are similar to those of almond oil 
and peanut oil. However, it has the advantage that it is less 
viscous than fixed oils and is more rapidly absorbed by body 
tissues.(3) 
Ethyl oleate has also been evaluated as a vehicle for 
subcutaneous injection.(4) 
8 Description 
Ethyl oleate occurs as a pale yellow to almost colorless, mobile, 
oily liquid with a taste resembling that of olive oil and a slight, 
but not rancid odor. 
Ethyl oleate is described in the USPNF 23 as consisting of 
esters of ethyl alcohol and high molecular weight fatty acids, 
principally oleic acid. A suitable antioxidant may be included. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for ethyl oleate. 
Test PhEur 2005 USPNF 23 
Characters . — 
Identification . . 
Specific gravity 0.866–0.874 0.866–0.874 
Viscosity — 55.15 mPa s 
Refractive index — 1.443–1.450 
Acid value 40.5 40.5 
Iodine value 75–90 75–85 
Saponification value 177–188 177–188 
Peroxide value 410 — 
Oleic acid 560.0% — 
Water content 41.0% — 
Total ash 40.1% — 
10 Typical Properties 
Boiling point: 205–2088C (some decomposition) 
Flash point: 175.38C 
Freezing point: 328C 
Moisture content: at 208C and 52% relative humidity, the 
equilibrium moisture content of ethyl oleate is 0.08%. 
Solubility: miscible with chloroform, ethanol (95%), ether, 
fixed oils, liquid paraffin, and most other organic solvents; 
practically insoluble in water. 
Surface tension: 32.3mN/m (32.3 dynes/cm) at 258C(3) 
Viscosity (dynamic): 3.9 mPa s (3.9 cP) at 258C(3) 
Viscosity (kinematic): 0.046mm2/s (4.6 cSt) at 258C(3) 
11 Stability and Storage Conditions 
Ethyl oleate should be stored in a cool, dry place in a small, 
well-filled, well-closed container, protected from light. When a 
partially filled container is used, the air should be replaced by 
nitrogen or another inert gas. Ethyl oleate oxidizes on exposure 
to air, resulting in an increase in the peroxide value. It remains 
clear at 58C, but darkens in color on standing. Antioxidants are 
frequently used to extend the shelf life of ethyl oleate. 
Protection from oxidation for over 2 years has been achieved 
by storage in amber glass bottles with the addition of 
combinations of propyl gallate, butylated hydroxyanisole, 
butylated hydroxytoluene, and citric or ascorbic acid.(5,6) A 
concentration of 0.03% w/v of a mixture of propyl gallate 
(37.5%), butylated hydroxytoluene (37.5%), and butylated 
hydroxyanisole (25%) was found to be the best antioxidant for 
ethyl oleate.(6) 
Ethyl oleate may be sterilized by heating at 1508C for 1 
hour. 
12 Incompatibilities 
Ethyl oleate dissolves certain types of rubber and causes others 
to swell.(7,8) It may also react with oxidizing agents.

13 Method of Manufacture 
Ethyl oleate is prepared by the reaction of ethanol with oleoyl 
chloride in the presence of a suitable hydrogen chloride 
acceptor. 
14 Safety 
Ethyl oleate is generally considered to be of low toxicity but 
ingestion should be avoided. Ethyl oleate has been found to 
cause minimal tissue irritation.(9) No reports of intramuscular 
irritation during use have been recorded. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and nitrile 
gloves are recommended. Ethyl oleate is flammable. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (transdermal 
preparation). Included in parenteral medicines licensed in the 
UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Methyl oleate; oleic acid. 
Methyl oleate 
Empirical formula: C19H36O2 
Molecular weight: 296.49 
CAS number: [112-69-9] 
Synonyms: methyl 9-octadecenoate; (Z)-9-octadecenoic acid, 
methyl ester. 
Boiling point: 168–1708C 
Density: 0.879 g/cm3 
Iodine number: 85.6 
Refractive index: nD
26 = 1.4510 
Solubility: miscible with ethanol (95%) and ether. 
Comments: prepared by refluxing oleic acid with p-toluenesulfonic 
acid in methanol. 
18 Comments 
The EINECS number for ethyl oleate is 203-889-5. 
19 Specific References 
1 Ory SJ, Hammond CB, Yancy SG, et al. Effect of a biodegradable 
contraceptive capsule (Capronor) containing levonorgestrel on 
gonadotropin, estrogen and progesterone levels. Am J Obstet 
Gynecol 1983; 145: 600–605. 
2 Kim C-K, Ryuu S-A, Park K-M. Preparation and physicochemical 
characterisation of phase inverted water/oil microemulsion containing 
cyclosporin A. Int J Pharm 1997; 147: 131–134. 
3 Howard JR, Hadgraft J. The clearance of oily vehicles following 
intramuscular and subcutaneous injections in rabbits. Int J Pharm 
1983; 16: 31–39. 
4 Radwan M. In vivo screening model for excipients and vehicles 
used in subcutaneous injections. Drug Dev Ind Pharm 1994; 20: 
2753–2762. 
5 Alemany P, Del Pozo A. Autoxidation of ethyl oleate: protection 
with antioxidants [in Spanish]. Galenica Acta 1963; 16: 335–338. 
6 Nikolaeva NM, Gluzman MK. Conditions for stabilizing ethyl 
oleate during storage [in Russian]. Farmatsiya 1977; 26: 25–28. 
7 Dexter MB, Shott MJ. The evaluation of the force to expel oily 
injection vehicles from syringes. J Pharm Pharmacol 1979; 31: 
497–500. 
8 Halsall KG. Calciferol injection and plastic syringes [letter]. Pharm 
J 1985; 235: 99. 
9 Hem SL, Bright DR, Banker GS, Pogue JP. Tissue irritation 
evaluation of potential parenteral vehicles. Drug Dev Commun 
1974–75; 1(5): 471–477. 
20 General References 
Spiegel AJ, Noseworthy MM. Use of nonaqueous solvents in parenteral 
products. J Pharm Sci 1963; 52: 917–927. 
21 Authors 
CG Cable. 
22 Date of Revision 
21 August 2005. 
Ethyl Oleate 275

Ethyl Vanillin 
1 Nonproprietary Names 
USPNF: Ethyl vanillin 
2 Synonyms 
Bourbonal; ethylprotal; ethylprotocatechuic aldehyde; 
4-hydroxy-3-ethoxybenzaldehyde; Rhodiarome; vanillal. 
3 Chemical Name and CAS Registry Number 
3-Ethoxy-4-hydroxybenzaldehyde [121-32-4] 
4 Empirical Formula and Molecular Weight 
C9H10O3 166.18 
5 Structural Formula 
6 Functional Category 
Flavoring agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ethyl vanillin is used as an alternative to vanillin, i.e., as a 
flavoring agent in foods, beverages, confectionery, and 
pharmaceuticals. It is also used in perfumery. 
Ethyl vanillin possesses a flavor and odor approximately 
three times as intense as vanillin, hence the quantity of material 
necessary to produce an equivalent vanilla flavor may be 
reduced, causing less discoloration to a formulation and 
potential savings in material costs. However, exceeding certain 
concentration limits may impart an unpleasant, slightly bitter 
taste to a product due to the intensity of the ethyl vanillin flavor. 
See Table I. 
Table I: Uses of ethyl vanillin. 
Use Concentration (%) 
Foods and confectionery 0.002–0.025 
Oral syrups 0.01 
8 Description 
White or slightly yellowish crystals with a characteristic intense 
vanilla odor and flavor. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for ethyl vanillin. 
Test USPNF 23 
Identification . 
Melting range 76.0–78.08C 
Loss on drying 41.0% 
Residue on ignition 40.1% 
Organic volatile impurities . 
Assay (dried basis) 98.0–101.0% 
10 Typical Properties 
Boiling point: 2858C 
Density (bulk): 1.05 g/cm3 
Flash point: 1278C 
Melting point: 76–788C 
Solubility: see Table III. 
Table III: Solubility of ethyl vanillin. 
Solvent Solubility at 208C 
unless otherwise stated 
Alkaline hydroxide solutions Freely soluble 
Chloroform Freely soluble 
Ethanol (95%) 1 in 2 
Ether Freely soluble 
Glycerin Soluble 
Propylene glycol Soluble 
Water 1 in 250 
1 in 100 at 508C 
11 Stability and Storage Conditions 
Store in a well-closed container, protected from light, in a cool, 
dry place. See Vanillin for further information. 
12 Incompatibilities 
Ethyl vanillin is unstable in contact with iron or steel forming a 
red-colored, flavorless compound. In aqueous media with 
neomycin sulfate or succinylsulfathiazole, tablets of ethyl 
vanillin produced a yellow color.(1) See Vanillin for other 
potential incompatibilities.

13 Method of Manufacture 
Unlike vanillin, ethyl vanillin does not occur naturally. It may 
be prepared synthetically by the same methods as vanillin, using 
guethol instead of guaiacol as a starting material; see Vanillin. 
14 Safety 
Ethyl vanillin is generally regarded as an essentially nontoxic 
and nonirritant material. However, cross-sensitization with 
other structurally similar molecules may occur; see Vanillin. 
The WHO has allocated an acceptable daily intake for ethyl 
vanillin of up to 3 mg/kg body-weight.(2) 
LD50 (guinea pig, IP): 1.14 g/kg(3,4) 
LD50 (mouse, IP): 0.75 g/kg 
LD50 (rabbit, oral): 3 g/kg 
LD50 (rabbit, SC): 2.5 g/kg 
LD50 (rat, oral): 1.59 g/kg 
LD50 (rat, SC): 3.5–4.0 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection is recommended. 
Heavy airborne concentrations of dust may present an 
explosion hazard. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(oral capsules, suspensions, and syrups). Included in nonparenteral 
medicines licensed in the UK. 
17 Related Substances 
Vanillin. 
18 Comments 
Ethyl vanillin can be distinguished analytically from vanillin by 
the yellow color developed in the presence of concentrated 
sulfuric acid. The EINECS number for ethyl vanillin is 204- 
464-7. 
19 Specific References 
1 Onur E, Yalcindag ON. Double incompatibility of ethyl vanillin 
(vanillal) in compressed tablets [in French]. Bull Soc Pharm 
Bordeaux 1970; 109(2): 49–51. 
2 FAO/WHO. Evaluation of certain food additives and contaminants. 
Forty-fourth report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1995; No. 859. 
3 Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. 
Cincinnati: US Department of Health, 1987: 721. 
4 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1729. 
20 General References 
Rees DI. Determination of vanillin and ethyl vanillin in food products. 
Chem Ind 1965; 1: 16–17. 
21 Authors 
PJ Weller. 
22 Date of Revision 
14 August 2005. 
Ethyl Vanillin 277

Ethylcellulose 
1 Nonproprietary Names 
BP: Ethylcellulose 
PhEur: Ethylcellulosum 
USPNF: Ethylcellulose 
2 Synonyms 
Aquacoat ECD; Aqualon; E462; Ethocel; Surelease. 
3 Chemical Name and CAS Registry Number 
Cellulose ethyl ether [9004-57-3] 
4 Empirical Formula and Molecular Weight 
Ethylcellulose with complete ethoxyl substitution (DS = 3) is 
C12H23O6(C12H22O5)nC12H23O5 where n can vary to provide 
a wide variety of molecular weights. Ethylcellulose, an ethyl 
ether of cellulose, is a long-chain polymer of b-anhydroglucose 
units joined together by acetal linkages. 
5 Structural Formula 
6 Functional Category 
Coating agent; flavoring fixative; tablet binder; tablet filler; 
viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ethylcellulose is widely used in oral and topical pharmaceutical 
formulations; see Table I. 
The main use of ethylcellulose in oral formulations is as a 
hydrophobic coating agent for tablets and granules.(1–8) 
Ethylcellulose coatings are used to modify the release of a 
drug,(7–10) to mask an unpleasant taste, or to improve the 
stability of a formulation; for example, where granules are 
coated with ethylcellulose to inhibit oxidation. Modifiedrelease 
tablet formulations may also be produced using 
ethylcellulose as a matrix former.(11–14) 
Ethylcellulose, dissolved in an organic solvent or solvent 
mixture, can be used on its own to produce water-insoluble 
films. Higher-viscosity ethylcellulose grades tend to produce 
stronger and more durable films. Ethylcellulose films may be 
modified to alter their solubility,(15) by the addition of 
hypromellose(16) or a plasticizer;(17–19) see Section 18. An 
aqueous polymer dispersion (or latex) of ethylcellulose such as 
Aquacoat ECD (FMC Biopolymer) or Surelease (Colorcon) 
may also be used to produce ethylcellulose films without the 
need for organic solvents. 
Drug release through ethylcellulose-coated dosage forms 
can be controlled by diffusion through the film coating. This 
can be a slow process unless a large surface area (e.g. pellets or 
granules compared with tablets) is utilized. In those instances, 
aqueous ethylcellulose dispersions are generally used to coat 
granules or pellets. Ethylcellulose-coated beads and granules 
have also demonstrated the ability to absorb pressure and hence 
protect the coating from fracture during compression.(19) 
High-viscosity grades of ethylcellulose are used in drug 
microencapsulation.(10,20–22) 
Release of a drug from an ethylcellulose microcapsule is a 
function of the microcapsule wall thickness and surface area. 
In tablet formulations, ethylcellulose may additionally be 
employed as a binder, the ethylcellulose being blended dry or 
wet-granulated with a solvent such as ethanol (95%). 
Ethylcellulose produces hard tablets with low friability, 
although they may demonstrate poor dissolution. 
Ethylcellulose has also been used as an agent for delivering 
therapeutic agents from oral (e.g. dental) appliances.(23) 
In topical formulations, ethylcellulose is used as a thickening 
agent in creams, lotions, or gels, provided an appropriate 
solvent is used.(24) Ethylcellulose has been studied as a stabilizer 
for emulsions.(25) 
Ethylcellulose is additionally used in cosmetics and food 
products. 
Table I: Uses of ethylcellulose. 
Use Concentration (%) 
Microencapsulation 10.0–20.0 
Sustained-release tablet coating 3.0–20.0 
Tablet coating 1.0–3.0 
Tablet granulation 1.0–3.0 
8 Description 
Ethylcellulose is a tasteless, free-flowing, white to light tancolored 
powder. 
9 Pharmacopeial Specifications 
See Tables II and III. 
10 Typical Properties 
Density (bulk): 0.4 g/cm3 
Glass transition temperature: 129–1338C(26) 
Moisture content: ethylcellulose absorbs very little water 
from humid air or during immersion, and that small 
amount evaporates readily.(27,28) See also Figure 1.

Table II: Pharmacopeial specifications for ethylcellulose. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Acidity or alkalinity . — 
Viscosity See Table III See Table III 
Loss on drying 43.0% 43.0% 
Residue on ignition — 40.4% 
Sulfated ash 40.5% — 
Lead — 410 ppm 
Heavy metals 420 ppm 420 mg/g 
Acetaldehyde 4100 ppm — 
Chlorides 40.1% — 
Organic volatile impurities — . 
Assay (of ethoxyl groups) 44.0–51.0% 44.0–51.0% 
Table III: Pharmacopeial specifications for ethylcellulose viscosity. 
Test PhEur 2005 USPNF 23 
Nominal viscosity 
>6 mPa s 75–140% of that stated 
for its nominal 
viscosity 
75–140% of that stated 
for its nominal 
viscosity 
6–10 mPa s 80–120% of that stated 
for its nominal 
viscosity 
80–120% of that stated 
for its nominal 
viscosity 
410 mPa s 80–120% of that stated 
for its nominal 
viscosity 
90–110% of that stated 
for its nominal 
viscosity 
Particle size distribution: see Table IV; see also Figures 2 and 3. 
Solubility: ethylcellulose is practically insoluble in glycerin, 
propylene glycol, and water. Ethylcellulose that contains less 
than 46.5% of ethoxyl groups is freely soluble in chloroform, 
methyl acetate, and tetrahydrofuran, and in mixtures 
of aromatic hydrocarbons with ethanol (95%). Ethylcellulose 
that contains not less than 46.5% of ethoxyl groups is 
freely soluble in chloroform, ethanol (95%), ethyl acetate, 
methanol, and toluene. 
Specific gravity: 1.12–1.15 g/cm3 
Viscosity: the viscosity of ethylcellulose is measured typically at 
258C using 5% w/v ethylcellulose dissolved in a solvent 
blend of 80% toluene :20% ethanol (w/w). Grades of 
ethylcellulose with various viscosities are commercially 
available; see Table IV. They may be used to produce 5% 
w/v solutions in organic solvent blends with viscosities 
nominally ranging from 7 to 100 mPa s (7–100 cP). Specific 
ethylcellulose grades, or blends of different grades, may be 
used to obtain solutions of a desired viscosity. Solutions of 
higher viscosity tend to be composed of longer polymer 
chains and produce strong and durable films. 
The viscosity of an ethylcellulose solution increases with 
an increase in ethylcellulose concentration; e.g. the viscosity 
of a 5% w/v solution of Ethocel Standard 4 Premium is 
4 mPa s (4 cP) and of a 25% w/v solution of the same 
ethylcellulose grade is 850 mPa s (850 cP). Solutions with a 
lower viscosity may be obtained by incorporating a higher 
percentage (30–40%) of a low-molecular-weight aliphatic 
alcohol such as ethanol, butanol, propan-2-ol, or n-butanol 
with toluene. The viscosity of such solutions depends almost 
entirely on the alcohol content and is independent of 
toluene. 
SEM: 1 
Excipient: Ethylcellulose 
Manufacturer: Hercules Ltd. 
Lot No.: 57911 
Magnfication: 60 Voltage: 10 kV 
SEM: 2 
Excipient: Ethylcellulose 10 mPa s (10 cP) fine powder 
Manufacturer: Dow Chemical Co. 
Magnification: 600 Voltage: 5kV 
Ethylcellulose 279

SEM: 3 
Excipient: Ethylcellulose 100 mPa s (100 cP) fine powder 
Manufacturer: Dow Chemical Co. 
Magnification: 600 Voltage: 5kV 
SEM: 4 
Excipient: Ethylcellulose 
Manufacturer: Hercules Ltd. 
Lot No.: 57911 
Magnfication: 600 Voltage: 10 kV 
In addition, nonpharmaceutical grades of ethylcellulose 
that differ in their ethoxyl content and degree of polymerization 
are available. 
Table IV: Summary of ethylcellulose grades, suppliers, viscosity, and 
particle size. 
Grade Supplier Solution 
viscosity 
(mPa s) 
Mean 
particle 
size (mm) 
Ethocel Std 4 Premium Dow Chemical 3.0–5.5 — 
N-7 Aqualon 5.6–8.0 — 
Ethocel Std 7FP Premium Dow Chemical 6.0–8.0 5.0–15.0 
Ethocel Std 7 Premium Dow Chemical 6.0–8.0 310.0 
T-10 Aqualon 8.0–11.0 — 
N-10 Aqualon 8.0–11.0 — 
Ethocel Std 10FP Premium Dow Chemical 9.0–11.0 3.0–15.0 
Ethocel Std 10P Premium Dow Chemical 9.0–11.0 375.0 
N-14 Aqualon 12.0–16.0 — 
Ethocel Std 20P Premium Dow Chemical 18.0–22.0 — 
N-22 Aqualon 18.0–24.0 — 
Ethocel Std 45P Premium Dow Chemical 41.0–49.0 — 
N-50 Aqualon 40.0–52.0 — 
N-100 Aqualon 80.0–105.0 — 
Ethocel Std 100FP Premium Dow Chemical 90.0–110.0 30.0–60.0 
Ethocel Std 100P Premium Dow Chemical 90.0–110.0 465.0 (
11 Stability and Storage Conditions 
Ethylcellulose is a stable, slightly hygroscopic material. It is 
chemically resistant to alkalis, both dilute and concentrated, 
and to salt solutions, although it is more sensitive to acidic 
materials than are cellulose esters. 
Ethylcellulose is subject to oxidative degradation in the 
presence of sunlight or UV light at elevated temperatures. This 
may be prevented by the use of antioxidant and chemical 
additives that absorb light in the 230–340nm range. 
Ethylcellulose should be stored at a temperature not 
exceeding 328C (908F) in a dry area away from all sources of 
heat. It should not be stored next to peroxides or other 
oxidizing agents. 
12 Incompatibilities 
Incompatible with paraffin wax and microcrystalline wax. 
13 Method of Manufacture 
Ethylcellulose is prepared by treating purified cellulose (sourced 
from chemical-grade cotton linters and wood pulp) with an 
alkaline solution, followed by ethylation of the alkali cellulose 
with chloroethane as shown below, where R represents the 
cellulose radical: 
RONa . C2H5Cl ! ROC2H5 . NaCl 
The manner in which the ethyl group is added to cellulose can 
be described by the degree of substitution (DS). The DS 
designates the average number of hydroxyl positions on the 
anhydroglucose unit that have been reacted with ethyl chloride. 
Since each anhydroglucose unit of the cellulose molecule has 
three hydroxyl groups, the maximum value for DS is three. 
280 Ethylcellulose

Figure 1: Equilibrium moisture content of ethylcellulose. 
Figure 2: Particle size distribution of ethylcellulose. 
14 Safety 
Ethylcellulose is widely used in oral and topical pharmaceutical 
formulations. It is also used in food products. Ethylcellulose is 
not metabolized following oral consumption and is therefore a 
noncalorific substance. Because ethylcellulose is not metabolized 
it is not recommended for parenteral products; parenteral 
use may be harmful to the kidneys. 
Figure 3: Particle size distribution of ethylcellulose (Ethocel). 
Ethylcellulose is generally regarded as a nontoxic, nonallergenic, 
and nonirritating material. 
As ethylcellulose is not considered to be a health hazard, the 
WHO has not specified an acceptable daily intake.(29) 
LD50 (rabbit, skin): >5 g/kg(30) 
LD50 (rat, oral): >5 g/kg 
15 Handling Precautions 
It is important to prevent fine dust clouds of ethylcellulose from 
reaching potentially explosive levels in the air. Ethylcellulose is 
combustible. Ethylcellulose powder may be an irritant to the 
eyes and eye protection should be worn. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral capsules, 
suspensions and tablets; topical emulsions and vaginal preparations). 
Included in nonparenteral medicines licensed in 
Europe. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Hydroxyethyl cellulose; hydroxyethylmethyl cellulose; methylcellulose. 
18 Comments 
Ethylcellulose is compatible with the following plasticizers: 
dibutyl phthalate; diethyl phthalate; dibutyl sebacate; triethyl 
citrate; tributyl citrate; acetylated monoglyceride; acetyl tributyl 
citrate; triacetin; dimethyl phthalate; benzyl benzoate; butyl 
and glycol esters of fatty acids; refined mineral oils; oleic acid; 
stearic acid; ethyl alcohol; stearyl alcohol; castor oil; corn oil; 
and camphor. 
Ethylcellulose has also been used as a backing membrane on 
mucoadhesive patches intended for buccal administration. The 
Ethylcellulose 281

membrane had high tensile strength, and provided excellent 
unidirectional drug flow.(31) Studies have also suggested 
ethylcellulose for use in floating microparticles based on lowdensity 
foam powder, for gastroretentive drug delivery 
systems.(32) 
A specification for ethylcellulose is contained in the Food 
Chemicals Codex (FCC). 
19 Specific References 
1 Ozturk AG, Ozturk SS, Palsson BO, et al. Mechanism of release 
from pellets coated with an ethyl cellulose-based film. J Control 
Release 1990; 14(3): 203–213. 
2 Narisawa S, Yoshino H, Hirakawa Y, Noda K. Porosity-controlled 
ethyl cellulose film coating. IV. Evaluation of mechanical strength 
of porous ethyl cellulose film. Chem Pharm Bull 1994; 42(7): 
1491–1495. 
3 Bodmeier R, Paeratakul O. The effect of curing on drug release and 
morphological properties of ethylcellulose pseudolatex-coated 
beads. Drug Dev Ind Pharm 1994; 20(9): 1517–1533. 
4 Dressman JB, Derbin GM, Ismailos G, et al. Circumvention of pHdependent 
release from ethyl cellulose-coated pellets. J Control 
Release 1995; 36(3): 251–260. 
5 Iyer U, Hong WH, Das N, Ghebre-Sellassie I. Comparative 
evaluation of three organic solvent and dispersion-based ethyl 
cellulose coating formulations. Pharm Technol 1990; 14(9): 68– 
86. 
6 Sarisuta N, Sirithunyalug J. Release rate of indomethacin from 
coated granules. Drug Dev Ind Pharm 1988; 14(5): 683–687. 
7 Porter SC. Controlled-release film coatings based on ethylcellulose. 
Drug Dev Ind Pharm 1989; 15(10): 1495–1521. 
8 Sadeghi F, Ford JL, Rubinstein MH, Rajabi-Siahboomi AR. Study 
of drug release from pellets coated with surelease containing 
hydroxypropylmethylcellulose. Drug Dev Ind Pharm 2001; 27(5): 
419–430. 
9 Goracinova K, Klisarova L, Simov A, et al. Preparation, physical 
characterization, mechanisms of drug/polymer interactions, and 
stability studies of controlled-release solid dispersion granules 
containing weak base as active substance. Drug Dev Ind Pharm 
1996; 22(3): 255–262. 
10 Lin S. Studies on microencapsulation. 14. Theophylline bioavailability 
after single oral-administration of sustained-release microcapsules. 
Curr Ther Res Clin Exp 1987; 41(4): 564–573. 
11 Pollock D, Sheskey P. Micronized ethylcellulose: opportunities in 
direct-compression controlled-release tablets. Pharm Technol 
1996; 20(9): 120–130. 
12 Klinger GH, Ghalli ES, Porter SC, Schwartz JB. Formulation of 
controlled release matrices by granulation with a polymer 
dispersion. Drug Dev Ind Pharm 1990; 16(9): 1473–1490. 
13 Katikaneni P, Upadrashta SM, Neau SH, Mitra AK. Ethyl cellulose 
matrix controlled-release tablets of a water-soluble drug. Int J 
Pharm 1995; 123: 119–125. 
14 Kulvanich P, Leesawat P, Patomchaiviwat V. Release characteristics 
of the matrices prepared from co-spray-dried powders of theophylline 
and ethylcellulose. Drug Dev Ind Pharm 2002; 28: 727–739. 
15 Kent DJ, Rowe RC. Solubility studies on ethyl cellulose used in film 
coating. J Pharm Pharmacol 1978; 30: 808–810. 
16 Rowe RC. The prediction of compatibility/incompatibility in 
blends of ethyl cellulose with hydroxypropyl methylcellulose or 
hydroxypropyl cellulose using 2-dimensional solubility parameter 
maps. J Pharm Pharmacol 1986; 38: 214–215. 
17 Saettone MF, Perini G, Rijli P, et al. Effect of different polymerplasticizer 
combinations on ‘in vitro’ release of theophylline from 
coated pellets. Int J Pharm 1995; 126: 83–88. 
18 Beck M, Tomka I. On the equation of state of plasticized ethyl 
cellulose of varying degrees of substitution. Macromolecules 1996; 
29(27): 8759–8766. 
19 Celik M. Compaction of multiparticulate oral dosage forms. In: 
Ghebre-Sellassie I, ed. Multiparticulate Oral Drug Delivery. New 
York: Marcel Dekker, 1994: 181–215. 
20 Robinson DH. Ethyl cellulose-solvent phase relationships relevant 
to coacervation microencapsulation processes. Drug Dev Ind 
Pharm 1989; 15(14–16): 2597–2620. 
21 Lavasanifar A, Ghalandari R, Ataei Z, et al. Microencapsulation 
of theophylline using ethyl cellulose: In vitro drug release and 
kinetic modeling. J Microencapsul 1997; 14(1): 91–100. 
22 Moldenhauer M, Nairn J. The control of ethyl cellulose microencapsulation 
using solubility parameters. J Control Release 1992; 
22: 205–218. 
23 Friedman M, Harrari D, Rimer A, Stabholz A. Inhibition of plaque 
formation by a sustained release delivery system for cetylpyridinium 
chloride. Int J Pharm 1988; 44: 243–247. 
24 Ruiz-Martinez A, Zouaki Y, Gallard-Lara V. In vitro evaluation of 
benzylsalicylate polymer interaction in topical formulation. Pharm 
Ind 2001; 63: 985–988. 
25 Melzer E, Kreuter J, Daniels R. Ethylcellulose: A new type of 
emulsion stabilizer. Eur J Pharm Biopharm 2003; 56: 23–27. 
26 Sakellariou P, Rowe RC, White EFT. The thermomechanical 
properties and glass transition temperatures of some cellulose 
derivatives used in film coating. Int J Pharm 1985; 27: 267–277. 
27 Callahan JC, Cleary GW, Elefant M, et al. Equilibrium moisture 
content of pharmaceutical excipients. Drug Dev Ind Pharm 1982; 
8(3): 355–369. 
28 Velazquez de la Cruz G, Torres J, Martin-Polo M. Temperature 
effects on the moisture sorption isotherms for methylcellulose and 
ethylcellulose films. J Food Engin 2001; 48: 91–94. 
29 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirty-fifth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1990: No. 
789. 
30 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1640. 
31 Sharma P, Hamsa V. Formulation and evaluation of buccal 
mucoadhesive patches of terbutaline sulphate. STP Pharma Sci 
2001; 11: 275–281. 
32 Streubel A, Siepmann J, Bodmeier R. Floating microparticles based 
on low density foam powder. Int J Pharm 2002; 241: 279–292. 
20 General References 
Dow Chemical Company. Technical literature: Ethocel premium 
polymers for pharmaceutical applications, 1998. 
Dow Chemical Company. Technical literature: Evaluation of fine 
particle size Ethocel polymer for use in controlled release matrix 
drug delivery, 1996. 
FMC Biopolymer. Technical literature: Aquacoat ECD ethylcellulose 
aqueous dispersion, 2004. 
Hercules Inc. Technical literature: Aqualon Ethylcellulose (EC) physical 
and chemical properties, 2002. 
Majewicz T, Podlas T. Cellulose ethers. In: Kroschwitz J, ed. 
Encyclopedia of Chemical Technology. New York: Wiley, 1993: 
541–563. 
Merflex Inc. Technical literature: Pharmaceutical Coatings Bulletin, 
1995; 102–103. 
Rekhi GS, Jambhekar SS. Ethylcellulose – a polymer review. Drug Dev 
Ind Pharm 1995; 21(1): 61–77. 
21 Authors 
TC Dahl. 
22 Date of Revision 
19 August 2005. 
282 Ethylcellulose

Ethylene Glycol Palmitostearate 
1 Nonproprietary Names 
BP: Ethylene glycol monopalmitostearate 
PhEur: Ethyleneglycoli monopalmitostearas 
2 Synonyms 
—
3 Chemical Name and CAS Registry Number 
Ethylene glycol palmitostearate 
See Sections 8 and 17. 
4 Empirical Formula and Molecular Weight 
See Section 8. 
5 Structural Formula 
See Section 8. 
6 Functional Category 
Emollient; emulsifying agent; stabilizing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ethylene glycol palmitostearate is used as a stabilizer for waterin-
oil emulsions, although it has poor emulsifying properties. It 
has emollient properties and is also used as an opacifying, 
thickening, and dispersing agent. 
In cosmetics, ethylene glycol palmitostearate is used as a 
‘fatty body’ for lipsticks, as a pearling agent in opalescent and 
cream shampoos, and as an additive for tanning lubricants. 
8 Description 
The PhEur 2005 describes ethylene glycol palmitostearate as a 
mixture of ethylene glycol monoesters and diesters of stearic 
and palmitic acids, produced from the condensation of ethylene 
glycol and stearic acid 50, of vegetable or animal origin. 
Ethylene glycol palmitostearate occurs as a white or almost 
white waxy solid. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for ethylene glycol 
palmitostearate. 
Test PhEur 2005 
Characters . 
Identification . 
Melting point 54–608C 
Acid value 43.0 
Iodine value 43.0 
Saponification value 170–195 
Composition of fatty acids 
Stearic acid 40.0–60.0% 
Total of palmitic acid and stearic acid 590.0% 
Free ethylene glycol 45.0% 
Total ash 40.1% 
10 Typical Properties 
Melting point: 54–608C 
Solubility: soluble in acetone and hot ethanol (95%); practically 
insoluble in water. 
11 Stability and Storage Conditions 
Ethylene glycol palmitostearate should be stored in a cool, dark 
place, protected from light. 
12 Incompatibilities 
—
13 Method of Manufacture 
Ethylene glycol palmitostearate is produced from the condensation 
of ethylene glycol with stearic acid 50 of vegetable or 
animal origin. 
14 Safety 
Ethylene glycol palmitostearate is mainly used in cosmetics and 
topical pharmaceutical formulations, where it is generally 
regarded as a relatively nontoxic and nonirritant material. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
Included in nonparenteral medicines licensed in Europe. 
17 Related Substances 
Diethylene glycol monopalmitostearate; ethylene glycol monopalmitate; 
ethylene glycol monostearate; glyceryl monostearate; 
glyceryl palmitostearate.

Diethylene glycol monopalmitostearate 
Synonyms: diethyleneglycoli monopalmitostearas; diethylene 
glycol palmitostearate. 
Description: the PhEur 2005 describes diethylene glycol 
monopalmitostearate as a mixture of diethylene glycol 
monoesters and diesters of stearic and palmitic acids. It 
contains not less than 45.0% of monoesters produced from 
the condensation of diethylene glycol and stearic acid 50 of 
vegetable or animal origin. Diethylene glycol monopalmitostearate 
occurs as a white or almost white waxy solid. 
Acid value: 44.0 
Iodine value: 43.0 
Melting point: 43–508C 
Saponification value: 150–170 
Solubility: soluble in acetone and hot ethanol (95%); practically 
insoluble in water. 
Ethylene glycol monopalmitate 
CAS number: [4219-49-2] 
Ethylene glycol monostearate 
Synonyms: ethylene glycol stearate; ethylene glycoli monostearas; 
ethyleni glycoli stearas; 2-hydroxyethyl ester stearic 
acid; Monestriol EN-A; Monthyle. 
CAS number: [111-60-4] 
Empirical formula: C20H40O3 
Molecular weight: 328.60 
Description: occurs as pale yellow flakes. 
Melting point: 57–638C 
Safety: LD50 (mouse, IP): 0.20 g/kg(1) 
18 Comments 
—
19 Specific References 
1 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1669. 
20 General References 
Sweetman S, ed. Martindale: The Complete Drug Reference. 34th edn. 
London: Pharmaceutical Press, 2005: 1411. 
21 Authors 
SC Owen, PJ Sheskey. 
22 Date of Revision 
12 August 2005. 
284 Ethylene Glycol Palmitostearate

Ethylene Vinyl Acetate 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Acetic acid, ethylene ester polymer with ethane; CoTran; 
ethylene/vinyl acetate copolymer; EVA; EVA copolymer; EVM; 
poly (ethylene-co-vinyl acetate); VA/ethylene copolymer; vinyl 
acetate/ethylene copolymer. 
3 Chemical Name and CAS Registry Number 
Ethylene vinyl acetate copolymer [24937-78-8] 
4 Empirical Formula and Molecular Weight 
(CH2CH2)x[CH2CH(CO2CH3)]y 
See Section 5. 
5 Structural Formula 
Ethylene vinyl acetate copolymer is a random copolymer of 
ethylene and vinyl acetate. 
6 Functional Category 
Membrane; transdermal backing. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ethylene vinyl acetate copolymers are used as membranes and 
backings in laminated transdermal drug delivery systems. They 
can also be incorporated as components in backings in 
transdermal systems. Ethylene vinyl acetate copolymers have 
been shown to be an effective matrix and membrane for the 
controlled delivery of atenolol(1,2) triprolidine,(3,4) and furosemide.(
5) The system for the controlled release of atenolol can be 
further developed using ethylene vinyl acetate copolymers and 
plasticizers.(1) 
8 Description 
Ethylene vinyl acetate is available as white waxy solids in pellet 
or powder form. Films are translucent. 
9 Pharmacopeial Specifications 
—
10 Typical Properties 
Density: 0.92–0.94 g/cm3 
Flash point: 2608C 
Melting point: 75–1028C depending on polymer ratios. 
Moisture vapor transmission rate: see Table I. 
Thickness: see Table I. 
Vinyl acetate content: see Table I. 
Table I: Characteristics of different CoTran (3M Drug Delivery 
Systems) film grades. 
Grade Vinyl acetate 
(%) 
Thickness (mm) Moisture vapor 
transmission rate 
(g/m2/24 h) 
CoTran 9706 9 101.6 26.4 
CoTran 9715 19 76.2 64.8 
CoTran 9716 19 101.6 48.6 
11 Stability and Storage Conditions 
Ethylene vinyl acetate copolymers are stable under normal 
conditions and should be stored in a cool, dry place. Films of 
ethylene vinyl acetate copolymers should be stored at 0–308C 
and less than 75% relative humidity. 
12 Incompatibilities 
Ethylene vinyl acetate is incompatible with strong oxidizing 
agents and bases. 
13 Method of Manufacture 
Various molecular weights of random ethylene vinyl acetate 
copolymers can be obtained by high-pressure radical polymerization, 
bulk continuous polymerization, or solution polymerization. 
14 Safety 
Ethylene vinyl acetate is mainly used in topical pharmaceutical 
applications as a membrane or film backing. Generally it is 
regarded as a relatively nontoxic and nonirritant excipient. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Ethylene vinyl acetate 
powder may form an explosive mixture with air. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (intrauterine 
suppository; ophthalmic preparations; periodontal film; transdermal 
film). Included in nonparenteral medicines licensed in 
the UK. 
17 Related Substances 
—
18 Comments 
Ethylene vinyl acetate copolymers have a wide variety of 
industrial uses. Properties of ethylene vinyl acetate copolymer 
films in terms of oxygen and moisture transfer rate are related

to the vinyl acetate content and thickness. Higher levels of vinyl 
acetate result in increased lipophilicity, increased oxygen and 
moisture vapor permeability, and increased clarity, flexibility, 
toughness, and solvent solubility. 
19 Specific References 
1 Kim J, Shin SC. Controlled release of atenolol from the ethylene– 
vinyl acetate matrix. Int J Pharm 2004; 273(1–2): 23–27. 
2 Shin SC, Choi JS. Enhanced bioavailability of atenolol by 
transdermal administration of the ethylene–vinyl acetate matrix 
in rabbits. Eur J Pharm Biopharm 2003; 56(3): 439–443. 
3 Shin SC, Lee HJ. Controlled release of triprolidine using ethylene– 
vinyl acetate membrane and matrix systems. Eur J Pharm 
Biopharm 2002; 54(2): 201–206. 
4 Shin SC, Lee HJ. Enhanced transdermal delivery of triprolidone 
from the ethylene–vinyl acetate matrix. Eur J Pharm Biopharm 
2002; 54(3): 325–328. 
5 Cho CW, Choi JS, Shin SC. Controlled release of furosemide from 
the ethylene-vinyl acetate matrix. Int J Pharm 2005; 299: 127– 
133. 
20 General References 
3M Drug Delivery Systems. CoTran. http://www.3m.com/us/ 
healthcare/manufacturers/dds/jhtml/backings_cotran.jhtml 
(accessed 16 May 2005). 
21 Authors 
S Edge, PM Young. 
22 Date of Revision 
16 August 2005. 
286 Ethylene Vinyl Acetate

Ethylparaben 
1 Nonproprietary Names 
BP: Ethyl hydroxybenzoate 
JP: Ethyl parahydroxybenzoate 
PhEur: Ethylis parahydroxybenzoas 
USPNF: Ethylparaben 
2 Synonyms 
E214; ethyl p-hydroxybenzoate; Ethyl parasept; 4-hydroxybenzoic 
acid ethyl ester; Solbrol A; Tegosept E. 
3 Chemical Name and CAS Registry Number 
Ethyl-4-hydroxybenzoate [120-47-8] 
4 Empirical Formula and Molecular Weight 
C9H10O3 166.18 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ethylparaben is widely used as an antimicrobial preservative in 
cosmetics,(1) food products, and pharmaceutical formulations. 
It may be used either alone or in combination with other 
paraben esters or with other antimicrobial agents. In cosmetics 
it is one of the most frequently used preservatives. 
The parabens are effective over a wide pH range and have a 
broad spectrum of antimicrobial activity, although they are 
most effective against yeasts and molds; see Section 10. 
Owing to the poor solubility of the parabens, paraben salts, 
particularly the sodium salt, are frequently used. However, this 
may cause the pH of poorly buffered formulations to become 
more alkaline. 
See Methylparaben for further information. 
SEM: 1 
Excipient: Ethylparaben 
Magnification: 600 
SEM: 2 
Excipient: Ethylparaben 
Magnification: 3000 
8 Description 
Ethylparaben occurs as a white, odorless or almost odorless, 
crystalline powder.

9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for ethylparaben. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Appearance of 
solution 
— . — 
Characters — . — 
Chloride 40.035% — — 
Heavy metals 420 ppm — — 
Acidity — . . 
Loss on drying 40.5% — 40.5% 
Melting range 116–1188C — 115–1188C 
Organic volatile 
impurities 
— — . 
Readily carbonizable 
substances 
. — — 
Related substances — . . 
Residue on ignition 40.1% 40.1% 40.05% 
Sulfate 40.024% — — 
Parahydroxybenzoic 
acid 
. — — 
Assay (dried basis) 599.0% 98.0–102.0% 99.0–100.5% 
10 Typical Properties 
Antimicrobial activity: ethylparaben exhibits antimicrobial 
activity from pH 4–8. Preservative efficacy decreases with 
increasing pH owing to the formation of the phenolate 
anion. Parabens are more active against yeasts and molds 
than against bacteria. They are also more active against 
Gram-positive than against Gram-negative bacteria. 
The activity of the parabens increases with increasing 
chain length of the alkyl moiety, but solubility decreases. 
Activity may be improved by using combinations of 
parabens since synergistic effects occur. Ethylparaben is 
commonly used with methylparaben and propylparaben in 
oral and topical formulations (such mixtures are commercially 
available; for example, Nipasept (Nipa Laboratories 
Inc.). Activity has also been reported to be improved by the 
addition of other excipients; see Methylparaben for further 
information. 
See Table II for minimum inhibitory concentrations of 
ethylparaben.(2) 
Boiling point: 297–2988C with decomposition. 
Melting point: 115–1188C 
Partition coefficient: the values for different vegetable oils vary 
considerably and are affected by the purity of the oil; see 
Table III.(3) 
Solubility: see Table IV. 
11 Stability and Storage Conditions 
Aqueous ethylparaben solutions at pH 3–6 can be sterilized by 
autoclaving, without decomposition.(4) At pH 3–6, aqueous 
solutions are stable (less than 10% decomposition) for up to 
about 4 years at room temperature, while solutions at pH 8 or 
above are subject to rapid hydrolysis (10% or more after about 
60 days at room temperature).(5) 
Ethylparaben should be stored in a well-closed container in 
a cool, dry place. 
Table II: Minimum inhibitory concentrations (MICs) for ethylparaben 
in aqueous solution.(2) 
Microorganism MIC (mg/mL) 
Aerobacter aerogenes ATCC 8308 1200 
Aspergillus niger ATCC 9642 500 
Aspergillus niger ATCC 10254 400 
Bacillus cereus var. mycoides ATCC 6462 1000 
Bacillus subtilis ATCC 6633 1000 
Candida albicans ATCC 10231 500 
Enterobacter cloacae ATCC 23355 1000 
Escherichia coli ATCC 8739 1000 
Escherichia coli ATCC 9637 1000 
Klebsiella pneumoniae ATCC 8308 500 
Penicillium chrysogenum ATCC 9480 250 
Penicillium digitatum ATCC 10030 250 
Proteus vulgaris ATCC 13315 500 
Pseudomonas aeruginosa ATCC 9027 >2000 
Pseudomonas aeruginosa ATCC 15442 >2000 
Pseudomonas stutzeri 1000 
Rhizopus nigricans ATCC 6227A 250 
Saccharomyces cerevisiae ATCC 9763 500 
Salmonella typhosa ATCC 6539 1000 
Serratia marcescens ATCC 8100 1000 
Staphylococcus aureus ATCC 6538P 1000 
Staphylococcus epidermidis ATCC 12228 1000 
Trichophyton mentagrophytes 125 
Table III: Partition coefficients for ethylparaben in vegetable oil and 
water.(3) 
Solvent Partition coefficient 
oil : water 
Corn oil 14.0 
Mineral oil 0.13 
Peanut oil 16.1 
Soybean oil 18.8 
Table IV: Solubility of ethylparaben in various solvents. 
Solvent Solubility at 208C 
unless otherwise stated 
Acetone Freely soluble 
Ethanol 1 in 1.4 
Ethanol (95%) 1 in 2 
Ether 1 in 3.5 
Glycerin 1 in 200 
Methanol 1 in 0.9 
Mineral oil 1 in 4000 
Peanut oil 1 in 100 
Propylene glycol 1 in 4 
Water 1 in 1250 at 158C 
1 in 910 
1 in 120 at 808C 
12 Incompatibilities 
The antimicrobial properties of ethylparaben are considerably 
reduced in the presence of nonionic surfactants as a result of 
micellization.(6) Absorption of ethylparaben by plastics has not 
288 Ethylparaben

been reported, although it appears probable given the behavior 
of other parabens. Ethylparaben is coabsorbed on silica in the 
presence of ethoxylated phenols.(7) Yellow iron oxide, ultramarine 
blue, and aluminum silicate extensively absorb ethylparaben 
in simple aqueous systems, thus reducing preservative 
efficacy.(8,9) 
Ethylparaben is discolored in the presence of iron and is 
subject to hydrolysis by weak alkalis and strong acids. 
See also Methylparaben. 
13 Method of Manufacture 
Ethylparaben is prepared by the esterification of p-hydroxybenzoic 
acid with ethanol (95%). 
14 Safety 
Ethylparaben and other parabens are widely used as antimicrobial 
preservatives in cosmetics, food products, and oral 
and topical pharmaceutical formulations. 
Systemically, no adverse reactions to parabens have been 
reported, although they have been associated with hypersensitivity 
reactions. Parabens, in vivo, have also been reported to 
exhibit estrogenic responses in fish.(10) The WHO has set an 
estimated total acceptable daily intake for methyl-, ethyl-, and 
propylparabens at up to 10 mg/kg body-weight.(11) 
LD50 (mouse, IP): 0.52 g/kg(12) 
LD50 (mouse, oral): 3.0 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Ethylparaben may be irritant 
to the skin, eyes, and mucous membranes and should be 
handled in a well ventilated environment. Eye protection, 
gloves, and a dust mask or respirator are recommended. 
16 Regulatory Status 
Accepted as a food additive in Europe. Included in the FDA 
Inactive Ingredients Guide (oral, otic, and topical preparations). 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Butylparaben; ethylparaben potassium; ethylparaben sodium; 
methylparaben; propylparaben. 
Ethylparaben potassium 
Empirical formula: C9H9KO3 
Molecular weight: 204.28 
CAS number: [36547-19-9] 
Synonyms: ethyl 4-hydroxybenzoate potassium salt; potassium 
ethyl hydroxybenzoate. 
Ethylparaben sodium 
Empirical formula: C9H9NaO3 
Molecular weight: 188.17 
CAS number: [35285-68-8] 
Synonyms: E215; ethyl 4-hydroxybenzoate sodium salt; 
sodium ethyl hydroxybenzoate. 
18 Comments 
See Methylparaben for further information. 
The EINECS number for ethylparaben is 204-399-4. 
19 Specific References 
1 Rastogi SC, Schouten A, de Kruijf N, Weijland JW. Contents of 
methyl-, ethyl-, propyl-, butyl- and benzylparaben in cosmetic 
products. Contact Dermatitis 1995; 32(1): 28–30. 
2 Haag TE, Loncrini DF. In: Kabara JJ, ed. Cosmetic and Drug 
Preservation. New York: Marcel Dekker, 1984: 63–77. 
3 Wan LSC, Kurup TRR, Chan LW. Partition of preservatives in oil/ 
water systems. Pharm Acta Helv 1986; 61(10–11): 308–313. 
4 Aalto TR, Firman MC, Rigler NE. p-Hydroxybenzoic acid esters 
as preservatives I: uses, antibacterial and antifungal studies, 
properties and determination. J Am Pharm Assoc (Sci) 1953; 42: 
449–457. 
5 Kamada A, Yata N, Kubo K, Arakawa M. Stability of phydroxybenzoic 
acid esters in acidic medium. Chem Pharm Bull 
1973; 21: 2073–2076. 
6 Aoki M, Kameta A, Yoshioka I, Matsuzaki T. Application of 
surface active agents to pharmaceutical preparations I: effect of 
Tween 20 upon the antifungal activities of p-hydroxybenzoic acid 
esters in solubilized preparations [in Japanese]. J Pharm Soc Jpn 
1956; 76: 939–943. 
7 Daniels R, Rupprecht H. Effect of coadsorption on sorption and 
release of surfactant paraben mixtures from silica dispersions. Acta 
Pharm Technol 1985; 31: 236–242. 
8 Sakamoto T, Yanagi M, Fukushima S, Mitsui T. Effects of some 
cosmetic pigments on the bactericidal activities of preservatives. J 
Soc Cosmet Chem 1987; 38: 83–98. 
9 Allwood MC. The adsorption of esters of p-hydroxybenzoic acid 
by magnesium trisilicate. Int J Pharm 1982; 11: 101–107. 
10 Pedersen KL, Pedersen SN, Christiansen LB, et al. The preservatives 
ethyl-, propyl-, and butylparaben are oestrogenic in an in vivo 
fish assay. Pharmacol Toxicol 2000; 86(3): 110–113. 
11 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications. 
Seventeenth report of the FAO/WHO expert committee on food 
additives. World Health Organ Tech Rep Ser 1974; No. 539. 
12 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2003–2004. 
20 General References 
Golightly LK, Smolinske SS, Bennett ML, et al. Pharmaceutical 
excipients: adverse effects associated with inactive ingredients in 
drug products (part I). Med Toxicol 1988; 3: 128–165. 
21 Authors 
R Johnson, R Steer. 
22 Date of Revision 
23 August 2005. 
Ethylparaben 289

Fructose 
1 Nonproprietary Names 
BP: Fructose 
JP: Fructose 
PhEur: Fructosum 
USP: Fructose 
2 Synonyms 
Advantose FS 95; Fructamyl; D-(–)-fructopyranose; b-D-fructose; 
fruit sugar; Krystar; laevulose; levulose. 
3 Chemical Name and CAS Registry Number 
D-Fructose [57-48-7] 
4 Empirical Formula and Molecular Weight 
C6H12O6 180.16 
5 Structural Formula 
See Section 18. 
6 Functional Category 
Dissolution enhancer; flavor enhancer; sweetening agent; tablet 
diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Fructose is used in tablets, syrups, and solutions as a flavoring 
and sweetening agent. 
The sweetness-response profile of fructose is perceived in the 
mouth more rapidly than that of sucrose and dextrose, which 
may account for the ability of fructose to enhance syrup or 
tablet fruit flavors and mask certain unpleasant vitamin or 
mineral ‘off-flavors’. 
The increased solubility of fructose in comparison to sucrose 
is advantageous in syrup or solution formulations that must be 
refrigerated, since settling or crystallization of ingredients is 
retarded. Similarly, the greater solubility and hygroscopicity of 
fructose over sucrose and dextrose helps to avoid ‘cap-locking’ 
(sugar crystallization around the bottle cap) in elixir preparations. 
Fructose also has greater solubility in ethanol (95%) and 
is therefore used to sweeten alcoholic formulations. 
The water activity of a sweetener influences product 
microbial stability and freshness. Fructose has a lower water 
activity and a higher osmotic pressure than sucrose. Syrup 
formulations may be made at lower dry-substance levels than 
sugar syrups without compromising shelf-life stability. It may 
be necessary to include a thickener or gelling agent to match the 
texture or viscosity of the sugar-equivalent formulation. 
Fructose is sweeter than the sugar alcohols mannitol and 
sorbitol, which are commonly used as tableting excipients. 
Although fructose is effective at masking unpleasant flavors in 
tablet formulations, tablets of satisfactory hardness and 
friability can only be produced by direct compression if tablet 
presses are operated at relatively slow speeds. However, by the 
combination of crystalline fructose with tablet-grade sorbitol in 
a 3 : 1 ratio, satisfactory direct-compression characteristics can 
be achieved. A directly compressible grade of fructose, 
containing a small amount of starch (Advantose FS 95, SPI 
Pharma) is also commercially available. Pregranulation of 
fructose with 3.5% povidone also produces a satisfactory tablet 
excipient.(1) The added sweetness of fructose may also be used 
to advantage by coating the surface of chewable tablets, 
lozenges, or medicinal gums with powdered fructose. 
The coprecipitation of fructose with hydrophobic drugs 
such as digoxin has been shown to enhance the dissolution 
profile of such drugs. Fructose apparently acts as a watersoluble 
carrier upon coprecipitation, thereby allowing hydrophobic 
drugs to be more readily wetted.(2) 
8 Description 
Fructose occurs as odorless, colorless crystals or a white 
crystalline powder with a very sweet taste. 
9 Pharmacopeial Specifications 
See Table I. 
10 Typical Properties 
Acidity/alkalinity: pH = 5.35 (9% w/v aqueous solution) 
Angle of repose: 38.88 for Advantose FS 95 
Density: 1.58 g/cm3. See also Table II. 
Heat of combustion: 15.3 kJ/g (3.66 kcal/g) 
Heat of solution: 50.2 kJ/g (12 kcal/g) 
Hygroscopicity: at 258C and relative humidities above 
approximately 60%, fructose absorbs significant amounts 
of moisture; see Figure 1. 
Melting point: 102–1058C (with decomposition) 
Osmolarity: a 5.05% w/v aqueous solution is isoosmotic with 
serum. 
Particle size distribution: the average particle size of standardgrade 
crystalline fructose is 170–450 mm. The average 
particle size of powdered fructose is 25–40 mm. 
Refractive index: see Table II. 
Solubility: see Table III. 
Specific rotation [a]D
20: 1328 to 928 (2% w/v aqueous 
solution). Note that fructose shows rapid and anomalous 
mutarotation involving pyranose–furanose interconversion.

The final value may be obtained in the presence of 
hydroxide ions. See also Section 18. 
Viscosity (dynamic): see Table II. 
Table I: Pharmacopeial specifications for fructose. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters — . — 
Color of solution . . . 
Acidity . . . 
pH 4.0–6.5 — — 
Specific optical rotation — –91.08 to –93.58 — 
Foreign sugars — . — 
Loss on drying 40.5% — 40.5% 
Residue on ignition 40.1% 40.1% 40.5% 
Chloride 40.018% — 40.018% 
Sulfate 40.024% — 40.025% 
Sulfite . — — 
Water — 40.5% — 
Arsenic 41.3 ppm — 41 ppm 
Barium — . — 
Calcium and magnesium 
(as calcium) 
. — 40.005% 
Lead — 40.5 ppm — 
Heavy metals 44 ppm — 45 ppm 
Hydroxymethylfurfural . . . 
Assay (dried basis) 598.0% — 98.0–102.0% 
Table II: Physical properties of aqueous fructose solutions at 208C. 
Concentration of aqueous 
fructose solution (% w/w) 
Density 
(g/cm3) 
Refractive 
index 
Viscosity, 
dynamic (mPa s) 
10 1.04 1.3477 1.35 
20 1.08 1.3633 1.80 
30 1.13 1.3804 2.90 
40 1.18 1.3986 5.60 
50 1.23 1.4393 34.0 
60 1.29 1.4853 309.2 
Table III: Solubility of fructose. 
Solvent Solubility at 208C 
Ethanol (95%) 1 in 15 
Methanol 1 in 14 
Water 1 in 0.3 
11 Stability and Storage Conditions 
Fructose is hygroscopic and absorbs significant amounts of 
moisture at relative humidities greater than 60%. Goods stored 
in the original sealed packaging at temperatures below 258C 
and a relative humidity of less than 60% can be expected to 
retain stability for at least 12 months. 
Aqueous solutions are most stable at pH 3–4 and 
temperatures of 4–708C; they may be sterilized by autoclaving. 
12 Incompatibilities 
Incompatible with strong acids or alkalis, forming a brown 
coloration. In the aldehyde form, fructose can react with 
amines, amino acids, peptides, and proteins. Fructose may 
cause browning of tablets containing amines. 
13 Method of Manufacture 
Fructose, a monosaccharide sugar, occurs naturally in honey 
and a large number of fruits. It may be prepared from inulin, 
dextrose, or sucrose by a number of methods. Commercially, 
fructose is mainly manufactured by crystallization from highfructose 
syrup derived from hydrolyzed and isomerized cereal 
starch or cane and beet sugar. 
Figure 1: Equilibrium moisture content of fructose at 258C. 
14 Safety 
Although it is absorbed more slowly than dextrose from the 
gastrointestinal tract, fructose is metabolized more rapidly. 
Metabolism of fructose occurs mainly in the liver, where it is 
converted partially to dextrose and the metabolites lactic acid 
and pyruvic acid. Entry into the liver and subsequent 
phosphorylation is insulin-independent. Further metabolism 
occurs by way of a variety of metabolic pathways. In healthy 
and well regulated diabetics, glycogenesis (glucose stored as 
glycogen) predominates. 
Excessive oral fructose consumption (>75 g daily) in the 
absence of dietary dextrose in any form (e.g., sucrose, starch, 
dextrin, etc.) may cause malabsorption in susceptible individuals, 
which may result in flatulence, abdominal pain, and 
diarrhea. Except in patients with hereditary fructose intolerance,(
3,4) there is no evidence to indicate that oral fructose 
intake at current levels is a risk factor in any particular disease, 
other than dental caries.(5) 
See also Section 18. 
Fructose 291

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Fructose may be irritant to 
the eyes. Eye protection and gloves are recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral solutions 
and suspensions; rectal preparations). Included in the Canadian 
List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Dextrose; high-fructose syrup; liquid fructose; powdered 
fructose; sucrose. 
High-fructose syrup 
Comments: a syrup most commonly containing 42% or 55% 
fructose, with the remainder consisting of dextrose and 
small amounts of oligosaccharides. It is a colorless, odorless, 
highly viscous syrup with a sweet taste. 
Liquid fructose 
Comments: a syrup containing 599.5% fructose, made by 
solubilizing crystalline fructose in water. It is a colorless, 
odorless, highly viscous syrup with a sweet taste. 
Powdered fructose 
Comments: finely ground crystalline fructose containing 42% 
silicon dioxide as a glidant. 
18 Comments 
Fructose can occur in both the furanose and pyranose forms. 
Fructose present in natural products occurs in the furanose 
form, while that produced by crystallization occurs in the 
pyranose form. An aqueous solution at 208C contains about 
20% of the furanose form. 
Although fructose has been proposed for use in the diabetic 
diet, it is not regarded as a suitable source of carbohydrate, 
although it does have value as a sweetening agent.(6) The British 
Diabetic Association has recommended that intake of fructose 
be limited to 25 g daily.(7) 
Fructose has been used as an alternative to dextrose in 
parenteral nutrition, but its use is not recommended by some 
because of the risk of lactic acidosis. Although popular in many 
countries, it has therefore been suggested that the use of 
intravenous infusions containing fructose and sorbitol should 
be abandoned.(4,8) 
Fructose is the sweetest of all sugars; see Table IV. A 
specification for fructose is contained in the Food Chemicals 
Codex (FCC). 
The EINECS number for fructose is 200-333-3. 
Table IV: Relative sweetness of fructose and other sugars. 
Sugar Relative sweetness at 258C 
(10% solids) 
Fructose 117 
Sucrose 100 
High fructose syrup-55 99 
High fructose syrup-42 92 
Dextrose 65 
19 Specific References 
1 Osberger TF. Tableting characteristics of pure crystalline fructose. 
Pharm Technol 1979; 3(6): 81–86. 
2 Ahmed SU, Madan PL. Evaluation of the in vitro release profile of 
digoxin from drug-carbohydrate coprecipitates. Drug Dev Ind 
Pharm 1991; 17: 831–842. 
3 Cox TM. An independent diagnosis: a treatable metabolic disorder 
diagnosed by molecular analysis of human genes. Br Med J 1990; 
300: 1512–1514. 
4 Collins J. Metabolic disease. Time for fructose solutions to go. 
Lancet 1993; 341: 600. 
5 Glinsman WH, Irausquin H, Park YK. Evaluation of Health 
Aspects of Sugars Contained in Carbohydrate Sweeteners: Report 
of Sugars Task Force. Washington, DC: Health and Human 
Services Center for Food Safety and Applied Nutrition, Food and 
Drug Administration, 1986. 
6 Anonymous. Has fructose a place in the diabetic diet? Drug Ther 
Bull 1980; 18(17): 67–68. 
7 Clarke BP. Is it harmful to a juvenile diabetic to substitute sorbitol 
and fructose for ordinary sugar? Br Med J 1987; 294: 422. 
8 Sweetman SC, ed. Martindale: The Complete Drug Reference, 
34th edn. London: Pharmaceutical Press, 2005: 1431–1432. 
20 General References 
Muldering KB. Placebo evaluation of selected sugar-based excipients in 
pharmaceutical and nutraceutical tableting. Pharm Technol 2000; 
24(5): 34, 36, 38, 40, 42, 44. 
21 Authors 
SC Owen. 
22 Date of Revision 
19 August 2005. 
292 Fructose

Fumaric Acid 
1 Nonproprietary Names 
USPNF: Fumaric acid 
2 Synonyms 
Allomaleic acid; allomalenic acid; boletic acid; butenedioic 
acid; E297; 1,2-ethenedicarboxylic acid; lichenic acid; transbutenedioic 
acid; NSC-2752; trans-1,2-ethylenedicarboxylic 
acid; U-1149; USAF EK-P-583. 
3 Chemical Name and CAS Registry Number 
(E)-2-Butenedioic acid [110-17-8] 
4 Empirical Formula and Molecular Weight 
C4H4O4 116.07 
5 Structural Formula 
6 Functional Category 
Acidulant; antioxidant; flavoring agent; therapeutic agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Fumaric acid is used primarily in liquid pharmaceutical 
preparations as an acidulant and flavoring agent. Fumaric 
acid may be included as the acid part of effervescent tablet 
formulations, although this use is limited as the compound has 
an extremely low solubility in water. It is also used as a 
chelating agent which exhibits synergism when used in 
combination with other true antioxidants. 
In the design of novel pelletized formulations manufactured 
by extrusion–spheronization, fumaric acid was used to aid 
spheronization, favoring the production of fine pellets.(1) It has 
also been investigated as an alternative filler to lactose in 
pellets.(2) 
Fumaric acid has been investigated as a lubricant for 
effervescent tablets(3) and copolymers of fumaric acid and 
sebacic acid have been investigated as bioadhesive microspheres.(
4) It has been used in film-coated pellet formulations as 
an acidifying agent and also to increase drug solubility.(5) 
Fumaric acid is also used as a food additive at concentrations 
up to 3600 ppm, and as a therapeutic agent in the 
treatment of psoriasis and other skin disorders.(6) 
8 Description 
Fumaric acid occurs as white, odorless or nearly odorless, 
granules or as a crystalline powder that is virtually nonhygroscopic. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for fumaric acid. 
Test USPNF 23 
Identification . 
Water 40.5% 
Residue on ignition 40.1% 
Heavy metals 40.001% 
Maleic acid 40.1% 
Organic volatile impurities . 
Assay (dried basis) 99.5–100.5% 
10 Typical Properties 
Acidity/alkalinity: 
pH = 2.45 (saturated aqueous solution at 208C); 
pH = 2.58 (0.1% w/v aqueous solution at 258C); 
pH = 2.25 (0.3% w/v aqueous solution at 258C); 
pH = 2.15 (0.5% w/v aqueous solution at 258C). 
Density: 1.635 g/cm3 at 208C 
Density (bulk): 0.77 g/cm3 
Density (tapped): 0.93 g/cm3 
Dissociation constant: 
pKa1 = 3.03 at 258C; 
pKa2 = 4.54 at 258C. 
Melting point: 2878C (closed capillary, rapid heating); partial 
carbonization and formation of maleic anhydride occur at 
2308C (open vessel); sublimes at 2008C. 
Boiling point: 2908C (sealed tube) 
Solubility: see Table II. 
11 Stability and Storage Conditions 
Fumaric acid is stable although it is subject to degradation by 
both aerobic and anaerobic microorganisms. When heated in 
sealed vessels with water at 150–1708C it forms (
)-malic acid. 
The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Fumaric acid undergoes reactions typical of an organic acid.

Table II: Solubility of fumaric acid. 
Solvent Solubility at 208C 
unless otherwise stated 
Acetone 1 in 58 at 308C 
Benzene Very slightly soluble 
Carbon tetrachloride Very slightly soluble 
Chloroform Very slightly soluble 
Ethanol 1 in 28 
Ethanol (95%) 1 in 17 at 308C 
Ether Slightly soluble 
1 in 139 at 258C 
Olive oil Very slightly soluble 
Propylene glycol 1 in 33 
Water 1 in 200 
1 in 432 at 08C 
1 in 303 at 108C 
1 in 159 at 258C 
1 in 94 at 408C 
1 in 42 at 608C 
1 in 10 at 1008C 
13 Method of Manufacture 
Commercially, fumaric acid may be prepared from glucose by 
the action of fungi such as Rhizopus nigricans, as a by-product 
in the manufacture of maleic and phthalic anhydrides, and by 
the isomerization of maleic acid using heat or a catalyst. 
On the laboratory scale, fumaric acid can be prepared by the 
oxidation of furfural with sodium chlorate in the presence of 
vanadium pentoxide. 
14 Safety 
Fumaric acid is used in oral pharmaceutical formulations and 
food products and is generally regarded as a relatively nontoxic 
and nonirritant material. However, acute renal failure and 
other adverse reactions have occurred following the topical and 
systemic therapeutic use of fumaric acid and fumaric acid 
derivatives in the treatment of psoriasis or other skin 
disorders.(6) Other adverse effects of oral therapy have included 
disturbances of liver function, gastrointestinal effects, and 
flushing.(6) 
The WHO has stated that the establishment of an estimated 
acceptable daily intake of fumaric acid or its salts was 
unnecessary since it is a normal constituent of body tissues.(7) 
LD50 (mouse, IP): 0.1 g/kg(8) 
LD50 (rat, oral): 9.3 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Fumaric acid may be 
irritating to the skin, eyes, and respiratory system and should 
be handled in a well-ventilated environment. Gloves and eye 
protection are recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral capsules, 
suspensions, syrups, extended release and sustained action 
chewable tablets). Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Citric acid monohydrate; malic acid; tartaric acid. 
18 Comments 
A specification for fumaric acid is contained in the Food 
Chemical Codex (FCC). 
The EINECS number for fumaric acid is 203-743-0. 
19 Specific References 
1 Law MFL, Deasy PB. Effect of common classes of excipients on 
extrusion-spheronization. J Microencapsul 1997; 14(5): 647–657. 
2 Bianchini R, Bruni G, Gazzaniga A, Vecchio C. Influence of 
extrusion-spheronization processing on the physical properties of 
d-indobufen pellets containing pH adjusters. Drug Dev Ind Pharm 
1992; 18(14): 1485–1503. 
3 Ro. scheisen G, Schmidt PC. The combination of factorial design 
and simplex method in the optimization of lubricants for 
effervescent tablets. Eur J Pharm Biopharm 1995; 41(5): 302–308. 
4 Chickering DE, Mathiowitz E. Bioadhesive microspheres: I. A 
novel electrobalance-based method to study adhesive interactions 
between individual microspheres and intestinal mucosa. J Control 
Release 1995; 34: 251–262. 
5 Munday DL. Film coated pellets containing verapamil hydrochloride: 
enhanced dissolution into neutral medium. Drug Dev Ind 
Pharm 2003; 29(5): 575–583. 
6 Sweetman SC, ed. Martindale: The Complete Drug Reference, 
34th edn. London: Pharmaceutical Press, 2005: 1147. 
7 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirty-fifth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1990; No. 
789. 
8 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1828. 
20 General References 
Allen LV. Featured excipient: flavor-enhancing agents. Int J Pharm 
2003; 7(1): 48–50. 
Malic and fumaric acids. Manuf Chem Aerosol News 1964; 35(12): 
56–59. 
Robinson WD, Mount RA. In: Kirk-Othmer Encyclopedia of Chemical 
Technology, vol. 14; 3rd edn. New York: Wiley-Interscience, 1981: 
770–793. 
21 Authors 
SC Owen. 
22 Date of Revision 
12 August 2005. 
294 Fumaric Acid

Gelatin 
1 Nonproprietary Names 
BP: Gelatin 
JP: Gelatin 
PhEur: Gelatina 
USPNF: Gelatin 
2 Synonyms 
Byco; Cryogel; gelatine; Instagel; Solugel. 
3 Chemical Name and CAS Registry Number 
Gelatin [9000-70-8] 
4 Empirical Formula and Molecular Weight 
Gelatin is a generic term for a mixture of purified protein 
fractions obtained either by partial acid hydrolysis (type A 
gelatin) or by partial alkaline hydrolysis (type B gelatin) of 
animal collagen. Gelatin may also be a mixture of both types. 
The protein fractions consist almost entirely of amino acids 
joined together by amide linkages to form linear polymers, 
varying in molecular weight from 15 000–250 000. 
The JP 2001 also includes a monograph for purified gelatin. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Coating agent; film-former; gelling agent; suspending agent; 
tablet binder; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Gelatin is widely used in a variety of pharmaceutical formulations, 
including its use as a biodegradable matrix material in an 
implantable delivery system,(1) although it is most frequently 
used to form either hard or soft gelatin capsules.(2–4) 
Gelatin capsules are unit-dosage forms that are filled with an 
active drug and are generally designed for oral administration. 
Although gelatin is poorly soluble in cold water, a gelatin 
capsule will swell in gastric fluid to rapidly release its contents. 
Hard capsules are manufactured in two pieces by dipping 
stainless steel pins into a gelatin solution, which is distributed 
evenly around the pin. The gelatin is then set with a blast of 
chilled air and dried to remove moisture. The capsule halves are 
then removed, trimmed and filled before they are joined and 
closed with a tamper-evident seal. The USPNF 23 permits 
gelatin that is used to produce hard capsules to contain various 
coloring agents, antimicrobial preservatives, and sodium lauryl 
sulfate. Manufacturers may also add a hardening agent, such as 
sucrose, to hard gelatin capsules. Capsules varying in size from 
0.13 to 1.37mL volume are commercially available. 
Soft gelatin capsules are formed from an aqueous gelatin 
solution that contains a plasticizer such as glycerin or sorbitol. 
Two soft gelatin strips are formed that run between suitable 
dies. As the dies meet, capsules are formed by injecting the 
filling material, followed by the capsule halves being sealed 
together. 
Gelatin is also used for the microencapsulation of drugs, 
where the active drug is sealed inside a microsized capsule 
or beadlet, which may then be handled as a powder. The 
first microencapsulated drugs (beadlets) were fish oils and 
oily vitamins in gelatin beadlets prepared by an emulsion 
process. 
Low-molecular-weight gelatin has been investigated for its 
ability to enhance the dissolution of orally ingested drugs.(5) 
Ibuprofen–gelatin micropellets have been prepared for the 
controlled release of the drug.(6) Other uses of gelatin include 
the preparation of pastes, pastilles, pessaries, and suppositories. 
In addition, it is used as a tablet binder and coating 
agent, and as a viscosity-increasing agent for solutions and 
semisolids. 
Therapeutically, gelatin has been used in the preparation of 
wound dressings(7) and has been used as a plasma substitute, 
although anaphylactoid reactions have been reported in the 
latter application.(8) Absorbable gelatin is available as sterile 
film, ophthalmic film, sterile sponge, sterile compressed sponge, 
and sterile powder from sponge. Gelatin sponge has hemostatic 
properties. 
Gelatin is also widely used in food products and photographic 
emulsions. 
8 Description 
Gelatin occurs as a light-amber to faintly yellow-colored, 
vitreous, brittle solid. It is practically odorless and tasteless and 
is available as translucent sheets and granules, or as a powder. 
9 Pharmacopeial Specifications 
See Table I. 
10 Typical Properties 
Acidity/alkalinity: for a 1% w/v aqueous solution at 258C: 
pH = 3.8–6.0 (type A); 
pH = 5.0–7.4 (type B). 
Density: 
1.325 g/cm3 for type A; 
1.283 g/cm3 for type B. 
Isoelectric point: 
7–9 for type A; 
4.7–5.3 for type B. 
Moisture content: 9–11%.(9) See also Figures 1 and 2.

Table I: Pharmacopeial specifications for gelatin. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters — . — 
Microbial contamination — 41000/g . 
Residue on ignition 42.0% — 42.0% 
Loss on drying 415.0% 415.0% — 
Odor and water-insoluble 
substances 
— — . 
Isoelectric point . . . 
Type A 7.0–9.0 6.0–9.5 — 
Type B 4.5–5.0 4.7–5.6 — 
Conductivity — 41 mS/cm — 
Sulfur dioxide — 450 ppm 40.15% 
Sulfite . — — 
Arsenic 41 ppm — 40.8 ppm 
Iron — 430 ppm — 
Chromium — 410 ppm — 
Zinc — 430 ppm — 
Heavy metals 450 ppm 450 ppm 450 ppm 
pH — 3.8–7.6 — 
Mercury 40.1 ppm — — 
Peroxides — 410 ppm — 
Phenolic preservatives — . — 
Gel strength — . — 
Figure 1: Equilibrium moisture content of gelatin (Pharmagel A). 
Solubility: practically insoluble in acetone, chloroform, ethanol 
(95%), ether, and methanol. Soluble in glycerin, acids, and 
alkalis, although strong acids or alkalis cause precipitation. 
In water, gelatin swells and softens, gradually absorbing 
between five and 10 times its own weight of water. Gelatin is 
soluble in hot water, forming a jelly, or gel, on cooling to 
35–408C. At temperatures >408C, the system exists as a sol. 
This gel–sol system is heat-reversible, the melting temperature 
being slightly higher than the setting point; the melting 
point can be varied by the addition of glycerin. 
Figure 2: Sorption–desorption isotherm of gelatin. 
Viscosity (dynamic): 
4.3–4.7 mPa s (4.3–4.7 cP) for a 6.67% w/v aqueous 
solution at 608C; 
18.5–20.5 mPa s (18.5–20.5 cP) for a 12.5% w/v aqueous 
solution at 608C. 
11 Stability and Storage Conditions 
Dry gelatin is stable in air. Aqueous gelatin solutions are also 
stable for long periods if stored under cool, sterile conditions. 
At temperatures above about 508C, aqueous gelatin solutions 
may undergo slow depolymerization and a reduction in gel 
strength may occur on resetting. Depolymerization becomes 
more rapid at temperatures above 658C, and gel strength may 
be reduced by half when a solution is heated at 808C for 1 hour. 
The rate and extent of depolymerization depends on the 
molecular weight of the gelatin, with a lower-molecular-weight 
material decomposing more rapidly.(10) 
Gelatin may be sterilized by dry heat. 
The bulk material should be stored in an airtight container 
in a cool, dry place. 
12 Incompatibilities 
Gelatin is an amphoteric material and will react with both acids 
and bases. It is also a protein and thus exhibits chemical 
properties characteristic of such materials; for example, gelatin 
may be hydrolyzed by most proteolytic systems to yield its 
amino acid components. 
Gelatin will also react with aldehydes and aldehydic sugars, 
anionic and cationic polymers, electrolytes, metal ions, 
plasticizers, preservatives, and surfactants. It is precipitated 
by alcohols, chloroform, ether, mercury salts, and tannic acid. 
Gels can be liquefied by bacteria unless preserved. 
Some of these interactions are exploited to favorably alter 
the physical properties of gelatin; for example, gelatin is mixed 
with a plasticizer, such as glycerin, to produce soft gelatin 
capsules and suppositories; see Section 7. 
296 Gelatin

13 Method of Manufacture 
Gelatin is extracted from animal tissues rich in collagen such as 
skin, sinews, and bone. Although it is possible to extract gelatin 
from these materials using boiling water, it is more practical to 
first pretreat the animal tissues with either acid or alkali. 
Gelatin obtained from the acid process is called type A, whereas 
gelatin obtained from the alkali process is called type B. 
In the USA, most type A gelatin is obtained from pig skins. 
This material is washed in cold water for a few hours to remove 
extraneous matter and is then digested in dilute mineral acid 
(HCl, H2SO4, H2SO3, or H3PO4) at pH 1–3 and 15–208C until 
maximum swelling has occurred. This process takes approximately 
24 hours. The swollen stock is then washed with water 
to remove excess acid, and the pH is adjusted to pH 3.5–4.0 for 
the conversion to gelatin by hot-water extraction. 
The hydrolytic extraction is carried out in a batch-type 
operation using successive portions of hot water at progressively 
higher temperatures until the maximum yield of gelatin is 
obtained. The gelatin solution is then chilled to form jelled 
sheets, which are dried in temperature-controlled ovens. The 
dried gelatin is ground to the desired particle size. 
In the alkali process, demineralized bones (ossein) or cattle 
skins are usually used. The animal tissue is held in a calcium 
hydroxide (lime) slurry for a period of 1–3 months at 15–208C. 
At the end of the liming, the stock is washed with cold water to 
remove as much of the lime as possible. The stock solution is 
then neutralized with acid (HCl, H2SO4, H3PO4) and the 
gelatin is extracted with water in an identical manner to that in 
the acid process. 
During the preparation of the bovine bones used in the 
production of gelatin, specified risk materials that could 
contain Transmissible Spongiform Encephalopathies (TSEs) 
vectors are removed. TSE infectivity is not present in 
pharmaceutical grade gelatin. 
14 Safety 
Gelatin is widely used in a variety of pharmaceutical formulations 
including oral and parenteral products. 
In general, when used in oral formulations gelatin may be 
regarded as a nontoxic and nonirritant material. However, 
there have been rare reports of gelatin capsules adhering to the 
esophageal lining, which may cause local irritation.(11) Hypersensitivity 
reactions, including serious anaphylactoid reactions, 
have been reported following the use of gelatin in parenteral 
products.(8) 
There have been concerns over the potential spread of BSE/ 
TSE infections through bovine derived products. However, the 
risk of such contamination of medicines is extremely low, to the 
point of being theoretical. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. Gelatin should be handled in a well-ventilated 
environment. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (dental 
preparations; inhalations; injections; oral capsules, pastilles, 
solutions, syrups and tablets; topical and vaginal preparations). 
Included in medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
—
18 Comments 
In the past there has been a significant amount of regulatory 
activity due to the attention given to bovine sourced gelatin 
manufacturing processes and the potential transmission of TSE 
vectors from raw bovine materials into gelatin. In Europe the 
criteria by which the safety is assured involves controlling the 
geographical sourcing of animals used; the nature of the tissue 
used (based on scientific data showing where animal BSE 
infectivity is located); and the method of production. 
Gelatin produced with hides as the starting material is 
considered much safer than using bones, although it is 
recommended that measures are undertaken to prevent crosscontamination 
with potentially contaminated materials. When 
gelatin is produced from bones, the bones should ideally be 
produced from countries classified as Geographical BSE Risk 
(GBR) I and II, although bones from GBR III countries can be 
used if the removal of vertebrae from the raw materials is 
assured (see Table II).(12) 
Various grades of gelatin are commercially available that 
differ in particle size, molecular weight, and other properties. 
Grading is usually by gel strength, expressed as ‘Bloom 
strength’, which is the weight in grams that, when applied 
under controlled conditions to a plunger 12.7mm in diameter, 
will produce a depression exactly 4mm deep in a matured gel 
containing 6.66% w/w of gelatin in water. 
Gelatin–acacia complex coacervation has been used in the 
preparation of microcapsules of vitamin A.(13) Pindolol-loaded 
alginate–gelatin beads have been developed for the sustained 
release of pindolol.(14) 
A specification for gelatin is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for gelatin is 232-554-6. 
Table II: The European Scientific Steering Committee classification of 
geographical BSE risk (GBR). 
GBR level Presence of one or more cattle clinically or pre-clinically 
infected with BSE in a geographical region/country 
I Highly unlikely 
II Unlikely but not excluded 
III Likely but not confirmed or confirmed at a lower level 
IV Confirmed at a higher level 
19 Specific References 
1 Fan H, Dash AK. Effect of cross-linking on the in vitro release 
kinetics of doxorubicin from gelatin implants. Int J Pharm 2001; 
213: 103–116. 
2 Armstrong NA, James KC, Pugh WKL. Drug migration in soft 
gelatin capsules. J Pharm Pharmacol 1982; 34 (Suppl.): 5P. 
3 Tu J, Wang L, Yang J, et al. Formulation and pharmacokinetics 
studies of acyclovir controlled-release capsules. Drug Dev Ind 
Pharm 2001; 27(7): 687–692. 
4 Podczeck F, Jones BE, ed. Pharmaceutical Capsules, 2nd edn. 
London: Pharmaceutical Press, 2004. 
5 Kimura S, Imai T, Otagiri M. Evaluation of low-molecular gelatin 
as a pharmaceutical additive for rapidly absorbed oral dosage 
formulations. Chem Pharm Bull 1991; 39: 1328–1329. 
6 Tayade PT, Kale RD. Encapsulation of water insoluble drug by a 
cross-linking technique: Effect of process and formulation 
Gelatin 297

variables on encapsulation efficiency, particle size, and in vitro 
dissolution rate. AAPS PharmSci 2004; 6(1): E12. 
7 Thomas S. Wound Management and Dressings. London: Pharmaceutical 
Press, 1990. 
8 Blanloeil Y, Gunst JP, Spreux A, et al. Severe anaphylactoid 
reactions after infusion of modified gelatin solution [in French]. 
Therapie 1983; 38: 539–546. 
9 Callahan JC, Cleary GW, Elefant M, et al. Equilibrium moisture 
content of pharmaceutical excipients. Drug Dev Ind Pharm 1982; 
8: 355–369. 
10 Ling WC. Thermal degradation of gelatin as applied to processing 
of gel mass. J Pharm Sci 1978; 67: 218–223. 
11 Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation 
Agents: A Handbook of Excipients. New York: Marcel Dekker, 
1989: 121–123. 
12 The European Agency for the Evaluation of Medicinal Products: 
Evaluation of Medicines for Human Use. London, 9 Dec 2002: 
EMEA/410/01 Rev. 2. 
13 Junnyaprasert VB, Mitrevej A, Sinchaipanid N, et al. Effect of 
process variables on the micro-encapsulation of vitamin A 
palmitate by gelatin-acacia coacervation. Drug Dev Ind Pharm 
2001; 27(6): 561–566. 
14 Almeida PF, Almeida AJ. Cross-linked alginate–gelatin beads: A 
new matrix for controlled release of pindolol. J Control Release 
2004; 97(3): 431–439. 
20 General References 
Fassihi AR, Parker MS. Influence of gamma radiation on the gel rigidity 
index and binding capability of gelatin. J Pharm Sci 1988; 77: 876. 
Hawley AR, Rowley G, Lough WJ, Chatham S. Physical and chemical 
characterization of thermosoftened bases for molten filled hard 
gelatin capsule formulations. Drug Dev Ind Pharm 1992; 18: 1719– 
1739. 
Jones B. Two-piece gelatin capsules: excipients for powder products, 
European practice. Pharm Technol Eur 1995; 7(10): 25, 28, 29, 30, 
34. 
Jones RT. The role of gelatin in pharmaceuticals. Manuf Chem Aerosol 
News 1977; 48(7): 23–24. 
Matthews B. BSE/TSE risks associated with active pharmaceuticals 
ingredients and starting materials: Situation in Europe and the 
global implications for healthcare manufacturers. PDA J Pharm Sci 
Technol 2001; 55: 295–329. 
Nadkarni SR, Yalkowsky SH. Controlled delivery of pilocarpine 1: in 
vitro characterization of gelfoam matrices. Pharm Res 1993; 10: 
109–112. 
Ofner CM, Schott H. Swelling studies of gelatin II: effect of additives. J 
Pharm Sci 1987; 76: 715–723. 
Ramsay Olocco K, Alexandrova L, Nellare R, et al. Pre-clinical and 
clinical evaluation of solution and soft gelatin capsule formulations 
for a BCS class 3 compound with atypical physicochemical 
properties. J Pharm Sci 2004; 93(9): 2214–2221. 
Ray-Johnson ML, Jackson IM. Temperature-related incompatibility 
between gelatin and calcium carbonate in sugar-coated tablets. J 
Pharm Pharmacol 1976; 28: 309–310. 
Singh S, Rao KVR, Venugopal K, Manikandan R. Alteration in 
dissolution characteristics of gelatin-containing formulations: a 
review of the problem, test methods, and solutions. Pharm Technol 
2002; 26(4): 36–58. 
Voigt R,Werchan D. Radioinduced changes of the properties of gelatin 
[in German]. Pharmazie 1986; 41: 120–123. 
Ward AG, Courts A, eds. The Science and Technology of Gelatin. 
London: Academic Press, 1977. 
21 Authors 
JC Price. 
22 Date of Revision 
23 August 2005. 
298 Gelatin

Glucose, Liquid 
1 Nonproprietary Names 
BP: Liquid glucose 
PhEur: Glucosum liquidum 
USPNF: Liquid glucose 
2 Synonyms 
Corn syrup; C*PharmSweet; Flolys; Glucomalt; glucose syrup; 
Glucosweet; Mylose; Roclys; starch syrup. 
3 Chemical Name and CAS Registry Number 
Liquid glucose. 
4 Empirical Formula and Molecular Weight 
See Section 8. 
5 Structural Formula 
See Section 8. 
6 Functional Category 
Coating agent; sweetening agent; tablet binder. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Liquid glucose is used as a base in oral solutions and syrups and 
also as a granulating and coating agent in tablet manufacture. 
In sugar solutions for tablet coating, liquid glucose is used to 
retard the crystallization of the sucrose. Liquid glucose is also 
used in confectionery products. See Table I. 
Table I: Uses of liquid glucose. 
Use Concentration (%) 
Confectionery 20–60 
Granulating agent 5–10 
Oral syrup vehicle 20–60 
Tablet coating 10–20 
8 Description 
Liquid glucose is an aqueous solution of several compounds, 
principally dextrose, dextrin, fructose, and maltose, with other 
oligosaccharides and polysaccharides. It is a colorless, odorless, 
and viscous sweet-tasting liquid, ranging in color from colorless 
to straw-colored. 
Liquid glucose is classified into four categories according to 
its degree of hydrolysis, expressed as dextrose equivalent (DE): 
Type I: 20–38 DE; 
Type II: 38–58 DE; 
Type III: 58–73 DE; 
Type IV: >73 DE. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for liquid glucose. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Acidity — . 
pH 4.0–6.0 — 
Water 430.0% 421.0% 
Residue on ignition 40.5 % 40.5% 
Sulfur dioxide 420 ppm(a) — 
Dextrose equivalent 420.0% — 
Sulfite — . 
Heavy metals 410 ppm 40.001% 
Starch — . 
Organic volatile impurities — . 
Assay (of dried matter) 570.0% — 
(a) Or 4400 ppm if intended for the production of hard boiled candies, provided the final 
product contains 450 ppm. 
10 Typical Properties 
Density: 1.43 g/cm3 at 208C 
Solubility: miscible with water; partially miscible with ethanol 
(90%). 
Viscosity (dynamic): 13.0–14.5 mPa s (13.0–14.5 cP) at 218C. 
11 Stability and Storage Conditions 
Liquid glucose should be stored in a well-closed container in a 
cool, dry place. Elevated temperatures will cause discoloration. 
12 Incompatibilities 
Incompatible with strong oxidizing agents. 
13 Method of Manufacture 
Liquid glucose is prepared by the incomplete acidic or 
enzymatic hydrolysis of starch. 
14 Safety 
Liquid glucose is used in oral pharmaceutical formulations and 
confectionery products and is generally regarded as a nontoxic 
and nonirritant material. It may be consumed by diabetics. 
See also Dextrose. 
LD50 (mouse, IV): 9 g/kg(1) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled.

16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(oral solutions, syrups, and tablets; topical emulsions and gels). 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Dextrin; dextrose; maltose. 
18 Comments 
A specification for glucose syrup is contained in the Food 
Chemicals Codex (FCC). The PhEur 2005 also includes a 
specification for glucose, liquid, spraydried 
The EINECS number for glucose is 200-075-1. 
19 Specific References 
1 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1860–1861. 
20 General References 
Dziedzic SZ, Kearsley MW, eds. Glucose Syrups: Science and 
Technology. New York: Elsevier Applied Science, 1984. 
Hoynak RX, Bolcenback GN. This is Liquid Sugar, 2nd edn. Yonkers, 
NY: Refined Syrup and Sugars Inc., 1966: 205, 226. 
Inglett GE, ed. Symposium on Sweeteners. New York: AVI, 1974. 
21 Authors 
A Day. 
22 Date of Revision 
1 August 2005. 
300 Glucose, Liquid

Glycerin 
1 Nonproprietary Names 
BP: Glycerol 
JP: Concentrated glycerin 
PhEur: Glycerolum 
USP: Glycerin 
2 Synonyms 
Croderol; E422; glycerine; Glycon G-100; Kemstrene; Optim; 
Pricerine; 1,2,3-propanetriol; trihydroxypropane glycerol. 
3 Chemical Name and CAS Registry Number 
Propane-1,2,3-triol [56-81-5] 
4 Empirical Formula and Molecular Weight 
C3H8O3 92.09 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; emollient; humectant; plasticizer; 
solvent; sweetening agent; tonicity agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Glycerin is used in a wide variety of pharmaceutical formulations 
including oral, otic, ophthalmic, topical, and parenteral 
preparations; see Table I. 
In topical pharmaceutical formulations and cosmetics, 
glycerin is used primarily for its humectant and emollient 
properties. In parenteral formulations, glycerin is used mainly 
as a solvent.(1) 
In oral solutions, glycerin is used as a solvent, sweetening 
agent, antimicrobial preservative, and viscosity-increasing 
agent. It is also used as a plasticizer and in film coatings.(
2,3) Glycerin is additionally used in topical formulations 
such as creams and emulsions.(4) 
Glycerin is used as a plasticizer of gelatin in the production 
of soft-gelatin capsules and gelatin suppositories. 
Glycerin is employed as a therapeutic agent in a variety of 
clinical applications,(5) and is also used as a food additive. 
Table I: Uses of glycerin. 
Use Concentration (%) 
Antimicrobial preservative <20 
Emollient 430 
Humectant 430 
Ophthalmic formulations 0.5–3.0 
Plasticizer in tablet film coating Variable 
Solvent for parenteral formulations 450 
Sweetening agent in alcoholic elixirs 420 
8 Description 
Glycerin is a clear, colorless, odorless, viscous, hygroscopic 
liquid; it has a sweet taste, approximately 0.6 times as sweet as 
sucrose. 
9 Pharmacopeial Specifications 
See Table II. See also Section 18. 
Table II: Pharmacopeial specifications for glycerin. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters . . — 
Appearance of solution . . . 
Acidity or alkalinity . . — 
Refractive index 41.470 1.470–1.475 — 
Aldehydes — 410 ppm — 
Related substances — . — 
Halogenated compounds — 435 ppm — 
Limit of chlorinated 
compounds 
— — . 
Sugars — . — 
Chloride 40.001% 410 ppm 40.001% 
Heavy metals 45 ppm 45 ppm 45 mg/g 
Water — 42.0% 45.0% 
Sulfated ash 40.01% 40.01% 40.01% 
Specific gravity 51.258 — 51.249 
Sulfate 40.002% — 40.002% 
Esters — . — 
Ammonium . — — 
Calcium . — — 
Arsenic 42 ppm — — 
Acrolein, glucose or other 
reducing substances 
. — — 
Fatty acids and esters . . . 
Organic volatile 
impurities 
— — . 
Readily carbonizable 
substances 
. — — 
Assay 598.0% 98.0–101.0% 99.0–101.0%

10 Typical Properties 
Boiling point: 2908C (with decomposition) 
Density: 
1.2656 g/cm3 at 158C; 
1.2636 g/cm3 at 208C; 
1.2620 g/cm3 at 258C. 
Flash point: 1768C (open cup) 
Freezing point: see Table III. 
Hygroscopicity: hygroscopic. 
Melting point: 17.88C 
Osmolarity: a 2.6% v/v aqueous solution is isoosmotic with 
serum. 
Refractive index: 
nD
15 = 1.4758; 
nD
20 = 1.4746; 
nD
25 = 1.4730. 
Solubility: see Table IV. 
Specific gravity: see Table V. 
Surface tension: 63.4mN/m (63.4 dynes/cm) at 208C. 
Vapor density (relative): 3.17 (air = 1) 
Viscosity (dynamic): see Table VI. 
Table III: Freezing points of aqueous glycerin solutions. 
Concentration of aqueous 
glycerin solution (% w/w) 
Freezing point (8C) 
10.0 –1.6 
20.0 –4.8 
30.0 –9.5 
40.0 –15.4 
50.0 –23 
60.0 –34.7 
66.7 –46.5 
80.0 –20.3 
90.0 –1.6 
Table IV: Solubility of glycerin. 
Solvent Solubility at 208C 
Acetone Slightly soluble 
Benzene Practically insoluble 
Chloroform Practically insoluble 
Ethanol (95%) Soluble 
Ether 1 in 500 
Ethyl acetate 1 in 11 
Methanol Soluble 
Oils Practically insoluble 
Water Soluble 
Table V: Specific gravity of glycerin. 
Concentration of aqueous 
glycerin solution (% w/w) 
Specific gravity at 208C 
10 1.024 
20 1.049 
30 1.075 
40 1.101 
50 1.128 
60 1.156 
Table VI: Viscosity (dynamic) of aqueous glycerin solutions. 
Concentration of aqueous 
glycerin solution (% w/w) 
Viscosity at 208C (mPa s) 
5 1.143 
10 1.311 
25 2.095 
50 6.05 
60 10.96 
70 22.94 
83 111.0 
11 Stability and Storage Conditions 
Glycerin is hygroscopic. Pure glycerin is not prone to oxidation 
by the atmosphere under ordinary storage conditions but it 
decomposes on heating, with the evolution of toxic acrolein. 
Mixtures of glycerin with water, ethanol (95%), and propylene 
glycol are chemically stable. 
Glycerin may crystallize if stored at low temperatures; the 
crystals do not melt until warmed to 208C. 
Glycerin should be stored in an airtight container, in a cool, 
dry place. 
12 Incompatibilities 
Glycerin may explode if mixed with strong oxidizing agents 
such as chromium trioxide, potassium chlorate, or potassium 
permanganate. In dilute solution, the reaction proceeds at a 
slower rate with several oxidation products being formed. 
Black discoloration of glycerin occurs in the presence of light, 
or on contact with zinc oxide or basic bismuth nitrate. 
An iron contaminant in glycerin is responsible for the 
darkening in color of mixtures containing phenols, salicylates, 
and tannin. 
Glycerin forms a boric acid complex, glyceroboric acid, that 
is a stronger acid than boric acid. 
13 Method of Manufacture 
Glycerin is mainly obtained from oils and fats as a by-product 
in the manufacture of soaps and fatty acids. It may also be 
obtained from natural sources by fermentation of, for example, 
sugar beet molasses in the presence of large quantities of 
sodium sulfite. Synthetically, glycerin may be prepared by the 
chlorination and saponification of propylene. 
14 Safety 
Glycerin occurs naturally in animal and vegetable fats and oils 
that are consumed as part of a normal diet. Glycerin is readily 
absorbed from the intestine and is either metabolized to carbon 
dioxide and glycogen or used in the synthesis of body fats. 
Glycerin is used in a wide variety of pharmaceutical 
formulations including oral, ophthalmic, parenteral, and 
topical preparations. Adverse effects are mainly due to the 
dehydrating properties of glycerin.(5) 
Oral doses are demulcent and mildly laxative in action. 
Large doses may produce headache, thirst, nausea, and 
hyperglycemia. The therapeutic parenteral administration of 
very large glycerin doses, 70–80 g over 30–60 minutes in adults 
to reduce cranial pressure, may induce hemolysis, hemoglobinuria, 
and renal failure.(6) Slower administration has no 
deleterious effects.(7) 
302 Glycerin

Glycerin may also be used orally in doses of 1.0–1.5 g/kg 
body-weight to reduce intraocular pressure. 
When used as an excipient or food additive, glycerin is not 
usually associated with any adverse effects and is generally 
regarded as a nontoxic and nonirritant material. 
LD50 (guinea pig, oral): 7.75 g/kg(8) 
LD50 (mouse, IP): 8.98 g/kg 
LD50 (mouse, IV): 4.25 g/kg 
LD50 (mouse, oral): 4.1 g/kg 
LD50 (mouse, SC): 0.09 g/kg 
LD50 (rabbit, IV): 0.05 g/kg 
LD50 (rat, IP): 4.42 g/kg 
LD50 (rat, oral): 12.6 g/kg 
LD50 (rat, SC): 0.1 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. In the UK, the recommended long-term (8-hour 
TWA) exposure limit for glycerin mist is 10 mg/m3.(9) Glycerin 
is combustible and may react explosively with strong oxidizing 
agents; see Section 12. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (dental pastes; 
buccal preparations; inhalations; injections; nasal and ophthalmic 
preparations; oral capsules, solutions, suspensions and 
tablets; otic, rectal, topical, transdermal, and vaginal preparations). 
Included in nonparenteral and parenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
—
18 Comments 
The EINECS number for glycerin is 200-289-5. 
Some pharmacopeias also contain specifications for diluted 
glycerin solutions. The JP 2001 contains a monograph for 
‘glycerin’ that contains 84–87% of propane-1,2,3-triol 
(C3H8O3). The PhEur 2005 contains a monograph for ‘glycerol 
85 per cent’ that contains 83.5–88.5% of propane-1,2,3-triol 
(C3H8O3). A specification for glycerin is contained in the Food 
Chemicals Codex (FCC). 
19 Specific References 
1 Spiegel AJ, Noseworthy MM. Use of nonaqueous solvents in 
parenteral products. J Pharm Sci 1963; 52: 917–927. 
2 Kumar V, Kang J, Yang T. Preparation and characterization of 
spray-dried oxidized cellulose particles. Pharm Dev Technol 2001; 
6(3): 449–458. 
3 Palviainen P, Heinamaki J, Myllarinen P, et al. Corn starches as 
film formers in aqueous-based film coating. Pharm Dev Technol 
2001; 6(3): 353–361. 
4 Viegas TX, Van-Winkle LL, Lehman PA, et al. Evaluation of 
creams and ointments as suitable formulations for peldesine. Int J 
Pharm 2001; 219(1–2): 73–80. 
5 Sweetman SC, ed. Martindale: The Complete Drug Reference, 
34th edn. London: Pharmaceutical Press, 2005: 1694–1695. 
6 Ha.gnevik K, Gordon E, Lins LE, et al. Glycerol-induced 
haemolysis with haemoglobinuria and acute renal failure. Lancet 
1974; i: 75–77. 
7 Welch KMA, Meyer JS, Okamoto S, et al. Glycerol-induced 
haemolysis. Report of three cases. [letter]. Lancet 1974; i: 416– 
417. 
8 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1865. 
9 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
Grissom CB, Chagovetz AM, Wang Z. Use of viscosigens to stabilize 
vitamin B12 solutions against photolysis. J Pharm Sci 1993; 82(6): 
641–643. 
Jungermann E, Sonntag NOV, eds. Glycerine: A Key Cosmetic 
Ingredient. New York: Marcel Dekker, 1991. 
Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 199–204. 
Staples R, Misher A, Wardell J. Gastrointestinal irritant effect of 
glycerin as compared with sorbitol and propylene glycol in rats and 
dogs. J Pharm Sci 1967; 56: 398–400. 
21 Authors 
JC Price. 
22 Date of Revision 
24 August 2005. 
Glycerin 303

Glyceryl Behenate 
1 Nonproprietary Names 
BP: Glycerol dibehenate 
PhEur: Glyceroli dibehenas 
USPNF: Glyceryl behenate 
2 Synonyms 
Compritol 888 ATO; 2,3-dihydroxypropyl docosanoate; docosanoic 
acid, 2,3-dihydroxypropyl ester; E471; glycerol behenate; 
glyceryl monobehenate. 
Note that tribehenin is used as a synonym for glyceryl 
tribehenate. 
3 Chemical Name and CAS Registry Number 
Docosanoic acid, monoester with glycerin [30233-64-8] 
(glyceryl behenate) 
Docosanoic acid, diester with glycerin [94201-62-4] (glyceryl 
dibehenate) 
Docosanoic acid, triester with glycerin [18641-57-1] (glyceryl 
tribehenate) 
4 Empirical Formula and Molecular Weight 
The PhEur 2005 (Suppl. 5.1) describes glyceryl dibehenate as a 
mixture of diacylglycerols, mainly dibehenoylglycerol, together 
with variable quantities of mono- and triacylglycerols (see 
Section 9). The USPNF 23 describes glyceryl behenate as a 
mixture of glycerides of fatty acids, mainly behenic acid. It 
specifies that the content of 1-monoglycerides should be 
12.0–18.0%. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Coating agent; tablet binder; tablet and capsule lubricant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Glyceryl behenate is used in cosmetics, foods, and oral 
pharmaceutical formulations. In cosmetics, it is mainly used 
as a viscosity-increasing agent in emulsions; see Table I. 
In pharmaceutical formulations, glyceryl behenate is mainly 
used as a tablet and capsule lubricant(1–3) and as a lipidic 
coating excipient. It has been investigated for the encapsulation 
of various drugs such as retinoids.(4) It has also been 
investigated for use in the preparation of sustained release 
tablets; (5–10) as a matrix-forming agent for the controlled 
release of water-soluble drugs;(10) and as a lubricant in oral 
solid dosage formulations, and it can also be used as a hot-melt 
coating agent sprayed onto a powder.(11) 
Table I: Uses of glyceryl behenate. 
Use Concentration (%) 
Lipophilic matrix or coating for sustained-released 
tablets and capsules 
>10.0 
Tablet and capsule lubricant 1.0–3.0 
Viscosity-increasing agent in silicon gels (cosmetics) 1.0–15.0 
Viscosity-increasing agent in w/o or o/w emulsions 
(cosmetics) 
1.0–5.0 
8 Description 
Glyceryl behenate occurs as a fine white powder or hard waxy 
mass with a faint odor. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for glyceryl behenate. 
Test PhEur 2005 
(Suppl. 5.1) 
USPNF 23 
Identification . . 
Characters . — 
Acid value 44.0 44 
Iodine value 43.0 43 
Saponification value 145–165 145–165 
Residue on ignition 40.1% 40.1% 
Nickel 41 ppm — 
Water 41.0% — 
Heavy metals — 40.001% 
Melting point 65–778C — 
Content of 1-monoglycerides — 12.0–18.0% 
Content of acylglycerols (glycerides) . — 
Monoacylglycerols 15.0–20.0% — 
Diacylglycerols 40–60% — 
Triacylglycerols 21–35% — 
Free glycerin 41.0% 41.0% 
Organic volatile impurities — . 
Composition of fatty acids . — 
Arachidic acid 410.0% — 
Behenic acid 583.0% — 
Erucic acid 43.0% — 
Lignoceric acid 43.0% — 
Palmitic acid 43.0% — 
Stearic acid 45.0% — 
10 Typical Properties 
Melting point: 65–778C 
Solubility: soluble, when heated, in chloroform and dichloromethane, 
practically insoluble in ethanol (95%), hexane, 
mineral oil, and water.

11 Stability and Storage Conditions 
Glyceryl behenate should be stored in a tight container, at a 
temperature less than 358C. 
12 Incompatibilities 
—
13 Method of Manufacture 
Glyceryl behenate is prepared by the esterification of glycerin 
by behenic acid (C22 fatty acid) without the use of catalysts. In 
the case of Compritol 888 ATO (Gattefosse.), raw materials 
used are of vegetable origin, and the esterified material is 
atomized by spray-cooling. 
14 Safety 
Glyceryl behenate is used in cosmetics, foods and oral 
pharmaceutical formulations and is generally regarded as a 
relatively nonirritant and nontoxic material. 
LD50 (mouse, oral): 5 g/kg(12) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantities of material handled. Glyceryl behenate emits 
acrid smoke and irritating fumes when heated to decomposition. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (capsules and 
tablets). Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Glyceryl palmitostearate. 
18 Comments 
The EINECS numbers are: 250-097-0 for glyceryl behenate; 
303-650-6 for glyceryl dibehenate; 242-471-7 for glyceryl 
tribehenate. 
19 Specific References 
1 Shah NH, Stiel D, Weiss M, et al. Evaluation of two new tablet 
lubricants – sodium stearyl fumarate and glyceryl behenate. 
Measurement of physical parameters (compaction, ejection and 
residual forces) in the tabletting process and the effect on the 
dissolution rate. Drug Dev Ind Pharm 1986; 12: 1329–1346. 
2 Baichwal AR, Augsburger LL. Variations in the friction coefficients 
of tablet lubricants and relationship to their physicochemical 
properties. J Pharm Pharmacol 1988; 40: 569–571. 
3 Brossard C, Ratsimbazafy V, des Ylouses DL. Modelling of 
theophylline compound release from hard gelatin capsules containing 
Gelucire matrix granules. Drug Dev Ind Pharm 1991; 17: 
1267–1277. 
4 Jenning V, Gohla SH. Encapsulation of retinoids in solid lipid 
nanoparticles (SLN). J Microencapsul 2001; 18(2): 149–158. 
5 El-Sayed GM, El-Said Y, Meshali MM, Schwartz JB. Kinetics of 
theophylline release from different tablet matrices. STP Pharma Sci 
1996; 6; 390–397. 
6 Prinderre P, Cauture E, Piccerelle P, et al. Evaluation of some 
protective agents on stability and controlled release of oral 
pharmaceutical forms by fluid bed technique. Drug Dev Ind 
Pharm 1997; 23: 817–826. 
7 Achanta AS, Adusumilli PS, James KW. Thermodynamic analysis 
of water interaction with excipient films. Drug Dev Ind Pharm 
2001; 27(3): 227–240. 
8 Achanta AS, Adusumilli PS, James KW, Rhodes CT. Hot-melt 
coating: water sorption behaviour of excipient films. Drug Dev Ind 
Pharm 2001; 27(3): 241–250. 
9 Hariharan M, Wowchuk C, Nkansah P, Gupta VK. Effect of 
formulation composition on the properties of controlled release 
tablets prepared by roller compression. Drug Dev Ind Pharm 
2004; 30(6): 565–572. 
10 Obaidat AA, Obaidat RM. Controlled release of tramadol 
hydrochloride from matrices prepared using glyceryl behenate. 
Eur J Pharm Biopharm 2001; 52(2): 231–235. 
11 Jannin V, Berard V, N’Diaye A, et al. Comparative study of the 
lubricant performance of Compritol (R) 888 ATD either used by 
blending or by hot melt coating. Int J Pharm 2003; 262(1–2): 39– 
45. 
12 Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. 
Cincinatti: US Department of Health, 1987. 
20 General References 
Gattefosse.. Technical literature: Compritol 888 ATO, 2000. 
Hamdani J, Moes AJ, Anighi K. Physical and thermal characterization 
of Precirol and Compritol as lipophilic glycerides used for the 
preparation of controlled-release matrix pellets. Int J Pharm 2003; 
260(1): 47–57. 
21 Authors 
LME McIndoe. 
22 Date of Revision 
12 August 2005. 
Glyceryl Behenate 305

Glyceryl Monooleate 
1 Nonproprietary Names 
BP: Glycerol mono-oleates 
PhEur: Glyceroli mono-oleates 
USPNF: Glyceryl monooleate 
2 Synonyms 
Aldo MO; Atlas G-695; Capmul GMO; glycerol-1-oleate; 
glyceryl mono-oleate; Kessco GMO; Ligalub; monolein; 
Monomuls 90-O18; mono-olein; a-mono-olein glycerol; 
Peceol; Priolube 1408; Stepan GMO; Tegin. 
3 Chemical Name and CAS Registry Number 
9-Octadecenoic acid (Z), monoester with 1,2,3-propanetriol 
[25496-72-4] 
4 Empirical Formula and Molecular Weight 
C21H40O4 356.55 (for pure material) 
Glyceryl monooleate is a mixture of the glycerides of oleic 
acid and other fatty acids, consisting mainly of the monooleate; 
see Section 8. 
5 Structural Formula 
6 Functional Category 
Bioadhesive; emollient; emulsifying agent; emulsion stabilizer; 
gelling agent; mucoadhesive; nonionic surfactant; sustainedrelease 
agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Glyceryl monooleate is a polar lipid that swells in water to give 
several phases with different rheological properties.(1) It is 
available in both nonemulsifying (n/e) and self-emulsifying (s/e) 
grades, the self-emulsifying grade containing about 5% of an 
anionic surfactant. 
The nonemulsifying grade is used in topical formulations as 
an emollient and as an emulsifying agent for water-in-oil 
emulsions. It is also a stabilizer for oil-in-water emulsions. The 
self-emulsifying grade is used as a primary emulsifier for oil-inwater 
systems.(2) 
Glyceryl monooleate gels in excess water, forming a highly 
ordered cubic phase that can be used to sustain the release of 
various water-soluble drugs.(3–6) It is also the basis of 
mucoadhesive drug delivery systems.(7,8) 
Glyceryl monooleate is reported to enhance transdermal(9) 
and buccal penetration.(10) 
8 Description 
The PhEur 2005 (Suppl. 5.1) describes glyceryl monooleate as 
being a mixture of monoacylglycerols, mainly mono-oleoylglycerol, 
together with variable quantities of di- and triacylglycerols. 
They are defined by the nominal content of 
monoacylglycerols (see Table I) and obtained by partial 
glycerolysis of vegetable oils mainly containing triacylglycerols 
of oleic acid or by esterification of glycerol by oleic acid, this 
fatty acid being of vegetable or animal origin. A suitable 
antioxidant may be added. 
Glyceryl monooleates occur as amber oily liquids, which 
may be partially solidified at room temperature and have a 
characteristic odor. 
Table I: Nominal content of acylglycerols in glycerol monooleate 
defined in the PhEur 2005 (Suppl. 5.1). 
Nominal content of acylglycerol (%) 
40 60 90 
Monoacylglycerols 32.0–52.0 55.0–65.0 90.0–101.0 
Diacylglycerols 30.0–50.0 15.0–35.0 <10.0 
Triacylglycerols 5.0–20.0 2.0–10.0 <2.0 
9 Pharmacopeial Specifications 
See Table II. 
10 Typical Properties 
Boiling point: 238–2408C 
Density: 0.942 g/cm3 
Flash point: 2168C 
HLB value: 3.3 (n/e); 4.1 (s/e). 
Melting point: 358C (see also Section 13) 
Refractive index: 1.4626 
Solubility: soluble in chloroform, ethanol (95%), ether, mineral 
oil, and vegetable oils; practically insoluble in water. The 
self-emulsifying grade is dispersible in water. 
Viscosity (kinematic): 100m2/s (100 cSt) at 408C 
11 Stability and Storage Conditions 
Glyceryl monooleate should be stored in an airtight container, 
protected from light in a cool, dry place.

Table II: Pharmacopeial specifications for glyceryl monooleate. 
Test PhEur 2005 
(Suppl. 5.1) 
USPNF 23 
Identification . . 
Characters . . 
Acid value 46.0% 46.0% 
Iodine value 65.0–95.0 65.0–95.0 
Peroxide value 412.0% 412.0% 
Saponification value 150–170 150–170 
Free glycerol 46.0% 46.0% 
Composition of fatty acids 
Palmitic acid 412.0% 412.0% 
Stearic acid 46.0% 46.0% 
Oleic acid 560.0% 560.0% 
Linoleic acid 435.0% 435.0% 
Linolenic acid 42.0% 42.0% 
Arachidic acid 42.0% 42.0% 
Eicosenoic acid 42.0% 42.0% 
Content of acylglycerol see Table I — 
Water 41.0% 41.0% 
Total ash 40.1% 40.1% 
12 Incompatibilities 
Glyceryl monooleate is incompatible with strong oxidizing 
agents. The self-emulsifying grade is incompatible with cationic 
surfactants. 
13 Method of Manufacture 
Glyceryl monooleate is prepared by the esterification of 
glycerol with fatty acids, chiefly oleic acid. As the fatty acids 
are not pure substances, but rather a mixture of fatty acids, the 
product obtained from the esterification will contain a mixture 
of esters, including stearic and palmitic. Di- and tri-esters may 
also be present. The composition and, therefore, the physical 
properties of glyceryl monooleate may thus vary considerably 
from manufacturer to manufacturer; e.g., the melting point 
may vary from 10–358C. 
14 Safety 
Glyceryl monooleate is used in oral and topical pharmaceutical 
formulations and is generally regarded as a relatively nonirritant 
and nontoxic excipient. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(oral capsules, oral powder, oral tablets; creams, controlledrelease 
transdermal films). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Glyceryl monostearate. 
18 Comments 
A specification for glyceryl monooleate is included in the Food 
Chemicals Codex (FCC). 
The EINECS number for glyceryl monooleate is 247-038-6. 
19 Specific References 
1 Engstrom S, Lindahl L,Wallin R, Engblom J. A study of polar lipid 
drug carrier systems undergoing a thermoreversible lamellar-tocubic 
phase transition. Int J Pharm 1992; 86: 137–145. 
2 Ganem-Quintanar A, Quintanar-Guerro D, Burri P. Mono-olein: a 
review of the pharmaceutical applications. Drug Dev Ind Pharm 
2000; 26(8): 809–820. 
3 Wyatt DM, Dorschel D. Cubic-phase delivery system composed of 
glyceryl monooleate and water for sustained release of watersoluble 
drugs. Pharm Technol 1992; 16: 116–130. 
4 Burrows R, Collett JH, Attwood D. The release of drugs from 
monoglyceride-water liquid crystalline phases. Int J Pharm 1994; 
111: 283–293. 
5 Longer M, Tyle P, Mauger JW. A cubic-phase oral drug delivery for 
controlled release of AG 337. Drug Dev Ind Pharm 1996; 22: 603– 
608. 
6 Chang CM, Bodmeier R. Low viscosity monoglyceride based drug 
delivery systems transforming into a highly viscous cubic phase. 
Int J Pharm 1998; 173: 51–60. 
7 Neilson LS, Schubert L, Hansen J. Bioadhesive drug delivery 
systems. 1. Characterization of mucoadhesive properties of 
systems based on glyceryl monooleate and glycerol monolinoleate. 
Eur J Pharm Sci 1998; 6(9): 231–239. 
8 Lee J, Young SA, Kellaway IW. Water quantitatively induces the 
mucoadhesion of liquid crystalline phases of glyceryl monooleate. 
J Pharm Pharmacol 2001; 53(5):629–636. 
9 Ogiso T, Iwaki M, Paku T. Effect of various enhancers on 
transdermal penetration of indomethacin and urea, and relationship 
between penetration parameters and enhancement factors. J 
Pharm Sci 1995; 84: 482–488. 
10 Lee J, Kellaway IW. Buccal permeation of (D-Ala(2), D-leu(5))enkephalin 
from liquid crystalline phases of glyceryl monooleate. Int 
J Pharm 2000; 195(1–2): 29–33. 
20 General References 
Eccleston GM. Emulsions and Microemulsions. In: Swarbrick J, Boylan 
JC, eds. Encyclopaedia of Pharmaceutical Technology, 2nd edn, vol. 
2. New York: Marcel Dekker, 2002: 1066–1085. 
Weiner AL. Lipid excipients in pharmaceutical dosage forms. In: 
Swarbrick J, Boylan JC, eds. Encyclopaedia of Pharmaceutical 
Technology, 2nd edn, vol. 2. New York: Marcel Dekker, 2002: 
1659–1673. 
21 Authors 
NA Armstrong. 
22 Date of Revision 
15 August 2005. 
Glyceryl Monooleate 307

Glyceryl Monostearate 
1 Nonproprietary Names 
BP: Glyceryl monostearate 40–55 
JP: Glyceryl monostearate 
PhEur: Glyceroli monostearas 40–55 
USPNF: Glyceryl monostearate 
Note that the USPNF 23 also includes a specification for monoand 
di-glycerides that corresponds to glyceryl monostearate 
40–55 in the PhEur 2005. 
2 Synonyms 
Capmul GMS-50; Cutina GMS; 2,3-dihydroxypropyl octadecanoate; 
glycerine monostearate; glycerin monostearate; 
glycerol monostearate; glycerol stearate; glyceryl stearate; 
GMS; Imwitor 191; Imwitor 900; Kessco GMS; Lipo GMS 
410; Lipo GMS 450; Lipo GMS 600; monoester with 1,2,3- 
propanetriol; monostearin; Myvaplex 600P; Myvatex; 1,2,3- 
propanetriol octadecanoate; Protachem GMS-450; Rita GMS; 
stearic acid, monoester with glycerol; stearic monoglyceride; 
Stepan GMS; Tegin; Tegin 503; Tegin 515; Tegin 4100; Tegin 
M; Unimate GMS. 
3 Chemical Name and CAS Registry Number 
Octadecanoic acid, monoester with 1,2,3-propanetriol 
[31566-31-1] 
4 Empirical Formula and Molecular Weight 
C21H42O4 358.6 
5 Structural Formula 
6 Functional Category 
Emollient; emulsifying agent; solubilizing agent; stabilizing 
agent; sustained-release ingredient; tablet and capsule lubricant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
The many varieties of glyceryl monostearate are used as 
nonionic emulsifiers, stabilizers, emollients, and plasticizers in a 
variety of food, pharmaceutical, and cosmetic applications. It 
acts as an effective stabilizer, that is, as a mutual solvent for 
polar and nonpolar compounds that may form water-in-oil or 
oil-in-water emulsions.(1,2) These properties also make it useful 
as a dispersing agent for pigments in oils or solids in fats, or as a 
solvent for phospholipids, such as lecithin. 
Glyceryl monostearate has also been used in a novel 
fluidized hot-melt granulation technique for the production of 
granules and tablets.(3) 
Glyceryl monostearate is a lubricant for tablet manufacturing 
and may be used to form sustained-release matrices for solid 
dosage forms.(4–6) Sustained-release applications include the 
formulation of pellets for tablets(7) or suppositories(8) and the 
preparation of a veterinary bolus.(9) Glyceryl monostearate has 
also been used as a matrix ingredient for a biodegradable, 
implantable, controlled-release dosage form.(10) 
When using glyceryl monostearate in a formulation, the 
possibility of polymorph formation should be considered. The 
a-form is dispersible and foamy, useful as an emulsifying agent 
or preservative. The denser, more stable, b-form is suitable for 
wax matrices. This application has been used to mask the flavor 
of clarithromycin in a pediatric formulation.(11) 
8 Description 
While the names glyceryl monostearate and mono- and diglycerides 
are used for a variety of esters of long-chain fatty 
acids, the esters fall into two distinct grades: 
40–55 percent monoglycerides: the PhEur 2005 describes 
glyceryl monostearate 40–55 as a mixture of monoacylglycerols, 
mostly monostearoylglycerol, together with quantities 
of di- and triacylglycerols. It contains 40–55% of 
monoacylglycerols, 30–45% of diacylglycerols, and 5–15% 
of triacylglycerols. This PhEur grade corresponds to monoand 
di-glycerides USPNF, which has similar specifications 
(not less than 40% monoglycerides). 
90 percent monoglycerides: the USPNF 23 (Suppl. 1) describes 
glyceryl monostearate as consisting of not less than 90% of 
monoglycerides, chiefly glyceryl monostearate (C21H42O4) 
and glyceryl monopalmitate (C19H38O4). 
The commercial products are mixtures of variable 
proportions of glyceryl monostearate and glyceryl monopalmitate. 
Glyceryl monostearate is a white to cream-colored, 
waxlike solid in the form of beads, flakes, or powder. It is 
waxy to the touch and has a slight fatty odor and taste. 
9 Pharmacopeial Specifications 
Table I compares the specifications for the 40–55% grades. 
Glyceryl monostearate PhEur and mono- and di-glycerides 
USPNF. PhEur divides glyceryl monostearate 40–55 into three 
types according to the proportion of stearic acid ester in the 
mixture, and those specifications are presented in Table II. 
Table III presents the specifications for glyceryl monostearate 
USPNF (90% monoglycerides). Since the JP specifications are 
broad enough to encompass both grades, JP is included in both 
Table I and Table III.

Table I: Pharmacopeial specifications for glyceryl monostearate 
(40–55%). 
Test JP 2001 PhEur 2005 USPNF 23(a) 
Identification . . — 
Acid value 415.0 43.0 44.0 
Iodine value 43.0 43.0 43.0 
Hydroxyl value — — 300–330 
Saponification value 157–170 158–177 155–165 
Melting point 5558C — — 
Residue on ignition 40.10% 40.10% 40.1% 
Acidity or alkalinity . — — 
Free glycerin — 46.0% 47.0% 
Composition of fatty 
acids 
— see Table II — 
Heavy metals — — 40.001% 
Nickel — 41 ppm — 
Water — 41.0% — 
Organic volatile 
impurities 
— — . 
Assay (monoglycerides) — 40.0–55.0% 440.0%(b) 
(a) mono- and di-glycerides 
(b) 90.0–110.0% of labeled amount 
Table II: Specifications for the composition of fatty acids in glyceryl 
monostearate 40–55. 
Glyceryl 
monostearate 
Fatty acid used in 
manufacturing 
Composition of fatty acids 
Stearic acid Sum of palmitic 
and stearic 
acids 
Type I Stearic acid 50 40.0–60.0% 490.0% 
Type II Stearic acid 70 60.0–80.0% 490.0% 
Type III Stearic acid 95 90.0–99.0% 496.0% 
Table III: Pharmacopeial specifications for glyceryl monostearate 
(90%). 
Test JP 2001 USPNF 23 
Identification . — 
Acid value 415.0 46.0 
Iodine value 43.0 43.0 
Hydroxyl value — 300–330 
Saponification value 157–170 155–165 
Melting point 5558C 5558C 
Residue on ignition 40.10% 40.5% 
Acidity or alkalinity . — 
Limit of free glycerin — 41.2% 
Composition of fatty acids — — 
Heavy metals — 40.001% 
Organic volatile impurities — . 
Assay (monoglycerides) — 490.0% 
10 Typical Properties 
A wide variety of glyceryl monostearate grades are commercially 
available, including self-emulsifying grades that contain 
small amounts of soap or other surfactants. Most grades are 
tailored for specific applications or made to user specifications 
and therefore have varied physical properties. 
HLB value: 3.8 
Flash point: 2408C 
Melting point: 55–608C 
Polymorphs: The a-form is converted to the b-form when 
heated at 508C.(12) 
Solubility: soluble in hot ethanol, ether, chloroform, hot 
acetone, mineral oil, and fixed oils. Practically insoluble in 
water, but may be dispersed in water with the aid of a small 
amount of soap or other surfactant. 
Specific gravity: 0.92 
11 Stability and Storage Conditions 
If stored at warm temperatures, glyceryl monostearate increases 
in acid value upon aging owing to the saponification of the ester 
with trace amounts of water. Effective antioxidants may be 
added, such as butylated hydroxytoluene and propyl gallate. 
Glyceryl monostearate should be stored in a tightly closed 
container in a cool, dry place, and protected from light. 
12 Incompatibilities 
The self-emulsifying grades of glyceryl monostearate are 
incompatible with acidic substances. 
13 Method of Manufacture 
Glyceryl monostearate is prepared by the reaction of glycerin 
with triglycerides from animal or vegetable sources, producing 
a mixture of monoglycerides and diglycerides. The diglycerides 
may be further reacted to produce the 90% monoglyceride 
grade. Another process involves reaction of glycerol with 
stearoyl chloride. 
The starting materials are not pure substances and therefore 
the products obtained from the processes contain a mixture of 
esters, including palmitate and oleate. Consequently, the 
composition, and therefore the physical properties, of glyceryl 
monostearate may vary considerably depending on the 
manufacturer. 
14 Safety 
Glyceryl monostearate is widely used in cosmetics, foods, and 
oral and topical pharmaceutical formulations and is generally 
regarded as a nontoxic and nonirritant material. 
LD50 (mouse, IP): 0.2 g/kg(13) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(oral capsules and tablets; ophthalmic, otic, rectal, topical, 
transdermal, and vaginal preparations). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian 
List of Acceptable Non-medicinal Ingredients. 
If glyceryl monostearate is produced from animal fats 
(tallow), there may be additional regulatory requirements that 
the source be free of contamination from bovine spongiform 
encephalopathy. 
Glyceryl Monostearate 309

17 Related Substances 
Glyceryl monooleate; glyceryl palmitostearate; self-emulsifying 
glyceryl monostearate. 
Self-emulsifying glyceryl monostearate 
Comments: a specification for self-emulsifying glyceryl monostearate 
was previously included in the PhEur. Selfemulsifying 
glyceryl monostearate is a grade of glyceryl 
monostearate to which an emusifying agent has been added. 
The emulsifier may be a soluble soap, a salt of a sulfated 
alcohol, a nonionic surfactant, or a quaternary compound. 
It is used primarily as an emulsifying agent for oils, fats, 
solvents, and waxes. Aqueous preparations should contain 
an antimicrobial preservative. 
18 Comments 
Glyceryl monostearate and other fatty acid monoesters are not 
efficient emulsifiers. However, they are useful emollients that 
are readily emulsified by common emulsifying agents and by 
incorporation of other fatty materials into the formulation. 
Addition of the monoester materials provides the creams with 
smoothness, fine texture, and improved stability. 
In topical applications, glyceryl monostearate is less drying 
than straight stearate creams, and is not drying when used in 
protective applications. A specification for glyceryl monostearate 
is contained in the Food Chemicals Codex (FCC). 
19 Specific References 
1 O’Laughlin R, Sachs C, Brittain H, et al. Effects of variations in 
physicochemical properties of glyceryl monostearate on the 
stability of an oil-in-water cream. J Soc Cosmet Chem 1989; 40: 
215–229. 
2 Rafiee-Tehrani M, Mehramizi A. In vitro release studies of 
piroxicam from oil-in-water creams and hydroalcoholic gel topical 
formulations. Drug Dev Ind Pharm 2000; 26(4): 409–414. 
3 Kidokoro M, Haramiishi Y, Sagasaki S, et al. Application of 
fluidized hot-melt granulation (FHMG) for the preparation of 
granules for tableting; properies of granules and tablets prepared 
by FHMG. Drug Dev Ind Pharm 2002; 28(1): 67–76. 
4 Peh KK, Yuen KH. Development and in vitro evaluation of a novel 
multiparticulate matrix controlled release formulation of theophylline. 
Drug Dev Ind Pharm 1995; 21: 1545–1555. 
5 Peh KK, Yuen KH. In vivo perfomance of a multiparticulate 
matrix, controlled release theophylline preparation. Drug Dev Ind 
Pharm 1995; 22: 349–355. 
6 Peh KK, Wong CF, Yuen KH. Possible mechanism for drug 
retardation from glyceryl monostearate matrix system. Drug Dev 
Ind Pharm 2000; 26: 447–450. 
7 Thomsen LJ, Schaefer T, Sonnergaard JM, Kristensen HG. 
Prolonged release matrix pellets prepared by melt pelletization. I. 
Process variables. Drug Dev Ind Pharm 1993; 19: 1867–1887. 
8 Adeyeye CM, Price J. Development and evaluation of sustainedrelease 
ibuprofen-wax microspheres. II. In vitro dissolution 
studies. Pharm Res 1994; 11: 575–579. 
9 Evrard B, Delattre L. In vitro evaluation of lipid matrices for the 
development of a sustained-release sulfamethazine bolus for 
lambs. Drug Dev Ind Pharm 1996; 22: 111–118. 
10 Peri D, Bogdansky S, Allababidi S, Shah JC. Development of an 
implantable, biodegradable, controlled drug delivery system for 
local antibiotic therapy. Drug Dev Ind Pharm 1994; 20: 1341– 
1352. 
11 Yajima T, Itai S, Takeuchi H, Kawashima Y. Optimum heat 
treatment conditions for masking the bitterness of clarithromycin 
wax matrix. Chem Pharm Bull 2003; 51(11): 1223–1226. 
12 Yajima T, Itai S, Takeuchi H, Kawashima Y. Determination of 
optimum processing temperature for transformation of glyceryl 
monostearate. Chem Pharm Bull 2002; 50(11): 1430–1433. 
13 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2757–2758. 
20 General References 
Eccleston GM. Emulsions. In: Swarbrick J, Boylan JC, eds. Encyclopedia 
of Pharmaceutical Technology, vol. 5. New York: Marcel 
Dekker, 1992: 137–188. 
Rieger MM. Glyceryl stearate: chemistry and use. Cosmet Toilet 1990; 
105(Nov): 51–54, 56–57. 
Schumacher GE. Glyceryl monostearate in some pharmaceuticals. Am J 
Hosp Pharm 1967; 24: 290–291. 
Wisniewski W, Golucki Z. Stability of glycerylmonostearate. Acta Pol 
Pharm 1965; 22: 296–298. 
21 Authors 
AK Taylor. 
22 Date of Revision 
20 May 2005. 
310 Glyceryl Monostearate

Glyceryl Palmitostearate 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Glycerin palmitostearate; glycerol palmitostearate; 2-[(1-oxohexadecyl)-
oxy]-1,3-propanediyl dioctadecanoate and 1,2,3- 
propane triol; Precirol ATO 5. 
3 Chemical Name and CAS Registry Number 
Octadecanoic acid, 2,3-dihydroxypropyl ester mixed with 
3-hydroxy-2-[(1-oxohexadecyl)-oxy] propyl octadecanoate 
[8067-32-1] 
4 Empirical Formula and Molecular Weight 
Glyceryl palmitostearate is a mixture of mono-, di-, and 
triglycerides of C16 and C18 fatty acids. 
5 Structural Formula 
See Sections 3 and 4. 
6 Functional Category 
Biodegradable material; coating agent; gelling agent; release 
modifying agent; sustained-release agent; tablet and capsule 
diluent; tablet and capsule lubricant; taste-masking agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Glyceryl palmitostearate is used in oral solid-dosage pharmaceutical 
formulations as a lubricant.(1,2) Disintegration times 
increase(3) and tablet strength decreases(4) with increase in 
mixing time. 
It is used as a lipophilic matrix for sustained-release tablet 
and capsule formulations.(5,6) Tablet formulations may be 
prepared by either granulation or a hot-melt technique,(7,8) the 
former producing tablets that have the faster release profile. 
Release rate decreases with increased glyceryl palmitostearate 
content.(5) 
Glyceryl palmitostearate is used to form microspheres, 
which may be used in capsules or compressed to form 
tablets,(9,10) pellets,(11) coated beads,(12) and biodegradable 
gels.(13) It is also used for taste-masking.(14) See Table I. 
Table I: Uses of glyceryl palmitostearate.(14) 
Use Concentration (%) 
Matrix for sustained release 10.0–25.0 
Tablet masking 2.0–6.0 
Tablet lubricant 1.0–3.0 
8 Description 
Glyceryl palmitostearate occurs as a fine white powder with a 
faint odor. 
9 Pharmacopeial Specifications 
—
10 Typical Properties 
Acid value: <6.0 
Boiling point: 2008C 
Color: <3 (Gardner scale) 
Free glycerin content: <1.0% 
Heavy metals: <10 ppm 
Hydroxyl value: 60–115 
Iodine value: <3 
Melting point: 52–558C 
1-Monoglycerides content: 8.0–17.0% 
Peroxide value: <3.0 
Saponification value: 175–195 
Solubility: freely soluble in chloroform and dichloromethane; 
practically insoluble in ethanol (95%), mineral oil, and 
water. 
Sulfated ash: <0.1% 
Unsaponifiable matter: <1.0% 
Water content: <1.0% 
11 Stability and Storage Conditions 
Glyceryl palmitostearate should not be stored at temperatures 
above 358C. For storage for periods over 1 month, glyceryl 
palmitostearate should be stored at a temperature of 5–158C in 
an airtight container, protected from light and moisture. 
12 Incompatibilities 
Glyceryl palmitostearate is incompatible with ketoprofen(15) 
and naproxen.(16) 
13 Method of Manufacture 
Glyceryl palmitostearate is manufactured, without a catalyst, 
by the direct esterification of palmitic and stearic acids with 
glycerol. 
14 Safety 
Glyceryl palmitostearate is used in oral pharmaceutical 
formulations and is generally regarded as an essentially 
nontoxic and nonirritant material. 
LD50 (rat, oral): >6 g/kg(14) 
15 Handling Precautions 
Observe normal handling precautions appropriate to the 
circumstances and quantity of material handled.

16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(oral suspension, oral tablet). Included in nonparenteral 
preparations licensed in Europe. Included in the Canadian 
List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Glyceryl behenate; glyceryl monostearate. 
18 Comments 
—
19 Specific References 
1 Holzer AW, Sjogren J. Evaluation of some lubricants by the 
comparison of friction coefficients and tablet properties. Acta 
Pharm Suec 1981; 18: 139–148. 
2 Allen LV. Featured excipient: capsule and tablet lubricants. Int J 
Pharm Compound 2000; 4(5): 390–392. 
3 Sekulovic D. Effect of Precirol ATO 5 on the properties of tablets. 
Pharmazie 1987; 42(1): 61–62. 
4 Velasco V, Munoz-Ruiz A, Mondero C, Jimenez-Castellanos R. 
Force–displacement parameters of maltodextrins after the addition 
of lubricants. Int J Pharm 1997; 152: 111–120. 
5 Saraiya K, Bolton S. Use of Precirol to prepare sustained release 
tablets of theophylline and quinidine gluconate. Drug Dev Ind 
Pharm 1990; 16(13): 1963–1969. 
6 Bodmeier R, Paeratakul O, Chen H, Zhang W. Formation of 
sustained release wax matrices within hard gelatin capsules in a 
fluidised bed. Drug Dev Ind Pharm 1990; 16: 1505–1519. 
7 Malamataris S, Panagopoulou A, Hatzipantou P. Controlled 
release from glycerol palmito-stearate matrices prepared by dryheat 
granulation and compression at elevated temperature. Drug 
Dev Ind Pharm 1991; 17(13): 1765–1777. 
8 Evrard B, Arnighi K, Beten D, et al. Influence of melting and 
rheological properties of fatty binders in the melt granulation 
process in a high sheer mixer. Drug Dev Ind Pharm 1999; 25(11): 
1177–1184. 
9 Shaikh NH, De Yanes SE, Shukla AJ, et al. Effect of different 
binders on release characteristics of theophylline from compressed 
microspheres. Drug Dev Ind Pharm 1991; 17: 793–804. 
10 Edimo A, Leterme P, Denis J, et al. Capacity of lipophilic auxiliary 
substances to give spheres by extrusion-spheronisation. Drug Dev 
Ind Pharm 1993; 19: 827–842. 
11 Pongjanyakul T, Medlicott NJ, Tucker IG. Melted glyceryl 
palmitostearate (GPS) pellets for protein delivery. Int J Pharm 
2004; 271(1–2): 53–62 
12 Mount DL, Schwortz JB. Formulation and compaction of nonfracturing 
deformable coated beads. Drug Dev Ind Pharm 1996; 
22(7): 609–621. 
13 Gao ZH, Shukla AJ, Johnson JR, Crowley WR. Controlled release 
of contraceptive steroids from biodegradable and injectable gel: in 
vivo evaluation. Pharm Res 1995; 12: 864–868. 
14 Gattefosse.. Technical literature: Precirol ATO 5, 2004. 
15 Botha SA, Lotter AP. Compatibility study between ketoprofen and 
tablet excipients using differential scanning calorimetry. Drug Dev 
Ind Pharm 1989; 15: 415–426. 
16 Botha SA, Lotter AP. Compatibility study between naproxen and 
tablet excipients using differential scanning calorimetry. Drug Dev 
Ind Pharm 1990; 16: 673–683. 
20 General References 
Chan HK, Chew NYK. Excipients-powder and solid dosage forms. In: 
Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical 
Technology, 2nd edn, vol. 2. New York: Marcel Dekker, 2002: 
1132–1142. 
Armstrong NA. Tablet manufacture. In: Swarbrick J, Boylan JC, eds. 
Encyclopedia of Pharmaceutical Technology, 2nd edn, vol. 3. New 
York: Marcel Dekker, 2002: 2713–2732. 
21 Authors 
NA Armstrong. 
22 Date of Revision 
16 August 2005. 
312 Glyceryl Palmitostearate

Glycofurol 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Glycofurol 75; tetraglycol; a-(tetrahydrofuranyl)-o-hydroxypoly(
oxyethylene); tetrahydrofurfuryl alcohol polyethylene 
glycol ether. 
Note: tetraglycol is also used as a synonym for tetrahydrofurfuryl 
alcohol. 
3 Chemical Name and CAS Registry Number 
a-[(Tetrahydro-2-furanyl)methyl]-o-hydroxy-poly(oxy-1,2- 
ethanediyl) [31692-85-0] 
4 Empirical Formula and Molecular Weight 
C9H18O4 (average) 190.24 (average) 
5 Structural Formula 
Glycofurol 75: n = 1–2 
6 Functional Category 
Penetration enhancer; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Glycofurol is used as a solvent in parenteral products for 
intravenous or intramuscular injection in concentrations up to 
50% v/v.(1–5) It has also been investigated, mainly in animal 
studies, for use as a penetration enhancer and solvent in 
topical(6) and intranasal formulations.(7–10) Glycofurol has also 
been used at 20% v/v concentration in a rectal formulation.(11) 
8 Description 
Glycofurol is a clear, colorless, almost odorless liquid, with a 
bitter taste; it produces a warm sensation on the tongue. 
9 Pharmacopeial Specifications 
—
10 Typical Properties 
Boiling point: 80–1008C for Glycofurol 75 
Density: 1.070–1.090 g/cm3 at 208C 
Hydroxyl value: 300–400 
Moisture content: 0.2–5% at ambient temperature and 30% 
relative humidity. 
Refractive index: nD
40 = 1.4545 
Solubility: see Table I. 
Table I: Solubility of glycofurol. 
Solvent Solubility at 208C 
Arachis oil Immiscible 
Castor oil Miscible(a) 
Ethanol (95%) Miscible in all proportions 
Glycerin Miscible in all proportions 
Isopropyl ether Immiscible 
Petroleum ether Immiscible 
Polyethylene glycol 400 Miscible in all proportions 
Propan-2-ol Miscible in all proportions 
Propylene glycol Miscible in all proportions 
Water Miscible in all proportions(a) 
(a) Cloudiness may occur. 
Viscosity (dynamic): 8–18 mPa s (8–18 cP) at 208C for Glycofurol 
75. 
11 Stability and Storage Conditions 
Stable if stored under nitrogen in a well-closed container 
protected from light, in a cool, dry place. 
12 Incompatibilities 
Incompatible with oxidizing agents. 
13 Method of Manufacture 
Glycofurol is prepared by the reaction of tetrahydrofurfuryl 
alcohol with ethylene oxide (followed by a special purification 
process in the case of Glycofurol 75). 
14 Safety 
Glycofurol is mainly used as a solvent in parenteral pharmaceutical 
formulations and is generally regarded as a relatively 
nontoxic and nonirritant material at the levels used as a 
pharmaceutical excipient. Glycofurol can be irritant when used 
undiluted; its tolerability is approximately the same as 
propylene glycol.(1,2) 
Glycofurol may have an effect on liver function and may 
have a low potential for interaction with hepatoxins or those 
materials undergong extensive hepatic metabolism.(4) 
LD50 (mouse, IV): 3.5 mL/kg(2) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled.

16 Regulatory Status 
Included in parenteral medicines licensed in Europe. 
17 Related Substances 
—
18 Comments 
Grades other than Glycofurol 75 may contain significant 
amounts of tetrahydrofurfuryl alcohol and other impurities. 
Glycofurol 75 meets an analytical specification which includes 
a requirement that the fraction in which n = 1 or 2 amounts to a 
minimum of 95%; see Section 5. 
19 Specific References 
1 Spiegelberg H, Schla. pfer R, Zbinden G, Studer A. A new injectable 
solvent (glycofurol) [in German]. Arzneimittelforschung 1956; 6: 
75–77. 
2 Spiegel AJ, Noseworthy MM. Use of non-aqueous solvents in 
parenteral products. J Pharm Sci 1963; 52: 917–927. 
3 Anschel J. Solvents and solubilisers in injections. Pharm Ind 1965; 
27: 781–787. 
4 Bury RW, Breen KJ, Desmond PV, et al. Disposition of intravenous 
glycofurol: effect of hepatic cirrhosis. Clin Pharmacol Ther 1984; 
36(1): 82–84. 
5 Tauboll E, Lindstro.m S, Klem W, Gjerstad L. A new injectable 
carbamazepine solution: antiepileptic effects and pharmaceutical 
properties. Epilepsy Res 1990; 7(1): 59–64. 
6 Lashmar UT, Hadgraft J, Thomas N. Topical application of 
penetration enhancers to the skin of nude mice: a histopathological 
study. J Pharm Pharmacol 1989; 41(2): 118–122. 
7 Bindseil E, Bechgaard E, Jorgensen L, Larsen R. Morphological 
examination of rabbit nasal mucosa after exposure to acetylsalicylic 
acid, glycofurol 75 and ephedrine. Int J Pharm 1995; 
119(1): 37–46. 
8 Bechgaard E, Gizurarson S, Hjortkjaer RK. Pharmacokinetic and 
pharmacodynamic response after intranasal administration of 
diazepam to rabbits. J Pharm Pharmacol 1997; 49(8): 747–750. 
9 NielsonHW, Bechgaard E, Twile B, et al. Intranasal administration 
of different liquid formulations of bumetanide to rabbits. Int J 
Pharm 2000; 204: 35–41. 
10 Bagger MA, Nielsen HW, Bechgaard E. Nasal bioavailability of 
peptide T in rabbits: absorption enhancement by sodium 
glycocholate and glycofurol. Eur J Pharm Sci 2001; 14(1): 69–74. 
11 Dale O, Sheffels P, Khorasch ED. Bioavailabilities of rectal and oral 
methadone in healthy subjects. Br J Clin Pharmacol 2004; 58(2): 
156–162. 
20 General References 
Mottu F, Laurent A, Rufenacht DA, Doelker E. Organic solvents for 
pharmaceutical parenterals and embolic liquids: a review of toxicity 
data. PDA J Pharm Sci Technol 2000; 54(6): 456–469. 
21 Authors 
PJ Weller. 
22 Date of Revision 
14 August 2005. 
314 Glycofurol

Guar Gum 
1 Nonproprietary Names 
BP: Guar galactomannan 
PhEur: Guar galactomannanum 
USPNF: Guar gum 
2 Synonyms 
E412; Galactosol; guar flour; jaguar gum; Meyprogat; Meyprodor; 
Meyprofin. 
3 Chemical Name and CAS Registry Number 
Galactomannan polysaccharide [9000-30-0] 
4 Empirical Formula and Molecular Weight 
(C6H12O6)n 220 000 
See Section 5. 
5 Structural Formula 
Guar gum consists of linear chains of (1!4)-b-D-mannopyranosyl 
units with a-D-galactopyranosyl units attached by 
(1!6) linkages. The ratio of D-galactose to D-mannose is 
between 1 : 1.4 and 1 : 2. See also Section 8. 
6 Functional Category 
Suspending agent; tablet binder; tablet disintegrant; viscosityincreasing 
agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Guar gum is a galactomannan, commonly used in cosmetics, 
food products, and pharmaceutical formulations. It has also 
been investigated in the preparation of sustained-release matrix 
tablets in the place of cellulose derivatives such as methylcellulose.(
1) 
In pharmaceuticals, guar gum is used in solid-dosage forms 
as a binder and disintegrant,(2–4) see Table I; in oral and topical 
products as a suspending, thickening, and stabilizing agent; and 
also as a controlled-release carrier. Guar gum has also been 
examined for use in colonic drug delivery.(5–9) Guar-gum-based 
three-layer matrix tablets have been used experimentally in oral 
controlled-release formulations.(10) 
Therapeutically, guar gum has been used as part of the diet 
of patients with diabetes mellitus.(11,12) It has also been used as 
an appetite suppressant, although its use for this purpose, in 
tablet form, is now banned in the UK;(12–14) see Section 14. 
Table I: Uses of guar gum. 
Use Concentration (%) 
Emulsion stabilizer 1 
Tablet binder Up to 10 
Thickener for lotions and creams Up to 2.5 
8 Description 
The USPNF 23 describes guar gum as a gum obtained from the 
ground endosperms of Cyamopsis tetragonolobus (L.) Taub. 
(Fam. Leguminosae). It consists chiefly of a high-molecularweight 
hydrocolloidal polysaccharide, composed of galactan 
and mannan units combined through glycoside linkages, which 
may be described chemically as a galactomannan. The PhEur 
2005 similarly describes guar galactomannan as being obtained 
from the seeds of Cyamopsis tetragonolobus (L.) Taub. by 
grinding the endosperms and subsequent partial hydrolysis. 
The main components are polysaccharides composed of Dgalactose 
and D-mannose in molecular ratios of 1 : 1.4 to 1 : 2. 
The molecule consists of a linear chain of b-(1!4)-glycosidically 
linked manno-pyranoses and single a-(1!6)-glycosidically 
linked galacto-pyranoses. See also Section 18. 
Guar gum occurs as an odorless or nearly odorless, white to 
yellowish-white powder with a bland taste. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for guar gum. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
pH (1% w/w solution) 5.5–7.5 — 
Apparent viscosity . — 
Microbial contamination 4103/g — 
Loss on drying 415.0% 415.0% 
Ash 41.8% 41.5% 
Acid-insoluble matter 47.0% 47.0% 
Arsenic — 43 ppm 
Lead — 40.001% 
Heavy metals — 40.002% 
Protein 45.0% 410.0% 
Starch — . 
Galactomannans — 566.0% 
Organic volatile impurities — . 
Tragacanth, sterculia gum, agar, 
alginates, and carrageenan 
. — 
10 Typical Properties 
Acidity/alkalinity: pH = 5.0–7.0 (1% w/v aqueous dispersion) 
Density: 1.492 g/cm3 
Solubility: practically insoluble in organic solvents. In cold or 
hot water, guar gum disperses and swells almost immediately 
to form a highly viscous, thixotropic sol. The optimum 
rate of hydration occurs at pH 7.5–9.0. Finely milled 
powders swell more rapidly and are more difficult to 
disperse. Two to four hours in water at room temperature 
are required to develop maximum viscosity. 
Viscosity (dynamic): 4.86 Pa s (4860 cP) for a 1% w/v dispersion. 
Viscosity is dependent upon temperature, time, 
concentration, pH, rate of agitation, and particle size of

the guar gum powder. Synergistic rheological effects may 
occur with other suspending agents such as xanthan gum; 
see Xanthan Gum. 
11 Stability and Storage Conditions 
Aqueous guar gum dispersions have a buffering action and are 
stable at pH 4.0–10.5. However, prolonged heating reduces the 
viscosity of dispersions. 
The bacteriological stability of guar gum dispersions may be 
improved by the addition of a mixture of 0.15% methylparaben 
and 0.02% propylparaben as a preservative. In food 
applications, benzoic acid, citric acid, sodium benzoate, or 
sorbic acid may be used. 
Guar gum powder should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Guar gum is compatible with most other plant hydrocolloids 
such as tragacanth. It is incompatible with acetone, ethanol 
(95%), tannins, strong acids, and alkalis. Borate ions, if present 
in the dispersing water, will prevent the hydration of guar gum. 
However, the addition of borate ions to hydrated guar gum 
produces cohesive structural gels and further hydration is then 
prevented. The gel formed can be liquefied by reducing the pH 
to below 7, or by heating. 
Guar gum may reduce the absorption of penicillin V from 
some formulations by a quarter.(15) 
13 Method of Manufacture 
Guar gum is obtained from the ground endosperm of the guar 
plant, Cyamopsis tetragonolobus (L.) Taub. (Fam. Leguminosae), 
which is grown in India, Pakistan, and the semiarid 
southwestern region of the USA. 
The seed hull can be removed by grinding, after soaking in 
sulfuric acid or water, or by charring. The embryo (germ) is 
removed by differential grinding, since each component 
possesses a different hardness. The separated endosperm, 
containing 80% galactomannan is then ground to different 
particle sizes depending upon final application. 
14 Safety 
Guar gum is widely used in foods and oral and topical 
pharmaceutical formulations. Excessive consumption may 
cause gastrointestinal disturbance such as flatulence, diarrhea, 
or nausea. Therapeutically, daily oral doses of up to 25 g of 
guar gum have been administered to patients with diabetes 
mellitus.(11) 
Although it is generally regarded as a nontoxic and 
nonirritant material, the safety of guar gum when used as 
an appetite suppressant has been questioned. When consumed, 
the gum swells in the stomach to promote a feeling of 
fullness. However, it is claimed that premature swelling of 
guar gum tablets may occur and cause obstruction of, or 
damage to, the esophagus. Consequently, appetite suppressants 
containing guar gum in tablet form have been banned in 
the UK.(12) However, appetite suppressants containing microgranules 
of guar gum are claimed to be safe.(13) The use of 
guar gum for pharmaceutical purposes is unaffected by the 
ban. 
In food applications, an acceptable daily intake of guar gum 
has not been specified by the WHO.(16) 
LD50 (hamster, oral): 6.0 g/kg(17) 
LD50 (mouse, oral): 8.1 g/kg 
LD50 (rabbit, oral): 7.0 g/kg 
LD50 (rat, oral): 6.77 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Guar gum may be irritating 
to the eyes. Eye protection, gloves, and a dust mask or 
respirator are recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral suspensions, 
syrups, and tablets; topical preparations; vaginal tablets). 
Also included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Acacia; tragacanth; xanthan gum. 
18 Comments 
Synthetic derivatives of guar gum such as guar acetate, guar 
phthalate, guar acetate phthalate, oxidized guar gum, and 
sodium carboxymethyl guar, have also been investigated for 
their pharmaceutical applications. In particular, sodium carboxymethyl 
guar gives a transparent gel and, when poured over 
a pool of mercury, produces a flexible, clear, transparent film. 
Sodium carboxymethyl guar has been used as a polymer matrix 
in transdermal patches.(18) 
A specification for guar gum is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for guar gum is 232-536-8. 
19 Specific References 
1 Khullar R, Khar RK, Agarwal SP. Guar gum as a hydrophilic 
matrix for preparation of theophylline controlled-release dosage 
form. Indian J Pharm Sci 1999; 61(6): 342–345. 
2 Feinstein W, Bartilucci AJ. Comparative study of selected disintegrating 
agents. J Pharm Sci 1966; 55: 332–334. 
3 Sakr AM, Elsabbagh HM. Evaluation of guar gum as a tablet 
additive: a preliminary report. Pharm Ind 1977; 39(4): 399–403. 
4 Duru C, Colombo P, Gaudy D, et al. A comparative study of the 
disintegrating efficiency of polysaccharides in a directly-tabletable 
formulation. Pharm Technol Int 1992; 4(5): 15, 16, 20, 22, 23. 
5 Adkin DA, Kenyon CJ, Lerner EI, et al. The use of scintigraphy to 
provide ‘‘proof of concept’’ for novel polysaccharide preparations 
designed for colonic drug delivery. Pharm Res 1997; 14(1): 103– 
107. 
6 Wong D, Larrabee S, Clifford K, et al. USP Dissolution Apparatus 
II (reciprocating cylinder) for screening of guar based colonic 
delivery formulations. J Control Release 1997; 47: 173–179. 
7 Sinha VR, Mittal BR, Bhatani KK, Kumria R. Colonic drug 
delivery of 5-fluoracil: an in vitro evaluation. Int J Pharm 2004; 
269(1): 101–108. 
8 Toti US, Aminabhavi TM. Modified guar gum matrix tablet for 
controlled release of diltriazem hydrochloride. J Control Release 
2004; 95(3): 567–577. 
316 Guar Gum

9 Tugcu Demiroez F, Acartuerk F, Takka S, Konus Boyunaga O. In 
vitro and in vivo evaluation of mesalazine-guar gum matrix tablets 
for colonic drug delivery. J Drug Target 2004; 12(2): 105–112. 
10 Al-Saiden SM, Krishnaiah YS, Satyanorayana V, et al. Pharmacokinetic 
evaluation of guar gum-based three-layer matrix tablets for 
oral controlled delivery of highly soluble metoprolol tartrate as a 
model drug. Eur J Pharm Biopharm 2004; 58(3): 697–703. 
11 Jenkins DJ, Wolever TM, Hockaday TD, et al. Treatment of 
diabetes with guar gum: reduction of urinary glucose loss in 
diabetics. Lancet 1977; ii: 779–780. 
12 Uusitupa MIJ. Fibre in the management of diabetes [letter]. Br Med 
J 1990; 301: 122. 
13 Levin R. Guar gum [letter]. Pharm J 1989; 242: 153. 
14 Anonymous. Guar slimming tablets ban. Pharm J 1989; 242: 611. 
15 Anonymous. Does guar reduce penicillin V absorption? Pharm J 
1987; 239: 123. 
16 WHO. Toxicological evaluation of some food additives including 
anticaking agents, antimicrobials, antioxidants, emulsifiers and 
thickening agents. WHO Food Addit Ser 1974; No. 5: 321–323. 
17 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1890. 
18 Paranjothy KLK, Thampi PP. Development of transdermal patches 
of verapamil hydrochloride using sodium carboxymethyl guar as a 
monolithic polymeric matrix and their in vitro release studies. 
Indian J Pharm Sci 1997; 59(2): 49–54. 
20 General References 
Ben-Kerrour L, Du. chene D, Puisieux F, Carstensen JT. Temperatureand 
concentration-dependence in pseudoplastic rheological equations 
for gum guar solutions. Int J Pharm 1980; 5: 59–65. 
Bhardwaj TR, Kanwary M, Lal R, Gupta A. Natural gums and 
modified natural gums as sustained-release carriers. Drug Dev Ind 
Pharm 2000; 26(10): 1025–1038. 
Goldstein AM, Alter EN, Seaman JK. Guar gum. In: Whistler RL, ed. 
Industrial Gums, 2nd edn. New York: Academic Press, 1973; 303– 
321. 
Tantry JS, Nagarsenker MS. Rheological study of guar gum. Indian J 
Pharm Sci 2001; 63(1): 74–76. 
Vemuri S. Flow and consistency index dependence of pseudoplastic 
guar gum solutions. Drug Dev Ind Pharm 1988; 14: 905–914. 
21 Authors 
AH Kibbe. 
22 Date of Revision 
12 August 2005. 
Guar Gum 317

Hectorite 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Hector clay; Hectabrite AW; Hectabrite DP; Ghassoulite; 
Laponite; SHCa-1; Strese & Hofmann’s Hectorite. 
3 Chemical Name and CAS Registry Number 
Hectorite [12173-47-6] 
4 Empirical Formula and Molecular Weight 
Na0.3(Mg,Li)3Si4O10(F,OH)2 383 
Hectorite is a naturally occurring phyllosilicate clay of the 
smectite (montmorillonite) group and is a principal component 
of bentonite clay. Hectorite is a mineral with an approximate 
empirical formula owing to the variability in cation substitution; 
see Table I. 
Table I: Approximate composition of hectorite based on chemical 
analysis. 
Component Wt % 
SiO2 53.68 
Al2O3 0.6 
MgO 25.34 
CaO 0.52 
Li2O 1.12 
Na2O 3.00 
K2O 0.07 
Cl– 0.31 
H2O. 8.24 
H2O– 7.28 
5 Structural Formula 
Hectorite is a natural mineral clay, obtained from altered 
volcanic ash with a high silica content. It is composed of two 
tetrahedral layers formed by phyllosilicate sheets and one 
octahedral layer. The apical oxygens of the two tetrahedral 
sheets project into the octahedral sheet. It is structurally similar 
to talc but differs by substitution, mainly in the octahedral 
layer. Common impurities include aluminum, calcium, chlorine, 
iron, potassium, and titanium. 
See Section 4. 
6 Functional Category 
Adsorbent; cosmetic ingredient; emulsifying agent; viscosityincreasing 
agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Hectorite is used widely in pharmaceutical preparations as an 
absorbent, emulsifier, stabilizer, suspending agent, thickener, 
and viscosity-controlling agent.(1) 
Hectorite is a component of other naturally occurring clays 
and hence may be suitable for use in similar pharmaceutical 
formulation applications as an adsorbent, oil-in-water emulsifying 
agent, suspending agent, or viscosity-increasing agent. It 
is also available as a synthetic material. Hectorite is used to 
modify the thixotropic behavior of pharmaceutical dispersions(
2) and for stabilizing oil-in-water emulsion bases.(3,4) 
When combined with an appropriate cation, hectorite exhibits 
properties suitable for use as a contrast agent.(5) 
8 Description 
Hectorite occurs as an odorless, white to cream-colored, waxy, 
dull powder composed of aggregates of colloidal-sized lathshaped 
crystals. 
SEM: 1 
Excipient: Hectorite (Hectabrite DP) 
Manufacturer: American Colloid Co. 
Lot No.: 58905 NFT 288 
Magnification: 500 
9 Pharmacopeial Specifications 
—
10 Typical Properties 
Cation exchange capacity: 43.9 meq/100 g 
Crystal data: space group C2/m, a = 5.2, b = 9.16, c = 16.0, b  998. 
Density (true): 2.5 g/cm3

SEM: 2 
Excipient: Hectorite (Hectabrite DP) 
Manufacturer: American Colloid Co. 
Lot No.: 58905 NFT 288 
Magnification:1000 
Hardness (Mohs): 1–2 
Moisture content: hectorite loses 10% of water up to 1508C; 
2% above 1508C. 
Refractive index: n = 1.500 
Specific surface area: 63.2m2/g. Hectorite swells on the 
addition of water. 
11 Stability and Storage Conditions 
Hectorite is a stable material and should be stored in a cool, dry 
place. 
12 Incompatibilities 
Contact between hectorite and hydrofluoric acid may generate 
heat. 
13 Method of Manufacture 
Naturally occurring hectorite is mined from weathered 
bentonite deposits. It is further processed to remove grit and 
impurities so that it is suitable for pharmaceutical and cosmetic 
applications. 
14 Safety 
Hectorite is a natural clay mineral that is not considered acutely 
toxic, therefore no toxicity values have been established. 
However, hectorite may contain small amounts of crystalline 
silica in the form of quartz. 
Dust can be irritating to the respiratory tract and eyes,(6) and 
contact with this material may cause drying of the skin. Chronic 
exposure to crystalline silica may have adverse effects on the 
respiratory system. EU labeling states that the material is not 
classified as dangerous. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material being handled. Avoid generating and 
breathing dust and use eye protection. For dusty conditions, eye 
protection, gloves, and a dust mask are recommended. The 
occupational exposure limits for hectorite are 5 mg/m3 (respirable) 
PEL-TWA, 3 mg/m3 (respirable) TLV-TWA, and 10 mg/m3 
(inhalable dust) TLV-TWA. 
16 Regulatory Status 
Reported in the EPA TSCA Inventory. 
17 Related Substances 
Attapulgite; bentonite; kaolin; magnesium aluminum silicate; 
quaternium 18-hectorite; saponite; stearalkonium hectorite; 
talc. 
Quaternium 18-hectorite 
CAS numbers: [71011-27-3]; [12001-31-9]. 
Synonyms: Bentone 38. 
Comments: quaternium 18-hectorite is used in cosmetics as a 
viscosity-controlling agent. It does not contain crystalline 
silica. The EINECS numbers for quaternium 18-hectorite 
are 234-406-6, and 234-406-6. 
Stearalkonium hectorite 
CAS numbers: [94891-33-5]; [71011-26-2]. 
Synonyms: Bentone 27. 
Comments: steralkonium hectorite is used in cosmetics as a 
viscosity-controlling agent. The EINECS numbers for 
stearalkonium hectorite are 305-633-9, and 275-126-4. 
18 Comments 
Polyethylene glycols 400, 1500, and 4000 have been shown to 
increase the consistency of hectorite dispersions.(7) 
The EINECS number for hectorite is 235-340-0. 
19 Specific References 
1 Ash M, Ash I. Handbook of Pharmaceutical Additives, 2nd edn. 
Endicott, NY: Synapse Information Resources, 2002: 487. 
2 Plaizier-Vercammen JA. Viscous behaviour of laponite XLG, a 
synthetic hectorite and its use in pharmaceutical dispersions. [In 
Dutch]. Farmaceutisch Tijdschrift voor Belgie 1994; 71(4–5): 2–9. 
3 Plaizier-Vercammen JA. Rheological properties of laponite XLG, a 
synthetic purified hectorite. Pharmazie 1992; 47(11): 856–861. 
4 Burdeska M, Asche H. Heat sterilization of O/W emulsions using 
nonionic cream bases as examples: formulation of heat stable 
cream bases. [In German]. Pharm Ind 1986; 48(10): 1171–1177. 
5 Balkus KJ, Shi J. A study of suspending agents for gadolinium(III)- 
exchanged hectorite. An oral magnetic resonance imaging contrast 
agent. Langmuir 1996; 12(26): 6277–6281. 
6 Elmore AR. Cosmetic Ingredient Review Panel. Final report on the 
safety assessment of aluminum silicate, calcium silicate, magnesium 
silicate, magnesium trisilicate, sodium magnesium silicate, 
zirconium silicate, attapulgite, bentonite, Fuller’s earth, hectorite, 
kaolin, lithium magnesium silicate, lithium magnes sodium silicate, 
montmorillonite, pyrophyllite, and zeolite. Int J Toxicol 2003; 22 
(Suppl. 1): 37–102. 
7 Omar SM, El-Nahhas SA, Khalil RM, Salama HA. Effect of 
polyethylene glycols on the rheological characteristics of Macaloid 
dispersions. J Drug Res 1994; 21(1–2): 91–103. 
20 General References 
Alexander P. Rheological additives. Manuf Chem 1986; 57(Jun): 49– 
51. 
Hectorite 319

Browne JE, Feldkamp JR, White JL, Hem SL. Characterization and 
adsorptive properties of pharmaceutical grade clays. J Pharm Sci. 
1980; 69(7): 816–823. 
Cormleyu I, Addison J. The in vitro cytotoxicity of some standard clay 
mineral dusts of respirable size. Clay Miner 1983; 18(2): 153–163. 
Earnest CE. Thermal analysis of hectorite. Part I. Thermogravimetry. 
Thermochim Acta 1983; 63: 277–289. 
Earnest CE. Thermal analysis of hectorite. Part II. Differential thermal 
analysis. Thermochim Acta 1983; 63: 291–306. 
Foshaq WR, Woodford AO. Bentonite magnesium clay mineral from 
California. Am Mineral 1936; 21: 238–244. 
Komadel PJ, Madejova J, Hanek J, et al. Dissolution of Hectorite in 
inorganic acids. Clays Clay Miner 1996; 44: 228–236. 
Trottonhorst R, Roberson HE. X-ray diffraction aspects of montmorillonites. 
Am Mineral 1973; 58: 73–80. 
Viseras C, Lopez-Galindo A. Characteristics of pharmaceutical grade 
phyllosilicate powders. Pharm Dev Technol 2000; 5(1): 47–52. 
21 Authors 
PE Luner. 
22 Date of Revision 
23 August 2005. 
320 Hectorite

Heptafluoropropane (HFC) 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
HFA227; HFC227; Dymel 227 EA/P; 2-hydroperfluoropropane; 
P-227; propellant 227; R-227; Solkane 227; Zephex 227 
EA. 
3 Chemical Name and CAS Registry Number 
1,1,1,2,3,3,3-Heptafluoropropane [431-89-0] 
4 Empirical Formula and Molecular Weight 
C3HF7 170.0 
5 Structural Formula 
6 Functional Category 
Aerosol propellant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Heptafluoropropane (P-227) is classified as a hydrofluorocarbon 
(HFC) aerosol propellant since the molecule consists only 
of carbon, fluorine, and hydrogen atoms. It does not contain 
any chlorine and consequently does not affect the ozone layer, 
nor does it have an effect upon global warming. It is therefore 
considered as an alternative propellant to CFCs for metereddose 
inhalers (MDIs). While some of its physical and chemical 
properties are known, little has been published in regard to its 
use as a replacement for CFCs in MDIs. 
The vapor pressure of heptafluoropropane (P-227) is 
somewhat lower than that of tetrafluoroethane and dichlorodifluoromethane 
but considerably higher than the vapor pressure 
used to formulate most MDIs. 
When heptafluoropropane (P-227) is used for pharmaceutical 
aerosols and MDIs, the pharmaceutical grade must be 
specified. Industrial grades may not be suitable due to their 
impurity profile. 
Similarly to tetrafluoroethane, heptafluoropropane is not a 
good solvent for medicinal agents or for the commonly used 
surfactants and dispersing agents used in the formulation of 
MDIs. 
There are several MDIs formulated with this propellant 
worldwide that contain a steroid as the active ingredient. A 
great deal of work is being carried out in regard to its use as a 
propellant for MDIs. 
8 Description 
Heptafluoropropane is a liquefied gas and exists as a liquid at 
room temperature when contained under its own vapor 
pressure, or as a gas when exposed to room temperature and 
atmospheric pressure. The liquid is practically odorless and 
colorless. The gas in high concentration has a faint etherlike 
odor. Heptafluoropropane is noncorrosive, nonirritating, and 
nonflammable. 
9 Pharmacopeial Specifications 
—
10 Typical Properties 
Boiling point: 16.58C 
Density: 
1.415 g/cm3 for liquid at 208C; 
1.323 g/cm3 for liquid at 408C. 
Flammability: nonflammable. 
Freezing point: 1318C 
Solubility: soluble 1 in 1725 parts of water at 208C. 
Surface tension: 6.96mN/m at 208C 
11 Stability and Storage Conditions 
Heptafluoropropane is a nonreactive and stable material. The 
liquefied gas is stable when used as a propellant and should be 
stored in a metal cylinder in a cool, dry place. 
12 Incompatibilities 
—
13 Method of Manufacture 
—
14 Safety 
Heptafluoropropane is used as a fire extinguisher and is 
applicable as a non-CFC propellant in various metered-dose 
inhalers. Heptafluoropropane is regarded as nontoxic and 
nonirritating when used as directed. No acute or chronic 
hazard is present when it is used normally. Inhaling high 
concentrations of heptafluoropropane vapors can be harmful 
and is similar to inhaling vapors of other propellants. 
Deliberate inhalation of vapors of heptafluoropropane can be 
dangerous and may cause death. The same labeling required of 
CFC aerosols would be required for those containing heptafluoropropane 
as a propellant (except for the EPA requirement). 
(See Chlorofluorocarbons (CFC), Section 14.) 
15 Handling Precautions 
Heptafluoropropane is usually encountered as a liquefied gas 
and appropriate precautions for handling such materials should 
be taken. Eye protection, gloves, and protective clothing are

recommended. Heptafluoropropane should be handled in a 
well-ventilated environment. The vapors are heavier than air 
and do not support life; therefore, when cleaning large tanks 
that have contained this propellant, adequate provisions for 
oxygen supply in the tanks must be made in order to protect 
workers cleaning the tanks. Although nonflammable, when 
heated to decomposition heptafluoropropane will emit hydrogen 
fluoride and carbon monoxide. 
16 Regulatory Status 
—
17 Related Substances 
Difluoroethane; tetrafluoroethane. 
18 Comments 
The main disadvantage of using heptafluoropropane is its lack 
of miscibility with water and its poor solubility characteristics 
when used with medicinal agents and the commonly used MDI 
surfactants. 
The use of heptafluoropropane as a propellant for MDIs has 
been the subject of many patents throughout the world. These 
patents cover the formulation of MDIs, the use of specific 
surfactants and cosolvents, etc., and the formulator is referred 
to the patent literature prior to formulating an MDI with any 
HFC as the propellant. The formulation of MDIs with 
tetrafluoroethane and heptafluoropropane propellant is complicated 
since they may serve as a replacement for dichlorodifluoromethane 
or dichlorotetrafluoroethane. The use of an 
HFC as the propellant also requires a change in manufacturing 
procedure, which necessitates a redesign of the filling and 
packaging machinery for an MDI. 
19 Specific References 
—
20 General References 
Pischtiak AH. Characteristics, supply and use of the hydrofluorocarbons 
HFA 227 and HFA 134 for medical aerosols in the past, 
present and future. Manufacturer’s perspectives. Chim Oggi 2002; 
20(3–4): 14–15, 17–19. 
21 Authors 
CJ Sciarra, JJ Sciarra. 
22 Date of Revision 
23 August 2005. 
322 Heptafluoropropane (HFC)

Hexetidine 
1 Nonproprietary Names 
BP: Hexetidine 
PhEur: Hexetidinum 
2 Synonyms 
5-Amino-1,3-bis(2-ethylhexyl)hexahydro-5-methylpyrimidine; 
5-amino-1,3-di(b-ethylhexyl)hexahydro-5-methylpyrimidine; 
1,3-bis(2-ethylhexyl)-5-methylhexahydropyrimidin-5-ylamine; 
1,3-bis(b-ethylhexyl)-5-methyl-5-aminohexahydropyrimidine; 
Glypesin; Hexigel; Hexocil; Hexoral; Hextril; Oraldene; 
Sterisil; Steri/Sol. 
3 Chemical Name and CAS Registry Number 
1,3-bis(2-Ethylhexyl)-5-methylhexahydro-5-pyrimidinamine 
[141-94-6] 
4 Empirical Formula and Molecular Weight 
C21H45N3 339.61 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; antiseptic. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Hexetidine is used as an antimicrobial preservative in cosmetics 
and nonparenteral pharmaceutical formulations. Therapeutically, 
hexetidine is mainly used as a 0.1% w/v solution in 
mouthwash formulations for the prevention and treatment of 
minor local infections, gingivitis, and mouth ulcers. 
8 Description 
Hexetidine is a colorless or faint yellow-colored oily liquid with 
a characteristic amine odor. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for hexetidine. 
Test PhEur 2005 
Identification . 
Characters . 
Relative density 0.864–0.870 
Refractive index 1.461–1.467 
Optical rotation 0.108 to .0.108 
Absorbance . 
Related substances . 
Sulfated ash 40.1% 
Heavy metals 410 ppm 
Assay 98.0–102.0% 
10 Typical Properties 
Antimicrobial activity: hexetidine is a nonantibiotic antimicrobial 
agent that possesses broad-spectrum antimicrobial 
activity against Gram-positive and Gram-negative bacteria 
and fungi such as Candida albicans.(1–4) Several studies have 
identified the antiplaque activity of hexetidine.(3–8) Hexetidine 
has been shown to be effective against isolates of 
Staphylococcus aureus and Pseudomonas aeruginosa in 
planktonic form and against biofilms of the same microorganisms 
on PVC.(1) Hexetidine has also been reported to 
reduce the adherence of Candida albicans to human buccal 
epithelial cells in vitro.(9) Hexetidine has been shown to be a 
promising candidate antimalarial agent, with IC50 values 
being comparable with those of quinine chlorohydrate and 
chloroquine sulfate.(10) See also Table II. 
Boiling point: 172–1768C 
Dissociation constant: pKa = 8.3 
Density: 0.864–0.870 at 208C 
Refractive index: nD
20 = 1.463–1.467 
Solubility: soluble in acetone, benzene, chloroform, dichloromethane, 
ethanol (95%), n-hexane, methanol, mineral 
acids, petroleum ether, and propylene glycol; very slightly 
soluble in water. 
Table II: Minimum inhibitory concentrations (MICs) for hexetidine. 
Microorganism MIC (mg/mL) 
Aspergillus niger <25 
Bacillus subtilis <25 
Candida albicans 250–500 
Escherichia coli >500 
Pseudomonas aeruginosa >500 
Staphylococcus aureus >25 
Staphylococcus epidermitis >6 
11 Stability and Storage Conditions 
Hexetidine is stable and should be stored in a well-closed 
container in a cool, dry place. Brass and copper equipment 
should not be used for the handling or storage of hexetidine.

12 Incompatibilities 
Hexetidine is incompatible with strong oxidizing agents. Salts 
are formed with mineral and organic acids; strong acids cause 
opening of the hexahydropyrimidine ring, releasing formaldehyde. 
13 Method of Manufacture 
Hexetidine is prepared by hydrogenation under pressure of 1,3- 
bis(2-ethylhexyl)-5-methyl-4-nitrohexahydropyriminine at 
1008C using Raney nickel as a catalyst. 
14 Safety 
Hexetidine is mainly used in mouthwashes as a bactericidal and 
fungicidal antiseptic. It is also used as an antimicrobial 
preservative and is generally regarded as a relatively nontoxic 
and nonirritant material at concentrations up to 0.1% w/v. 
Allergic contact dermatitis and altered olfactory and taste 
perception have occasionally been reported. Hexetidine is toxic 
when administered intravenously. 
Solutions of hexetidine in oil at concentrations of 5–10% 
w/v cause strong primary irritations without sensitization in 
humans. Long-term toxicological studies of up to 0.1% w/w of 
hexetidine in food for 1 year do not show any toxic effect. 
Fetotoxicity, embryotoxicity, and teratogenicity studies in rats 
of doses up to 50 mg/kg/day exhibit no sign of toxicity. 
LD100 (cat, IV): 5–20 mg/kg 
LD50 (dog, oral): 1.60 g/kg 
LD50 (mouse, IP): 0.142 g/kg 
LD50 (mouse, oral): 1.52 g/kg 
LD50 (rat, oral): 0.61–1.43 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Hexetidine may be harmful 
upon inhalation or on contact with the skin or eyes. Eye 
protection and gloves are recommended. When significant 
quantities are being handled, the use of a respirator with an 
appropriate gas filter is recommended. 
16 Regulatory Status 
Included in nonparenteral formulations licensed in Europe. 
17 Related Substances 
—
18 Comments 
Hexetidine has been quantitatively determined in both commercial 
formulations and saliva using a reversed-phase HPLC 
method,(11) with determination being possible at concentrations 
below the published minimum inhibitory concentrations 
for a selection of microorganisms. 
The EINECS number for hexetidine is 205-513-5. 
19 Specific References 
1 Gorman SP, McGovern JG, Woolfson AD, et al. The concomitant 
development of poly(vinyl chloride)-related biofilm and antimicrobial 
resistance in relation to ventilator-associated pneumonia. 
Biomaterials 2001; 22(20): 2741–2747. 
2 Guiliana G, Pizzo G, Milici ME, Giangreco R. In vitro activities of 
antimicrobial agents against Candida species. Oral Surg Oral Med 
Oral Pathol Oral Radiol Endod 1999; 87(1): 44–49. 
3 Williams MJR, Adams D, Hillam DG, Ashley KC. The effect of 
hexetidine 0.1% in the control of dental plaque. Br Dent J 1987; 
163(9): 300–302. 
4 Wile DB, Dinsdale JRM, Joynson DHM. Hexetidine (Oraldene) – 
a report on its antibacterial and antifungal properties on the oral 
flora in healthy subjects. Curr Med Res Opin 1986; 10(2): 82–88. 
5 Bokor M. The effect of hexetidine spray on dental plaque 
following periodontal surgery. J Clin Periodontol 1996; 23(12): 
1080–1083. 
6 Roberts WR, Addy M. Comparison of the in vivo and in vitro 
antibacterial properties of antiseptic mouthrinses containing 
chlorhexidine, alexidine, cetylpyridinium chloride and hexetidine 
– relevance to mode of action. J Clin Periodontol 1981; 8(4): 295– 
310. 
7 Pilloni AP, Buttini G, Giannerelli D, et al. Antimicrobial action of 
Nitens mouthwash (cetylpyridinium naproxenate) on multiple 
isolates of pharyngeal microbes: a controlled study against 
chlorhexidine, benzydamine, hexetidine, amoxicillin clavulanate, 
clarithromycin and cefaclor. Chemotherapy 2002; 48(4): 168–173 
8 Sharma NC, Galustians HJ, Qaqish J, et al. Antiplaque and 
antigingivitis effectiveness of a hexetidine mouthwash. J Clin 
Periodontol 2003; 30(7): 590–594. 
9 Jones DS, McGovern JG,Woolfson AD, Gorman SP. The effects of 
hexetidine (Oraldene) on the adherence of Candida albicans to 
human buccal epithelial cells in vitro and ex vivo and on in vitro 
morphogenesis. Pharm Res 1997; 14(12): 1765–1771. 
10 Gozalbes R, Galvez J, Moreno A, Garcia-Domenech R. Discovery 
of new antimalarial compounds by use of molecular connectivity 
techniques. J Pharm Pharmacol 1999; 51(2): 111–117. 
11 McCoy CP, Jones DS, McGovern JG, et al. Determination of the 
salivary retention of hexetidine in-vivo by high-performance liquid 
chromatography. J Pharm Pharmacol 2000; 52(11): 1355–1359. 
20 General References 
Eley BM. Antibacterial agents in the control of supragingival plaque – a 
review. Br Dent Rev 1999; 186(6): 286–296. 
Jones DS, McGovern JG, Woolfson AD, et al. Physicochemical 
characterization of hexetidine-impregnated endotracheal tube 
poly(vinyl chloride) and resistance to adherence of respiratory 
bacterial pathogens. Pharm Res 2002; 19(6): 818–824. 
21 Authors 
DS Jones, CP McCoy. 
22 Date of Revision 
17 August 2005. 
324 Hexetidine

Hydrocarbons (HC) 
1 Nonproprietary Names 
(a) USPNF: Butane 
(b) USPNF: Isobutane 
(c) USPNF: Propane 
2 Synonyms 
(a) A-17; Aeropres 17; n-butane; E943a 
(b) A-31; Aeropres 31; E943b; 2-methylpropane 
(c) A-108; Aeropres 108; dimethylmethane; E944; propyl 
hydride 
3 Chemical Name and CAS Registry Number 
(a) Butane [106-97-8] 
(b) 2-Methylpropane [75-28-5] 
(c) Propane [74-98-6] 
4 Empirical Formula and Molecular Weight 
(a) C4H10 58.12 
(b) C4H10 58.12 
(c) C3H8 44.10 
5 Structural Formula 
6 Functional Category 
Aerosol propellant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Propane, butane, and isobutane are hydrocarbons (HC). They 
are used as aerosol propellants: alone, in combination with 
each other, and in combination with a hydrofluoroalkane 
(HFA) propellant. They are used primarily in topical pharmaceutical 
aerosols (particularly aqueous foam and some spray 
products). 
Depending upon the application, the concentration of 
hydrocarbon propellant range is 5–95% w/w. Foam aerosols 
generally use about 4–5% w/w of a hydrocarbon propellant 
consisting of isobutane (84.1%) and propane (15.9%), or 
isobutane alone. Spray-type aerosols utilize propellant concentrations 
of 50% w/w and higher.(1) 
Hydrocarbon propellants are also used in cosmetics and 
food products as aerosol propellants. 
Only highly purified hydrocarbon grades can be used for 
pharmaceutical formulations since they may contain traces of 
unsaturated compounds that not only contribute a slight odor 
to a product but may also react with other ingredients. 
8 Description 
Hydrocarbon propellants are liquefied gases and exist as 
liquids at room temperature when contained under their own 
vapor pressure, or as gases when exposed to room temperature 
and atmospheric pressure. They are essentially clear, colorless, 
odorless liquids but may have a slight etherlike odor. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for hydrocarbons from the 
USPNF 23. 
Test Butane Isobutane Propane 
Identification . . . 
Water 40.001% 40.001% 40.001% 
High-boiling residues 45 mg/mL 45 mg/mL 45 mg/mL 
Acidity of residue . . . 
Sulfur compounds . . . 
Assay 597.0% 595.0% 598.0% 
10 Typical Properties 
See Table II for selected typical properties. 
11 Stability and Storage Conditions 
Butane and the other hydrocarbons used as aerosol propellants 
are stable compounds and are chemically nonreactive when 
used as propellants. They are, however, highly flammable and 
explosive when mixed with certain concentrations of air; see 
Section 10.(2) They should be stored in a well-ventilated area, in 
a tightly sealed cylinder. Exposure to excessive heat should be 
avoided.

12 Incompatibilities 
Other than their lack of miscibility with water, butane and the 
other hydrocarbon propellants do not have any practical 
incompatibilities with the ingredients commonly used in 
pharmaceutical aerosol formulations. Hydrocarbon propellants 
are generally miscible with nonpolar materials and some 
semipolar compounds such as ethanol. 
13 Method of Manufacture 
Butane and isobutane are obtained by the fractional distillation, 
under pressure, of crude petroleum and natural gas. They may 
be purified by passing through a molecular sieve to remove any 
unsaturated compounds that are present. 
Propane is prepared by the same method. It may also be 
prepared by a variety of synthetic methods. 
14 Safety 
The hydrocarbons are not generally regarded as toxic materials 
when used as aerosol propellants. However, deliberate inhalation 
of aerosol products containing hydrocarbon propellants 
can be fatal. 
15 Handling Precautions 
Butane and the other hydrocarbon propellants are liquefied 
gases and should be handled with appropriate caution. Direct 
contact of liquefied gas with the skin is hazardous and may 
result in serious cold burn injuries. Protective clothing, rubber 
gloves, and eye protection are recommended. 
Butane, isobutane, and propane are asphyxiants and should 
be handled in a well-ventilated environment; it is recommended 
that environmental oxygen levels are monitored and not 
permitted to fall below a concentration of 18% v/v. These 
vapors do not support life; therefore when cleaning large tanks, 
adequate provisions for oxygen supply must be provided for 
personnel cleaning the tanks. Butane is highly flammable and 
explosive and must only be handled in an explosion-proof 
room that is equipped with adequate safety warning devices 
and explosion-proof equipment. 
To fight fires, the flow of gas should be stopped and dry 
powder extinguishers should be used. 
16 Regulatory Status 
GRAS listed. Butane, isobutane, and propane are accepted for 
use as food additives in Europe. Included in the FDA Inactive 
Ingredients Guide (aerosol formulations for topical application). 
Included in nonparental medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Dimethyl ether. 
18 Comments 
Although hydrocarbon aerosol propellants are relatively 
inexpensive, nontoxic, and environmentally friendly (since 
they are not damaging to the ozone layer and are not 
greenhouse gases), their use is limited by their flammability. 
While hydrocarbon propellants are primarily used in topical 
aerosol formulations, it is possible that butane may also be 
useful in metered-dose inhalers as a replacement for chlorofluorocarbons. 
Various blends of hydrocarbon propellants that have a 
range of physical properties suitable for different applications 
are commercially available, e.g., CAP30 (Calor Gas Ltd.) is a 
mixture of 11% propane, 29% isobutane, and 60% butane. A- 
46 (Aeropres) is a commonly used mixture for aerosol foams 
and consists of about 85% isobutane and 15% propane. The 
number following the letter denotes the approximate vapor 
pressure of the blend or mixture. 
19 Specific References 
1 Sciarra JJ. Pharmaceutical aerosols. In: Banker GS, Rhodes CT, 
eds. Modern Pharmaceutics, 3rd edn. New York: Marcel Dekker, 
1996: 547–574. 
2 Dalby RN. Prediction and assessment of flammability hazards 
associated with metered-dose inhalers containing flammable 
propellants. Pharm Res 1992; 9: 636–642. 
Table II: Selected typical properties for hydrocarbon propellants. 
Butane Isobutane Propane 
Autoignition temperature 4058C 4208C 4688C 
Boiling point 0.58C 11.78C –42.18C 
Critical pressure 3.80MPa (37.47 atm) 3.65MPa (36 atm) 4.26 MPa (42.01 atm) 
Critical temperature 1528C 1358C 96.88C 
Density: liquid at 208C 0.58 g/cm3 0.56 g/cm3 0.50 g/cm3 
Explosive limits 
Lower limit 1.9% v/v 1.8% v/v 2.2% v/v 
Upper limit 8.5% v/v 8.4% v/v 9.5% v/v 
Flash point 628C 838C 104.58C 
Freezing point 138.38C 159.78C 187.78C 
Kauri-butanol value 19.5 17.5 15.2 
Vapor density 
Absolute 2.595 g/m3 2.595 g/m3 1.969 g/m3 
Relative 2.046 (air = 1) 2.01 (air = 1) 1.53 (air = 1) 
Vapor pressure at 218C 113.8 kPa (16.5 psig) 209.6 kPa (30.4 psig) 758.4 kPa (110.0 psig) 
Vapor pressure at 54.58C — 661.9 kPa (96.0 psig) 1765.1 kPa (256 psig) 
326 Hydrocarbons (HC)

20 General References 
Johnson MA. The Aerosol Handbook, 2nd edn. Caldwell: WE 
Dorland, 1982: 199–255, 335–361. 
Randall DS. Solving the problems of hydrocarbon propellants. Manuf 
Chem Aerosol News 1979; 50(4): 43, 44, 47. 
Sanders PA. Handbook of Aerosol Technology, 2nd edn. New York: 
Van Nostrand Reinhold, 1979: 36–44. 
Sciarra JJ. Pharmaceutical aerosols. In: Lackman L, Lieberman HA, 
Kanig JL, eds. The Theory and Practice of Industrial Pharmacy, 3rd 
edn. Philadelphia: Lea and Febiger, 1986: 589–618. 
Sciarra CJ, Sciarra JJ. Aerosols. In: Gennaro AR, ed. Remington: The 
Science and Practice of Pharmacy, 20th edn. Baltimore, MD: 
Lippincott Williams and Wilkins, 2000: 963–979. 
Sciarra JJ. Aerosol suspensions and emulsions. In: Lieberman H, Rieger 
M, Banker G, eds. Pharmaceutical Dosage Forms: Disperse 
Systems, vol. 2, 2nd edn. New York: Marcel Dekker, 1996: 319– 
356. 
Sciarra JJ, Stoller L. The Science and Technology of Aerosol Packaging. 
New York: Wiley, 1974: 131–137. 
21 Authors 
CJ Sciarra, JJ Sciarra. 
22 Date of Revision 
23 August 2005. 
Hydrocarbons (HC) 327

Hydrochloric Acid 
1 Nonproprietary Names 
BP: Hydrochloric acid 
JP: Hydrochloric acid 
PhEur: Acidum hydrochloridum concentratum 
USPNF: Hydrochloric acid 
2 Synonyms 
Chlorohydric acid; concentrated hydrochloric acid; E507. 
3 Chemical Name and CAS Registry Number 
Hydrochloric acid [7647-01-0] 
4 Empirical Formula and Molecular Weight 
HCl 36.46 
5 Structural Formula 
HCl 
6 Functional Category 
Acidifying agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Hydrochloric acid is widely used as an acidifying agent, in a 
variety of pharmaceutical and food preparations (see Section 
16). It may also be used to prepare dilute hydrochloric acid, 
which in addition to its use as an excipient has some therapeutic 
use, intravenously in the management of metabolic alkalosis, 
and orally for the treatment of achlorhydria. See Section 17. 
8 Description 
Hydrochloric acid occurs as a clear, colorless, fuming aqueous 
solution of hydrogen chloride, with a pungent odor. 
The JP 2001 specifies that hydrochloric acid contains 
35.0–38.0% w/w of HCl; the PhEur 2005 specifies that 
hydrochloric acid contains 35.0–39.0% w/w of HCl; and the 
USPNF 23 specifies that hydrochloric acid contains 
36.5–38.0% w/w of HCl. See also Section 9. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for hydrochloric acid. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters . . — 
Appearance of solution — . — 
Residue on ignition 41.0mg — 40.008% 
Residue on evaporation — 40.01% — 
Bromide or iodide . — . 
Free bromine . — . 
Free chlorine . 44 ppm . 
Sulfate . 420 ppm . 
Sulfite . — . 
Arsenic 41 ppm — — 
Heavy metals 45 ppm 42 ppm 45 ppm 
Mercury 40.04 ppm — — 
Assay (of HCl) 35.0–38.0% 35.0–39.0% 36.5–38.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 0.1 (10% v/v aqueous solution) 
Boiling point: 1108C (constant boiling mixture of 20.24% w/w 
HCl) 
Density: 1.18 g/cm3 at 208C 
Freezing point: 248C 
Refractive index: nD
20 = 1.342 (10% v/v aqueous solution) 
Solubility: miscible with water; soluble in diethyl ether, ethanol 
(95%), and methanol. 
11 Stability and Storage Conditions 
Hydrochloric acid should be stored in a well-closed, glass or 
other inert container at a temperature below 308C. Storage in 
close proximity to concentrated alkalis, metals, and cyanides 
should be avoided. 
12 Incompatibilities 
Hydrochloric acid reacts violently with alkalis, with the 
evolution of a large amount of heat. Hydrochloric acid also 
reacts with many metals, liberating hydrogen. 
13 Method of Manufacture 
Hydrochloric acid is an aqueous solution of hydrogen chloride 
gas produced by a number of methods including: the reaction of 
sodium chloride and sulfuric acid; the constituent elements; as a 
by-product from the electrolysis of sodium hydroxide; and as a 
by-product during the chlorination of hydrocarbons. 
14 Safety 
When used diluted, at low concentration, hydrochloric acid is 
not usually associated with any adverse effects. However, the 
concentrated solution is corrosive and can cause severe damage 
on contact with the eyes and skin, or if ingested. 
LD50 (mouse, IP): 1.4 g/kg(1) 
LD50 (rabbit, oral): 0.9 g/kg

15 Handling Precautions 
Caution should be exercised when handling hydrochloric acid 
and suitable protection against inhalation and spillage should 
be taken. Eye protection, gloves, face mask, apron, and 
respirator are recommended, depending on the circumstances 
and quantity of hydrochloric acid handled. Spillages should be 
diluted with copious amounts of water and run to waste. 
Splashes on the skin and eyes should be treated by immediate 
and prolonged washing with large amounts of water and 
medical attention should be sought. Fumes can cause irritation 
to the eyes, nose, and respiratory system; prolonged exposure 
to fumes may damage the lungs. In the UK, the recommended 
short-term exposure limit for hydrogen chloride gas and 
aerosol mists is 8 mg/m3 (5 ppm). The long-term exposure limit 
(8-hour TWA) is 2 mg/m3 (1 ppm).(2) 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (dental 
solutions; epidural injections, IM, IV, and SC injections, 
inhalations, ophthalmic preparations, oral solutions, nasal, 
otic, rectal, and topical preparations). Included in parenteral 
and nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Dilute hydrochloric acid. 
Dilute hydrochloric acid 
Synonyms: acidum hydrochloridum dilutum; diluted hydrochloric 
acid. 
Density: 1.05 g/cm3 at 208C 
Comments: the JP 2001 and PhEur 2005 specify that dilute 
hydrochloric acid contains 9.5–10.5% w/w of HCl and is 
prepared by mixing 274 g of hydrochloric acid with 726 g of 
water. The USPNF 23 specifies 9.5–10.5% w/v of HCl, 
prepared by mixing 226mL of hydrochloric acid with 
sufficient water to make 1000 mL. 
18 Comments 
In pharmaceutical formulations, dilute hydrochloric acid is 
usually used as an acidifying agent in preference to hydrochloric 
acid. Hydrochloric acid is also used therapeutically as 
an escharotic.(3) The PhEur 2005 also contains a specification 
for hydrochloric acid, dilute; see Section 17. 
A specification for hydrochloric acid is contained in the 
Food Chemicals Codex (FCC). 
The EINECS number for hydrochloric acid is 231-595-7. 
19 Specific References 
1 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1980. 
2 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
3 Sweetman S, ed. Martindale: The Complete Drug Reference, 34th 
edn. London: Pharmaceutical Press, 2005: 1699. 
20 General References 
Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients Directory 1996. Tokyo: Yakuji Nippo, 1996: 228. 
21 Authors 
SC Owen. 
22 Date of Revision 
12 August 2005. 
Hydrochloric Acid 329

Hydroxyethyl Cellulose 
1 Nonproprietary Names 
BP: Hydroxyethylcellulose 
PhEur: Hydroxyethylcellulosum 
USPNF: Hydroxyethyl cellulose 
2 Synonyms 
Cellosize HEC; cellulose hydroxyethyl ether; cellulose hydroxyethylate; 
ethylhydroxy cellulose; ethylose; HEC; HE 
cellulose; 2-hydroxyethyl cellulose ether; hydroxyethyl ether 
cellulose; hydroxyethyl starch; hyetellose; Natrosol; oxycellulose; 
Tylose PHA. 
3 Chemical Name and CAS Registry Number 
Cellulose, 2-hydroxyethyl ether [9004-62-0] 
4 Empirical Formula and Molecular Weight 
The USPNF 23 describes hydroxyethyl cellulose as a partially 
substituted poly(hydroxyethyl) ether of cellulose. It is available 
in several grades that vary in viscosity and degree of 
substitution; some grades are modified to improve their 
dispersion in water. The grades are distinguished by appending 
a number indicative of the apparent viscosity in mPa s, of a 2% 
w/v solution measured at 208C. Hydroxyethyl cellulose may 
also contain a suitable anticaking agent. 
See Section 10. 
5 Structural Formula 
where R is H or [—CH2CH2O—]mH 
6 Functional Category 
Coating agent; suspending agent; tablet binder; thickening 
agent; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Hydroxyethyl cellulose is a nonionic, water-soluble polymer 
widely used in pharmaceutical formulations. It is primarily used 
as a thickening agent in ophthalmic(1) and topical formulations,(
2) although it is also used as a binder(3) and film-coating 
agent for tablets.(4) It is present in lubricant preparations for dry 
eye, contact lens care, and dry mouth.(5) 
The concentration of hydroxyethyl cellulose used in a 
formulation is dependent upon the solvent and the molecular 
weight of the grade. 
Hydroxyethyl cellulose is also widely used in cosmetics. 
8 Description 
Hydroxyethyl cellulose occurs as a light tan or cream to whitecolored, 
odorless and tasteless, hygroscopic powder. 
SEM: 1 
Excipient: Hydroxyethyl cellulose (Natrosol) 
Manufacturer: Aqualon 
Magnification: 120 
9 Pharmacopeial Specifications 
See Table I. 
10 Typical Properties 
Acidity/alkalinity: pH = 5.5–8.5 for a 1% w/v aqueous 
solution. 
Ash: 
2.5% w/w for Cellosize; 
3.5% w/w for Natrosol. 
Autoignition temperature: 4208C 
Density (bulk): 
0.35–0.61 g/cm3 for Cellosize; 
0.60 g/cm3 for Natrosol. 
Melting point: softens at 135–1408C, decomposes at about 
2058C.

SEM: 2 
Excipient: Hydroxyethyl cellulose (Natrosol) 
Manufacturer: Aqualon 
Magnification: 600 
Table I: Pharmacopeial specifications for hydroxyethyl cellulose 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Appearance of solution . — 
Viscosity 75.0–140.0% . 
pH 5.5–8.5 6.0–8.5 
Loss on drying 410.0% 410.0% 
Lead — 40.001% 
Residue on ignition 44.0% 45.0% 
Chlorides 41.0% — 
Heavy metals 420 ppm 420 mg/g 
Organic volatile impurities — . 
Nitrates . — 
Glyoxal 420 ppm — 
Ethylene oxide 41 ppm — 
2-Chloroethanol 45 ppm — 
Nitrates . — 
Moisture content: commercially available grades of hydroxyethylcellulose 
contain less than 5% w/w of water. 
However, as hydroxyethyl cellulose is hygroscopic, the 
amount of water absorbed depends upon the initial moisture 
content and the relative humidity of the surrounding air. 
Typical equilibrium moisture values for Natrosol 250 at 
258C are: 6% w/w at 50% relative humidity and 29% w/w 
at 84% relative humidity. 
Particle size distribution: 
Cellosize: 100% through a US #80 mesh (177 mm); 
Natrosol (regular grind): 10% retained on a US #40 mesh 
(420 mm); 
Natrosol (X-grind): 0.5% retained on a US #60 mesh 
(250 mm). 
Refractive index: nD
20 = 1.336 for a 2% w/v aqueous solution. 
Solubility: hydroxyethyl cellulose is soluble in either hot or cold 
water, forming clear, smooth, uniform solutions. Practically 
insoluble in acetone, ethanol (95%), ether, toluene, and 
most other organic solvents. In some polar organic solvents, 
such as the glycols, hydroxyethyl cellulose either swells or is 
partially soluble. 
Specific gravity: 1.38–1.40 for Cellosize; 1.0033 for a 2% w/v 
aqueous hydroxyethyl cellulose solution. 
Surface tension: see Table II. 
Table II: Surface tension (mN/m) of different Cellosize (Amerchol 
Corp.) grades at 258C 
Concentration 
of aqueous 
solution 
(% w/v) 
Cellosize grade 
WP-02 WP-09 WP-300 QP-4400 QP-52000 QP-100M 
0.01 65.8 65.7 66.4 66.3 65.9 66.1 
0.1 65.3 65.4 65.8 65.3 65.4 65.4 
1.0 64.4 65.1 65.5 65.8 66.1 66.3 
2.0 64.2 65.0 66.3 67.3 — — 
5.0 64.1 64.7 — — — — 
10.0 64.4 65.9 — — — — 
Viscosity (dynamic): hydroxyethyl cellulose is available in a 
wide range of viscosity types; e.g. Cellosize is manufactured 
in 11 regular viscosity grades. Hydroxyethyl cellulose 
grades differ principally in their aqueous solution viscosities 
which range from 2–20 000 mPa s for a 2% w/v aqueous 
solution. Two types of Cellosize are produced, a WP-type, 
which is a normal-dissolving material, and a QP-type, which 
is a rapid-dispersing material. 
The lowest viscosity grade (02) is available only in the 
WP-type. Five viscosity grades (09, 3, 40, 300, and 4400) 
are produced in both WP- and QP-types. Five high-viscosity 
grades (10000, 15000, 30000, 52000, and 100 M) are 
produced only in the QP-type. 
For the standard Cellosize grades and types available and 
their respective viscosity ranges in aqueous solution, see 
Table III. 
Natrosol 250 has a degree of substitution of 2.5 and is 
produced in 10 viscosity types. The suffix ‘R’ denotes that 
Natrosol has been surface-treated with glyoxal to aid in 
solution preparation; see Table IV. 
Aqueous solutions made using a rapidly dispersing 
material may be prepared by dispersing the hydroxyethyl 
cellulose in mildly agitated water at 20–258C. When the 
hydroxyethyl cellulose has been thoroughly wetted, the 
temperature of the solution may be increased to 60–708C to 
increase the rate of dispersion. Making the solution slightly 
alkaline also increases the dispersion process. Typically, 
complete dispersion may be achieved in approximately an 
hour by controlling the temperature, pH, and rate of 
stirring. 
Normally dispersing grades of hydroxyethyl cellulose 
require more careful handling to avoid agglomeration 
during dispersion; the water should be stirred vigorously. 
Alternatively, a slurry of hydroxyethyl cellulose may be 
prepared in a nonaqueous solvent, such as ethanol, prior to 
dispersion in water. 
See also Section 11 for information on solution stability. 
Hydroxyethyl Cellulose 331

Table III: Approximate viscosities of various grades of aqueous 
Cellosize (Amerchol Corp.) solutions at 258C. 
Type Grade Concentration 
(% w/v) 
Viscosity (mPa s)(a) 
Low High 
WP 02 5 7–14 14–20 
WP and 
QP 
09 5 60–100 100–140 
3 5 220–285 285–350 
40 2 70–110 110–150 
300 2 250–325 325–400 
4400 2 4 200–4 700 700–5 200 
QP 10000 2 5 700 6 500 
15000 2 15 000–18 000 18 000–21 000 
30000 1 950–1 230 1 230–1 500 
52000 1 1 500–1 800 1 800–2 100 
100M 1 2 500 3 000 
(a) Cellosize viscosity grades are available in narrower ranges, as noted by the Low and High 
designation. 
Table IV: Approximate viscosities of various grades of aqueous 
Natrosol 250 (Aqualon Inc.) solutions at 258C. 
Type Viscosity (mPa s) for varying concentrations (% w/v) 
1% 2% 5% 
HHR 3 400–5 000 — — 
H4R 2 600–3 300 — — 
HR 1 500–2 500 — — 
MHR 800–1 500 — — 
MR — 4 500–6 500 — 
KR — 1 500–2 500 — 
GR — 150–400 — 
ER — 25–105 — 
JR — — 150–400 
LR — — 75–150 
11 Stability and Storage Conditions 
Hydroxyethyl cellulose powder is a stable though hygroscopic 
material. 
Aqueous solutions of hydroxyethyl cellulose are relatively 
stable at pH 2–12 with the viscosity of solutions being largely 
unaffected. However, solutions are less stable below pH 5 
owing to hydrolysis. At high pH, oxidation may occur. 
Increasing the temperature reduces the viscosity of aqueous 
hydroxyethyl cellulose solutions. However on cooling, the 
original viscosity is restored. Solutions may be subjected to 
freeze–thawing, high-temperature storage, or boiling without 
precipitation or gelation occurring. 
Hydroxyethyl cellulose is subject to enzymatic degradation, 
with consequent loss in viscosity of its solutions.(6) Enzymes 
that catalyze this degradation are produced by many bacteria 
and fungi present in the environment. For prolonged storage, 
an antimicrobial preservative should therefore be added to 
aqueous solutions. Aqueous solutions of hydroxyethyl cellulose 
may also be sterilized by autoclaving. 
Hydroxyethyl cellulose powder should be stored in a wellclosed 
container, in a cool, dry place. 
12 Incompatibilities 
Hydroxyethyl cellulose is insoluble in most organic solvents. It 
is incompatible with zein and partially compatible with the 
following water-soluble compounds: casein; gelatin; methylcellulose; 
polyvinyl alcohol, and starch. 
Hydroxyethyl cellulose can be used with a wide variety of 
water-soluble antimicrobial preservatives. However, sodium 
pentachlorophenate produces an immediate increase in viscosity 
when added to hydroxyethyl cellulose solutions. 
Hydroxyethyl cellulose has good tolerance for dissolved 
electrolytes, although it may be salted out of solution when 
mixed with certain salt solutions. For example, the following 
salt solutions will precipitate a 10% w/v solution of Cellosize 
WP-09 and a 2% w/v solution of Cellosize WP-4400: sodium 
carbonate 50% and saturated solutions of aluminum sulfate; 
ammonium sulfate; chromic sulfate; disodium phosphate; 
magnesium sulfate; potassium ferrocyanide; sodium sulfate; 
sodium sulfite; sodium thiosulfate; and zinc sulfate. 
Natrosol is soluble in most 10% salt solutions, excluding 
sodium carbonate and sodium sulfate, and many 50% salt 
solutions with the exception of the following: aluminum 
sulfate; ammonium sulfate; diammonium phosphate; disodium 
phosphate; ferric chloride; magnesium sulfate; potassium 
ferrocyanide; sodium metaborate; sodium nitrate; sodium 
sulfite; trisodium phosphate; and zinc sulfate. Natrosol 150 is 
generally more tolerant of dissolved salts than is Natrosol 250. 
Hydroxyethyl cellulose is also incompatible with certain 
fluorescent dyes or optical brighteners, and certain quaternary 
disinfectants which will increase the viscosity of aqueous 
solutions. 
13 Method of Manufacture 
A purified form of cellulose is reacted with sodium hydroxide to 
produce a swollen alkali cellulose, which is chemically more 
reactive than untreated cellulose. The alkali cellulose is then 
reacted with ethylene oxide to produce a series of hydroxyethyl 
cellulose ethers. 
The manner in which ethylene oxide is added to cellulose 
can be described by two terms, the degree of substitution (DS) 
and the molar substitution (MS). The DS designates the average 
number of hydroxyl positions on the anhydroglucose unit that 
have been reacted with ethylene oxide. Since each anhydroglucose 
unit of the cellulose molecule has three hydroxyl groups, 
the maximum value for DS is 3. MS is defined as the average 
number of ethylene oxide molecules that have reacted with each 
anhydroglucose unit. Once a hydroxyethyl group is attached to 
each unit, it can further react with additional groups in an endto-
end formation. This reaction can continue and there is no 
theoretical limit for MS. 
14 Safety 
Hydroxyethyl cellulose is primarily used in ophthalmic and 
topical pharmaceutical formulations. It is generally regarded as 
an essentially nontoxic and nonirritant material.(7,8) 
Acute and subacute oral toxicity studies in rats have shown 
no toxic effects attributable to hydroxyethyl cellulose consumption; 
the hydroxyethyl cellulose being neither absorbed 
nor hydrolyzed in the rat gastrointestinal tract. However, 
although used in oral pharmaceutical formulations, hydroxyethyl 
cellulose has not been approved for direct use in food 
products; see Section 16. 
Glyoxal-treated hydroxyethyl cellulose is not recommended 
for use in oral pharmaceutical formulations or topical 
332 Hydroxyethyl Cellulose

preparations that may be used on mucous membranes. 
Hydroxyethyl cellulose is also not recommended for use in 
parenteral products. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Hydroxyethyl cellulose dust 
may be irritant to the eyes and eye protection is recommended. 
Excessive dust generation should be avoided to minimize the 
risks of explosion. Hydroxyethyl cellulose is combustible. 
When heated to decomposition, hydroxyethyl cellulose 
emits acrid smoke and irritating vapors, in which case a 
ventilator is recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (ophthalmic 
preparations; oral syrups and tablets; otic and topical preparations). 
Included in nonparenteral medicines licensed in the UK. 
Hydroxyethyl cellulose is not currently approved for use in 
food products in Europe or the USA, although it is permitted 
for use in indirect applications such as packaging. This 
restriction is due to the high levels of ethylene glycol residues 
that are formed during the manufacturing process. 
17 Related Substances 
Hydroxyethylmethyl cellulose; hydroxypropyl cellulose; 
hypromellose; methylcellulose. 
18 Comments 
The limited scope for the use of hydroxyethyl cellulose in 
foodstuffs is in stark contrast to its widespread application as 
an excipient in oral pharmaceutical formulations. 
Hydroxyethyl cellulose hydrogels may also be used in 
various delivery systems.(9) 
19 Specific References 
1 Grove J, Durr M, Quint M-P, Plazonnet B. The effect of vehicle 
viscosity on the ocular bioavailability of L-653328. Int J Pharm 
1990; 66: 23–28. 
2 Gauger LJ. Hydroxyethylcellulose gel as a dinoprostone vehicle. 
Am J Hosp Pharm 1984; 41: 1761–1762. 
3 Delonca H, Joachim J, Mattha A. Influence of temperature on 
disintegration and dissolution time of tablets with a cellulose 
component as binder [in French]. J Pharm Belg 1978; 33: 171– 
178. 
4 Kova. cs B, Mere.nyi G. Evaluation of tack behavior of coating 
solutions. Drug Dev Ind Pharm 1990; 16(15): 2302–2323. 
5 Sweetman SC, ed. Martindale: The Complete Drug Reference, 
34th edn. London: Pharmaceutical Press, 2005: 1579. 
6 Wirick MG. Study of the substitution pattern of hydroxyethyl 
cellulose and its relationship to enzymic degradation. J Polym Sci 
1968; 6(Part A-1): 1705–1718. 
7 Anonymous. Final report on the safety assessment of hydroxyethylcellulose, 
hydroxypropylcellulose, methylcellulose, hydroxypropyl 
methylcellulose and cellulose gum. J Am Coll Toxicol 
1986; 5(3): 1–60. 
8 Durand-Cavagna G, Delort P, Duprat P, et al. Corneal toxicity 
studies in rabbits and dogs with hydroxyethyl cellulose and 
benzalkonium chloride. Fundam Appl Toxicol 1989; 13: 500–508. 
9 Li J, Xu Z. Physical characterization of a chitosan-based hydrogel 
delivery system. J Pharm Sci 2002; 91(7): 1669–1677. 
20 General References 
Amerchol Corp. Technical literature: Cellosize, hydroxyethyl cellulose, 
1993. 
Amerchol Corp. Technical literature: Cellosize, hydroxyethyl cellulose, 
2002. 
Aqualon. Technical literature: Natrosol, hydroxyethyl cellulose, 1999. 
Chauveau C, Maillols H, Delonca H. Natrosol 250 part 1: 
characterization and modeling of rheological behavior [in French]. 
Pharm Acta Helv 1986; 61: 292–297. 
Doelker E. Cellulose derivatives. Adv Polym Sci 1993; 107: 199–265. 
Haugen P, Tung MA, Runikis JO. Steady shear flow properties, 
rheological reproducibility and stability of aqueous hydroxyethylcellulose 
dispersions. Can J Pharm Sci 1978; 13: 4–7. 
Klug ED. Some properties of water-soluble hydroxyalkyl celluloses and 
their derivatives. J Polym Sci 1971; 36(Part C): 491–508. 
Rufe RG. Cellulose polymers in cosmetics and toiletries. Cosmet 
Perfum 1975; 90(3): 93–94, 99–100. 
21 Authors 
RJ Harwood. 
22 Date of Revision 
17 August 2005. 
Hydroxyethyl Cellulose 333

Hydroxyethylmethyl Cellulose 
1 Nonproprietary Names 
BP: Hydroxyethylmethylcellulose 
PhEur: Methylhydroxyethylcellulosum 
2 Synonyms 
Cellulose, 2-hydroxyethyl methyl ester; Culminal MHEC; 
HEMC; hydroxyethyl methylcellulose; hymetellose; MHEC; 
methylhydroxyethylcellulose; Tylopur MH; Tylopur MHB; 
Tylose MB; Tylose MH; Tylose MHB. 
3 Chemical Name and CAS Registry Number 
Hydroxyethylmethylcellulose [9032-42-2] 
4 Empirical Formula and Molecular Weight 
The PhEur 2005 describes hydroxyethylmethyl cellulose as a 
partly O-methylated and O-(2-hydroxyethylated) cellulose. 
Various different grades are available, which are distinguished 
by appending a number indicative of the apparent viscosity in 
millipascal seconds (mPa s) of a 2% w/v solution measured at 
208C. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Coating agent; suspending agent; tablet binder; thickening 
agent; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Hydroxyethylmethyl cellulose is used as an excipient in a wide 
range of pharmaceutical products, including oral tablets and 
suspensions and topical gel preparations.(1) It has similar 
properties to methylcellulose, but the hydroxyethyl groups 
make it more readily soluble in water and solutions are more 
tolerant of salts and have a higher coagulation temperature. 
8 Description 
A white, yellowish-white or grayish-white powder or granules, 
hygroscopic after drying. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for hydroxyethylmethyl 
cellulose. 
Test PhEur 2005 
Identification . 
Appearance of solution . 
pH 5.5–8.0 
Apparent viscosity . 
Chlorides 40.5% 
Heavy metals 420 ppm 
Loss on drying 410.0% 
Sulfated ash 41.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 5.5–8.0 (2% w/v aqueous solution) 
Moisture content: 410% 
Solubility: hydroxyethylmethyl cellulose is practically insoluble 
in hot water (above 608C), acetone, ethanol (95%), ether, 
and toluene. It dissolves in cold water to form a colloidal 
solution. 
Viscosity (dynamic): 22–30 mPa s (22–30 cP) for a 2% w/v 
aqueous solution at 208C. 
11 Stability and Storage Conditions 
Hydroxyethylmethyl cellulose is hygroscopic and should 
therefore be stored under dry conditions away from heat. 
12 Incompatibilities 
—
13 Method of Manufacture 
—
14 Safety 
Hydroxyethylmethyl cellulose is used as an excipient in various 
oral and topical pharmaceutical preparations and is generally 
regarded as an essentially nontoxic and nonirritant material. 
See Hypromellose for further information. 

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of the material handled. Eye protection and gloves 
are recommended. 
16 Regulatory Status 
GRAS listed. Included in nonparenteral medicines licensed in 
Europe (oral suspensions, tablets, and topical preparations).

17 Related Substances 
Ethylcellulose; hydroxyethyl cellulose; hypromellose; methylcellulose. 
18 Comments 
—
19 Specific References 
1 Bogdanova S. Model suspensions of indomethacin ‘solvent 
deposited’ on cellulose polymers. Pharmazie 2000; 55(11): 829– 
832. 
20 General References 
—
21 Authors 
SC Owen, PJ Sheskey. 
22 Date of Revision 
2 August 2005. 
Hydroxyethylmethyl Cellulose 335

Hydroxypropyl Cellulose 
1 Nonproprietary Names 
BP: Hydroxypropylcellulose 
JP: Hydroxypropylcellulose 
PhEur: Hydroxypropylcellulosum 
USPNF: Hydroxypropyl cellulose 
2 Synonyms 
Cellulose, hydroxypropyl ether; E463; hyprolose; Klucel; 
Methocel; Nisso HPC; oxypropylated cellulose. 
3 Chemical Name and CAS Registry Number 
Cellulose, 2-hydroxypropyl ether [9004-64-2] 
4 Empirical Formula and Molecular Weight 
The PhEur 2005 and USPNF 23 describe hydroxypropyl 
cellulose as a partially substituted poly(hydroxypropyl) ether 
of cellulose. It may contain not more than 0.6% of silica or 
another suitable anticaking agent. Hydroxypropyl cellulose is 
commercially available in a number of different grades that 
have various solution viscosities. Molecular weight has a range 
of 50 000–1 250 000; see also Section 10. 
5 Structural Formula 
R is H or [CH2CH(CH3)O]mH 
6 Functional Category 
Coating agent; emulsifying agent; stabilizing agent; suspending 
agent; tablet binder; thickening agent; viscosity-increasing 
agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Hydroxypropyl cellulose is widely used in oral and topical 
pharmaceutical formulations; see Table I. 
In oral products, hydroxypropyl cellulose is primarily used 
in tableting as a binder,(1) film-coating,(2) and extended-releasematrix 
former.(3–5) Concentrations of hydroxypropyl cellulose 
of 2–6% w/w may be used as a binder in either wet-granulation 
or dry, direct-compression tableting processes.(6–10) Concentrations 
of 15–35% w/w of hydroxypropyl cellulose may be used 
to produce tablets with an extended drug release.(11) The 
release rate of a drug increases with decreasing viscosity of 
hydroxypropyl cellulose. The addition of an anionic surfactant 
similarly increases the viscosity of hydroxypropyl cellulose and 
hence decreases the release rate of a drug. Typically, a 5% w/w 
solution of hydroxypropyl cellulose may be used to film-coat 
tablets. Aqueous solutions containing hydroxypropyl cellulose 
along with an amount of methyl cellulose or ethanolic solutions 
have been used.(12–14) Stearic acid or palmitic acid may be 
added to ethanolic hydroxypropyl cellulose solutions as 
plasticizers. Environmental concerns have limited the use of 
ethanol in film coating solutions. A low-substituted hydroxypropyl 
cellulose is used as a tablet disintegrant; see Hydroxypropyl 
Cellulose, Low-substituted. 
Hydroxypropyl cellulose is also used in microencapsulation 
processes and as a thickening agent. In topical formulations, 
hydroxypropyl cellulose is used in transdermal patches and 
ophthalmic preparations.(15–17) 
Hydroxypropyl cellulose is also used in cosmetics and in 
food products as an emulsifier and stabilizer. 
Table I: Uses of hydroxypropyl cellulose. 
Use Concentration (%) 
Extended release-matrix former 15–35 
Tablet binder 2–6 
Tablet film coating 5 
8 Description 
Hydroxypropyl cellulose is a white to slightly yellow-colored, 
odorless and tasteless powder. See also Section 10. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for hydroxypropyl cellulose. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters — . — 
Apparent viscosity . . . 
Appearance of solution . . — 
pH (1 in 100) 5.0–7.5 5.0–8.5 5.0–8.0 
Loss on drying 45.0% 47.0% 45.0% 
Residue on ignition 40.5% — 40.2% 
Sulfated ash — 41.6% — 
Arsenic 42 ppm — — 
Chlorides . 40.5% — 
Lead — — 40.001% 
Heavy metals 420 ppm 420 ppm 20 mg/g 
Silica — 40.6% — 
Organic volatile impurities — — . 
Sulfate 40.048% — — 
Assay of hydroxypropoxy 
groups 
53.4–77.5% — 480.5%

10 Typical Properties 
Acidity/alkalinity: pH = 5.0–8.5 for a 1%w/v aqueous solution. 
Density (bulk): 0.5 g/cm3 
Interfacial tension: 12.5mN/m for a 0.1% w/v aqueous 
solution compared with mineral oil. 
Melting point: softens at 1308C; chars at 260–2758C. 
Moisture content: hydroxypropyl cellulose absorbs moisture 
from the atmosphere; the amount of water absorbed 
depends upon the initial moisture content and the temperature 
and relative humidity of the surrounding air. Typical 
equilibrium moisture content values at 258C are 4% w/w at 
50% relative humidity and 12% w/w at 84% relative 
humidity. See Table III. See also Figure I. 
Table III: Moisture content of Klucel (Aqualon). 
Grade Molecular weight Moisture (%) 
Klucel EF 80 000 0.59 
Klucel LF 95 000 2.21 
Klucel JF 140 000 1.44 
Klucel GF 370 000 1.67 
Klucel MF 850 000 1.52 
Klucel HF 1 150 000 4.27 
Figure 1: Equilibrium moisture content of various grades of hydroxypropyl 
cellulose. 
*: Klucel GF (Aqualon, Lot #4996). 
~: Klucel JF (Aqualon, Lot #4753). 
!: Klucel LF (Aqualon, Lot #4965). 
&: Klucel EF (Aqualon, Lot #1223). 
Particle size distribution: 
Klucel (regular grind), 95% through a US #30 mesh 
(590 mm), and 99% through a US #20 mesh (840 mm); 
Klucel (X-grind), 100% through a US #60 mesh (250 mm), 
and 80% through a US #100 mesh (149 mm). 
Refractive index: nD
20 = 1.3353 for a 2% w/v aqueous solution. 
Solubility: soluble 1 in 10 parts dichloromethane; 1 in 2.5 parts 
ethanol (95%); 1 in 2 parts methanol; 1 in 5 parts propan-2- 
ol; 1 in 5 parts propylene glycol; and 1 in 2 parts water. 
Practically insoluble in aliphatic hydrocarbons; aromatic 
hydrocarbons; carbon tetrachloride; petroleum distillates; 
glycerin; and oils. 
Hydroxypropyl cellulose is freely soluble in water below 
388C, forming a smooth, clear, colloidal solution. In hot 
water, it is insoluble and is precipitated as a highly swollen 
floc at a temperature between 40 and 458C. Hydroxypropyl 
cellulose is soluble in many cold or hot polar organic 
solvents such as dimethyl formamide; dimethyl sulfoxide; 
dioxane; ethanol (95%); methanol; propan-2-ol (95%); and 
propylene glycol. There is no tendency for precipitation in 
hot organic solvents. However, the grade of hydroxypropyl 
cellulose can have a marked effect upon solution quality in 
some organic liquids that are borderline solvents, such as 
acetone; butyl acetate; cyclohexanol; dichloromethane; 
lactic acid; methyl acetate; methyl ethyl ketone; propan-2- 
ol (99%); and tert-butanol. The higher-viscosity grades of 
hydroxypropyl cellulose tend to produce slightly inferior 
solutions. However, the solution quality in borderline 
solvents can often be greatly improved by the use of small 
quantities (5–15%) of a cosolvent. For example, dichloromethane 
is a borderline solvent for Klucel HF and solutions 
have a granular texture, but a smooth solution may be 
produced by adding 10% methanol. 
Hydroxypropyl cellulose is compatible with a number of 
high-molecular-weight, high-boiling waxes and oils, and can 
be used to modify certain properties of these materials. 
Examples of materials that are good solvents for hydroxypropyl 
cellulose at an elevated temperature are acetylated 
monoglycerides, glycerides, pine oil, polyethylene glycol, 
and polypropylene glycol. 
Specific gravity: 1.2224 for particles; 1.0064 for a 2% w/v 
aqueous solution at 208C. 
Surface tension: see Table IV. 
Table IV: Surface tension (mN/m) of aqueous solutions of Nisso HPC 
(Nippon Soda Co. Ltd.) at 208C. 
Grade Surface tension (mN/m) at 208C for aqueous 
solutions of stated concentration 
0.01% 0.1% 1.0% 10.0% 
Nisso HPC-L 51.0 49.1 46.3 45.8 
Nisso HPC-M 54.8 49.7 46.3 — 
Viscosity (dynamic): a wide range of viscosity types are 
commercially available; see Table V. Solutions should be 
prepared by gradually adding the hydroxypropyl cellulose 
to a vigorously stirred solvent. Increasing concentration 
produces solutions of increased viscosity. See also Section 11 
for information on solution stability. 
Table V: Viscosity of aqueous solutions of Klucel (Aqualon) at 258C. 
Grade Viscosity (mPa s) of various aqueous solutions of 
stated concentration 
1% 2% 5% 10% 
Klucel HF 1500–3000 — — — 
Klucel MF — 4000–6500 — — 
Klucel GF — 150–400 — — 
Klucel JF — — 150–400 — 
Klucel LF — — 75–150 — 
Klucel EF — — — 200–600 
Hydroxypropyl Cellulose 337

SEM: 1 
Excipient: Hydroxypropyl cellulose (Klucel) 
Manufacturer: Aqualon 
Magnification: 60 
SEM: 2 
Excipient: Hydroxypropyl cellulose (Klucel) 
Manufacturer: Aqualon 
Magnification: 600 
11 Stability and Storage Conditions 
Hydroxypropyl cellulose powder is a stable material, although 
it is hygroscopic after drying. 
Aqueous solutions of hydroxypropyl cellulose are stable at 
pH 6.0–8.0, with the viscosity of solutions being relatively 
unaffected. However, at low pH aqueous solutions may 
undergo acid hydrolysis, resulting in chain scission and hence 
a decrease in solution viscosity. The rate of hydrolysis increases 
with increasing temperature and hydrogen ion concentration. 
At high pH, alkali-catalyzed oxidation may degrade the 
polymer and result in a decrease in viscosity of solutions. 
This degradation can occur owing to the presence of dissolved 
oxygen or oxidizing agents in a solution. 
Increasing temperature causes the viscosity of aqueous 
solutions to decrease gradually until the viscosity drops 
suddenly at about 458C owing to the limited solubility of 
hydroxypropyl cellulose. However, this process is reversible 
and on cooling the original viscosity is restored. 
The high level of substitution of hydroxypropyl cellulose 
improves the resistance of the polymer to degradation by molds 
and bacteria.(14) However, aqueous solutions are susceptible to 
degradation under severe conditions and a viscosity decrease 
may occur. Certain enzymes produced by microbial action will 
degrade hydroxypropyl cellulose in solution.(18) Therefore, for 
prolonged storage, an antimicrobial preservative should be 
added to aqueous solutions. Solutions of hydroxypropyl 
cellulose in organic solvents do not generally require preservatives. 
Ultraviolet light will also degrade hydroxypropyl cellulose 
and aqueous solutions may therefore decrease slightly in 
viscosity if exposed to light for several months. 
Aqueous hydroxypropyl cellulose solutions have optimum 
stability when the pH is maintained at 6.0–8.0, and also when 
the solution is protected from light, heat, and the action of 
microorganisms. 
Hydroxypropyl cellulose powder should be stored in a wellclosed 
container in a cool, dry place. 
12 Incompatibilities 
Hydroxypropyl cellulose in solution demonstrates some 
incompatibility with substituted phenol derivatives, such as 
methylparaben and propylparaben. The presence of anionic 
polymers may increase the viscosity of hydroxypropyl cellulose 
solutions. 
The compatibility of hydroxypropyl cellulose with inorganic 
salts varies depending upon the salt and its concentration; see 
Table VI. Hydroxypropyl cellulose may not tolerate high 
concentrations of other dissolved materials. 
The balance of the hydrophilic–lipophilic properties of the 
polymer, which are required for dual solubility, reduces its 
ability to hydrate with water and it therefore tends to be salted 
out in the presence of high concentrations of other dissolved 
materials. 
The precipitation temperature of hydroxypropyl cellulose is 
lower in the presence of relatively high concentrations of other 
dissolved materials that compete for the water in the system; see 
Table VII. 
13 Method of Manufacture 
A purified form of cellulose is reacted with sodium hydroxide to 
produce a swollen alkali cellulose that is chemically more 
reactive than untreated cellulose. The alkali cellulose is then 
reacted with propylene oxide at elevated temperature and 
pressure. The propylene oxide can be substituted on the 
cellulose through an ether linkage at the three reactive 
hydroxyls present on each anhydroglucose monomer unit of 
the cellulose chain. Etherification takes place in such a way that 
hydroxypropyl substituent groups contain almost entirely 
secondary hydroxyls. The secondary hydroxyl present in the 
side chain is available for further reaction with the propylene 
oxide, and ‘chaining-out’ may take place. This results in the 
338 Hydroxypropyl Cellulose

Table VI: Compatibility of hydroxypropyl cellulose (Nisso HPC) with 
inorganic salts in aqueous solutions.(a) 
Salt Concentration of salt (% w/w) 
2 3 5 7 10 30 50 
Aluminum sulfate S S I I I I I 
Ammonium nitrate S S S S S I I 
Ammonium sulfate S S I I I I I 
Calcium chloride S S S S S T I 
Dichromic acid S S S S S S S 
Disodium hydrogenphosphate S S I I I I I 
Ferric chloride S S S S S I I 
Potassium ferrocyanide S S S I I I I 
Silver nitrate S S S S S S T 
Sodium acetate S S S S I I I 
Sodium carbonate S S I I I I I 
Sodium chloride S S S S I I I 
Sodium nitrate S S S S S I I 
Sodium sulfate S S I I I I I 
Sodium sulfite S S I I I I I 
Sodium thiosulfate T T T I I I I 
(a) S, completely soluble; T, turbid white; I, insoluble. 
Table VII: Variation in precipitation temperature of hydroxypropyl 
cellulose (Klucel H) in the presence of other materials. 
Ingredients and concentrations Precipitation temperature (8C) 
1% Klucel H 41 
1% Klucel H . 1.0% sodium chloride 38 
1% Klucel H . 5.0% sodium chloride 30 
0.5% Klucel H . 10% sucrose 41 
0.5% Klucel H . 30% sucrose 32 
0.5% Klucel H . 40% sucrose 20 
0.5% Klucel H . 50% sucrose 7 
formation of side chains containing more than 1 mole of 
combined propylene oxide. 
14 Safety 
Hydroxypropyl cellulose is widely used as an excipient in oral 
and topical pharmaceutical formulations. It is also used 
extensively in cosmetics and food products. 
Hydroxypropyl cellulose is generally regarded as an 
essentially nontoxic and nonirritant material.(19,20) However, 
the use of hydroxypropyl cellulose as a solid ocular insert has 
been associated with rare reports of discomfort or irritation, 
including hypersensitivity and edema of the eyelids. Adverse 
reactions to hydroxypropyl cellulose are rare. However, it has 
been reported that a single patient developed contact dermatitis 
due to hydroxypropyl cellulose in a transdermal estradiol 
patch.(21) 
The WHO has not specified an acceptable daily intake for 
hydroxypropyl cellulose since the levels consumed were not 
considered to represent a hazard to health.(22) Excessive 
consumption of hydroxypropyl cellulose may, however, have 
a laxative effect. 
LD50 (rat, IV): 0.25 g/kg(23) 
LD50 (rat, oral): 10.2 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Hydroxypropyl cellulose 
dust may be irritant to the eyes; eye protection is recommended. 
Excessive dust generation should be avoided to minimize the 
risk of explosions. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral capsules 
and tablets; topical and transdermal preparations). Included in 
nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Hydroxyethyl cellulose; hydroxypropyl cellulose, low-substituted; 
hypromellose. 
18 Comments 
Hydroxypropyl cellulose is a thermoplastic polymer that can be 
processed by virtually all fabrication methods used for plastics. 
It is also used in hot-melt extruded films for topical use. 
When it is produced with chlorpheniramine maleate, the matrix 
is stabilized, allowing film processing at lower temperatures.(24) 
Mucoadhesive hydroxypropyl cellulose microspheres have 
been prepared for powder inhalation preparations.(25) A 
specification for hydroxypropyl cellulose is included in the 
Food Chemicals Codex (FCC). 
19 Specific References 
1 SkinnerGW, HarcumWW, Barnum PE, Guo JH. The evaluation of 
fine-particle hydroxypropylcellulose as a roller compaction binder 
in pharmaceutical applications. Drug Dev In Pharm 1999; 25(10): 
1121–1128. 
2 Aqualon. Technical literature: Klucel EF Pharm Hydroxypropylcellulose. 
Use in plasticizer-free aqueous coating, 2000. 
3 Aqualon. Technical literature: Klucel Hydroxypropylcellulose 
application in a sustained release matrix capsule dosage form, 
2004. 
4 Alderman DA. Sustained release compositions comprising Hydroxypropyl 
cellulose ethers. United States Patent No. 4,704,285; 
1987. 
5 Lee DY, Chen CM. Delayed pulse release hydrogel matrix tablet. 
United States Patent No. 6,103,263; 2000. 
6 Machida Y, Nagai T. Directly compressed tablets containing 
hydroxypropyl cellulose in addition to starch or lactose. Chem 
Pharm Bull 1974; 22: 2346–2351. 
7 Delonca H, Joachim J, Mattha AG. Binding activity of hydroxypropyl 
cellulose (200 000 and 1 000 000 mol. wt.) and its effect 
on the physical characteristics of granules and tablets. Farmaco 
(Prat) 1977; 32: 157–171. 
8 Delonca H, Joachim J, Mattha A. Effect of temperature on 
disintegration and dissolution time of tablets with a cellulose 
component as a binder [in French]. J Pharm Belg 1978; 33: 171– 
178. 
9 Stafford JW, Pickard JF, Zink R. Temperature dependence of the 
disintegration times of compressed tablets containing hydroxypropyl 
cellulose as binder. J Pharm Pharmacol 1978; 30: 1–5. 
10 Kitamori N, Makino T. Improvement in pressure-dependent 
dissolution of trepibutone tablets by using intragranular disintegrants. 
Drug Dev Ind Pharm 1982; 8: 125–139. 
11 Johnson JL, Holinej J, Williams MD. Influence of ionic strength on 
matrix integrity and drug release from hydroxypropyl cellulose 
compacts. Int J Pharm 1993; 90: 151–159. 
Hydroxypropyl Cellulose 339

12 Lindberg NO. Water vapour transmission through free films of 
hydroxypropyl cellulose. Acta Pharm Suec 1971; 8: 541–548. 
13 Banker G, Peck G, Williams E, et al. Evaluation of hydroxypropylcellulose 
and hydroxypropylmethylcellulose as aqueous based 
film coatings. Drug Dev Ind Pharm 1981; 7: 693–716. 
14 Banker G, Peck G, Williams E, et al. Microbiological considerations 
of polymer solutions used in aqueous film coating. Drug Dev 
Ind Pharm 1982; 8: 41–51. 
15 Cohen EM, Grim WM, Harwood RJ, Mehta GN. Solid state 
ophthalmic medication. United States Patent No. 4,179,497; 1979. 
16 Harwood RJ, Schwartz JB. Drug release from compression molded 
films: preliminary studies with pilocarpine. Drug Dev Ind Pharm 
1982; 8: 663–682. 
17 Dumortier G, Zuber M, Chast F, et al. Systemic absorption of 
morphine after ocular administration: evaluation of morphine salt 
insert in vitro and in vivo. Int J Pharm 1990; 59: 1–7. 
18 Wirick MG. Study of the enzymic degradation of CMC and other 
cellulose ethers. J Polym Sci 1968; 6(Part A-1): 1965–1974. 
19 Anonymous. Final report on the safety assessment of hydroxyethylcellulose, 
hydroxypropylcellulose, methylcellulose, hydroxypropyl 
methylcellulose and cellulose gum. J Am Coll Toxicol 1986; 
5(3): 1–60. 
20 Aqualon. Technical literature: Klucel hydroxypropylcellulose 
summary of toxicological investigations, 2004. 
21 Schwartz BK, Clendenning WE. Allergic contact dermatitis from 
hydroxypropyl cellulose in a transdermal estradiol patch. Contact 
Dermatitis 1988; 18(2): 106–107. 
22 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirty-fifth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1990; No. 
789. 
23 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2053. 
24 Repka MA, McGinty JW. Influence of chlorpheniramine maleate 
on topical hydroxypropylcellulose films produced by hot melt 
extrusion. Pharm Dev Technol 2001; 6(3): 297–304. 
25 Sakagami M, Sakon K, Kinoshita W, Makino Y. Enhanced 
pulmonary absorption following aerosol administration of 
mucoadhesive powder microspheres. J Control Release 2001; 
77(1–2): 117–129. 
20 General References 
Aqualon. Technical literature: Klucel, hydroxypropyl cellulose, a 
nonionic water-soluble polymer, physical and chemical properties, 
1987. 
Aqualon. Technical literature: Klucel Hydroxypropylcellulose, Pharmgrade 
for pharmaceutical uses, 2004. 
Doelker E. Cellulose derivatives. Adv Polym Sci 1993; 107: 199–265. 
Ganz AJ. Thermoplastic food production. United States Patent No. 
3,769,029; 1973. 
Klug ED. Some properties of water-soluble hydroxyalkyl celluloses and 
their derivatives. J Polym Sci 1971; 36(Part C): 491–508. 
Nippon Soda Co. Ltd. Technical literature: Nisso HPC, 1993. 
Opota O, Maillols H, Acquier R, et al. Rheological behavior of aqueous 
solutions of hydroxypropylcellulose: influence of concentration and 
molecular mass [in French]. Pharm Acta Helv 1988; 63: 26–32. 
21 Authors 
RJ Harwood. 
22 Date of Revision 
17 August 2005. 
340 Hydroxypropyl Cellulose

Hydroxypropyl Cellulose, Low-substituted 
1 Nonproprietary Names 
JP: Low-substituted hydroxypropylcellulose 
USPNF: Low-substituted hydroxypropyl cellulose 
2 Synonyms 
Hyprolose, low-substituted; L-HPC. 
3 Chemical Name and CAS Registry Number 
Cellulose, 2-hydroxypropyl ether (low-substituted) [78214-41- 
2] 
4 Empirical Formula and Molecular Weight 
The USPNF 23 describes low-substituted hydroxypropyl 
cellulose as a low-substituted hydroxypropyl ether of cellulose. 
When dried at 1058C for 1 hour, it contains not less than 
5.0% and not more than 16.0% of hydroxypropoxy groups 
(—OCH2CHOHCH3). Low-substituted hydroxypropyl cellulose 
is commercially available in a number of different grades 
that have different particle sizes and substitution levels. 
5 Structural Formula 
R is H or [CH2CH(CH3)O]mH 
6 Functional Category 
Tablet and capsule disintegrant; tablet binder. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Low-substituted hydroxypropyl cellulose is widely used in oral 
solid-dosage forms. It is primarily used in tableting as a 
disintegrant, and as a binder in wet granulation. It has been 
used in the preparation of rapidly disintegrating tablets 
produced by direct compression methods.(1,2) In addition, 
low-substituted hydroxypropyl cellulose has been used to delay 
the release of drug from a tablet matrix.(3) 
There are a number of grades that have different particle 
sizes and substitution levels. LH-11 has the medium substitution 
level and the largest particle size, and is typically used as an 
anticapping agent and disintegrant for direct compression. LH- 
21 is used as a binder and disintegrant for tablets through the 
wet-granulation process. LH-31 is a small-particle grade used 
especially for extrusion to produce granules, as it has a small 
particle size that is better for passing a screen. Lower 
substitution grades LH-22 and LH-32 can be used when high 
binding strength is not necessary. If higher binding strength is 
needed, higher substitution grades LH-20 and LH-30 are also 
available. 
The typical content of low-substituted hydroxypropyl 
cellulose in a formulation is approximately 5–25%. 
8 Description 
Low-substituted hydroxypropyl cellulose occurs as a white to 
yellowish white powder or granules. It is odorless or has a 
slight, characteristic odor, and it is tasteless. 
SEM: 1 
Excipient: Low-substituted hydroxypropyl cellulose, type LH-11 
Manufacturer: Shin-Etsu 
Magnification: 350 
SEM: 2 
Excipient: Low-substituted hydroxypropyl cellulose, type LH-21 
Manufacturer: Shin-Etsu 
Magnification: 350

SEM: 3 
Excipient: Low-substituted hydroxypropyl cellulose, type LH-31 
Manufacturer: Shin-Etsu 
Magnification: 350 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for hydroxypropyl cellulose, 
low substituted. 
Test JP 2001 USPNF 23 
Identification . . 
Chloride 40.335% 40.36% 
Heavy metals 410 ppm 40.001% 
Arsenic 42 ppm — 
pH 5.0–7.5 — 
Loss on drying 46.0% 45.0% 
Residue on ignition 41.0% 40.5% 
Assay (of hydroxypropoxy groups) 5.0–16.0% 5.0–16.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 5.0–7.5 for 1% w/v aqueous suspension. 
Angle of repose: see Table II. 
Ash: 0.3–0.4% 
Density (bulk): see Table II. 
Density (tapped): see Table II. 
Melting point: decomposition at 2758C. 
Moisture content: 
8% at 33% relative humidity; 
38% at 95% relative humidity. 
Specific gravity: 1.46 
Solubility: practically insoluble in ethanol (95%) and in ether. 
Dissolves in a solution of sodium hydroxide (1 in 10) and 
produces a viscous solution. Insoluble, but swells in water. 
11 Stability and Storage Conditions 
Low-substituted hydroxypropyl cellulose is a stable, though 
hygroscopic, material. The powder should be stored in a wellclosed 
container. 
Table II: Typical properties of hydroxypropyl cellulose, lowsubstituted, 
for selected grades. 
Grade Hydroxypropoxy 
content (%) 
Angle of 
repose (8) 
Average 
particle 
size (mm) 
Density 
(bulk) 
(g/cm3) 
Density 
(tapped) 
(g/cm3) 
LH-11 11 49 50 0.32 0.56 
LH-21 11 45 40 0.36 0.62 
LH-31 11 49 25 0.28 0.59 
LH-22 8 48 40 0.36 0.62 
LH-32 8 53 25 0.28 0.59 
LH-20 13 48 40 0.36 0.62 
LH-30 13 51 25 0.28 0.59 
12 Incompatibilities 
Alkaline substances may interact. If a tablet formulation 
contains such a material, its disintegration may be extended 
after storage. 
13 Method of Manufacture 
Low-substituted hydroxypropyl cellulose is manufactured by 
reacting alkaline cellulose with propylene oxide at elevated 
temperature. Following the reaction, the product is recrystallized 
by neutralization, washed, and milled. 
14 Safety 
Low-substituted hydroxypropyl cellulose is generally regarded 
as a nontoxic and nonirritant material. 
Animal toxicity studies showed no adverse effects in rats fed 
orally 6 g/kg/day over 6 months. No teratogenic effects were 
noted in rabbits and rats fed 5 g/kg/day.(4–7) 
LD50 (rat, oral): 15 g/kg(4) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Excessive dust generation 
should be avoided to minimize the risk of explosions. 
16 Regulatory Status 
Approved for use in pharmaceuticals in Europe, Japan, USA, 
and other countries. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Hydroxypropyl cellulose. 
18 Comments 
—
19 Specific References 
1 Kawashima Y, Takeuchi H, Hino T, et al. Low-substituted 
hydroxypropylcellulose as a sustained-drug release matrix base 
or disintegrant depending on its particle size and loading in 
formulation. Pharm Res 1993; 10(3): 351–355. 
2 Ishikawa T, Mukai B, Shiaishi S, et al. Preparation of rapidly 
disintegrating tablet using new types of microcrystalline cellulose 
(PH-M series) and low-substituted hydroxypropylcellulose or 
342 Hydroxypropyl Cellulose, Low-substituted

spherical sugar granules by direct compression method. Chem 
Pharm Bull 2001; 49(2): 134–139. 
3 Jeko ZB, Sipos T, Kertai EH, Mezey G. Comparison of dissolutionrate 
curves of carbamazepine from different hydrophilic matrix 
tablets. Acta Pharm 1999; 49: 267–273. 
4 Kitagawa H, Yano H, Saito H, Fukuka Y. Acute, subacute and 
chronic toxicities of hydroxypropylcellulose of low-substitution in 
rats. Pharmacometrics 1976; 12: 41–66. 
5 Kitagawa H, Saito H, Yokoshima T, et al. Absorption, distribution, 
excretion and metabolism of 14C-hydroxypropylcellulose of lowsubstitution. 
Pharmacometrics 1976; 12: 33–39. 
6 Kitagawa H, Satoh T, Saito H, et al. Teratological study of 
hydroxypropylcellulose of low substitution (L-HPC) in rabbits. 
Pharmacometrics 1978; 16: 259–269. 
7 Kitagawa H, Saito H. General pharmacology of hydroxypropylcellulose 
of low substitution (L-HPC). Pharmacometrics 1978; 16: 
299–302. 
20 General References 
Shin-Etsu Chemical Co. Ltd. Technical literature: L-HPC, lowsubstituted 
hydroxypropyl cellulose, 1991. 
Shin-Etsu Chemical Co. Ltd. Technical literature: L-HPC, NF Disintegrant-
binder, 2000. 
21 Authors 
RJ Harwood. 
22 Date of Revision 
17 August 2005. 
Hydroxypropyl Cellulose, Low-substituted 343

Hydroxypropyl Starch 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
E1440; hydroxylpropyl starch. 
3 Chemical Name and CAS Registry Number 
Hydroxypropyl starch [113894-92-1] 
4 Empirical Formula and Molecular Weight 
Hydroxypropyl starch is a derivative of natural starch; it is 
described in the JPE 2004 as a hydroxypropyl ether of corn 
starch. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Binder; disintegrant; emulsifying agent; thickening agent; 
viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Hydroxypropyl starch is a modified starch and has been used in 
combination with carrageenan in the production of soft 
capsules.(1,2) Hydroxypropyl starch has been used experimentally 
in hydrophilic matrices, where it was shown to be an 
effective matrix for tablets designed for controlled-release drug 
delivery systems.(3) It has also been used experimentally in the 
production of hydrophilic matrices by direct compression.(4) 
It is used in antiseptics and is used widely in cosmetics. It is 
also used analytically as a bioseparation aqueous-phaseforming 
polymer.(5) 
8 Description 
Hydroxypropyl starch occurs as a free-flowing white to offwhite 
coarse powder. 
9 Pharmacopeial Specifications 
See Section 18. 
10 Typical Properties 
Acidity/alkalinity: pH = 4.5–7.0 (10% w/v aqueous dispersion). 
Solubility: practically insoluble in water, ethanol (95%), and 
ether. 
11 Stability and Storage Conditions 
Hydroxypropyl starch is stable at high humidity and is 
considered to be inert under normal conditions. It is stable in 
emulsion systems at pH 3–9. 
12 Incompatibilities 
See Section 18. 
13 Method of Manufacture 
Hydroxypropyl starch is produced industrially from natural 
starch, using propylene oxide as the modifying reagent in the 
presence of alkali, adding hydroxypropyl (CH(OH)CH2CH3) 
groups at the OH positions by an ether linkage. 
14 Safety 
Hydroxypropyl starch is widely used in cosmetics and food 
products. It is also used in oral pharmaceutical formulations. 
TheWHOhas set an acceptable daily intake for hydroxypropyl 
starch at ‘not limited’ since it was well tolerated on oral 
consumption.(6) 
LD50 (rat, oral): 0.218 g/kg(7) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
17 Related Substances 
—
18 Comments 
Hydroxypropyl starch–methyl methacrylate (HS-MMA) has 
been used experimentally in hydrophilic matrices produced by 
direct compression.(4) Pregelatinized hydroxypropyl starch has 
been shown to exhibit good disintegrating properties, and can 
be used as a binder in wet granulation.(8) 
Although it is not currently included in the pharmacopeias, a 
specification for hydroxypropyl starch is included in the 
Japanese Pharmaceutical Excipients (JPE) 2004; see Table I.(9) 
Hydroxypropyl starch is compatible with cationic ingredients 
(monovalent, divalent), oils, emollients, and silicone. 
The EINECS number for hydroxypropyl starch is 232- 
679-6.

Table I: JPE 2004 specification for hydroxypropyl starch. 
Test JPE 2004 
Description . 
Identification . 
pH 5.0–7.5 
Chloride 40.142% 
Heavy metals 420 ppm 
Arsenic 45 ppm 
Loss on drying 415.0% 
Residue on ignition 40.5% 
Content of hydroxypropyl group after drying 2.0–7.0% 
19 Specific References 
1 Draper PR, Tanner KE, Getz JJ, et al. Film forming compositions 
comprising modified starches and iota-carrageenan and methods 
for manufacturing soft capsules using the same. International 
Patent WO 013677; 1999. 
2 Cardinal Health. Vegicaps soft capsules. http://www.cardinal.com/ 
pts/content/delivery/dd-oral-vegicaps.asp (accessed 26 May 2005). 
3 Goni I, Ferrero MC, Jimenez-Castellanos RM, Gurruchaga M. 
Synthesis of hydroxypropyl methacrylate/polysaccharide graft 
copolymers as matrices for controlled release tablets. Drug Dev 
Ind Pharm 2002; 28(9): 1101–1115. 
4 Ferrero MC, Velasco MV, Mun. oz A, et al. Drug release from a 
family of graft copolymers of methyl methacrylate. I. Int J Pharm 
1997; 149: 233–240. 
5 Venacio A, Teixeira JA, Mota M. Evaluation of crude hydroxypropyl 
starch as a bioseparation aqueous-phase-forming polymer. 
Biotechnol Prog 1993; 9(6): 635–639. 
6 FAO/WHO. Fifteenth Report of the Joint FAO/WHO Expert 
Committee on Food Additives.World Health Organ Tech Rep Ser 
1972; No. 488. 
7 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2054. 
8 Visavarungroj N, Remon JP. An evaluation of hydroxypropyl 
starch as disintegrant and binder in tablet formulation. Drug Dev 
Ind Pharm 1991; 17(10): 1389–1396. 
9 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004: 425–427. 
20 General References 
—
21 Authors 
D Thassu, SA Shah. 
22 Date of Revision 
15 August 2005. 
Hydroxypropyl Starch 345

Hypromellose 
1 Nonproprietary Names 
BP: Hypromellose 
JP: Hydroxypropylmethylcellulose 
PhEur: Hypromellosum 
USP: Hypromellose 
2 Synonyms 
Benecel MHPC; E464; hydroxypropyl methylcellulose; 
HPMC; Methocel; methylcellulose propylene glycol ether; 
methyl hydroxypropylcellulose; Metolose; Tylopur. 
3 Chemical Name and CAS Registry Number 
Cellulose hydroxypropyl methyl ether [9004-65-3] 
4 Empirical Formula and Molecular Weight 
The PhEur 2005 describes hypromellose as a partly Omethylated 
and O-(2-hydroxypropylated) cellulose. It is available 
in several grades that vary in viscosity and extent of 
substitution. Grades may be distinguished by appending a 
number indicative of the apparent viscosity, in mPa s, of a 2% 
w/w aqueous solution at 208C. Hypromellose defined in the 
USP 28 specifies the substitution type by appending a four-digit 
number to the nonproprietary name: e.g., hypromellose 1828. 
The first two digits refer to the approximate percentage content 
of the methoxy group (OCH3). The second two digits refer to 
the approximate percentage content of the hydroxypropoxy 
group (OCH2CH(OH)CH3), calculated on a dried basis. It 
contains methoxy and hydroxypropoxy groups conforming to 
the limits for the types of hypromellose stated in Table I. 
Molecular weight is approximately 10 000–1 500 000. The JP 
2001 includes three separate monographs for hypromellose: 
hydroxypropylmethylcellulose 2208, 2906, and 2910, respectively. 
5 Structural Formula 
where R is H, CH3, or CH3CH(OH)CH2 
6 Functional Category 
Coating agent; film-former; rate-controlling polymer for 
sustained release; stabilizing agent; suspending agent; tablet 
binder; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Hypromellose is widely used in oral, ophthalmic and topical 
pharmaceutical formulations. 
In oral products, hypromellose is primarily used as a tablet 
binder,(1) in film-coating,(2–7) and as a matrix for use in 
extended-release tablet formulations.(8–12) Concentrations 
between 2% and 5% w/w may be used as a binder in either 
wet- or dry-granulation processes. High-viscosity grades may 
be used to retard the release of drugs from a matrix at levels of 
10–80% w/w in tablets and capsules. 
Depending upon the viscosity grade, concentrations of 
2–20% w/w are used for film-forming solutions to film-coat 
tablets. Lower-viscosity grades are used in aqueous film-coating 
solutions, while higher-viscosity grades are used with organic 
solvents. Examples of film-coating materials that are commercially 
available include AnyCoat C, Spectracel, and Pharmacoat. 
Hypromellose is also used as a suspending and thickening 
agent in topical formulations. Compared with methylcellulose, 
hypromellose produces aqueous solutions of greater clarity, 
with fewer undispersed fibers present, and is therefore preferred 
in formulations for ophthalmic use. Hypromellose at concentrations 
between 0.45–1.0% w/w may be added as a thickening 
agent to vehicles for eye drops and artificial tear solutions. 
Hypromellose is also used as an emulsifier, suspending 
agent, and stabilizing agent in topical gels and ointments. As a 
protective colloid, it can prevent droplets and particles from 
coalescing or agglomerating, thus inhibiting the formation of 
sediments. 
In addition, hypromellose is used in the manufacture of 
capsules, as an adhesive in plastic bandages, and as a wetting 
agent for hard contact lenses. It is also widely used in cosmetics 
and food products. 
8 Description 
Hypromellose is an odorless and tasteless, white or creamywhite 
fibrous or granular powder. See also Section 10. 
9 Pharmacopeial Specifications 
See Table I. 
10 Typical Properties 
Acidity/alkalinity: pH = 5.5–8.0 for a 1% w/w aqueous 
solution. 
Ash: 1.5–3.0%, depending upon the grade and viscosity. 
Autoignition temperature: 3608C 
Density (bulk): 0.341 g/cm3 
Density (tapped): 0.557 g/cm3 
Density (true): 1.326 g/cm3 
Melting point: browns at 190–2008C; chars at 225–2308C. 
Glass transition temperature is 170–1808C. 
Moisture content: hypromellose absorbs moisture from the 
atmosphere; the amount of water absorbed depends upon 
the initial moisture content and the temperature and relative 
humidity of the surrounding air. See Figure 1.

SEM: 1 
Excipient: Hypromellose 
Manufacturer: Dow Chemical Co. 
Lot No.: ME20012N11 
Magnification: 600 Voltage: 5kV 
SEM: 2 
Excipient: Hypromellose 
Manufacturer: Dow Chemical Co. 
Lot No.: ME20012N11 
Magnification: 60 Voltage: 5kV 
Solubility: soluble in cold water, forming a viscous colloidal 
solution; practically insoluble in chloroform, ethanol 
(95%), and ether, but soluble in mixtures of ethanol and 
dichloromethane, mixtures of methanol and dichloromethane, 
and mixtures of water and alcohol. Certain grades 
of hypromellose are soluble in aqueous acetone solutions, 
mixtures of dichloromethane and propan-2-ol, and other 
organic solvents. See also Section 11. 
Specific gravity: 1.26 
Table I: Pharmacopeial specifications for hypromellose. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters — . — 
Appearance of solution . . — 
pH (1% w/w solution) 5.0–8.0 5.5–8.0 — 
Apparent viscosity . . . 
Loss on drying 45.0% 410.0% 45.0% 
Residue on ignition 41.5% — — 
For viscosity grade 
>50 mPa s 
— — 41.5% 
For viscosity grade 
450 mPa s 
— — 43.0% 
For type 1828 of all 
viscosities 
— — 45.0% 
Sulfated ash — 41.0% — 
Chlorides 40.284% 40.5% — 
Heavy metals 410 ppm 420 ppm 40.001% 
Iron 4100 ppm — — 
Arsenic 42 ppm — — 
Organic volatile 
impurities 
— — . 
Methoxy content 
Type 1828 — — 16.5–20.0% 
Type 2208 19.0–24.0% — 19.0–24.0% 
Type 2906 27.0–30.0% — 27.0–30.0% 
Type 2910 28.0–30.0% — 28.0–30.0% 
Hydroxypropoxy content 
Type 1828 — — 23.0–32.0% 
Type 2208 4.0–12.0% — 4.0–12.0% 
Type 2906 4.0–7.5% — 4.0–7.5% 
Type 2910 7.0–12.0% — 7.0–12.0% 
Figure 1: Absorption–desorption isotherm for hypromellose. 
^: Sorption 
&: Desorption 
Viscosity (dynamic): a wide range of viscosity types are 
commercially available. Aqueous solutions are most commonly 
prepared, although hypromellose may also be 
dissolved in aqueous alcohols such as ethanol and propan- 
2-ol provided the alcohol content is less than 50% w/w. 
Dichloromethane and ethanol mixtures may also be used to 
prepare viscous hypromellose solutions. Solutions prepared 
Hypromellose 347

using organic solvents tend to be more viscous; increasing 
concentration also produces more viscous solutions; see 
Table II. 
Table II: Typical viscosity values for 2% (w/v) aqueous solutions of 
Methocel (Dow Chemical Co.). Viscosities measured at 208C. 
Methocel product USP 28 
designation 
Nominal viscosity 
(mPa s) 
Methocel K100 Premium LVEP 2208 100 
Methocel K4M Premium 2208 4000 
Methocel K15M Premium 2208 15 000 
Methocel K100M Premium 2208 100 000 
Methocel E4M Premium 2910 4000 
Methocel F50 Premium 2906 50 
Methocel E10M Premium CR 2906 10 000 
Methocel E3 Premium LV 2906 3 
Methocel E5 Premium LV 2906 5 
Methocel E6 Premium LV 2906 6 
Methocel E15 Premium LV 2906 15 
Methocel E50 Premium LV 2906 50 
Metolose 60SH 2910 50, 4000, 10 000 
Metolose 65SH 2906 50, 400, 1500, 4000 
Metolose 90SH 2208 100, 400, 4000, 15 000 
To prepare an aqueous solution, it is recommended that 
hypromellose is dispersed and thoroughly hydrated in about 
20–30% of the required amount of water. The water should 
be vigorously stirred and heated to 80–908C, then the 
remaining hypromellose should be added. Sufficient cold 
water should then be added to produce the required volume. 
When a water-miscible organic solvent such as ethanol 
(95%), glycol, or mixtures of ethanol and dichloromethane 
are used, the hypromellose should first be dispersed into the 
organic solvent, at a ratio of 5–8 parts of solvent to 1 part of 
hypromellose. Cold water is then added to produce the 
required volume. 
11 Stability and Storage Conditions 
Hypromellose powder is a stable material, although it is 
hygroscopic after drying. 
Solutions are stable at pH 3–11. Increasing temperature 
reduces the viscosity of solutions. Hypromellose undergoes a 
reversible sol–gel transformation upon heating and cooling, 
respectively. The gel point is 50–908C, depending upon the 
grade and concentration of material. 
Aqueous solutions are comparatively enzyme-resistant, 
providing good viscosity stability during long-term storage.(13) 
However, aqueous solutions are liable to microbial spoilage 
and should be preserved with an antimicrobial preservative: 
when hypromellose is used as a viscosity-increasing agent in 
ophthalmic solutions, benzalkonium chloride is commonly 
used as the preservative. Aqueous solutions may also be 
sterilized by autoclaving; the coagulated polymer must be 
redispersed on cooling by shaking. 
Hypromellose powder should be stored in a well-closed 
container, in a cool, dry place. 
12 Incompatibilities 
Hypromellose is incompatible with some oxidizing agents. 
Since it is nonionic, hypromellose will not complex with 
metallic salts or ionic organics to form insoluble precipitates. 
13 Method of Manufacture 
A purified form of cellulose, obtained from cotton linters or 
wood pulp, is reacted with sodium hydroxide solution to 
produce a swollen alkali cellulose that is chemically more 
reactive than untreated cellulose. The alkali cellulose is then 
treated with chloromethane and propylene oxide to produce 
methyl hydroxypropyl ethers of cellulose. The fibrous reaction 
product is then purified and ground to a fine, uniform powder 
or granules. 
14 Safety 
Hypromellose is widely used as an excipient in oral and topical 
pharmaceutical formulations. It is also used extensively in 
cosmetics and food products. 
Hypromellose is generally regarded as a nontoxic and 
nonirritant material, although excessive oral consumption may 
have a laxative effect.(14) The WHO has not specified an 
acceptable daily intake for hypromellose since the levels 
consumed were not considered to represent a hazard to 
health.(15) 
LD50 (mouse, IP): 5 g/kg(16) 
LD50 (rat, IP): 5.2 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Hypromellose dust may be 
irritant to the eyes and eye protection is recommended. 
Excessive dust generation should be avoided to minimize the 
risks of explosion. Hypromellose is combustible. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (ophthalmic 
preparations; oral capsules, suspensions, syrups, and tablets; 
topical and vaginal preparations). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Hydroxyethyl cellulose; hydroxyethylmethyl cellulose; hydroxypropyl 
cellulose; hypromellose phthalate; methylcellulose. 
18 Comments 
Powdered or granular, surface-treated grades of hypromellose 
are also available that are dispersible in cold water. These are 
not recommended for oral use. A specification for hypromellose 
is contained in the Food Chemicals Codex (FCC). 
19 Specific References 
1 Chowhan ZT. Role of binders in moisture-induced hardness 
increase in compressed tablets and its effect on in vitro disintegration 
and dissolution. J Pharm Sci 1980; 69: 1–4. 
2 Rowe RC. The adhesion of film coatings to tablet surfaces – the 
effect of some direct compression excipients and lubricants. J 
Pharm Pharmacol 1977; 29: 723–726. 
3 Rowe RC. The molecular weight and molecular weight distribution 
of hydroxypropyl methylcellulose used in the film coating of 
tablets. J Pharm Pharmacol 1980; 32: 116–119. 
348 Hypromellose

4 Banker G, Peck G, Jan S, Pirakitikulr P. Evaluation of hydroxypropyl 
cellulose and hydroxypropyl methyl cellulose as aqueous 
based film coatings. Drug Dev Ind Pharm 1981; 7: 693–716. 
5 Okhamafe AO, York P. Moisture permeation mechanism of some 
aqueous-based film coats. J Pharm Pharmacol 1982; 34 (Suppl.): 
53P. 
6 Alderman DA, Schulz GJ. Method of making a granular, cold 
water dispersible coating composition for tablets. United States 
Patent No. 4,816,298; 1989. 
7 Patell MK. Taste masking pharmaceutical agents. United States 
Patent No. 4,916,161; 1990. 
8 Hardy JG, Kennerley JW, Taylor MJ, et al. Release rates from 
sustained-release buccal tablets in man. J Pharm Pharmacol 1982; 
34 (Suppl.): 91P. 
9 Hogan JE. Hydroxypropylmethylcellulose sustained release technology. 
Drug Dev Ind Pharm 1989; 15: 975–999. 
10 Shah AC, Britten NJ, Olanoff LS, Badalamenti JN. Gel-matrix 
systems exhibiting bimodal controlled release for oral delivery. J 
Control Release 1989; 9: 169–175. 
11 Wilson HC, Cuff GW. Sustained release of isomazole from matrix 
tablets administered to dogs. J Pharm Sci 1989; 78: 582–584. 
12 Dahl TC, Calderwood T, Bormeth A, et al. Influence of 
physicochemical properties of hydroxypropyl methylcellulose on 
naproxen release from sustained release matrix tablets. J Control 
Release 1990; 14: 1–10. 
13 Banker G, Peck G, Williams E, et al. Microbiological considerations 
of polymer solutions used in aqueous film coating. Drug Dev 
Ind Pharm 1982; 8: 41–51. 
14 Anonymous. Final report on the safety assessment of hydroxyethylcellulose, 
hydroxypropylcellulose, methylcellulose, hydroxypropyl 
methylcellulose and cellulose gum. J Am Coll Toxicol 1986; 
5(3): 1–60. 
15 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirty-fifth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1990; No. 
789. 
16 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2054. 
20 General References 
Doelker E. Cellulose derivatives. Adv Polym Sci 1993; 107: 199–265. 
Dow Chemical Company. Technical literature: Methocel cellulose 
ethers in aqueous systems for tablet coating, 2000. 
Li CL, Martini LG, Ford JL, Roberts M. The use of hypromellose in 
oral drug delivery. J Pharm Pharmacol 2005; 57: 533–546. 
Malamataris S, Karidas T, Goidas P. Effect of particle size and sorbed 
moisture on the compression behavior of some hydroxypropyl 
methylcellulose (HPMC) polymers. Int J Pharm 1994; 103: 205– 
215. 
Papadimitriou E, Buckton G, Efentakis M. Probing the mechanisms of 
swelling of hydroxypropylmethylcellulose matrices. Int J Pharm 
1993; 98: 57–62. 
Parab PV, Nayak MP, Ritschel WA. Influence of hydroxypropyl 
methylcellulose and of manufacturing technique on in vitro 
performance of selected antacids. Drug Dev Ind Pharm 1985; 11: 
169–185. 
Radebaugh GW, Murtha JL, Julian TN, Bondi JN. Methods for 
evaluating the puncture and shear properties of pharmaceutical 
polymeric films. Int J Pharm 1988; 45: 39–46. 
Rowe RC. Materials used in the film coating of oral dosage forms. In: 
Florence AT, ed. Critical Reports on Applied Chemistry, vol. 6. 
Oxford: Blackwell Scientific, 1984: 1–36. 
Sako K, Sawada T, Nakashima H, et al. Influence of water soluble fillers 
in hydroxypropylmethylcellulose matrices on in vitro and in vivo 
drug release. J Control Release 2002; 81: 165–172. 
Sebert P, Andrianoff N, Rollet M. Effect of gamma irradiation on 
hydroxypropylmethylcellulose powders: consequences on physical, 
rheological and pharmacotechnical properties. Int J Pharm 1993; 
99: 37–42. 
Shin-Etsu Chemical Co. Ltd. Metolose. http://www.metolose.jp/e/ 
pharmaceutical/metolose.shtml (accessed 25 August 2005). 
Shin-Etsu Chemical Co. Ltd. Technical literature: Pharmacoat hydroxypropyl 
methylcellulose, 1990. 
Wan LSC, Heng PWS, Wong LF. The effect of hydroxypropylmethylcellulose 
on water penetration into a matrix system. Int J Pharm 
1991; 73: 111–116. 
21 Authors 
RJ Harwood. 
22 Date of Revision 
17 August 2005. 
Hypromellose 349

Hypromellose Acetate Succinate 
1 Nonproprietary Names 
USPNF: Hypromellose acetate succinate 
2 Synonyms 
Aqoat; Aqoat AS-HF/HG; Aqoat AS-LF/LG; Aqoat AS-MF/ 
MG; cellulose, 2-hydroxypropyl methyl ether, acetate succinate; 
HPMCAS. 
3 Chemical Name and CAS Registry Number 
Cellulose, 2-hydroxypropylmethyl ether, acetate hydrogen 
butanedioate [71138-97-1] 
4 Empirical Formula and Molecular Weight 
Hypromellose acetate succinate is a mixture of acetic acid and 
monosuccinic acid esters of hydroxypropylmethyl cellulose.(
1–4) It is available in several grades, which vary in extent 
of substitution, mainly of acetyl and succinoyl groups, and in 
particle size (fine or granular). When dried at 1058C for one 
hour, it contains 12.0–28.0% of methoxy groups; 4.0–23.0% 
of hydroxypropoxy groups; 2.0–16.0% of acetyl groups; and 
4.0–28.0% of succinoyl groups. 
The molecular weight of hypromellose acetate succinate is 
approximately 55 000–93 000 Daltons, measured by gel 
permeation chromatography using polyethylene oxide as a 
relative reference standard. 
5 Structural Formula 
Where -OR represents one of the following functional 
groups -hydroxyl, methoxyl, 2-hydroxypropoxyl, acetyl, or 
succinoyl. 
6 Functional Category 
Component of controlled-release or sustained-release dosage 
forms; enteric coating agent; film-forming agent; solid dispersion 
vehicle. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Hypromellose acetate succinate is commonly used in oral 
pharmaceutical formulations as a film coating, as well as 
enteric coating material for tablets or granules.(5–7) It is 
insoluble in gastric fluid but will swell and dissolve rapidly in 
the upper intestine. For aqueous film-coating purposes, a 
dispersion of hypromellose acetate succinate fine powder and 
triethyl citrate (as a plasticizer) in water is commonly 
utilized.(4,8,9) Organic solvents can also be used as vehicles for 
applying this polymer as a film coating. 
Hypromellose acetate succinate may be used alone or in 
combination with other soluble or insoluble binders in the 
preparation of granules with sustained drug-release properties; 
the release rate is pH-dependent. 
Dispersions of poorly soluble drugs with hypromellose 
acetate succinate are prepared using techniques such as 
mechanical grinding, solvent evaporation, and melt extrusion.(
10–14) 
8 Description 
Hypromellose acetate succinate is a white to off-white powder 
or granules.(4) It has a faint acetic acid-like odor and a barely 
detectable taste. Hypromellose acetate succinate is available in 
several grades, according to the pH at which the polymer 
dissolves (low, L; medium, M; and high, H) and its 
predominant particle size (cohesive fine powder, F; or freeflowing 
granules, G). 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for hypromellose acetate 
succinate. 
Test USPNF 23 
(Suppl. 2) 
Identification . 
Viscosity . 
Loss on drying 40.5.0% 
Residue on ignition 40.20% 
Heavy metals 40.001% 
Limit of free acetic and succinic acids . 
Content of acetyl and succinyl groups . 
Content of methoxy and 2–hydroxypropoxy groups . 
10 Typical Properties 
Density (bulk): 
0.2–0.3 g/cm3 for Aqoat MF (Shin Etsu); 
0.2–0.5 g/cm3 for Aqoat MG (Shin Etsu). 
Density (tapped): 
0.3–0.5 g/cm3 for Aqoat MF (Shin Etsu); 
0.3–0.6 g/cm3 for Aqoat MG (Shin Etsu). 
Density (true): 1.27–1.29 g/cm3(4) 
Equilibrium moisture content: 2–3% w/w at ambient temperature 
and humidity (258C, 40% RH).(4) See also Figure 1. 
Glass transition temperature: 113 
28C (differential scanning 
calorimetry; dried sample) 
Particle size distribution: 10% < 1 mm; 50% < 5 mm; 90% 
< 10 mm for Aqoat MF (Shin Etsu).

10% < 200 mm; 50% < 800 mm; 90% < 1000 mm for 
Aqoat MG (Shin Etsu). 
Solubility: practically insoluble in ethanol (95%), hexane, 
unbuffered water, and xylene. On the addition of acetone, or 
a mixture of ethanol (95%) and dichloromethane (1 : 1), a 
clear or turbid viscous liquid is produced. Hypromellose 
acetate succinate can be dissolved in buffers of pH greater 
than 4.5 with the rank order of solubility for the various 
grades (see Section 8) increasing with the ratio of acetyl over 
succinoyl substitution. The exact pH value at which the 
polymer dissolves depends on the buffer type and ionic 
strength, although the rank order for the different grades is 
independent of the buffer used. 
Viscosity (dynamic): see Figure 2. 
Figure 1: Viscosity of different grades of Aqoat (Shin-Etsu).(4) 
Figure 2: Equilibrium moisture content of Aqoat (Shin-Etsu) at different 
relative humidities.(4) 
SEM: 1 
Excipient: Aqoat MF 
Manufacturer: Shin Etsu 
Magnification: 1000 
SEM: 2 
Excipient: Aqoat MG 
Manufacturer: Shin Etsu 
Magnification: 50 
11 Stability and Storage Conditions 
Hypromellose acetate succinate should be stored in a wellclosed 
container, in a cool, dry place. In such storage 
conditions, hypromellose acetate succinate is a stable material. 
It is stable for four years after manufacturing.(4) Hypromellose 
acetate succinate is hygroscopic. It is hydrolyzed to acetic acid 
and succinic acid, and the hypromellose polymer starts to form 
if dissolved in 1 mol/L sodium hydroxide for more than two 
hours.(15) The hydrolysis is the main degradation pathway that 
is responsible for increasing amounts of free acids in storage, 
especially upon exposure to moisture. 
Hypromellose Acetate Succinate 351

12 Incompatibilities 
Hypromellose acetate succinate is incompatible with strong 
acids or bases, oxidizing agents, and sustained levels of elevated 
humidity. 
13 Method of Manufacture 
Hypromellose acetate succinate is produced by the esterification 
of hypromellose with acetic anhydride and succinic 
anhydride, in a reaction medium of a carboxylic acid, such as 
acetic acid, and using an alkali carboxylate, such as sodium 
acetate, as catalyst.(16) The fibrous reaction product is 
precipitated out by adding a large volume of water to the 
reaction medium. Purification is achieved by thorough washing 
with water. The granular grade of hypromellose acetate 
succinate that is so obtained can be pulverized to a fine powder 
if required. 
14 Safety 
The safety and pharmacological profiles of hypromellose 
acetate succinate are similar to those of other ether and ester 
derivatives of cellulose.(17–21) All nonclinical studies reported in 
the literature identify no target organs for toxicity by 
hypromellose acetate succinate.(22,23) It has also been reported 
that hypromellose acetate succinate does not alter fertility in 
rats, does not produce any developmental anomalies in rats and 
rabbits, and does not alter perinatal and postnatal development 
in rats when assessed up to 2500 mg/kg.(24–27) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Hypromellose acetate 
succinate dust may be irritant to the eyes. Excessive dust 
generation should be avoided to minimize the risks of 
explosions. Avoid contact with open flame, heat, or sparks. 
Avoid contact with acids, peroxides, and other oxidizing 
materials. Eye protection is recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide for use in oral 
preparations (capsules, and delayed-action preparations). 
Hypromellose acetate succinate has been approved for use in 
commercial pharmaceutical products in the USA and in Japan. 
17 Related Substances 
Carboxymethyl cellulose; cellulose acetate; cellulose acetate 
phthalate; cellulose, microcrystalline; ethylcellulose; hypromellose; 
hypromellose phthalate; hydroxyethyl cellulose; hydroxypropyl 
cellulose; methylcellulose. 
18 Comments 
A specification for hypromellose acetate succinate is also 
included in the Japanese Pharmaceutical Excipients (JPE); see 
Table II. 
Table II: JPE specification for hypromellose acetate succinate. 
Test JPE 1998(1,2) 
LG, LF MG, MF HG, HF 
Appearance Conforms Conforms Conforms 
Identification Conforms Conforms Conforms 
Viscosity (mm2/s) 2.4–3.6 2.4–3.6 2.4–3.6 
Heavy metals (%w/w) 40.001 40.001 40.001 
Arsenic (%w/w) 40.0002 40.0002 40.0002 
Free succinic acid (%)(a) 41.0 41.0 41.0 
Loss on drying (%) 45.0 45.0 45.0 
Residue on ignition (%) 40.20 40.20 40.20 
Methoxyl content (%) 20.0–24.0 21.0–25.0 22.0–26.0 
Hydroxypropoxyl content (%) 5.0–9.0 5.0–9.0 6.0–10.0 
Acetyl content (%) 5.0–9.0 7.0–11.0 10.0–14.0 
Succinoyl content (%) 14.0–18.0 10.0–14.0 4.0–8.0 
(a) The titration method in JPE is only capable of monitoring the total free acid amount, which is 
here termed free succinic acid. It has been demonstrated that the total free acids consists of free 
acetic and succinic acids.(15) 
A new accurate and robust analytical method based on 
liquid chromatography has been developed for the analysis of 
free organic acids, and acetyl and succinoyl substitutions in 
hypromellose acetate succinate.(15) It provides efficient separation 
and sensitive quantitation of free acetic and succinic acids. 
Another new analytical method based on liquid chromatography 
has also been developed for the analysis of methoxyl 
and 2-hydroxypropoxyl substitutions in hypromellose acetate 
succinate.(28) 
19 Specific References 
1 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
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2 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
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8 Anderson NR, Oren PL, Ogura T, Fujii T. United States Patent No. 
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9 Nagai T, Obara S, Kokubo H, Hoshi N. Application of HPMC and 
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12 Miyajima M, Yamaguchi Y, Tsunematsu T, Toshihisa O. Pharmaceutical 
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352 Hypromellose Acetate Succinate

13 Takeichi Y, Baba K, Kinouchi Y, et al. Combinative improving 
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1990; 38: 2547–2551. 
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15 Chen R, Sekulic S, Zelesky T. Development and validation of a 
cost-effective, efficient, and robust liquid chromatographic method 
for the simultaneous determination of the acetyl and succinoyl 
content in hydroxypropyl methylcellulose acetate succinate polymer. 
J AOAC Int 2002; 85(4): 824–831. Correction: 85(6), 125A. 
16 Onda Y, Muto H, Maruyama K. Ether-ester derivatives of cellulose 
and their applications. United States Patent No. 4,226,981; 1980. 
17 Final report on the safety assessment of hydroxyethylcellulose, 
methylcellulose, hydroxypropyl methylcellulose and cellulose 
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18 Informatics: GRAS (Generally Recognized as Safe) Food ingredients—
cellulose and derivatives. For the FDA National Technical 
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19 Obara S, Muto H, Shigeno H, et al. A three month repeated oral 
administration study of a low viscosity grade of hydroxypropyl 
methylcellulose in rats. J Toxicol Sci 1999; 24: 33–43. 
20 Frawley JP. Studies on the gastro-intestinal absorption of purified 
sodium carboxymethylcellulose. Food Cosmet Toxicol 1964; 2: 
539–543. 
21 Kitagawa H, Satoh T, Yokoshima T, Nanbo T. Absorption, 
distribution and excretion of hydroxypropyl methylcellulose 
phthalate in the rat. Pharmacometrics 1971; 5: 1–4. 
22 Hoshi N, Ueno K, Yano H, Hirashima K, Kitagawa H. General 
pharmacological studies of hydroxypropylmethyl cellulose acetate 
succinate in experimental animals. J Toxicol Sci 1985; 10: 129– 
146. 
23 Hoshi N, Yano H, Hirashima K, Kitagawa H, Fukuda Y. 
Toxicological studies of hydroxypropylmethyl cellulose acetate 
succinate—Acute toxicity in rats and rabbits, and subchronic and 
chronic toxicities in rats. J Toxicol Sci 1985; 10: 147–185. 
24 Hoshi N, Ueno K, Igarashi T, et al. Studies of hydroxypropylmethyl 
cellulose acetate succinate on fertility in rats. J Toxicol Sci 
1985; 10: 187–201. 
25 Hoshi N, Ueno K, Igarashi T, et al. Teratological studies of 
hydroxypropylmethyl cellulose acetate succinate in rats. J Toxicol 
Sci 1985; 10: 203–226. 
26 Hoshi N, Ueno K, Igarashi T, et al. Teratological study of 
hydroxypropylmethyl cellulose acetate succinate in rabbits. J 
Toxicol Sci 1985; 10: 227–234. 
27 Hoshi N, Ueno K, Igarashi T, et al. Effects of offspring induced by 
oral administration of hydroxypropylmethyl cellulose acetate 
succinate to the female rats in peri and post natal periods. J 
Toxicol Sci 1985; 10: 235–255. 
28 Rashan J, Chen R, Zelesky T, Sekulic S. Developing an alternative 
liquid chromatographic method for determining methoxyl and 2- 
hydroxypropoxyl content in cellulose ether derivatives. J AOAC 
Int 2003; 86(4): 694–702. 
20 General References 
Doelker E. Cellulose derivatives. In: Adv Polym Sci 1993; 107: 199– 
265. 
Tanno F, Nishiyama Y, Kokubo H, Obora S. Evaluation of 
hypromellose acetate succinate (HPMCAS) as a carrier in solid 
dispersions. Drug Dev Ind Pharm 2004; 30(1): 9–17. 
21 Authors 
R Chen, BC Hancock, RM Shanker. 
22 Date of Revision 
24 August 2005. 
Hypromellose Acetate Succinate 353

Hypromellose Phthalate 
1 Nonproprietary Names 
BP: Hypromellose phthalate 
JP: Hydroxypropylmethylcellulose phthalate 
PhEur: Hypromellosi phthalas 
USPNF: Hypromellose phthalate 
2 Synonyms 
Cellulose phthalate hydroxypropyl methyl ether; HPMCP; 
hydroxypropyl methylcellulose benzene-1,2-dicarboxylate; 2- 
hydroxypropyl methylcellulose phthalate; methylhydroxypropylcellulose 
phthalate. 
3 Chemical Name and CAS Registry Number 
Cellulose, hydrogen 1,2-benzenedicarboxylate, 2-hydroxypropyl 
methyl ether [9050-31-1] 
4 Empirical Formula and Molecular Weight 
Hypromellose phthalate is a cellulose in which some of the 
hydroxyl groups are replaced with methyl ethers, 2-hydroxypropyl 
ethers, or phthalyl esters. Several different types of 
hypromellose phthalate are commercially available with 
molecular weights in the range 20 000–200 000. Typical 
average values are 80 000–130 000.(1) 
5 Structural Formula 
6 Functional Category 
Coating agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Hypromellose phthalate is widely used in oral pharmaceutical 
formulations as an enteric coating material for tablets or 
granules.(2–8) Hypromellose phthalate is insoluble in gastric 
fluid but will swell and dissolve rapidly in the upper intestine. 
Generally, concentrations of 5–10% of hypromellose phthalate 
are employed with the material being dissolved in either a 
dichloromethane : ethanol (50 : 50) or an ethanol : water 
(80 : 20) solvent mixture. Hypromellose phthalate can normally 
be applied to tablets and granules without the addition of a 
plasticizer or other film formers, using established coating 
techniques. However, the addition of a small amount of 
plasticizer or water can avoid film cracking problems; many 
commonly used plasticizers, such as diacetin, triacetin, diethyl 
and dibutyl phthalate, castor oil, acetyl monoglyceride, and 
polyethylene glycols, are compatible with hypromellose phthalate. 
Tablets coated with hypromellose phthalate disintegrate 
more rapidly than tablets coated with cellulose acetate phthalate. 
Hypromellose phthalate can be applied to tablet surfaces 
using a dispersion of the micronized hypromellose phthalate 
powder in an aqueous dispersion of a suitable plasticizer such 
as triacetin, triethyl citrate, or diethyl tartrate along with a 
wetting agent.(9) 
Hypromellose phthalate may be used alone or in combination 
with other soluble or insoluble binders in the preparation 
of granules with sustained drug-release properties; the release 
rate is pH-dependent. Since hypromellose phthalate is tasteless 
and insoluble in saliva, it can also be used as a coating to mask 
the unpleasant taste of some tablet formulations. Hypromellose 
phthalate has also been co-precipitated with a poorly soluble 
drug to improve dissolution characteristics.(10) 
8 Description 
Hypromellose phthalate occurs as white to slightly off-white, 
free-flowing flakes or as a granular powder. It is odorless or 
with a slightly acidic odor and has a barely detectable taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for hypromellose phthalate. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters — . — 
Water 45.0% 45.0% 45.0% 
Viscosity (208C) . — . 
Residue on ignition 40.20% 40.20% 40.20% 
Chloride 40.07% 40.07% 40.07% 
Heavy metals 410 ppm 410 ppm 40.001% 
Free phthalic acid 41.0% 41.0% 41.0% 
Organic volatile impurities — — . 
Phthalyl content — 21.0–35.0% 21.0–35.0% 
Type 200731 27.0–35.0% — — 
Type 220824 21.0–27.0% — —

10 Typical Properties 
Angle of repose: 
378 for HP-50; 
398 for HP-55; 
388 for HP-55S.(11) 
Density: 
1.82 g/cm3 for HP-50; 
1.65 g/cm3 for HP-55.(11) 
Density (bulk): 
0.278 g/cm3 for HP-50; 
0.275 g/cm3 for HP-55; 
0.239 g/cm3 for HP-55S.(11) 
Density (tapped): 
0.343 g/cm3 for HP-50; 
0.306 g/cm3 for HP-55; 
0.288 g/cm3 for HP-55S.(11) 
Melting point: 1508C. Glass transition temperature is 1378C 
for HP-50 and 1338C for HP-55.(12) 
Moisture content: hypromellose phthalate is hygroscopic; it 
takes up 2–5% of moisture at ambient temperature and 
humidity conditions. For the moisture sorption isotherm of 
HP-50 measured at 258C, see Figure 1. 
Particle size distribution: see Figure 2. 
Solubility: readily soluble in a mixture of acetone and methyl or 
ethyl alcohol (1 : 1), in a mixture of methyl alcohol and 
dichloromethane (1 : 1), and in aqueous alkali. Practically 
insoluble in water and dehydrated alcohol and very slightly 
soluble in acetone. The solubilities of the HP-50 and HP-55 
grades, in various solvents and solvent mixtures, are shown 
in Table II.(11) 
Viscosity: see Figures 3 and 4. 
Table II: Solubility of hypromellose phthalate (HP-50 and HP-55, Shin- 
Etsu Chemical Co. Ltd.). 
Solvent Solubility 
HP-50 HP-55 
Acetone S/I S 
Acetone : dichloromethane S/I S 
Acetone : ethanol S/S S 
Acetone : methanol S S 
Acetone : 2-propanol S/S S 
Acetone : water (95 : 5) S S 
Benzene : methanol S S 
Dichloromethane S/I S/I 
Dichloromethane : ethanol S S 
Dichloromethane : methanol S S 
Dichloromethane : 2-propanol S/S S 
Dioxane S S 
Ethanol (95%) S/I S/I 
Ethyl acetate X S/I 
Ethyl acetate : ethanol S/S S 
Ethyl acetate : methanol S S 
Ethyl acetate : 2-propanol S/I S 
Methanol S/I S/I 
Methyl ethyl ketone S/I S 
Propan-2-ol X S/I 
Note: solubilities are for the pure solvent, or a (1 : 1) solvent mixture, unless otherwise indicated. 
S = soluble, clear solution. 
S/S = slightly soluble, cloudy solution. 
S/I = swells but insoluble. 
X = insoluble. 
SEM: 1 
Excipient: Hypromellose phthalate (HP-55) 
Manufacturer: Shin-Etsu Chemical Co. Ltd. 
Magnification: 60 
SEM: 2 
Excipient: Hypromellose phthalate (HP-55) 
Manufacturer: Shin-Etsu Chemical Co. Ltd. 
Magnification: 600 
11 Stability and Storage Conditions 
Hypromellose phthalate is chemically and physically stable at 
ambient temperature for at least 3–4 years and for 2–3 months 
at 408C and 75% relative humidity.(11) It is stable on exposure 
to UV light for up to 3 months at 258C and 70% relative 
humidity. Drums stored in a cool, dry place should be brought 
to room temperature before opening to prevent condensation of 
moisture on inside surfaces. After 10 days at 608C and 100% 
relative humidity, 8–9% of carbyoxybenzoyl group were 
hydrolyzed. In general, hypromellose phthalate is more stable 
than cellulose acetate phthalate. At ambient storage conditions, 
hypromellose phthalate is not susceptible to microbial attack. 
Hypromellose Phthalate 355

Figure 1: Equilibrium moisture content of hypromellose phthalate 
(Shin-Etsu Chemical Co. Ltd.) at 258C.(11) 
*: HP-50 
&: HP-55 
~: HP-55S 
Figure 2: Particle size distribution of hypromellose phthalate (Shin- 
Etsu Chemical Co. Ltd).(11) 
*: HP-50 
&: HP-55 
~: HP-55S 
Figure 3: Dynamic viscosity of hypromellose phthalate (HP-50) (Shin- 
Etsu Chemical Co. Ltd.) in various solvent mixtures at 
208C.(11) 
*: Acetone : ethanol (1 : 1) 
&: Dichloromethane : ethanol (1 : 1) 
~: Ethanol : water (1 : 1) 
Figure 4: Dynamic viscosity of hypromellose phthalate (HP-55) (Shin- 
Etsu Chemical Co. Ltd.) in various solvent mixtures at 
208C.(11) 
*: Acetone : ethanol (1 : 1) 
&: Dichloromethane : ethanol (1 : 1) 
~: Ethanol : water (8 : 2) 
356 Hypromellose Phthalate

12 Incompatibilities 
Incompatible with strong oxidizing agents. 
Splitting of film coatings has been reported rarely, most 
notably with coated tablets that contain microcrystalline 
cellulose and calcium carboxymethylcellulose. Film splitting 
has also occurred when a mixture of acetone : propan-2-ol or 
dichloromethane : propan-2-ol has been used as the coating 
solvent, or when coatings have been applied in conditions of 
low temperature and humidity. However, film splitting may be 
avoided by careful selection of formulation composition, 
including solvent, by use of a higher molecular weight grade 
of polymer, or by suitable selection of plasticizer. 
The addition of more than about 10% titanium dioxide to a 
coating solution of hypromellose phthalate, which is used to 
produce a colored film coating, may result in coating with 
decreased elasticity and resistance to gastric fluid.(11) 
13 Method of Manufacture 
Hypromellose phthalate is prepared by the esterification of 
hypromellose with phthalic anhydride. The degree of alkyloxy 
and carboxybenzoyl substitution determines the properties of 
the polymer and in particular the pH at which it dissolves in 
aqueous media. 
14 Safety 
Hypromellose phthalate is widely used, primarily as an enteric 
coating agent, in oral pharmaceutical formulations. Chronic 
and acute animal feeding studies on several different species 
have shown no evidence of teratogenicity or toxicity associated 
with hypromellose phthalate.(13–17) Hypromellose phthalate is 
generally regarded as a nonirritant and nontoxic material. 
LD50 (rat, oral): >15 g/kg(13) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. Although no threshold limit value has been set 
for hypromellose phthalate, it should be handled in a wellventilated 
environment and the generation of dust should be 
minimized. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral capsules 
and tablets). Included in nonparenteral medicines licensed in 
the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Cellulose acetate phthalate; hypromellose. 
18 Comments 
Various grades of hypromellose phthalate are available with 
differing degrees of substitution and physical properties, e.g., 
grades HP-50, HP-55, and HP-55S (Shin-Etsu Chemical Co 
Ltd). See Table III. 
The number following ‘HP’ in each grade designation refers 
to the pH value (10) at which the polymer dissolves in 
aqueous buffer solutions. The designation ‘S’ in HP-55S 
indicates a higher molecular weight grade, which produces 
films with a greater resistance to cracking. 
Table III: Types of hypromellose phthalate available from Shin-Etsu 
Chemical Co. Ltd. 
Property Grade of hypromellose phthalate 
HP-50 HP-55 HP-55S 
Substitution type 220824 200731 200731 
Hydroxypropoxy content 6–10% 5–9% 5–9% 
Methoxy content 20–24% 18–22% 18–22% 
Phthalyl content 21–27% 27–35% 27–35% 
Molecular weight 84 000 78 000 132 000 
In the USA, the substitution type is indicated by a six digit 
number: the first two digits represent the approximate 
percentage content of methoxy groups; the next two digits 
represent the approximate percentage content of hydroxypropoxy 
groups; and the final two digits represent the approximate 
percentage content of phthalyl groups. 
To dissolve hypromellose phthalate in acetone : ethanol 
(95%) or dichloromethane : alcohol solvent systems, the 
hypromellose phthalate should first be well dispersed in alcohol 
before adding acetone or dichloromethane. When using 
acetone : dichloromethane, hypromellose phthalate should be 
first dispersed in the dichloromethane and then the acetone 
added to the system. A specification for hypromellose phthalate 
is contained in the Food Chemicals Codex (FCC). 
19 Specific References 
1 Rowe RC. Molecular weight studies on hydroxypropyl methylcellulose 
phthalate (HP55). Acta Pharm Technol 1982; 28(2): 
127–130. 
2 Ehrhardt L, Patt L, Schindler E. Optimization of film coating 
systems [in German]. Pharm Ind 1973; 35: 719–722. 
3 Delporte JP, Jaminet F. Influence of formulation of enteric coated 
tablets on the bioavailability of the drug [in French]. J Pharm Belg 
1976; 31: 263–276. 
4 Patt L, Hartmann V. Solvent residues in film forming agents [in 
German]. Pharm Ind 1976; 38: 902–906. 
5 Stafford JW. Enteric film coating using completely aqueous 
dissolved hydroxypropyl methyl cellulose phthalate spray solutions. 
Drug Dev Ind Pharm 1982; 8: 513–530. 
6 Thoma K, Heckenmu. ller H, Oschmann R. Resistance and 
disintegration behaviour of gastric juice resistant drugs [in 
German]. Pharmazie 1987; 42: 832–836. 
7 Thoma K, Heckenmu. ller H. Impact of film formers and plasticizers 
on stability of resistance and disintegration behaviour [in German]. 
Pharmazie 1987; 42: 837–841. 
8 Takada K, Oh-Hashi M, Furuya Y, et al. Enteric solid dispersion of 
ciclosporin A (CiA) having potential to deliver CiA into 
lymphatics. Chem Pharm Bull 1989; 37: 471–474. 
9 Muhammad NA, Boisvert W, Harris MR, Weiss J. Evaluation of 
hydroxypropyl methylcellulose phthalate 50 as film forming 
polymer from aqueous dispersion systems. Drug Dev Ind Pharm 
1992; 18: 1787–1797. 
10 Sertsou G, Butler J, Hempenstall J, Rades T. Solvent change coprecipitation 
with hydroxypropyl methylcellulose phthalate to 
improve dissolution characteristics of a poorly water-soluble drug. 
J Pharm Pharmacol 2002; 54(8): 1041–1047. 
11 Shin-Etsu Chemical Co. Ltd. Technical literature: Hydroxypropyl 
methylcellulose phthalate, 1993. 
Hypromellose Phthalate 357

12 Sakellariou P, Rowe RC, White EFT. The thermomechanical 
properties and glass transition temperature of some cellulose 
derivatives used in film coating. Int J Pharm 1985; 27: 267–277. 
13 Kitagawa H, Kawana H, Satoh T, Fukuda Y. Acute and subacute 
toxicities of hydroxypropyl methylcellulose phthalate. Pharmacometrics 
1970; 4(6): 1017–1025. 
14 Kitagawa H, Satoh T, Yokoshima T, Nanbo T. Absorption, 
distribution and excretion of hydroxypropyl methylcellulose 
phthalate in the rat. Pharmacometrics 1971; 5(1): 1–4. 
15 Ito R, Toida S. Studies on the teratogenicity of a new enteric 
coating material, hydroxypropyl methylcellulose phthalate 
(HPMCP) in rats and mice. J Med Soc Toho-Univ 1972; 19(5): 
453–461. 
16 Kitagawa H, Yano H, Fukuda Y. Chronic toxicity of hydroxypropylmethylcellulose 
phthalate in rats. Pharmacometrics 1973; 
7(5): 689–701. 
17 Kitagawa H, Yokoshima T, Nanbo T, Hasegawa M. Absorption, 
distribution, excretion and metabolism of 14C-hydroxypropyl 
methylcellulose phthalate. Pharmacometrics 1974; 8(8): 1123– 
1132. 
20 General References 
Deasy PB, O’Connell MJM. Correlation of surface characteristics with 
ease of production and in vitro release of sodium salicylate from 
various enteric coated microcapsules prepared by pan coating. J 
Micoencapsul 1984; 1(3): 217–227. 
Doelker E. Cellulose derivatives. Adv Polym Sci 1993; 107: 199–265. 
Rowe RC. Materials used in the film coating of oral dosage forms. In: 
Florence AT, ed. Critical Reports on Applied Chemistry, vol. 6. 
Oxford: Blackwell Scientific, 1984: 1–36. 
21 Authors 
SR Goskonda, JC Lee. 
22 Date of Revision 
15 August 2005. 
358 Hypromellose Phthalate

Imidurea 
1 Nonproprietary Names 
USPNF: Imidurea 
2 Synonyms 
Biopure 100; Germall 115; imidazolidinyl urea; 
methanebis[N,N0 (5-ureido-2,4-diketotetrahydroimidazole)- 
N,N-dimethylol]; 1,10-methylenebis{3-[3-(hydroxymethyl)- 
2,5-dioxo-4-imidazolidinyl]urea}; Tri-Stat IU. 
3 Chemical Name and CAS Registry Number 
N, N00-Methylenebis{N0-[3-(hydroxymethyl)-2,5-dioxo-4-imidazolidinyl]
urea} [39236-46-9] 
4 Empirical Formula and Molecular Weight 
C11H16N8O8 388.29 (for anhydrous) 
C11H16N8O8.H2O 406.33 (for monohydrate) 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Imidurea is a broad-spectrum antimicrobial preservative used 
in cosmetics and topical pharmaceutical formulations; typical 
concentrations used are 0.03–0.5% w/w. It is effective between 
pH 3–9 and is reported to have synergistic effects when used 
with parabens; see Section 10. 
8 Description 
Imidurea is a white, free-flowing odorless powder. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for imidurea. 
Test USPNF 23 
Identification . 
Color and clarity of solution . 
pH (1% w/v solution) 6.0–7.5 
Loss on drying 43.0% 
Residue on ignition 43.0% 
Heavy metals 40.001% 
Organic volatile impurities . 
Nitrogen content (dried basis) 26.0–28.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 6.0–7.5 (1% w/v aqueous solution). 
Antimicrobial activity: predominantly an antibacterial preservative, 
imidurea also has some selective antifungal properties. 
Used at concentrations between 0.03–0.5% w/w it is 
effective between pH 3–9, although preservative efficacy is 
best seen in slightly acidic solutions. Synergistic effects have 
been reported and preservative activity is considerably 
enhanced, particularly against fungi, when used in combination 
with parabens.(1,2) A cosmetic formulation containing 
0.5% imidurea, 0.2% methylparaben, and 0.1% 
propylparaben was effectively preserved against various 
Pseudomonas species.(3) For reported minimum inhibitory 
concentrations (MICs), see Table II.(4) 
Table II: Minimum inhibitory concentrations (MICs) for imidurea. 
Microorganism MIC (mg/mL) 
Aspergillus niger 8000 
Candida albicans 8000 
Escherichia coli 2000 
Klebsiella pneumoniae 2000 
Penicillium notatum 8000 
Pseudomonas aeruginosa 2000 
Pseudomonas cepacia 2000 
Pseudomonas fluorescens 2000 
Staphylococcus aureus 1000 
Solubility: soluble in water and in glycerol, but insoluble in 
almost all organic solvents.(4) See also Table III. 
11 Stability and Storage Conditions 
Imidurea is hygroscopic and should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Imidurea is compatible with other preservatives including 
sorbic acid and quaternary ammonium compounds.(5) It is 
also compatible with other pharmaceutical and cosmetic 
excipients including proteins, nonionic surfactants, and 
lecithin.(6)

Table III: Solubility of imidurea. 
Solvent Solubility at 208C 
Ethanol Very slightly soluble 
Ethanol (90%) Very slightly soluble 
Ethanol (70%) 1 in 330 
Ethanol (60%) 1 in 25 
Ethanol (50%) 1 in 2.5 
Ethanol (30%) 1 in 0.8 
Ethylene glycol(a) 1 in 0.7 
Glycerin(a) 1 in 1 
Methanol Very slightly soluble 
Mineral oil Practically insoluble 
Propan-2-ol Practically insoluble 
Propylene glycol(a) 1 in 0.8 
Sesame oil Very slightly soluble 
Water 1 in 0.5 
(a) Slow to dissolve and requires heating and stirring. 
13 Method of Manufacture 
Imidurea is commercially prepared by a complex synthetic 
route. 
14 Safety 
Imidurea is widely used in cosmetics and topical pharmaceutical 
formulations and is generally regarded as a nontoxic and 
nonirritant material.(5) However, there have been some reports 
of contact dermatitis associated with imidurea, although these 
are relatively few considering its widespread use in cosmetics.(
7–10) 
Although imidurea releases formaldehyde, it does not 
appear to be associated with cross-sensitization with formaldehyde 
or other formaldehyde-releasing compounds. 
LD50 (mouse, oral): 7.2 g/kg(11,12) 
LD50 (rabbit, skin): > 8 g/kg 
LD50 (rat, oral): 11.3 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Imidurea may be irritant to 
the eyes. Eye protection and gloves are recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (topical 
preparations). Accepted for use in cosmetics in Europe and 
the USA. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Diazolidinyl urea. 
Diazolidinyl urea 
Empirical formula: C8H14N4O7 
Molecular weight: 278.23 
CAS number: [78491-02-8] 
Synonyms: Germall II; N-(hydroxymethyl)-N-(1,3-dihydroxymethyl-
2,5-dioxo-4-imidazolidinyl)-N0-(hydroxymethyl) 
urea. 
Appearance: white, free-flowing hygroscopic powder, with a 
faint characteristic odor. 
Antimicrobial activity: similar to imidurea.(13,14) Diazolidinyl 
urea is the most active of the imidazolidinyl family of 
preservatives. Used in concentrations of 0.1–0.5% w/w, at 
pH 3–9, it has predominantly antibacterial properties. 
Typical MICs are: Aspergillus niger 4000 mg/mL; Candida 
albicans 8000 mg/mL; Escherichia coli 1000 mg/mL; Pseudomonas 
aeruginosa 1000 mg/mL; Staphylococcus aureus 
250 mg/mL. 
Solubility: very soluble in water. 
Safety:
LD50 (mouse, oral): 3.7 g/kg(15) 
LD50 (rat, oral): 2.6 g/kg 
Comments: the EINECS number for diazolidinyl urea is 278- 
928-2. 
18 Comments 
Imidurea is the best known of a family of heterocyclic urea 
derivatives that are effective antimicrobial preservatives. 
Diazolidinyl urea has the greatest antimicrobial activity. 
The EINECS number for imidurea is 254-372-6. 
19 Specific References 
1 Jacobs G, Henry SM, Cotty VF. The influence of pH, emulsifier, 
and accelerated ageing upon preservative requirements of o/w 
emulsions. J Soc Cosmet Chem 1975; 26: 105–117. 
2 Rosen WE, Berke PA, Matzin T, Peterson AF. Preservation of 
cosmetic lotions with imidazolidinyl urea plus parabens. J Soc 
Cosmet Chem 1977; 28: 83–87. 
3 Berke PA, Rosen WE. Imidazolidinyl urea activity against 
pseudomonas. J Soc Cosmet Chem 1978; 29: 757–766. 
4 Wallha. usser KH. Imidazolidinyl urea. In: Kabara JJ, ed. Cosmetic 
and Drug Preservation Principles and Practice. New York: Marcel 
Dekker, 1984: 655–657. 
5 Rosen WE, Berke PA. Germall 115: a safe and effective modern 
preservative. Cosmet Toilet 1977; 92(3): 88–89. 
6 Rosen WE, Berke PA. Germall 115 and nonionic emulsifiers. 
Cosmet Toilet 1979; 94(12): 47–48. 
7 Fisher AA. Cosmetic dermatitis: part II. Reactions to some 
commonly used preservatives. Cutis 1980; 26: 136, 137, 141, 
142, 147–148. 
8 Dooms-Goossens A, De Boulle K, Dooms M, Degreef H. 
Imidazolidinyl urea dermatitis. Contact Dermatitis 1986; 14(5): 
322–324. 
9 O’Brien TJ. Imidazolidinyl urea (Germall 115) causing cosmetic 
dermatitis. Aust J Dermatol 1987; 28(1): 36–37. 
10 Ziegler V, Ziegler B, Kipping D. Dose-response sensitization 
experiments with imidazolidinyl urea. Contact Dermatitis 1988; 
19(3): 236–237. 
11 Elder RL. Final report of the safety assessment for imidazolidinyl 
urea. J Environ Pathol Toxicol 1980; 4(4): 133–146. 
12 Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. 
Cincinnati: US Department of Health, 1987: 5023. 
13 Berke PA, Rosen WE. Germall II: a new broad-spectrum cosmetic 
preservative. Cosmet Toilet 1982; 97(6): 49–53. 
14 Wallha. usser KH. Germall II. In: Kabara JJ, ed. Cosmetic and Drug 
Preservation Principles and Practice. New York: Marcel Dekker, 
1984: 657–659. 
15 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2072. 
20 General References 
Berke PA, Rosen WE. Germall, a new family of antimicrobial 
preservatives for cosmetics. Am Perfum Cosmet 1970; 85(3): 55– 
59. 
360 Imidurea

Croshaw B. Preservatives for cosmetics and toiletries. J Soc Cosmet 
Chem 1977; 28: 3–16. 
Decker RL, Wenninger JA. Frequency of preservative use in cosmetic 
formulas as disclosed to FDA-1987. Cosmet Toilet 1987; 102(12): 
21–24. 
Rosen WE, Berke PA. Germall 115: a safe and effective preservative. In: 
Kabara JJ, ed. Cosmetic and Drug Preservation Principles and 
Practice. New York: Marcel Dekker, 1984: 191–205. 
21 Authors 
RT Guest. 
22 Date of Revision 
25 August 2005. 
Imidurea 361

Inulin 
1 Nonproprietary Names 
BP: Inulin 
USPNF: Inulin 
2 Synonyms 
Beneo; Frutafit; oligofructose; polyfructose; Raftiline. 
3 Chemical Name and CAS Registry Number 
Inulin [9005-80-5] 
4 Empirical Formula and Molecular Weight 
C6H11O4(C6H11O4)nOH 5000 
5 Structural Formula 
Inulin is a naturally occurring polysaccharide consisting of a 
linear chain of linked D-fructose molecules, having one terminal 
glucose molecule. 
6 Functional Category 
Diagnostic aid; sweetening agent; tablet binder. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Inulin has many potential uses in pharmaceutical applications, 
as a filler–binder in tablet formulations;(1) to stabilize 
therapeutic proteins;(2) or to enhance the dissolution of 
lipophilic drugs.(3) Methacrylated inulin hydrogels have been 
investigated for the development of colon-specific drug delivery 
systems.(4) 
Inulin is used as a diagnostic agent to measure the 
glomerular filtration rate.(5) It is used in the food industry as 
a sweetener and stabilizer; and also as a pro-biotic, where it has 
been shown to provide protection against inflammatory and 
malignant colonic diseases in animals.(6,7) It is also used as a 
noncaloric dietary fiber supplement. 
8 Description 
Inulin occurs as an odorless white powder with a neutral to 
slightly sweet taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for inulin. 
Test BP 2004 USPNF 23 
Identification . . 
Acidity . 4.5–7.0 
Clarity and color of solution. . 
Microbial limit — 41000/g 
Loss on drying 410.0% 410.0% 
Specific rotation –36.58 to –40.58 –32.08 to –40.08 
Residue on ignition 40.1% 40.05% 
Sulfate 4200 ppm 40.05% 
Calcium 4270 ppm 40.5% 
Chloride 4170 ppm 40.014% 
Heavy metals — 45 ppm 
Arsenic 41 ppm — 
Lead 42 ppm — 
Oxalate . — 
Glucose and fructose . . 
Assay (dried basis) — 94.0–102.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 4.5–7.0 (10% w/v aqueous solution) 
Density: 1.35 g/cm3 
Hygroscopicity: hygroscopic in moist air. 
Melting point: 1788C 
Solubility: soluble in hot water and solutions of dilute acids and 
alkalis; slightly soluble in cold water and organic solvents. 
Specific gravity: 1.35 
11 Stability and Storage Conditions 
Inulin is slightly hygroscopic and should be stored at cool to 
normal temperatures, in air-tight and water-tight containers. 
12 Incompatibilities 
Inulin is incompatible with strong oxidizing agents. 
13 Method of Manufacture 
Inulin is extracted from the tubers of Dahlia variabilis, 
Helianthus, in a procedure similar to the extraction of sugar 
from sugar beet.

14 Safety 
Inulin is a naturally occurring plant polysaccharide and is one 
of the major constituents of the Compositae family. Inulin is 
recommended to diabetics, as it has a mild sweet taste, but is 
not absorbed and does not affect blood sugar levels. It is used 
widely in the food industry as a sweetener and stabilizer. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Inulin may cause mild 
irritation to the skin and the eyes. Eye protection and gloves are 
recommended. 
16 Regulatory Status 
GRAS listed. 
17 Related Substances 
—
18 Comments 
Hollow spheres of inulin have been found to have both brittle 
and ductile properties. On compression, these spheres will 
undergo fragmentation followed by plastic deformation, 
resulting in better compressibility over solid inulin spheres. In 
its amorphous state, inulin has a high glass transition 
temperature, slow crystallization, and low hygroscopicity. As 
a binder in solid dosage forms, inulin can increase the 
dissolution rate of drugs such as diazepam and can enhance 
the stability of other lipophilic drug molecules.(3,8) Experimentally, 
methacrylated inulin hydrogels have been synthesized 
specifically for colon targeting.(9,10) 
Inulin is used as a diagnostic agent to measure the 
glomerular filtration rate. It has also entered the food 
supplement market as a prebiotic and as a noncaloric dietary 
fiber supplement. Radio-labelled forms of inulin are available 
as radiochemicals for research. 
19 Specific References 
1 Eissens AC, Bolhuis GK, Hinrichs WL, FrijlinkHW. Inulin as fillerbinder 
for tablets prepared by direct compaction. Eur J Pharm Sci 
2002; 15(1): 31–38. 
2 Eriksson HJ, Hinrichs WL, Van Veen B, et al. Investigations into 
the stabilization of drugs by sugar glasses: I. Tablets prepared from 
stabilized alkaline phosphate. Int J Pharm 2002; 249(1–2): 59–70. 
3 International Pharmaceutical Excipients Council Europe. IPEC 
Europe News Jan 2003. 
4 Van den Mooter G, Vervoort L, Kinget R. Characterization of 
methacrylated inulin hydrogels designed for colon targeting: in 
vitro release of BSA. Pharm Res 2003; 20(2): 303–307. 
5 Windfeld S, Jonassen TE, Christensen S. [3H]Inulin as a marker for 
glomerular filtration rate. Am J Physiol Renal Physiol 2003; 
285(3): 575–576. 
6 Reddy BS, Hamid R, Rao CV. Effect of dietary oligofructose and 
inulin on colonic preneoplastic abberant crypt foci inhibition. 
Carcinogenesis 1997; 18(7): 1371–1374. 
7 Delzenne N, Cherbut C, Neyrinck A. Prebiotics: actual and 
potential effects in inflammatory and malignant colonic diseases. 
Curr Opin Clin Nutr Metab Care 2003; 6(5): 581–586. 
8 Bolhuis GK, Eissens AC, Adrichem TP, et al. Hollow filler-binders 
as excipients for direct compaction. Pharm Res 2003; 20(3): 515– 
518. 
9 Maris B, Verheyden L, Van Reeth K, et al. Synthesis and 
characterization of inulin-azo hydrogels designed for colon 
targeting. Int J Pharm 2001; 213: 143–152. 
10 Vervoort L, Van der Mooter G, Ausutijns P, et al. Inulin hydrogels 
as carriers for colonic drug targetting: I. Synthesis and characterization 
of methacrylated inulin and hydrogel formation. Pharm 
Res 1997; 14(12): 1730–1737. 
20 General References 
—
21 Authors 
JT Irwin. 
22 Date of Revision 
24 August 2005. 
Inulin 363

Iron Oxides 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
(a) Iron oxide black: Bayferrox 306; black magnetic oxide; 
black oxide, precipitated; black rouge; CI 77499; E172; ethiops 
iron; ferric ferrous oxide; ferrosoferric oxide; iron oxide; iron 
(II, III) oxide; iron (III) oxide; iron (II) oxide, black; iron oxides 
(Fe3O4); magnetite; pigment black 11; triiron tetraoxide. 
(b) Iron (III) oxide hydrated: Bayferrox 920Z; CI 77492; E172; 
ferric hydroxide; ferric hydroxide oxide; ferric hydrate; ferric 
oxide hydrated; iron hydrate; iron hydroxide; iron hydroxide 
oxide; yellow ochre; yellow iron oxide. 
(c) Iron oxide red: anhydrous ferric oxide; anhydrous iron (III) 
oxide; Bayferrox 105M; CI 77499; diiron trioxide; E172; 
mapico red; red ferric oxide. 
(d) Iron oxide yellow monohydrate: E172; hydrated ferric 
oxide; iron (III) oxide monohydrate, yellow; mapico yellow; 
pigment yellow 42; yellow ferric oxide. 
3 Chemical Name and CAS Registry Number 
Iron oxides [977053-38-5] 
(a) Iron oxide black [1317-61-9] 
(b) Iron (III) oxide hydrated [20344-49-4] 
(c) Iron oxide red [1309-37-1] 
(d) Iron oxide yellow monohydrate [51274-00-1] 
4 Empirical Formula and Molecular Weight 
(a) Fe3O4 231.54 
(b) FeHO2 88.85 
(c) Fe2O3 159.70 
(d) Fe2O3H2O 177.70 
5 Structural Formula 
Iron oxides are defined as inorganic compounds consisting of 
any one of or combinations of synthetically prepared iron 
oxides, including the hydrated forms. 
6 Functional Category 
Colorants. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Iron oxides are widely used in cosmetics, foods, and 
pharmaceutical applications as colorants and UV absorbers.(
1–3) As inorganic colorants they are becoming of increasing 
importance as a result of the limitations affecting some 
synthetic organic dyestuffs. However, iron oxides also have 
restrictions in some countries on the quantities that may be 
consumed and technically their use is restricted because of their 
limited color range and their abrasiveness. 
8 Description 
Iron oxides occur as yellow, red, black, or brown powder. The 
color depends on the particle size and shape, and the amount of 
combined water. 
9 Pharmacopeial Specifications 
—
10 Typical Properties 
Density: 5.1 g/cm3 for iron oxide black (Fe3O4) 
Melting point: 15388C for iron oxide black (Fe3O4) 
Solubility: soluble in strong mineral acids; practically insoluble 
in water (for iron oxide black, Fe3O4). 
11 Stability and Storage Conditions 
Iron oxides should be stored in well-closed containers stored in 
a cool, dry, place. 
12 Incompatibilities 
Iron oxides have been reported to make hard gelatin capsules 
brittle at higher temperatures when the residual moisture is 
11–12%. This factor affects the use of iron oxides for coloring 
hard gelatin capsules, and will limit the amount that can be 
incorporated into the gelatin material. 
13 Method of Manufacture 
Fe2. salt solutions are precipitated and oxidized to black or 
brown iron oxide. 
14 Safety 
Iron oxides are widely used in cosmetics, foods, and oral and 
topical pharmaceutical applications. They are generally 
regarded as nontoxic and nonirritant excipients. The use of 
iron oxide colorants is limited in some countries, such as the 
USA, to a maximum ingestion of 5mg of elemental iron per 
day. 
For iron oxide red (Fe2O3): 
LD50 (mouse, IP): 5.4 g/kg(4) 
LD50 (rat, IP): 5.5 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of the material handled. In the UK, the 
occupational exposure limits for iron oxide fumes (as Fe) are 
5 mg/m3 long-term (8-hour TWA) and 10 mg/m3 short-term.(5) 
16 Regulatory Status 
Accepted for use as a food additive in Europe. Included in 
nonparenteral medicines licensed in many countries including 
Japan, UK, and USA.

Table I: Joint FAO/WHO Expert Committee on Food Additive 
specifications for iron oxides. 
Test FAO/WHO 
Water-soluble matter 41.0% 
Barium 450 mg/kg 
Cadmium 410 mg/kg 
Chromium 4100 mg/kg 
Copper 450 mg/kg 
Mercury 41 mg/kg 
Nickel 4100 mg/kg 
Zinc 4100 mg/kg 
Arsenic 43 mg/kg 
Lead 410 mg/kg 
Assay . 
17 Related Substances 
—
18 Comments 
The EINECS number for iron oxide red (Fe2O3) is 215-168-2. 
The EINECS number for iron oxide black (Fe3O4) is 215-277- 
5. 
Although iron oxides are not included in any pharmacopeias, 
the Joint FAO/WHO Expert Committee on Food 
Additives has issued specifications for iron oxides, see Table 
I.(6) Specifications for iron oxide black,(7) iron oxide red,(8) and 
iron oxide yellow monohydrate(9) are included in the Japanese 
Pharmaceutical Excipients (JPE) 2004; see Table II. 
19 Specific References 
1 Rowe RC. Opacity of tablet film coatings. J Pharm Pharmacol 
1984; 36: 569–572. 
2 Rowe RC. Synthetic iron oxides: ideal for pharmaceutical colorants. 
Pharm Int 1984; 5: 221–224. 
3 Ceschel GC, Gibellini M. Use of iron oxides in the film coating of 
tablets. Farmaco Ed Prat 1980; 35: 553–563. 
4 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2111–2112. 
Table II: Specifications for iron oxide black, iron oxide red, and iron 
oxide yellow monohydrate from JPE 2004. 
Test JPE 2004 
Iron oxide 
black (a) 
Iron oxide 
red (c) 
Iron oxide yellow 
monohydrate (d) 
Description . . . 
Identification . . . 
Purity . . . 
Heavy metals 430 ppm 430 ppm 430 ppm 
Arsenic 410 ppm 42 ppm 42 ppm 
Loss on ignition — — 10.0–13.0% 
Water-soluble 
substances 
. . . 
Loss on drying 41.0% — — 
Assay 590.0% 
(dried basis) 
598.0% 598.0% 
5 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
6 Joint FAO/WHO Expert committee on Food Additives (1992). 
Iron oxides. http://apps3.fao.org/jecfa/additive_specs/docs/0/additive-
0230.htm (accessed 12 May 2005). 
7 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004: 102–103. 
8 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004: 746–747. 
9 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004: 939. 
20 General References 
—
21 Authors 
LY Galichet. 
22 Date of Revision 
17 August 2005. 
Iron Oxides 365

Isomalt 
1 Nonproprietary Names 
BP: Isomalt 
PhEur: Isomaltum 
2 Synonyms 
GalenIQ; hydrogenated isomaltulose; hydrogenated palatinose; 
E953; Isomaltidex 16500; Palatinit. 
3 Chemical Name and CAS Registry Number 
Isomalt [64519-82-0] 
Isomalt is a mixture of two stereoisomers: 
6-O-a-D-glucopyranosyl-D-sorbitol (1,6-GPS) [534-73-6] 
1-O-a-D-glucopyranosyl-D-mannitol dihydrate (1,1-GPM) 
[20942-99-8] 
4 Empirical Formula and Molecular Weight 
C12H24O11 344.32 (for anhydrous) 
C12H24O112H2O 380.32 (for dihydrate) 
5 Structural Formula 
Generally, isomalt comprises a mixture of 1,6-GPS and 1,1- 
GPM. 1,6-GPS crystallizes without water and is more soluble 
than 1,1-GPM. By shifting the ratio of the two components, the 
solubility and crystal water content can be adjusted, see Section 
10. GalenIQ 720 has a GPM: GPS ratio of 1 : 1; GalenIQ 721 
has a GPM: GPS ratio of 1 : 3. 
6 Functional Category 
Base for medicated confectionery; coating agent; granulating 
agent; sweetening agent; tablet and capsule diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Isomalt is a noncariogenic excipient used in a variety of 
pharmaceutical preparations including tablets or capsules, 
coatings, sachets, and suspensions, and in effervescent tablets. 
It can also be used in direct compression and wet granulation.(1) 
In buccal applications such as chewable tablets it is 
commonly used because of its negligible negative heat of 
solution, mild sweetness, and ‘mouth feel’.(2,3) It is also used 
widely in lozenges, sugar-free chewing gum, and hard-boiled 
candies, and as a sweetening agent in confectionery for diabetics. 
See also Section 18. 
8 Description 
Isomalt is a sugar alcohol (polyol) that occurs as a white or 
almost white powder or granular or crystalline substance. It has 
a pleasant sugarlike taste with a mild sweetness approximately 
50–60% of that of sucrose.(2–4) 
9 Pharmacopeial Specifications 
See Table I. See also Section 18. 
10 Typical Properties 
Angle of repose: see Table II. 
Compressibility: compression characteristics may vary, depending 
on the grade of isomalt used; see Figure 1. 
Density (bulk): see Table II. 
Density (tapped): see Table II. 
Density (true): 
1.52 g/cm3 for 1,6-GPS; 
1.47 g/cm3 for 1,1-GPM. 
Flowability: powder is cohesive; granules are free flowing.(2) 
Glass transition temperature: 
638C for a 1 : 3 mixture of 1,1-GPM and 1,6-GPS; 
688C for 1,1-GPM; 
598C for 1,6-GPS.(2) 
Heat of combustion: 0.017 kJ/kg(5) 
Heat of solution: .14.6 kJ/mol for an equimolar mixture of 
1,1-GPM and 1,6-GPS.(2) 
Hygroscopicity: not hygroscopic until 85% RH, at 258C.(2) See 
also Figure 2. 
Melting point: 
141–1618C for a 1 : 3 mixture of 1,1-GPM and 1,6-GPS; 
166–1688C for 1,6-GPS; 
168–1718C for 1,1-GPM.(2) 
Minimum ignition temperature: >4608C 
Moisture content: see Figure 2.

Particle size distribution: 
approximately 90% >100 mm for GalenIQ 720; 
approximately 58% >20 mm for GalenIQ 800; 
approximately 99% >200 mm for GalenIQ 960. 
pH: 3–10(3) 
Solubility: see Figure 3. 
SEM: 1 
Excipient: GalenIQ 720 
Manufacturer: Palatinit GmbH 
Magnification: 400 Voltage: 5kV 
SEM: 2 
Excipient: GalenIQ 721 
Manufacturer: Palatinit GmbH 
Magnification: 400 Voltage: 5kV 
SEM: 3 
Excipient: GalenIQ 810 
Manufacturer: Palatinit GmbH 
Magnification: 65 Voltage:10 kV 
SEM: 4 
Excipent: GalenIQ 981 
Manufacturer: Palatinit GmbH 
Magnification: 90 Voltage: 5kV 
Table I: Pharmacopoeial specifications for isomalt. 
Test PhEur 2005 
Identification . 
Characters . 
Related products . 
Conductivity 420 mScm–1 
Reducing sugars 40.3% 
Lead 40.5 ppm 
Nickel 41 ppm 
Water 47.0% 
Assay 98.0–102.0% 
Table II: Typical physical properties of selected commercially 
available isomalt grades, GalenIQ (Palatinit GmbH). 
Grade Angle of 
repose (8) 
Density 
(bulk) 
(g/cm3) 
Density 
(tapped) 
(g/cm3) 
GalenIQ 720 38 0.43 0.48 
GalenIQ 721 37 0.42 0.45 
GalenIQ 800 — 0.50 0.65 
GalenIQ 810 — 0.59 0.70 
GalenIQ 960 33 0.82 — 
GalenIQ 980 — 0.82 — 
GalenIQ 981 — 0.78 — 
GalenIQ 990 — 0.85 — 
Isomalt 367

SEM: 5 
Excipent: GalenIQ 990 
Manufacturer: Palatinit GmbH 
Magnification: 130 Voltage: 10 kV 
11 Stability and Storage Conditions 
Isomalt has very good thermal and chemical stability. When it is 
melted, no changes in the molecular structure are observed. It 
exhibits considerable resistance to acids and microbial influences.(
1) Isomalt is non-hygroscopic, and at 258C does not 
significantly absorb additional water up to a relative humidity 
(RH) of 85%; paracetamol (acetaminophen) tablets based on 
isomalt were stored for 6 months at 85% RH at 208C and 
retained their physical aspect.(1) 
Figure 1: Tablet crushing strength of isomalt (GalenIQ 720, Palatinit 
GmbH). 
Formulation: 99.5% isomalt, 0.5% magnesium stearate 
Tablet weight: 240mg 
Diameter: 8mm 
Press: Fette P1200 
Punch: concave 
Figure 2: Sorption isotherms of isomalt DC types.(a,b) 
&: Adsorption GalenIQ 720 (Palatinit GmbH) 
&: Desorption GalenIQ 720 (Palatinit GmbH) 
– – –: Crystal water GalenIQ 720 (Palatinit GmbH) 
*: Adsorption GalenIQ 721 (Palatinit GmbH) 
*: Desorption GalenIQ 721 (Palatinit GmbH) 
– – –: Crystal water GalenIQ 721 (Palatinit GmbH) 
(a) Measured using Dynamic Vapor Sorption, Su.dzucker AG. 
(b) 1,6-GPS occurs without crystal water and 1,1-GPM crystallizes with 2 mol crystal water (the 
initial water content in commercial forms, see Section 18). The starting point of the curves 
depends on the water content. The content of free water in the product is typically 0.5–1.0%. 
Figure 3: Solubility of isomalt types in water.(2) 
&: GalenIQ 720 (Palatinit GmbH) 
*: GalenIQ 721 (Palatinit GmbH) 
If stored under normal ambient conditions, isomalt is 
chemically stable for many years. When it is stored in an 
unopened container at 208C and 60% RH, a re-evaluation after 
3 years is recommended. 
Isomalt does not undergo browning reactions; it has no 
reducing groups, therefore it does not react with other 
ingredients in a formulation (e.g. with amines in Maillard 
reactions). 
12 Incompatibilities 
— 
368 Isomalt

13 Method of Manufacture 
Isomalt is produced from food-grade sucrose in a two-stage 
process. Beet sugar is converted by enzymatic transglucosidation 
into the reducing disaccharide isomaltulose. This undergoes 
catalytical hydrogenation to produce isomalt. 
14 Safety 
Isomalt is used in oral pharmaceutical formulations, confectionery, 
and food products. It is generally regarded as a 
nontoxic, nonallergenic, and nonirritant material. 
Toxicological and metabolic studies on isomalt(5–10) have 
been summarized in a WHO report prepared by the FAO/ 
WHO Expert Committee (JECFA), resulting in an acceptable 
daily intake of ‘not specified’.(11) 
The glycosidic linkage between the mannitol or sorbitol 
moiety and the glucose moiety is very stable, limiting the 
hydrolysis and absorption of isomalt in the small intestine. 
There is no significant increase in the blood glucose level after 
oral intake, and glycemic response is very low, making isomalt 
suitable for diabetics. The majority of isomalt is fermented in 
the large intestine. In general, isomalt is tolerated very well, 
although excessive consumption may result in laxative 
effects.(12–14) 
Isomalt is not fermented by bacteria present in the mouth, 
therefore no significant amount of organic acid is produced that 
attacks tooth enamel.(15–17) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection, gloves, and a 
dust mask or respirator are recommended. 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. 
17 Related Substances 
—
18 Comments 
Compression of isomalt without lubrication is difficult, and 
problems such as die wall sticking, capping, and lamination 
have been observed. The addition of a lubricant such as 
magnesium stearate will reduce die wall adhesion. Co-extrusion 
of isomalt with paracetamol (acetaminophen) significantly 
improved the tableting properties of the mixtures, compared 
to physical mixtures of drug and isomalt.(18) Direct molding is 
also a potentially suitable technique for producing isomaltbased 
tablets.(18) 
It is anticipated that a specification for isomalt will soon be 
included in the USPNF.(19) 
A variety of different grades of isomalt are commercially 
available that have different applications, e.g. GalenIQ 720 
and 721 are used in direct compression, GalenIQ 810 is used in 
wet granulation, GalenIQ 981 is used in coatings, and 
GalenIQ 990 is used in boilings. 
19 Specific References 
1 Ndindayino F, Henrist D, Kiekens F, et al. Characterization and 
evaluation of isomalt performance in direct compression. Int J 
Pharm 1999; 189: 113–124. 
2 Palatinit GmbH. Technical literature: Isomalt, GalenIQ, 2005. 
3 Cerestar. Technical literature: IsoMaltidex, 2002. 
4 Schiweck H. Palatinit—Production, technological characteristics 
and analytical study of foods containing Palatinit. Alimenta 1980; 
(19): 5–16. 
5 Livesey G. The energy values of dietary fibre and sugar alcohols for 
man. Nutr Res Rev 1992; (5): 61–84. 
6 Waalkens-Berendsen DH, Koeter HB, van Marwijk MW. Embryotoxicity/
teratogenicity of isomalt in rats and rabbits. Food Chem 
Toxicol 1990; 28(1): 1–9. 
7 Smits-Van Prooije AE, De Groot AP, Dreef-Van Der Meullen HC, 
Sinkeldam EJ. Chronic toxicity and carcinogenicity study of 
isomalt in rats and mice. Food Chem Toxicol 1990; 28(4): 243– 
251. 
8 Waalkens-Berendsen DH, Koeter HB, Sinkeldam EJ. Multigeneration 
reproduction study of isomalt in rats. Food Chem Toxicol 
1990; 28(1): 11–19. 
9 Waalkens-Berendsen DH, Koeter HB, Schlu. ter G, Renhof M. 
Developmental toxicity of isomalt in rats. Food Chem Toxicol 
1989; 27(10): 631–637. 
10 Pometta D, Trabichet D, Spengler M. Effects of a 12 week 
administration of isomalt on metabolic control in type-II-diabetics. 
Akt Erna. hrung 1985; 10: 174–177. 
11 FAO/WHO. Toxicological evaluation of certain food additives and 
contaminants. Twentieth report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1987; No. 539. 
12 Livesey G. Tolerance of low-digestible carbohydrates: a general 
view. Br J Nutr 2001; 85: S1, S7–S16. 
13 Paige DM, Bayless TM, Davis LR. Palatinit digestibility in 
children. Nutr Res 1992; 12: 27–37. 
14 Storey DM, Lee A, Zumbe A. The comparative gastrointestinal 
response of young children to the ingestion of 25 g sweets 
containing sucrose or isomalt. Br J Nutr 2002; 87(4): 291–297. 
15 Featherstone DB. Effect of isomalt sweetener on the caries process: 
A review. J Clin Dent 1995; 5: 82–85. 
16 Van de Hoeven JS. Influence of disaccharide alcohols on the oral 
microflora. Caries Res 1979; 13: 301–306. 
17 Gehring F, Karle EJ. The sugar substitute Palatinit with special 
emphasis on microbial and caries-preventing aspects. Z Erna. rung 
1981; 20: 96–106. 
18 Ndindayino F, Vervaet C, Van den Mooter G, Remon JP. Direct 
compression and moulding properties of co-extruded isomalt/drug 
mixtures. Int J Pharm 2002; 235: 159–168. 
19 Isomalt. Pharmacopeial Forum 2005; 31(1): 89–92. 
20 General References 
Bauer KH, Lehmann K, Osterwald HP, Rothgang G. Coated 
Pharmaceutical Dosage Forms: Fundamentals, Manufacturing 
Techniques, Biopharmaceutical Aspects, Test Methods and Raw 
Materials. Stuttgart: Medpharm Scientific Publications, 1998: 
280. 
Do. rr T, Willibald-Ettle I. Evaluation of the kinetics of dissolution of 
tablets and lozenges consisting of saccharides and sugar substitutes. 
Pharm Ind 1996; 58: 947–952. 
Fritzsching B, Schmidt T. A survey of isomalt as a sugarfree excipient 
for nutraceuticals. Pharmaceutical Manufacturing and Packing 
Sourcer 2000(Sept); 70–72. 
Iida K, Leuenberger H, Fueg LM, et al. Effect of mixing of fine 
carrier particles on dry powder inhalation property of salbutamol 
sulfate (SS). Yakugaku-zasshi, J Pharm Soc Jpn 2000; 120(1): 113– 
119. 
O’Brien Nabors L, ed. Alternative Sweeteners: An Overview, 3rd edn. 
New York: Marcel Dekker, 2001: 553. 
Isomalt 369

Ndindayino F, Henrist D, Kiekens F, et al. Direct compression 
properties of melt-extruded isomalt. Int J Pharm 2002; 235(1–2): 
149–157. 
Ndindayino F, Vervaet C, Van-den-Mooter G, Remon JP. Bioavailability 
of hydrochlorothiazide from isomalt-based moulded tablets. 
Int J Pharm 2002; 246: 199–202. 
Palatinit GmbH. http://www.palatinit.com/en/Homepage/ (accessed 1 
September 2005). 
21 Authors 
B Fritzsching, O Luhn, A Schoch. 
22 Date of Revision 
15 September 2005. 
370 Isomalt

Isopropyl Alcohol 
1 Nonproprietary Names 
BP: Isopropyl alcohol 
JP: Isopropanol 
PhEur: Alcohol isopropylicus 
USP: Isopropyl alcohol 
2 Synonyms 
Dimethyl carbinol; IPA; isopropanol; petrohol; 2-propanol; 
sec-propyl alcohol. 
3 Chemical Name and CAS Registry Number 
Propan-2-ol [67-63-0] 
4 Empirical Formula and Molecular Weight 
C3H8O 60.1 
5 Structural Formula 
6 Functional Category 
Disinfectant; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Isopropyl alcohol (propan-2-ol) is used in cosmetics and 
pharmaceutical formulations primarily as a solvent in topical 
formulations.(1) It is not recommended for oral use owing to its 
toxicity; see Section 14. 
Although it is used in lotions, the marked degreasing 
properties of isopropyl alcohol may limit its usefulness in 
preparations used repeatedly. Isopropyl alcohol is also used as a 
solvent both for tablet film-coating and for tablet granulation,(
2) where the isopropyl alcohol is subsequently removed by 
evaporation. It has also been shown to significantly increase the 
skin permeability of nimesulide from carbomer 934.(3) 
Isopropyl alcohol has some antimicrobial activity (see 
Section 10) and a 70% v/v aqueous solution is used as a 
topical disinfectant. Therapeutically, isopropyl alcohol has 
been investigated for the treatment of postoperative nausea or 
vomiting.(4) 
8 Description 
Isopropyl alcohol is a clear, colorless, mobile, volatile, 
flammable liquid with a characteristic, spirituous odor 
resembling that of a mixture of ethanol and acetone; it has a 
slightly bitter taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for isopropyl alcohol. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Appearance of 
solution 
— . — 
Absorbance — . — 
Characters — . . 
Specific gravity 0.785–0.788 0.785–0.789 0.783–0.787 
Refractive index — 1.376–1.379 1.376–1.378 
Acidity or alkalinity . . . 
Water 40.75% 40.5% — 
Nonvolatile residue 41.0mg 420 ppm 40.005% 
Distillation range 81–838C — — 
Benzene — . — 
Peroxides — . — 
Assay — — 599.0% 
10 Typical Properties 
Antimicrobial activity: isopropyl alcohol is bactericidal; at 
concentrations greater than 70% v/v it is a more effective 
antibacterial preservative than ethanol (95%). The bactericidal 
effect of aqueous solutions increases steadily as the 
concentration approaches 100% v/v. Isopropyl alcohol is 
ineffective against bacterial spores. 
Autoignition temperature: 4258C 
Boiling point: 82.48C 
Dielectric constant: D20 = 18.62 
Explosive limits: 2.5–12.0% v/v in air. 
Flammability: flammable. 
Flash point: 11.78C (closed cup); 138C (open cup). The water 
azeotrope has a flash point of 168C. 
Freezing point: 89.58C 
Melting point: 88.58C 
Moisture content: 0.1–13% w/w for commercial grades (13% 
w/w corresponds to the water azeotrope). 
Refractive index: 
nD
20 = 1.3776; 
nD
25 = 1.3749. 
Solubility: miscible with benzene, chloroform, ethanol (95%), 
ether, glycerin, and water. Soluble in acetone; insoluble in 
salt solutions. Forms an azeotrope with water, containing 
87.4% w/w isopropyl alcohol (boiling point 80.378C). 
Specific gravity: 0.786 
Vapor density (relative): 2.07 (air = 1) 
Vapor pressure: 
133.3 Pa (1mmHg) at 26.18C; 
4.32 kPa (32.4 mmHg) at 208C; 
5.33 kPa (40 mmHg) at 23.88C; 
13.33 kPa (100 mmHg) at 39.58C. 
Viscosity (dynamic): 2.43 mPa s (2.43 cP) at 208C

11 Stability and Storage Conditions 
Isopropyl alcohol should be stored in an airtight container in a 
cool, dry place. 
12 Incompatibilities 
Incompatible with oxidizing agents such as hydrogen peroxide 
and nitric acid, which cause decomposition. Isopropyl alcohol 
may be salted out from aqueous mixtures by the addition of 
sodium chloride, sodium sulfate, and other salts, or by the 
addition of sodium hydroxide. 
13 Method of Manufacture 
Isopropyl alcohol may be prepared from propylene; by the 
catalytic reduction of acetone, or by fermentation of certain 
carbohydrates. 
14 Safety 
Isopropyl alcohol is widely used in cosmetics and topical 
pharmaceutical formulations. It is readily absorbed from the 
gastrointestinal tract and may be slowly absorbed through 
intact skin. Prolonged direct exposure of isopropyl alcohol to 
the skin may result in cardiac and neurological deficits.(5) In 
neonates, isopropyl alcohol has been reported to cause 
chemical burns following topical application.(6,7) 
Isopropyl alcohol is metabolized more slowly than ethanol, 
primarily to acetone. Metabolites and unchanged isopropyl 
alcohol are mainly excreted in the urine. 
Isopropyl alcohol is about twice as toxic as ethanol and 
should therefore not be administered orally; isopropyl alcohol 
also has an unpleasant taste. Symptoms of isopropyl alcohol 
toxicity are similar to those for ethanol except that isopropyl 
alcohol has no initial euphoric action and gastritis and vomiting 
are more prominent; see Alcohol. Delta osmolality may be 
useful as rapid screen test to identify patients at risk of 
complications from ingestion of isopropyl alcohol.(8) The lethal 
oral dose is estimated to be about 120–250mL although toxic 
symptoms may be produced by 20 mL. 
Adverse effects following parenteral administration of up to 
20mL of isopropyl alcohol diluted with water have included 
only a sensation of heat and a slight lowering of blood pressure. 
However, isopropyl alcohol is not commonly used in parenteral 
products. 
Although inhalation can cause irritation and coma, the 
inhalation of isopropyl alcohol has been investigated in 
therapeutic applications.(3) 
Isopropyl alcohol is most frequently used in topical 
pharmaceutical formulations where it may act as a local 
irritant.(9) When applied to the eye it can cause corneal burns 
and eye damage. 
LD50 (dog, oral): 4.80 g/kg(9) 
LD50 (mouse, oral): 3.6 g/kg 
LD50 (mouse, IP): 4.48 g/kg 
LD50 (mouse, IV): 1.51 g/kg 
LD50 (rabbit, oral): 6.41 g/kg 
LD50 (rabbit, skin): 12.8 g/kg 
LD50 (rat, IP): 2.74 g/kg 
LD50 (rat, IV): 1.09 g/kg 
LD50 (rat, oral): 5.05 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Isopropyl alcohol may be 
irritant to the skin, eyes, and mucous membranes upon 
inhalation. Eye protection and gloves are recommended. 
Isopropyl alcohol should be handled in a well-ventilated 
environment. In the UK, the long-term (8-hour TWA) exposure 
limit for isopropyl alcohol is 999 mg/m3 (400 ppm); the shortterm 
(15-minute) exposure limit is 1250 mg/m3 (500 ppm).(10) 
OSHA standards state that IPA 8-hour time weighted average 
airborne level in the workplace cannot exceed 400 ppm. 
Isopropyl alcohol is flammable and produces toxic fumes on 
combustion. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral capsules, 
tablets, and topical preparations). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Propan-1-ol. 
Propan-1-ol 
Empirical formula: C3H8O 
Molecular weight: 60.1 
CAS number: [71-23-8] 
Synonyms: propanol; n-propanol; propyl alcohol; propylic 
alcohol. 
Autoignition temperature: 5408C 
Boiling point: 97.28C 
Dielectric constant: D25 = 22.20 
Explosive limits: 2.15–13.15% v/v in air. 
Flash point: 158C (closed cup) 
Melting point: –1278C 
Refractive index: nD
20 = 1.3862 
Solubility: miscible with ethanol (95%), ether, and water. 
Specific gravity: 0.8053 at 208C 
Viscosity (dynamic): 2.3 mPa s (2.3 cP) at 208C 
Comments: propan-1-ol is more toxic than isopropyl alcohol. 
In the UK, the long-term (8-hour TWA) exposure limit for 
propan-1-ol is 500 mg/m3 (200 ppm); the short-term (15- 
minute) exposure limit is 625 mg/m3 (250 ppm).(10) 
18 Comments 
A specification for isopropyl alcohol is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for isopropyl alcohol is 200-661-7. 
19 Specific References 
1 Rafiee Tehrani H, Mehramizi A. In vitro release studies of 
piroxicam from oil-in-water creams and hydroalcoholic gel topical 
formulations. Drug Dev Ind Pharm 2000; 26(4): 409–414. 
2 Ruckmani K, Muneera MS, Vijaya R. Eudragit matrices for 
sustained release of ketorolac tromethamine: formulation and 
kinetics of release. Boll Chim Form 2000; 139: 205–208. 
3 Guengoer S, Bergisadi N. Effect of penetration enhancers on in 
vitro percutaneous penetration of nimesulide through rat skin. 
Pharmazie 2004; 59: 39–41. 
4 Merritt BA, Okyere CP, Jasinski DM. Isopropyl alcohol inhalation: 
alternative treatment of postoperative nausea and vomiting. Nurs 
Res 2002; 51(2): 125–128. 
372 Isopropyl Alcohol

5 Leeper SC, Almatari AL, Ingram JD, Ferslew KE. Topical 
absorption of isopropyl alcohol induced cardiac neurological 
deficits in an adult female with intact skin. Vet Hum Toxicol 2000; 
42: 15–17. 
6 Schick JB, Milstein JM. Burn hazard of isopropyl alcohol in the 
neonate. Pediatrics 1981; 68: 587–588. 
7 Weintraub Z, Iancu TC. Isopropyl alcohol burns. Pediatrics 1982; 
69: 506. 
8 Monaghan MS, Ackerman BH, Olsen KM, et al. Use of delta 
osmolality to predict serum isopropanol and acetone concentrations. 
Pharmacotherapy 1993; 13(1): 60–63. 
9 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2148–2149. 
10 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
—
21 Authors 
CP McCoy. 
22 Date of Revision 
12 August 2005. 
Isopropyl Alcohol 373

Isopropyl Myristate 
1 Nonproprietary Names 
BP: Isopropyl myristate 
PhEur: Isopropylis myristas 
USPNF: Isopropyl myristate 
2 Synonyms 
Crodamol IPM; Estol IPM; isopropyl ester of myristic acid; 
Kessco IPM 95; Lexol IPM-NF; myristic acid isopropyl ester; 
Rita IPM; Stepan IPM; Tegosoft M; tetradecanoic acid, 1- 
methylethyl ester; Waglinol 6014. 
3 Chemical Name and CAS Registry Number 
1-Methylethyl tetradecanoate [110-27-0] 
4 Empirical Formula and Molecular Weight 
C17H34O2 270.5 
5 Structural Formula 
6 Functional Category 
Emollient; oleaginous vehicle; skin penetrant; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Isopropyl myristate is a nongreasy emollient that is absorbed 
readily by the skin. It is used as a component of semisolid bases 
and as a solvent for many substances applied topically. 
Applications in topical pharmaceutical and cosmetic formulations 
include bath oils; make-up; hair and nail care products; 
creams; lotions; lip products; shaving products; skin lubricants; 
deodorants; otic suspensions; and vaginal creams; see Table I. 
For example, isopropyl myristate is a self-emulsifying component 
of a proposed cold cream formula,(1) which is suitable for 
use as a vehicle for drugs or dermatological actives; it is also 
used cosmetically in stable mixtures of water and glycerol.(2) 
Isopropyl myristate is used as a penetration enhancer for 
transdermal formulations and has been used in conjunction 
with therapeutic ultrasound and iontophoresis.(3) It has been 
used in a water-oil gel prolonged-release emulsion and in 
various microemulsions. Isopropyl myristate has also been used 
in microspheres, and significantly increased the release of drug 
from etoposide-loaded microspheres.(4) 
Table I: Uses of isopropyl myristate. 
Use Concentration (%) 
Detergent 0.003–0.03 
Otic suspension 0.024 
Perfumes 0.5–2.0 
Microemulsions <50 
Soap 0.03–0.3 
Topical aerosols 2.0–98.0 
Topical creams and lotions 1.0–10.0 
8 Description 
Isopropyl myristate is a clear, colorless, practically odorless 
liquid of low viscosity that congeals at about 58C. It consists of 
esters of propan-2-ol and saturated high molecular weight fatty 
acids, principally myristic acid. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for isopropyl myristate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Appearance of solution . — 
Specific gravity — 0.846–0.854 
Relative density 0.853 0.846–0.854 
Refractive index 1.434–1.437 1.432–1.436 
Residue on ignition 40.1% 40.1% 
Acid value 41.0 41.0 
Saponification value 202–212 202–212 
Iodine value 41.0 41.0 
Appearance of solution . — 
Viscosity 5–6 mPa s — 
Water 40.1% — 
Organic volatile impurities — . 
Assay (as C17H34O2) 590.0% 590.0% 
10 Typical Properties 
Boiling point: 140.28C at 266 Pa (2mmHg) 
Flash point: 153.58C (closed cup) 
Freezing point: 58C 
Solubility: soluble in acetone, chloroform, ethanol (95%), ethyl 
acetate, fats, fatty alcohols, fixed oils, liquid hydrocarbons, 
toluene, and waxes. Dissolves many waxes, cholesterol, or 
lanolin. Practically insoluble in glycerin, glycols, and water. 
Viscosity (dynamic): 5–7 mPa s (5–7 cP) at 258C 
11 Stability and Storage Conditions 
Isopropyl myristate is resistant to oxidation and hydrolysis and 
does not become rancid. It should be stored in a well-closed 
container in a cool, dry place and protected from light.

12 Incompatibilities 
When isopropyl myristate comes into contact with rubber, there 
is a drop in viscosity with concomitant swelling and partial 
dissolution of the rubber; contact with plastics, e.g. nylon and 
polyethylene, results in swelling. Isopropyl myristate is 
incompatible with hard paraffin, producing a granular mixture. 
It is also incompatible with strong oxidizing agents. 
13 Method of Manufacture 
Isopropyl myristate may be prepared either by the esterification 
of myristic acid with propan-2-ol or by the reaction of 
myristoyl chloride and propan-2-ol with the aid of a suitable 
dehydrochlorinating agent. A high-purity material is also 
commercially available, produced by enzymatic esterification 
at low temperature. 
14 Safety 
Isopropyl myristate is widely used in cosmetics and topical 
pharmaceutical formulations and is generally regarded as a 
nontoxic and nonirritant material.(5–7) 
LD50 (mouse, oral): 49.7 g/kg(8) 
LD50 (rabbit, skin): 5 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (otic, topical, 
transdermal, and vaginal preparations). Used in nonparenteral 
medicines licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Isopropyl palmitate. 
18 Comments 
The EINECS number for isopropyl myristate is 203-751-4. 
19 Specific References 
1 Jimenez SMM, Fresno CMJ, Selles Flores E. Proposal and 
pharmacotechnical study of a modern dermo-pharmaceutical 
formulation for cold cream. Boll Chim Farm 1996; 135: 364–373. 
2 Ayannides CA, Ktistis G. Stability estimation of emulsions of 
isopropyl myristate in mixtures of water and glycerol. J Cosmet Sci 
2002; 53(3): 165–173. 
3 Fang JY, Fang CL, Huang YB. Transdermal iontopheresis of 
sodium nonivaride acetate III: combined effect of pretreatment by 
penetration enhancers. Int J Pharm 1997; 149: 183–195. 
4 Schaefer MJ, Singh J. Effect of isopropyl myristic acid ester on the 
physical characteristics and in vitro release of etoposide from 
PLGA microspheres. AAPS PharmTechSci 2000; 1(4): 32. 
5 Stenba.ck F, Shubik P. Lack of toxicity and carcinogenicity of some 
commonly used cutaneous agents. Toxicol Appl Pharmacol 1974; 
30: 7–13. 
6 Opdyke DL. Monographs on fragrance raw materials. Food 
Cosmet Toxicol 1976; 14(4): 307–338. 
7 Guillot JP, Martini MC, Giauffret JY. Safety evaluation of cosmetic 
raw materials. J Soc Cosmet Chem 1977; 28: 377–393. 
8 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2164. 
20 General References 
Fitzgerald JE, Kurtz SM, Schardein JL, Kaump DH. Cutaneous and 
parenteral studies with vehicles containing isopropyl myristate and 
peanut oil. Toxicol Appl Pharmacol 1968; 13: 448–453. 
Nakhare S, Vyas SP. Prolonged release of rifampicin from internal phase 
of multiple w/o/w emulsion systems. Indian J Pharm Sci 1995; 57: 
71–77. 
21 Authors 
AK Taylor. 
22 Date of Revision 
16 August 2005. 
Isopropyl Myristate 375

Isopropyl Palmitate 
1 Nonproprietary Names 
BP: Isopropyl palmitate 
PhEur: Isopropylis palmitas 
USPNF: Isopropyl palmitate 
2 Synonyms 
Crodamol IPP; Emerest 2316; hexadecanoic acid isopropyl 
ester; hexadecanoic acid 1-methylethyl ester; isopropyl hexadecanoate; 
Kessco IPP; Lexol IPP-NF; Liponate IPP; palmitic 
acid isopropyl ester; Protachem IPP; Rita IPP; Stepan IPP; 
Tegosoft P; Unimate IPP; Waglinol 6016; Wickenol 111. 
3 Chemical Name and CAS Registry Number 
1-Methylethyl hexadecanoate [142-91-6] 
4 Empirical Formula and Molecular Weight 
C19H38O2 298.51 
5 Structural Formula 
6 Functional Category 
Emollient; oleaginous vehicle; skin penetrant; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Isopropyl palmitate is a nongreasy emollient with good 
spreading characteristics, used in topical pharmaceutical 
formulations and cosmetics such as: bath oils; creams; lotions; 
make-up; hair care products; deodorants; lip products; suntan 
preparations; and pressed powders; see Table I. 
Isopropyl palmitate has also been used in controlled-release 
percutaneous films, and has also been investigated in the 
production of reversed sucrose ester vesicles, as well as 
microemulsions.(1) 
Table I: Uses of isopropyl palmitate. 
Use Concentration (%) 
Detergent 0.005–0.02 
Perfume 0.2–0.8 
Soap 0.05–0.2 
Topical aerosol spray 3.36 
Topical creams and lotions 0.05–5.5 
8 Description 
Isopropyl palmitate is a clear, colorless to pale yellow-colored, 
practically odorless viscous liquid that solidifies at less than 
168C. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for isopropyl palmitate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Acid value 41.0 41.0 
Appearance of solution . — 
Characters — . 
Iodine value 41.0 41.0 
Organic volatile impurities — . 
Relative density 0.850–0.855 0.850–0.855 
Residue on ignition 40.1% 40.1% 
Refractive index 1.436–1.440 1.435–1.438 
Saponification value 183–193 183–193 
Viscosity 5–10 mPa s — 
Water 40.1% — 
Assay (of C19H38O2) 590.0% 590.0% 
10 Typical Properties 
Boiling point: 1608C at 266 Pa (2 mmHg) 
Freezing point: 13–158C 
Solubility: soluble in acetone, chloroform, ethanol (95%), ethyl 
acetate, mineral oil, propan-2-ol, silicone oils, vegetable oils, 
and aliphatic and aromatic hydrocarbons; practically 
insoluble in glycerin, glycols, and water. 
Surface tension: 29mN/m for Tegosoft P at 258C 
Viscosity (dynamic): 5–10 mPa s (5–10 cP) at 258C 
11 Stability and Storage Conditions 
Isopropyl palmitate is resistant to oxidation and hydrolysis and 
does not become rancid. It should be stored in a well-closed 
container, above 168C, and protected from light. 
12 Incompatibilities 
See Isopropyl Myristate. 
13 Method of Manufacture 
Isopropyl palmitate is prepared by the reaction of palmitic acid 
with propan-2-ol in the presence of an acid catalyst. A highpurity 
material is also commercially available, which is 
produced by enzymatic esterification at low temperatures.

14 Safety 
Isopropyl palmitate is widely used in cosmetics and topical 
pharmaceutical formulations, and is generally regarded as a 
relatively nontoxic and nonirritant material.(2–4) 
LD50 (mouse, IP): 0.1 g/kg(5) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (topical and 
transdermal preparations). Used in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Isopropyl myristate. 
18 Comments 
The EINECS number for isopropyl palmitate is 205-571-1. 
19 Specific References 
1 Mollee H, De Vrind J, De Vringer T. Stable reversed vesicles in oil: 
characterization studies and encapsulation of model compounds. J 
Pharm Sci 2000; 89(7): 930–939. 
2 Frosch PJ, Kligman AM. The chamber-scarification test for 
irritancy. Contact Dermatitis 1976; 2: 314–324. 
3 Guillot JP, Martini MC, Giauffret JY. Safety evaluation of cosmetic 
raw materials. J Soc Cosmet Chem 1977; 28: 377–393. 
4 Opdyke DL, Letizia C. Monographs on fragrance raw materials. 
Food Cosmet Toxicol 1982; 20 (Suppl.): 633–852. 
5 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2165. 
20 General References 
—
21 Authors 
AK Taylor. 
22 Date of Revision 
18 August 2005. 
Isopropyl Palmitate 377

Kaolin 
1 Nonproprietary Names 
BP: Heavy kaolin 
JP: Kaolin 
PhEur: Kaolinum ponderosum 
USP: Kaolin 
Note that the PhEur 2005 contains a monograph on heavy 
kaolin (kaolinum ponderosum). The BP 2004 in addition to the 
monograph for heavy kaolin also contains monographs for 
light kaolin (natural) and light kaolin. 
See also Sections 4 and 9. 
2 Synonyms 
Argilla; bolus alba; China clay; E559; kaolinite; Lion; porcelain 
clay; Sim 90; weisserton; white bole. 
3 Chemical Name and CAS Registry Number 
Hydrated aluminum silicate [1332-58-7] 
4 Empirical Formula and Molecular Weight 
Al2H4O9Si2 258.16 
The USP 28 describes kaolin as a native hydrated aluminum 
silicate, powdered and freed from gritty particles by elutriation. 
The BP 2004 similarly describes light kaolin but additionally 
states that it contains a suitable dispersing agent. Light kaolin 
(natural) BP contains no dispersing agent. Heavy kaolin is 
described in the BP 2004 and PhEur 2005 as a purified, natural 
hydrated aluminum silicate of variable composition. The JP 
2001 describes kaolin as a native hydrous aluminum silicate. 
5 Structural Formula 
Al2O32SiO22H2O 
6 Functional Category 
Adsorbent; suspending agent; tablet and capsule diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Kaolin is a naturally occurring mineral used in oral and topical 
pharmaceutical formulations. 
In oral medicines, kaolin has been used as a diluent in tablet 
and capsule formulations; it has also been used as a suspending 
vehicle. In topical preparations, sterilized kaolin has been used 
in poultices and as a dusting powder. Therapeutically, kaolin 
has been used in oral antidiarrheal preparations.(1,2) 
8 Description 
Kaolin occurs as a white to grayish-white colored, unctuous 
powder free from gritty particles. It has a characteristic earthy 
or claylike taste and when moistened with water it becomes 
darker in color and develops a claylike odor. 
SEM: 1 
Excipient: Kaolin USP 
Manufacturer: Georgia Kaolin Co. 
Lot No.: 1672 
Magnification: 60 Voltage: 10 kV 
SEM: 2 
Excipient: Kaolin USP 
Manufacturer: Georgia Kaolin Co. 
Lot No.: 1672 
Magnification: 600 Voltage: 10 kV

9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for kaolin. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters — . — 
Acidity or alkalinity . . — 
Microbial limit — 4103/g . 
Loss on ignition 415.0% — 415.0% 
Acid-soluble substances . 41.0% 42.0% 
Organic impurities — . — 
Foreign matter . — — 
Adsorption power — . — 
Swelling power — . — 
Plasticity . — — 
Arsenic 42 ppm — — 
Calcium — 4250 ppm — 
Carbonate . — . 
Chloride — 4250 ppm — 
Heavy metals 450 ppm 450 ppm(a) — 
Iron 4500 ppm — . 
Lead — — 40.001% 
Sulfate — 40.1% — 
Organic volatile impurities — — . 
(a)When intended for internal use, the limit is set at 425 ppm. 
10 Typical Properties 
Acidity/alkalinity: pH = 4.0–7.5 for a 20% w/v aqueous slurry. 
Hardness (Mohs): 2.0, very low. 
Hygroscopicity: at relative humidities between about 15–65%, 
the equilibrium moisture content at 258C is about 1% w/w, 
but at relative humidities above about 75%, kaolin absorbs 
small amounts of moisture. 
Particle size distribution: median size = 0.6–0.8 mm. 
Refractive index: 1.56 
Solubility: practically insoluble in diethyl ether, ethanol (95%), 
water, other organic solvents, cold dilute acids, and 
solutions of alkali hydroxides. 
Specific gravity: 2.6 
Viscosity (dynamic): 300 mPa s (300 cP) for a 70% w/v aqueous 
suspension. 
Whiteness: 85–90% of the brightness of MgO. 
11 Stability and Storage Conditions 
Kaolin is a stable material. Since it is a naturally occurring 
material, kaolin is commonly contaminated with microorganisms 
such as Bacillus anthracis, Clostridium tetani, and 
Clostridium welchii. However, kaolin may be sterilized by 
heating at a temperature greater than 1608C for not less than 1 
hour. When moistened with water kaolin darkens and becomes 
plastic. 
Kaolin should be stored in a well-closed container in a cool, 
dry place. 
12 Incompatibilities 
The adsorbent properties of kaolin may influence the absorption 
of other orally administered drugs. Drugs reportedly 
affected by kaolin include amoxicillin;(3) ampicillin;(3) cimetidine;(
4) digoxin;(5) lincomycin; phenytoin;(6) and tetracycline. 
Warfarin absorption by rat intestine in vitro was reported not 
to be affected by kaolin.(7) With clindamycin, the rate (but not 
the amount) of absorption was affected by kaolin.(8) 
13 Method of Manufacture 
Kaolin is a hydrated aluminum silicate obtained by mining 
naturally occurring mineral deposits. Large deposits are found 
in Georgia, USA and in Cornwall, England. 
Mined kaolin is powdered and freed of coarse, gritty 
particles either by elutriation or by screening. Impurities such as 
ferric oxide, calcium carbonate, and magnesium carbonate are 
removed with an electromagnet and by treatment with 
hydrochloric acid and/or sulfuric acids. 
14 Safety 
Kaolin is used in oral and topical pharmaceutical formulations 
and is generally regarded as an essentially nontoxic and 
nonirritant material. 
Oral doses of about 2–6 g of kaolin every 4 hours have 
been administered in the treatment of diarrhea.(1,2) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. The chronic inhalation of 
kaolin dust can cause diseases of the lung (silicosis or 
kaolinosis).(9) Eye protection and a dust mask are recommended. 
In the UK, the long-term (8-hour TWA) exposure limit 
for kaolin respirable dust is 2 mg/m3.(10) 
16 Regulatory Status 
Accepted in Europe as a food additive in certain applications. 
Included in the FDA Inactive Ingredients Guide (oral capsules, 
powders, syrups, and tablets; topical preparations). Included in 
nonparenteral medicines licensed in the UK. 
17 Related Substances 
Bentonite; magnesium aluminum silicate. 
18 Comments 
Kaolin is considered in most countries to be an archaic diluent. 
The name kaolinite was historically used to describe the 
processed mineral, while the name kaolin was used for the 
unprocessed clay. However, the two names have effectively 
become synonymous and kaolin is now generally the only name 
used. A specification for kaolin is contained in the Food 
Chemicals Codex (FCC). The EINECS number for kaolin is 
310-127-6. 
19 Specific References 
1 Bergman HD. Diarrhea and its treatment. Commun Pharm 1999; 
91(3): 31–35. 
2 Sweetman SC, ed. Martindale: The Complete Drug Reference, 
34th edn. London: Pharmaceutical Press, 2005: 1268. 
3 Khalil SAH, Mortada LM, El-Khawas M. Decreased bioavailability 
of ampicillin and amoxicillin in presence of kaolin. Int J 
Pharm 1984; 19: 233–238. 
Kaolin 379

4 Ganjian F, Cutie AJ, Jochsberger T. In vitro adsorption studies of 
cimetidine. J Pharm Sci 1980; 69: 352–353. 
5 Albert KS, Ayres JW, Di Santo AR, et al. Influence of kaolin-pectin 
suspension on digoxin bioavailability. J Pharm Sci 1978; 67: 
1582–1586. 
6 McElnay JC, D’Arcy PF, Throne O. Effect of antacid constituents, 
kaolin and calcium citrate on phenytoin absorption. Int J Pharm 
1980; 7: 83–88. 
7 McElnay JC, HarronDW, D’Arcy PF, Collier PS. The interaction of 
warfarin with antacid constituents in the gut. Experientia 1979; 
35: 1359–1360. 
8 Albert KS, DeSante KA,Welch RD, DiSanto AR. Pharmacokinetic 
evaluation of a drug interaction between kaolin-pectin and 
clindamycin. J Pharm Sci 1978; 67: 1579–1582. 
9 Lesser M, Zia M, Kilburn KH. Silicosis in kaolin workers and 
firebrick makers. South Med J 1978; 71: 1242–1246. 
10 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
Allen LV. Featured excipient: capsule and tablet diluents. Int J Pharm 
Compound 2000; 4(4): 306–310, 324–325. 
Allwood MC. The adsorption of esters of p-hydroxybenzoic acid by 
magnesium trisilicate. Int J Pharm 1982; 11: 101–107. 
Onyekweli AO, Usifoh CO, Okunrobo LO, Zuofa JD. Adsorptive 
property of kaolin in some drug formulations. Trop J Pharm Res 
2003; 2: 155–159. 
21 Authors 
A Palmieri. 
22 Date of Revision 
7 June 2005. 
380 Kaolin

Lactic Acid 
1 Nonproprietary Names 
BP: Lactic acid 
JP: Lactic acid 
PhEur: Acidum lacticum 
USP: Lactic acid 
2 Synonyms 
E270; Eco-Lac; 2-hydroxypropanoic acid; a-hydroxypropionic 
acid; DL-lactic acid; Lexalt L; milk acid; Patlac LA; Purac 88 
PH; racemic lactic acid. 
3 Chemical Name and CAS Registry Number 
2-Hydroxypropionic acid [50-21-5] 
(R)-(–)-2-Hydroxypropionic acid [10326-41-7] 
(S)-(.)-2-Hydroxypropionic acid [79-33-44] 
(RS)-(
)-2-Hydroxypropionic acid [598-82-3] 
See also Section 8. 
4 Empirical Formula and Molecular Weight 
C3H6O3 90.08 
5 Structural Formula 
6 Functional Category 
Acidifying agent; acidulant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Lactic acid is used in beverages, foods, cosmetics, and 
pharmaceuticals (see Table I) as an acidifying agent and 
acidulant. 
In topical formulations, particularly cosmetics, it is used for 
its softening and conditioning effect on the skin. Lactic acid 
may also be used in the production of biodegradable polymers 
and microspheres, such as poly(D-lactic acid), used in drug 
delivery systems.(1,2) See also Aliphatic Polyesters. 
Lactic acid is also used as a food preservative. Therapeutically, 
lactic acid is used in injections, in the form of lactate, as a 
source of bicarbonate for the treatment of metabolic acidosis; 
as a spermicidal agent; in pessaries for the treatment of 
leukorrhea; in infant feeds; and in topical formulations for 
the treatment of warts. 
Table I: Uses of lactic acid. 
Use Concentration (%) 
Injections 0.012–1.16 
Topical preparations 0.015–6.6 
8 Description 
Lactic acid consists of a mixture of 2-hydroxypropionic acid, its 
condensation products, such as lactoyllactic acid and other 
polylactic acids, and water. It is usually in the form of the 
racemate, (RS)-lactic acid, but in some cases the (S)-(.)-isomer 
is predominant. 
Lactic acid is a practically odorless, colorless or slightly 
yellow-colored, viscous, hygroscopic, nonvolatile liquid. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for lactic acid. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Appearance of solution — . — 
Specific rotation — — 0.058 to 
.0.058 
Calcium — 4200 ppm — 
Heavy metals 410 ppm 410 ppm 40.001% 
Iron 45 ppm — — 
Sulfate 40.01% 4200 ppm . 
Chloride 40.036% — . 
Citric, oxalic, phosphoric, 
and tartaric acids 
. . . 
Ether-insoluble substances — . — 
Cyanide . — — 
Sugars and other reducing 
substances 
. . . 
Glycerin and mannitol . — — 
Methanol and methyl esters — 450 ppm — 
Reducing substances — . — 
Readily carbonizable 
substances 
. — . 
Bacterial endotoxins — 45 IU/g — 
Volatile fatty acids . . — 
Residue on ignition 40.1% 40.1% 43.0mg 
Sulfated ash — 40.1% 40.05% 
Assay . 88.0–92.0% 88.0–92.0% 
10 Typical Properties 
Boiling point: 1228C at 2 kPa (15 mmHg) 
Dissociation constant: pKa = 4.14 at 22.58C 
Flash point: >1108C 
Heat of combustion: 15.13 kJ/kg (3615 cal/kg) 
Melting point: 178C

Osmolarity: a 2.3% w/v aqueous solution is isoosmotic with 
serum. 
Refractive index: nD
20 = 1.4251 
Solubility: miscible with ethanol (95%), ether, and water; 
practically insoluble in chloroform. 
Specific heat: 2.11 J/g (0.505 cal/g) at 208C 
Specific gravity: 1.21 
Specific rotation [a]D
21: 
2.68 (8% w/v aqueous solution) for (R)-form; 
.2.68 (2.5% w/v aqueous solution) for (S)-form. 
Viscosity (dynamic): 28.5 mPa s (28.5 cP) for 85% aqueous 
solution at 258C. 
11 Stability and Storage Conditions 
Lactic acid is hygroscopic and will form condensation products 
such as polylactic acids on contact with water. The equilibrium 
between the polylactic acids and lactic acid is dependent on 
concentration and temperature. At elevated temperatures lactic 
acid will form lactide, which is readily hydrolyzed back to lactic 
acid. 
Lactic acid should be stored in a well-closed container in a 
cool, dry place. 
12 Incompatibilities 
Incompatible with oxidizing agents, iodides, and albumin. 
Reacts violently with hydrofluoric acid and nitric acid. 
13 Method of Manufacture 
Lactic acid is prepared by the fermentation of carbohydrates, 
such as glucose, sucrose, and lactose, with Bacillus acidi lacti or 
related microorganisms. On a commercial scale, whey, corn 
starch, potatoes, or molasses are used as a source of 
carbohydrate. Lactic acid may also be prepared synthetically 
by the reaction between acetaldehyde and carbon monoxide at 
130–2008C under high pressure, or by the hydrolysis of 
hexoses with sodium hydroxide. 
Lactic acid prepared by the fermentation of sugars is 
levorotatory; lactic acid prepared synthetically is racemic. 
However, lactic acid prepared by fermentation becomes 
dextrorotatory on dilution with water owing to the hydrolysis 
of (R)-lactic acid lactate to (S)-lactic acid. 
14 Safety 
Lactic acid occurs in appreciable quantities in the body as an 
end product of the anaerobic metabolism of carbohydrates and, 
while harmful in the concentrated form (see Section 15), can be 
considered nontoxic at the levels at which it is used as an 
excipient. A 1% v/v solution, for example, is harmless when 
applied to the skin. 
There is evidence that neonates have difficulty in metabolizing 
(R)-lactic acid and this isomer and the racemate should 
therefore not be used in foods intended for infants aged less 
than 3 months old.(3) 
There is no evidence that lactic acid is carcinogenic, 
teratogenic, or mutagenic. 
LD50 (guinea pig, oral): 1.81 g/kg(4) 
LD50 (mouse, oral): 4.88 g/kg 
LD50 (mouse, SC): 4.5 g/kg 
LD50 (rat, oral): 3.73 g/kg 
15 Handling Precautions 
Lactic acid is caustic in concentrated form and can cause burns 
on contact with the skin and eyes. It is harmful if swallowed, 
inhaled, or absorbed through the skin. Observe precautions 
appropriate to the circumstances and quantity of material 
handled. Eye protection, rubber gloves, and respirator are 
recommended. It is advisable to handle the compound in a 
chemical fume hood and to avoid repeated or prolonged 
exposure. Spillages should be diluted with copious quantities of 
water. In case of excessive inhalation, remove the patient to a 
well-ventilated environment and seek medical attention. Lactic 
acid presents no fire or explosion hazard but emits acrid smoke 
and fumes when heated to decomposition. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (IM, IV, and SC 
injections, oral syrups and tablets, topical and vaginal 
preparations). Included in medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Aliphatic polyesters; sodium lactate. 
18 Comments 
A specification for lactic acid is contained in the Food 
Chemicals Codex (FCC). The EINECS number for lactic acid 
is 200-018-0. 
19 Specific References 
1 Brophy MR, Deasy P. Biodegradable polyester polymers as drug 
carriers. In: Swarbrick J, Boylan JC, eds. Encyclopedia of 
Pharmaceutical Technology, vol. 2. New York: Marcel Dekker, 
1990: 1–25. 
2 Kim IS, Jeong YI, Cho CS, Kim SH. Core–shell type polymeric 
nanoparticles composed of poly(L-lactic acid) and poly(N-isopropylacrylamide). 
Int J Pharm 2000; 211: 1–8. 
3 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and specifications. Seventeenth 
report of the FAO/WHO expert committee on food additives. 
World Health Organ Tech Rep Ser 1974; No. 539. 
4 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2196. 
20 General References 
Al-Shammary FJ, Mian NAZ, Mian MS. Lactic acid. In: Brittain HG, 
ed. Analytical Profiles of Drug Substances and Excipients, vol. 22. 
San Diego: Academic Press, 1993: 263–316. 
21 Authors 
MG Lee. 
22 Date of Revision 
15 August 2005. 
382 Lactic Acid

Lactitol 
1 Nonproprietary Names 
BP: Lactitol monohydrate 
PhEur: Lactitolum monohydricum 
USPNF: Lactitol 
2 Synonyms 
E966; b-galactosido-sorbitol; Finlac DC; lactil; lactite; lactobiosit; 
lactosit; Lacty. 
3 Chemical Name and CAS Registry Number 
4-O-(b-D-Galactopyranosyl)-D-glucitol [585-86-4] 
4-O-(b-D-Galactopyranosyl)-D-glucitol monohydrate [81025- 
04-9] 
4-O-(b-D-Galactopyranosyl)-D-glucitol dihydrate [81025- 
03-8] 
4 Empirical Formula and Molecular Weight 
C12H24O11 344.32 (anhydrous) 
C12H24O11H2O 362.34 (monohydrate) 
C12H24O112H2O 380.35 (dihydrate) 
5 Structural Formula 
6 Functional Category 
Sweetening agent; tablet and capsule diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Lactitol is used as a noncariogenic replacement for sucrose. It is 
also used as a diluent in solid dosage forms.(1) A directcompression 
form is available,(2,3) as is a direct-compression 
blend of lactose and lactitol. Lactitol is also used therapeutically 
in the treatment of hepatic encephalopathy and as a laxative; 
see Section 14. 
8 Description 
Lactitol occurs as white orthorhombic crystals. It is odorless 
with a sweet taste that imparts a cooling sensation. It is 
available in powdered form and in a range of crystal sizes. The 
directly compressible form is a water-granulated product of 
microcrystalline aggregates. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for lactitol. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Appearance of solution . — 
Acidity or alkalinity . — 
Specific optical rotation .13.58 to .15.58 — 
Related substances 41.0% 41.5% 
Reducing sugars 40.2% 40.2% as dextrose 
Lead 40.5 ppm — 
Nickel 41 ppm — 
Water 
monohydrate 4.5–5.5% 4.5–5.5% 
dihydrate — 9.5–10.5% 
anhydrous — 40.5% 
Microbial contamination 4103/g — 
Residue on ignition 40.1% 40.5% 
Heavy metals — 45 mg/g 
Organic volatile impurities — . 
Assay 96.5–102.0% 98.0–101.0% 
10 Typical Properties 
Acidity–alkalinity: pH = 4.5–7.0 (10% w/v solution). 
Density: 1.54 g/cm3 
Heat of solution: 54 J/g 
Loss of water of crystallization: 145–1858C 
Moisture content: 4.5–5.5% for the monohydrate; 40.5% for 
the anhydrous. 
Osmolarity: a 7% w/v aqueous solution is isoosmotic with 
serum. 
Refractive index: 
nD
20 = 1.3485 (10% solution); 
nD
20 = 1.3650 (20% solution); 
nD
20 = 1.3827 (30% solution); 
nD
20 = 1.4018 (40% solution); 
nD
20 = 1.4228 (50% solution); 
nD
20 = 1.4466 (60% solution). 
Solubility: slightly soluble in ethanol (95%) and ether. Soluble 1 
in 1.75 of water at 208C; 1 in 1.61 at 308C; 1 in 1.49 at 
408C; 1 in 1.39 at 508C. 
Specific rotation [a]D
20: .14.58 to .158 
Viscosity (dynamic): 
1.3 mPa s (1.3 cP) for 10% solution at 208C; 
1.9 mPa s (1.9 cP) for 20% solution at 208C;

3.4 mPa s (3.4 cP) for 30% solution at 208C; 
6.9 mPa s (6.9 cP) for 40% solution at 208C; 
18.9 mPa s (18.9 cP) for 50% solution at 208C; 
80.0 mPa s (80.0 cP) for 60% solution at 208C. 
11 Stability and Storage Conditions 
Lactitol as the monohydrate is nonhygroscopic and is stable 
under humid conditions. It is stable to heat and does not take 
part in the Maillard reaction. In acidic solution, lactitol slowly 
hydrolyzes to sorbitol and galactose. Lactitol is very resistant to 
microbiological breakdown and fermentation. Store in a wellclosed 
container. When the compound is stored in an unopened 
container at 258C and 60% relative humidity, a shelf-life in 
excess of 3 years is appropriate. 
12 Incompatibilities 
—
13 Method of Manufacture 
Lactitol is produced by the catalytic hydrogenation of lactose. 
14 Safety 
Lactitol is regarded as a nontoxic and nonirritant substance. It 
is not fermented significantly in the mouth, and is not 
cariogenic.(4) It is not absorbed in the small intestine, but is 
broken down by microflora in the large intestine,(5) and is 
metabolized independently of insulin. In large doses it has a 
laxative effect; therapeutically, 10–20 g daily in a single oral 
dose is administered for this purpose. 
LD50 (mouse, oral): >23 g/kg(6) 
LD50 (rat, oral): 30 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection is recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
17 Related Substances 
—
18 Comments 
Finlac DC is a commercially available water-granulated directly 
compressible lactitol.(2) 
Lactitol has a sweetening power about one-third that of 
sucrose. It does not promote dental caries and has a caloric 
value of 9.9 J/g (2.4 cal/g). 
The EINECS number for lactitol is 209-566-5. 
19 Specific References 
1 Allen LV. Featured excipient: capsule and tablet diluents. Int J 
Pharm Compound 2000; 4(4): 306–310, 324–325. 
2 Armstrong NA. Direct compression characteristics of lactitol. 
Pharm Technol Eur 1998; 10(2): 42–46. 
3 Muzikova J. A study of compressibility of directly compacting 
forms of lactitol. Ceska Slov Form 2003; 52(5): 241–243. 
4 Grenby TH, Philips A, Mistry M. Studies on the dental properties 
of lactitol compared with five other bulk sweeteners in vitro. Caries 
Res 1989; 23: 315–319. 
5 Grimble GK, Patil DH, Silk DBA. Assimilation of lactitol, an 
unabsorbed disaccharide in the normal human colon. Gut 1988; 
29: 1666–1671. 
6 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2198. 
20 General References 
Armstrong NA. Tablet manufacture. In: Swarbrick J, Boylan JC, eds. 
Encyclopedia of Pharmaceutical Technology, 2nd edn, vol. 3. New 
York: Marcel Dekker, 2002: 2713–2732. 
van Uyl CH. Technical and commercial aspects of the use of lactitol in 
foods as a reduced-calorie bulk sweetener. Dev Sweeteners 1987; 3: 
65–81. 
van Velthuijsen JA. Food additives derived from lactose: lactitol and 
lactitol palmitate. J Agric Food Chem 1979; 27: 680–686. 
21 Authors 
NA Armstrong. 
22 Date of Revision 
16 August 2005. 
384 Lactitol

Lactose, Anhydrous 
1 Nonproprietary Names 
BP: Anhydrous lactose 
JP: Anhydrous lactose 
PhEur: Lactosum anhydricum 
USPNF: Anhydrous lactose 
2 Synonyms 
Anhydrous Lactose NF 60M; Anhydrous Lactose NF Direct 
Tableting; Lactopress Anhydrous; lactosum; lattioso; milk 
sugar; Pharmatose DCL 21; Pharmatose DCL 22; saccharum 
lactis; Super-Tab Anhydrous. 
3 Chemical Name and CAS Registry Number 
O-b-D-galactopyranosyl-(1!4)-b-D-glucopyranose [63-42-3] 
4 Empirical Formula and Molecular Weight 
C12H22O11 342.30 
5 Structural Formula 
The PhEur 2005 describes anhydrous lactose as O-b-Dgalactopyranosyl-(
1!4)-b-D-glucopyranose; or a mixture of 
O-b-D-galactopyranosyl-(1!4)-a-D-glucopyranose and O-b-Dgalactopyranosyl-(
1!4)-b-D-glucopyranose. The USPNF 23 
describes anhydrous lactose as being primarily b-lactose or a 
mixture of a- and b-lactose. The JP 2001 describes anhydrous 
lactose as b-lactose or a mixture of b-lactose and a-lactose. 
6 Functional Category 
Binding agent; directly compressible tableting excipient; 
lyophilization aid; tablet and capsule filler. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Anhydrous lactose is widely used in direct compression 
tableting applications and as a tablet and capsule filler and 
binder. Anhydrous lactose can be used with moisture-sensitive 
drugs due to its low moisture content. 
See also Lactose, Monohydrate; Lactose, Spray-Dried. 
8 Description 
Lactose occurs as white to off-white crystalline particles or 
powder. Several different brands of anhydrous lactose are 
commercially available which contain anhydrous b-lactose and 
anhydrous a-lactose. Anhydrous lactose typically contains 
70–80% anhydrous b-lactose and 20–30% anhydrous alactose. 
SEM: 1 
Excipient: Pharmatose DCL 21 
Manufacturer: DMV International 
Magnification: 200 Voltage: 1.5 kV 
9 Pharmacopeial Specifications 
See Table I.

SEM: 2 
Excipient: Pharmatose DCL 22 
Manufacturer: DMV International 
Magnification: 55 Voltage: 1.5 kV 
SEM: 3 
Excipient: Super-Tab Anhydrous 
Manufacturer: New Zealand Lactose 
Magnification: 500 Voltage: 10 kV 
10 Typical Properties 
Angle of repose: 398 for Pharmatose DCL 21 and 388 for 
Super-Tab Anhydrous. 
Brittle fracture index: 0.0362 
Bonding index: 0.0049 (at compression pressure 177.8 MPa)(a) 
Density (true): 1.589 g/cm3 for anhydrous b-lactose; 
1.567 g/cm3 for Super-Tab Anhydrous. 
Density (bulk): 0.68 g/cm3 for Pharmatose DCL 21; 0.67 g/cm3 
for Pharmatose DCL 22; 0.65 g/cm3 for Super-Tab Anhydrous. 
Density (tapped): 0.88 g/cm3 for Pharmatose DCL 21; 
0.79 g/cm3 for Pharmatose DCL 22; 0.87 g/cm3 for Super- 
Tab Anhydrous. 
Table I: Pharmacopeial specifications for lactose anhydrous. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Appearance/color of 
solution 
. . . 
Characters — . — 
Optical rotation .54.4 to 
.55.98 
.54.4 to 
.55.98 
.54.4 to 
.55.98 
Acidity or alkalinity . . . 
Heavy metals 45 ppm 45 ppm 45 mg/g 
Absorbance 
210–220 nm 40.25 40.25 40.25 
270–300 nm 40.07 40.07 40.07 
Loss on drying 40.5% .(a) 40.5% 
Water 41.0% 41.0% 41.0% 
Residue on ignition 40.1% — 40.1% 
Sulfated ash — 40.1% — 
Microbial limit 
Aerobic bacteria 4100/g 4102/g 4100/g 
Fungi and yeast 450/g — 450/g 
Escherichia coli . . . 
Salmonella . — — 
Isomer ratio . .(a) . 
(a) Not a mandatory test. 
Melting point: 
223.08C for anhydrous a-lactose; 
252.28C for anhydrous b-lactose; 
232.08C (typical) for commercial anhydrous lactose. 
Particle size distribution: see Table II. 
Permanent deformation pressure: 521.0MPa (at compression 
pressure 177.8 MPa)(a) 
Reduced modulus of elasticity: 5315 (at compression pressure 
177.8 MPa)(a) 
Solubility: soluble in water; sparingly soluble in ethanol (95%) 
and ether. 
Specific surface area: 0.41m2/g for Pharmatose DCL 22; 
0.37m2/g for Super-Tab Anhydrous. 
Specific rotation [a]D
25 : 54.48 to 55.98 
Tensile strength: 2.577MPa (at compression pressure 
177.8 MPa)(a) 
Water content: 40.5% loss on drying and 41.0% water 
content for Anhydrous Lactose NF Direct Tableting and 
Anhydrous Lactose NF 60M; 0.2% loss on drying and 
0.5% water content for Pharmatose DCL 21 (typical); 
0.2% loss on drying and 0.2% water content for 
Pharmatose DCL 22 (typical); 0.15% loss on drying for 
Super-Tab Anhydrous (typical). 
(a) Methods for characterizing the mechanical properties of compacts of pharmaceutical 
ingredients are specified in the Handbook of Pharmaceutical Excipients, 3rd edn.(1) 
11 Stability and Storage Conditions 
Mold growth may occur under humid conditions (80% RH 
and above). Lactose may develop a brown coloration on 
storage, the reaction being accelerated by warm, damp 
conditions; see Section 12. At 808C and 80% RH, tablets 
containing anhydrous lactose have been shown to expand 1.2 
times after one day.(2) 
Lactose anhydrous should be stored in a well-closed 
container in a cool, dry place. 
386 Lactose, Anhydrous

12 Incompatibilities 
Lactose anhydrous is incompatible with strong oxidizers. When 
mixtures containing a hydrophobic leukotriene antagonist and 
anhydrous lactose or lactose monohydrate were stored for six 
weeks at 408C and 75% RH, the mixture containing anhydrous 
lactose showed greater moisture uptake and drug degradation.(
3) 
Studies have also shown that in blends of roxifiban acetate 
(DMP-754) and lactose anhydrous, the presence of lactose 
anhydrous accelerated the hydrolysis of the ester and amidine 
groups.(4) 
See Lactose, Monohydrate. 
13 Method of Manufacture 
There are two anhydrous forms of lactose: a-lactose and blactose. 
The anhydrous forms that are commercially available 
may exhibit hygroscopicity at high relative humidities. Anhydrous 
lactose is produced by roller drying a solution of lactose 
above 93.58C. The resulting product is then milled and sieved. 
Two anhydrous a-lactoses can be prepared using special drying 
techniques: one is unstable and hygroscopic, the other exhibits 
good compaction properties.(5) However, these materials are 
not commercially available. 
14 Safety 
Lactose is widely used in pharmaceutical formulations as a 
diluent and filler-binder in oral capsule and tablet formulations. 
It may also be used in intravenous injections. Adverse reactions 
to lactose are largely due to lactose intolerance, which occurs in 
individuals with a deficiency of the intestinal enzyme lactase, 
and is associated with oral ingestion of amounts well over those 
in solid dosage forms. 
See Lactose, Monohydrate. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of materials handled. Excessive generation of 
dust, or inhalation of dust, should be avoided. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IM, IV, and SC 
injections; oral capsules and tablets; inhalation preparations; 
rectal, transdermal, and vaginal preparations). Included in 
nonparenteral and parenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Lactose, monohydrate; lactose, spray-dried. 
18 Comments 
Lactose anhydrous has been used experimentally in hydrophilic 
matrix tablet formulations(6) and evaluated for dry powder 
inhalation applications.(7,8) Partial hydration of anhydrous 
lactose increases the specific surface area and reduces the flow 
properties of powders but has no effect on compactibility.(9) A 
specification for lactose is included in the Food Chemicals 
Codex (FCC); see Lactose, Monohydrate. The EINECS number 
for lactose anhydrous is 200-559-2. 
19 Specific References 
1 Kibbe AH, ed. Handbook of Pharmaceutical Excipients, 3rd edn. 
London andWashington, DC: Pharmaceutical Press and American 
Pharmaceutical Association, 2000: 642–643. 
2 Du J, Hoag SW. The influence of excipients on the moisture 
senstitive drugs aspirin and niacinamide: comparison of tablets 
containing lactose monohydrate with tablets containing anhydrous 
lactose. Pharm Dev Tech 2001; 6(2): 159–166. 
3 Jain R, Railkar AS, Malick AW, et al. Stability of a hydrophobic 
drug in presence of hydrous and anhydrous lactose. Eur J Pharm 
Biopharm; 1998; 46(2): 177–182. 
4 Badawy SI, Williams RC, Gilbert DC. Effect of different acids on 
solid state stability of an ester prodrug of a IIb/IIIa glycoprotein 
receptor antagonist. Pharm Dev Technol 1999; 4(3): 325–331. 
5 Lerk CF, Andreae AC, de Boer AH, et al. Increased binding 
capacity and flowability of alpha-lactose monohydrate after 
dehydration. J Pharm Pharmacol 1983; 35(11): 747–748. 
6 Heng PW, Chan LW, Easterbrook MG, Li X. Investigation of the 
influence of mean HPMC particle size and number of polymer 
particles on the release of aspirin from swellable hydrophilic 
matrix tablets. J Control Release 2001; 76(1–2): 39–49. 
7 Larhrib H, Zeng XM, Martin GP, et al. The use of different grades 
of lactose as a carrier for aerosolized salbutamol sulphate. Int J 
Pharm 1999; 191(1): 1–14. 
8 Vanderbist F,Wery B, Moyano-Pavon I, Moes AJ. Optimization of 
a dry powder inhaler formulation of nacystelyn, a new mucoactive 
agent. J Pharm Pharmacol 1999; 51(11): 1229–1234. 
Table II: Particle size distribution of selected commercially available lactoses. 
Supplier/grade Percentage less than stated size 
<45 mm <53 mm <75 mm <150 mm <250 mm 
Borculo Domo Ingredients 
Lactopress Anhydrous — 430 — — 580 
Lactopress Anhydrous 250 420 — — 40–65 580 
DMV International 
Pharmatose DCL 21 15 — — 50 85 
Pharmatose DCL 22 5 — — 35 75 
Quest International Inc. (Sheffield Products) 
Anhydrous Lactose NF Direct Tableting — — 20–30 35–68 80–90 
Anhydrous Lactose NF 60M — — 10–40 45–83 95–100 
Lactose New Zealand 
Super-Tab Anhydrous — — 16 39 69 
Lactose, Anhydrous 387

9 Cal S, Iglesias G, Souto C, et al. Effects of hydration on the 
properties of a roller-dried b-lactose for direct compression. Int J 
Pharm 1996; 129: 253–261. 
20 General References 
Bolhuis GK, Chowhan ZT. Materials for direct compaction. In: 
Alderborn G, Nystrom C, eds. Pharmaceutical Powder Compaction 
Technology. New York: Marcel Dekker, 1996: 469–473. 
Borculo Domo Ingredients. Technical literature: Lactopress Anhydrous, 
Lactopress Anhydrous 250, 2003. 
DMV International. Technical literature: Pharmatose DCL 21, 2003. 
DMV International. Technical literature: Pharmatose DCL 22, 2004. 
Lactose New Zealand. Technical literature: Super-Tab Anhydrous, 
2004. 
Quest International Inc. (Sheffield Products). Technical literature: 
Anhydrous Lactose NF Direct Tableting, Anhydrous Lactose NF 
60M, 2004. 
21 Authors 
S Edge, A Kibbe, K Kussendrager. 
22 Date of Revision 
27 August 2005. 
388 Lactose, Anhydrous

Lactose, Monohydrate 
1 Nonproprietary Names 
BP: Lactose monohydrate 
PhEur: Lactosum monohydricum 
JP: Lactose 
USPNF: Lactose monohydrate 
2 Synonyms 
See Tables II and III. 
3 Chemical Name and CAS Registry Number 
O-b-D-Galactopyranosyl-(1!4)-a-D-glucopyranose monohydrate 
[64044-51-5] 
4 Empirical Formula and Molecular Weight 
C12H22O11H2O 360.31 
5 Structural Formula 
The USPNF 23 describes lactose monohydrate as a natural 
disaccharide, obtained from milk, which consists of one 
galactose and one glucose moiety. The PhEur 2005 describes 
lactose monohydrate as the monohydrate of O-b-D-galactopyranosyl-(
1!4)-a-D-glucopyranose. It is stated in the USPNF 23 
that lactose monohydrate may be modified as to its physical 
characteristics, and may contain varying proportions of 
amorphous lactose. 
6 Functional Category 
Binding agent; diluent for dry-powder inhalers; tablet binder; 
tablet and capsule diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Lactose is widely used as a filler or diluent in tablets and 
capsules, and to a more limited extent in lyophilized products 
and infant formulas.(1–13) Lactose is also used as a diluent in 
dry-powder inhalation.(14–16) Various lactose grades are 
commercially available that have different physical properties 
such as particle size distribution and flow characteristics. This 
permits the selection of the most suitable material for a 
particular application; for example, the particle size range 
selected for capsules is often dependent on the type of 
encapsulating machine used. Usually, fine grades of lactose 
are used in the preparation of tablets by the wet-granulation 
method or when milling during processing is carried out, since 
the fine size permits better mixing with other formulation 
ingredients and utilizes the binder more efficiently. 
Other applications of lactose include use in lyophilized 
products, where lactose is added to freeze-dried solutions to 
increase plug size and aid cohesion. Lactose is also used in 
combination with sucrose (approximately 1 : 3) to prepare 
sugar-coating solutions. 
Direct-compression grades of lactose monohydrate are 
available as granulated/agglomerated a-lactose monohydrate, 
containing small amounts of anhydrous lactose. 
Direct-compression grades are often used to carry lower 
quantities of drug and this permits tablets to be made without 
granulation. 
Other directly compressible lactoses are spray-dried lactose 
and anhydrous lactose. See Lactose, Spray-Dried, Lactose, 
Anhydrous. 
8 Description 
In the solid state, lactose appears as various isomeric forms, 
depending on the crystallization and drying conditions, i.e. alactose 
monohydrate, b-lactose anhydrous, and a-lactose 
anhydrous. The stable crystalline forms of lactose are a-lactose 
monohydrate, b-lactose anhydrous, and stable a-lactose 
anhydrous. 
Lactose occurs as white to off-white crystalline particles or 
powder. Lactose is odorless and slightly sweet-tasting; a-lactose 
is approximately 20% as sweet as sucrose, while b-lactose is 
40% as sweet. 
SEM: 1 
Excipient: Pharmatose 125M 
Manufacturer: DMV International 
Magnification: 100 Voltage: 1.5 kV

SEM: 2 
Excipient: Pharmatose DCL 15 
Manufacturer: DMV International 
SEM: 3 
Excipient: Wyndale Milled 100 Mesh 
Manufacturer: Lactose New Zealand 
Magnification: 50 Voltage: 10 kV 
SEM: 4 
Excipient: Wyndale Sieved 80 Mesh 
Manufacturer: Lactose New Zealand 
Magnification: 50 Voltage: 10 kV 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for lactose, monohydrate. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters . . — 
Appearance of 
solution 
. . . 
Acidity or alkalinity . . . 
Specific optical 
rotation 
.54.4 to 
.55.98 
.54.4 to 
.55.98 
.54.4 to 
.55.98 
Absorbance 
at 210–220nm 40.25 40.25 40.25 
at 270–300nm 40.07 40.07 40.07 
Heavy metals 45 ppm 45 ppm 45 mg/g 
Water 4.5–5.5%(a) 4.5–5.5% 4.5–5.5% 
Sulfated ash 40.1% 40.1% — 
Microbial limit 
Aerobic 
bacteria 
4100/g 4102/g 4100/g 
Fungi and yeast 450/g — 450/g 
Escherichia coli . . . 
Salmonella . — — 
Residue on ignition — — 40.1% 
Loss on drying 40.5%(b) — 40.5%(c) 
(a) 4.0–5.5% for granulated powder. 
(b) For the granulated powder, not more than 1.0%. 
(c) Modified monohydrate form, not more than 1.0%. 
10 Typical Properties 
Angle of repose: 338 for Pharmatose DCL 15; 328 for 
Tablettose 70 and Tablettose 80. 
Brittle fracture index: 
0.0749 (at compression pressure 189.5 MPa); 
0.0883 (at compression pressure 191.0 MPa).(a) 
Bonding index: 
0.0081 (at compression pressure 189.5 MPa); 
0.0052 (at compression pressure 191.0 MPa).(a) 
Compression pressure: 18.95–19.10 kN/cm2 
Density (true): 1.545 g/cm3 (a-lactose monohydrate) 
Density (bulk): see Table II. 
Density (tapped): see Table II. 
Melting point: 201–2028C (for dehydrated a-lactose monohydrate) 
Moisture content: lactose monohydrate contains approximately 
5% w/w water of crystallization and normally has 
a range of 4.5–5.5% w/w water content. See Table II. 
Particle size distribution: see Table III. 
Permanent deformation pressure: 
370.0MPa (at compression pressure 189.5 MPa); 
485.0MPa (at compression pressure 191.0 MPa).(a) 
Reduced modulus of elasticity: 
1472 (at compression pressure 189.5 MPa); 
5155 (at compression pressure 191.0 MPas).(a) 
Solubility: see Table IV. 
Specific surface area: 0.08–0.14m2/g for Lactochem Crystals 
and Lactochem Lactohale;(14) 0.23m2/g for Pharmatose 
200M. 
Specific rotation [a]D
20: .54.48 to .55.98 as a 10% w/v 
solution. Lactose exhibits mutarotation and an equilibrium 
390 Lactose, Monohydrate

mixture containing 62% b-lactose and 38% a-lactose is 
obtained instantly on the addition of a trace of ammonia. 
Tensile strength: 
2.987 MPa (at compression pressure 189.5 MPa); 
2.517 MPa (at compression pressure 191.0 MPa).(a) 
Water content: see Table II. 
(a) Methods for characterizing the mechanical properties of compacts of pharmaceutical 
ingredients are specified in the Handbook of Pharmaceutical Excipients, 3rd edn.(17) 
Table IV: Solubility of lactose. 
Solvent Solubility at 208C unless otherwise stated 
Chloroform Practically insoluble 
Ethanol Practically insoluble 
Ether Practically insoluble 
Water 1 in 5.24 
1 in 3.05 at 408C 
1 in 2.30 at 508C 
1 in 1.71 at 608C 
1 in 0.96 at 808C 
11 Stability and Storage Conditions 
Mold growth may occur under humid conditions (80% relative 
humidity and above). Lactose may develop a brown coloration 
on storage, the reaction being accelerated by warm, damp 
conditions; see Section 12. The purities of different lactoses can 
vary and color evaluation may be important, particularly if 
white tablets are being formulated. The color stabilities of 
various lactoses also differ. 
Solutions show mutorotation; see Section 10. 
Lactose should be stored in a well-closed container in a cool, 
dry place. 
12 Incompatibilities 
A Maillard-type condensation reaction is likely to occur 
between lactose and compounds with a primary amine group 
to form brown, or yellow-brown-colored products.(18) 
Lactose is also incompatible with amino acids, aminophylline,(
19) amfetamines,(20) and lisinopril.(21) 
13 Method of Manufacture 
Lactose is a natural disaccharide consisting of galactose and 
glucose and is present in the milk of most mammals. 
Commercially, lactose is produced from the whey of cows’ 
milk; whey being the residual liquid of the milk following 
cheese and casein production. Cows’ milk contains 4.4–5.2% 
lactose; lactose constitutes 38% of the total solid content of 
milk. 
a-Lactose monohydrate is prepared by crystallization from 
supersaturated solutions below 93.58C. Various crystalline 
shapes are prism, pyramidal, and tomahawk; these are 
dependent on the method of precipitation and crystallization. 
Direct compression grades of a-lactose monohydrate are 
prepared by granulation/agglomeration and spray-drying. 
14 Safety 
Lactose is widely used in pharmaceutical formulations as a filler 
and filler-binder in oral capsule and tablet formulations. It may 
also be used in intravenous injections. Adverse reactions to 
Table II: Typical physical properties of selected commercially 
available lactose, monohydrate. 
Supplier/grade Density (bulk) 
(g/cm3) 
Density 
(tapped) 
(g/cm3) 
Water 
content 
(%) 
Borculo Domo Ingredients 
Lactochem Coarse Crystals 0.75 0.88 — 
Lactochem Crystals 0.74 0.86 — 
Lactochem Fine Crystals 0.73 0.85 — 
Lactochem Extra Fine 
Crystals 
0.73 0.86 — 
Lactochem Coarse Powder 0.71 0.95 — 
Lactochem Regular Powder 0.62 0.92 — 
Lactochem Powder 0.64 0.89 — 
Lactochem Fine Powder 0.61 0.84 — 
Lactochem Extra Fine 
Powder 
0.45 0.74 — 
Lactochem Super Fine 
Powder 
0.47 0.74 — 
DMV International 
Pharmatose DCL 15 0.50 0.64 4.8 
Pharmatose 50M 0.71 0.83 5.2 
Pharmatose 80M 0.76 0.91 5.2 
Pharmatose 90M 0.74 0.89 5.2 
Pharmatose 100M 0.73 0.88 5.2 
Pharmatose 110M 0.73 0.89 5.2 
Pharmatose 125M 0.67 0.86 5.2 
Pharmatose 150M 0.60 0.88 5.2 
Pharmatose 200M 0.56 0.84 5.2 
Pharmatose 350M 0.51 0.80 5.2 
Pharmatose 450M 0.48 0.75 5.2 
HMS Coarse Powder 0.77 0.95 5.2 
HMS Extrafine Crystal 0.75 0.90 5.2 
HMS Regular Grade Fine 
Powder 
0.64 0.89 5.2 
HMS Impalpable 0.58 0.85 5.2 
Foremost Farms USA 
NF Lactose 310 0.66 0.92 4.8–5.2 
NF Lactose 312 0.53 0.81 4.8–5.2 
NF Lactose 313 0.44 0.72 4.8–5.2 
Meggle GmbH 
CapsuLac 60 0.59 0.70 5.2 
GranuLac 70 0.72 0.90 5.2 
GranuLac 140 0.66 0.89 5.2 
GranuLac 200 0.54 0.80 5.2 
GranuLac 230 0.47 0.76 5.2 
PrismaLac 40 0.47 0.54 5.2 
SacheLac 80 0.60 0.71 5.2 
SorboLac 400 0.36 0.78 5.2 
SpheroLac 100 0.69 0.84 5.2 
Tablettose 100 0.54 0.74 5.2 
Tablettose 80 0.57 0.72 5.2 
Tablettose 70 0.51 0.62 — 
Inhalac 70 0.60 0.66 5.2 
Inhalac 120 0.68 0.78 5.2 
Inhalac 230 0.69 0.80 5.2 
Quest International Inc. (Sheffield Products) 
Lactose Monohydrate NF 
80M 
— — 4.5–5.5 
Lactose Monohydrate NF 
Capsulating Grade 
— — 4.5–5.5 
Lactose Monohydrate NF 
Impalpable 
— — 4.5–5.5 
Lactose, Monohydrate 391

Table III: Particle size distribution of selected commercially available lactose, monohydrate. 
Supplier/grade Typical particle size distribution (%) 
<10 mm <32 mm <45 mm <63 mm <75 mm <100 mm <150 mm <200 mm <250 mm <315 mm <400 mm <600 mm <800 mm 
Borculo Domo Ingredients 
Lactochem Coarse Crystals — — — — — — 30–80 — >65 — >90(a) — — 
Lactochem Crystals — — — — 5–30 — 55–95 — >90 — — — — 
Lactochem Fine Crystals — — — — <30 — — — >90 — — — — 
Lactochem Extra Fine Crystal — — — — 10–45 — — — >99 — — — — 
Lactochem Coarse Powder — — — — 40–70 — <75 — >95 — — — — 
Lactochem Powder — — — — 65–80 >85(b) >95 — — — — — — 
Lactochem Fine Powder — — — — >80 — >98 — — — — — — 
Lactochem Super Fine Powder — — >95 — — — — — — — — — — 
Lactochem Microfine 90 — — — — — — — — — — — — 
DMV International 
Pharmatose DCL15 — — — — 25 — 60 — — — — — — 
Pharmatose 50M — — — — — — — <20 — — >80 — — 
Pharmatose 80M — — — — — <20 — — 70–90 >95 — — — 
Pharmatose 90M — — — <15 — 15–30 55–95 — — 100 — — — 
Pharmatose 100M — — — <15 — — 60–80 — >99 — — — — 
Pharmatose 110M — — — <20 — 30–60 75–90 — — 100 — — — 
Pharmatose 125M — — <40 40–70 — >90 97–100 — — — — — — 
Pharmatose 150M — — <50 — — >70 >85 — — 100 — — — 
Pharmatose 200M — — 50–65 — — >90 >69 — 99–100 — — — — 
Pharmatose 350M — — >60 — — >69 — — 100 — — — — 
Pharmatose 450M — — >90 >98 — — 100 — — — — — — 
HMS Coarse Powder — — 10 — — 30 — — — — — — — 
HMS Extrafine Crystals — — — — 17 — 70 — 99 — — — — 
HMS Regular Grade Fine Powder — — 45 — — — 90 — — 100 — — — 
HMS Impalpable — — 55 — — 87 — — 99.7 — — — — 
Foremost Farms USA 
NF Lactose 310 — — — — 24–50 — — — — — — — — 
NF Lactose 312 — — 64–80 — 94–100 — — — — — — — — 
NF Lactose 313 — — 91–98 — 99–100 — — — — — — — — 
Meggle GmbH 
CapsuLac 60 — — — — — 5 15 — 60 — 99 — — 
GranuLac 70 — — — — — 50 — — — — 99.5 — — 
GranuLac 140 — 30 — — — 90 100 — — — — — — 
GranuLac 200 — 55 — — — 96 — — — — — — — 
GranuLac 230 — 75 — 96 — 99.5 — — — — — — — 
PrismaLac 40 — — — — — — — 4 — — — — 100 
SacheLac 80 — — — — — 5 — — 63 — 100 — — 
SorboLac 400 — 95 — 99.5 — — — — — — — — — 
SpheroLac 100 — — — 9 — — 78 98 99.5 — — — — 
Tablettose 100 — — — 12 — 22 42 — 77 — 98 — — 
Tablettose 80 — — — 13 — — — — — — 93 — — 
Tablettose 70 — — — 1 — — 25 56 — — 97 — — 
Inhalac 70 — — — — — — — 50 — — — — — 
392 Lactose, Monohydrate

Supplier/grade Typical particle size distribution (%) 
<10 mm <32 mm <45 mm <63 mm <75 mm <100 mm <150 mm <200 mm <250 mm <315 mm <400 mm <600 mm <800 mm 
Inhalac 120 — — — — — — 50 90 — — — — — 
Inhalac 230 — — — — — 50 — — — — — — — 
Lactose New Zealand 
Wyndale Milled 100 Mesh — — — — 35 — — — — — — — — 
Wyndale Milled 150 Mesh — — — — 67 — — — — — — — — 
Wyndale Milled 200 Mesh — — — — 81 — — — — — — — — 
Wyndale Milled 300 Mesh — — — — 89 — — — — — — — — 
Wyndale Milled 350 Mesh — — 75 — — — — — 100 — — — — 
Wyndale Milled 450 Mesh — — 88 96 — — — — — — — — — 
Wyndale Sieved 40 Mesh — — — — — — 3 — 17 — — 93 — 
Wyndale Sieved 60 Mesh — — — — 1 — 7 — 28 — — 100 — 
Wyndale Sieved 80 Mesh — — — — 4 — 18 — 61 — — 100 — 
Wyndale Sieved 100 Mesh — — — — 10 — 74 — 100 — — — — 
Wyndale Sieved 125 Mesh — — 35 62 — — — — — — — — — 
Wyndale Sieved Special Dense — — — — 9 — 38 — 74 — — 100 — 
Quest International Inc. (Sheffield Products) 
Lactose Monohydrate NF 80M — — — — 65–90 — 93–99.5 — 99.5–100 — — — — 
Lactose Monohydrate NF Capsulating 
Grade 
— — — — 58–70 — 92–100 — — — — — — 
Lactose Monohydrate NF Impalpable — — — — >90 — 98.5–100 — — — — — — 
(a)<425 mm. 
(b)<106 mm. 
Lactose, Monohydrate 393

lactose are largely attributed to lactose intolerance, which 
occurs in individuals with a deficiency of the intestinal enzyme 
lactase.(22–25) This results in lactose being undigested and may 
lead to cramps, diarrhea, distension, and flatulence. In lactosetolerant 
individuals, lactase hydrolyzes lactose in the small 
intestine to glucose and galactose, which are then absorbed. 
Lactase levels are normally high at birth, and levels decline 
rapidly in early childhood. Malabsorption of lactose (hypolactasia) 
may occur at an early age (4–8 years) and varies 
among different ethnic groups. Lactose is excreted unchanged 
when administered intravenously. 
The symptoms of lactose intolerance are caused by the 
osmotic effect of the unabsorbed lactose, which increases water 
and sodium levels in the lumen. Unabsorbed lactose, upon 
reaching the colon, can be fermented by colonic flora, which 
produces gas, causing abdominal distension and discomfort. A 
lactose tolerance test has been developed based on the 
measurement of blood glucose level and the hydrogen level in 
the breath. However, its usefulness has been questioned as the 
test is based on a 50 g dose of lactose. 
Approximately 10–20% of lactose-intolerant individuals, in 
two studies, showed clinical symptoms of intolerance after 
ingestion of 3–5 g of lactose.(22,23) In one of the studies,(22) 75% 
of the subjects had symptoms with 12 g of lactose (equivalent to 
250mL of milk). In another,(23) eight out of 13 individuals 
developed diarrhea after the administration of 20 g of lactose, 
and nine out of 13 after the administration of 25 g. 
Lower doses of lactose produce fewer adverse effects, and 
lactose is better tolerated if taken with other foods. As a result, 
there is a significant population with lactose malabsorption 
who are still able to ingest normal amounts of lactose, such as 
that in milk, without the development of adverse side effects.(24) 
Most adults consume about 25 g of lactose per day (500mL 
of milk) without symptoms.(25,26) When symptoms appear, they 
are usually mild and dose-related. The dose of lactose in most 
pharmaceuticals seldom exceeds 2 g per day. It is unlikely that 
severe gastrointestinal symptoms can be attributed to the 
lactose in a conventional oral solid-dosage form, especially in 
adults who have not previously been diagnosed as severely 
lactose-intolerant. However, anecdotal reports of drug-induced 
diarrhea due to lactose intolerance have been made following 
administration of pharmaceutical preparations containing 
lactose. 
It has also been suggested that lactose intolerance may have 
a role in irritable bowel syndrome, but this role is currently 
unclear.(27) 
In the past, there have been concerns over the transmissible 
spongiform encephalopathies (TSE) contamination of animalderived 
products. However, in the light of current scientific 
knowledge, and irrespective of geographical origin, milk and 
milk derivatives are reported as unlikely to present any risk of 
TSE contamination; TSE risk is negligible if the calf rennet is 
produced in accordance with regulations.(28) 
LD50 (rat, IP): >10 g/kg 
LD50 (rat, oral): >10 g/kg 
LD50 (rat, SC): >5 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Excessive generation of dust, 
or inhalation of dust, should be avoided. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IM, IV, and SC 
injections; oral capsules and tablets; inhalation preparations; 
rectal, transdermal, and vaginal preparations). Included in 
nonparenteral and parenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Lactose, anhydrous; lactose, spray-dried. 
18 Comments 
A number of different grades of lactose are commercially 
available that vary in their physical properties and many studies 
have been reported in the literature comparing the behavior of 
these various materials in different formulations.(6,9–11) A 
number of co-processed excipients which contain lactose are 
available for direct-compression applications: co-processed 
lactose and starch (Starlac, Meggle/Roquette Fre.res),(29) lactose 
and microcrystalline cellulose (Microcelac, Meggle);(30) lactose 
and cellulose powder (Cellactose, Meggle),(31,32) lactose, 
povidone, and crospovidone (Ludipress, BASF). 
Lactose may exhibit complex thermoanalytical transitions 
because of its several crystalline, as well as amorphous, forms. 
Differential scanning calorimetry (DSC) can be used effectively 
to characterize the composition.(33–35) For example, a-lactose 
becomes anhydrous at approximately 1208C. a-Lactose monohydrate 
may also contain a small quantity of the b-form. 
The CAS number for lactose monohydrate, cycloic form is 
[10039-26-6]; and the CAS number for lactose monohydrate, 
open form is [64044-51-5]. A specification for lactose is 
included in the Food Chemicals Codex (FCC). 
The EINECS number for lactose is 200-559-2. 
19 Specific References 
1 Alpar O, Hersey JA, Shotton E. The compressions properties of 
lactose. J Pharm Pharmacol 1970; 22 (Suppl.): 1S–7S. 
2 Bolhuis GK, Lerk CF. Comparative evaluation of excipients for 
direct compression, I. Pharm Weekbl 1974; 109: 945–955. 
3 Vromans H, de Boer AH, Bolhuis GK, et al. Studies on the tableting 

properties of lactose: the effect of initial particle size on binding 
properties and dehydration characteristics of a-lactose monohydrate. 
In: Rubinstein MH, ed. Pharmaceutical Technology: 
Tableting Technology, vol. 1. Chichester: Ellis Horwood, 1987: 
31–42. 
4 Thwaites PM, Mashadi AB, Moore WD. An investigation of the 
effect of high speed mixing on the mechanical and physical 
properties of direct compression lactose. Drug Dev Ind Pharm 
1991; 17: 503–517. 
5 Riepma KA, Dekker BG, Lerk CF. The effect of moisture sorption 
on the strength and internal surface area of lactose tablets. Int J 
Pharm 1992; 87: 149–159. 
6 C. elik M, Okutgen E. A feasibility study for the development of a 
prospective compaction functionality test and the establishment of 
a compaction data bank. Drug Dev Ind Pharm 1993; 19: 2309– 
2334. 
7 Lerk CF. Consolidation and compaction of lactose. Drug Dev Ind 
Pharm 1993; 19: 2359–2398. 
8 Otsuka M, Ohtani H, Otsuka K, Kaneniwa N. Effect of humidity 
on solid-state isomerization of various kinds of lactose during 
grinding. J Pharm Pharmacol 1993; 45: 2–5. 
9 Bolhuis GK, Lerk CF. Comparative evaluation of excipients for 
direct compression. Pharm Weekbl 1973; 108: 469–481. 
10 Paronen P. Behaviour of some direct compression adjuvants during 
the tabletting process. STP Pharma 1986; 2(19): 682–688. 
394 Lactose, Monohydrate

11 Zuurman K, Riepma KA, Bolhuis GK, et al. The relationship 
between bulk density and compactibility of lactose granulations. 
Int J Pharm 1994; 102: 1–9. 
12 Bernabe I, Di Martino P, Joris E, et al. An attempt at explaining the 
variability of the compression capacity of lactose. Pharm Technol 
Eur 1997; 9(1): 42–51. 
13 Hwang RC, Peck GR. A systematic evaluation of the compression 
and tablet characteristics of various types of lactose and dibasic 
calcium phosphate. Pharm Technol 2001; 25(6): 54–68. 
14 Steckel H, Markefka P, TeWierik H, Kammelar R. Functionality 
testing of inhalation grade lactose. Eur J Pharm Biopharm 2004; 
57: 495–505. 
15 Kawashima Y, Serigano T, Hino T, et al. Effect of surface 
morphology of carrier lactose on dry powder inhalation property 
of pranlukast hydrate. Int J Pharm 1998; 172: 179–188. 
16 Larhrib H, Zeng XM, Martin GP, et al. The use of different grades 
of lactose as a carrier for aerosolised salbutamol sulfate. Int J 
Pharm 1999; 191: 1–14. 
17 Kibbe AH, ed. Handbook of Pharmaceutical Excipients, 3rd edn. 
London andWashington, DC: Pharmaceutical Press and American 
Pharmaceutical Association 2000: 642–643. 
18 Castello RA, Mattocks AM. Discoloration of tablets containing 
amines and lactose. J Pharm Sci 1962; 51: 106–108. 
19 Hartauer KJ, Guilroy JK. A comparison of diffuse reflectance FTIR 
spectroscopy and DSC in the characterization of a drug– 
excipient interaction. Drug Dev Ind Pharm 1991; 17: 617–630. 
20 Blaug SM, Huang W. Interaction of dextroamphetamine sulfate 
with spray-dried lactose. J Pharm Sci 1972; 61: 1770–1775. 
21 Eyjolfsson R. Lisinopril–lactose incompatibility. Drug Dev Ind 
Pharm 1998; 24: 797–798. 
22 Bedine MS, Bayless TM. Intolerance of small amounts of lactose by 
individuals with low lactase levels. Gastroenterology 1973; 65: 
735–743. 
23 Gudmand-Hoyer E, Simony K. Individual sensitivity to lactose in 
lactose malabsorption. Am J Dig Dis 1977; 22(3): 177–181. 
24 Pray WS. Lactose intolerance. US Pharm 1990; 15(11): 24, 26, 28, 
29. 
25 Suarez FL, Savaiano Dennis A. Diet, genetics, and lactose 
intolerance. Food Technol 1997; 51(3): 74–76. 
26 Suarez FL, Savaiano DA, Levitt MD. A comparison of symptoms 
after the consumption of milk or lactose-hydrolyzed milk by 
people with self-reported lactose intolerance. N Engl J Med 1995; 
333: 1–4. 
27 Spanier JA, Howden CW, Jones MP. A systemic review of 
alternative therapies in the irritable bowel syndrome. Arch Intern 
Med 2003; 163(3): 265–274. 
28 The European Agency for the Evaluation of Medicinal Products. 
Evaluation of Medicines for Human Use. London, 9 Dec 2002: 
EMEA/410/01 Rev. 2. 
29 Hauschild K, Picker-Freyer KM. Evaluation of a new coprocessed 
compound based on lactose and maize starch for tablet formulation. 
AAPS Pharm Sci 2004; 6(2): e16. 
30 Michoel A, Rombaut P, Verhoye A. Comparative evaluation of coprocessed 
lactose and microcrystalline cellulose with their physical 
mixtures in the formulation of folic acid tablets. Pharm Dev 
Technol 2002; 7(1): 79–87. 
31 Reimerdes D, Aufmuth KP. Tabletting with co-processed lactose– 
cellulose excipient. Manuf Chem 1992; 63(12): 21, 23, 24. 
32 Casalderrey M, Souto C, Concheiro A, et al. A comparison of drug 
loading capacity of cellactose with two ad hoc processed lactosecellulose 
direct compression excipients. Chem Pharm Bull (Tokyo) 
2004; 52(4): 398–401. 
33 Chidavaenzi OC, Buckton G, Koosha K, Pathak R. The use of 
thermal techniques to assess the impact of feed concentration on 
the amorphous content and polymorphic forms present in spray 
dried lactose. Int J Pharm 1997; 159: 67–74. 
34 Hill VL, Craig DQM, Feely LC. Characterisation of spray-dried 
lactose using modulated differential scanning calorimetry. Int J 
Pharm 1998; 161: 95–107. 
35 Lerk CF, Andreae AC, de Boer AH, et al. Alterations of a-lactose 
during differential scanning calorimetry. J Pharm Sci 1984; 73: 
856–857. 
20 General References 
BASF. Technical literature: Ludipress, 2004. 
Bolhuis GK, Chowhan ZT. Materials for direct compaction. In: 
Alderborn G, Nystro.m C, eds. Pharmaceutical Powder Compaction 
Technology. New York: Marcel Dekker, 1996: 459–469. 
Borculo Domo Ingredients. Technical literature: Lactochem, 2003. 
DMV International. Technical literature: Pharmatose, 2003. 
Foremost Farms USA. Technical literature: NF Lactose 310, NF 
Lactose 312, NF Lactose 313, 2004. 
Meggle GmbH. Technical literature: Lactose excipients, 2004. 
Pearce S. Lactose: the natural excipient. Manuf Chem 1986; 57(10): 
77–80. 
Quest International Inc. (Sheffield Products). Technical literature: 
Lactose Monohydrate NF 80M, NF Capsulating, NF Impalpable, 
2004. 
Rajah KK, Blenford DE, eds. The ALM Guide to Lactose Properties 
and Uses. The Hague: The Association of Lactose Manufacturers, 
1998. 
Roquette Fre.res. Technical literature: Starlac, 2004. 
Smith IJ, Parry-Billings M. The inhalers of the future? A review of dry 
powder devices on the market today. Pulm Pharmacol Ther 2003; 
16: 79–95. 
21 Authors 
S Edge, A Kibbe, K Kussendrager. 
22 Date of Revision 
28 August 2005. 
Lactose, Monohydrate 395

Lactose, Spray-Dried 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
FlowLac 100; Lactopress Spray-Dried; NF Lactose–316 Fast 
Flo; NF Lactose–315; Pharmatose DCL 11; Pharmatose DCL 
14; Super-Tab Spray-Dried. 
3 Chemical Name and CAS Registry Number 
Spray-dried lactose is a mixture of amorphous lactose, which is 
a 1 : 1 mixture of a-and-b-lactose, and O-b-D-galactopyranosyl-(
1!4)-a-D-glucopyranose monohydrate [64044-51-5]. 
4 Empirical Formula and Molecular Weight 
C12H22O11 342.30 (for amorphous) 
C12H22O11H2O 360.31 (for monohydrate) 
5 Structural Formula 
See Lactose, Anhydrous and Lactose, Monohydrate. 
6 Functional Category 
Binding agent; directly compressible tablet excipient; tablet and 
capsule diluent; tablet and capsule filler. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Spray-dried lactose is widely used as a binder, filler-binder, and 
flow aid in direct compression tableting. 
See also Lactose, Monohydrate; Lactose, Anhydrous. 
8 Description 
Lactose occurs as white to off-white crystalline particles or 
powder. It is odorless and slightly sweet-tasting. Spray-dried 
direct-compression grades of lactose are generally composed of 
80–90% specially prepared pure a-lactose monohydrate along 
with 10–20% of amorphous lactose. 
SEM: 1 
Excipient: Pharmatose DC 11 
Manufacturer: DMV International 
Magnification: 300 Voltage: 5kV 
SEM: 2 
Excipient: Super-Tab Spray-Dried 
Manufacturer: Lactose New Zealand 
Magnification: 500 Voltage: 10 kV 
9 Pharmacopeial Specifications 
See Section 18. 
10 Typical Properties 
Angle of repose: see Table I. 
Bonding index: 0.0044 for NF Lactose–315 (compression 
pressure 54.90 MPa)(a)

SEM: 3 
Excipient: Lactopress Spray-Dried 
Manufacturer: Borculo Domo 
Brittle fracture index: 0.1671 for NF Lactose–315 (compression 
pressure 54.90 MPa)(a) 
Density bulk: see Table I. 
Reduced modulus of elasticity: 5648 for NF Lactose–315 
(compression pressure 5.49–54.90 MPa)(a) 
Tensile strength: 2.368 MPa for NF Lactose–315 (compression 
pressure 54.90 MPa)(a) 
Water content: see Table I. 
(a) Methods for characterizing the mechanical properties of compacts of pharmaceutical 
ingredients are specified in the Handbook of Pharmaceutical Excipients, 3rd edn.(1) 
11 Stability and Storage Conditions 
Spray-dried lactose should be stored in a well-closed container 
in a cool, dry place. 
12 Incompatibilities 
See Lactose, Anhydrous and Lactose, Monohydrate. 
13 Method of Manufacture 
A suspension of a-lactose monohydrate crystals in a lactose 
solution is atomized and dried in a spray drier.(2,3) Approximately 
10–20% of the total amount of lactose is in solution and 
the remaining 80–90% is present in the crystalline form. The 
spray-drying process predominantly produces spherical particles. 
The compactibility of the material and its flow characteristics 
are a function of the primary particle size of the lactose 
monohydrate and the amount of amorphous lactose.(4) 
14 Safety 
Lactose is widely used in pharmaceutical formulations as a 
diluent in oral capsule and tablet formulations. It may also be 
used in intravenous injections. 
Adverse reactions to lactose are largely due to lactose 
intolerance, which occurs in individuals with a deficiency of the 
enzyme lactase. 
See Lactose, Monohydrate. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material being handled. Excessive generation of 
dust, or inhalation of dust, should be avoided. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IM, IV, and SC 
injections; oral capsules and tablets; inhalation preparations; 
rectal, transdermal, and vaginal preparations). Included in 
nonparenteral and parenteral medicines licensed in the UK. 
17 Related Substances 
Lactose, anhydrous; lactose, monohydrate. 
18 Comments 
Spray-dried lactose was one of the first direct-compression 
excipients. Spray-dried lactose typically comprises lactose 
monohydrate and amorphous lactose (see Section 8); see 
Lactose, Monohydrate for the relevant pharmacopeial information. 
It has been shown that during the spray-drying process the 
effects of nozzle orifice diameter and atomization air flow 
control the droplet size during atomization; however, it has also 
been demonstrated that increasing feed concentration results in 
Table I: Typical physical properties of selected commercially available spray-dried lactose. 
Supplier/grade Angle of repose (8) Density (bulk) (g/cm3) Density (tapped) (g/cm3) Water content (%) 
Borculo Domo Ingredients 
Lactopress Spray-Dried — — — — 
Lactopress Spray-Dried 250 — — — — 
DMV International 
Pharmatose DCL 11 30 0.61 0.73 5.0 
Pharmatose DCL 14 29 0.61 0.72 5.0 
Foremost Farms 
NF Lactose–316 Fast-Flo — 0.58 0.67 4.8–5.2 
NF Lactose–315 — 0.67 0.78 4.8–5.2 
Meggle GmbH 
FlowLac 100 28 0.62 0.73 5.0–5.2 
Lactose New Zealand 
Super-Tab Spray-Dried 31 0.62 0.79 — 
Lactose, Spray-Dried 397

increased shell thickness of hollow particles that are formed.(5) 
The physical properties of spray-dried lactose produced from 
alchoholic media are directly affected by the ethanol-to-water 
ratio in the feed solution. Lactose spray-dried from pure 
ethanol was shown to be 100% crystalline, whereas lactose 
spray-dried from pure water was 100% amorphous. Furthermore, 
the surface area of the spray-dried lactose increased as a 
function of amorphous content.(6) Spray-dried lactoses exhibit 
good flow properties.(7) 
Polyethylene glycol (PEG) 4000, when spray-dried with 
lactose, has been shown to accelerate the rate and extent of 
crystallization of lactose.(8) It has also been shown that spraydried 
lactose composite particles containing an ion complex of 
chitosan are suitable for the dry-coating of tablets.(9) Spraydried 
lactose and crystallized spray-dried lactose have been 
evaluated for dry powder inhalation.(10,11) Amorphous spraydried 
lactose has also been studied in composites with PVP.(12) 
See also Lactose, Anhydrous and Lactose, Monohydrate. 
19 Specific References 
1 Kibbe AH, ed. Handbook of Pharmaceutical Excipients, 3rd edn. 
London andWashington, DC: Pharmaceutical Press and American 
Pharmaceutical Association, 2000: 642–643. 
2 Hutton JT, Ellen G, Palmer GM, Valley C. Lactose product and 
method. United States Patent No. 3,639,170; 1972. 
3 Vromans H, Kussendrager KD, Van Den Biggelaar HA. Spraydried 
lactose and process for preparing the same. United States 
Patent No. 4,802,926; 1989. 
4 Vromans H, Bolhuis GK, Lerk CF, et al. Studies on the properties 
of lactose. VII. The effect of variations in primary particle size and 
percentage of amorphous lactose in spray-dried lactose. Int J 
Pharm 1987; 35(1–2): 29–37. 
5 Elversson J, Millqvist-Fureby A, Alderborn G, Elofsson U. Droplet 
and particle size relationship and shell thickness of inhalable lactose 
particles during spray drying. J Pharm Sci 2003; 92(4): 900–910. 
6 Harjunen PI, Lehto VP, Vaelisaari J, et al. Effects of ethanol to 
water ratio in feed solution on the crystallinity of spray dried 
lactose. Drug Dev Ind Pharm 2002; 28(8): 949–955. 
7 Bhattachar SN, Hedden DB, Olsofsky AM, et al. Evaluation of the 
vibratory feeder method for assessment of powder flow properties. 
Int J Pharm 2004; 269: 385–392. 
8 Corrigan DO, Healy AM, Corrigan OI. The effects of spray drying 
solutions of polyethylene glycol (PEG) and lactose/PEG on their 
physicochemical properties. Int J Pharm 2002; 235(1–2): 193–205. 
9 Takeuchi H, Yasuji T, Yamamoto H, Kawashima Y. Spray dried 
lactose composite particles containing an ion complex of alginate– 
chitosan for designing a dry coated tablet having a time controlled 
releasing function. Pharm Res 2000; 17: 94–99. 
10 Kawashima Y, Serigano T, Hino T, et al. Effect of surface 
morphology of carrier lactose on dry powder inhalation property 
of pralukast hydrate. Int J Pharm 1998; 172: 179–188. 
11 Harjunen P, Letho VP, Martimo K, et al. Lactose modifications 
enhance its drug performance in the novel multiple dose Taifun (R) 
DPI. Eur J Pharm Sci 2002; 16(4–5): 313–321. 
12 Berggren J, Frenning G, Alderborn G. Compression behaviour and 
tablet-forming ability of spray-dried amorphous composite particles. 
Eur J Pharm Sci 2004; 22: 191–200. 
20 General References 
Bolhuis GK, Chowhan ZT. Materials for direct compaction. In: 
Alderborn G, Nystro.m C, eds. Pharmaceutical Powder Compaction 
Technology. New York: Marcel Dekker, 1996: 473–476. 
Borculo Domo Ingredients. Technical literature: Lactopress Spray- 
Dried, Lactopress Spray-Dried 250, 2003. 
DMV International. Technical literature: Pharmatose DCL 11, 
Pharmatose DCL 14, 2004. 
Fell JT, Newton JM. The characterization of the form of lactose in 
spray-dried lactose. Pharm Acta Helv 1970; 45: 520–522. 
Fell JT, Newton JM. The production and properties of spray-dried 
lactose, part 1: the construction of an experimental spray drier and 
the production of spray-dried lactose under various conditions of 
operation. Pharm Acta Helv 1971; 46: 226–247. 
Fell JT, Newton JM. The production and properties of spray-dried 
lactose, part 2: the physical properties of samples of spray-dried 
lactose produced on an experimental drier. Pharm Acta Helv 1971; 
46: 425–430. 
Fell JT, Newton JM. The production and properties of spray-dried 
lactose, part 3: the compaction properties of samples of spray-dried 
lactose produced on an experiemental drier. Pharm Acta Helv 1971; 
46: 441–447. 
Foremost Farms USA. Technical literature: NF Lactose-316 Fast Flo, 
2004. 
Meggle GmbH. Technical literature: Lactose excipients, 2004. 
New Zealand Lactose. Technical literature: Super-Tab Spray-Dried, 
2004. 
Price R, Young PM. Visualisation of the crystallisation of lactose from 
the amorphous state. J Pharm Sci 2004; 93: 155–164. 
21 Authors 
S Edge, A Kibbe, K Kussendrager. 
22 Date of Revision 
5 August 2005. 
Table II: Particle size distribution of selected commercially available spray-dried lactose. 
Supplier/grade Percentage less than stated size 
<32 mm <45 mm <75 mm <100 mm <150 mm <250 mm 
Borculo Domo Ingredients 
Lactopress Spray-Dried — 425 — 30–60(a) — 565 
Lactopress Spray-Dried 250 — 415 450 30–60 — 598 
DMV International 
Pharmatose DCL 11 — 10 — 40 — 100 
Pharmatose DCL 14 — 10 — 40 — 100 
Foremost Farms 
NF Lactose–316 Fast-Flo — — 20–40 45–70(a) — 99.5–100 
NF Lactose–315 — — 25–45 45–70(a) — — 
Meggle GmbH 
FlowLac 100 6 — — 34 — 98 
Lactose New Zealand 
Super-Tab Spray-Dried — — 14 — 52 97 
(a)<106 mm. 
398 Lactose, Spray-Dried

Lanolin 
1 Nonproprietary Names 
BP: Wool fat 
JP: Purified lanolin 
PhEur: Adeps lanae 
USP: Lanolin 
2 Synonyms 
Cera lanae; E913; lanolina; lanolin anhydrous; Protalan 
anhydrous; purified lanolin; refined wool fat. 
3 Chemical Name and CAS Registry Number 
Anhydrous lanolin [8006-54-0] 
4 Empirical Formula and Molecular Weight 
The USP 28 describes lanolin as the purified wax-like substance 
obtained from the wool of the sheep, Ovis aries Linne. (Fam. 
Bovidae), that has been cleaned, decolorized, and deodorized. It 
contains not more than 0.25% w/w of water and may contain 
up to 0.02% w/w of a suitable antioxidant; the PhEur 2005 
specifies up to 200 ppm of butylated hydroxytoluene as an 
antioxidant. 
See also Section 18. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Emulsifying agent; ointment base. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Lanolin is widely used in topical pharmaceutical formulations 
and cosmetics. 
Lanolin may be used as a hydrophobic vehicle and in the 
preparation of water-in-oil creams and ointments. When mixed 
with suitable vegetable oils or with soft paraffin, it produces 
emollient creams that penetrate the skin and hence facilitate the 
absorption of drugs. Lanolin mixes with about twice its own 
weight of water, without separation, to produce stable 
emulsions that do not readily become rancid on storage. 
See also Section 18. 
8 Description 
Lanolin is a pale yellow-colored, unctuous, waxy substance 
with a faint, characteristic odor. Melted lanolin is a clear or 
almost clear, yellow liquid. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for lanolin. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . — 
Characters . . — 
Melting range 37–438C 38–448C 38–448C 
Acidity and alkalinity . — . 
Loss on drying 40.5% 40.5% 40.25% 
Residue on ignition 40.1% — 40.1% 
Sulfated ash — 40.15% — 
Water-soluble acids and 
alkalis 
— . . 
Water-soluble oxidizable 
substances 
. . . 
Chloride 40.036% 4150 ppm 40.035% 
Ammonia . — . 
Acid value 41.0 41.0 — 
Iodine value 18–36 — 18–36 
Peroxide value — 420 — 
Saponification value — 90–105 — 
Water absorption 
capacity 
— . — 
Paraffins — 41.0% — 
Petrolatum . — . 
Foreign substances 
(pesticide residues) 
— . . 
Butylated hydroxytoluene — 4200 ppm — 
10 Typical Properties 
Autoignition temperature: 4458C 
Density: 0.932–0.945 g/cm3 at 158C 
Flash point: 2388C 
Refractive index: nD
40 = 1.478–1.482 
Solubility: freely soluble in benzene, chloroform, ether, and 
petroleum spirit; sparingly soluble in cold ethanol (95%), 
more soluble in boiling ethanol (95%); practically insoluble 
in water. 
11 Stability and Storage Conditions 
Lanolin may gradually undergo autoxidation during storage. 
To inhibit this process, the inclusion of butylated hydroxytoluene 
is permitted as an antioxidant. Exposure to excessive or 
prolonged heating may cause anhydrous lanolin to darken in 
color and develop a strong rancidlike odor. However, lanolin 
may be sterilized by dry heat at 1508C. Ophthalmic ointments 
containing lanolin may be sterilized by filtration or by exposure 
to gamma irradiation.(1) 
Lanolin should be stored in a well-filled, well-closed 
container protected from light, in a cool, dry place. Normal 
storage life is 2 years. 
12 Incompatibilities 
Lanolin may contain prooxidants, which may affect the 
stability of certain active drugs.

13 Method of Manufacture 
Lanolin is a naturally occurring wax-like material obtained 
from the wool of sheep, Ovis aries Linne. (Fam. Bovidae). 
Crude lanolin is saponified with a weak alkali and the 
resultant saponified fat emulsion is centrifuged to remove the 
aqueous phase. The aqueous phase contains a soap solution 
from which, on standing, a layer of partially purified lanolin 
separates. This material is then further refined by treatment 
with calcium chloride, followed by fusion with unslaked lime to 
dehydrate the lanolin. The lanolin is finally extracted with 
acetone and the solvent is removed by distillation. 
14 Safety 
Lanolin is widely used in cosmetics and a variety of topical 
pharmaceutical formulations. 
Although generally regarded as a nontoxic and nonirritant 
material, lanolin and lanolin derivatives are associated with 
skin hypersensitivity reactions and the use of lanolin in subjects 
with known sensitivity should be avoided.(2,3) Other reports 
suggest that ‘sensitivity’ arises from false positives in patch 
testing.(4) However, skin hypersensitivity is relatively uncommon;(
5) the incidence of hypersensitivity to lanolin in the 
general population is estimated to be around 5 per million.(6) 
Sensitivity is thought to be associated with the content of 
free fatty alcohols present in lanolin products rather than the 
total alcohol content.(7) The safety of pesticide residues in 
lanolin products has also been of concern.(8,9) However, highly 
refined ‘hypoallergenic’ grades of lanolin and grades with low 
pesticide residues are commercially available.(10) See also 
Section 18. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (ophthalmic, 
otic, topical, and vaginal preparations). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian 
List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Cholesterol; hydrogenated lanolin; lanolin, hydrous; lanolin 
alcohols; modified lanolin. 
See also Section 18. 
Hydrogenated lanolin 
Synonyms: adeps lanae hydrogenatus; hydrogenated wool fat. 
Acid value: 41.0 
Hydroxyl value: 140–180 
Melting point: 45–558C 
Saponification value: 48.0 
Water: 43.0% 
Comments: some pharmacopeias, such as the PhEur 2005, 
contain a monograph for hydrogenated lanolin. This 
material is a mixture of higher aliphatic alcohols and sterols 
obtained from the direct, high-pressure, high-temperature 
hydrogenation of lanolin during which the esters and acids 
present are reduced to the corresponding alcohols. Hydrogenated 
lanolin may contain a suitable antioxidant; the 
PhEur 2005 specifies not more than 200 ppm of butylated 
hydroxytoluene. 
Modified lanolin 
Comments: some pharmacopeias, such as the USP 28, contain a 
monograph for modified lanolin. This material is lanolin 
that has been processed to reduce the contents of free lanolin 
alcohols and detergent and pesticide residues. It contains not 
more than 0.25% w/w of water. The USP 28 specifies that it 
may contain not more than 0.02% w/w of a suitable 
antioxidant. 
18 Comments 
Lanolin (the anhydrous material) may be confused in some 
instances with hydrous lanolin since the USP formerly 
contained monographs for ‘lanolin’ and ‘anhydrous lanolin’ 
in which the name ‘lanolin’ referred to the material containing 
25–30% w/w of purified water. However, in the USP 28 the 
former lanolin monograph (hydrous lanolin) is deleted and the 
monograph for anhydrous lanolin is renamed ‘lanolin’. 
Since lanolin is a natural product obtained from various 
geographical sources, its physical characteristics such as color, 
consistency, iodine value, saponification value, and hydroxyl 
value may vary for the products from different sources. 
Consequently, formulations containing lanolin from different 
sources may also have different physical properties. 
Awide range of grades of lanolin are commercially available 
that have been refined to different extents in order to produce 
hypoallergenic grades or grades with low pesticide contents. 
Many lanolin derivatives are also commercially available 
that have properties similar to those of the parent material and 
include: acetylated lanolin; ethoxylated or polyoxyl lanolin 
(water-soluble); hydrogenated lanolin; isopropyl lanolate; 
lanolin oil; lanolin wax; liquid lanolin; and water-soluble 
lanolin. 
A specification for anhydrous lanolin is contained in the 
Food Chemicals Codex (FCC), where it is described as being 
used as a masticatory substance in chewing gum base. The 
EINECS number for lanolin is 232-348-6. 
19 Specific References 
1 Smith GG, Fonner DE, Griffin JC. New process for the 
manufacture of sterile ophthalmic ointments. Bull Parenter Drug 
Assoc 1975; 29: 18–25. 
2 Anonymous. Lanolin allergy. Br Med J 1973; 2: 379–380. 
3 Breit J, Bandmann H-J. Dermatitis from lanolin. Br J Dermatol 
1973; 88: 414–416. 
4 Kligman AM. The myth of lanolin allergy. Contact Dermatitis 
1998; 39: 103–107. 
5 Wakelin SH, Smith H, White IR, et al. A retrospective analysis of 
contact allergy to lanolin. Br J Dermatol 2001; 145(1): 28–31. 
6 Clark EW. Estimation of the general incidence of specific lanolin 
allergy. J Soc Cosmet Chem 1975; 26: 323–335. 
7 Clark EW, Cronin E, Wilkinson DS. Lanolin with reduced 
sensitizing potential: a preliminary note. Contact Dermatitis 
1977; 3(2): 69–74. 
8 Copeland CA, Raebel MA,Wagner SL. Pesticide residue in lanolin 
[letter]. J Am Med Assoc 1989; 261: 242. 
9 Cade PH. Pesticide residue in lanolin [letter]. J Am Med Assoc 
1989; 262: 613. 
10 Steel I. Pure lanolin in treating compromised skin. Manuf Chem 
1999; 70(9): 16–17. 
400 Lanolin

20 General References 
Barnett G. Lanolin and derivatives. Cosmet Toilet 1986; 101(3): 23–44. 
Osborne DW. Phase behavior characterization of ointments containing 
lanolin or a lanolin substitute. Drug Dev Ind Pharm 1993; 19: 
1283–1302. 
Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 225–229. 
21 Authors 
AJ Winfield. 
22 Date of Revision 
15 August 2005. 
Lanolin 401

Lanolin Alcohols 
1 Nonproprietary Names 
BP: Wool alcohols 
PhEur: Alcoholes adipis lanae 
USPNF: Lanolin alcohols 
2 Synonyms 
Alcoholia lanae; alcolanum; Argowax; Hartolan; lanalcolum; 
Ritawax; wool wax alcohols. 
3 Chemical Name and CAS Registry Number 
Lanolin alcohols [8027-33-6] 
4 Empirical Formula and Molecular Weight 
Lanolin alcohols is a crude mixture of steroidal and triterpene 
alcohols, including not less than 30% cholesterol, and 10–13% 
isocholesterol. The USPNF 23 permits the inclusion of up to 
0.1% w/w of a suitable antioxidant, while the PhEur 2005 
specifies that lanolin alcohols may contain up to 200 ppm of 
butylated hydroxytoluene as an antioxidant. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Emulsifying agent; ointment base. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Lanolin alcohols is used in topical pharmaceutical formulations 
and cosmetics as a hydrophobic vehicle with emollient properties, 
e.g., in preparations for dry skin and dry eyes. It is also 
used in the preparation of water-in-oil creams and ointments at 
concentrations as low as 2% w/w. The proportion of water that 
can be incorporated into petrolatum is increased threefold by 
the addition of 5% lanolin alcohols. Such emulsions do not 
crack upon the addition of citric, lactic, or tartaric acids. 
8 Description 
Lanolin alcohols is a pale yellow to golden brown-colored solid 
that is plastic when warm but brittle when cold. It has a faint 
characteristic odor. See also Section 4. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for lanolin alcohols. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Melting range 5588C 5568C 
Acidity and alkalinity . . 
Clarity of solution . — 
Loss on drying 40.5% 40.5% 
Residue on ignition 40.1% 40.15% 
Copper — 45 ppm 
Acid value 42.0 42.0 
Hydroxyl value 120–180 — 
Peroxide value 415 — 
Saponification value 412 412 
Water absorption capacity . — 
Butylated hydroxytoluene 4200 ppm — 
Content of sterols (as cholesterol) 530.0% 530.0% 
10 Typical Properties 
Solubility: freely soluble in chloroform, dichloromethane, ether, 
and light petroleum; soluble 1 in 25 parts of boiling ethanol 
(95%); slightly soluble in ethanol (90%); practically 
insoluble in water. 
11 Stability and Storage Conditions 
Lanolin alcohols may gradually undergo autoxidation during 
storage. Store in a well-closed, well-filled container, protected 
from light, in a cool, dry place. Normal storage life is 
approximately 2 years. 
12 Incompatibilities 
Incompatible with coal tar, ichthammol, phenol, and resorcinol. 
13 Method of Manufacture 
Lanolin alcohols is prepared by the saponification of lanolin 
followed by separation of the fraction containing cholesterol 
and other alcohols. 
14 Safety 
Lanolin alcohols is widely used in cosmetics and topical 
pharmaceutical formulations and is generally regarded as a 
nontoxic material. However, lanolin alcohols may be irritant to 
the skin and hypersensitivity can occur in some individuals.(1) 
See also Lanolin. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled.

16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (ophthalmic 
and topical preparations). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Cholesterol; lanolin; lanolin, hydrous; petrolatum and lanolin 
alcohols; mineral oils. 
18 Comments 
Water-in-oil emulsions prepared with lanolin alcohols, unlike 
those made with lanolin, do not show surface darkening, nor 
do they develop an objectionable odor in hot weather. 
The EINECS number for lanolin alcohols is 232-430-1. 
19 Specific References 
1 Wakelin SH, Smith H, White IR, et al. A retrospective analysis of 
contact allergy to lanolin. B J Dermatol 2001; 145(1): 28–31. 
20 General References 
Barnett G. Lanolin and derivatives. Cosmet Toilet 1986; 101(3): 23–44. 
Khan AR, Iyer BV, Cirelli RA, Vasavada RC. In vitro release of salicylic 
acid from lanolin alcohols–ethylcellulose films. J Pharm Sci 1984; 
73: 302–305. 
Osborne DW. Phase behavior characterization of ointments containing 
lanolin or a lanolin substitute. Drug Dev Ind Pharm 1993; 19: 
1283–1302. 
Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 225–229. 
21 Authors 
AJ Winfield. 
22 Date of Revision 
15 August 2005. 
Lanolin Alcohols 403

Lanolin, Hydrous 
1 Nonproprietary Names 
BP: Hydrous wool fat 
JP: Hydrous lanolin 
PhEur: Adeps lanae cum aqua 
2 Synonyms 
Lipolan. 
3 Chemical Name and CAS Registry Number 
Hydrous lanolin [8020-84-6] 
4 Empirical Formula and Molecular Weight 
The JP 2001 describes hydrous lanolin as a mixture of lanolin 
and 25–30% w/w purified water. The PhEur 2005 describes 
hydrous lanolin as a mixture of lanolin and 25% w/w purified 
water; see also Section 18. The PhEur 2005 additionally 
permits the inclusion of up to 150 ppm of butylated hydroxytoluene 
as an antioxidant. 
See also Lanolin. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Emulsifying agent; ointment base. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Hydrous lanolin is widely used in topical pharmaceutical 
formulations and cosmetics in applications similar to those for 
lanolin. 
Hydrous lanolin is commonly used in the preparation of 
water-in-oil creams and ointments. More water may be 
incorporated into hydrous lanolin than into lanolin. 
See also Section 18. 
8 Description 
Hydrous lanolin is a pale yellow-colored, unctuous substance 
with a faint characteristic odor. When melted by heating on a 
water bath, hydrous lanolin separates into a clear oily layer and 
a clear water layer. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for hydrous lanolin. 
Test JP 2001 PhEur 2005 
Identification . . 
Characters . . 
Melting point 398C 38–448C 
Acidity and alkalinity . — 
Water absorption capacity — . 
Water-soluble acids and alkalis . . 
Water-soluble oxidizable substances . . 
Chloride 40.036% 4115 ppm 
Ammonia . — 
Paraffins . 41.0% 
Petrolatum . — 
Acid value 41.0 40.8 
Peroxide value — 415 
Iodine value 18–36 — 
Saponification value — 67–79 
Butylated hydroxytoluene — 4150 ppm 
Nonvolatile matter (wool fat content) 70–75% 72.5–77.5% 
Sulfated ash — 40.1% 
10 Typical Properties 
Solubility: practically insoluble in chloroform, ether, and water. 
Only the fat component of hydrous lanolin is soluble in 
organic solvents. 
11 Stability and Storage Conditions 
Hydrous lanolin should be stored in a well-filled, well-closed 
container protected from light, in a cool, dry place. Normal 
storage life is 2 years. 
See also Lanolin. 
12 Incompatibilities 
See Lanolin. 
13 Method of Manufacture 
Lanolin is melted, and sufficient purified water is gradually 
added with constant stirring. 
14 Safety 
Hydrous lanolin is used in cosmetics and a number of topical 
pharmaceutical formulations and is generally regarded as a 
nontoxic and nonirritant material, although it has been 
associated with hypersensitivity reactions. See Lanolin for 
further information. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled.

16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (ophthalmic, 
topical, transdermal, and vaginal preparations). Included in 
nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Cholesterol; lanolin; lanolin alcohols. 
18 Comments 
Lanolin (the anhydrous material) may be confused in some 
instances with hydrous lanolin since the USP formerly 
contained monographs for ‘lanolin’ and ‘anhydrous lanolin’ 
in which the name ‘lanolin’ referred to the material containing 
25–30% w/w of purified water. 
19 Specific References 
—
20 General References 
Barnett G. Lanolin and derivatives. Cosmet Toilet 1986; 101(3): 23–44. 
Osborne DW. Phase behavior characterization of ointments containing 
lanolin or a lanolin substitute. Drug Dev Ind Pharm 1993; 19: 
1283–1302. 
Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 225–229. 
21 Authors 
AJ Winfield. 
22 Date of Revision 
15 August 2005. 
Lanolin, Hydrous 405

Lauric Acid 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
C-1297; dodecanoic acid; dodecoic acid; duodecylic acid; ndodecanoic 
acid; Hydrofol acid 1255; Hydrofol acid 1295; 
Hystrene 9512; laurostearic acid; Neo-fat 12; Neo-fat 12–43; 
Ninol AA62 Extra; 1-undecanecarboxylic acid; vulvic acid; 
Wecoline 1295. 
3 Chemical Name and CAS Registry Number 
Dodecanoic acid [143-07-7] 
4 Empirical Formula and Molecular Weight 
C12H24O2 200.32 
5 Structural Formula 
6 Functional Category 
Emulsifying agent; food additive; lubricant; surfactant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Lauric acid is widely used in cosmetics and food products. In 
pharmaceutical applications it has also been examined for use 
as an enhancer for topical penetration and transdermal 
absorption,(1–11) rectal absorption,(12,13) buccal delivery,(14) 
and intestinal absorption.(15,16) It is also useful for stabilizing 
oil-in-water emulsions.(17) Lauric acid has also been evaluated 
for use in aerosol formulations.(18) 
8 Description 
Lauric acid occurs as a white crystalline powder with a slight 
odor of bay oil. 
9 Pharmacopeial Specifications 
—
10 Typical Properties 
Boiling point: 298.98C (at 760 mmHg). 
Density: 
0.883 g/cm3 at 208C; 
0.8679 g/cm3 at 508C. 
Enthalpy of fusion: 36.3 kJ mol–1 
Melting point: 43.2–43.88C 
Partition coefficient: Log P (octanol : water) = 4.6 
Refractive index: 
nD
82 = 1.418; 
nD
70 = 1.423; 
nD
45 = 1.432. 
Solubility: 4.81 mg/mL at 258C. Very soluble in ether, ethanol 
(95%), and methanol; soluble in acetone; slightly soluble in 
chloroform; miscible with benzene. 
Specific gravity: 0.9 
Surface tension: 26.6mN/m at 708C 
Vapor pressure: 
10 Pa at 1008C; 
100 Pa at 1288C. 
Viscosity (dynamic): 7.3 mPa s at 508C 
Viscosity (kinematic): 8.41 mPa s at 508C 
11 Stability and Storage Conditions 
Lauric acid is stable at normal temperatures and should be 
stored in a cool, dry place. Avoid sources of ignition and 
contact with incompatible materials. 
12 Incompatibilities 
Lauric acid is incompatible with strong bases, reducing agents, 
and oxidizing agents. 
13 Method of Manufacture 
Lauric acid is a fatty carboxylic acid isolated from vegetable 
and animal fats or oils. For example, coconut oil and palm 
kernel oil both contain high proportions of lauric acid. 
Isolation from natural fats and oils involves hydrolysis, 
separation of the fatty acids, hydrogenation to convert 
unsaturated fatty acids to saturated acids, and finally distillation 
of the specific fatty acid of interest. 
14 Safety 
Lauric acid is widely used in cosmetic preparations, in the 
manufacture of food-grade additives, and in pharmaceutical 
formulations. General exposure to lauric acid occurs through 
the consumption of food and through dermal contact with 
cosmetics, soaps, and detergent products. Lauric acid is toxic 
when administered intravenously. 
Occupational exposure may cause local irritation of eyes, 
nose, throat, and respiratory tract,(19) although lauric acid is 
considered safe and nonirritating for use in cosmetics.(20) No 
toxicological effects were observed when lauric acid was 
administered to rats at 35% of the diet for 2 years.(21) Acute 
exposure tests in rabbits indicate mild irritation.(20) After 
subcutaneous injection into mice, lauric acid was shown to be 
noncarcinogenic.(22) 
LD50 (mouse, IV): 0.13 g/kg(23,24) 
LD50 (rat, oral): 12 g/kg

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. No occupational exposure 
limits have been established. Under conditions of frequent use 
or heavy exposure, respiratory protection may be required. 
When heated, lauric acid emits an acrid smoke and irritating 
fumes; therefore, use in a well-ventilated area is recommended. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(oral capsules and tablets). Lauric acid is listed as a food 
additive in the EAFUS list compiled by the FDA. Reported in 
the EPA TSCA Inventory. 
17 Related Substances 
Capric acid; myristic acid; palmitic acid; sodium laurate; stearic 
acid. 
Capric acid 
Empirical formula: C10H20O2 
Molecular weight: 172.2 
CAS number: [334-48-5] 
Synonyms: n-capric acid; caprinic acid; caprynic acid; carboxylic 
acid C10; decanoic acid; n-decanoic acid; decoic 
acid; decyclic acid; n-decylic acid; 1-nonanecarboxylic acid. 
Appearance: white to pale yellow crystals with an unpleasant 
odor. 
Acid value: 320–330 
Boiling point: 2708C 
Melting point: 31.58C 
Refractive index: nD
40 = 1.4288 
Comments: capric acid is used as a flavoring agent in 
pharmaceutical preparations, providing a citrus-like flavor. 
It is used in cosmetics as an emulsifying agent. A 
specification for capric acid is included in the Food 
Chemicals Codex (FCC). The EINECS number for capric 
acid is 206-376-4. 
Sodium laurate 
Empirical formula: C12H23O2Na 
Molecular weight: 222.34 
CAS number: [629-25-4] 
Comments: sodium laurate is used as an emulsifying agent and 
surfactant in cosmetics. The EINECS number for sodium 
laurate is 211-082-4. 
18 Comments 
Although not included in any pharmacopeias, a specification 
for lauric acid is contained in the Food Chemicals Codex 
(FCC);(25) see Table I. 
The EINECS number for lauric acid is 205-582-1. 
19 Specific References 
1 Kravchenko IA, Golovenko NY, Larionov VB, et al. Effect of lauric 
acid on transdermal penetration of phenazepam in vivo. Bull Exp 
Biol Med 2003; 136(6): 579–581. 
2 Chisty MNA, Bellantone RA, Taft DR, Plakogiannis FM. In vitro 
evaluation of the release of albuterol sulfate from polymer gels: 
effect of fatty acids on drug transport across biological 
membranes. Drug Dev Ind Pharm 2002; 28(10): 1221–1229. 
Table I: FCC specification for lauric acid.(24) 
Test FCC 1996 
Acid value 252–287 
Heavy metals 410 mg/kg 
Iodine value 43 
Residue on ignition 40.1% 
Saponification value 253–287 
Solidification point 26–448C 
Unsaponifiable matter 40.3% 
Water 40.2% 
3 Stott PW, Williams AC, Barry BW. Mechanistic study into the 
enhanced transdermal permeation of a model beta-blocker, 
propranolol, by fatty acids: A melting point depression effect. Int 
J Pharm 2001; 219(1–2): 161–176. 
4 Morimoto K, Haruta T, Tojima H, Takeuchi Y. Enhancing 
mechanisms of saturated fatty acids on the permeations of 
indomethacin and 6-carboxyfluorescein through rat skins. Drug 
Dev Ind Pharm 1995; 21(17): 1999–2012. 
5 Ogiso T, Iwak IM, Hirota T, et al. Comparison of the in vitro 
penetration of propiverine with that of terodiline. Biol Pharm Bull 
1995; 18(7): 968–975. 
6 Aungst BJ, Blake JA, Hussain MA. Contributions of drug 
solubilization, partitioning, barrier disruption, and solvent permeation 
to the enhancement of skin permeation of various 
compounds with fatty acids and amines. Pharm Res 1990; 7(7): 
712–718. 
7 Ogiso T, Shintani M. Mechanism for the enhancement effect of 
fatty acids on the percutaneous absorption of propranolol. J 
Pharm Sci 1990; 79(12): 1065–1071. 
8 Pfister WR, Hsieh DST. Permeation enhancers compatible with 
transdermal drug delivery systems. Part I: Selection and formulation 
considerations. Pharm Technol 1990; 14(9): 132–140. 
9 Green PG, Hadgraft J, Wolff M. Physicochemical aspects of the 
transdermal delivery of bupranolol. Int J Pharm 1989; 55(2–3): 
265–269. 
10 Green PG, Guy RH, Hadgraft J. In vitro and in vivo enhancement 
of skin permeation with oleic and lauric acids. Int J Pharm 1988; 
48(1–3): 103–111. 
11 Green PG, Hadgraft J. Facilitated transfer of cationic drugs across 
a lipoidal membrane by oleic acid and lauric acid. Int J Pharm 
1987; 37(3): 251–255. 
12 Ogiso T, Iwaki M, Kashitani Y, Yamashita K. Enhancement effect 
of lauric acid on the rectal absorption of propranolol from 
suppository in rats. Chem Pharm Bull 1991; 39(10): 2657–2661. 
13 Muranishi S. Characteristics of drug absorption via the rectal 
route. Methods Find Exp Clin Pharmacol 1984; 12: 763–772. 
14 Shojaei AH, Chang RK, Guo X, et al. Systemic drug delivery via 
the buccal mucosal route. Pharm Technol 2001; 25(6): 70–81. 
15 Constantinides PP, Welzel G, Ellens H, et al. Water-in-oil 
microemulsions containing medium-chain fatty acids/salts: formulation 
and intestinal absorption enhancement evaluation. 
Pharm Res 1996; 13(2): 210–215. 
16 Yamada K, Murakami M, Yamamoto A, et al. Improvement of 
intestinal absorption of thyrotropin-releasing hormone by chemical 
modification with lauric acid. J Pharm Pharmacol 1992; 44(9): 
717–721. 
17 Buszello K, Harnisch S, Muller RH, Muller BW. The influence of 
alkali fatty acids on the properties and the stability of parenteral 
O/W emulsions modified with Solutol HS 15. Eur J Pharm 
Biopharm 2000; 49(2): 143–149. 
18 Gupta PK, Hickey AJ. Contemporary approaches in aerosolized 
drug delivery to the lung. J Control Release 1991; 17(2): 129–147. 
19 Health Evaluation Report on Lauric Acid Exposure during Flaking 
and Bagging Operations at Emery Industries, Los Angeles, CA. 
National Institute for Occupational Safety and Health, HHE 80- 
160-897, NTIS Doc. No. PB 82-25694-2, 1981. 
Lauric Acid 407

20 Final report on the safety assessment of oleic acid, lauric acid, 
palmitic acid, myristic acid, and stearic acid. J Am Coll Toxicol 
1987; 6(3): 321–401. 
21 Verschueren K, ed. Handbook of Environmental Data of Organic 
Chemicals, 2nd edn. New York: Van Nostrand Reinhold, 1983: 
793. 
22 Swern D, Wieder R, McDonough M, et al. Investigation of fatty 
acids and derivatives for carcinogenic activity. Cancer Res 1970; 
30: 1037. 
23 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2204. 
24 Oro R,Wretlind A. Pharmacological effects of fatty acids, triolein, 
and cottonseed oil. Acta Pharmacol Toxicol 1961; 18: 141. 
25 Food Chemicals Codex, 4th edn. Washington, DC: National 
Academy Press, 1996: 218. 
20 General References 
—
21 Authors 
PE Luner. 
22 Date of Revision 
19 August 2005. 
408 Lauric Acid

Lecithin 
1 Nonproprietary Names 
USPNF: Lecithin 
See also Section 4. 
2 Synonyms 
E322; egg lecithin; LSC 5050; LSC 6040; mixed soybean 
phosphatides; ovolecithin; Phosal 53 MCT; Phospholipon 100 
H; soybean lecithin; soybean phospholipids; Sternpur; vegetable 
lecithin. 
3 Chemical Name and CAS Registry Number 
Lecithin [8002-43-5] 
The chemical nomenclature and CAS Registry numbering of 
lecithin is complex. The commercially available lecithin, used in 
cosmetics, pharmaceuticals, and food products, is a complex 
mixture of phospholipids and other materials. However, it may 
be referred to in some literature sources as 1,2-diacyl-sn-glycero- 
3-phosphocholine (trivial chemical name, phosphatidylcholine). 
This material is the principal constituent of egg lecithin and has 
the same CAS Registry Number. The name lecithin and the CAS 
Registry Number above are thus used to refer to both lecithin 
and phosphatidylcholine in some literature sources. 
Another principal source of lecithin is from an extract of 
soybeans (CAS [8030-76-0]). Egg yolk lecithin (CAS [93685- 
90-6]) is also listed in Chemical Abstracts. 
See also Section 4. 
4 Empirical Formula and Molecular Weight 
The USPNF 23 describes lecithin as a complex mixture of 
acetone-insoluble phosphatides that consists chiefly of phosphatidylcholine, 
phosphatidylethanolamine, phosphatidylserine, 
and phosphatidylinositol, combined with various amounts 
of other substances such as triglycerides, fatty acids, and 
carbohydrates as separated from a crude vegetable oil source. 
The composition of lecithin (and hence also its physical 
properties) varies enormously depending upon the source of the 
lecithin and the degree of purification. Egg lecithin, for 
example, contains 69% phosphatidylcholine and 24% phosphatidylethanolamine, 
while soybean lecithin contains 21% 
phosphatidylcholine, 22% phosphatidylethanolamine, and 
19% phosphatidylinositol, along with other components.(1) 
5 Structural Formula 
a-Phosphatidylcholine 
R1 and R2 are fatty acids, which may be different or 
identical. 
Lecithin is a complex mixture of materials; see Section 4. 
The structure above shows phosphatidylcholine, the principal 
component of egg lecithin, in its a-form. In the b-form, the 
phosphorus-containing group and the R2 group exchange 
positions. 
6 Functional Category 
Emollient; emulsifying agent; solubilizing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Lecithins are used in a wide variety of pharmaceutical 
applications; see Table I. They are also used in cosmetics(2) 
and food products. 
Lecithins are mainly used in pharmaceutical products as 
dispersing, emulsifying, and stabilizing agents and are included 
in intramuscular and intravenous injections, parenteral nutrition 
formulations, and topical products such as creams and 
ointments. 
Lecithins are also used in suppository bases,(3) to reduce the 
brittleness of suppositories, and have been investigated for their 
absorption-enhancing properties in an intranasal insulin 
formulation.(4) Lecithins are also commonly used as a 
component of enteral and parenteral nutrition formulations. 
There is evidence that phosphatidylcholine (a major 
component of lecithin) is important as a nutritional supplement 
to fetal and infant development. Furthermore, choline is a 
required component of FDA-approved infant formulas.(5) 
Other studies have indicated that lecithin can protect against 
alcohol cirrhosis of the liver, lower serum cholesterol levels, and 
improve mental and physical performance.(6) 
Liposomes in which lecithin is included as a component of 
the bilayer have been used to encapsulate drug substances; their 
potential as novel delivery systems has been investigated.(7) 
This application generally requires purified lecithins combined 
in specific proportions. 
Therapeutically, lecithin and derivatives have been used as a 
pulmonary surfactant in the treatment of neonatal respiratory 
distress syndrome. 
Table I: Uses of lecithin. 
Use Concentration (%) 
Aerosol inhalation 0.1 
IM injection 0.3–2.3 
Oral suspensions 0.25–10.0 
8 Description 
Lecithins vary greatly in their physical form, from viscous 
semiliquids to powders, depending upon the free fatty acid 
content. They may also vary in color from brown to light 
yellow, depending upon whether they are bleached or

unbleached or on the degree of purity. When they are exposed 
to air, rapid oxidation occurs, also resulting in a dark yellow or 
brown color. 
Lecithins have practically no odor. Those derived from 
vegetable sources have a bland or nutlike taste, similar to that 
of soybean oil. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for lecithin. 
Test USPNF 23 
Water 41.5% 
Lead 40.001% 
Heavy metals 420 mg/g 
Acid value . 
Hexane-insoluble matter 40.3% 
Acetone-insoluble matter — 
Organic volatile impurities . 
10 Typical Properties 
Density: 
0.97 g/cm3 for liquid lecithin; 
0.5 g/cm3 for powdered lecithin. 
Iodine number: 
95–100 for liquid lecithin; 
82–88 for powdered lecithin. 
Isoelectric point: 3.5 
Saponification value: 196 
Solubility: lecithins are soluble in aliphatic and aromatic 
hydrocarbons, halogenated hydrocarbons, mineral oil, and 
fatty acids. They are practically insoluble in cold vegetable 
and animal oils, polar solvents, and water. When mixed with 
water, however, lecithins hydrate to form emulsions. 
11 Stability and Storage Conditions 
Lecithins decompose at extreme pH. They are also hygroscopic 
and subject to microbial degradation. When heated, lecithins 
oxidize, darken, and decompose. Temperatures of 160–1808C 
will cause degradation within 24 hours. 
Fluid or waxy lecithin grades should be stored at room 
temperature or above; temperatures below 108C may cause 
separation. 
All lecithin grades should be stored in well-closed containers 
protected from light and oxidation. Purified solid lecithins 
should be stored in tightly closed containers at subfreezing 
temperatures. 
12 Incompatibilities 
Incompatible with esterases owing to hydrolysis. 
13 Method of Manufacture 
Lecithins are essential components of cell membranes and, in 
principle, may be obtained from a wide variety of living matter. 
In practice, however, lecithins are usually obtained from 
vegetable products such as soybean, peanut, cottonseed, 
sunflower, rapeseed, corn, or groundnut oils. Soybean lecithin 
is the most commercially important vegetable lecithin. Lecithin 
obtained from eggs is also commercially important and was the 
first lecithin to be discovered. 
Vegetable lecithins are obtained as a by-product in the 
vegetable oil refining process. Polar lipids are extracted with 
hexane and, after removal of the solvent, a crude vegetable oil is 
obtained. Lecithin is then removed from the crude oil by water 
extraction. Following drying, the lecithin may be further 
purified.(1) 
With egg lecithin, a different manufacturing process must 
be used since the lecithin in egg yolks is more tightly bound to 
proteins than in vegetable sources. Egg lecithin is thus obtained 
by solvent extraction from liquid egg yolks using acetone 
or from freeze-dried egg yolks using ethanol (95%).(1) 
Synthetic lecithins may also be produced. 
14 Safety 
Lecithin is a component of cell membranes and is therefore 
consumed as a normal part of the diet. Although excessive 
consumption may be harmful, it is highly biocompatible and 
oral doses of up to 80 g daily have been used therapeutically in 
the treatment of tardive dyskinesia.(8) When used in topical 
formulations, lecithin is generally regarded as a nonirritant and 
nonsensitizing material.(2) The Cosmetic Ingredients Review 
Expert Panel (CIR) has reviewed lecithin and issued a tentative 
report revising the safe concentration of the material from 
1.95% to 15.0% in rinse-off and leave-in products. They note, 
however, that there are insufficient data to rule on products that 
are likely to be inhaled.(9) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Lecithins may be irritant to 
the eyes; eye protection and gloves are recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (inhalations; 
IM and IV injections; otic preparations; oral capsules, 
suspensions and tablets; rectal, topical, and vaginal preparations). 
Included in nonparenteral and parenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
—
18 Comments 
Poloxamer lecithin organogels have been used in topical 
formulations for the delivery of non-steroidal anti-inflammatory 
drugs.(10) 
Lecithins contain a variety of unspecified materials; care 
should therefore be exercised in the use of unpurified lecithin in 
injectable or topical dosage forms, as interactions with the 
active substance or other excipients may occur. Unpurified 
lecithins may also have a greater potential for irritancy in 
formulations. 
Supplier’s literature should be consulted for information on 
the different grades of lecithin available and their applications 
in formulations. 
410 Lecithin

A specification for lecithin is contained in the Food 
Chemicals Codex (FCC). The EINECS number for lecithin is 
232-307-2. 
19 Specific References 
1 Schneider M. Achieving purer lecithin. Drug Cosmet Ind 1992; 
150(2): 54, 56, 62, 64, 66, 101–103. 
2 Anonymous. Lecithin: its composition, properties and use in 
cosmetic formulations. Cosmet Perfum 1974; 89(7): 31–35. 
3 Novak E, Osborne DW, Matheson LE, et al. Evaluation of 
cefmetazole rectal suppository formulation. Drug Dev Ind Pharm 
1991; 17(3): 373–389. 
4 Anonymous. Intranasal insulin formulation reported to be 
promising. Pharm J 1991; 247: 17. 
5 US Congress. Infant Formula Act of 1980. Public Law 96-359, 
1980. 
6 Canty D, Zeisel S, Jolitz A. Lecithin and Choline Research Update 
on Health and Nutrition. FortWayne, IN: Central Soya Company, 
Inc, 1996. 
7 Grit M, Zuidam NJ, Underberg WJM, Crommelin DJA. Hydrolysis 
of partially saturated egg phosphatidylcholine in aqueous 
liposome dispersions and the effect of cholesterol incorporation on 
hydrolysis kinetics. J Pharm Pharmacol 1993; 45: 490–495. 
8 Growdon JH, Gelenberg AJ, Doller J, et al. Lecithin can suppress 
tardive dyskinesia [letter]. N Engl J Med 1978; 298: 1029–1030. 
9 Anonymous. ‘The Rose Sheet’ FDC Reports 1997; 18(39): 8. 
10 Franckum J, Ramsey D, Das NG, Das SK. Pluronic lecithin 
organogel for local delivery of anti-inflammatory drugs. Int J 
Pharm Compound 2004; 8(2): 101–105. 
20 General References 
Arias C, Rueda C. Comparative study of lipid systems from various 
sources by rotational viscometry and potentiometry. Drug Dev Ind 
Pharm 1992; 18: 1773–1786. 
Hanin I, Pepeu G, eds. Phospholipids: Biochemical, Pharmaceutical 
and Analytical Considerations. New York: Plenum Press, 1990. 
21 Authors 
K Fowler. 
22 Date of Revision 
24 August 2005. 
Lecithin 411

Leucine 
1 Nonproprietary Names 
JP: L-Leucine 
PhEur: Leucinum 
USP: Leucine 
2 Synonyms 
a-Aminoisocaproic acid; L-a-aminoisocaproic acid; 2-amino-4- 
methylpentanoic acid; 2-amino-4-methylvaleric acid; a-aminog-
methylvaleric acid; 1,2-amino-4-methylvaleric acid; DL-leucine; 
L-leucine; leu; 4-methylnorvaline. 
3 Chemical Name and CAS Registry Number 
L-Leucine [61-90-5] 
4 Empirical Formula and Molecular Weight 
C6H13NO2 131.20 
5 Structural Formula 
6 Functional Category 
Antiadherent; flavoring agent; lubricant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Leucine is used in pharmaceutical formulations as a flavoring 
agent.(1) It has been used experimentally as an antiadherent to 
improve the deagglomeration of disodium cromoglycate 
microparticles in inhalation preparations;(2) and as a tablet 
lubricant.(3) Leucine copolymers have been shown to successfully 
produce stable drug nanocrystals in water.(4) 
8 Description 
Leucine occurs as a white or almost off-white crystalline 
powder or shiny flakes. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for leucine. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters . . — 
Optical rotation .14.58 to 
.16.08 
.14.58 to 
.16.08 
.14.98 to 
.17.38 
pH 5.56.5 — 5.57.0 
Appearance of 
solution 
. . — 
Chloride 40.021% 4200 ppm 40.05% 
Sulfate 40.028% 4300 ppm 40.03% 
Ammonium 40.02% 4200 ppm — 
Ninhydrin-positive 
substances 
— . — 
Iron — 410 ppm 40.003% 
Heavy metals 420 ppm 410 ppm 40.0015% 
Arsenic 42 ppm — — 
Other amino acids . — — 
Loss on drying 40.30% 40.5% 40.2% 
Residue on ignition 40.10% 40.1% 40.4% 
Organic volatile 
impurities 
— — . 
Assay 598.5% 98.5101.5% 98.5101.5% 
10 Typical Properties 
Density: 1.293 g/cm3 
Dissociation constant: pKa = 2.35 at 138C. 
Isoelectric point: 6.04 
Melting point: 2938C 
Solubility: soluble in acetic acid, ethanol (99%) and water. 
Practically insoluble in ether. 
11 Stability and Storage Conditions 
Leucine is sensitive to light and moisture and should be stored 
in an airtight container in a cool, dark, dry place. 
12 Incompatibilities 
Leucine is incompatible with strong oxidizing agents. 
13 Method of Manufacture 
Leucine is produced microbially by incubating an amino-acidproducing 
microorganism including but not exclusive to 
Pseudomonas, Escherichia, Bacillus, or Staphylococcus in the 
presence of oxygen and a hydrocarbon. The nutrient medium 
should contain an inhibitory amount of a growth inhibitor that 
is a chemically similar derivative of leucine, e.g: methylallylglycine, 
a-hydrozinoisocaproic acid, or b-cyclopentanealanine, 
so as to inhibit the growth of the organism except for at least 
one mutant that is resistant to the inhibitory effect. The 
resistant mutant is then isolated and grown in the presence of 
oxygen and the hydrocarbon in the absence of the inhibitor. 
The mutant cells are then harvested and a nutrient medium is

formed that includes a hydrocarbon as the sole source of 
carbon. Finally, the harvested cells are incubated in the medium 
in the presence of oxygen.(5) 
14 Safety 
Leucine is an essential amino acid and is consumed as part of a 
normal diet. It is generally regarded as a nontoxic and 
nonirritant material. It is moderately toxic by the subcutaneous 
route.
LD50 (rat, IP): 5.379 g/kg(6) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of the material handled. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IV infusion; 
oral tablets). Included in nonparenteral medicines licensed in 
the UK. 
17 Related Substances 
DL-Leucine 
DL-Leucine 
Empirical formula: C6H13NO2 
Molecular weight: 131.20 
Appearance: white leaflets. 
Dissociation constant: 
pKa1 = 2.36; 
pKa2 = 9.60. 
Solubility: soluble in ethanol (90%) and water. Practically 
insoluble in ether. 
18 Comments 
A specification for leucine is included in the Food Chemicals 
Codex (FCC). The EINECS number for leucine is 200-522-0. 
19 Specific References 
1 Ash M, Ash I. Handbook of Pharmaceutical Additives, 2nd edn. 
Endicott, NY: Synapse Information Resources, 2002: 542. 
2 Abdolhossien RN, Kambiz G, Mohahhadali B, Morteza R. The 
effect of vehicle on physical properties and aerosolisation 
behaviour of disodium cromoglycate microparticles spray dried 
alone or with L-leucine. Int J Pharm 2004; 285: 97–108. 
3 Gusman S, Gregoriades D. Effervescent potassium chloride tablet. 
United States Patent No. 3,903,255; 1975. 
4 Lee J, Lee SJ, Choi JY, et al. Amphiphilic amino acid copolymers as 
stabilizers for the preparation of nanocrystal dispersion. Eur J 
Pharm Sci 2005; 24: 441–449. 
5 Mobil Oil Corp. Synthesis of amino acids. UK Patent No. 
1 071 935; 1967. 
6 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2224. 
20 General References 
—
21 Authors 
GE Amidon. 
22 Date of Revision 
25 August 2005. 
Leucine 413

Linoleic Acid 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Emersol 310; Emersol 315; leinoleic acid; 9-cis,12-cis-linoleic 
acid; 9,12-linoleic acid; linolic acid; cis,cis-9,12-octadecadienoic 
acid; Pamolyn; Polylin No. 515; telfairic acid. 
3 Chemical Name and CAS Registry Number 
(Z,Z)-9,12-Octadecadienoic acid [60-33-3] 
4 Empirical Formula and Molecular Weight 
C18H32O2 280.45 
5 Structural Formula 
6 Functional Category 
Dietary supplement; emulsifying agent; skin penetrant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Linoleic acid is used in topical transdermal formulations,(1–14) 
in oral formulations as an absorption enhancer,(15,16) and in 
topical cosmetic formulations as an emulsifying agent.(17) It is 
also administered in parenteral emulsions as a dietary supplement. 
8 Description 
Linoleic acid occurs as a colorless to light-yellow-colored oil. 
9 Pharmacopeial Specifications 
See Section 18. 
10 Typical Properties 
Boiling point: 2308C at 16mmHg 
Density: 0.9007 g/cm3 
Iodine value: 181.1 
Melting point: –58C 
Refractive index: nD
20 = 1.4699 
Solubility: freely soluble in ether; soluble in ethanol (95%); 
miscible with dimethylformamide, fat solvents, and oils. 
11 Stability and Storage Conditions 
Linoleic acid is sensitive to air, light, moisture, and heat. It 
should be stored in a tightly sealed container under an inert 
atmosphere and refrigerated. 
12 Incompatibilities 
Linoleic acid is incompatible with bases, strong oxidizing 
agents, and reducing agents. 
13 Method of Manufacture 
Linoleic acid is obtained by extraction from various vegetable 
oils such as safflower oil. 
14 Safety 
Linoleic acid is widely used in cosmetics and topical pharmaceutical 
formulations and is generally regarded as a nontoxic 
material. On exposure to the eyes, skin, and mucous 
membranes, linoleic acid can cause mild irritation. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Gloves and eye protection are 
recommended. 
16 Regulatory Status 
GRAS listed. Approved for use in foods in Europe and the USA. 
17 Related Substances 
Ethyl linoleate; methyl linoleate. 
Ethyl linoleate 
Empirical formula: C20H36O2 
CAS number: [544-35-4] 
Synonyms: linoleic acid ethyl ester; 9,12-octadecadienoic acid 
ethyl ester; vitamin F. 
Comments: ethyl linoleate is used in pharmaceutical formulations 
as an emollient and humactent. It is also used as a 
solvent for fats. The EINECS number for ethyl linoleate is 
208-868-4. 
Methyl linoleate 
Empirical formula: C19H34O2 
CAS number: [112-63-0] 
Synonyms: 9,12-octadecadienoic acid, methyl ester. 
Comments: methyl linoleate is used in cosmetics as an 
emollient. The EINECS number for methyl linoleate is 
203-993-0. 
18 Comments 
Studies have shown that conjugated linoleic acid increases 
paracellular permeability across human intestinal-like Caco-2

cell monolayers, and consequently may also, as a dietary 
supplement, increase calcium absorption in vivo.(16) 
Linoleic acid has been shown to reduce skin irritation 
following acute perturbations, exhibiting clinical effects that 
are comparable to glucocorticoids.(17) 
A pre-emulsified linoleic acid system has been used to 
investigate the protective actions of phenolic compounds 
against lipid peroxidation.(18) 
Although not included in any pharmacopeias, a specification 
for linoleic acid is contained in the Food Chemicals Codex 
(FCC); see Table I. 
The EINECS number for linoleic acid is 200-470-9. 
Table I: FCC Specification for linoleic acid.(19) 
Test FCC 1996 
Identification . 
Acid value 196–202 
Heavy metals 410 mg/kg 
Iodine value 145–160 
Residue on ignition 40.01% 
Saponification value 194–202 
Unsaponifiable matter 42.0% 
Water 40.5% 
Assay 560% 
19 Specific References 
1 Gwak HS, Chun IK. Effect of vehicles and penetration enhancers 
on the in vitro percutaneous absorption of tenoxicam through 
hairless mouse skin. Int J Pharm 2002; 236(1–2): 57–64. 
2 Bhattachrya A, Ghosal SK. Effect of hydrophobic permeation 
enhancers on the release and skin permeation kinetics from matrix 
type transdermal drug delivery system of ketotifen fumarate. Acta 
Pol Pharm 2001; 58(2): 101–105. 
3 Gwack HS, Chun IK. Effect of vehicles and enhancers on the in 
vitro skin permeation of aspalatone and its enzymatic degradation 
across rat skins. Arch Pharm Res 2001; 24(6): 572–577. 
4 Shin SC, Shin EY, Chow CW. Enhancing effects of fatty acids on 
piroxicam permeation through rat skins. Drug Dev Ind Pharm 
2000; 26(5): 563–566. 
5 Meaney CM, O’Driscoll CM. Comparison of the permeation 
enhancement potential of simple bile salt and mixed bile salt: fatty 
acid micellar systems using the Caco-2 cell culture model. Int J 
Pharm 2000; 207(10): 21–30. 
6 Effect of hydrophobic permeation enhancers on the release and 
skin permeation kinetics from matrix type transdermal drug 
delivery system of ketotifen fumarate. Eastern Pharmacist 2000; 
43: 109–112. 
7 Tanojo H, Junginger HE. Skin permeation enhancement by fatty 
acids. J Dispers Sci Technol 1999; 20(1–2): 127–138. 
8 Bhatia KS, Singh J. Synergistic effect of iontophoresis and a series 
of fatty acids on LHRH permeability through porcine skin. J 
Pharm Sci 1998; 87: 462–469. 
9 Santoyo S, Arellano A, Ygartua P, Martin C. Penetration enhancer 
effects on the in vitro percutaneous absorption of piroxicam 
through rat skin. Int J Pharm 1995; 117(18): 219–224. 
10 Carelli V, Di Colo G, Nannipieri E, Serafini MF. Enhancement 
effects in the permeation of alprazolam through hairless mouse 
skin. Int J Pharm 1992; 88(8): 89–97. 
11 Ibrahim SA, Hafez E, El-Shanawany SM, et al. Formulation and 
evaluation of some topical antimycotics. Part 3. Effect of 
promotors on the in vitro and in vivo efficacy of clotrimazole 
ointment. Bull Pharm Sci Assiut Univ 1991; 14(1–2): 82–94. 
12 Swafford SK, Bergmann WR, Migliorese KG, et al. Characterization 
of swollen micelles containing linoleic acid in a microemulsion 
system. J Soc Cosmet Chem 1991; 42: 235–247. 
13 Mahjour M, Mauser BE, Fawzi MB. Skin permeation enhancement 
effects of linoleic acid and Azone on narcotic analgesics. Int J 
Pharm 1989; 56(1): 1–11. 
14 Gwak HS, Oh IS, Chun IK. Transdermal delivery of ondansetron 
hydrochloride: effects of vehicles and penetration enhancers. Drug 
Dev Ind Pharm 2004; 30(2): 187–194. 
15 Muranushi N, Nakajima Y, KinugawaM, et al. Mechanism for the 
inducement of the intestinal absorption of poorly absorbed drugs 
by mixed micelles. Part 2. Effect of the incorporation of various 
lipids on the permeability of liposomal membranes. Int J Pharm 
1980; 4: 281–290. 
16 Jewell C, Cashmen KD. The effect of conjugated linoleic acid and 
medium-chain fatty acids on transepithelial calcium transport in 
human intestine-like Caco-2 cells. Br J Nutr 2003; 89(5): 639–647. 
17 Schurer NY. Implementation of fatty acid carriers to skin irritation 
and the epidermal barrier. Contact Dermatitis 2002; 47(4): 199– 
205. 
18 Cheng Z, Ren J, Li Y, et al. Establishment of a quantitative 
structure–activity relationship model for evaluating and predicting 
the protective potentials of phenolic antioxidants on lipid 
peroxidation. J Pharm Sci 2003; 92(3): 475–484. 
19 Food Chemicals Codex, 4th edn. Washington, DC: National 
Academy Press, 1996: 227. 
20 General References 
—
21 Authors 
MS Tesconi. 
22 Date of Revision 
9 August 2005. 
Linoleic Acid 415

Macrogol 15 Hydroxystearate 
1 Nonproprietary Names 
BP: Macrogol 15 hydroxystearate 
PhEur: Macrogoli 15 hydroxystearas 
2 Synonyms 
12-Hydroxyoctadecanoic acid polymer with a-hydro-o-hydroxypoly(
oxy-1,2-ethanediyl); polyethylene glycol 660 
12-hydroxystearate; Solutol HS 15. 
3 Chemical Name and CAS Registry Number 
Polyethylene glycol-15-hydroxystearate [70142-34-6] 
4 Empirical Formula and Molecular Weight 
The PhEur 2005 describes macrogol 15 hydroxystearate as a 
mixture of mainly monoesters and diesters of 12-hydroxystearic 
acid and macrogols obtained by the ethoxylation of 12- 
hydroxystearic acid. The number of moles of ethylene oxide 
reacted per mole of 12-hydroxystearic acid is 15 (nominal 
value). It contains about 30% free macrogols. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Dissolution enhancer; nonionic surfactant; solubilizing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Macrogol 15 hydroxystearate is frequently used in preclinical 
testing of drugs, mainly for IV and other parenteral applications.(
1–4) The solubilizing capacity for some tested drugs 
(clotrimazole, carbamazepine, 17b-estradiol, sulfathiazole, and 
piroxicam) increases almost linearly with increasing concentration 
of solubilizing agent; see Figure 1. This is due to the 
formation of spherical micelles even at high concentrations of 
macrogol 15 hydroxystearate. Similarly, tests have revealed 
that viscosity increases with increasing amount of solubilizer, 
but the amount of solubilized drugs does not have any 
additional influence on the kinematic viscosity; see Figure 2. 
Lipid nanocapsules comprising macrogol 15 hydroxystearate 
and soybean phosphatidylcholine containing 3% docetaxel 
have been successfully prepared by a solvent-free inversion 
process. 
8 Description 
Macrogol 15 hydroxystearate is a yellowish-white waxy mass 
at room temperature, which becomes liquid at approximately 
308C. 
Figure 1: Solubilizing capacity of macrogol 15 hydroxystearate 
(Solutol HS 15, BASF Plc). 
^: Solutol HS 15 with clotrimazole 
&: Solutol HS 15 with 17b-estradiol 
~: Polysorbate 80 with clotrimazole 
~: Polysorbate 80 with 17b-estradiol 
Figure 2: Kinematic viscosity of macrogol 15 hydroxystearate 
(Solutol HS 15, BASF Plc). 
^: Solutol HS 15 
&: Solutol HS 15 with clotrimazole 
~: Polysorbate 80 
~: Polysorbate 80 with clotrimazole 
9 Pharmacopeial Specifications 
See Table I. 
10 Typical Properties 
Acidity/alkalinity: pH = 6–7 (10% w/v aqueous solution at 
208C) 
Critical micelle concentration: 0.005–0.02% 
Density: 1.03 g/cm3 
Flash point: 2728C 
HLB value: 14–16 
Ignition temperature: 3608C

Table I: Pharmacopeial specifications for macrogol 15 
hydroxystearate. 
Test PhEur 2005 
Identification . 
Characters . 
Solution appearance . 
Acid value 41.0 
Hydroxyl value 90–110 
Iodine value 42.0 
Peroxide value 45.0 
Saponification value 53–63 
Free macrogols 27.0–39.0% 
Ethylene oxide 41 ppm 
Dioxane 450 ppm 
Nickel 41 ppm 
Water 41% 
Total ash 40.3% 
Solidification temperature: 25–308C 
Solubility: soluble in ethanol, propan-2-ol, and water to form 
clear solutions. The solubility in water decreases with 
increasing temperature. It is insoluble in liquid paraffin. 
Viscosity (dynamic): 12 mPa s (12 cP) for a 30% w/v aqueous 
solution at 258C; 73 mPa s (73 cP) for a 30% w/v aqueous 
solution at 608C. 
11 Stability and Storage Conditions 
Macrogol 15 hydroxystearate has a high chemical stability. The 
prolonged action of heat may induce physical separation into a 
liquid and a solid phase after cooling, which can be reversed by 
subsequent homogenization. Macrogol 15 hydroxystearate is 
stable for at least 24 months if stored in unopened airtight 
containers at room temperature (maximum 258C). Aqueous 
solutions of macrogol 15 hydroxystearate can be heat-sterilized 
(1218C, 2.1 bar). The pH may drop slightly during heating, 
which should be taken into account. Separation into phases 
may also occur, but agitating the hot solution can reverse this. 
Aqueous solutions can be stabilized with the standard 
preservatives used in pharmaceuticals. 
12 Incompatibilities 
—
13 Method of Manufacture 
Macrogol 15 hydroxystearate is produced by reacting 15 moles 
of ethylene oxide with 1 mole of 12-hydroxystearic acid. 
14 Safety 
Macrogol 15 hydroxystearate is used in parenteral pharmaceutical 
preparations in concentrations up to 50% to solubilize 
diclofenac, propanidid, and vitamin K1. It has also been used in 
preclinical formulations in preparing supersaturated injectable 
formulations of water-insoluble molecules. It is generally 
regarded as a relatively nontoxic and nonirritant excipient. 
Macrogol 15 hydroxystearate is reported to not be 
mutagenic in bacteria, mammalian cell cultures and mammals. 
LD50 (rat, oral): >20 g/kg(5) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
—
17 Related Substances 
Polyethylene glycol. 
18 Comments 
Macrogol 15 hydroxystearate is not restricted solely to 
parenteral use, but is also suitable for oral applications. 
19 Specific References 
1 von Corswant C, Thoren P, Engstro.m S. Triglyceride-based 
microemulsion for intravenous administration of sparingly soluble 
substances. J Pharm Sci 1998; 87: 200–208. 
2 Buszello K, Harnisch S, Mu. ller RH, Mu. ller BW. The influence of 
alkali fatty acids on the properties and the stability of parenteral 
O/W emulsions modified with Solutol HS 15. Eur J Pharm 
Biopharm 2000; 49: 143–149. 
3 Bittner B, Mountfield RJ. Formulations and related activities for 
the oral administration of poorly water-soluble compounds in 
early discovery animal studies. Pharm Ind 2002; 64: 800. 
4 Strickley R. Solubilizing excipients in oral and injectable formulations. 
Pharm Res 2004; 21: 201–230. 
5 BASF. Solutol HS 15. http://www.pharma-solutions.basf.com/ 
(50jqle450ewrum55koxl2kmy)/products.aspx?GrpID=60 
(accessed 18 May 2005). 
20 General References 
Coon JS, Clodfeller K, Buckingham L, Bines S. Reversal of VP-16 
resistance by Solutol HS 15. Proc Am Assoc Cancer Res 1993; 34: 
323. 
Coon JS, Knudson W, Clodfelter K, et al. Solutol HS 15, nontoxic 
polyoxyethylene esters of 12-hydroxystearic acid, reverses multidrug 
resistance. Cancer Res 1991; 51(3): 897–902. 
Fro.mming K-H, Kraus C, Mehnert W. Physico-chemical properties of 
the mixed micellar system of Solutol HS 15 and sodium 
deoxycholate. Acta Pharm Technol 1990; 36: 214–220. 
LorenzW, Schmal A, Schult H, et al. Histamine release and hypotensive 
reactions in dogs by solubilizing agents and fatty acids: analysis of 
various components in Cremophor EL and development of a 
compound with reduced toxicity. Agents Actions 1982; 12: 64–80. 
Smith DB, Ewen C, Mackintosh J, et al. A phase I and pharmacokinetic 
study of amphethinile. Br J Cancer 1988; 57: 623–627. 
Woodburn K, Sykes E, Kessel D. Interactions of Solutol HS 15 and 
Cremophor EL with plasma lipoproteins. Int J Biochem Cell Biol 
1995; 27: 693–699. 
21 Authors 
J-P Mittwollen, T Schmeller. 
22 Date of Revision 
25 May 2005. 
Macrogol 15 Hydroxystearate 417

Magnesium Aluminum Silicate 
1 Nonproprietary Names 
BP: Aluminium magnesium silicate 
PhEur: Aluminii magnesii silicas 
USPNF: Magnesium aluminum silicate 
2 Synonyms 
Aluminosilicic acid, magnesium salt; aluminum magnesium 
silicate; Carrisorb; Gelsorb; Magnabite; magnesium aluminosilicate; 
magnesium aluminum silicate, colloidal; magnesium 
aluminum silicate, complex colloidal; Neusilin; Pharmsorb; 
silicic acid, aluminum magnesium salt; Veegum. 
3 Chemical Name and CAS Registry Number 
Aluminum magnesium silicate [12511-31-8] 
Magnesium aluminum silicate [1327-43-1] 
4 Empirical Formula and Molecular Weight 
Magnesium aluminum silicate is a polymeric complex of 
magnesium, aluminum, silicon, oxygen, and water. The average 
chemical analysis is conventionally expressed as oxides: 
Silicon dioxide 61.1% 
Magnesium oxide 13.7% 
Aluminum oxide 9.3% 
Titanium dioxide 0.1% 
Ferric oxide 0.9% 
Calcium oxide 2.7% 
Sodium oxide 2.9% 
Potassium oxide 0.3% 
Carbon dioxide 1.8% 
Water of combination 7.2% 
5 Structural Formula 
The complex is composed of a three-lattice layer of octahedral 
alumina and two tetrahedral silica sheets. The aluminum is 
substituted to varying degrees by magnesium (with sodium or 
potassium for balance of electrical charge). Additional elements 
present in small amounts include iron, lithium, titanium, 
calcium, and carbon. 
6 Functional Category 
Adsorbent; stabilizing agent; suspending agent; tablet and 
capsule disintegrant; tablet binder; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Magnesium aluminum silicate has been used for many years in 
the formulation of tablets, ointments, and creams. It is used in 
oral and topical formulations as a suspending and stabilizing 
agent either alone or in combination with other suspending 
agents.(1–3) The viscosity of aqueous dispersions may be greatly 
increased by combination with other suspending agents, such 
as xanthan gum, owing to synergistic effects, see Xanthan 
Gum. In tablets, magnesium aluminum silicate is used as a 
binder and disintegrant in conventional or slow-release 
formulations.(4,5) See Table I. 
Magnesium aluminum silicate may cause bioavailability 
problems with certain drugs, see Section 12. 
Table I: Uses of magnesium aluminum silicate. 
Use Concentration (%) 
Adsorbent 10–50 
Binding agent 2–10 
Disintegrating agent 2–10 
Emulsion stabilizer (oral) 1–5 
Emulsion stabilizer (topical) 2–5 
Suspending agent (oral) 0.5–2.5 
Suspending agent (topical) 1–10 
Stabilizing agent 0.5–2.5 
Viscosity modifier 2–10 
8 Description 
The USPNF 23 describes magnesium aluminum silicate as a 
blend of colloidal montmorillonite and saponite that has been 
processed to remove grit and nonswellable ore components. 
Four types of magnesium aluminum silicate are defined: types 
IA, IB, IC, and IIA. These types differ according to their 
viscosity and ratio of aluminum and magnesium content, see 
Table II. 
The PhEur 2005 describes magnesium aluminum silicate 
(aluminium magnesium silicate) as a mixture of particles with 
colloidal particle size of montmorillonite and saponite, free 
from grit and nonswellable ore. 
Magnesium aluminum silicate occurs as off-white to creamy 
white, odorless, tasteless, soft, slippery small flakes, or as a fine, 
micronized powder. Flakes vary in shape and size from about 
0.3  0.4mm to 1.0  2.0mm and about 25–240 mm thick. 
Many flakes are perforated by scattered circular holes 
20–120 mm in diameter. Under dark-field polarized light, 
innumerable bright specks are observed scattered over the 
flakes. The powder varies from 45 to 297 mm in size. 
Table II: Magnesium aluminum silicate types defined in the USPNF 
23. 
Type Viscosity 
(mPa s) 
Al content/ 
Mg content 
IA 225–600 0.5–1.2 
IB 150–450 0.5–1.2 
IC 800–2200 0.5–1.2 
IIA 100–300 1.4–2.8 
9 Pharmacopeial Specifications 
See Table III.

Table III: Pharmacopeial specifications for magnesium aluminum 
silicate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Viscosity (5% w/v suspension) — See Table II 
Microbial limits 4103/g 4103/g 
pH (5% w/v suspension) 9.0–10.0 9.0–10.0 
Acid demand — . 
Loss on drying 48.0% 48.0% 
Arsenic 43 ppm 43 ppm 
Lead 415 ppm 40.0015% 
Assay for Al and Mg content 95.0–105.0 . 
10 Typical Properties 
Acid demand: 6–8mL of 0.1N HCl is required to reduce the 
pH of 1 g to pH 4. 
Density: 2.418 g/cm3 
Moisture content: 6.0–9.98%.(6) See also Figures 1, 2 and 3.(6) 
Particle size distribution: see Section 8. 
Solubility: practically insoluble in alcohols, water, and organic 
solvents. 
Swelling capacity: swelling properties are reversible. Magnesium 
aluminum silicate swells to many times its original 
volume in water to form colloidal dispersions and may be 
dried and rehydrated any number of times. 
Viscosity (dynamic): dispersions in water at the 1–2% w/v level 
are thin colloidal suspensions. At 3% w/v and above, 
dispersions are opaque. As the concentration is increased 
above 3% w/v, the viscosity of aqueous dispersions increases 
rapidly; at 4–5% w/v, dispersions are thick, white colloidal 
sols, while at 10% w/v firm gels are formed. Dispersions are 
thixotropic at concentrations greater than 3% w/v. The 
viscosity of the suspension increases with heating or addition 
of electrolytes, and at higher concentrations with aging. 
Figure 1: Equilibrium moisture content of magnesium aluminum 
silicate (Veegum HV). 
Figure 2: Sorption–desorption isotherm of magnesium aluminum 
silicate (Pharmasorb). 
Figure 3: Sorption–desorption isotherm of magnesium aluminum 
silicate (Pharmasorb colloidal). 
11 Stability and Storage Conditions 
Magnesium aluminum silicate is stable indefinitely when stored 
under dry conditions. It is stable over a wide pH range, has 
base-exchange capacity, absorbs some organic substances, and 
is compatible with organic solvents. 
Magnesium aluminum silicate should be stored in a wellclosed 
container, in a cool, dry place. 
Magnesium Aluminum Silicate 419

SEM: 1 
Excipient: magnesium aluminum silicate (Veegum) 
Manufacturer: RT Vanderbilt Co., Inc. 
Lot No.: 61A-1 
Magnification: 600 Voltage: 10 kV 
SEM: 2 
Excipient: magnesium aluminum silicate (Veegum) 
Manufacturer: RT Vanderbilt Co., Inc. 
Lot No.: 61A-1 
Magnification: 2400 Voltage: 10 kV 
SEM: 3 
Excipient: magnesium aluminum silicate (Veegum F) 
Manufacturer: RT Vanderbilt Co., Inc. 
Lot No: 61A-2 
Magnification: 600 Voltage: 10 kV 
SEM: 4 
Excipient: magnesium aluminum silicate (Veegum F) 
Manufacturer: RT Vanderbilt Co., Inc. 
Lot No.: 61A-2 
Magnification: 2400 Voltage: 10 kV 
420 Magnesium Aluminum Silicate

12 Incompatibilities 
Owing to its inert nature, magnesium aluminum silicate has few 
incompatibilities but is generally unsuitable for acidic solutions 
below pH 3.5. Magnesium aluminum silicate, as with other 
clays, may adsorb some drugs.(7,8) This can result in low 
bioavailability if the drug is tightly bound or slowly desorbed, 
e.g., amfetamine sulfate,(4) tolbutamide,(9) warfarin sodium,(10) 
and diazepam.(11) 
13 Method of Manufacture 
Magnesium aluminum silicate is obtained from silicate ores of 
the montmorillonite group, which show high magnesium 
content. The ore is blended with water to form a slurry to 
remove impurities and separate out the colloidal fraction. The 
refined colloidal dispersion is drum-dried to form a small flake, 
which is then micro-atomized to form various powder grades. 
14 Safety 
Magnesium aluminum silicate is generally regarded as nontoxic 
and nonirritating at the levels employed as a pharmaceutical 
excipient. Subacute animal feeding studies in rats and dogs fed 
magnesium aluminum silicate at 10% of the diet, for 90 days, 
were negative, including autopsy and histopathological examinations.(
12) 
LD50 (rat, oral): > 16 g/kg(13) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. Adequate ventilation should be provided and 
dust generation minimized. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral granules, 
solutions, suspensions and tablets; rectal; and topical preparations; 
vaginal preparations). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Attapulgite; bentonite; kaolin; magnesium silicate; magnesium 
trisilicate; montmorillonite; saponite; talc. 
Montmorillonite 
Empirical formula: Al2O54SiO24H2O 
CAS number: [1318-93-0] 
Comments: a naturally occurring silicate clay. 
18 Comments 
The EINECS number for magnesium aluminum silicate is 215- 
478-8. 
19 Specific References 
1 Polon JA. The mechanisms of thickening by inorganic agents. J Soc 
Cosmet Chem 1970; 21: 347–363. 
2 Farley CA, Lund W. Suspending agents for extemporaneous 
dispensing: evaluation of alternatives to tragacanth. Pharm J 
1976; 216: 562–566. 
3 Attama AA, Chuku AJ, Muko KN, Adikwu MU. Effect of Veegum 
on the suspending properties of Mucuna gum. Boll Chem Farm 
1997; 136: 549–553. 
4 McGinity JW, Lach JL. Sustained-release applications of montmorillonite 
interaction with amphetamine sulfate. J Pharm Sci 
1977; 66: 63–66. 
5 McGinity JW, Harris MR. Optimization of slow-release tablet 
formulations containing montmorillonite I: properties of tablets. 
Drug Dev Ind Pharm 1980; 6: 399–410. 
6 Grab FL, Johnson JH, Monaco AL, Winfield AJ. Magnesium 
aluminum silicate. In: Handbook of Pharmaceutical Excipients. 
Washington, DC and London: American Pharmaceutical Association 
and The Pharmaceutical Society of Great Britain, 1986: 166– 
169. 
7 McGinity JW, Lach JL. In vitro adsorption of various pharmaceuticals 
to montmorillonite. J Pharm Sci 1976; 65: 896–902. 
8 McGinity JW, Harris MR. Increasing dissolution rates of poorlysoluble 
drugs by adsorption to montmorillonite. Drug Dev Ind 
Pharm 1980; 6: 35–48. 
9 Varley AB. The generic inequivalence of drugs. J Am Med Assoc 
1968; 206: 1745–1748. 
10 Wagner JG, Welling PG, Lee KP, Walker JE. In vivo and in vitro 
availability of commercial warfarin tablets. J Pharm Sci 1971; 60: 
666–677. 
11 Munzel K. The desorption of medicinal substances from adsorbents 
in oral pharmaceutical suspensions. Acta Pharmacol Toxicol 
1971; 29 (Suppl. 3): 81–87. 
12 Sakai K, Moriguchi K. Effect of magnesium aluminosilicate 
administered to pregnant mice on pre- and postnatal development 
of offsprings. Oyo Yakri 1975; 9: 703. 
13 Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. 
Cincinnati: US Department of Health, 1987. 
20 General References 
RT Vanderbilt Co., Inc. Technical literature: Veegum, the versatile 
ingredient for pharmaceutical formulations, 1992. 
Wai K, DeKay HG, Banker GS. Applications of the montmorillonites in 
tablet making. J Pharm Sci 1966; 55: 1244–1248. 
Yokoi H, Enomoto S, Takahashi H. Effect of magnesium aluminosilicate 
on fluidity of pharmaceutical powders [in Japanese]. J Pharm 
Soc Jpn 1978; 98: 418–425. 
21 Authors 
A Palmieri. 
22 Date of Revision 
8 August 2005. 
Magnesium Aluminum Silicate 421

Magnesium Carbonate 
1 Nonproprietary Names 
BP: Heavy magnesium carbonate 
Light magnesium carbonate 
JP: Magnesium carbonate 
PhEur: Magnesii subcarbonas ponderosus 
Magnesii subcarbonas levis 
USP: Magnesium carbonate 
2 Synonyms 
Carbonic acid, magnesium salt (1:1); carbonate magnesium; 
hydromagnesite; E504. See Sections 4 and 17. 
3 Chemical Name and CAS Registry Number 
Magnesium carbonate anhydrous [546-93-0] 
See also Sections 4 and 17. 
4 Empirical Formula and Molecular Weight 
Magnesium carbonate is not a homogeneous material but may 
consist of the normal hydrate, the basic hydrate, and the 
anhydrous material MgCO3, which is rarely encountered. Basic 
magnesium carbonate is probably the most common form, and 
may vary in formula between light magnesium carbonate, 
(MgCO3)3Mg(OH)23H2O, and magnesium carbonate hydroxide, 
(MgCO3)4Mg(OH)25H2O. Normal magnesium carbonate 
is a hydrous magnesium carbonate with a varying amount 
of water, MgCO3xH2O. 
See also Sections 8, 13 and 17. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Adsorbent; antacid; tablet and capsule diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
As an excipient, magnesium carbonate is mainly used as a 
directly compressible tablet diluent in concentrations up to 
45% w/w. Heavy magnesium carbonate produces tablets with 
high crushing strength, low friability, and good disintegration 
properties.(1–4) However, magnesium carbonate can have 
varying effects on dissolution and stability.(5,6) See also Section 
12. Magnesium carbonate has been incorporated in microsphere 
formulations for the purpose of stabilizing encapsulated 
proteins.(7) Magnesium carbonate is also used to absorb 
liquids, such as flavors, in tableting processes. 
Magnesium carbonate is additionally used as a food additive 
and therapeutically as an antacid. 
See Table I. 
Table I: Uses of magnesium carbonate. 
Use Concentration (%) 
Absorbent of liquid, in tableting 0.5–1.0 
Tablet excipient (direct compression) 445 
8 Description 
Magnesium carbonate occurs as light, white-colored friable 
masses or as a bulky, white-colored powder. It has a slightly 
earthy taste and is odorless but, since it has a high absorptive 
ability, magnesium carbonate can absorb odors. 
The USP 28 describes magnesium carbonate as either a basic 
hydrated magnesium carbonate or a normal hydrated magnesium 
carbonate. However, the PhEur 2005 describes 
magnesium carbonate as being a hydrated basic magnesium 
carbonate in two separate monographs: heavy magnesium 
carbonate and light magnesium carbonate. The molecular 
formulas for heavy magnesium carbonate and light magnesium 
carbonate vary, but heavy magnesium carbonate may generally 
be regarded as the tetrahydrate [(MgCO3)3Mg(OH)24H2O], 
while light magnesium carbonate may be regarded as the 
trihydrate [(MgCO3)3Mg(OH)23H2O]. 
The molecular weights of the heavy and light forms of 
magnesium carbonate are 383.32 and 365.30, respectively. 
SEM: 1 
Excipient: Magnesium carbonate USP 
Manufacturer: Mallinckrodt Chemicals Co. 
Lot No.: KJGJ 
Magnification: 60 Voltage: 20 kV

SEM: 2 
Excipient: Magnesium carbonate USP 
Manufacturer: Mallinckrodt Chemicals Co. 
Lot No.: KJGJ 
Magnification: 600 Voltage: 20 kV 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for magnesium carbonate. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters — . — 
Microbial limits — — . 
Color of solution — . — 
Soluble salts 410.0mg 41.0% 41.0% 
Acid-insoluble 
substances 
42.5mg 40.05% 40.05% 
Arsenic 45 ppm 42 ppm 44 ppm 
Calcium 40.6% 40.75% 40.45% 
Heavy metals 430 ppm 420 ppm 40.003% 
Iron 4200 ppm 4400 ppm 40.02% 
Chloride — 40.07% — 
Assay (as MgO) 40.044.0% 40.0–45.0% 40.0–43.5% 
Note that except where indicated all of the PhEur 2005 test limits apply to both the heavy and 
light forms of magnesium carbonate. 
10 Typical Properties 
Angle of repose: 
42–508 for granular heavy magnesium carbonate; 
56–608 for spray-dried heavy magnesium carbonate.(3) 
Density (bulk): 
Heavy magnesium carbonate: 0.207–0.56 g/cm3;(8) 
Light magnesium carbonate: 0.12 g/cm3. 
Density (tapped): 
Heavy magnesium carbonate: 0.314–0.783 g/cm3;(8) 
Light magnesium carbonate: 0.21 g/cm3. 
Density (true): Heavy magnesium carbonate: 
1.966–2.261 g/cm3(8) 
Moisture content: at relative humidities between 15% and 65% 
the equilibrium moisture content of heavy magnesium 
carbonate at 258C is about 1% w/w; at relative humidities 
above 75% the equilibrium moisture content at 258C is 
about 5% w/w.(3) 
Particle size distribution: 
Heavy magnesium carbonate: 7–43 mm median particle 
size(8) 
Light magnesium carbonate: 99.95% through a 44.5 mm 
(#350 mesh) sieve for light magnesium carbonate. 
Solubility: practically insoluble in water but soluble in water 
containing carbon dioxide. Insoluble in ethanol (95%) and 
other solvents. Magnesium carbonate dissolves and effervesces 
on contact with dilute acids. 
Specific surface area: 
7.8–18.2m2/g for granular heavy magnesium carbonate; 
4.4–15.5m2/g for spray-dried heavy magnesium carbonate;(
3) 
14.64–14.78m2/g for basic heavy magnesium carbonate. 
11 Stability and Storage Conditions 
Magnesium carbonate is stable in dry air and on exposure to 
light. The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Incompatible with phenobarbital sodium,(4,9) diazepam solution 
at a pH 55,(10) some binary powder mixtures,(11) 
lansoprazole,(5) and formaldehyde.(12) Acids will dissolve 
magnesium carbonate, with the liberation of carbon dioxide. 
Slight alkalinity is imparted to water. Magnesium carbonate 
was also found to increase the dissolution of acetazolamide 
formulations at a pH of 1.12; however, dissolution was 
retarded at a pH of 7.4.(6) 
13 Method of Manufacture 
Depending upon the manufacturing process used, the composition 
of the magnesium carbonate obtained may vary from 
normal hydrated magnesium carbonate to basic hydrated 
magnesium carbonate. 
Light magnesium carbonate may be manufactured by 
saturating an aqueous suspension of dolomite, CaMg(CO3)2, 
with carbon dioxide under pressure. On increase of the 
temperature, calcium carbonate precipitates almost entirely. 
The filtered solution is then heated to boiling; the magnesium 
bicarbonate in the solution loses carbon dioxide and water, and 
light magnesium carbonate precipitates. 
Heavy magnesium carbonate may be manufactured by 
mixing a hot concentrated solution of magnesium chloride or 
magnesium sulfate with a solution of sodium carbonate. The 
heavy magnesium carbonate may be either precipitated to 
produce a granular material or spray-dried. Varying the 
temperature of the reaction solutions produces heavy magnesium 
carbonate with differing physical properties: e.g., material 
with a higher specific surface area is produced at a lower 
reaction temperature. Low processing temperature provided 
the largest surface area, which produced optimum granules or 
spray-dried powder.(3) If dilute magnesium chloride or magnesium 
sulfate solutions are used for the reaction, a less dense 
material is produced. 
Magnesium Carbonate 423

Magnesium carbonates in varying states of hydration are 
also found as minerals in nature. 
14 Safety 
Magnesium carbonate is used as an excipient in oral soliddosage 
pharmaceutical formulations and is generally regarded 
as an essentially nontoxic and nonirritant material. However, 
the use of magnesium salts, such as magnesium carbonate, is 
contraindicated in patients with renal impairment. In addition, 
the probable oral lethal dose in humans has been estimated at 
0.5–5.0 g/kg body weight.(12) 
On contact with gastric acid, magnesium carbonate reacts in 
the stomach to form soluble magnesium chloride and carbon 
dioxide. Magnesium carbonate should therefore not be used as 
an antacid by those individuals whose stomachs cannot tolerate 
the evolution of carbon dioxide. Some magnesium is absorbed 
but is usually excreted in the urine. As with other magnesium 
salts, magnesium carbonate has a laxative effect and may cause 
diarrhea. 
Therapeutically, the usual dose of magnesium carbonate as 
an antacid is 250–500 mg, and 2.0–5.0 g as a laxative. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Magnesium carbonate may 
be irritant to the eyes; eye protection is recommended. OSHA 
standards state that IPA 8-hour time weighted airborne average 
is 10 mg/m3.(12) 
16 Regulatory Acceptance 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (oral capsules and tablets). 
Included in nonparenteral medicines licensed in the UK. 
17 Related Substances 
Magnesium carbonate anhydrous; magnesium carbonate 
hydroxide; normal magnesium carbonate. 
Magnesium carbonate anhydrous 
Empirical formula: MgCO3 
Molecular weight: 84.31 
CAS number: [546-93-0] 
Synonyms: carbonic acid, magnesium salt anhydrous (1 : 1); 
E504; magnesite. 
Appearance: odorless, white-colored bulky powder or light, 
friable masses. 
Melting point: decomposes at 3508C. 
Magnesium carbonate hydroxide 
Empirical formula: (MgCO3)4Mg(OH)25H2O 
Molecular weight: 485.65 
CAS number: [39409-82-0] 
Synonyms: carbonic acid, magnesium salt (1 : 1), mixture with 
magnesium hydroxide and magnesium hydrate; dypingite; 
E504. 
Appearance: odorless, white-colored bulky powder or light, 
friable masses. 
Melting point: on heating at 7008C it is converted into 
magnesium oxide. 
Specific gravity: 1.45 
Comments: the EINECS number for magnesium carbonate 
hydroxide is 235-192-7. 
Normal magnesium carbonate 
Empirical formula: MgCO3xH2O 
CAS number: [23389-33-5] 
Synonyms: carbonic acid, magnesium salt (1 : 1), hydrate; 
magnesium carbonate, normal hydrate; E504. 
Appearance: odorless, white-colored bulky powder or light, 
friable masses. 
18 Comments 
Magnesium carbonate has been found to increase the dissolution 
of acetazolamide formulations at a pH of 1.12; however, 
dissolution was retarded at a pH of 7.4.(6) Magnesium 
carbonate has also been shown to alter the pharmacokinetics 
of halofantrine, increasing the time to reach maximum plasma 
concentration and reducing maximum plasma concentrations.(
13) Because drug interactions can occur with a variety 
of antacids,(14) the potential for these effects should be 
considered when designing pharmaceutical formulations containing 
magnesium carbonate. 
A specification for magnesium carbonate is contained in the 
Food Chemicals Codex (FCC). The EINECS number for 
magnesium carbonate is 208-915-9. 
19 Specific References 
1 Haines-Nutt RF. The compression properties of magnesium and 
calcium carbonates. J Pharm Pharmacol 1976; 28: 468–470. 
2 Armstrong NA, Cham T-M. Changes in the particle size and size 
distribution during compaction of two pharmaceutical powders 
with dissimilar consolidation mechanisms. Drug Dev Ind Pharm 
1986; 12: 2043–2059. 
3 Cham T-M. The effect of the specific surface area of heavy 
magnesium carbonate on its tableting properties. Drug Dev Ind 
Pharm 1987; 13(9–11): 1989–2015. 
4 Peterson CL, Perry DL, Masood H, et al. Characterization of 
antacid compounds containing both aluminum and magnesium. II: 
Codried powders. Pharm Res 1993; 10(7): 1005–1007. 
5 Tabata T, Makino T, Kikuta J, et al. Manufacturing method of 
stable enteric granules of a new antiulcer drug (lansoprazole). 
Drug Dev Ind Pharm 1994; 20(9): 1661–1672. 
6 Hashim F, El-Din EZ. Effect of some excipients on the dissolution 
of phenytoin and acetazolamide from capsule formulations. Acta 
Pharm Fenn 1989; 98: 197–204. 
7 Sandor M, Riechel A, Kaplan I, Mathiowitz E. Effect of lecithin 
and MgCO3 as additives on the enzymatic activity of carbonic 
anhydrase encapsulated in poly(lactide-co-glycolide) (PLGA) 
microspheres. Biochimica et Biophysica Acta 2002; 1570(1): 63– 
74. 
8 Freitag F, Kleinebudde P. How do roll compaction / dry 
granulation affect the tabletting behaviour of inorganic materials? 
Comparison of four magnesiumcarbonates. Eur J Pharm Sci 2003; 
19: 281–289. 
9 Nagavi BG, Mithal BM, Marwadi PR, Dutta R. Solid phase 
interaction of phenobarbitone sodium with some adjuvants. 
Indian J Pharm Sci 1983; 45(Jul-Aug): 175–177. 
10 Jain GK, Kakkar AP. Interaction study of diazepam with excipients 
in liquid and solid state. Indian Drugs 1992; 29(July): 545–546. 
11 Jain GK, Kakkar AP. Interaction study of diazepam with excipients 
in binary powder form. Indian Drugs 1992; 29(July): 453–454. 
12 Hazardous Substances Data Bank (2005). Magnesium carbonate, 
http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB (accessed 7 
June 2005). 
424 Magnesium Carbonate

13 Aideloje SO, Onyeji CO, Ugwu NC. Altered pharmacokinetics of 
halofantrine by an antacid, magnesium carbonate. Eur J Pharm 
Biopharm 1998; 46(3): 299–303. 
14 Sadowski DC. Drug interactions with antacids: mechanisms and 
clinical significance. Drug Safety 1994; 11(6): 395–407. 
20 General References 
Freitag F, Kleinebudde P. How do roll compaction / dry granulation 
affect the tableting behaviour of inorganic materials? Microhardness 
of ribbons and mercury porosimetry measurements of tablets. 
Eur J Pharm Sci 2004; 22: 325–333. 
Jaiyeoba KT, Spring MS. The granulation of ternary mixtures: the effect 
of solubility of the excipients. J Pharm Pharmacol 1980; 32: 1–5. 
Khaled KA. Formulation and evaluation of hydrochlorothiazide 
liquisolid tablets. Saudi Pharm J 1998; 6(Jan): 39–46. 
Law MFL, Deasy PB. Effect of common classes of excipients on 
extrusion-spheronization. J Microencapsul 1997; 14(May): 647– 
657. 
21 Authors 
BF Truitt. 
22 Date of Revision 
7 June 2005. 
Magnesium Carbonate 425

Magnesium Oxide 
1 Nonproprietary Names 
BP: Heavy magnesium oxide and Light magnesium oxide 
JP: Magnesium oxide 
PhEur: Magnesii oxidum ponderosum (Magnesium oxide, 
heavy) and Magnesii oxidum leve (Magnesium oxide, light) 
USP: Magnesium oxide 
See Section 8. 
2 Synonyms 
Calcined magnesia; calcinated magnesite; Destab; E530; 
Magcal; Magchem 100; Maglite; magnesia; magnesia monoxide; 
magnesia usta; Magnyox; Marmag; Oxymag; periclase. 
3 Chemical Name and CAS Registry Number 
Magnesium oxide [1309-48-4] 
4 Empirical Formula and Molecular Weight 
MgO 40.30 
5 Structural Formula 
MgO 
6 Functional Category 
Anticaking agent; emulsifying agent; glidant; tablet and capsule 
diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Magnesium oxide is used as an alkaline diluent in solid-dosage 
forms to modify the pH of tablets.(1) It can be added to soliddosage 
forms to bind excess water and keep the granulation 
dry. In combination with silica, magnesium oxide can be used 
as an auxiliary glidant.(2) It is also used as a food additive and 
as an antacid, either alone or in conjunction with aluminum 
hydroxide. Magnesium oxide is additionally used as an osmotic 
laxative and a magnesium supplement to treat deficiency states. 
8 Description 
Two forms of magnesium oxide exist: a bulky form termed light 
magnesium oxide and a dense form termed heavy magnesium 
oxide. The USP 28 defines both forms in a single monograph, 
while other pharmacopeias have separate monographs for each 
form. For the heavy variety, 5 g occupies a volume of about 
10–20 mL; for the light variety, 5 g occupies a volume of about 
40–50mL as defined by the USP 28. 
Both forms of magnesium oxide occur as fine, white, 
odorless powders. They possess a cubic crystal structure. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for magnesium oxide. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Loss on ignition 410.0% 48.0% 410.0% 
Color of solution — . — 
Free alkali and soluble salts . — 42.0% 
Soluble substances — 42.0% — 
Acid-insoluble substances 40.1% 40.1% 40.1% 
Arsenic 410 ppm 44 ppm — 
Calcium — 41.5% 41.1% 
Calcium oxide . — — 
Carbonate . — — 
Heavy metals 440 ppm 430 ppm 420 mg/g 
Iron 4500 ppm . 40.05% 
Heavy magnesium oxide — 40.07% — 
Light magnesium oxide — 40.1% — 
Chloride — . — 
Heavy magnesium oxide — 40.1% — 
Light magnesium oxide — 40.15% — 
Fluoride 40.08% — — 
Sulfate — 41.0% — 
Assay 596.0% 98.0– 
100.5% 
96.0– 
100.5% 
10 Typical Properties 
Acidity/alkalinity: pH = 10.3 (saturated aqueous solution) 
Boiling point: 36008C 
Melting point: 28008C 
Particle size distribution: 99.98% less than 45 mm in size (light 
magnesium oxide). 
Refractive index: 1.735 
Solubility: soluble in dilute acids and ammonium salt solutions; 
very slightly soluble in pure water (solubility is increased by 
carbon dioxide); practically insoluble in ethanol (95%). 
Specific gravity: 3.581 g/cm3 at 258C 
11 Stability and Storage Conditions 
Magnesium oxide is stable at normal temperatures and 
pressures. However, it forms magnesium hydroxide in the 
presence of water. Magnesium oxide is hygroscopic and rapidly 
absorbs water and carbon dioxide on exposure to the air, the 
light form more readily than the heavy form. 
The bulk material should be stored in an airtight container 
in a cool, dry place. 
12 Incompatibilities 
Magnesium oxide is a basic compound and as such can react 
with acidic compounds in the solid state to form salts such as 
Mg(ibuprofen)2 or degrade alkaline-labile drugs.(3) Adsorption 
of various drugs onto magnesium oxide has been reported, such 
as antihistamines,(4) antibiotics (especially tetracyclines),(5) 
salicylates,(6) atropine sulfate,(7) hyoscyamine hydrobromide,(7) 
paracetamol, chloroquine,(8) and anthranilic acid derivatives 
have been reported to adsorb onto the surface of magnesium

oxide.(9) Magnesium oxide can also complex with polymers, 
e.g. Eudragit RS, to retard drug release(10–12) and can interact 
in the solid state with phenobarbitone sodium.(13) Magnesium 
oxide can also reduce the bioavailability of phenytoin,(14) 
trichlormethiazide,(15) and anti-arrhythmics.(16) The presence 
of magnesium oxide can also have a negative impact on the 
solid-state chemical stability of drugs, such as diazepam.(17) 
13 Method of Manufacture 
Magnesium oxide occurs naturally as the mineral periclase. It 
can be manufactured by many processes. Limestone containing 
the mineral dolomite is calcinated at high temperatures to 
produce dolime, which then reacts with magnesium chloriderich 
sea water to produce magnesium hydroxide and calcium 
chloride.(18) The magnesium hydroxide is then calcinated to 
produce magnesium oxide and water. In another process, 
mined magnesite (MgCO3) is calcinated to produce magnesium 
oxide and carbon dioxide.(18) Purification methods include 
crushing and size separation, heavy-media separation, and 
froth flotation. Producing magnesium oxide from sea water is a 
process that involves heating magnesium chloride concentrated 
brine from the Dead Sea. The magnesium chloride decomposes 
into magnesium oxide and hydrochloric acid.(18) Magnesium 
oxide may also be produced by the thermal decomposition of 
magnesium chloride, magnesium sulfate, magnesium sulfite, 
nesquehonite, and the basic carbonate 5MgO4CO25H2O. 
Purification of the magnesium oxide produced through thermal 
degradation is carried out by filtration or sedimentation. 
14 Safety 
Magnesium oxide is widely used in oral formulations as an 
excipient and as a therapeutic agent. Therapeutically, 
250–500mg is administered orally as an antacid and 2–5 g as 
an osmotic laxative. Magnesium oxide is generally regarded as 
a nontoxic material when employed as an excipient, although 
adverse effects, due to its laxative action, may occur if high 
doses are ingested orally. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Magnesium oxide may be 
harmful if inhaled, ingested, or absorbed through the skin in 
quantity and is irritating to the eyes and respiratory system. 
Gloves, eye protection, and a dust mask or respirator are 
recommended. In the US and UK, the long-term (8-hour TWA) 
occupational exposure limits for magnesium oxide, calculated 
as magnesium, are 10 mg/m3 for total dust and 4 mg/m3 for 
respirable dust.(18,19) The short-term (15-minute) limit for 
respirable dust is 10 mg/m3.(18,19) 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral capsules 
and tablets). Included in nonparenteral medicines licensed in 
the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
— 
18 Comments 
A specification for magnesium oxide is contained in the Food 
Chemicals Codex (FCC). The EINECS number for magnesium 
oxide is 215-171-9. 
19 Specific References 
1 Patel H, Stalcup A, Dansereau R, Sakr A. The effect of excipients 
on the stability of levothroxine sodium pentahydrate tablets. Int J 
Pharm 2003; 264: 35–43. 
2 Kirk RE, Othmer DF. Encyclopedia of Chemical Technology, 4th 
edn, vol 1. New York: Wiley, 1995: 107. 
3 Tugrul TK, Needham TE, Seul CJ, Finnegan PM. Solid-state 
interaction of magnesium oxide and ibuprofen to form a salt. 
Pharm Res 1989; 6(9): 804–808. 
4 Nada AH, Etman MA, Ebian AR. In vitro adsorption of 
mepyramine maleate onto some adsorbents and antacids. Int J 
Pharm 1989; 53: 175–179. 
5 Khalil SA, Daabis NA, Naggar VF, Motawi MM. The in vitro 
adsorption of some antibiotics on antacids. Pharmazie 1976; 31: 
105–109. 
6 Naggar VF, Khalil SA, Daabis NA. The in-vitro adsorption of some 
antirheumatics on antacids. Pharmazie 1976; 31: 461–465. 
7 Singh A, Mital H. Adsorption of atropine sulfate and hyoscyamine 
hydrobromide by various antacids. Acta Pharm Technol 1979; 
25(3): 217–224. 
8 Iwuagwu MA, Aloko KS. Adsorption of paracetamol and 
chloroquine phosphate by some antacids. J Pharm Pharmacol 
1992; 44: 655–658. 
9 Monkhouse DC, Lach JL. Drug–Excipient Interactions. Can J 
Pharm Sci 1972; 7: 29–46. 
10 Shanghavi NM, Bijlani CP, Kamath PR, Sarwade VB. Matrix 
tablets of salbutamol sulfate. Drug Dev Ind Pharm 1990; 16: 
1955–1961. 
11 Racz I, Antal I, Plachy J. Formulation of controlled release drug 
preparations with antacid effect. Pharmazie 1996; 51(May); 323– 
327. 
12 Racz I, Zelko R, Bihari E, Bucsek M. Effect of eudragit type 
polymers on the drug release from magnesium oxide granules 
produced by laboratory fluidization. Drug Dev Ind Pharm 1995; 
21(18): 2085–2096. 
13 Nagavi BG, Mithal BM, Marwade PR, Dutta R. Solid phase 
interaction of phenobarbitone sodium with some adjuvants. 
Indian J Pharm Sci 1983; 45(Jul–Aug): 175–177. 
14 D’Arcy PF, McElnay JC. Drug–antacid interactions: assessment of 
clinical importance. Drug Intell Clin Pharm 1987; 21: 607–617. 
15 Takahashi H, Watanabe Y, Shimamura H, Sugito K. Effect of 
magnesium oxide on trichlormethiazide bioavailability. J Pharm 
Sci 1985; 74: 862–865. 
16 Remon JP, Belpaire F, Van-Severen R, Braeckman P. Interaction of 
antacids with anti-arrhythmics. Part 5. Effect of aluminum 
hydroxide and magnesium oxide on the bioavailability of 
quinidine, procainamide, and propranolol in dogs. Arzneimittel 
Forschung 1983; 33(1): 117–120. 
17 Jain G, Kakkar A. Interaction of diazepam with excipients in 
binary powder form. Indian Drugs 1992; 29(Jul): 453–454. 
18 Kirk RE, Othmer DF. Encyclopedia of Chemical Technology, 4th 
edn., vol. 15. New York: Wiley, 1995: 703–707 
19 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
—
21 Authors 
JT Colvin. 
22 Date of Revision 
26 April 2005. 
Magnesium Oxide 427

Magnesium Silicate 
1 Nonproprietary Names 
JP: Magnesium silicate 
USPNF: Magnesium silicate 
2 Synonyms 
E553a; synthetic magnesium silicate. 
3 Chemical Name and CAS Registry Number 
Silicic acid, magnesium salt [1343-88-0] 
4 Empirical Formula and Molecular Weight 
MgOSiO2xH2O 
See also Sections 5 and 17. 
5 Structural Formula 
Magnesium silicate is a compound of magnesium oxide and 
silicon dioxide. See also Section 17. 
The JP 2001 states that magnesium silicate contains not less 
than 45.0% of silicon dioxide (SiO2: molecular weight 60.08) 
and not less than 20.0% of magnesium oxide (MgO: 40.30), 
and the ratio of percentage (%) of magnesium oxide to silicon 
dioxide is not less than 2.2 and not more than 2.5. 
The USPNF 23 describes magnesium silicate as a compound 
of magnesium oxide (MgO) and silicon dioxide (SiO2) that 
contains not less than 15.0% of MgO and not less than 67.0% 
of SiO2 calculated on the ignited basis. 
6 Functional Category 
Anticaking agent; glidant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Magnesium silicate is used in oral pharmaceutical formulations 
and food products as a glidant and an anticaking agent. 
8 Description 
Magnesium silicate occurs as an odorless and tasteless, fine, 
white-colored powder that is free from grittiness. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for magnesium silicate. 
Test JP 2001 USPNF 23 
Identification . . 
pH (10% aqueous suspension) — 7.0–10.8 
Loss on drying — 415% 
Soluble salts 40.02 g 43.0% 
Chloride 40.053% — 
Free alkali . . 
Heavy metals 430 ppm 420 mg/g 
Arsenic 45 ppm — 
Sulfate 40.48% — 
Organic volatile impurities — . 
Loss on ignition 434% 415% 
Fluoride — 410 ppm 
Lead — 40.001% 
Acid-consuming capacity . — 
Ratio of SiO2 to MgO 2.2–2.5 2.5–4.5 
Assay for MgO 520.0% 515% 
Assay for SiO2 545.0% 567% 
10 Typical Properties 
Moisture content: magnesium silicate is slightly hygroscopic. 
Solubility: practically insoluble in ethanol (95%), ether, and 
water. 
11 Stability and Storage Conditions 
Magnesium silicate should be stored in a well-closed container 
in a cool, dry place. 
12 Incompatibilities 
Magnesium silicate may decrease the oral bioavailability of 
drugs such as mebeverine hydrochloride,(1) sucralfate, and 
tetracycline, via chelation or binding, when they are taken 
together. The dissolution rate of folic acid,(2) erythromycin 
stearate,(3) paracetamol,(4) and chloroquine phosphate,(4) may 
be retarded by adsorption onto magnesium silicate. Antimicrobial 
preservatives, such as parabens, may be inactivated 
by the addition of magnesium silicate.(5) 
Magnesium silicate is readily decomposed by mineral acids. 
13 Method of Manufacture 
Magnesium silicate may be prepared from sodium silicate and 
magnesium sulfate. The silicate also occurs in nature as the 
minerals meerschaum, parasepiolite, and sepiolite. 
14 Safety 
Magnesium silicate is used in oral pharmaceutical formulations 
and is generally regarded as an essentially nontoxic and 
nonirritant material. 
Orally administered magnesium silicate is neutralized in the 
stomach to form magnesium chloride and silicon dioxide; some

magnesium is absorbed. Caution should be used when greater 
than 50 mEq of magnesium is given daily to persons with 
impaired renal function, owing to the risk of hypermagnesemia. 
Reported adverse effects include the formation of bladder 
and renal calculi following the regular use, for many years, of 
magnesium silicate as an antacid.(6,7) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection is recommended. 
16 Regulatory Acceptance 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral tablets). 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Magnesium aluminum silicate; magnesium metasilicate; magnesium 
orthosilicate; magnesium trisilicate; talc. 
Magnesium metasilicate 
Comments: magnesium metasilicate (MgSiO3) occurs in nature 
as the minerals clinoenstatite, enstatite, and protoenstatite. 
Magnesium orthosilicate 
Comments: magnesium orthosilicate (Mg2SiO4) occurs in 
nature as the mineral forsterite. 
18 Comments 
A specification for magnesium silicate is contained in the Food 
Chemicals Codex (FCC). The EINECS number for magnesium 
silicate is 215-681-1. 
19 Specific References 
1 Al-Gohary OMN. An in vitro study of the interaction between 
mebeverine hydrochloride and magnesium trisilicate powder. Int J 
Pharm 1991; 67: 89–95. 
2 Iwuagwu MA, Jideonwo A. Preliminary investigations into the invitro 
interaction of folic acid with magnesium trisilicate and edible 
clay. Int J Pharm 1990; 65: 63–67. 
3 Arayne MS, Sultana N. Erythromycin–antacid interaction. Pharmazie 
1993; 48: 599–602. 
4 Iwuagwu MA, Aloko KS. Adsorption of paracetamol and 
chloroquine phosphate by some antacids. J Pharm Pharmacol 
1992; 44: 655–658. 
5 Allwood MC. The adsorption of esters of p-hydroxybenzoic acid 
by magnesium trisilicate. Int J Pharm 1982; 11: 101–107. 
6 Joekes AM, Rose GA, Sutor J. Multiple renal silica calculi. Br Med 
J 1973; 1: 146–147. 
7 Levison DA, Crocker PR, Banim S, Wallace DMA. Silica stones in 
the urinary bladder. Lancet 1982; i: 704–705. 
20 General References 
Anonymous. The silicates: attapulgite, kaolin, kieselguhr, magnesium 
trisilicate, pumice, talc. Int J Pharmaceut Compound 1998; 2(2): 
162–163. 
21 Authors 
A Palmieri. 
22 Date of Revision 
8 August 2005. 
Magnesium Silicate 429

Magnesium Stearate 
1 Nonproprietary Names 
BP: Magnesium stearate 
JP: Magnesium stearate 
PhEur: Magnesii stearas 
USPNF: Magnesium stearate 
2 Synonyms 
Magnesium octadecanoate; octadecanoic acid, magnesium salt; 
stearic acid, magnesium salt. 
3 Chemical Name and CAS Registry Number 
Octadecanoic acid magnesium salt [557-04-0] 
4 Empirical Formula and Molecular Weight 
C36H70MgO4 591.34 
The USPNF 23 describes magnesium stearate as a compound 
of magnesium with a mixture of solid organic acids that 
consists chiefly of variable proportions of magnesium stearate 
and magnesium palmitate (C32H62MgO4). The PhEur 2005 
describes magnesium stearate as a mixture of magnesium salts 
of different fatty acids consisting mainly of stearic acid and 
palmitic acid and in minor proportions other fatty acids. 
5 Structural Formula 
[CH3(CH2)16COO]2Mg 
6 Functional Category 
Tablet and capsule lubricant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Magnesium stearate is widely used in cosmetics, foods, and 
pharmaceutical formulations. It is primarily used as a lubricant 
in capsule and tablet manufacture at concentrations between 
0.25% and 5.0% w/w. It is also used in barrier creams. See also 
Section 18. 
8 Description 
Magnesium stearate is a very fine, light white, precipitated or 
milled, impalpable powder of low bulk density, having a faint 
odor of stearic acid and a characteristic taste. The powder is 
greasy to the touch and readily adheres to the skin. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for magnesium stearate. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters — . — 
Microbial limits . . . 
Aerobic microbes 41000/g 4103/g 4103/g 
Fungi and yeasts 4500/g — 4500/g 
Acidity or alkalinity . . . 
Acid value of the fatty acid — 195–210 — 
Freezing point — 5538C — 
Nickel — 45 ppm — 
Cadmium — 43 ppm — 
Specific surface area — — . 
Loss on drying 46.0% 46.0% 46.0% 
Chloride 40.1% 40.1% 40.1% 
Sulfate 41.0% 40.5% 41.0% 
Lead — 410 ppm 40.001% 
Heavy metals 420 ppm — — 
Relative stearic/palmitic 
content 
. . . 
Organic volatile impurities — — . 
Assay (dried, as Mg) 4.0–5.0% 4.0–5.0% 4.0–5.0% 
10 Typical Properties 
Crystalline forms: high-purity magnesium stearate has been 
isolated as a trihydrate, a dihydrate, and an anhydrate. 
Density (bulk): 0.159 g/cm3 
Density (tapped): 0.286 g/cm3 
Density (true): 1.092 g/cm3 
Flash point: 2508C 
Flowability: poorly flowing, cohesive powder. 
Melting range: 
117–1508C (commercial samples); 
126–1308C (high purity magnesium stearate). 
Solubility: practically insoluble in ethanol, ethanol (95%), ether 
and water; slightly soluble in warm benzene and warm 
ethanol (95%). 
Specific surface area: 1.6–14.8m2/g 
11 Stability and Storage Conditions 
Magnesium stearate is stable and should be stored in a wellclosed 
container in a cool, dry place. 
12 Incompatibilities 
Incompatible with strong acids, alkalis, and iron salts. Avoid 
mixing with strong oxidizing materials. Magnesium stearate 
cannot be used in products containing aspirin, some vitamins, 
and most alkaloidal salts.

SEM: 1 
Excipient: Magnesium stearate 
Magnification: 600 
SEM: 2 
Excipient: Magnesium stearate 
Magnification: 2400 
13 Method of Manufacture 
Magnesium stearate is prepared either by the interaction of 
aqueous solutions of magnesium chloride with sodium stearate 
or by the interaction of magnesium oxide, hydroxide, or 
carbonate with stearic acid at elevated temperatures. 
14 Safety 
Magnesium stearate is widely used as a pharmaceutical 
excipient and is generally regarded as being nontoxic following 
oral administration. However, oral consumption of large 
quantities may produce a laxative effect or mucosal irritation. 
No toxicity information is available relating to normal 
routes of occupational exposure. Limits for heavy metals in 
magnesium stearate have been evaluated in terms of magnesium 
stearate worst-case daily intake and heavy metal 
composition.(1) 
Toxicity assessments of magnesium stearate in rats have 
indicated that it is not irritating to the skin, and is nontoxic 
when administered orally or inhaled.(2,3) 
Magnesium stearate has not been shown to be carcinogenic 
when implanted into the bladder of mice.(4) 
LD50 (rat, inhalation): >2 mg/L(2) 
LD50 (rat, oral): >10 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. Excessive inhalation of magnesium stearate dust 
may cause upper respiratory tract discomfort, coughing, and 
choking. Magnesium stearate should be handled in a wellventilated 
environment; a respirator is recommended. 
16 Regulatory Acceptance 
GRAS listed. Accepted as a food additive in the UK. Included in 
the FDA Inactive Ingredients Guide (oral capsules, powders, 
and tablets; buccal and vaginal tablets; topical preparations). 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Calcium stearate; magnesium aluminum silicate; stearic acid; 
zinc stearate. 
18 Comments 
Magnesium stearate is hydrophobic and may retard the 
dissolution of a drug from a solid dosage form; the lowest 
possible concentration is therefore used in such formulations.(
5–10) Capsule dissolution is also sensitive to both the 
amount of magnesium stearate in the formulation and the 
mixing time; higher levels of magnesium stearate and long 
mixing times can result in the formation of hydrophobic 
powder beds that do not disperse after the capsule shell 
dissolves.(11,12) 
An increase in the coefficient of variation of mixing and a 
decrease in the dissolution rate have been observed following 
blending of magnesium stearate with a tablet granulation. 
Tablet dissolution rate and crushing strength decreased as the 
time of blending increased; and magnesium stearate may also 
increase tablet friability. Blending times with magnesium 
stearate should therefore be carefully controlled.(13–29) 
The existence of various crystalline forms of magnesium 
stearate has been established.(30–34) A trihydrate, a dihydrate, 
and an anhydrate have been isolated,(5,32,33,35) and an 
amorphous form has been observed.(36) While the hydrate 
forms are stable in the presence of moisture, the anhydrous 
form adsorbs moisture at relative humidity up to 50%, and at 
higher humidities rehydrates to form the trihydrate. The 
anhydrate can be formed by drying either of the hydrates at 
1058C.(33) 
Magnesium Stearate 431

It has not been conclusively established which form of pure 
magnesium stearate possesses the best lubricating properties.(
31,32,36,37) Commercial lots of magnesium stearate generally 
consist of mixtures of crystalline forms.(32,34,36–40) 
Because of the possibility of conversion of crystalline forms 
during heating, consideration should be given to the pretreatment 
conditions employed when determining physical properties 
of magnesium stearate powders such as surface area.(41) 
Physical properties of magnesium stearate can vary among 
batches from different manufacturers(40) because the solid-state 
characteristics of the powder are influenced by manufacturing 
variables.(31) Variations in the physical properties of different 
lots of magnesium stearate from the same vendor have also 
been observed.(40) Presumably because of these variations, it 
has not been possible to conclusively correlate the dissolution 
rate retardation with observed lubricity.(42) 
However, various physical properties of different batches 
of magnesium stearate such as specific surface area, particle 
size, crystalline structure, moisture content, and fatty acid 
composition have been correlated with lubricant efficacy.(
32,36,39,40,43–47) Due to variations in the specific surface 
area, the USPNF 23 labeling states that specific surface area and 
the method specified for its determination should be listed on 
the label. Reduction in dissolution caused by the effects of 
magnesium stearate in some cases can be overcome by 
including a highly swelling disintegrant in the formulation.(48) 
There is evidence to suggest that the hydrophobic nature of 
magnesium stearate can vary from batch to batch owing to the 
presence of water-soluble, surface-active impurities such as 
sodium stearate. Batches containing very low concentrations of 
these impurities have been shown to retard the dissolution of a 
drug to a greater extent than when using batches that contain 
higher levels of impurities.(42) One study related lubricity to the 
fatty acid composition (stearate : palmitate) of lubricant lots for 
tablet formulations based on compaction data and tablet 
material properties.(47) However, other studies have indicated 
that fatty acid composition has no influence on lubricant 
activity(32) and high-purity magnesium stearate was as effective 
a lubricant as the commercial material.(10) Moisture sorption at 
different relative humidities can result in morphological 
changes in the magnesium stearate.(49,50) 
A specification for magnesium stearate is included in the 
Food Chemicals Codex (FCC). The EINECS number for 
magnesium stearate is 209-150-3. 
19 Specific References 
1 Chowhan ZT. Harmonization of excipient standards. In: Weiner 
ML, Kotkoskie LA, eds. Excipient Toxicity and Safety. New York: 
Marcel Dekker, 2000: 321–354. 
2 Anonymous. Final report of the safety assessment of lithium 
stearate, aluminum distearate, aluminum stearate, aluminum 
tristearate, ammonium stearate, calcium stearate, magnesium 
stearate, potassium stearate, sodium stearate, and zinc stearate. 
J Am Coll Toxicol 1982; 1: 143–177. 
3 Sondergaard D, Meyer O, Wurtzen G. Magnesium stearate given 
perorally to rats: a short term study. Toxicology 1980; 17: 51–55. 
4 Boyland E, Busby ER, Dukes CE, et al. Further experiments on 
implantation of materials into the urinary bladder of mice. Br J 
Cancer 1964; 18: 575–581. 
5 Levy G, Gumtow RH. Effect of certain formulation factors on 
dissolution rate of the active ingredient III: tablet lubricants. 
J Pharm Sci 1963; 52: 1139–1144. 
6 Ganderton D. The effect of distribution of magnesium stearate on 
the penetration of a tablet by water. J Pharm Pharmacol 1969; 21 
(Suppl.): 9S–18S. 
7 Caldwell HC. Dissolution of lithium and magnesium from lithium 
carbonate capsules containing magnesium stearate. J Pharm Sci 
1974; 63: 770–773. 
8 Chowhan ZT, Amaro AA, Chow YP. Tablet-to-tablet dissolution 
variability and its relationship to the homogeneity of a watersoluble 
drug. Drug Dev Ind Pharm 1982; 8: 145–168. 
9 Lerk CF, Bolhuis GK, Smallenbroek AJ, Zuurman K. Interaction of 
tablet disintegrants and magnesium stearate during mixing II: 
effect on dissolution rate. Pharm Acta Helv 1982; 57: 282–286. 
10 Hussain MSH, York P, Timmins P. Effect of commercial and high 
purity magnesium stearates on in-vitro dissolution of paracetamol 
DC tablets. Int J Pharm 1992; 78: 203–207. 
11 Samyn JC, Jung WY. In vitro dissolution from several experimental 
capsule formulations. J Pharm Sci 1970; 59: 169–175. 
12 Murthy KS, Samyn JC. Effect of shear mixing on in vitro drug 
release of capsule formulations containing lubricants. J Pharm Sci 
1977; 66: 1215–1219. 
13 Ragnarsson G, Holzer AW, Sjogren J. The influence of mixing time 
and colloidal silica on the lubricating properties of magnesium 
stearate. Int J Pharm 1979; 3: 127–131. 
14 Bolhuis GK, Lerk CF, Broersma P. Mixing action and evaluation of 
tablet lubricants in direct compression. Drug Dev Ind Pharm 
1980; 6: 573–589. 
15 Bossert J, Stamm A. Effect of mixing on the lubrication of 
crystalline lactose by magnesium stearate. Drug Dev Ind Pharm 
1980; 6: 573–589. 
16 Bolhuis GK, Smallenbroek AJ, Lerk CF. Interaction of tablet 
disintegrants and magnesium stearate during mixing I: effect on 
tablet disintegration. J Pharm Sci 1981; 70: 1328–1330. 
17 Sheikh-Salem M, Fell JT. The influence of magnesium stearate on 
time dependent strength changes in tablets. Drug Dev Ind Pharm 
1981; 7: 669–674. 
18 Stewart PJ. Influence of magnesium stearate on the homogeneity of 
a prednisone granule ordered mix. Drug Dev Ind Pharm 1981; 7: 
485–495. 
19 Jarosz PJ, Parrott EL. Effect of tablet lubricants on axial and radial 
work of failure. Drug Dev Ind Pharm 1982; 8: 445–453. 
20 Mitrevej KT, Augsburger LL. Adhesion of tablets in a rotary tablet 
press II: effects of blending time, running time, and lubricant 
concentration. Drug Dev Ind Pharm 1982; 8: 237–282. 
21 Khan KA, Musikabhumma P, Rubinstein MH. The effect of 
mixing time of magnesium stearate on the tableting properties of 
dried microcrystalline cellulose. Pharm Acta Helv 1983; 58: 109– 
111. 
22 Johansson ME. Investigations of the mixing time dependence of 
the lubricating properties of granular and powdered magnesium 
stearate. Acta Pharm Suec 1985; 22: 343–350. 
23 Johansson ME. Influence of the granulation technique and starting 
material properties on the lubricating effect of granular magnesium 
stearate. J Pharm Pharmacol 1985; 37: 681–685. 
24 Chowhan ZT, Chi LH. Drug–excipient interactions resulting from 
powder mixing III: solid state properties and their effect on drug 
dissolution. J Pharm Sci 1986; 75: 534–541. 
25 Chowhan ZT, Chi LH. Drug–excipient interactions resulting from 
powder mixing IV: role of lubricants and their effect on in vitro 
dissolution. J Pharm Sci 1986; 75: 542–545. 
26 Johansson ME, Nicklasson M. Influence of mixing time, particle 
size and colloidal silica on the surface coverage and lubrication of 
magnesium stearate. In: Rubinstein MH, ed. Pharmaceutical 
Technology: Tableting Technology. Chichester: Ellis Horwood, 
1987: 43–50. 
27 Wang LH, Chowhan ZT. Drug–excipient interactions resulting 
from powder mixing V: role of sodium lauryl sulfate. Int J Pharm 
1990; 60: 61–78. 
28 Muzikova J, Horacek J. The dry binders, Vivapur 102, Vivapur 12 
and the effect of magnesium stearate on the strength of tablets 
containing these substances. Ceske Slov Farm 2003; 52(4): 176– 
180. 
29 Muzikova J. Effect of magnesium stearate on the tensile strength of 
tablets made with the binder Prosolv SMCC 90. Ceska Slow Farm 
2002; 51(1): 41–43. 
30 Muller BW. The pseudo-polymorphism of magnesium stearate. 
Zbl Pharm 1977; 116(12): 1261–1266. 
432 Magnesium Stearate

31 Miller TA, York P. Physical and chemical characteristics of some 
high purity magnesium stearate and palmitate powders. Int J 
Pharm 1985; 23: 55–67. 
32 Ertel KD, Carstensen JT. Chemical, physical, and lubricant 
properties of magnesium stearate. J Pharm Sci 1988; 77: 625–629. 
33 Ertel KD, Carstensen JT. An examination of the physical properties 
of pure magnesium stearate. Int J Pharm 1988; 42: 171–180. 
34 Wada Y, Matsubara T. Pseudo-polymorphism and crystalline 
transition of magnesium stearate. Thermochim Acta 1992; 196: 
63–84. 
35 Sharpe SA, Celik M, Newman AW, Brittain HG. Physical 
characterization of the polymorphic variations of magensium 
stearate and magnesium palmitate hydrate species. Struct Chem 
1997; 8(1): 73–84. 
36 Leinonen UI, Jalonen HU, Vihervaara PA, Laine ESU. Physical and 
lubrication properties of magnesium stearate. J Pharm Sci 1992; 
81(12): 1194–1198. 
37 Muller BW. Polymorphism of magnesium stearate and the 
influence of the crystal structure on the lubricating behavior of 
excipients. Acta Pharm Suec 1981; 18: 74–75. 
38 Brittain HG. Raw materials. Drug Dev Ind Pharm 1989; 15(13): 
2083–2103. 
39 Dansereau R, Peck GE. The effect of the variability in the physical 
and chemical properties of magnesium stearate on the properties of 
compressed tablets. Drug Dev Ind Pharm 1987; 13: 975–999. 
40 Barra J, Somma R. Influence of the physicochemical variability of 
magnesium stearate on its lubricant properties: possible solutions. 
Drug Dev Ind Pharm 1996; 22(11): 1105–1120. 
41 Phadke DS, Collier JL. Effect of degassing temperature on the 
specific surface area and other physical properties of magnesium 
stearate. Drug Dev Ind Pharm 1994; 20(5): 853–858. 
42 Billany MR, Richards JH. Batch variation of magnesium stearate 
and its effect on the dissolution rate of salicylic acid from solid 
dosage forms. Drug Dev Ind Pharm 1982; 8: 497–511. 
43 Frattini C, Simioni L. Should magnesium stearate be assessed in the 
formulation of solid dosage forms by weight or by surface area? 
Drug Dev Ind Pharm 1984; 10: 1117–1130. 
44 Bos CE, Vromans H, Lerck CF. Lubricant sensitivity in relation to 
bulk density for granulations based on starch or cellulose. Int J 
Pharm 1991; 67: 39–49. 
45 Phadke DS, Eichorst JL. Evaluation of particle size distribution and 
specific surface area of magnesium stearate. Drug Dev Ind Pharm 
1991; 17: 901–906. 
46 Steffens KJ, Koglin J. The magnesium stearate problem. Manuf 
Chem 1993; 64(12): 16, 17, 19. 
47 Marwaha SB, Rubinstein MH. Structure-lubricity evaluation of 
magnesium stearate. Int J Pharm 1988; 43(3): 249–255. 
48 Desai DS, Rubitski BA, Varia SA, Newman AW. Physical 
interactions of magnesium stearate with starch-derived disintegrants 
and their effects on capsule and tablet dissolution. Int J 
Pharm 1993; 91(2–3): 217–226. 
49 Swaminathan V, Kildisig DO. An examination of the moisture 
sorption characteristics of commercial magnesium stearate. AAPS 
PharSciTech 2001; 2(4): 28. 
50 Bracconi P, Andres C, Ndiaye A. Structural properties of 
magnesium stearate pseudopolymorphs: effect of temperature. 
Int J Pharm 2003; 262 (1–2): 109–124. 
20 General References 
Bohidar NR, Restaino FA, Schwartz JB. Selecting key pharmaceutical 
formulation factors by regression analysis. Drug Dev Ind Pharm 
1979; 5: 175–216. 
Butcher AE, Jones TM. Some physical characteristics of magnesium 
stearate. J Pharm Pharmacol 1972; 24: 1P–9P. 
Ford JL, Rubinstein MH. An investigation into some pharmaceutical 
interactions by differential scanning calorimetry. Drug Dev Ind 
Pharm 1981; 7: 675–682. 
Johansson ME. Granular magnesium stearate as a lubricant in tablet 
formulations. Int J Pharm 1984; 21: 307–315. 
Jones TM. The effect of glidant addition on the flowability of bulk 
particulate solids. J Soc Cosmet Chem 1970; 21: 483–500. 
Pilpel N. Metal stearates in pharmaceuticals and cosmetics. Manuf 
Chem Aerosol News 1971; 42(10): 37–40. 
York P. Tablet lubricants. In: Florence AT, ed. Materials Used in 
Pharmaceutical Formulation. London: Society of Chemical Industry 
1984: 37–70. 
Zanowiak P. Lubrication in solid dosage form design and manufacture. 
In: Swarbick J, Boylan JC, eds. Encyclopedia of Pharmaceutical 
Technology, vol. 9. New York: Marcel Dekker, 1990: 87–112. 
21 Authors 
LV Allen, PE Luner. 
22 Date of Revision 
9 August 2005. 
Magnesium Stearate 433

Magnesium Trisilicate 
1 Nonproprietary Names 
BP: Magnesium trisilicate 
PhEur: Magnesii trisilicas 
USP: Magnesium trisilicate 
2 Synonyms 
E553(a); magnesium mesotrisilicate; silicic acid, magnesium 
salt (1 : 2), hydrate. 
3 Chemical Name and CAS Registry Number 
Magnesium trisilicate [14987-04-3] 
4 Empirical Formula and Molecular Weight 
Mg2Si3O8xH2O 260.86 (anhydrous) 
5 Structural Formula 
2MgO3SiO2xH2O 
6 Functional Category 
Anticaking agent; glidant; therapeutic agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Magnesium trisilicate is used in oral pharmaceutical formulations 
and food products as a glidant. It is also used 
therapeutically as an antacid, and also for the treatment of 
ciprofloxacin overdose or toxicity.(1) 
8 Description 
The USP 28 describes magnesium trisilicate as a compound of 
magnesium oxide and silicon dioxide with varying proportions 
of water. It contains not less than 20% of magnesium oxide and 
not less than 45% of silicon dioxide. The PhEur 2005 similarly 
describes magnesium trisilicate as having a variable composition 
corresponding to the approximate formula 
Mg2Si3O8xH2O. It contains not less than 29% of magnesium 
oxide and not less than the equivalent of 65% of silicon 
dioxide, both calculated with reference to the ignited substance. 
Magnesium trisilicate occurs as an odorless and tasteless, 
fine, white-colored powder that is free from grittiness. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for magnesium trisilicate. 
Test PhEur 2005 USP 28 
Identification . . 
Ratio of SiO2 to MgO — 2.10–2.37 
Loss on ignition 17.0–34.0% 17.0–34.0% 
Water-soluble salts 41.5% 41.5% 
Chloride 4500 ppm 40.055% 
Sulfates 40.5% 40.5% 
Alkalinity . . 
Arsenic 44 ppm 48 ppm 
Heavy metals 440 ppm 40.003% 
Acid-absorbing capacity 4100.0 mL 140–160 mL 
Assay of MgO 529.0%(a) 520.0% 
Assay of SiO2 565.0%(a) 545.0% 
(a) With reference to the ignited substance. 
10 Typical Properties 
Moisture content: magnesium trisilicate is slightly hygroscopic. 
At relative humidities of 15–65%, the equilibrium moisture 
content at 258C is 17–23% w/w; at relative humidities of 
75–95%, the equilibrium moisture content is 24–30% w/w. 
Solubility: practically insoluble in diethyl ether, ethanol (95%) 
and water. 
11 Stability and Storage Conditions 
Magnesium trisilicate is stable if stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Magnesium trisilicate, when taken with drugs such as 
mebeverine hydrochloride,(2) proguanil,(3) norfloxacin,(4) 
sucralfate, and tetracycline, may cause a reduction in bioavailability 
via binding or chelation. The dissolution rate of folic 
acid,(5) erythromycin stearate,(6) paracetamol, and chloroquine 
phosphate(7) may be retarded by adsorption onto magnesium 
trisilicate. Antimicrobial preservatives, such as the parabens, 
may be inactivated by the addition of magnesium trisilicate.(8) 
Magnesium trisilicate is also readily decomposed by mineral 
acids. 
13 Method of Manufacture 
Magnesium trisilicate may be prepared from sodium silicate 
and magnesium sulfate. It also occurs in nature as the minerals 
meerschaum, parasepiolite, and sepiolite. 
14 Safety 
Magnesium trisilicate is used in oral pharmaceutical formulations 
and is generally regarded as an essentially nontoxic and 
nonirritant material. 
When administered orally, magnesium trisilicate is neutralized 
in the stomach to form magnesium chloride and silicon

dioxide; some magnesium may be absorbed. Caution should be 
used when concentrations greater than 50 mEq of magnesium 
are given daily to persons with impaired renal function, owing 
to the risk of hypermagnesemia. 
Therapeutically, up to about 2 g of magnesium trisilicate 
may be taken daily as an antacid. 
Reported adverse effects include the potential for osmotic 
diarrhea in the elderly using antacids containing magnesium 
trisilicate;(9) and the potential for the formation of bladder and 
renal calculi following the long-term use of magnesium 
trisilicate as an antacid.(10,11) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection is recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral tablets). 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Calcium silicate; magnesium aluminum silicate; magnesium 
silicate; magnesium trisilicate anhydrous; talc. 
Calcium silicate 
Appearance: white to off-white-colored, free-flowing powder 
that remains free-flowing after absorbing relatively large 
amounts of water or other liquids. 
Solubility: practically insoluble in water. Forms a gel with 
mineral acids. 
Handling precautions: in the UK, the long-term (8-hour TWA) 
occupational exposure standards for calcium silicate are 
10 mg/m3 for total inhalable dust and 4 mg/m3 for respirable 
dust.(12) 
Comments: many different forms of calcium silicate are known 
such as CaSiO3, Ca2SiO4, and Ca3SiO5. Usually these occur 
in the hydrated form and contain varying amounts of water 
of crystallization. Calcium silicate is used in pharmaceutical 
formulations as a glidant and anticaking agent.(13) Also used 
in food products (GRAS listed). The EINECS number for 
calcium silicate is 215-710-8. 
Magnesium trisilicate anhydrous 
Empirical formula: Mg2Si3O8 
Molecular weight: 260.86 
CAS number: [14987-04-3] 
18 Comments 
Magnesium trisilicate is regarded as a type of magnesium 
silicate. The EU food additive code E553(a) has been applied to 
both. The EINECS number for magnesium trisilicate is 239- 
076-7. 
19 Specific References 
1 Ofoefule SI, Okonta M. Adsorption studies of ciprofloxacin: 
evaluation of magnesium trisilicate, kaolin and starch as alternatives 
for the management of ciprofloxacin poisoning. Boll Chim 
Farm 1999; 138: 239–242. 
2 Al-Gohary OMN. An in vitro study of the interaction between 
mebeverine hydrochloride and magnesium trisilicate powder. Int J 
Pharm 1991; 67: 89–95. 
3 Onyeji CO, Babalola CP. The effect of magnesium trisilicate on 
proguanil absorption. Int J Pharm 1993; 100: 249–252. 
4 Okhamafe AO, Akerele JO, Chukuka CS. Pharmacokinetic 
interactions of norfloxacin with some metallic medicinal agents. 
Int J Pharm 1991; 68: 11–18. 
5 Iwuagwu MA, Jideonwo A. Preliminary investigations into the invitro 
interaction of folic acid with magnesium trisilicate and edible 
clay. Int J Pharm 1990; 65: 63–67. 
6 Arayne MS, Sultana N. Erythromycin–antacid interaction. Pharmazie 
1993; 48: 599–602. 
7 Iwuagwu MA, Aloko KS. Adsorption of paracetamol and 
chloroquine phosphate by some antacids. J Pharm Pharmacol 
1992; 44(8): 655–658. 
8 Allwood MC. The adsorption of esters of p-hydroxybenzoic acid 
by magnesium trisilicate. Int J Pharm 1982; 11: 101–107. 
9 Ratnaike RN, Jones TE. Mechanisms of drug-induced diarrhoea in 
the elderly. Drugs & Aging 1998; 13: 245–253. 
10 Joekes AM, Rose GA, Sutor J. Multiple renal silica calculi. Br Med 
J 1973; 1: 146–147. 
11 Levison DA, Crocker PR, Banim S, Wallace DMA. Silica stones in 
the urinary bladder. Lancet 1982; I: 704–705. 
12 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
13 Asano T, Tsubuku S, Sugawara S, et al. Changes in volume and 
compression energy upon compression of calcium silicate tablets. 
Drug Dev Ind Pharm 1997; 23: 679–685. 
20 General References 
Anonymous. The silicates: attapulgite, kaolin, kieselguhr, magnesium 
trisilicate, pumice, talc. Int J Pharm Compound 1998; 2(2): 162– 
163. 
21 Authors 
AS Kearney. 
22 Date of Revision 
19 August 2005. 
Magnesium Trisilicate 435

Malic Acid 
1 Nonproprietary Names 
PhEur: Acidum malicum 
USPNF: Malic acid 
2 Synonyms 
Apple acid; E296; 2-hydroxy-1,4-butanedioic acid; hydroxybutanedioic 
acid; 1-hydroxy-1,2-ethanedicarboxylic acid; 
hydroxysuccinic acid; 2-hydroxysuccinic acid; DL-malic acid. 
3 Chemical Name and CAS Registry Number 
Hydroxybutanedioic acid [6915-15-7] 
(RS)-(
)-Hydroxybutanedioic acid [617-48-1] 
4 Empirical Formula and Molecular Weight 
C4H6O5 134.09 
5 Structural Formula 
6 Functional Category 
Acidulant; antioxidant; chelating and buffering agent; flavoring 
agent; therapeutic agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Malic acid is used in pharmaceutical formulations as a generalpurpose 
acidulant. It possesses a slight apple flavor and is used 
as a flavoring agent to mask bitter tastes and provide tartness. 
Malic acid is also used as an alternative to citric acid in 
effervescent powders, mouthwashes, and tooth-cleaning 
tablets. 
In addition, malic acid has chelating and antioxidant 
properties. It may be used with butylated hydroxytoluene as a 
synergist in order to retard oxidation in vegetable oils. In food 
products it may be used in concentrations up to 420 ppm. 
Therapeutically, malic acid has been used topically in 
combination with benzoic acid and salicylic acid to treat burns, 
ulcers, and wounds. It has also been used orally and 
parenterally, either intravenously or intramuscularly, in the 
treatment of liver disorders, and as a sialagogue.(1) 
8 Description 
White or nearly white, crystalline powder or granules having a 
slight odor and a strongly acidic taste. It is hygroscopic. The 
synthetic material produced commercially in Europe and the 
USA is a racemic mixture, whereas the naturally occurring 
material found in apples and many other fruits and plants is 
levorotatory. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for malic acid. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Residue on ignition 40.1% 40.1% 
Appearance of solution . — 
Water-insoluble substances 40.1% 40.1% 
Heavy metals 420 ppm 40.002% 
Fumaric acid — 40.1% 
Maleic acid — 40.05% 
Optical rotation –0.18 to .0.18 — 
Organic volatile impurities — . 
Related substances . — 
Water 42.0% — 
Assay 99.0–101.0% 99.0–100.5% 
10 Typical Properties 
Data shown below are for the racemate. See Section 17 for 
other data for the D- and L- forms. 
Acidity/alkalinity: pH = 2.35 (1% w/v aqueous solution at 
258C) 
Boiling point: 1508C (with decomposition) 
Density (bulk): 0.81 g/cm3 
Density (tapped): 0.92 g/cm3 
Dissociation constant: 
pKa1 = 3.40 at 258C; 
pKa2 = 5.05 at 258C. 
Melting point: 131–1328C 
Solubility: freely soluble in ethanol (95%) and water but 
practically insoluble in benzene. A saturated aqueous 
solution contains about 56% malic acid at 208C. See Table 
II. 
Table II: Solubility of malic acid. 
Solvent Solubility at 208C 
Acetone 1 in 5.6 
Diethyl ether 1 in 119 
Ethanol (95%) 1 in 2.6 
Methanol 1 in 1.2 
Propylene glycol 1 in 1.9 
Water 1 in 1.5–2.0 
Specific gravity: 
1.601 at 208C; 
1.250 (saturated aqueous solution at 258C).

Viscosity (dynamic): 6.5 mPa s (6.5 cP) for a 50% w/v aqueous 
solution at 258C. 
11 Stability and Storage Conditions 
Malic acid is stable at temperatures up to 1508C. At 
temperatures above 1508C it begins to lose water very slowly 
to yield fumaric acid; complete decomposition occurs at about 
1808C to give fumaric acid and maleic anhydride. 
Malic acid is readily degraded by many aerobic and 
anaerobic microorganisms. Conditions of high humidity and 
elevated temperatures should be avoided to prevent caking. 
The effects of grinding and humidity on malic acid have also 
been investigated.(2) 
The bulk material should be stored in a well-closed 
container, in a cool, dry place. 
12 Incompatibilities 
Malic acid can react with oxidizing materials. Aqueous 
solutions are mildly corrosive to carbon steels. 
13 Method of Manufacture 
Malic acid is manufactured by hydrating maleic and fumaric 
acids in the presence of suitable catalysts. The malic acid 
formed is then separated from the equilibrium product mixture. 
14 Safety 
Malic acid is used in oral, topical, and parenteral pharmaceutical 
formulations in addition to food products, and is generally 
regarded as a relatively nontoxic and nonirritant material. 
However, concentrated solutions may be irritant. 
LD50 (rat, oral): 1.6 g/kg(3) 
LD50 (rat, IP): 0.1 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Malic acid, and concentrated 
malic acid solutions may be irritant to the skin, eyes, and 
mucous membranes. Gloves and eye protection are recommended. 
16 Regulatory Status 
GRAS listed. Both the racemic mixture and the levorotatory 
isomer are accepted as food additives in Europe. The DL- and Lforms 
are included in the FDA Inactive Ingredients Guide (oral 
preparations). Included in nonparenteral and parenteral 
medicines licensed in the UK. Included in the Canadian List 
of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Citric acid; fumaric acid; D-Malic acid; -Malic acid; tartaric 
acid. 
D-Malic acid 
Empirical formula: C4H6O5 
Molecular weight: 134.09 
CAS number: [636-61-3] 
Synonyms: (R)-(.)-hydroxybutanedioic acid; D-(.)-malic acid. 
Melting point: 99–1018C 
Specific rotation [a]D
20: .5.28 (in acetone at 188C). 
L-Malic acid 
Empirical formula: C4H6O5 
Molecular weight: 134.09 
CAS number: [97-67-6] 
Synonyms: apple acid; (S)-(–)-hydroxybutanedioic acid; L-(–)- 
malic acid. 
Boiling point: 1408C (with decomposition) 
Melting point: 99–1008C 
Solubility: practically insoluble in benzene. See also Table III. 
Table III: Solubility of L-malic acid 
Solvent Solubility at 208C 
Acetone 1 in 1.6 
Diethyl ether 1 in 37 
Dioxane 1 in 1.3 
Ethanol (95%) 1 in 1.2 
Methanol 1 in 0.51 
Water 1 in 2.8 
Specific gravity: 1.595 at 208C 
Specific rotation [a]D
20: 5.78 (in acetone at 188C) 
18 Comments 
A specification for malic acid is contained in the Food Chemical 
Codex (FCC). The EINECS number for malic acid is 202-601- 
5. 
19 Specific References 
1 Sweetman SC, ed. Martindale: The Complete Drug Reference, 
34th edn. London: Pharmaceutical Press, 2005: 1709. 
2 Piyarom S, Yonemochi E, Oguchi T, Yamamoto K. Effects of 
grinding and humidification on the transformation of conglomerate 
to racemic compound in optically active drugs. J Pharm 
Pharmacol 1997; 49: 384–389. 
3 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2273. 
20 General References 
Allen LV. Featured excipient: flavor enhancing agents. Int J Pharm 
Compound 2003: 7(1): 48–50. 
Anonymous. Malic and fumaric acids. Manuf Chem Aerosol News 
1964; 35(12): 56–59. 
Berger SE. In: Kirk-Othmer Encyclopedia of Chemical Technology, vol. 
13, 3rd edn. New York: Wiley-Interscience, 1981: 103. 
21 Authors 
SC Owen. 
22 Date of Revision 
12 August 2005. 
Malic Acid 437

Maltitol 
1 Nonproprietary Names 
BP: Maltitol 
PhEur: Maltitolum 
2 Synonyms 
Amalty; C*PharmMaltidex; E965; hydrogenated maltose; 
Malbit; Maltisorb; Maltit; D-maltitol. 
3 Chemical Name and CAS Registry Number 
4-O-a-D-Glucopyranosyl-D-glucitol [585-88-6] 
4 Empirical Formula and Molecular Weight 
C12H24O11 344.32 
5 Structural Formula 
6 Functional Category 
Coating agent; diluent; granulating agent; sweetening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Maltitol is widely used in the pharmaceutical industry in the 
formulation of oral dosage forms. It is a noncariogenic bulk 
sweetener, approximately as sweet as sucrose, well adapted as a 
diluent for different oral dosage forms, wet granulation, and 
hard coating. 
8 Description 
Maltitol occurs as a white, odorless, sweet, crystalline powder. 
It is a disaccharide consisting of one glucose unit linked with 
one sorbitol unit via an a-(1!4) bond. 
SEM: 1 
Excipient: Maltisorb P200 
Manufacturer: Roquette Fre`res 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for maltitol. 
Test PhEur 2005 
Identification . 
Characters . 
Appearance of solution . 
Conductivity 420 mScm1 
Reducing sugars 40.2% 
Related substances . 
Lead 40.5 ppm 
Nickel 41 ppm 
Water 41.0% 
Microbial contamination 
Aerobic bacteria 4102/g 
Fungi 4102/g 
Bacterial endotoxins . 
Assay (dried basis) 98.0–102.0% 
10 Typical Properties 
Compressibility: 9.5% 
Density (bulk): 0.79 g/cm3 (1) 
Density (tapped): 0.95 g/cm3 (1) 
Flowability: 5 seconds(1) 
Melting point: 148–1518C

Particle size distribution: 95% 4 500 mm, 40% 5 100 mm in 
size for Maltisorb P200 (Roquette); 95% 4 200 mm, 50% 
5 100 mm in size for Maltisorb P90 (Roquette). 
Solubility: freely soluble in water. See also Table II. 
Viscosity (dynamic): see Table III. 
Table II: Solubility of maltitol (Maltisorb).(1) 
Solvent Solubility at 208C unless otherwise stated 
Water 1 in 0.67 
1 in 0.48 at 408C 
1 in 0.33 at 608C 
1 in 0.22 at 808C 
1 in 0.18 at 908C 
Table III: Viscosity (dynamic) of aqueous maltitol (Maltisorb) solutions 
at 208C.(1) 
Concentration of aqueous maltitol solution (% w/v) Viscosity (mPa s) 
10 8 
20 10 
30 11 
40 15 
50 24 
60 70 
11 Stability and Storage Conditions 
Maltitol has good thermal and chemical stability. When it is 
heated at temperatures above 2008C, decomposition begins 
(depending on time, temperature, and other prevailing conditions). 
Maltitol does not undergo browning reactions with 
amino acids, and absorbs atmospheric moisture only at relative 
humidities of 89% and above, at 208C. 
12 Incompatibilities 
—
13 Method of Manufacture 
Maltitol is obtained from hydrogenated maltose syrup. Starch 
is hydrolyzed to yield a high-concentration maltose syrup, 
which is hydrogenated with a catalyst. After purification and 
concentration, the syrup is crystallized. 
14 Safety 
Maltitol is used in oral pharmaceutical formulations, confectionery, 
and food products and is considered to be 
noncariogenic. It is generally regarded as a nontoxic, nonallergenic, 
and nonirritant material. 
Digestion of maltitol follows two different metabolic pathways: 
absorption in the small intestine and fermentation in the 
large intestine (colon). These two metabolic pathways must 
thus be considered when evaluating the energy value. 
The hydrolysis of maltitol in the small intestine releases 
sorbitol and glucose. Glucose is actively transported and 
rapidly absorbed, whereas sorbitol absorption is passive. The 
nonabsorbed sorbitol and nonhydrolyzed maltitol are fermented 
by the microflora in the colon. The relative importance of 
the two absorption pathways depends on numerous individual 
factors and is related to the quantity of maltitol ingested. 
Excessive oral consumption (>50 g daily) may cause flatulence 
and diarrhea. 
Maltitol exhibits a low glycemic index and can therefore, 
under medical supervision, have a place in the diet of diabetic 
patients. The intake of maltitol must be taken into account for 
the calculation of the daily glucidic allowance. 
The WHO in considering the safety of maltitol did not set a 
value for the acceptable daily intake since the levels used in food 
to achieve a desired effect were not considered a hazard to 
health.(2,3) 
15 Handling Precautions 
Observe normal precautions appropriate to circumstances and 
quantity of material handled. Eye protection and gloves are 
recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in oral pharmaceutical formulations. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Sorbitol. 
18 Comments 
Maltitol is not fermented by oral bacteria and is neither 
acidogenic nor cariogenic. A specification for maltitol syrup is 
contained in the Food Chemicals Codex (FCC). The EINECS 
number for maltitol is 209-567-0. 
19 Specific References 
1 Roquette Fre`res. Technical literature: Maltisorb crystalline maltitol, 
1999. 
2 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirty-third report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1989; No. 776. 
3 FAO/WHO. Evaluation of certain food additives and contaminants. 
Forty-sixth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1997; No. 
868. 
20 General References 
Moskowitz AH. Maltitol and hydrogenated starch hydrolysate. In: 
Nabors LO, Gelardi RC, eds. Alternative Sweeteners, 2nd edn. New 
York: Marcel Dekker, 1991: 259–282. 
Portman MO, Kilcast D. Psycho-physical characterization of new 
sweeteners of commercial importance for the EC food industry. 
Food Chem 1996; 56(3): 291–302. 
21 Authors 
X Duriez. 
22 Date of Revision 
26 August 2005. 
Maltitol 439

Maltitol Solution 
1 Nonproprietary Names 
BP: Liquid maltitol 
PhEur: Maltitolum liquidum 
USPNF: Maltitol solution 
2 Synonyms 
E965; hydrogenated glucose syrup; Finmalt L; Lycasin HBC; 
Lycasin 80/55; Maltisorb 75/75; Maltisweet 3145; maltitol 
syrup. 
3 Chemical Name and CAS Registry Number 
Maltitol solution [9053-46-7] 
4 Empirical Formula and Molecular Weight 
The PhEur 2005 describes liquid maltitol as an aqueous 
solution of a hydrogenated, partly hydrolyzed starch, with not 
less than 68% w/w of solid matter and not more than 85% 
w/w. This is composed of a mixture of mainly D-maltitol 
(550% w/w), D-sorbitol (48% w/w), and hydrogenated oligoand 
polysaccharides, all quoted on an anhydrous basis. 
The USPNF 23 describes maltitol solution as an aqueous 
solution of a hydrogenated, partially hydrolyzed starch. It 
contains, on the anhydrous basis, not less than 50% w/w of 
D-maltitol (C12H24O11) and not more than 8.0% w/w of 
D-sorbitol (C6H14O6). See also Section 18. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Suspending agent; sweetening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Maltitol solution is used in oral pharmaceutical formulations as 
a bulk sweetening agent, either alone or in combination with 
other excipients, such as sorbitol. Maltitol solution is also used 
as a suspending agent in oral suspensions as an alternative to 
sucrose syrup since it is viscous, noncariogenic, and has a low 
calorific value. It is also noncrystallizing and therefore prevents 
‘cap-locking’ in syrups and elixirs. 
Maltitol solution is additionally used in the preparation of 
pharmaceutical lozenges(1) and is also used in confectionery 
and food products. 
8 Description 
Maltitol solution is a colorless and odorless, clear viscous 
liquid. It is sweet-tasting (approximately 75% the sweetness of 
sucrose). 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for maltitol solution. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Appearance of solution . — 
Conductivity 410 mScm1 — 
pH — 5.0–7.5 
Reducing sugars 40.2% 40.3% 
Lead 40.5 ppm — 
Nickel 41 ppm 41 ppm 
Water 15.0–32.0% 431.5% 
Residue on ignition — 40.1% 
Maltitol (dried basis) 550.0% 550.0% 
Sorbitol (dried basis) 48.0% 48.0% 
10 Typical Properties 
Boiling point: 1058C 
Flash point: >1508C 
Density: 1.36 g/cm3 at 208C 
Heat of combustion: 10.0 kJ/g (2.4 kcal/g) 
Osmolarity: the osmolarity of an aqueous maltitol solution is 
similar to that of a sucrose solution of the same concentration. 
A 10% v/v aqueous solution of Lycasin 80/55 
(Roquette) is iso-osmotic with serum. 
Refractive index: nD
20 = 1.478 
Solubility: miscible with ethanol (provided the ethanol concentration 
is less than 55%), glycerin, propylene glycol, and 
water. Insoluble in mineral and vegetable oils. 
Viscosity (dynamic): maltitol solution is a viscous, syrupy, 
liquid. At 208C, a solution of Lycasin 80/55 (Roquette) 
containing 75% of dry substances has a viscosity of 
approximately 2000 mPa s (2000 cP). With increasing temperature, 
the viscosity of a maltitol solution is reduced; see 
Figure 1. The viscosity of maltitol solutions also decreases 
with decreasing concentration of dry solids, at a constant 
temperature. Maltitol solution may also be mixed with 
sorbitol solution to obtain blends of a desired viscosity. 
11 Stability and Storage Conditions 
Maltitol solution is stable for at least 2 years at room 
temperature and pH 3–9. Following storage for 3 months at 
508C, maltitol solution at pH 2 underwent slight hydrolysis 
(1.2%) and became yellow colored. At pH 3, and the same 
storage conditions, no color change was apparent although 
very slight hydrolysis occurred (0.2%). At pH 4–9, no 
hydrolysis occurred although a very slight yellow color was 
formed under alkaline conditions.(2)

Figure 1: Viscosity of maltitol solution (Lycasin 80/55), containing 
75% of dry substances, at different temperatures. 
Formulations containing maltitol solution should be preserved 
with an antimicrobial preservative such as sodium 
benzoate or a mixture of parabens. Maltitol solution is 
noncrystallizing. 
Maltitol solution should be stored in a well-closed container, 
in a cool, dry place. 
12 Incompatibilities 
—
13 Method of Manufacture 
Maltitol solution is prepared by the hydrogenation of a highmaltose 
syrup that is obtained from starch by enzymatic 
hydrolysis. The maltitol solution produced from this process 
consists of the hydrogenated homologs of the oligosaccharides 
contained in the original syrup. 
14 Safety 
Maltitol solution is used in oral pharmaceutical formulations, 
confectionery, and food products and is considered to be less 
cariogenic than sucrose.(3–6) It is generally regarded as a 
nontoxic, nonallergenic, and nonirritant material. However, 
excessive oral consumption (more than 50 g daily) may cause 
flatulence and diarrhea. 
The WHO, in considering the safety of maltitol solution, did 
not set a value for the acceptable daily intake since the levels 
used in food to achieve a desired effect were not considered a 
hazard to health.(7,8) 
LD50 (rat, IP): 20 g/kg(9) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
Accepted for use in confectionery, foods, and nonparenteral 
pharmaceutical formulations in Europe and the USA. Included 
in the Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Maltitol; sorbitol. 
18 Comments 
Hydrogenated glucose syrup is a generic term used to describe 
aqueous mixtures containing mainly D-maltitol, along with Dsorbitol 
and hydrogenated oligosaccharides and polysaccharides. 
Such mixtures can vary widely in their composition and 
hence physical and chemical properties. Products containing up 
to 90% of maltitol are usually known as maltitol syrup or 
maltitol solution. Preparations containing a minimum of 98% 
of maltitol are designated maltitol. 
19 Specific References 
1 Grenby TH. Dental properties of antiseptic throat lozenges 
formulated with sugars or Lycasin. J Clin Pharm Ther 1995; 20: 
235–241. 
2 Roquette. Technical literature: Lycasin the sweetener for sugarless 
pharmaceuticals. 1993. 
3 Frostell G, Birkhed D. Acid production from Swedish Lycasin 
(candy quality) and French Lycasin (80/55) in human dental 
plaques. Caries Res 1978; 12: 256–263. 
4 Grenby TH. Dental and nutritional effects of Lycasins replacing 
sucrose in the diet of laboratory rats. J Dent Res 1982; 61: 557. 
5 Wu. rsch P, Koellreutter B. Maltitol and maltotriitol as inhibitors of 
acid production in human dental plaque. Caries Res 1982; 16: 90– 
95. 
6 Havenaar R, Drost JS, de Stoppelaar JD, et al. Potential 
cariogenicity of Lycasin 80/55 in comparison to starch, sucrose, 
xylitol, sorbitol and L-sorbose in rats. Caries Res 1984; 18: 375– 
384. 
7 FAO/WHO. Evaluation of certain food additives and contaminants: 
Thirty-third report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1989; 
No. 776. 
8 FAO/WHO. Evaluation of certain food additives and contaminants: 
Forty-sixth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1997; No. 
868. 
9 Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. 
Cincinnati: US Department of Health, 1987. 
20 General References 
Le Bot Y. Lycasin for confections. Manuf Confect 1983; (Dec): 69–74. 
21 Authors 
X Duriez. 
22 Date of Revision 
26 August 2005. 
Maltitol Solution 441

Maltodextrin 
1 Nonproprietary Names 
BP: Maltodextrin 
PhEur: Maltodextrinum 
USPNF: Maltodextrin 
2 Synonyms 
C*Dry MD; C*PharmDry; Glucidex; Glucodry; Lycatab 
DSH; Maldex; Malta*Gran; Maltrin; Maltrin QD; Paselli 
MD10 PH; Rice*Trin; Star-Dri; Tapi. 
3 Chemical Name and CAS Registry Number 
Maltodextrin [9050-36-6] 
4 Empirical Formula and Molecular Weight 
(C6H10O5)nH2O 900–9000 
The USPNF 23 describes maltodextrin as a nonsweet, 
nutritive saccharide mixture of polymers that consist of 
D-glucose units, with a dextrose equivalent (DE) less than 20; 
see also Section 18. The D-glucose units are linked primarily by 
a-(1!4) bonds but there are branched segments linked by 
a-(1!6) bonds. It is prepared by the partial hydrolysis of a 
food-grade starch with suitable acids and/or enzymes. 
5 Structural Formula 
6 Functional Category 
Coating agent; tablet and capsule diluent; tablet binder; 
viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Maltodextrin is used in tablet formulations as a binder and 
diluent in both direct-compression and wet-granulation or 
agglomeration processes.(1–7) Maltodextrin appears to have no 
adverse effect on the rate of dissolution of tablet and capsule 
formulations; magnesium stearate 0.5–1.0% may be used as a 
lubricant. It has been used as a carrier in a spray-dried 
redispersible oil-in-water emulsion to improve the bioavailability 
of poorly soluble drugs.(8) Maltodextrin may also be 
used as a tablet film former in aqueous film-coating processes. 
Maltodextrin grades with a high DE value are particularly 
useful in chewable tablet formulations. 
Maltodextrin may also be used in pharmaceutical formulations 
to increase the viscosity of solutions and to prevent the 
crystallization of syrups. Therapeutically, maltodextrin is often 
used as a carbohydrate source in oral nutritional supplements 
because solutions with a lower osmolarity than isocaloric 
dextrose solutions can be prepared. At body osmolarity, 
maltodextrin solutions provide a higher caloric density than 
sugars. 
Maltodextrin is also widely used in confectionery and food 
products, as well as personal care applications. See Table I. 
Table I: Uses of maltodextrin. 
Use Concentration (%) 
Aqueous film-coating 2–10 
Carrier 10–99 
Crystallization inhibitor for lozenges and syrups 5–20 
Osmolarity regulator for solutions 10–50 
Spray-drying aid 20–80 
Tablet binder (direct compression) 2–40 
Tablet binder (wet granulation) 3–10 
8 Description 
Maltodextrin occurs as a nonsweet, odorless, white powder or 
granules. The solubility, hygroscopicity, sweetness, and compressibility 
of maltodextrin increase as the DE increases. The 
USPNF 23 states that it may be physically modified to improve 
its physical and functional characteristics. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for maltodextrin. 
Test PhEur 2005 USPNF 23 
Identification . — 
Characters . — 
Microbial limits . . 
pH (20% w/v solution) 4.0–7.0 4.0–7.0 
Loss on drying 46.0% 46.0% 
Residue on ignition 40.5% 40.5% 
Heavy metals 410 ppm 45 ppm 
Protein — 40.1% 
Sulfur dioxide 420 ppm 440 ppm 
Dextrose equivalent . 420

SEM: 1 
Excipient: Maltodextrin (Maltrin M100) 
Manufacturer: Grain Processing Corp. 
Magnification: 100 
SEM: 2 
Excipient: Maltodextrin (Maltrin QD M500) 
Manufacturer: Grain Processing Corp. 
Magnification: 100 
10 Typical Properties 
Angle of repose: 
35.28 for Maltrin QD M500;(5) 
28.48 for Maltrin M510.(5) 
Density (bulk): 
0.43 g/cm3 for Lycatab DSH; 
0.26 g/cm3 for Maltrin QD M500; 
0.51 g/cm3 for Maltrin M040; 
0.54 g/cm3 for Maltrin M050; 
0.54 g/cm3 for Maltrin M100; 
0.57 g/cm3 for Maltrin M150; 
0.61 g/cm3 for Maltrin M180; 
0.30 g/cm3 for Maltrin QD M440; 
0.56 g/cm3 for Maltrin M510; 
0.37 g/cm3 for Maltrin QD M550; 
0.40 g/cm3 for Maltrin QD M580; 
0.13 g/cm3 for Maltrin M700. 
Density (tapped): 
0.63 g/cm3 for Lycatab DSH; 
0.32 g/cm3 for Maltrin QD M500; 
0.54 g/cm3 for Maltrin M510.(5) 
Density (true): 
1.419 g/cm3; 
1.334 g/cm3 for Maltodextrin FCC; 
1.410 g/cm3 for Maltrin M500; 
1.425 g/cm3 for Maltrin M510. 
Moisture content: hygroscopicity increases as DE increases. 
Maltodextrin is slightly hygroscopic at relative humidities 
less than 50%. At relative humidities greater than 50%, the 
hygroscopicity of maltodextrin increases nonlinearly. 
Particle size distribution: Maltrin is available in various grades 
with different particle size distributions. 
For Lycatab DSH: maximum of 15% greater than 
200 mm, and minimum of 80% greater than 50 mm in size. 
Solubility: freely soluble in water; slightly soluble in ethanol 
(95%). Solubility increases as DE increases. 
Specific surface area: 
0.54m2/g for Maltrin QD M500; 
0.31m2/g for Maltrin M510.(5) 
Viscosity (dynamic): less than 20 mPa s (20 cP) for a 20% w/v 
aqueous solution of Lycatab DSH. The viscosity of 
maltodextrin solutions decreases as the DE increases. 
Viscosity is 3.45 mPa s for a 20% w/v aqueous dispersion 
of Star-Dri (Tate & Lyle). 
11 Stability and Storage Conditions 
Maltodextrin is stable for at least 1 year when stored at a cool 
temperature (<308C) and less than 50% relative humidity. 
Maltodextrin solutions may require the addition of an 
antimicrobial preservative. 
Maltodextrin should be stored in a well-closed container in 
a cool, dry place. 
12 Incompatibilities 
Under certain pH and temperature conditions maltodextrin 
may undergo Maillard reactions with amino acids to produce 
yellowing or browning. Incompatible with strong oxidizing 
agents. 
13 Method of Manufacture 
Maltodextrin is prepared by heating and treating starch with 
acid and/or enzymes in the presence of water. This process 
partially hydrolyzes the starch, to produce a solution of glucose 
polymers of varying chain length. This solution is then filtered, 
concentrated, and dried to obtain maltodextrin. 
Maltodextrin 443

14 Safety 
Maltodextrin is a readily digestible carbohydrate with a 
nutritional value of approximately 17 kJ/g (4 kcal/g). In the 
USA, it is generally recognized as safe (GRAS) as a direct 
human food ingredient at levels consistent with current good 
manufacturing practices. As an excipient, maltodextrin is 
generally regarded as a nonirritant and nontoxic material. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection is recommended. 
Maltodextrin should be handled in a well-ventilated 
environment and excessive dust generation should be avoided. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(oral tablets and granules). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Corn syrup solids; dextrates; dextrin; starch. 
Corn syrup solids 
Comments: corn syrup solids are glucose polymers with a DE 
520 and are prepared, in a similar manner to maltodextrin, 
by the partial hydrolysis of starch. 
18 Comments 
Various different grades of maltodextrin are commercially 
available for food and pharmaceutical applications from a 
number of suppliers: e.g. Lycatab DS (Roquette Fre`res), 
Maltrin (Grain Processing Corp.) and Star-Dri (Tate & Lyle). 
The grades have different physical properties such as solubility 
and viscosity, depending upon their DE value. The dextrose 
equivalent (DE) value is a measure of the extent of starchpolymer 
hydrolysis and is defined as the reducing power of a 
substance expressed in grams of D-glucose per 100 g of the dry 
substance. 
A specification for maltodextrin is contained in the Food 
Chemicals Codex (FCC). The EINECS number for maltodextrin 
is 232-940-4. 
19 Specific References 
1 Li LC, Peck GE. The effect of moisture content on the compression 
properties of maltodextrins. J Pharm Pharmacol 1990; 42(4): 272– 
275. 
2 Li LC, Peck GE. The effect of agglomeration methods on the 
micrometric properties of a maltodextrin product Maltrin 150. 
Drug Dev Ind Pharm 1990; 16: 1491–1503. 
3 Papadimitriou E, Efentakis M, Choulis NH. Evaluation of 
maltodextrins as excipients for direct compression tablets and 
their influence on the rate of dissolution. Int J Pharm 1992; 86: 
131–136. 
4 Visavarungroj N, Remon JP. Evaluation of maltodextrin as 
binding agent. Drug Dev Ind Pharm 1992; 18: 1691–1700. 
5 Mollan MJ, C. elik M. Characterization of directly compressible 
maltodextrins manufactured by three different processes. Drug 
Dev Ind Pharm 1993; 19: 2335–2358. 
6 Mun. oz-Ruiz A, Monedero Perales MC, Velasco Antequera MV, 
Jime.nez-Castellanos MR. Physical and rheological properties of 
raw materials. STP Pharma (Sci) 1993; 3: 307–312. 
7 Symecko CW, Romero AJ, Rhodes CT. Comparative evaluation of 
two pharmaceutical binders in the wet granulation of hydrochlorothiazide: 
Lycatb DSH vs. Kollidon 30. Drug Dev Ind Pharm 
1993; 19: 1131–1141. 
8 Dollo G, Le Carre P, Guerin A, et al. Spray-dried redispersible oilin-
water emulsion to improve oral bioavailability of poorly soluble 
drugs. Eur J Pharm Sci 2003; 19(4): 273–280. 
20 General References 
Grain Processing Corporation. Technical literature: Maltrin maltodextrins 
and corn syrup solids for pharmaceuticals, 1998. 
Primera Foods. Maltodextrins. http://www.primerafoods.com/mss.asp 
(accessed 24 August 2005). 
Roquette Fre`res. Technical literature: Lycatab DSH excipient for wet 
granulation, 1992. 
Shah A, Buckton G, Booth S. Characterisation of maltodextrins using 
isothermal microcalorimetry. J Pharm Pharmacol 2000; 52 (Suppl.): 
183. 
21 Authors 
SO Freers. 
22 Date of Revision 
24 August 2005. 
444 Maltodextrin

Maltol 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
3-Hydroxy-2-methyl-(1,4-pyran); 3-hydroxy-2-methyl-4-pyrone; 
larixinic acid; 2-methyl-3-hydroxy-4-pyrone; 2-methyl 
pyromeconic acid; Palatone; Veltol. 
3 Chemical Name and CAS Registry Number 
3-Hydroxy-2-methyl-4H-pyran-4-one [118-71-8] 
4 Empirical Formula and Molecular Weight 
C6H6O3 126.11 
5 Structural Formula 
6 Functional Category 
Flavor enhancer; flavoring agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Maltol is used in pharmaceutical formulations and food 
products as a flavoring agent or flavor enhancer. In foods, it 
is used at concentrations up to 30 ppm, particularly with fruit 
flavorings, although it is also used to impart a freshly baked 
odor and flavor to bread and cakes. When used at concentrations 
of 5–75 ppm, maltol potentiates the sweetness of a food 
product, permitting a reduction in sugar content of up to 15% 
while maintaining the same level of sweetness. Maltol is also 
used at low levels in perfumery. 
8 Description 
White crystalline solid with a characteristic, caramel-like odor 
and taste. In dilute solution it possesses a sweet, strawberry-like 
or pineapple-like flavor and odor. 
9 Pharmacopeial Specifications 
See Section 18. 
10 Typical Properties 
Acidity/alkalinity: pH = 5.3 (0.5% w/v aqueous solution) 
Melting point: 162–1648C (begins to sublime at 938C) 
Solubility: see Table I. 
Table I: Solubility of maltol. 
Solvent Solubility at 208C 
Chloroform Freely soluble 
Diethyl ether Sparingly soluble 
Ethanol (95%) 1 in 21 
Glycerin 1 in 80 
Propan-2-ol 1 in 53 
Propylene glycol 1 in 28 
Water 1 in 83 
11 Stability and Storage Conditions 
Maltol solutions may be stored in glass or plastic containers. 
The bulk material should be stored in a well-closed container, 
protected from light, in a cool, dry place. See also Section 12. 
12 Incompatibilities 
Concentrated solutions in metal containers, including some 
grades of stainless steel, may discolor on storage. 
13 Method of Manufacture 
Maltol is mainly isolated from naturally occurring sources such 
as beechwood and other wood tars; pine needles; chicory; and 
the bark of young larch trees. It may also be synthesized by the 
alkaline hydrolysis of streptomycin salts or by a number of 
other synthetic methods. 
14 Safety 
Maltol is generally regarded as an essentially nontoxic and 
nonirritant material. In animal feeding studies, it has been 
shown to be well tolerated with no adverse toxic, reproductive, 
or embryogenic effects observed in rats and dogs fed daily 
intakes of up to 200 mg/kg of maltol, for 2 years.(1) The WHO 
has set an acceptable daily intake for maltol at up to 1 mg/kg 
body-weight.(2) A case of allergic contact dermatitis, attributed 
to the use of maltol in a lip ointment, has been reported.(3) 
LD50 (chicken, oral): 3.72 g/kg(4) 
LD50 (guinea pig, oral): 1.41 g/kg 
LD50 (mouse, oral): 0.85 g/kg 
LD50 (mouse, SC): 0.82 g/kg 
LD50 (rabbit, oral): 1.62 g/kg 
LD50 (rat, oral): 1.41 g/kg

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Maltol should be used in a 
well-ventilated environment. Eye protection is recommended. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(oral solutions and syrups). Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Ethyl maltol. 
18 Comments 
Maltol is a good chelating agent and various metal complexes, 
e.g., aluminum maltol and ferric maltol have been 
investigated as potentially useful therapeutic or experimental 
agents.(5–8) 
Maltol is a constituent of Korean red ginseng.(9) 
Although not included in any pharmacopeias, a specification 
for maltol is contained in the Food Chemicals Codex 
(FCC), see Table II.(10) 
Table II: Food Chemicals Codex specifications for maltol. 
Test FCC 1996 
Identification . 
Heavy metals (as lead) 40.002% 
Lead 410 ppm 
Melting range 160–1648C 
Residue on ignition 40.2% 
Water 40.5% 
Assay 599.0% 
19 Specific References 
1 Gralla EJ, Stebbins RB, Coleman GL, Delahunt CS. Toxicity 
studies with ethyl maltol. Toxicol Appl Pharmacol 1969; 15: 604– 
613. 
2 FAO/WHO. Evaluation of certain food additives. Twenty-fifth 
report of the joint FAO/WHO expert committee on food additives. 
World Health Organ Tech Rep Ser 1981; No. 669. 
3 Taylor AE, Lever L, Lawrence CM. Allergic contact dermatitis 
from strawberry lipsalve. Contact Dermatitis 1996; 34(2): 142– 
143. 
4 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2275. 
5 Finnegan MM, Rettig SJ, Orvig C. A neutral water-soluble 
aluminum complex of neurological interest. J Am Chem Soc 
1986; 108: 5033–5035. 
6 Barrand MA, Callingham BA, Hider RC. Effects of the pyrones, 
maltol and ethyl maltol, on iron absorption from the rat small 
intestine. J Pharm Pharmacol 1987; 39: 203–211. 
7 Singh RK, Barrand MA. Lipid peroxidation effects of a novel iron 
compound, ferric maltol. A comparison with ferrous sulfate. J 
Pharm Pharmacol 1990; 42: 276–279. 
8 Kelsey SM, Hider RC, Bloor JR, et al. Absorption of low and 
therapeutic doses of ferric maltol, a novel ferric iron compound, in 
iron deficient subjects using a single dose iron absorption test. J 
Clin Pharm Ther 1991; 16: 117–122. 
9 Wei J. Studies on the constituents of Korean red ginseng – the 
isolation and identification of 3-hydroxy-2-methyl-4-pyrone [in 
Chinese]. Acta Pharmaceutica Sinica 1982; 17: 549–550. 
10 Food Chemicals Codex, 4th edn. Washington, DC: National 
Academy Press, 1996: 240–241. 
20 General References 
—
21 Authors 
PJ Weller. 
22 Date of Revision 
11 August 2005. 
446 Maltol

Maltose 
1 Nonproprietary Names 
JP: Maltose 
USPNF: Maltose 
2 Synonyms 
Advantose 100; Finetose; Finetose F; 4-O-a-D-glucopyranosylb-
D-glucose; 4-(a-D-glucosido)-D-glucose; malt sugar; maltobiose; 
Maltodiose; Maltose HH; Maltose HHH; Sunmalt; 
Sunmalt S. 
3 Chemical Name and CAS Registry Number 
4-O-a-D-Glucopyranosyl-b-D-glucopyranose anhydrous [69- 
79-4] 
4-O-a-D-Glucopyranosyl-b-D-glucopyranose monohydrate 
[6363-53-7] 
4 Empirical Formula and Molecular Weight 
C12H22O11 342.31 (anhydrous) 
C12H22O11H2O 360.31 (monohydrate) 
5 Structural Formula 
6 Functional Category 
Sweetening agent; tablet diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Maltose is a disaccharide carbohydrate widely used in foods 
and pharmaceuticals. In parenteral products, maltose may be 
used as a source of sugar, particularly for diabetic patients. 
Crystalline maltose is used as a direct-compression tablet 
excipient in chewable and nonchewable tablets.(1–3) 
8 Description 
Maltose occurs as white crystals or as a crystalline powder. It is 
odorless and has a sweet taste approximately 30% that of 
sucrose. 
SEM: 1 
Excipient: Crystalline maltose 
Manufacturer: SPI Pharma Group 
Lot No.: 8K110947 
Magnification: 100 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for maltose. 
Test JP 2001 USPNF 23 
Identification . . 
Specific rotation .1268 to .1318 — 
pH 4.5–6.5 — 
for anhydrous — 3.7–4.4 
for monohydrate — 4.0–5.5 
Clarity and color of solution . — 
Chloride <0.018% — 
Sulfate <0.024% — 
Heavy metals <4 ppm 45 ppm 
Arsenic <1.3 ppm — 
Dextrin, soluble starch and sulfite. . 
Nitrogen <0.01% — 
Related substances . — 
Loss on drying <0.5% — 
Water — — 
for anhydrous — 41.5% 
for monohydrate — 5.0–6.5% 
Residue on ignition <0.10% 40.05% 
Assay (dried basis) >98.0% >92.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 4.5–6.5 for a 10% w/v aqueous 
solution.

Angle of repose: 37.18 for Advantose 100.(3) 
Density (bulk): 0.67–0.72 g/cm3 for Advantose 100.(1) 
Density (tapped): 0.73–0.81 g/cm3 for Advantose 100.(1) 
Dissociation constant: pKa = 12.05 at 218C 
Flash point: >1498C for Advantose 100.(1) 
Flowability: 18% (Carr compressibility index) for Advantose 
100.(3) 
Melting point: 120–1258C.(4) 
Particle size distribution: 15–20% greater than 300 mm, and 
70–75% greater than 150 mm in size for Advantose 100.(1) 
Specific surface area: 0.08m2/g for Advantose 100.(1) 
Solubility: very soluble in water; very slightly soluble in cold 
ethanol (95%); practically insoluble in ether. 
11 Stability and Storage Conditions 
Maltose should be stored in a well-closed container in a cool, 
dry place. 
12 Incompatibilities 
Maltose may react with oxidizing agents. 
13 Method of Manufacture 
Maltose monohydrate is prepared by the enzymatic degradation 
of starch. 
14 Safety 
Maltose is used in oral and parenteral pharmaceutical 
formulations and is generally regarded as an essentially 
nontoxic and nonirritant material. However, there has been a 
single report of a liver transplantation patient with renal failure 
who developed hyponatremia following intravenous infusion 
of normal immunoglobulin in 10% maltose. The effect, which 
recurred on each of four successive infusions, resembled that of 
hyperglycemia and was thought to be due to accumulation of 
maltose and other osmotically active metabolites in the 
extracellular fluid.(4) 
LD50 (mouse, IV): 26.8 g/kg(5) 
LD50 (mouse, SC): 38.6 g/kg 
LD50 (rabbit, IV): 25.2 g/kg 
LD50 (rat, IP): 30.6 g/kg 
LD50 (rat, IV): 15.3 g/kg 
LD50 (rat, oral): 34.8 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection, rubber or 
plastic gloves, and a dust respirator are recommended. When 
heated to decomposition, maltose emits acrid smoke and 
irritating fumes. 
16 Regulatory Status 
In the USA, maltose is considered as a food by the FDA and is 
therefore not subject to food additive and GRAS regulations. 
Included in the FDA Inactive Ingredients Guide (oral solutions). 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. Included in parenteral products available in a 
number of countries worldwide. 
17 Related Substances 
Glucose, liquid. 
18 Comments 
Crystalline maltose, e.g. Advantose 100 (SPI Pharma Group), is 
spray-dried to produce spherical particles with good flow 
properties. The material is also nonhygroscopic and is highly 
compressible. 
The EINECS number for maltose is 200-716-5. 
19 Specific References 
1 SPI Pharma Group. Technical literature: Advantose 100 maltose, 
2004. 
2 Bowe KE, Billig JL, Schwartz JB, et al. Crystalline maltose: a direct 
compression pharmaceutical excipient. Pharm Technol Eur 1998; 
10(5): 34, 36, 37, 40. 
3 Mulderrig KB. Placebo evaluation of selected sugar-based excipients 
in pharmaceutical and nutraceutical tableting. Pharm 
Technol 2000; 24(5): 34, 36, 38, 40, 42, 44. 
4 Palevsky PM, Rendulic D, Diven WF. Maltose-induced hyponatremia. 
Ann Intern Med 1993; 118(7): 526–528. 
5 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2275. 
20 General References 
Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients Directory 1996. Tokyo: Yakuji Nippo, 1996: 299. 
21 Authors 
H Wang. 
22 Date of Revision 
11 August 2005. 
448 Maltose

Mannitol 
1 Nonproprietary Names 
BP: Mannitol 
JP: D-Mannitol 
PhEur: Mannitolum 
USP: Mannitol 
2 Synonyms 
Cordycepic acid; C*PharmMannidex; E421; manna sugar; 
D-mannite; mannite; Mannogem; Pearlitol. 
3 Chemical Name and CAS Registry Number 
D-Mannitol [69-65-8] 
4 Empirical Formula and Molecular Weight 
C6H14O6 182.17 
5 Structural Formula 
6 Functional Category 
Diluent; diluent for lyphilized preparations; sweetening agent; 
tablet and capsule diluent; tonicity agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Mannitol is widely used in pharmaceutical formulations and 
food products. In pharmaceutical preparations it is primarily 
used as a diluent (10–90% w/w) in tablet formulations, where it 
is of particular value since it is not hygroscopic and may thus be 
used with moisture-sensitive active ingredients.(1,2) 
Mannitol may be used in direct-compression tablet applications,(
3–7) for which the granular and spray-dried forms are 
available, or in wet granulations.(8) Granulations containing 
mannitol have the advantage of being dried easily. Specific 
tablet applications include antacid preparations, glyceryl 
trinitrate tablets, and vitamin preparations. Mannitol is 
commonly used as an excipient in the manufacture of chewable 
tablet formulations because of its negative heat of solution, 
sweetness, and ‘mouth feel’.(9,10) 
In lyophilized preparations, mannitol (20–90% w/w) has 
been included as a carrier to produce a stiff, homogeneous cake 
that improves the appearance of the lyophilized plug in a 
vial.(11–20) A pyrogen-free form is available specifically for this 
use.
Mannitol has also been used to prevent thickening in 
aqueous antacid suspensions of aluminum hydroxide (<7% 
w/v). It has been suggested as a plasticizer in soft-gelatin 
capsules, as a component of sustained-release tablet formulations,(
21) and as a carrier in dry powder inhalers.(22,23) It is also 
used as a diluent in rapidly dispersing oral dosage forms.(24,25) 
It is used in food applications as a bulking agent. 
Therapeutically, mannitol administered parenterally is used 
as an osmotic diuretic, as a diagnostic agent for kidney 
function, as an adjunct in the treatment of acute renal failure, 
and as an agent to reduce intracranial pressure, treat cerebral 
edema, and reduce intraocular pressure. Given orally, mannitol 
is not absorbed significantly from the GI tract, but in large 
doses it can cause osmotic diarrhea; see Section 14. 
8 Description 
Mannitol is D-mannitol. It is a hexahydric alcohol related to 
mannose and is isomeric with sorbitol. 
Mannitol occurs as a white, odorless, crystalline powder, or 
free-flowing granules. It has a sweet taste, approximately as 
sweet as glucose and half as sweet as sucrose, and imparts a 
cooling sensation in the mouth. Microscopically, it appears as 
orthorhombic needles when crystallized from alcohol. Mannitol 
shows polymorphism.(26) 
9 Pharmacopeial Specifications 
See Table I. 
SEM: 1 
Excipient: Mannitol 
Manufacturer: Merck 
Magnification: 50 Voltage: 3.5 kV

SEM: 2 
Excipient: Mannitol 
Manufacturer: Merck 
Magnification: 500 Voltage: 3.5 kV 
SEM: 3 
Excipient: Mannitol powder 
Manufacturer: SPI Polyols Inc. 
Lot No: 3140G8 
Magnification: 100 
10 Typical Properties 
Compressibility: see Figure 1. 
Density (bulk): 
0.430 g/cm3 for powder; 
0.7 g/cm3 for granules. 
Density (tapped): 
0.734 g/cm3 for powder; 
0.8 g/cm3 for granules. 
Density (true): 1.514 g/cm3 
Dissociation constant: pKa = 13.5 at 188C 
Flash point: <1508C 
Flowability: powder is cohesive, granules are free flowing. 
Heat of combustion: 16.57 kJ/g (3.96 kcal/g) 
Heat of solution: 120.9 J/g (28.9 cal/g) at 258C 
Melting point: 166–1688C 
SEM: 4 
Excipient: Mannitol granular 
Manufacturer: SPI Polyols Inc. 
Lot No: 2034F8 
Magnification: 100 
Moisture content: see Figure 2. 
Osmolarity: a 5.07% w/v aqueous solution is isoosmotic with 
serum. 
Particle size distribution: 
Pearlitol 300 DC: maximum of 0.1% greater than 500 mm 
and minimum of 90% greater than 200 mm in size; 
Pearlitol 400 DC: maximum of 20% greater than 500 mm 
and minimum of 85% greater than 100 mm in size; 
Pearlitol 500 DC: maximum of 0.5% greater than 841 mm 
and minimum of 90% greater than 150 mm in size. 
Average particle diameter is 250 mm for Pearlitol 300 
DC, 360 mm for Pearlitol 400 DC and 520 mm for Pearlitol 
500 DC.(27) See also Figure 3. 
Table I: Pharmacopeial specifications for mannitol. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters — . — 
Solution 
appearance 
. . — 
Melting range 166–1698C 165–1708C 164–1698C 
Specific rotation .1378 to .1458 .238 to .258 .1378 to .1458 
Conductivity – 420 mScm1 — 
Acidity . — . 
Loss on drying 40.3% 40.5% 40.3% 
Chloride 40.007% — 40.007% 
Sulfate 40.01% — 40.01% 
Arsenic 41.3 ppm — 41 ppm 
Lead – 40.5 ppm — 
Nickel . 41 ppm — 
Heavy metals 45 ppm — — 
Reducing sugars . 40.2% . 
Residue on ignition 40.10% — — 
Related substances — 40.1% — 
Bacterial endotoxins — 44 IU/g(a) — 
Microbial 
contamination 
— 4100/g — 
Assay (dried basis) 5 98.0% 98.0–102.0% 96.0–101.5% 
(a) Test applied only if the mannitol is to be used in the manufacture of parenteral dosage forms. 
450 Mannitol

Table II: Solubility of mannitol. 
Solvent Solubility at 208C 
Alkalis Soluble 
Ethanol (95%) 1 in 83 
Ether Practically insoluble 
Glycerin 1 in 18 
Propan-2-ol 1 in 100 
Water 1 in 5.5 
Figure 1: Compression characteristics of granular mannitol (Pearlitol, 
Roquette Fre`res). 
*: Pearlitol 300DC 
&: Pearlitol 400DC 
~: Pearlitol 500DC 
Tablet diameter: 20mm 
Lubricant: magnesium stearate 0.7% w/w for Pearlitol 
400DC and Pearlitol 500DC; magnesium stearate 1% 
w/w for Pearlitol 300DC. 
Refractive index: nD
20 = 1.333 
Solubility: see Table II. 
Specific surface area: 0.37–0.39m2/g 
11 Stability and Storage Conditions 
Mannitol is stable in the dry state and in aqueous solutions. 
Solutions may be sterilized by filtration or by autoclaving and if 
necessary may be autoclaved repeatedly with no adverse 
physical or chemical effects.(28) In solution, mannitol is not 
attacked by cold, dilute acids or alkalis, nor by atmospheric 
oxygen in the absence of catalysts. Mannitol does not undergo 
Maillard reactions. 
The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Mannitol solutions, 20% w/v or stronger, may be salted out by 
potassium chloride or sodium chloride.(29) Precipitation has 
been reported to occur when a 25% w/v mannitol solution was 
allowed to contact plastic.(30) Sodium cephapirin at 2 mg/mL 
and 30 mg/mL concentration is incompatible with 20% w/v 
aqueous mannitol solution. Mannitol is incompatible with 
xylitol infusion and may form complexes with some metals 
such as aluminum, copper, and iron. Reducing sugar impurities 
in mannitol have been implicated in the oxidative degradation 
of a peptide in a lyophilized formation.(31) Mannitol was found 
to reduce the oral bioavailability of cimetidine compared to 
sucrose.(32) 
13 Method of Manufacture 
Mannitol may be extracted from the dried sap of manna and 
other natural sources by means of hot alcohol or other selective 
solvents. It is commercially produced by the catalytic or 
electrolytic reduction of monosaccharides such as mannose 
and glucose. 
Figure 2: Sorption–desorption isotherm for mannitol. 
^: Sorption equilibrium moisture 
&: Desorption equilibrium moisture 
Figure 3: Particle size distribution of mannitol powder. 
Mannitol 451

14 Safety 
Mannitol is a naturally occurring sugar alcohol found in 
animals and plants; it is present in small quantities in almost all 
vegetables. Laxative effects may occur if mannitol is consumed 
orally in large quantities.(33) If it is used in foods as a bodying 
agent and daily ingestion of over 20 g is foreseeable, the 
product label should bear the statement ‘excessive consumption 
may have a laxative effect’. After intravenous injection, 
mannitol is not metabolized to any appreciable extent and is 
minimally reabsorbed by the renal tubule, about 80% of a dose 
being excreted in the urine in 3 hours.(34) 
A number of adverse reactions to mannitol have been 
reported, primarily following the therapeutic use of 20% w/v 
aqueous intravenous infusions.(35) The quantity of mannitol 
used as an excipient is considerably less than that used 
therapeutically and is consequently associated with a lower 
incidence of adverse reactions. However, allergic, hypersensitive-
type reactions may occur when mannitol is used as an 
excipient. 
An acceptable daily intake of mannitol has not been 
specified by the WHO since the amount consumed as a 
sweetening agent was not considered to represent a hazard to 
health.(36) 
LD50 (mouse, IP): 14 g/kg(37) 
LD50 (mouse, IV): 7.47 g/kg 
LD50 (mouse, oral): 22 g/kg 
LD50 (rat, IV): 9.69 g/kg 
LD50 (rat, oral): 13.5 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Mannitol may be irritant to 
the eyes; eye protection is recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (IP, IM, IV, and 
SC injections; infusions; buccal, oral and sublingual tablets, 
powders and capsules; ophthalmic preparations; topical solutions). 
Included in nonparenteral and parenteral medicines 
licensed in the UK. 
17 Related Substances 
Sorbitol. 
18 Comments 
Mannitol is an isomer of sorbitol, the difference between the 
two polyols occurring in the planar orientation of the OH 
group on the second carbon atom. Each isomer is characterized 
by its own individual set of properties, the most important 
difference being the response to moisture. Sorbitol is hygroscopic, 
while mannitol resists moisture sorption, even at high 
relative humidities. 
Granular mannitol flows well and imparts improved flow 
properties to other materials. However, it usually cannot be 
used with concentrations of other materials exceeding 25% by 
weight. Recommended levels of lubricant are 1% w/w calcium 
stearate or 1–2% w/w magnesium stearate. Suitable binders for 
preparing granulations of powdered mannitol are gelatin, 
methylcellulose 400, starch paste, povidone, and sorbitol. 
Usually, 3–6 times as much magnesium stearate or 1.5–3 times 
as much calcium stearate is needed for lubrication of mannitol 
granulations than is needed for other excipients. 
Mannitol has been reported to sublime at 1308C.(38) 
A specification for mannitol is contained in the Food 
Chemicals Codex (FCC). The EINECS number for mannitol is 
200-711-8. 
19 Specific References 
1 Allen LV. Featured excipient: capsule and tablet diluents. Int J 
Pharm Compound 2000; 4(4): 306–310, 324–325. 
2 Yoshinari T, Forbes RT, York P, Kawashima Y. Improved 
compaction properties of mannitol after a moisture induced 
polymorphic transition. Int J Pharm 2003; 258(1–2): 121–131. 
3 Kanig JL. Properties of fused mannitol in compressed tablets. J 
Pharm Sci 1964; 53: 188–192. 
4 Ward DR, Lathrop LB, Lynch MJ. Dissolution and compatibility 
considerations for the use of mannitol in solid dosage forms. J 
Pharm Sci 1969; 58: 1464–1467. 
5 Ghanem AH, Sakr FM, Abdel-Ghany G. Mechanical and physical 
properties of sulfamethoxazole-mannitol solid dispersion in tablet 
form. Acta Pharm Fenn 1986; 95: 167–172. 
6 Debord B, Lefebvre C, Guyot-Hermann AM, et al. Study of 
different crystalline forms of mannitol: comparative behaviour 
under compression. Drug Dev Ind Pharm 1987; 13: 1533–1546. 
7 Molokhia AM, Al-Shora HI, Hammad AA. Aging of tablets 
prepared by direct compression of bases with different moisture 
content. Drug Dev Ind Pharm 1987; 13: 1933–1946. 
8 Mendes RW, Goll S, An CQ. Wet granulation: a comparison of 
Manni-Tab and mannitol. Drug Cosmet Ind 1978; 122(3): 36, 38, 
40, 44, 87–88. 
9 Daoust RG, Lynch MJ. Mannitol in chewable tablets. Drug 
Cosmet Ind 1963; 93(1): 26–28, 88, 92, 128–129. 
10 Herman J, Remon JP. Aluminium-magnesium hydroxide tablets: 
effect of processing and composition of granulating solution on the 
granule properties and in vitro antacid performance. Drug Dev Ind 
Pharm 1988; 14: 1221–1234. 
11 Couriel B. Advances in lyophilization technology. Bull Parenter 
Drug Assoc 1977; 31: 227–236. 
12 Williams NA, Lee Y, Polli GP, Jennings TA. The effects of cooling 
rate on solid phase transitions and associated vial breakage 
occurring in frozen mannitol solutions. J Parenter Sci Technol 
1986; 40: 135–141. 
13 Stella VJ, Umprayn K, Waugh WN. Development of parenteral 
formulations of experimental cytotoxic agents I: rhizoxin (NSC- 
332598). Int J Pharm 1988; 43: 191–199. 
14 Williams NA, Dean T. Vial breakage by frozen mannitol solutions: 
correlation with thermal characteristics and effect of stereoisomerism, 
additives, and vial configuration. J Parenter Sci Technol 1991; 
45: 94–100. 
15 Chan HK, Au-Yeung KL, Gonda I. Development of a mathematical 
model for the water distribution in freeze-dried solids. Pharm 
Res 1999; 16(5): 660–665. 
16 Pyne A, Surana R, Suryanarayanan R. Crystallization of mannitol 
below Tg0 during freeze-drying in binary and ternary aqueous 
systems. Pharm Res 2002; 19: 901–908. 
17 Pyne A, Chatterjee K, Suryanarayanan R. Solute crystallisation in 
mannitol-glycine systems. Implications on protein stabilisation in 
freeze-dried formulations. J Pharm Sci 2003; 92(11): 2272–2283. 
18 Cavatur RK, Vemuri NM, Pyne A, et al. Crystallization behavior 
of mannitol in frozen aqueous solutions. Pharm Res 2002; 19: 
894–900. 
19 Izutsu K-I, Kojima S. Excipient crystallinity and its proteinstructure-
stabilizing effect during freeze-drying. J Pharm Pharmacol 
2002; 54: 1033–1039. 
20 Johnson RE, Kirchoff CF, Gand HE. Mannitol-sucrose mixtures: 
versatile formulations for protein lyophilisation. J Pharm Sci 2002; 
91(4): 914–922. 
21 Parab PV, Oh CK, Ritschel WA. Sustained release from Precirol 
(glycerol palmito-stearate) matrix. Effect of mannitol and hydroxypropyl 
methylcellulose on the release of theophylline. Drug 
Dev Ind Pharm 1986; 12: 1309–1327. 
452 Mannitol

22 Tee SK, Marriott C, Zeng XM, Martin GP. Use of different sugars 
as fine and coarse carriers for aerosolised salbutamol sulphate. Int 
J Pharm 2000; 208: 111–123. 
23 Steckel H, Bolzen N. Alternative sugars as potential carriers for dry 
powder inhalers. Int J Pharm 2004; 270(1–2): 297–306. 
24 Lee KJ, Kang A, Delfino JJ, et al. Evaluation of critical formulation 
factors in the development of a rapidly dispersing captopril 
oral dosage form. Drug Dev Ind Pharm 2003; 29(9): 
967–979. 
25 Seager H. Drug development products and the Zydis fast 
dissolving dosage form. J Pharm Pharmacol 1998; 50: 375–382. 
26 Bauer H, Herkert T, Bartels M, et al. Investigations on 
polymorphism of mannitol/sorbitol mixtures after spray drying 
using differential scanning calorimetry, x-ray diffraction and near 
infrared spectroscopy. Pharm Ind 2000; 62(3): 231–235. 
27 Roquette Fre`res. Technical literature: Pearlitol, 2004. 
28 Murty BSR, Kapoor JN. Properties of mannitol injection 
(25%) after repeated autoclavings. Am J Hosp Pharm 1975; 32: 
826–827. 
29 Jacobs J. Factors influencing drug stability in intravenous 
infusions. J Hosp Pharm 1969; 27: 341–347. 
30 Epperson E. Mannitol crystallization in plastic containers [letter]. 
Am J Hosp Pharm 1978; 35: 1337. 
31 Dubost DC, Kaufman MJ, Zimmerman JA, et al. Characterization 
of a solid state reaction product from a lyophilized formulation of 
a cyclic heptapeptide. A novel example of an excipient-induced 
oxidation. Pharm Res 1996; 13: 1811–1814. 
32 Adkin DA, Davis SS, Sparrow RA, et al. The effect of mannitol on 
the oral bioavailability of cimetidine. J Pharm Sci 1995; 84: 1405– 
1409. 
33 Anonymous. Flatulence, diarrhoea, and polyol sweeteners. Lancet 
1983; ii: 1321. 
34 Porter GA, Starr A, Kimsey J, Lenertz H. Mannitol hemodilution– 
perfusion: the kinetics of mannitol distribution and excretion 
during cardiopulmonary bypass. J Surg Res 1967; 7: 447–456. 
35 McNeill IY. Hypersensitivity reaction to mannitol. Drug Intell Clin 
Pharm 1985; 19: 552–553. 
36 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirtieth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1987; No. 
751. 
37 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1944–1945. 
38 Weast RC, ed. Handbook of Chemistry and Physics, 60th edn. 
Boca Raton: CRC Press, 1979: c-369. 
20 General References 
Armstrong NA. Tablet manufacture. Diluents. In: Swarbrick J, Boylan 
JC, eds. Encyclopedia of Pharmaceutical Technology, 2nd edn, vol. 
3. New York: Marcel Dekker, 2002: 2713–2732. 
Pikal MJ. Freeze drying. In: Swarbrick J, Boylan JC, eds. Encyclopedia 
of Pharmaceutical Technology, 2nd edn, vol. 2. New York: Marcel 
Dekker, 2002: 1299–1326. 
21 Authors 
NA Armstrong. 
22 Date of Revision 
16 August 2005. 
Mannitol 453

Medium-chain Triglycerides 
1 Nonproprietary Names 
BP: Medium-chain triglycerides 
PhEur: Triglycerida saturata media 
USPNF: Medium-chain triglycerides 
2 Synonyms 
Bergabest; caprylic/capric triglyceride; Captex 300; Captex 
355; Crodamol GTC/C; glyceryl tricaprylate/caprate; Labrafac 
CC; MCToil; Miglyol 810; Miglyol 812; Myritol; Neobee M5; 
Nesatol; oleum neutrale; oleum vegetable tenue; thin vegetable 
oil; Waglinol 3/9280. 
3 Chemical Name and CAS Registry Number 
Medium-chain triglycerides [73398-61-5] 
4 Empirical Formula and Molecular Weight 
500 (average) 
The PhEur 2005 describes medium-chain triglycerides as the 
fixed oil extracted from the hard, dried fraction of the 
endosperm of Cocos nucifera L. or from the dried endosperm 
of Elaeis guineenis Jacq. They consist of a mixture of 
triglycerides of saturated fatty acids, mainly of caprylic acid 
and of capric acid. They contain not less than 95% of saturated 
fatty acids. 
5 Structural Formula 
See also Section 4. 
6 Functional Category 
Emulsifying agent; solvent; suspending agent; therapeutic 
agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Medium-chain triglycerides have been used in a variety of 
pharmaceutical formulations including oral, parenteral, and 
topical preparations. 
In oral formulations, medium-chain triglycerides are used as 
the base for the preparation of oral emulsions, microemulsions, 
self-emulsifying systems, solutions, or suspensions of drugs that 
are unstable or insoluble in aqueous media, e.g. calciferol. 
Medium-chain triglycerides have also been investigated as 
intestinal-absorption enhancers(1,2) and have additionally been 
used as a filler in capsules and sugar-coated tablets, and as a 
lubricant or antiadhesion agent in tablets. 
In parenteral formulations, medium-chain triglycerides have 
similarly been used in the production of emulsions, solutions, 
or suspensions intended for intravenous administration.(3–9) 
Medium-chain triglycerides have been particularly investigated 
for their use in total parenteral nutrition (TPN) regimens in 
combination with long-chain triglycerides.(4) 
In cosmetics and topical pharmaceutical preparations, 
medium-chain triglycerides are used as a component of 
ointments, creams, and liquid emulsions.(5) In rectal formulations, 
medium-chain triglycerides have been used in the 
preparation of suppositories containing labile materials. 
Therapeutically, medium-chain triglycerides have been used 
as nutritional agents.(10) Diets containing medium-chain 
triglycerides are used in conditions associated with the 
malabsorption of fat, such as cystic fibrosis, since mediumchain 
triglycerides are more readily digested than long-chain 
triglycerides. Medium-chain triglycerides provide 35 kJ 
(8.3 kcal) of energy per gram. 
Although similar to long-chain triglycerides, medium-chain 
triglycerides have a number of advantages in pharmaceutical 
formulations, which include better spreading properties on the 
skin; no impedance of skin respiration; good penetration 
properties; good emollient and cosmetic properties; no visible 
film on the skin surface; good compatibility; good solvent 
properties; and good stability against oxidation. 
8 Description 
A colorless to slightly yellowish oily liquid that is practically 
odorless and tasteless. It solidifies at about 08C. The oil is free 
from catalytic residues or the products of cracking. 
9 Pharmacopeial Specifications 
See Table I. 
10 Typical Properties 
Acid value: 
40.1 for Crodamol GTC/C; 
40.1 for Miglyol 810; 
40.1 for Miglyol 812; 
40.05 for Neobee M5. 
Cloud point: 
458C for Crodamol GTC/C; 
108C for Miglyol 810; 
108C for Miglyol 812. 
Color: 
460 (Hazen color index) for Crodamol GTC/C; 
490 (Hazen color index) for Miglyol 810; 
460 (Hazen color index) for Miglyol 812; 
4100 (Hazen color index) for Neobee M5. 
Density: 
0.94–0.96 g/cm3 for Crodamol GTC/C at 208C; 
0.94–0.95 g/cm3 for Miglyol 810 at 208C; 
0.94–0.95 g/cm3 for Miglyol 812 at 208C; 
0.94 g/cm3 for Neobee M5 at 208C.

Table I: Pharmacopeial specifications for medium-chain triglycerides. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Appearance . . 
Alkaline impurities . . 
Relative density 0.93–0.96 0.93–0.96 
Refractive index 1.440–1.452 1.440–1.452 
Viscosity 25–33 mPa s 25–33 mPa s 
Acid value 40.2 40.2 
Hydroxyl value 410 410 
Iodine value 41.0 41.0 
Peroxide value 41.0 41.0 
Saponification value 310–360 310–360 
Unsaponifiable matter 40.5% 40.5% 
Composition of fatty acids 
Caproic acid 42.0% 42.0% 
Caprylic acid 50.0–80.0% 50.0–80.0% 
Capric acid 20.0–50.0% 20.0–50.0% 
Lauric acid 43.0% 43.0% 
Myristic acid 41.0% 41.0% 
Heavy metals(a) 410 ppm 410 ppm 
Water 40.2% 40.2% 
Total ash 40.1% 40.1% 
Chromium 40.05 ppm 40.05 ppm 
Copper(a) 40.1 ppm 40.1 ppm 
Lead(a) 40.1 ppm 40.1 ppm 
Nickel(a) 40.2 ppm 40.1 ppm 
Tin(a) 40.1 ppm 40.1 ppm 
(a) For medium-chain triglycerides intended for use in parenteral nutrition, the test for heavy 
metals is replaced by the tests for chromium, copper, lead, nickel, and tin. 
Freezing point: 58C for Neobee M5 
Hydroxyl value: 48 for Neobee M5 
Iodine number: 
41.0 for Crodamol GTC/C; 
40.5 for Miglyol 810; 
40.5 for Miglyol 812; 
40.5 for Neobee M5. 
Moisture content: 
40.15% w/w for Crodamol GTC/C; 
40.10% w/w for Miglyol 810; 
40.10% w/w for Miglyol 812; 
40.15% w/w for Neobee M5. 
Peroxide value: 
41.0 for Miglyol 810; 
41.0 for Miglyol 812; 
40.5 for Neobee M5. 
Refractive index: 
1.4485–1.4500 for Crodamol GTC/C at 208C; 
1.4485–1.4505 for Miglyol 810 at 208C; 
1.4490–1.4510 for Miglyol 812 at 208C; 
1.4480–1.4510 for Neobee M5 at 208C. 
Saponification value: 
325–345 for Crodamol GTC/C; 
335–355 for Miglyol 810; 
325–345 for Miglyol 812; 
335–360 for Neobee M5. 
Solubility: soluble in all proportions at 208C in acetone, 
benzene, 2-butanone, carbon tetrachloride, chloroform, 
dichloromethane, ethanol, ethanol (95%), ether, ethyl 
acetate, petroleum ether, special petroleum spirit (boiling 
range 80–1108C), propan-2-ol, toluene, and xylene. Miscible 
with long-chain hydrocarbons and triglycerides; 
practically insoluble in water. 
Surface tension: 
32.2 mN/m for Crodamol GTC/C at 258C; 
31.0 mN/m for Miglyol 810 at 208C; 
31.1 mN/m for Miglyol 812 at 208C; 
32.3 mN/m for Neobee M5 at 258C. 
Viscosity (dynamic): 
27–30 mPa s (27–30 cP) for Miglyol 810 at 208C; 
28–32 mPa s (28–32 cP) for Miglyol 812 at 208C; 
23 mPa s (23 cP) for Neobee M5 at 258C. 
11 Stability and Storage Conditions 
Medium-chain triglycerides are stable over the wide range of 
storage temperatures that can be experienced in tropical and 
temperate climates. Ideally, however, they should be stored at 
temperatures not exceeding 258C and not exposed to temperatures 
above 408C for long periods. 
In the preparation of microemulsions and self-emulsifying 
systems, emulsions, or aqueous suspensions of medium-chain 
triglycerides, care should be taken to avoid microbiological 
contamination of the preparation, since lipase-producing 
microorganisms, which become active in the presence of 
moisture, can cause hydrolysis of the triglycerides. Hydrolysis 
of the triglycerides is revealed by the characteristic unpleasant 
odor of free medium-chain fatty acids. 
Medium-chain triglycerides may be sterilized by maintaining 
at 1708C for 1 hour. 
At low temperatures, samples of medium-chain triglycerides 
may become viscous or solidify. Samples should therefore be 
well melted and mixed before use, although overheating should 
be avoided. 
Medium-chain triglycerides should be stored protected from 
light in a well-filled and well-closed container. When stored dry, 
in sealed containers, medium-chain triglycerides remain stable 
for many years. 
12 Incompatibilities 
Preparations containing medium-chain triglycerides should not 
come into contact with polystyrene containers or packaging 
components since the plastic rapidly becomes brittle upon 
contact. Low-density polyethylene should also not be used as a 
packaging material as the medium-chain triglycerides readily 
penetrate the plastic, especially at high temperatures, forming 
an oily film on the outside. High-density polyethylene is a 
suitable packaging material. Closures based on phenol resins 
should be tested before use for compatibility with mediumchain 
triglycerides. Polyvinyl chloride packaging should also be 
tested for compatibility since medium-chain triglycerides can 
dissolve some plasticisers, such as phthalates, out of the plastic. 
Materials recommended as safe for packaging mediumchain 
triglycerides are low-density polyethylene, polypropylene, 
glass, and metal. 
13 Method of Manufacture 
Medium-chain triglycerides are obtained from the fixed oil 
extracted from the hard, dried fraction of the endosperm of 
Cocos nucifera L. Hydrolysis of the fixed oil followed by 
distillation yields the required fatty acids, which are then reesterified 
to produce the medium-chain triglycerides. 
Although the PhEur 2005 specifies that medium-chain fatty 
acids are obtained from coconut oil, medium-chain triglycerides 
are also to be found in substantial amounts in the kernel 
Medium-chain Triglycerides 455

oils of certain other types of palm-tree, e.g., palm kernel oil and 
babassu oil. Some animal products, such as milk-fat, also 
contain small amounts (up to 4%) of the medium-chain fatty 
acid esters. 
14 Safety 
Medium-chain triglycerides are used in a variety of pharmaceutical 
formulations including oral, parenteral, and topical 
products and are generally regarded as essentially nontoxic and 
nonirritant materials. 
In acute toxicology studies in animals and humans, no 
irritant or other adverse reactions have been observed; for 
example, when they were patch-tested on more than 100 
individuals, no irritation was produced on either healthy or 
eczematous skin. Medium-chain triglycerides are not irritating 
to the eyes. 
Similarly, chronic toxicology studies in animals have shown 
no harmful adverse effects associated with medium-chain 
triglycerides following inhalation or intraperitoneal, oral, and 
parenteral administration. 
In humans, administration of 0.5 g/kg body-weight mediumchain 
triglycerides to healthy individuals produced no change 
in blood or serum triglycerides compared to subjects receiving 
the same dose of the long-chain triglyceride triolein. 
In patients consuming diets based on medium-chain 
triglycerides, adverse effects reported include abdominal pain 
and diarrhea. 
LD50 (mouse, IV): 3.7 g/kg 
LD50 (mouse, oral): 29.6 g/kg 
LD50 (rat, oral): 33.3 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(topical preparations). Included in nonparenteral and parenteral 
medicines licensed in Europe. Included in the Canadian List 
of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Suppository bases, hard fat; vegetable oil, hydrogenated. 
18 Comments 
—
19 Specific References 
1 Swenson ES, Curatolo WJ. Intestinal permeability enhancement 
for proteins, peptides and other drugs: mechanisms and potential 
toxicity. Adv Drug Del Rev 1992; 8: 39–92. 
2 Spencer SA, Stammers JP, Hull D. Evaluation of a special low birth 
weight formula, with and without the use of medium chain 
triglycerides. Early Hum Dev 1986; 13: 87–95. 
3 Bach A, Guisard D, Metais P, Debry G. Metabolic effects following 
a short and medium-chain triglycerides load in dogs I: infusion of 
an emulsion of short and medium-chain triglycerides. Arch Sci 
Physiol 1972; 26: 121–129. 
4 Hatton J, Record KE, Bivins BA, et al. Safety and efficacy of a lipid 
emulsion containing medium-chain triglycerides. Clin Pharm 
1990; 9: 366–371. 
5 Adams U, Neuwald F. Comparative studies of the release of 
salicylic acid from medium-chain triglyceride gel and paraffin 
ointment bases: in vitro and in vivo. Pharm Ind 1982; 44: 625– 
629. 
6 Pietkiewicz J, Sznitowska M. The choice of lipids and surfactants 
for injectable extravenous microspheres. Pharmazie 2004; 59: 
325–326. 
7 Schaub E, Kern C, Landau R. Pain on injection: a double-blind 
comparison of propofol with lidocaine pretreatment versus 
propofol formulated with long- and medium-chain triglycerides. 
Anaesth Analg 2004; 99: 1699–1702. 
8 Cournarie F, Savelli MP, Rosilio V, Bretez F, et al. Insulin-loaded 
w/o/w multiple emulsions: comparison of the performances of 
systems prepared with medium-chain triglycerides and fish oil. Eur 
J Pharm Biopharm 2004; 58: 477–482. 
9 Holmberg I, Aksnes L, Berlin T, et al. Absorption of a 
pharmacological dose of vitamin D3 from two different lipid 
vehicles in man: comparison of peanut oil and a medium chain 
triaglyceride. Biopharm Drug Dispos 1990; 11: 807–815. 
10 Ruppin DC, Middleton WRJ. Clinical use of medium-chain 
triglycerides. Drugs 1980; 20: 216–224. 
20 General References 
Akkar A, Namsolleck P, Blaut M, Muller RH. Solubilizing poorly 
soluble antimycotic agents by emulsification via a solvent-free 
process. AAPS Pharm Sci Tech 2004; 5: E24. 
21 Authors 
MJ Lawrence. 
22 Date of Revision 
22 August 2005. 
456 Medium-chain Triglycerides

Meglumine 
1 Nonproprietary Names 
BP: Meglumine 
JP: Meglumine 
PhEur: Megluminum 
USP: Meglumine 
2 Synonyms 
1-Methylamino-1-deoxy-D-glucitol; N-methylglucamine; Nmethyl-
D-glucamine. 
3 Chemical Name and CAS Registry Number 
1-Deoxy-1-(methylamino)-D-glucitol [6284-40-8] 
4 Empirical Formula and Molecular Weight 
C7H17NO5 195.21 
5 Structural Formula 
6 Functional Category 
Organic base. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Meglumine is an organic base used as a pH-adjusting agent and 
solubilizing agent primarily in the preparation of soluble salts 
of iodinated organic acids used as X-ray contrast media. 
8 Description 
Meglumine occurs as a white to slightly yellow-colored 
crystalline powder; it is odorless or with a slight odor. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for meglumine. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters — . — 
Appearance of 
solution 
. . . 
Melting range 128–1318C  
128–1328C 
Specific optical 
rotation 
16.0 to 
17.08 
16.0 to 
17.08 
15.7 to 
17.38 
Reducing 
substances 
— 40.2% — 
Loss on drying 40.5% 40.5% 41.0% 
Residue on ignition 40.10% 40.1% 40.1% 
Absence of reducing 
substances 
. — . 
Bacterial endotoxins — 41.5 IU/g — 
Heavy metals 410 ppm 410 ppm 40.002% 
Iron — 410 ppm — 
Arsenic 41 ppm — — 
Chloride 40.009% 4100 ppm — 
Sulfate 40.019% 4150 ppm — 
Assay 599.0% 99.0–101.0% 99.0–100.5% 
10 Typical Properties 
Acidity/alkalinity: pH = 10.5 (1% w/v aqueous solution). 
Dissociation constant: pKa = 9.5 at 208C 
Melting point: 128–1328C 
Osmolarity: a 5.02% w/v aqueous solution is iso-osmotic with 
serum. 
Solubility: see Table II. 
Table II: Solubility of meglumine. 
Solvent Solubility at 208C unless otherwise stated 
Chloroform Practically insoluble 
Ethanol (95%) 1 in 80 
1 in 4.8 at 708C 
Ether Practically insoluble 
Water 1 in 1 
Specific rotation [a]D
20: 16.58 (10% w/v aqueous solution) 
11 Stability and Storage Conditions 
Meglumine does not polymerize or dehydrate unless heated 
above 1508C for prolonged periods. 
The bulk material should be stored in a well-closed 
container in a cool, dry place. Meglumine should not be stored 
in aluminum containers since it reacts to evolve hydrogen gas; it 
discolors if stored in containers made from copper or copper 
alloys. Stainless steel containers are recommended.

12 Incompatibilities 
Incompatible with aluminum, copper, mineral acids, and 
oxidizing materials. Differential scanning calorimeter studies 
suggest meglumine is incompatible with glipizide.(1) 
13 Method of Manufacture 
Meglumine is prepared by the imination of glucose and 
monomethylamine, in an alcoholic solution, followed by 
catalytic hydrogenation. 
14 Safety 
Meglumine is widely used in parenteral pharmaceutical 
formulations and is generally regarded as a nontoxic material 
at the levels usually employed as an excipient. 
LD50 (mouse, IP): 1.68 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Meglumine should be 
handled in a well-ventilated environment and eye protection, 
gloves, and a respirator are recommended. Exposure to 
meglumine dust should be kept below 10 mg/m3 for total 
inhalable dust (8-hour TWA) or 5 mg/m3 for respirable dust (8- 
hour TWA). There is a risk of explosion when meglumine dust 
is mixed with air. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (injections; oral 
tablets). Included in parenteral medicines licensed in the UK. 
17 Related Substances 
Eglumine. 
Eglumine 
Empirical formula: C8H19NO5 
Molecular weight: 209.24 
CAS number: [14216-22-9] 
Synonyms: 1-deoxy-1-(ethylamino)-D-glucitol; N-ethylglucamine. 
Melting point: 1388C 
Comments: eglumine is prepared similarly to meglumine except 
that monoethylamine is used as the precursor, instead of 
monomethylamine. 
18 Comments 
—
19 Specific References 
1 Verma RK, Garg S. Selection of excipients for extended release 
formulations of glipizide through drug-excipient compatibility 
testing. J Pharm Biomed Anal 2005; 38: 633–644. 
20 General References 
Bremecker KD, Seidel K, Bo. hner A. Polyacrylate gels: use of new bases 
in drug formulation [in German]. Dtsch Apoth Ztg 1990; 130(8): 
401–403. 
Chromy V, Kulhanek V, Fischer J. D-(–)-N-Methylglucamine buffer for 
pH 8.5 to 10.5. Clin Chem 1978; 24(2): 379–381. 
Chromy V, Zahradnicek L, Voznicek J. Use of N-methyl-D-glucamine as 
buffer in the determination of serum alkaline phosphatase activity. 
Clin Chem 1981; 27(10): 1729–1732. 
Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients Directory 1996. Tokyo: Yakuji Nippon, 1996: 305. 
21 Authors 
PJ Weller. 
22 Date of Revision 
11 August 2005. 
458 Meglumine

Menthol 
1 Nonproprietary Names 
BP: Racementhol 
JP: dl-Menthol 
PhEur: Mentholum racemicum 
USP: Menthol 
2 Synonyms 
Hexahydrothymol; 2-isopropyl-5-methylcyclohexanol; 4-isopropyl-
1-methylcyclohexan-3-ol; 3-p-menthanol; p-menthan- 
3-ol; dl-menthol; peppermint camphor; racemic menthol. 
3 Chemical Name and CAS Registry Number 
(1RS,2RS,5RS)-(
)-5-Methyl-2-(1-methylethyl)cyclohexanol 
[15356-70-4] 
Note that the following CAS numbers have also been used: 
[1490-04-6] and [89-78-1]. 
4 Empirical Formula and Molecular Weight 
C10H20O 156.27 
5 Structural Formula 
6 Functional Category 
Flavoring agent; therapeutic agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Menthol is widely used in pharmaceuticals, confectionery, and 
toiletry products as a flavoring agent or odor enhancer. In 
addition to its characteristic peppermint flavor, l-menthol, 
which occurs naturally, also exerts a cooling or refreshing 
sensation that is exploited in many topical preparations. Unlike 
mannitol, which exerts a similar effect due to a negative heat of 
solution, l-menthol interacts directly with the body’s coldness 
receptors. d-Menthol has no cooling effect, while racemic 
menthol exerts an effect approximately half that of l-menthol. 
When used to flavor tablets, menthol is generally dissolved 
in ethanol (95%) and sprayed onto tablet granules and not used 
as a solid excipient. 
Menthol has been investigated as a skin-penetration 
enhancer and is also used in perfumery, tobacco products, 
chewing gum and as a therapeutic agent. See Table I. 
Table I: Uses of menthol. 
Use Concentration (%) 
Pharmaceutical products 
Inhalation 0.02–0.05 
Oral suspension 0.003 
Oral syrup 0.005–0.015 
Tablets 0.2–0.4 
Topical formulations 0.05–10.0 
Cosmetic products 
Toothpaste 0.4 
Mouthwash 0.1–2.0 
Oral spray 0.3 
8 Description 
Racemic menthol is a mixture of equal parts of the (1R,2S,5R)- 
and (1S,2R,5S)-isomers of menthol. It is a free-flowing or 
agglomerated crystalline powder, or colorless, prismatic, or 
acicular shiny crystals, or hexagonal or fused masses with a 
strong characteristic odor and taste. The crystalline form may 
change with time owing to sublimation within a closed vessel. 
The USP 28 specifies that menthol may be either naturally 
occurring l-menthol or synthetically prepared racemic or dlmenthol. 
However, the JP 2001 and PhEur 2005, along with 
other pharmacopeias, include two separate monographs for 
racemic and l-menthol. 
Figure 1: Photomicrograph of large DL-menthol crystals; magnification 
7. Manufacturer: Charkit Chemical Corp., USA. 
9 Pharmacopeial Specifications 
See Table II.

Table II: Pharmacopeial specifications for menthol. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Acidity or alkalinity — . — 
Congealing range 27–288C — . 
Melting point 
dl-menthol — 348C — 
l-menthol 42– 448C 438C 41– 448C 
Specific optical 
rotation 
dl-menthol 2 to .28 0.2 to .0.28 2 to .28 
l-menthol 45 to 518 — 45 to 518 
Readily oxidizable 
substances 
— — . 
Chromatographic 
purity 
— — . 
Related substances — . — 
Appearance of 
solution 
— . — 
Nonvolatile residue . — 40.05% 
Residue on 
evaporation 
— 40.05% — 
Organic volatile 
impurities 
— — . 
Thymol . — — 
Nitromethane or 
nitroethane 
. — — 
Assay 598.0% — — 
10 Typical Properties 
Boiling point: 2128C 
Flash point: 918C 
Melting point: 348C 
Refractive index: nD
20 = 1.4615 
Solubility: very soluble in ethanol (95%), chloroform, ether, 
fatty oils and liquid paraffin; soluble in acetone and 
benzene; very slightly soluble in glycerin; practically 
insoluble in water. 
Specific gravity: 0.904 at 158C 
Specific rotation [a]D
20: –2 to .28 (10% w/v alcoholic solution) 
See also Section 17. 
11 Stability and Storage Conditions 
A formulation containing menthol 1% w/w in aqueous cream 
has been reported to be stable for up to 18 months when stored 
at room temperature.(1) 
Menthol should be stored in a well-closed container at a 
temperature not exceeding 258C, since it sublimes readily. 
12 Incompatibilities 
Incompatible with: butylchloral hydrate; camphor; chloral 
hydrate; chromium trioxide; b-naphthol; phenol; potassium 
permanganate; pyrogallol; resorcinol; and thymol. 
13 Method of Manufacture 
Menthol occurs widely in nature as l-menthol and is the 
principal component of peppermint and cornmint oils obtained 
from the Mentha piperita and Mentha arvensis species. 
Commercially, l-menthol is mainly produced by extraction 
from these volatile oils. It may also be prepared by partial or 
total synthetic methods. 
Racemic menthol is prepared synthetically via a number of 
routes, e.g. by hydrogenation of thymol. 
14 Safety 
Almost all toxicological data for menthol relate to its use as a 
therapeutic agent rather than as an excipient. Inhalation or 
ingestion of large quantities can result in serious adverse 
reactions such as ataxia(2) and CNS depression.(3) Although 
menthol is essentially nonirritant there have been some reports 
of hypersensitivity following topical application.(4,5) In a Polish 
study approximately 1% of individuals were determined as 
being sensitive to menthol.(6) 
The WHO has set an acceptable daily intake of menthol at 
up to 0.4 mg/kg body-weight.(7) 
LD50 (rat, IM): 10.0 g/kg(8) 
LD50 (rat, oral): 3.18 g/kg 
15 Handling Precautions 
May be harmful by inhalation or ingestion in large quantities; 
may be irritant to the skin, eyes, and mucous membranes. 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (dental 
preparations, inhalations, oral aerosols, capsules, solutions, 
suspensions, syrups, and tablets, also topical preparations). 
Included in nonparenteral medicines licensed in the UK. 
Accepted for use in foods and confectionery as a flavoring 
agent of natural origin. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
d-Menthol; l-menthol; thymol. 
d-Menthol 
Empirical formula: C10H20O 
Molecular weight: 156.27 
CAS number: [15356-60-2] 
Synonyms: (1S,2R,5S)-(.)-5-methyl-2-(1-methylethyl)cyclohexanol. 
Appearance: colorless, prismatic or acicular, shiny crystals, 
without the characteristic odor, taste, and cooling effect of lmenthol. 
The crystalline form may change with time owing 
to sublimation within a closed vessel. 
Flash point: 918C 
Melting point: 43–448C 
Specific rotation [a]D
23: .488 (10% w/v alcoholic solution) 
l-Menthol 
Empirical formula: C10H20O 
Molecular weight: 156.27 
CAS number: [2216-51-5] 
Synonyms: levomenthol; levomentholum; (1R,2S,5R)-(–)-5- 
methyl-2-(1-methylethyl)cyclohexanol. 
Appearance: colorless, prismatic, or acicular, shiny crystals, 
with a strong, characteristic odor, taste, and cooling effect. 
460 Menthol

The crystalline form may change with time owing to 
sublimation within a closed vessel. 
Flash point: >1008C 
Melting point: 41–448C 
Refractive index: nD
20 = 1.4600 
Specific rotation [a]D
20: 508 (10% w/v alcoholic solution) 
Safety:
LD50 (mouse, IP): 6.6 g/kg(8) 
LD50 (mouse, oral): 3.4 g/kg 
LD50 (rat, IP): 0.7 g/kg 
LD50 (rat, oral): 3.3 g/kg 
18 Comments 
It should be noted that considerable variation in the chemical 
composition of natural menthol oils can occur depending upon 
their country of origin. The EINECS number for menthol is 
201-939-0. 
19 Specific References 
1 Gallagher P, Jones S. A stability and validation study of 1% w/w 
menthol in aqueous cream. Int J Pharm Pract 1997; 5: 101–104. 
2 Luke E. Addiction to mentholated cigarettes [letter]. Lancet 1962; 
i: 110–111. 
3 O’Mullane NM, Joyce P, Kamath SV, et al. Adverse CNS effects of 
menthol-containing olabas oil [letter]. Lancet 1982; i: 1121. 
4 Papa CM, Shelley WB. Menthol hypersensitivity. J Am Med Assoc 
1964; 189: 546–548. 
5 Hayakawa R, Yamamura M, Sugiura M. Contact dermatitis from 
l-menthol. Cosmet Toilet 1996; 111(7): 28–29. 
6 Rudzki E, Kleniewska D. The epidemiology of contact dermatitis 
in Poland. Br J Dermatol 1970; 83: 543–545. 
7 FAO/WHO. Evaluation of certain food additives: Fifty-first report 
of the joint FAO/WHO expert committee on food additives.World 
Health Organ Tech Rep Ser 2000; No. 891. 
8 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2297. 
20 General References 
Bauer K, Garbe D, Surburg H. Common Fragrance and Flavor 
Materials. Weinheim: VCH, 1990: 43–46. 
Eccles R. Menthol and related cooling compounds. J Pharm Pharmacol 
1994; 46: 618–630. 
Walker T. Menthol. Properties, uses and some methods of manufacture. 
Manuf Chem Aerosol News 1967; 53. 
21 Authors 
BA Langdon, MP Mullarney. 
22 Date of Revision 
26 August 2005. 
Menthol 461

Methylcellulose 
1 Nonproprietary Names 
BP: Methylcellulose 
JP: Methylcellulose 
PhEur: Methylcellulosum 
USP: Methylcellulose 
2 Synonyms 
Benecel; Culminal MC; E461; Methocel; Metolose. 
3 Chemical Name and CAS Registry Number 
Cellulose methyl ether [9004-67-5] 
4 Empirical Formula and Molecular Weight 
Methylcellulose is a long-chain substituted cellulose in which 
approximately 27–32% of the hydroxyl groups are in the form 
of the methyl ether. The various grades of methylcellulose have 
degrees of polymerization in the range 50–1000, with 
molecular weights (number average) in the range 
10 000–220 000 Da. The degree of substitution of methylcellulose 
is defined as the average number of methoxyl (CH3O) 
groups attached to each of the anhydroglucose units along the 
chain. The degree of substitution also affects the physical 
properties of methylcellulose, such as its solubility. 
5 Structural Formula 
The structure shown is with complete substitution of the 
available hydroxyl units of methoxyl substitution. Note that 
methoxyl substitution can occur at any combination of the 
hydroxyl groups of the anhydroglucose ring of cellulose at 
positions 2, 3, and 6. See Section 4. 
6 Functional Category 
Coating agent; emulsifying agent; suspending agent; tablet and 
capsule disintegrant; tablet binder; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Methylcellulose is widely used in oral and topical pharmaceutical 
formulations; see Table I. 
In tablet formulations, low- or medium-viscosity grades of 
methylcellulose are used as binding agents, the methylcellulose 
being added either as a dry powder or in solution.(1–3) Highviscosity 
grades of methylcellulose may also be incorporated in 
tablet formulations as a disintegrant.(4) Methylcellulose may be 
added to a tablet formulation to produce sustained-release 
preparations.(5) 
Tablet cores may also be spray-coated with either aqueous 
or organic solutions of highly substituted low-viscosity grades 
of methylcellulose to mask an unpleasant taste or to modify the 
release of a drug by controlling the physical nature of the 
granules.(6) Methylcellulose coats are also used for sealing 
tablet cores prior to sugar coating. 
Low-viscosity grades of methylcellulose are used to emulsify 
olive, peanut, and mineral oils.(7) They are also used as 
suspending or thickening agents for orally administered liquids, 
methylcellulose commonly being used in place of sugar-based 
syrups or other suspension bases.(8) Methylcellulose delays the 
settling of suspensions and increases the contact time of drugs, 
such as antacids, in the stomach. 
High-viscosity grades of methylcellulose are used to thicken 
topically applied products such as creams and gels. 
In ophthalmic preparations, a 0.5–1.0% w/v solution of a 
highly substituted, high-viscosity grade of methylcellulose has 
been used as a vehicle for eye drops.(9) However, hypromellosebased 
formulations are now preferred for ophthalmic preparations. 
Therapeutically, methylcellulose is used as a bulk laxative; it 
has also been used to aid appetite control in the management of 
obesity, but there is little evidence supporting its efficacy. 
Table I: Uses of methylcellulose. 
Use Concentration (%) 
Bulk laxative 5.0–30.0 
Creams, gels, and ointments 1.0–5.0 
Emulsifying agent 1.0–5.0 
Ophthalmic preparations 0.5–1.0 
Suspensions 1.0–2.0 
Sustained-release tablet matrix 5.0–75.0 
Tablet binder 1.0–5.0 
Tablet coating 0.5–5.0 
Tablet disintegrant 2.0–10.0 
8 Description 
Methylcellulose occurs as a white, fibrous powder or granules. 
It is practically odorless and tasteless. It should be labeled to 
indicate its viscosity type (viscosity of a 1 in 50 solution). 
9 Pharmacopeial Specifications 
See Table II. 
10 Typical Properties 
Acidity/alkalinity: pH = 5.5–8.0 for a 1% w/v aqueous 
suspension.

Table II: Pharmacopeial specifications for methylcellulose. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters — . — 
Appearance of solution . . — 
pH 5.0–8.0 5.5–8.0 — 
Apparent viscosity . . . 
Arsenic 42 ppm — — 
Loss on drying 45.0% 410.0% 45.0% 
Residue on ignition 41.0% 41.0% 41.5% 
Chlorides 40.284% 40.5% — 
Iron 4100 ppm — — 
Heavy metals 410 ppm 420 ppm 40.001% 
Organic volatile 
impurities 
— — . 
Assay (of methoxyl 
groups) 
26.0–33.0% — 27.5–31.5% 
Angle of repose: 40–508 
Autoignition temperature: 3608C 
Degree of substitution: 1.64–1.92 
Density (bulk): 0.276 g/cm3 
Density (tapped): 0.464 g/cm3 
Density (true): 1.341 g/cm3 
Melting point: begins to brown at 190–2008C; begins to char at 
225–2308C. 
Refractive index of solution: 
nD
20 = 1.336 (2% aqueous solution). 
Solubility: practically insoluble in acetone, methanol, chloroform, 
ethanol (95%), ether, saturated salt solutions, toluene, 
and hot water. Soluble in glacial acetic acid and in a mixture 
of equal volumes of ethanol and chloroform. In cold water, 
methylcellulose swells and disperses slowly to form a clear 
to opalescent, viscous, colloidal dispersion. 
Surface tension: 
53–59mN/m (53–59 dynes/cm) for a 0.05% w/v solution at 
258C; 
45–55mN/m for 0.1% at 208C. 
Interfacial tension of solution versus paraffin oil is 
19–23mN/m for 0.1% w/v solution at 208C. 
Viscosity (dynamic): various grades of methylcellulose are 
commercially available that vary in their degree of 
polymerization. Aqueous solutions at concentrations of 
2% w/v will produce viscosities between 5 and 
75 000 mPa s. Individual grades of methylcellulose have a 
stated, narrowly defined viscosity range measured for a 2% 
w/v solution. The viscosity of solutions may be increased by 
increasing the concentration of methylcellulose. Increased 
temperatures reduce the viscosity of solutions until gel 
formation occurs at 50–608C. The process of thermogelation 
is reversible, with a viscous solution being reformed on 
cooling. See also Table III. 
Table III: Typical viscosity values for 2% w/v aqueous solutions of 
Methocel (Dow Chemical Co.) at 208C. 
Methocel grade Viscosity (mPa s) 
A4MP 4000 
A15-LV 15 
A15CP 1500 
A4CP 400 
SEM: 1 
Excipient: Methylcellulose 
Manufacturer: Dow Chemical Co. 
Lot No.: KC16012N21 
Magnification: 60 
SEM: 2 
Excipient: Methylcellulose 
Manufacturer: Dow Chemical Co. 
Lot No.: KC16012N21 
Magnification: 600 
11 Stability and Storage Conditions 
Methylcellulose powder is stable, although slightly hygroscopic. 
The bulk material should be stored in an airtight 
container in a cool, dry place. 
Solutions of methylcellulose are stable to alkalis and dilute 
acids at pH 3–11, at room temperature. At pH less than 3, acidcatalyzed 
hydrolysis of the glucose–glucose linkages occurs and 
the viscosity of methylcellulose solutions is reduced.(10) On 
heating, solution viscosity is reduced until gel formation occurs 
at approximately 508C; see Section 10. 
Methylcellulose solutions are liable to microbial spoilage 
and antimicrobial preservatives should therefore be used. 
Methylcellulose 463

Solutions may also be sterilized by autoclaving, although this 
process can decrease the viscosity of a solution.(11,12) The 
change in viscosity after autoclaving is related to solution pH. 
Solutions at pH less than 4 had viscosities reduced by more 
than 20% subsequent to autoclaving.(11) 
12 Incompatibilities 
Methylcellulose is incompatible with aminacrine hydrochloride; 
chlorocresol; mercuric chloride; phenol; resorcinol; tannic 
acid; silver nitrate; cetylpyridinium chloride; p-hydroxybenzoic 
acid; p-aminobenzoic acid; methylparaben; propylparaben; 
and butylparaben. 
Salts of mineral acids (particularly polybasic acids), phenols, 
and tannins will coagulate solutions of methylcellulose, 
although this can be prevented by the addition of ethanol 
(95%) or glycol diacetate. Complexation of methylcellulose 
occurs with highly surface-active compounds such as tetracaine 
and dibutoline sulfate. 
High concentrations of electrolytes increase the viscosity of 
methylcellulose mucilages owing to the ‘salting out’ of 
methylcellulose. With very high concentrations of electrolytes, 
the methylcellulose may be completely precipitated in the form 
of a discrete or continuous gel. Methylcellulose is incompatible 
with strong oxidizing agents. 
13 Method of Manufacture 
Methylcellulose is prepared from wood pulp (cellulose) by 
treatment with alkali followed by methylation of the alkali 
cellulose with methyl chloride. The product is then purified and 
ground to powder form. 
14 Safety 
Methylcellulose is widely used in a variety of oral and topical 
pharmaceutical formulations. It is also extensively used in 
cosmetics and food products and is generally regarded as a 
nontoxic, nonallergenic, and nonirritant material.(13) 
Following oral consumption, methylcellulose is not digested 
or absorbed and is therefore a noncaloric material. Ingestion of 
excessive amounts of methylcellulose may temporarily increase 
flatulence and gastrointestinal distension. 
In the normal individual, oral consumption of large 
amounts of methylcellulose has a laxative action and mediumor 
high-viscosity grades are therefore used as bulk laxatives. 
Esophageal obstruction may occur if methylcellulose is 
swallowed with an insufficient quantity of liquid. Consumption 
of large quantities of methylcellulose may additionally interfere 
with the normal absorption of some minerals. However, this 
and the other adverse effects discussed above relate mainly to 
the use of methylcellulose as a bulk laxative and are not 
significant factors when methylcellulose is used as an excipient 
in oral preparations. 
Methylcellulose is not commonly used in parenteral 
products, although it has been used in intra-articular and 
intramuscular injections. Studies in rats have suggested that 
parenterally administered methylcellulose may cause glomerulonephritis 
and hypertension.(13) 
The WHO has not specified an acceptable daily intake of 
methylcellulose since the level of use in foods was not 
considered to be a hazard to health.(14) 
LD50 (mouse, IP): 275 g/kg(15) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Dust may be irritant to the 
eyes and eye protection should be worn. Excessive dust 
generation should be avoided to minimize the risk of explosion. 
Methylcellulose is combustible. Spills of the dry powder or 
solution should be cleaned up immediately, as the slippery film 
that forms can be dangerous. 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (sublingual tablets; IM 
injections; nasal preparations; ophthalmic preparations; oral 
capsules, oral suspensions, and oral tablets; topical and vaginal 
preparations). Included in nonparenteral medicines licensed in 
the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Ethylcellulose; hydroxyethyl cellulose; hydroxyethylmethyl 
cellulose; hypromellose. 
18 Comments 
The thermal gelation temperature for methylcellulose decreases 
as a function of concentration. The presence of additives can 
increase or decrease the thermal gelation temperature. The 
presence of drugs can influence the properties of methylcellulose 
gels.(16) In addition, the viscosity of methylcellulose 
solutions can be modified by the presence of drugs or other 
additives.(17) Aqueous solutions of methylcellulose can be 
frozen and do not undergo phase separation upon freezing. 
Methylcellulose is best dissolved in water by one of three 
methods, the most suitable being chosen for a particular 
application. 
The most commonly used method is to add methylcellulose 
initially to hot water. The appropriate quantity of methylcellulose 
required to produce a solution of specified viscosity is 
mixed with water at 708C; about half the desired final volume 
of water is used. Cold water or ice is then added to the hot 
methylcellulose slurry in order to reduce the temperature to 
below 208C. A clear, aqueous methylcellulose solution is 
obtained. 
Alternatively, either methylcellulose powder may be dryblended 
with another powder prior to mixing with cold water, 
or methylcellulose powder may be moistened with an organic 
solvent such as ethanol (95%) prior to the addition of water. 
In general, methylcellulose solutions exhibit pseudoplastic 
flow and there is no yield point. Nonthixotropic flow properties 
are observed below the gelation temperature. 
Note that some cellulose ether products possess hydroxypropyl 
substitutions in addition to methyl substitutions but are 
designated with the same trade name in a product line, differing 
only by a unique identifier code. These products should not be 
confused with the products that contain only methyl substitutions. 
A specification for methylcellulose is contained in the 
Food Chemicals Codex (FCC). 
19 Specific References 
1 Wan LSC, Prasad KPP. Uptake of water by excipients in tablets. Int 
J Pharm 1989; 50: 147–153. 
464 Methylcellulose

2 Funck JAB, Schwartz JB, Reilly WJ, Ghali ES. Binder effectiveness 
for beads with high drug levels. Drug Dev Ind Pharm 1991; 17: 
1143–1156. 
3 Itiola OA, Pilpel N. Formulation effects on the mechanical 
properties of metronidazole tablets. J Pharm Pharmacol 1991; 
43: 145–147. 
4 Esezobo S. Disintegrants: effects of interacting variables on the 
tensile strengths and dissolution times of sulfaguanidine tablets. Int 
J Pharm 1989; 56: 207–211. 
5 Sanghavi NM, Kamath PR, Amin DS. Sustained release tablets of 
theophylline. Drug Dev Ind Pharm 1990; 16: 1843–1848. 
6 Wan LSC, Lai WF. Factors affecting drug release from drug-coated 
granules prepared by fluidized-bed coating. Int J Pharm 1991; 72: 
163–174. 
7 Wojdak H, Drobnicka B, Zientarska G, Gadomska-Nowak M. 
The influence of selected properties on the stability of pharmaceutical 
emulsions. Pharmazie 1991; 46: 120–125. 
8 Dalal PS, Narurkar MM. In vitro and in vivo evaluation of 
sustained release suspensions of ibuprofen. Int J Pharm 1991; 73: 
157–162. 
9 El Gawad A, Ramadan EM, El Helw AM. Formulation and 
stability of saluzide eye drops. Pharm Ind 1987; 49: 751–754. 
10 Huikari A, Karlsson A. Viscosity stability of methylcellulose 
solutions at different pH and temperature. Acta Pharm Fenn 1989; 
98(4): 231–238. 
11 Huikari A. Effect of heat sterilization on the viscosity of 
methylcellulose solutions. Acta Pharm Fenn 1986; 95(1): 9–17. 
12 Huikari A, Hinkkanen R, Michelsson H, et al. Effect of heat 
sterilization on the molecular weight of methylcellulose determined 
using high pressure gel filtration chromatography and viscometry. 
Acta Pharm Fenn 1986; 95(3): 105–111. 
13 Anonymous. Final report on the safety assessment of hydroxyethylcellulose, 
hydroxypropylcellulose, methylcellulose, hydroxypropyl 
methylcellulose and cellulose gum. J Am Coll Toxicol 1986; 
5(3): 1–60. 
14 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirty-fifth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1990: No. 
789. 
15 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2408. 
16 Mitchell K, Ford JL, Armstrong DJ, et al. Influence of drugs on the 
properties of gels and swelling characteristics of matrices containing 
methylcellulose or hydroxypropylmethylcellulose. Int J Pharm 
1993; 100(1–3): 165–173. 
17 Huikari A, Kristoffersson E. Rheological properties of methylcellulose 
solutions: general flow properties and effects of added 
substances. Acta Pharm Fenn 1985; 94(4): 143–154. 
20 General References 
Doelker E. Cellulose derivatives. Adv Polym Sci 1993; 107: 199–265. 
Hladon T, Gorecki M, Pawlaczyk HJ. Physicochemical interactions of 
drugs with excipients in suspensions. Acta Pol Pharm 1986; 43(5): 
471–480. 
Mitchell K, Ford JL, Armstrong DJ, et al. Influence of substitution type 
on the performance of methylcellulose and hydroxypropylmethylcellulose 
in gels and matrices. Int J Pharm 1993; 100(1–3): 143– 
154. 
Rowe RC. The molecular weight of methyl cellulose used in 
pharmaceutical formulation. Int J Pharm 1982; 11: 175–179. 
Tapia Villanueva C, Sapag Hagar J. Methylcellulose: its pharmaceutical 
applications. Acta Farm Bonaerense 1995; 14(Jan–Mar): 41–47. 
Wan LS, Prasad KP. Influence of quantity of granulating liquid on water 
uptake and disintegration of tablets with methylcellulose. Pharm 
Ind 1989; 51(1): 105–109. 
Wan LS, Prasad KP. Studies on the swelling of composite disintegrant– 
methylcellulose films. Drug Dev Ind Pharm 1990; 16(2): 191–200. 
21 Authors 
LV Allen, PE Luner. 
22 Date of Revision 
9 August 2005. 
Methylcellulose 465

Methylparaben 
1 Nonproprietary Names 
BP: Methyl hydroxybenzoate 
JP: Methyl parahydroxybenzoate 
PhEur: Methylis parahydroxybenzoas 
USPNF: Methylparaben 
2 Synonyms 
E218; 4-hydroxybenzoic acid methyl ester; methyl p-hydroxybenzoate; 
Nipagin M; Uniphen P-23. 
3 Chemical Name and CAS Registry Number 
Methyl-4-hydroxybenzoate [99-76-3] 
4 Empirical Formula and Molecular Weight 
C8H8O3 152.15 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Methylparaben is widely used as an antimicrobial preservative 
in cosmetics, food products, and pharmaceutical formulations; 
see Table I. It may be used either alone or in combination with 
other parabens or with other antimicrobial agents. In cosmetics, 
methylparaben is the most frequently used antimicrobial 
preservative.(1) 
The parabens are effective over a wide pH range and have a 
broad spectrum of antimicrobial activity, although they are 
most effective against yeasts and molds. Antimicrobial activity 
increases as the chain length of the alkyl moiety is increased, but 
aqueous solubility decreases; therefore a mixture of parabens is 
frequently used to provide effective preservation. Preservative 
efficacy is also improved by the addition of propylene glycol 
(2–5%), or by using parabens in combination with other 
antimicrobial agents such as imidurea; see Section 10. 
Owing to the poor solubility of the parabens, paraben salts 
(particularly the sodium salt) are more frequently used in 
formulations. However, this raises the pH of poorly buffered 
formulations. 
Methylparaben (0.18%) together with propylparaben 
(0.02%) has been used for the preservation of various 
parenteral pharmaceutical formulations; see Section 14. 
Table I: Uses of methylparaben. 
Use Concentration (%) 
IM, IV, SC injections(a) 0.065–0.25 
Inhalation solutions 0.025–0.07 
Intradermal injections 0.10 
Nasal solutions 0.033 
Ophthalmic preparations(a) 0.015–0.2 
Oral solutions and suspensions 0.015–0.2 
Rectal preparations 0.1–0.18 
Topical preparations 0.02–0.3 
Vaginal preparations 0.1–0.18 
(a) See Section 14. 
8 Description 
Methylparaben occurs as colorless crystals or a white crystalline 
powder. It is odorless or almost odorless and has a slight 
burning taste. 
SEM: 1 
Excipient: Methylparaben 
Supplier: Bate Chemical Co. Ltd. 
Magnification: 600 
9 Pharmacopeial Specifications 
See Table II.

Table II: Pharmacopeial specifications for methylparaben. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters — . — 
Appearance of solution — . . 
Acidity — . . 
Heavy metals 420 ppm — — 
Impurities — . . 
Loss on drying 40.5% — — 
Parahydroxybenzoic 
acid 
. — — 
Chlorides 40.035% — — 
Melting range — — 125–1288C 
Readily carbonizable 
substances 
. — . 
Organic volatile 
impurities 
— — . 
Related substances — . — 
Residue on ignition 40.10% 40.1% 40.1% 
Assay (dried basis) 599.0% 98.0–102.0% 99.0–100.5% 
10 Typical Properties 
Antimicrobial activity: see Table III. Methylparaben exhibits 
antimicrobial activity of pH 4–8. Preservative efficacy 
decreases with increasing pH owing to the formation of 
the phenolate anion. Parabens are more active against yeasts 
and molds than against bacteria. They are also more active 
against Gram-positive bacteria than against Gram-negative 
bacteria. 
Table III: Minimum inhibitory concentrations (MICs) of 
methylparaben in aqueous solution.(4) 
Microorganism MIC (mg/mL) 
Aerobacter aerogenes ATCC 8308 2000 
Aspergillus oryzae 600 
Aspergillus niger ATCC 9642 1000 
Aspergillus niger ATCC 10254 1000 
Bacillus cereus var. mycoides ATCC 6462 2000 
Bacillus subtilis ATCC 6633 2000 
Candida albicans ATCC 10231 2000 
Enterobacter cloacae ATCC 23355 1000 
Escherichia coli ATCC 8739 1000 
Escherichia coli ATCC 9637 1000 
Klebsiella pneumoniae ATCC 8308 1000 
Penicillium chrysogenum ATCC 9480 500 
Penicillium digitatum ATCC 10030 500 
Proteus vulgaris ATCC 8427 2000 
Proteus vulgaris ATCC 13315 1000 
Pseudomonas aeruginosa ATCC 9027 4000 
Pseudomonas aeruginosa ATCC 15442 4000 
Pseudomonas stutzeri 2000 
Rhizopus nigricans ATCC 6227A 500 
Saccharomyces cerevisiae ATCC 9763 1000 
Salmonella typhosa ATCC 6539 1000 
Sarcina lutea 4000 
Serratia marcescens ATCC 8100 1000 
Staphylococcus aureus ATCC 6538P 2000 
Staphylococcus epidermidis ATCC 12228 2000 
Trichoderma lignorum ATCC 8678 250 
Trichoderma mentagrophytes 250 
Methylparaben is the least active of the parabens; 
antimicrobial activity increases with increasing chain length 
of the alkyl moiety. Activity may be improved by using 
combinations of parabens as synergistic effects occur. 
Therefore, combinations of methyl-, ethyl-, propyl-, and 
butylparaben are often used together. Activity has also been 
reported to be enhanced by the addition of other excipients 
such as: propylene glycol (2–5%);(2) phenylethyl alcohol;(3) 
and edetic acid.(4) Activity may also be enhanced owing to 
synergistic effects by using combinations of parabens with 
other antimicrobial preservatives such as imidurea.(5) 
The hydrolysis product p-hydroxybenzoic acid has 
practically no antimicrobial activity. 
See also Section 12. 
Density (true): 1.352 g/cm3 
Dissociation constant: pKa = 8.4 at 228C 
Melting point: 125–1288C 
Partition coefficients: values for different vegetable oils vary 
considerably and are affected by the purity of the oil; see 
Table IV. 
Solubility: see Table V. 
Table IV: Partition coefficients of methylparaben in vegetable oil and 
water.(6,7) 
Solvent Partition coefficient 
oil : water 
Almond oil 7.5 
Castor oil 6.0 
Corn oil 4.1 
Diethyl adipate 200 
Isopropyl myristate 18.0 
Lanolin 7.0 
Mineral oil 0.1 
Peanut oil 4.2 
Soybean oil 6.1 
Table V: Solubility of methylparaben in various solvents.(4) 
Solvent Solubility at 258C 
unless otherwise stated 
Ethanol 1 in 2 
Ethanol (95%) 1 in 3 
Ethanol (50%) 1 in 6 
Ether 1 in 10 
Glycerin 1 in 60 
Mineral oil Practically insoluble 
Peanut oil 1 in 200 
Propylene glycol 1 in 5 
Water 1 in 400 
1 in 50 at 508C 
1 in 30 at 808C 
11 Stability and Storage Conditions 
Aqueous solutions of methylparaben at pH 3–6 may be 
sterilized by autoclaving at 1208C for 20 minutes, without 
decomposition.(8) Aqueous solutions at pH 3–6 are stable (less 
than 10% decomposition) for up to about 4 years at room 
temperature, while aqueous solutions at pH 8 or above are 
subject to rapid hydrolysis (10% or more after about 60 days 
storage at room temperature); see Tables VI and VII.(9) 
Methylparaben 467

Methylparaben should be stored in a well-closed container 
in a cool, dry place. 
Table VI: Predicted rate constants and half-lives for methylparaben 
dissolved in dilute hydrochloric acid solution, at 258C. 
Initial pH 
of solution 
Rate constant 
k 
 s(a) (hour1) 
Half-life 
t1=2 
 s(a) (day) 
1 (1.086 
 0.005)  104 266 
 13 
2 (1.16 
 0.12)  105 2 490 
 260 
3 (6.1 
 1.5)  107 47 000 
 12 000 
4 (3.27 
 0.64)  107 88 000 
 17 000 
(a) Indicates the standard error. 
Table VII: Predicted remaining amount of methylparaben dissolved in 
dilute hydrocholoric acid solution, after autoclaving. 
Initial pH 
of solution 
Rate constant 
k 
 s(a) (hour1) 
Predicted residual 
amount after 
autoclaving (%) 
1 (4.96 
 0.16)  101 84.77 
 0.46 
2 (4.49 
 0.37)  102 98.51 
 0.12 
3 (2.79 
 0.57)  103 99.91 
 0.02 
4 (1.49 
 0.22)  103 99.95 
 0.01 
(a) Indicates the standard error. 
12 Incompatibilities 
The antimicrobial activity of methylparaben and other parabens 
is considerably reduced in the presence of nonionic 
surfactants, such as polysorbate 80, as a result of micellization.(
10,11) However, propylene glycol (10%) has been shown to 
potentiate the antimicrobial activity of the parabens in the 
presence of nonionic surfactants and prevents the interaction 
between methylparaben and polysorbate 80.(12) 
Incompatibilities with other substances, such as bentonite,(
13) magnesium trisilicate,(14) talc, tragacanth,(15) sodium 
alginate,(16) essential oils,(17) sorbitol,(18) and atropine,(19) have 
been reported. It also reacts with various sugars and related 
sugar alcohols.(20) 
Absorption of methylparaben by plastics has also been 
reported; the amount absorbed is dependent upon the type of 
plastic and the vehicle. It has been claimed that low-density and 
high-density polyethylene bottles do not absorb methylparaben.(
21) 
Methylparaben is discolored in the presence of iron and is 
subject to hydrolysis by weak alkalis and strong acids. 
13 Method of Manufacture 
Methylparaben is prepared by the esterification of p-hydroxybenzoic 
acid with methanol. 
14 Safety 
Methylparaben and other parabens are widely used as 
antimicrobial preservatives in cosmetics and oral and topical 
pharmaceutical formulations. Although parabens have also 
been used as preservatives in injections and ophthalmic 
preparations, they are now generally regarded as being 
unsuitable for these types of formulations owing to the irritant 
potential of the parabens. These experiences may depend on 
immune responses to enzymatically formed metabolites of the 
parabens in the skin. 
Parabens are nonmutagenic, nonteratogenic, and noncarcinogenic. 
Sensitization to the parabens is rare, and these 
compounds do not exhibit significant levels of photocontact 
sensitization or phototoxicity. 
Hypersensitivity reactions to parabens, generally of the 
delayed type and appearing as contact dermatitis, have been 
reported. However, given the widespread use of parabens as 
preservatives, such reactions are relatively uncommon; the 
classification of parabens in some sources as high-rate 
sensitizers may be overstated.(22) 
Immediate hypersensitivity reactions following injection of 
preparations containing parabens have also been 
reported.(23–25) Delayed-contact dermatitis occurs more frequently 
when parabens are used topically, but has also been 
reported to occur after oral administration.(26–28) 
Unexpectedly, preparations containing parabens may be 
used by patients who have reacted previously with contact 
dermatitis provided they are applied to another, unaffected, 
site. This has been termed the paraben paradox.(29) 
Concern has been expressed over the use of methylparaben 
in infant parenteral products because bilirubin binding may be 
affected, which is potentially hazardous in hyperbilirubinemic 
neonates.(30) 
The WHO has set an estimated total acceptable daily intake 
for methyl-, ethyl-, and propylparabens at up to 10 mg/kg 
body-weight.(31) 
LD50 (dog, oral): 3.0 g/kg(32) 
LD50 (mouse, IP): 0.96 g/kg 
LD50 (mouse, SC): 1.20 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Methylparaben may be 
irritant to the skin, eyes, and mucous membranes and should be 
handled in a well-ventilated environment. Eye protection, 
gloves, and a dust mask or respirator are recommended. 
16 Regulatory Status 
Methylparaben and propylparaben are affirmed GRAS Direct 
Food Substances in the USA at levels up to 0.1%. All esters 
except the benzyl ester are allowed for injection in Japan. In 
cosmetics, the EU and Brazil allow use of each paraben at 
0.4%, but the total of all parabens may not exceed 0.8%. The 
upper limit in Japan is 1.0%. 
Accepted for use as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (IM, IV, and SC injections; 
inhalation preparations; ophthalmic preparations; oral capsules, 
tablets, solutions and suspensions; otic, rectal, topical, 
and vaginal preparations). Included in medicines licensed in the 
UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Butylparaben; ethylparaben; methylparaben potassium; 
methylparaben sodium; propylparaben. 
Methylparaben potassium 
Empirical formula: C8H7KO3 
Molecular weight: 190.25 
CAS number: [26112-07-2] 
468 Methylparaben

Synonyms: methyl 4-hydroxybenzoate potassium salt; potassium 
methyl hydroxybenzoate. 
Comments: methylparaben potassium may be used instead of 
methylparaben because of its greater aqueous solubility. 
Methylparaben sodium 
Empirical formula: C8H7NaO3 
Molecular weight: 174.14 
CAS number: [5026-62-0] 
Synonyms: E219; methyl 4-hydroxybenzoate sodium salt; 
sodium methyl hydroxybenzoate; soluble methyl hydroxybenzoate. 
Appearance: a white, odorless or almost odorless, hygroscopic 
crystalline powder. 
Acidity/alkalinity: pH = 9.5–10.5 (0.1% w/v aqueous solution) 
Solubility: 1 in 50 of ethanol (95%); 1 in 2 of water; practically 
insoluble in fixed oils. 
Comments: methylparaben sodium may be used instead of 
methylparaben because of its greater aqueous solubility. 
However, it may cause the pH of a formulation to become 
more alkaline. 
18 Comments 
The EINECS number for methylparaben is 202-785-7. In 
addition to the most commonly used paraben esters, some other 
less-common esters have also been used; see Table VIII. A 
specification for methylparaben is contained in the Food 
Chemicals Codex (FCC). 
Table VIII: CAS numbers of less common paraben esters. 
Name CAS Number 
Benzylparaben 94-18-8 
Isobutylparaben 4247-02-3 
Isopropylparaben 4191-73-5 
19 Specific References 
1 Decker RL, Wenninger JA. Frequency of preservative use in 
cosmetic formulas as disclosed to FDA—1987. Cosmet Toilet 
1987; 102(12): 21–24. 
2 Prickett PS, Murray HL, Mercer NH. Potentiation of preservatives 
(parabens) in pharmaceutical formulations by low concentrations 
of propylene glycol. J Pharm Sci 1961; 50: 316–320. 
3 Richards RME, McBride RJ. Phenylethanol enhancement of 
preservatives used in ophthalmic preparations. J Pharm Pharmacol 
1971; 23: 141S–146S. 
4 Haag TE, Loncrini DF. Esters of para-hydroxybenzoic acid. In: 
Kabara JJ, ed. Cosmetic and Drug Preservation. New York: 
Marcel Dekker, 1984: 63–77. 
5 Rosen WE, Berke PA, Matzin T, Peterson AF. Preservation of 
cosmetic lotions with imidazolidinyl urea plus parabens. J Soc 
Cosmet Chem 1977; 28: 83–87. 
6 Hibbott HW, Monks J. Preservation of emulsions—p-hydroxybenzoic 
ester partition coefficient. J Soc Cosmet Chem 1961; 12: 
2–10. 
7 Wan LSC, Kurup TRR, Chan LW. Partition of preservatives in oil/ 
water systems. Pharm Acta Helv 1986; 61: 308–313. 
8 Aalto TR, Firman MC, Rigler NE. p-Hydroxybenzoic acid esters 
as preservatives I: uses, antibacterial and antifungal studies, 
properties and determination. J Am Pharm Assoc (Sci) 1953; 42: 
449–457. 
9 Kamada A, Yata N, Kubo K, Arakawa M. Stability of phydroxybenzoic 
acid esters in acidic medium. Chem Pharm Bull 
1973; 21: 2073–2076. 
10 Aoki M, Kameta A, Yoshioka I, Matsuzaki T. Application of 
surface active agents to pharmaceutical preparations I: effect of 
Tween 20 upon the antifungal activities of p-hydroxybenzoic acid 
esters in solubilized preparations [in Japanese]. J Pharm Soc Jpn 
1956; 76: 939–943. 
11 Patel N, Kostenbauder HB. Interaction of preservatives with 
macromolecules I: binding of parahydroxybenzoic acid esters by 
polyoxyethylene 20 sorbitan monooleate (Tween 80). J Am Pharm 
Assoc (Sci) 1958; 47: 289–293. 
12 Poprzan J, deNavarre MG. The interference of nonionic emulsifiers 
with preservatives VIII. J Soc Cosmet Chem 1959; 10: 81–87. 
13 Yousef RT, El-Nakeeb MA, Salama S. Effect of some pharmaceutical 
materials on the bactericidal activities of preservatives. Can J 
Pharm Sci 1973; 8: 54–56. 
14 Allwood MC. The adsorption of esters of p-hydroxybenzoic acid 
by magnesium trisilicate. Int J Pharm 1982; 11: 101–107. 
15 Eisman PC, Cooper J, Jaconia D. Influence of gum tragacanth on 
the bactericidal activity of preservatives. J Am Pharm Assoc (Sci) 
1957; 46: 144–147. 
16 Myburgh JA, McCarthy TJ. The influence of suspending agents on 
preservative activity in aqueous solid/liquid dispersions. Pharm 
Weekbl (Sci) 1980; 2: 143–148. 
17 Chemburkar PB, Joslin RS. Effect of flavoring oils on preservative 
concentrations in oral liquid dosage forms. J Pharm Sci 1975; 64: 
414–417. 
18 Runesson B, Gustavii K. Stability of parabens in the presence of 
polyols. Acta Pharm Suec 1986; 23: 151–162. 
19 Deeks T. Oral atropine sulfate mixtures. Pharm J 1983; 230: 481. 
20 Ma M, Lee T, Kwong E. Interaction of methylparaben preservative 
with selected sugars and sugar alcohols. J Pharm Sci 2002; 91(7): 
1715–1723. 
21 Kakemi K, Sezaki H, Arakawa E, et al. Interactions of parabens 
and other pharmaceutical adjuvants with plastic containers. Chem 
Pharm Bull 1971; 19: 2523–2529. 
22 Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation 
Agents: A Handbook of Excipients. New York: Marcel Dekker, 
1989: 298–300. 
23 Aldrete JA, Johnson DA. Allergy to local anesthetics. J Am Med 
Assoc 1969; 207: 356–357. 
24 Latronica RJ, Goldberg AF, Wightman JR. Local anesthetic 
sensitivity: report of a case. Oral Surg 1969; 28: 439–441. 
25 Nagel JE, Fuscaldo JT, Fireman P. Paraben allergy. J Am Med 
Assoc 1977; 237: 1594–1595. 
26 Micha. elsson G, Juhlin L. Urticaria induced by preservatives and 
dye additives in food and drugs. Br J Dermatol 1973; 88: 525–532. 
27 Warin RP, Smith RJ. Challenge test battery in chronic urticaria. Br 
J Dermatol 1976; 94: 401–406. 
28 Kaminer Y, Apter A, Tyano S, et al. Delayed hypersensitivity 
reaction to orally administered methylparaben. Clin Pharm 1982; 
1(5): 469–470. 
29 Fisher AA. Cortaid cream dermatitis and the ‘‘paraben paradox’’ 
[letter]. J Am Acad Dermatol 1982; 6: 116–117. 
30 Loria CJ, Escheverria P, Smith AL. Effect of antibiotic formulations 
in serum protein: bilirubin interaction of newborn infants. J 
Pediatr 1976; 89(3): 479–482. 
31 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications. 
Seventeenth report of the joint FAO/WHO expert committee on 
food additives.World Health Organ Tech Rep Ser 1974: No. 539. 
32 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2004. 
20 General References 
Bando H, Mohri S, Yamashita F, et al. Effects of skin metabolism on 
percutaneous penetration of lipophilic drugs. J Pharm Sci 1997; 
86(6): 759–761. 
Forster S, Buckton G, Beezer AE. The importance of chain length on the 
wettability and solubility of organic homologs. Int J Pharm 1991; 
72: 29–34. 
Methylparaben 469

Golightly LK, Smolinske SS, Bennett ML, et al. Pharmaceutical 
excipients: adverse effects associated with inactive ingredients in 
drug products (part I). Med Toxicol 1988; 3: 128–165. 
Grant DJW, Mehdizadeh M, Chow AH-L, Fairbrother JE. Non-linear 
van’t Hoff solubility–temperature plots and their pharmaceutical 
interpretation. Int J Pharm 1984; 18: 25–38. 
Jian L, Li Wan Po A. Ciliotoxicity of methyl- and propyl-phydroxybenzoates: 
a dose-response and surface-response study. J 
Pharm Pharmacol 1993; 45: 925–927. 
Jones PS, Thigpen D, Morrison JL, Richardson AP. p-Hydroxybenzoic 
acid esters as preservatives III: the physiological disposition of phydroxybenzoic 
acid and its esters. J Am Pharm Assoc (Sci) 1956; 
45: 268–273. 
Kostenbauder HB. Physical chemical aspects of preservative selection 
for pharmaceutical and cosmetic emulsions. Dev Ind Microbiol 
1962; 1: 286–296. 
Marouchoc SR. Cosmetic preservation. Cosmet Technol 1980; 2(10): 
38–44. 
Matthews C, Davidson J, Bauer E, et al. p-Hydroxybenzoic acid esters 
as preservatives II: acute and chronic toxicity in dogs, rats and mice. 
J Am Pharm Assoc (Sci) 1956; 45: 260–267. 
Sakamoto T, Yanagi M, Fukushima S, Mitsui T. Effects of some 
cosmetic pigments on the bactericidal activities of preservatives. J 
Soc Cosmet Chem 1987; 38: 83–98. 
Sokol H. Recent developments in the preservation of pharmaceuticals. 
Drug Standards 1952; 20: 89–106. 
21 Authors 
R Johnson, R Steer. 
22 Date of Revision 
23 August 2005. 
470 Methylparaben

Mineral Oil 
1 Nonproprietary Names 
BP: Liquid paraffin 
JP: Liquid paraffin 
PhEur: Paraffinum liquidum 
USP: Mineral oil 
2 Synonyms 
Avatech; Drakeol; heavy mineral oil; heavy liquid petrolatum; 
liquid petrolatum; paraffin oil; Sirius; white mineral oil. 
3 Chemical Name and CAS Registry Number 
Mineral oil [8012-95-1] 
4 Empirical Formula and Molecular Weight 
Mineral oil is a mixture of refined liquid saturated aliphatic 
(C14–C18) and cyclic hydrocarbons obtained from petroleum. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Emollient; lubricant; oleaginous vehicle; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Mineral oil is used primarily as an excipient in topical 
pharmaceutical formulations, where its emollient properties 
are exploited as an ingredient in ointment bases; see Table I. It is 
additionally used in oil-in-water emulsions,(1–5) as a solvent, 
and as a lubricant in capsule and tablet formulations, and to a 
limited extent as a mold-release agent for cocoa butter 
suppositories. It has also been used in the preparation of 
microspheres.(6–8) 
Therapeutically, mineral oil has been used as a laxative, see 
Section 14. It is indigestible and thus has limited absorption. 
Mineral oil is used in ophthalmic formulations for its lubricant 
properties. It is also used in cosmetics and some food 
products.(9) 
Table I: Uses of mineral oil. 
Use Concentration (%) 
Ophthalmic ointments 3.0–60.0 
Otic preparations 0.5–3.0 
Topical emulsions 1.0–32.0 
Topical lotions 1.0–20.0 
Topical ointments 0.1–95.0 
8 Description 
Mineral oil is a transparent, colorless, viscous oily liquid, 
without fluorescence in daylight. It is practically tasteless and 
odorless when cold, and has a faint odor of petroleum when 
heated. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for mineral oil. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . — 
Specific gravity 0.860–0.890 0.827–0.890 0.845–0.905 
Viscosity 537mm2/s(a) 110–230 mPa s(b) 534.5mm2/s(c) 
Odor . — — 
Acidity or alkalinity . . . 
Heavy metals 410 ppm — — 
Arsenic 42 ppm — — 
Solid paraffin . . . 
Sulfur compounds . — — 
Polycyclic aromatic 
compounds 
. . — 
Limit of polynuclear 
compounds 
. — . 
Readily carbonizable 
substances 
. . . 
(a) At 37.88C. 
(b) At 208C. 
(c) At 408C. 
10 Typical Properties 
Boiling point: >3608C 
Flash point: 210–2248C 
Pour point: 12.2 to 9.48C 
Refractive index: nD
20 = 1.4756–1.4800 
Surface tension: 35mN/m at 258C. 
Solubility: practically insoluble in ethanol (95%), glycerin, and 
water; soluble in acetone, benzene, chloroform, carbon 
disulfide, ether, and petroleum ether. Miscible with volatile 
oils and fixed oils, with the exception of castor oil. 
Viscosity (dynamic): 110–230 mPa s at 208C. 
11 Stability and Storage Conditions 
Mineral oil undergoes oxidation when exposed to heat and 
light. Oxidation begins with the formation of peroxides, 
exhibiting an ‘induction period’. Under ordinary conditions, 
the induction period may take months or years. However, once 
a trace of peroxide is formed, further oxidation is autocatalytic 
and proceeds very rapidly. Oxidation results in the formation of 
aldehydes and organic acids, which impart taste and odor. 
Stabilizers may be added to retard oxidation; butylated 
hydroxyanisole, butylated hydroxytoluene, and alpha tocopherol 
are the most commonly used antioxidants.

Mineral oil may be sterilized by dry heat. 
Mineral oil should be stored in an airtight container, 
protected from light, in a cool, dry place. 
12 Incompatibilities 
Incompatible with strong oxidizing agents. 
13 Method of Manufacture 
Mineral oil is obtained by distillation of petroleum. The lighter 
hydrocarbons are first removed by distillation and the residue is 
then redistilled between 330–3908C. The distillate is chilled and 
the solid fractions are removed by filtration. The filtrate is then 
further purified and decolorized by high-pressure hydrogenation 
or sulfuric acid treatment; the purified filtrate is then 
filtered through adsorbents. The liquid portion obtained is 
distilled and the portion boiling below 3608C is discarded. A 
suitable stabilizer may be added to the mineral oil; see Section 
11. 
14 Safety 
Mineral oil is used as an excipient in a wide variety of 
pharmaceutical formulations; see Section 16. It is also used in 
cosmetics and in some food products. 
Therapeutically, mineral oil has been used in the treatment 
of constipation, as it acts as a lubricant and stool softener when 
taken orally. Daily doses of up to 45mL have been administered 
orally, while doses of up to 120mL have been used as an enema. 
However, excessive dosage of mineral oil, either orally or 
rectally, can result in anal seepage and irritation and its oral use 
as a laxative is not considered desirable. 
Chronic oral consumption of mineral oil may impair the 
appetite and interfere with the absorption of fat-soluble 
vitamins. Prolonged use should be avoided. Mineral oil is 
absorbed to some extent when emulsified and can lead to 
granulomatous reactions. Similar reactions also occur upon 
injection of the oil;(10) injection may also cause vasospasm. 
The most serious adverse reaction to mineral oil is lipoid 
pneumonia caused by aspiration of the oil.(11,12) Mineral oil 
can enter the bronchial tree without eliciting the cough 
reflex.(13) With the reduction in the use of mineral oil in nasal 
formulations, the incidence of lipoid pneumonia has been 
greatly reduced. However, lipoid pneumonia has also been 
associated with the use of mineral oil-containing cosmetics(14) 
and ophthalmic preparations.(15) It is recommended that 
products containing mineral oil not be used in very young 
children, the elderly, or persons with debilitating illnesses. 
Given its widespread use in many topical products, mineral 
oil has been associated with few instances of allergic reactions. 
The WHO has not specified an acceptable daily intake of 
mineral oil given the low concentration consumed in foods.(16) 
LD50 (mouse, oral): 22 g/kg(17) 
15 Handling Precautions 
Observe precautions appropriate to the circumstances and 
quantity of material handled. Avoid inhalation of vapors and 
wear protective clothing to prevent skin contact. Mineral oil is 
combustible. 
16 Regulatory Status 
GRAS listed. Accepted in the UK for use in certain food 
applications. Included in the FDA Inactive Ingredients Guide 
(dental preparations, IV injections, ophthalmic preparations, 
oral capsules and tablets, otic, topical, transdermal, and vaginal 
preparations). Included in nonparenteral medicines licensed in 
the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Mineral oil and lanolin alcohols; light mineral oil; paraffin; 
petrolatum. 
18 Comments 
Mineral oil in completely filled soft plastic tubes showed 
bubbles of gas after gamma irradiation. The bubbles were 
larger at higher levels of radiation. The iodine value also 
increased after high and low levels of irradiation. 
19 Specific References 
1 Zatz JL. Effect of formulation additives on flocculation of 
dispersions stabilized by a non-ionic surfactant. Int J Pharm 
1979; 4: 83–86. 
2 Wepierre J, Adrangui M, Marty JP. Factors in the occlusivity of 
aqueous emulsions. J Soc Cosmet Chem 1982; 33: 157–167. 
3 Fong-Spaven F, Hollenbeck RG. Thermal rheological analysis of 
triethanolamine-stearate stabilized mineral oil in water emulsions. 
Drug Dev Ind Pharm 1986; 12: 289–302. 
4 Abd Elbary A, Nour SA, Ibrahim I. Physical stability and 
rheological properties of w/o/w emulsions as a function of 
electrolytes. Pharm Ind 1990; 52: 357–363. 
5 Jayaraman SC, Ramachandran C, Weiner N. Topical delivery of 
erythromycin from various formulations: an in-vivo hairless mouse 
study. J Pharm Sci 1996; 85: 1082–1084. 
6 Zinotti C, Kedzierewicz F, Hoffman M, Maincent P. Preparation 
and characterization of ethyl cellulose microspheres containing 5- 
fluorouracil. J Microencapsul 1994; 11: 555–563. 
7 O’Donnell PB, Iwata M, McGinty JW. Properties of multiphase 
microspheres of poly(D, 2-lactic-co-glycolic acid) prepared by a 
potentiometric dispersion technique. J Microencapsul 1995; 12: 
155–163. 
8 Bachtsi AR, Kiparissides C. An experimental investigation of 
enzyme release from poly(vinyl alcohol) crosslinked microspheres. 
J Microencapsul 1995; 12: 23–35. 
9 Anonymous. Mineral hydrocarbons to be banned from foods. 
Pharm J 1989; 242: 187. 
10 Bloem JJ, van derWaal I. Paraffinoma of the face: a diagnostic and 
therapeutic problem. Oral Surg 1974; 38: 675–680. 
11 Volk BW, Nathanson L, Losner S, et al. Incidence of lipoid 
pneumonia in a survey of 389 chronically ill patients. Am J Med 
1951; 10: 316–324. 
12 Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 231–234. 
13 Bennet JC, Plum F, eds. Textbook of Medicine. Philadelphia: WB 
Saunders, 1996: 407–408, 1016. 
14 Becton DL, Lowe JE, Falleta JM. Lipoid pneumonia in an 
adolescent girl secondary to use of lip gloss. J Pediatr 1984; 105: 
421–423. 
15 Prakash UBS, Rosenow EC. Pulmonary complications from 
ophthalmic preparations. Mayo Clin Proc 1990; 65: 521. 
16 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirty-seventh report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1991: No. 806. 
17 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2554–2555. 
472 Mineral Oil

20 General References 
Davis SS, Khanderia MS. Rheological characterization of Plastibases 
and the effect of formulation variables on the consistency of these 
vehicles part 3: oscillatory testing. Int J Pharm Technol Prod Manuf 
1981; 2(Apr): 13–18. 
Deasy PB, Gouldson MP. In-vitro evaluation of pellets containing 
enteric coprecipitates of nifedipine formed by non-aqueous spheronization. 
Int J Pharm 1996; 132: 131–141. 
Gosselin RE, Smith RP, Hodge HC, eds. Clinical Toxicology of 
Commercial Products, 5th edn. Baltimore: Williams & Wilkins, 
1984: II-156–157. 
Rhodes RK. Highly refined petroleum products in skin lotions. Cosmet 
Perfum 1974; 89(3): 53–56. 
21 Authors 
SC Owen. 
22 Date of Revision 
17 August 2005. 
Mineral Oil 473

Mineral Oil, Light 
1 Nonproprietary Names 
BP: Light liquid paraffin 
JP: Light liquid paraffin 
PhEur: Paraffinum perliquidum 
USPNF: Light mineral oil 
2 Synonyms 
905 (mineral hydrocarbons); Citation; light liquid petrolatum; 
light white mineral oil. 
3 Chemical Name and CAS Registry Number 
Light mineral oil [8012-95-1] 
4 Empirical Formula and Molecular Weight 
Light mineral oil is a mixture of refined liquid saturated 
hydrocarbons obtained from petroleum. It is less viscous and 
has a lower specific gravity than mineral oil. 
5 Structural Formula 
A mixture of refined liquid hydrocarbons, essentially paraffins 
and naphthenic in nature, obtained from petroleum. 
6 Functional Category 
Emollient; oleaginous vehicle; solvent; tablet and capsule 
lubricant; therapeutic agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Light mineral oil is used in applications similar to those of 
mineral oil. It is used primarily as an excipient in topical 
pharmaceutical formulations where its emollient properties are 
exploited in ointment bases;(1–3) see Table I. It is also used in 
ophthalmic formulations.(4,5) Light mineral oil is additionally 
used in oil-in-water and polyethlylene glycol/gylcerol emulsions;(
6–9) as a solvent and lubricant in capsules and tablets; as a 
solvent and penetration enhancer in transdermal preparations;(
10) and as the oily medium used in the microencapsulation 
of many drugs.(11–20) 
Light mineral oil is also used in cosmetics and certain food 
products. 
Table I: Uses of light mineral oil. 
Use Concentration (%) 
Ophthalmic ointments 415.0 
Otic preparations 450.0 
Topical emulsions 1.0–20.0 
Topical lotions 7.0–16.0 
Topical ointments 0.2–23.0 
8 Description 
Light mineral oil is a transparent, colorless liquid, without 
fluorescence in daylight. It is practically tasteless and odorless 
when cold, and has a faint odor when heated. The USPNF 23 
specifies that light mineral oil may contain a suitable stabilizer. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for light mineral oil. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . — 
Specific gravity 0.830–0.870 0.810–0.875 0.818–0.880 
Viscosity 437mm2/s(a) 25–80 mPa s 433.5mm2/s(b) 
Acidity or alkalinity . . — 
Heavy metals 410 ppm — — 
Arsenic 42 ppm — — 
Sulfur compounds . — — 
Readily 
carbonizable 
substances 
. . . 
Polycyclic aromatic 
compounds 
. . — 
Limit of polynuclear 
compounds 
— — . 
Odor . — — 
Solid paraffin . . . 
(a) At 37.88C. 
(b) At 408C. 
10 Typical Properties 
Solubility: soluble in chloroform, ether, and hydrocarbons; 
sparingly soluble in ethanol (95%); practically insoluble in 
water. 
11 Stability and Storage Conditions 
Light mineral oil undergoes oxidation when exposed to heat 
and light. Oxidation begins with the formation of peroxides, 
exhibiting an ‘induction period’. Under typical storage conditions, 
the induction period may take months or years. However, 
once a trace of peroxide is formed, further oxidation is 
autocatalytic and proceeds very rapidly. Oxidation results in 
the formation of aldehydes and organic acids, which impart 
taste and odor. The USPNF 23 permits the addition of suitable 
stabilizers to retard oxidation, butylated hydroxyanisole, 
butylated hydroxytoluene, and alpha tocopherol being the 
most commonly used antioxidants. 
Light mineral oil may be sterilized by dry heat. 
Light mineral oil should be stored in an airtight container in 
a cool, dry place and protected from light.

12 Incompatibilities 
Incompatible with strong oxidizing agents. 
13 Method of Manufacture 
Light mineral oil is obtained by the distillation of petroleum. A 
suitable stabilizer may be added to the oil; see Section 11. 
See also Mineral Oil for further information. 
14 Safety 
Light mineral oil is used in applications similar to those of 
mineral oil. Mineral oil is considered safe by the FDA for direct 
use in foods. However, oral ingestion of large doses of light 
mineral oil or chronic consumption may be harmful. Chronic 
use may impair appetite and interfere with the absorption of 
fat-soluble vitamins. It is absorbed to some extent when 
emulsified, leading to granulomatous reactions. Oral and 
intranasal use of mineral oil or products containing mineral 
oil by infants or children is not recommended because of the 
possible danger of causing lipoid pneumonia. 
See Mineral Oil for further information. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Since light mineral oil is 
combustible, it should not be handled or stored near heat, 
sparks, or flame. Light mineral oil should not be mixed with or 
stored with strong oxidants. Inhalation of mineral oil vapors 
may be harmful. 
16 Regulatory Status 
GRAS listed. Accepted in the UK for use in certain food 
applications. Light mineral oil is included in the FDA Inactive 
Ingredients Guide (ophthalmic preparations, oral capsules and 
tablets, otic, rectal, topical, and transdermal preparations). 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Mineral oil; mineral oil and lanolin alcohols; paraffin; 
petrolatum. 
18 Comments 
—
19 Specific References 
1 Jolly ER. Clinical evaluation of baby oil as a dermal moisturizer. 
Cosmet Toilet 1976; 91: 51–52. 
2 Magdassi S, Frenkel M, Garti N. Correlation between nature of 
emulsifier and multiple emulsion stability. Drug Dev Ind Pharm 
1985; 11: 791–798. 
3 Tanaka S, Takashima Y, Murayama H, Tsuchiya S. Solubility and 
distribution of dexamethasone acetate in oil-in-water creams and 
its release from the creams. Chem Pharm Bull 1985; 33: 3929– 
3934. 
4 Merritt JC, Perry DD, Russell DN, Jones BF. Topical 
9- 
tetrahydrocannabinol and aqueous dynamics in glaucoma. J Clin 
Pharmacol 1981; 21: 467S–471S. 
5 Jay WM, Green K. Multiple-drop study of topically applied 1% 
delta 9-tetrahydrocannabinol in human eyes. Arch Ophthalmol 
1983; 101: 591–593. 
6 Hallworth GW, Carless JE. Stablization of oil-in-water emulsions 
by alkyl sulfates: influence of the nature of the oil on stability. J 
Pharm Pharmacol 1972; 24: 71–83. 
7 Magdassi S. Formation of oil-in-polyethylene glycol/water emulsions. 
J Disper Sci Technol 1988; 9: 391–399. 
8 Magdassi S, Frank SG. Formation of oil in glycerol/water 
emulsions: effect of surfactant ethylene oxide content. J Disper 
Sci Technol 1990; 11: 519–528. 
9 Moaddel T, Frierg SE. Phase equilibria and evaporation rates in a 
four component emulsion. J Disper Sci Technol 1995; 16: 69–97. 
10 Pfister WR, Hsieh DST. Permeation enhancers compatible with 
transdermal drug delivery systems part II: system design considerations. 
Pharm Technol 1990; 14(10): 54, 56–58, 60. 
11 Beyger JW, Nairn JG. Some factors affecting the microencapsulation 
of pharmaceuticals with cellulose acetate phthalate. J Pharm 
Sci 1986; 75: 573–578. 
12 Pongpaibul Y, WhitworthCW. Preparation and in vitro dissolution 
characteristics of propranolol microcapsules. Int J Pharm 1986; 
33: 243–248. 
13 Sheu M-T, Sokoloski TD. Entrapment of bioactive compounds 
within native albumin beads III: evaluation of parameters affecting 
drug release. J Parenter Sci Technol 1986; 40: 259–265. 
14 D’Onofrio GP, Oppenheim RC, Bateman NE. Encapsulated 
microcapsules. Int J Pharm 1979; 2: 91–99. 
15 Huang HP, Ghebre Sellassie I. Preparation of microspheres of 
water-soluble pharmaceuticals. J Microencapsul 1989; 6(2): 219– 
225. 
16 Ghorab MM, Zia H, Luzzi LA. Preparation of controlled release 
anticancer agents I: 5-fluorouracil–ethyl cellulose microspheres. J 
Microencapsul 1990; 7(4): 447–454. 
17 Ruiz R, Sakr A, Sprockel OL. A study on the manufacture and in 
vitro dissolution of terbutaline sulfate microcapsules and their 
tablets. Drug Dev Ind Pharm 1990; 16: 1829–1842. 
18 Sanghvi SP, Nairn JG. Phase diagram studies for microencapsulation 
of pharmaceuticals using cellulose acetate trimellitate. J 
Pharm Sci 1991; 80: 394–398. 
19 Iwata M, McGinity JW. Preparation of multi-phase microspheres 
of poly(D,L-lactic acid) and poly(D,L-lactic co-glycolic acid) 
containing a w/o emulsion by a multiple emulsion solvent 
evaporation technique. J Microencapsul 1992; 9(2): 201–214. 
20 Sanghvi SP, Nairn JG. Effect of viscosity and interfacial tension on 
particle size of cellulose acetate trimellitate microspheres. J 
Microencapsul 1992; 9(2): 215–227. 
20 General References 
Allen LV. Featured excipient: capsule and tablet lubricants. Int J Pharm 
Compound 2000; 4(5): 390–392. 
Allen LV. Featured excipient: oleaginous vehicles. Int J Pharm 
Compound 2000; 4(6): 470–473, 484–485. 
See also Mineral Oil. 
21 Authors 
SC Owen. 
22 Date of Revision 
11 August 2005. 
Mineral Oil, Light 475

Mineral Oil and Lanolin Alcohols 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Amerchol L-101; liquid paraffin and lanolin alcohols; Protalan 
M-16; Protalan M-26. 
3 Chemical Name and CAS Registry Number 
Mineral oil [8012-95-1] 
Lanolin alcohols [8027-33-6] 
4 Empirical Formula and Molecular Weight 
A mixture of mineral oil and lanolin alcohols. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Emollient; emulsifying agent; plasticizer. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Mineral oil and lanolin alcohols is an oily liquid used in topical 
pharmaceutical formulations and cosmetics as an emulsifying 
agent with emollient properties; see Table I. It is used as a 
primary emulsifier in the preparation of water-in-oil creams 
and lotions and as an auxiliary emulsifier and stabilizing agent 
in oil-in-water creams and lotions. 
Table I: Uses of mineral oil and lanolin alcohols. 
Use Concentration (%) 
Emollient 3.0–6.0 
Emulsifier in w/o creams and lotions 5.0–15.0 
Emulsifier in o/w creams and lotions 0.5–6.0 
8 Description 
A pale yellow-colored, oily liquid with a faint characteristic 
sterol odor. 
9 Pharmacopeial Specifications 
—
10 Typical Properties 
Acid value: 41 
Arsenic: 42 ppm 
Ash: 40.2% 
Heavy metals: 420 ppm 
HLB value: 8 
Hydroxyl value: 10–15 
Iodine number: 412 
Microbiological count: the total bacterial count, when packaged, 
is less than 10 per gram of sample. 
Moisture content: 40.2% 
Saponification value: 42 
Solubility: soluble 1 in 2 parts of chloroform, 1 in 4 parts of 
castor oil, and 1 in 4 parts of corn oil. Practically insoluble in 
ethanol (95%) and water. Precipitation occurs in hexane. 
Specific gravity: 0.840–0.860 at 258C 
11 Stability and Storage Conditions 
Mineral oil and lanolin alcohols is stable and should be stored 
in a well-closed container in a cool, dry place. 
12 Incompatibilities 
Lanolin alcohols is incompatible with coal tar, ichthammol, 
phenol, and resorcinol. 
13 Method of Manufacture 
Lanolin alcohols is dissolved in mineral oil. 
14 Safety 
Mineral oil and lanolin alcohols is generally regarded as an 
essentially nontoxic and nonirritant material. However, lanolin 
alcohols may be irritant to the skin and causes hypersensitivity 
in some individuals.(1) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
Accepted for use in topical pharmaceutical formulations and 
cosmetics. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Lanolin alcohols; mineral oil; petrolatum and lanolin alcohols. 
18 Comments 
See Lanolin Alcohols and Mineral Oil for further information.

19 Specific References 
1 Wakelin SH, Smith H, White IR, et al. A retrospective analysis of 
contact allergy to lanolin. Br J Dermatol 2001; 145(1): 28–31. 
20 General References 
Davis SS. Viscoelastic properties of pharmaceutical semisolids I: 
ointment bases. J Pharm Sci 1969; 58: 412–418. 
Prosperio G, Gatti S, Genesi P. Lanolin and its derivatives for cosmetic 
creams and lotions. Cosmet Toilet 1980; 95(4): 81–85. 
21 Authors 
AH Kibbe. 
22 Date of Revision 
11 August 2005. 
Mineral Oil and Lanolin Alcohols 477

Monoethanolamine 
1 Nonproprietary Names 
BP: Ethanolamine 
USPNF: Monoethanolamine 
2 Synonyms 
b-Aminoethyl alcohol; colamine; ethylolamine; b-hydroxyethylamine; 
2-hydroxyethylamine. 
3 Chemical Name and CAS Registry Number 
2-Aminoethanol [141-43-5] 
4 Empirical Formula and Molecular Weight 
C2H7NO 61.08 
5 Structural Formula 
6 Functional Category 
Alkalizing agent; emulsifying agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Monoethanolamine is used primarily in pharmaceutical formulations 
for buffering purposes and in the preparation of 
emulsions. Other uses include as a solvent for fats and oils and 
as a stabilizing agent in an injectable dextrose solution of 
phenytoin sodium. 
Monoethanolamine is also used to produce a variety of salts 
with therapeutic uses. For example, a salt of monoethanolamine 
with vitamin C is used for intramuscular injection, while 
the salicylate and undecenoate monoethanolamine salts are 
utilized respectively in the treatment of rheumatism and as an 
antifungal agent. However, the most common therapeutic use 
of monoethanolamine is in the production of ethanolamine 
oleate injection, which is used as a sclerosing agent.(1) 
8 Description 
Monoethanolamine is a clear, colorless or pale yellow-colored, 
moderately viscous liquid with a mild, ammoniacal odor. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for monoethanolamine. 
Test BP 2004 USPNF 23 
Identification . — 
Characters . — 
Specific gravity 1.014–1.023 1.013–1.016 
Refractive index 1.453–1.459 — 
Related substances 42.0% — 
Distilling range — 167–1738C 
Residue on ignition — 40.1% 
Organic volatile impurities — . 
Assay 98.0–100.5% 98.0–100.5% 
10 Typical Properties 
Acidity/alkalinity: pH = 12.1 for a 0.1N aqueous solution. 
Boiling point: 170.88C 
Critical temperature: 3418C 
Density: 
1.0117 g/cm3 at 258C; 
0.9998 g/cm3 at 408C; 
0.9844 g/cm3 at 608C. 
Dissociation constant: pKa = 9.4 at 258C 
Flash point (open cup): 938C 
Hygroscopicity: very hygroscopic. 
Melting point: 10.38C 
Refractive index: nD
20 = 1.4539 
Solubility: see Table II. 
Table II: Solubility of monoethanolamine. 
Solvent Solubility at 208C 
Acetone Miscible 
Benzene 1 in 72 
Chloroform Miscible 
Ethanol (95%) Miscible 
Ethyl ether 1 in 48 
Glycerol Miscible 
Methanol Miscible 
Water Miscible 
Surface tension: 48.8mN/m at 208C 
Vapor density (relative): 2.1 (air = 1) 
Vapor pressure: 53.3 Pa (0.4 mmHg) at 208C 
Viscosity (dynamic): 
18.95 mPa s (18.95 cP) at 258C; 
5.03 mPa s (5.03 cP) at 608C. 
11 Stability and Storage Conditions 
Monoethanolamine is very hygroscopic and is unstable when 
exposed to light. Aqueous monoethanolamine solutions may be 
sterilized by autoclaving. 
When monoethanolamine is stored in large quantities, 
stainless steel is preferable for long-term storage. Copper, 
copper alloys, zinc, and galvanized iron are corroded by amines

and should not be used for construction of storage containers. 
Ethanolamines readily absorb moisture and carbon dioxide 
from the air; they also react with carbon dioxide. This can be 
prevented by sealing the monoethanolamine under an inert gas. 
Smaller quantities of monoethanolamine should be stored in an 
airtight container, protected from light, in a cool, dry place. 
12 Incompatibilities 
Monoethanolamine contains both a hydroxy group and a 
primary amine group and will thus undergo reactions 
characteristic of both alcohols and amines. Ethanolamines 
will react with acids to form salts and esters. Discoloration and 
precipitation will take place in the presence of salts of heavy 
metals. Monoethanolamine reacts with acids, acid anhydrides, 
acid chlorides, and esters to form amide derivatives, and with 
propylene carbonate or other cyclic carbonates to give the 
corresponding carbonates. 
As a primary amine, monoethanolamine will react with 
aldehydes and ketones to yield aldimines and ketimines. 
Additionally, monoethanolamine will react with aluminum, 
copper, and copper alloys to form complex salts. A violent 
reaction will occur with acrolein, acrylonitrile, epichlorohydrin, 
propiolactone, and vinyl acetate. 
13 Method of Manufacture 
Monoethanolamine is prepared commercially by the ammonolysis 
of ethylene oxide. The reaction yields a mixture of 
monoethanolamine, diethanolamine, and triethanolamine, 
which is separated to obtain the pure products. Monoethanolamine 
is also produced from the reaction between nitromethane 
and formaldehyde. 
14 Safety 
Monoethanolamine is an irritant, caustic material, but when it 
is used in neutralized parenteral and topical pharmaceutical 
formulations it is not usually associated with adverse effects, 
although hypersensitivity reactions have been reported. Monoethanolamine 
salts are generally regarded as being less toxic 
than monoethanolamine. 
LD50 (mouse, IP): 0.05 g/kg(2) 
LD50 (mouse, oral): 0.7 g/kg 
LD50 (rabbit, skin): 1.0 g/kg 
LD50 (rat, IM): 1.75 g/kg 
LD50 (rat, IP): 0.07 g/kg 
LD50 (rat, IV): 0.23 g/kg 
LD50 (rat, oral): 1.72 g/kg 
LD50 (rat, SC): 1.5 g/kg 
15 Handling Precautions 
When handling concentrated solutions of monoethanolamine, 
personal protective equipment such as an appropriate respirator, 
chemically resistant gloves, safety goggles, and other 
protective clothing should be worn. Transfer or prepare 
monoethanolamine solutions only in a chemical fume hood. 
Vapors may flow along surfaces to distant ignition sources 
and flash back. Closed containers exposed to heat may explode. 
Contact with strong oxidizers may cause fire. 
In the UK, the short-term (15-minute) occupational exposure 
limit for monoethanolamine is 15 mg/m3 (6 ppm) and the 
long-term exposure limit (8-hour TWA) is 7.6 mg/m3 
(3 ppm).(3) 
16 Regulatory Status 
Included in parenteral and nonparenteral medicines licensed in 
the UK and US. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Diethanolamine; triethanolamine. 
18 Comments 
The EINECS number for monoethanolamine is 205-483-3. 
19 Specific References 
1 Crotty B, Wood LJ, Willett IR, et al. The management of acutely 
bleeding varices by injection sclerotherapy. Med J Aust 1986; 145: 
130–133. 
2 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1607–1608. 
3 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
Kubis A, Jadach W, Malecka K. Studies on the release of solubilized 
drugs from ointment bases. Pharmazie 1984; 39: 168–170. 
21 Authors 
SR Goskonda, JC Lee. 
22 Date of Revision 
15 August 2005. 
Monoethanolamine 479

Monosodium Glutamate 
1 Nonproprietary Names 
USPNF: Monosodium glutamate 
2 Synonyms 
Chinese seasoning; E621; glutamic acid monosodium salt; 
glutamic acid, sodium salt; MSG; monosodium L-glutamate 
monohydrate; natrii glutamas; sodium L-glutamate; sodium 
glutamate monohydrate; sodium hydrogen L-(.)-2-aminoglutarate 
monohydrate. 
3 Chemical Name and CAS Registry Number 
Glutamic acid monosodium salt monohydrate [142-47-2] 
4 Empirical Formula and Molecular Weight 
C5H8NO4Na 169.13 (anhydrous) 
C5H8NO4NaH2O 187.13 (monohydrate) 
5 Structural Formula 
6 Functional Category 
Buffering agent; flavor enhancer. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Monosodium glutamate is used in oral pharmaceutical 
formulations as a buffer and a flavor enhancer. For example, 
it is used with sugar to improve the palatability of bitter-tasting 
drugs and can reduce the metallic taste of iron-containing 
liquids. However, the most widespread use of monosodium 
glutamate is as a flavor enhancer in food products. Typically, 
0.2–0.9% is used in normally salted foods, although products 
such as soy protein can contain 10–30%. The use of 
monosodium glutamate in food products has been controversial 
owing to the relatively high number of adverse reactions 
attributed to the substance, which gives rise to the so-called 
‘Chinese Restaurant Syndrome’ (see Section 18). 
8 Description 
Monosodium glutamate occurs as white free-flowing crystals 
or a crystalline powder. It is practically odorless and has a meatlike 
taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for monosodium glutamate. 
Test USPNF 23 
Identification . 
Clarity and color of solution . 
Specific rotation .24.88 to .25.38 
pH (5% solution) 6.7–7.2 
Loss on drying 40.5% 
Chloride 40.25% 
Lead 410 ppm 
Heavy metals 40.002% 
Organic volatile impurities . 
Assay 99.0–100.5% 
10 Typical Properties 
Acidity/alkalinity: pH = 7.0 (0.2% w/v aqueous solution) 
Melting point: 2328C 
Solubility: soluble in water; sparingly soluble in ethanol (95%). 
Specific rotation [a]D
25 .24.28 to .25.58 at 258C (8.0% w/v in 
1.0N HCl) 
11 Stability and Storage Conditions 
Aqueous solutions of monosodium glutamate may be sterilized 
by autoclaving. Monosodium glutamate should be stored in a 
tight container in a cool, dry place. 
12 Incompatibilities 
—
13 Method of Manufacture 
Monosodium glutamate is the monosodium salt of the 
naturally occurring L-form of glutamic acid. It is commonly 
manufactured by fermentation of carbohydrate sources such as 
sugar beet molasses. In general, sugar beet products are used in 
Europe and the USA. Other carbohydrate sources such as sugar 
cane and tapioca are used in Asia. 
14 Safety 
Monosodium glutamate is widely used in foods and oral 
pharmaceutical formulations. It is generally regarded as 
moderately toxic on ingestion or intravenous administration. 
Adverse effects include somnolence, hallucinations and distorted 
perceptions, headache, dyspnea, nausea or vomiting, and 
dermatitis. The lowest lethal oral dose in humans is reported to 
be 43 mg/kg.(1) See also Section 18. 
LD50 (cat, SC): 8.0 g/kg(1) 
LD50 (guinea pig, IP): 15 g/kg 
LD50 (mouse, IP): 3.8 g/kg 
LD50 (mouse, IV): 30 g/kg 
LD50 (mouse, oral): 11.4 g/kg 
LD50 (mouse, SC): 8.2 g/kg 
LD50 (rat, IP): 4.3 g/kg

LD50 (rat, IV): 3.3 g/kg 
LD50 (rat, oral): 16.6 g/kg 
LD50 (rat, SC): 5.6 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. When heated to decomposition, 
monosodium glutamate emits toxic fumes of NOx and 
Na2O. 
16 Regulatory Status 
GRAS listed. Accepted in Europe for use as a food additive in 
certain applications. Included in the FDA Inactive Ingredients 
Guide (oral syrup). Included in nonparenteral medicines 
licensed in the UK. 
17 Related Substances 
—
18 Comments 
Monosodium glutamate has been associated with reports of 
adverse reactions termed ‘Chinese Restaurant Syndrome’ after 
it was first self-reported by a physician who regularly 
experienced numbness and palpitations after consuming 
Chinese food.(2) 
Subsequent to this first report, numerous other anecdotal 
reports of adverse reactions to monosodium glutamate were 
made, with symptoms occurring at doses of 1.5–12 g. Reactions 
include paresthesias or a skin burning sensation, facial pressure 
or tightness sensation, and substernal chest pressure. Severity of 
reaction corresponded with increased dose. Reports of ‘Chinese 
Restaurant Syndrome’ in children are rare. A variety of other 
adverse reactions to monosodium glutamate have also been 
reported including flushing, asthma,(3) headache, behavioral 
abnormalities, and ventricular tachycardia.(4) 
Placebo-controlled, blinded, trials of monosodium glutamate 
consumption have, however, largely failed to reproduce 
the full effects of ‘Chinese Restaurant Syndrome’ as it was 
originally described and symptoms may be simply due to 
dyspepsia. Some dose-dependent adverse reactions may be 
attributed to monosodium glutamate, with doses of 5 g 
producing reactions in 30% of individuals tested.(5) In the 
USA, the FDA has stated that monosodium glutamate and 
related substances are safe food ingredients for most people 
when used at ‘customary’ levels.(6) 
Monosodium glutamate monohydrate 32 g is approximately 
equivalent to anhydrous monosodium glutamate 29 g 
or glutamic acid 25 g. Each gram of monosodium glutamate 
monohydrate represents 5.3 mmol (5.3 mEq) of sodium. 
A specification for monosodium glutamate is contained in 
the Food Chemicals Codex (FCC). The EINECS number for 
monosodium glutamate is 205-538-1. 
19 Specific References 
1 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2573. 
2 Kwok HM. Chinese restaurant syndrome. N Engl J Med 1968; 
278: 796. 
3 Allen DH, Baker GH. Chinese restaurant asthma. N Engl J Med 
1981; 305: 1154–1155. 
4 Smolinske SC. Handbook of Food, Drug and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 235–241. 
5 Kenney RA. The Chinese restaurant syndrome: an anecdote 
revisited. Food Chem Toxicol 1986; 24: 351–354. 
6 Anonymous. Monosodium glutamate safe for most people, says 
FDA. Pharm J 1996; 256: 83. 
20 General References 
Chevassus H, Renard E, Bertrand G, et al. Effects of oral monosodium 
L-glutamate on insulin secretion and glucose tolerance in healthy 
volunteers. Br J Clin Pharmacol 2002; 53(6): 641–643. 
Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients Directory 1996. Tokyo: Yakuji Nippo, 1996: 335. 
Walker R. The significance of excursions above the ADI. Case study: 
monosodium glutamate. Reg Toxicol Pharmacol 1999; 30: S119– 
S121. 
21 Authors 
PJ Weller. 
22 Date of Revision 
14 August 2005. 
Monosodium Glutamate 481

Monothioglycerol 
1 Nonproprietary Names 
USPNF: Monothioglycerol 
2 Synonyms 
1-Mercaptoglycerol; 1-mercapto-2,3-propanediol; monothioglycerin; 
a-monothioglycerol; thioglycerin; 1-thioglycerol. 
3 Chemical Name and CAS Registry Number 
3-Mercapto-1,2-propanediol [96-27-5] 
4 Empirical Formula and Molecular Weight 
C3H8O2S 108.16 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; antioxidant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Monothioglycerol is used as an antioxidant in pharmaceutical 
formulations, mainly in parenteral preparations.(1) Monothioglycerol 
is reported to have some antimicrobial activity.(2–4) It is 
also widely used in cosmetic formulations such as depilating 
agents. 
Therapeutically, monothioglycerol has been used in a 
0.02% w/w aqueous solution to stimulate wound healing, 
and as a 0.1% w/w jelly in atrophic rhinitis. 
8 Description 
Monothioglycerol occurs as a colorless or pale-yellow colored, 
viscous, hygroscopic liquid with a slight odor of sulfide. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for monothioglycerol. 
Test USPNF 23 
Specific gravity 1.241–1.250 
Refractive index 1.521–1.526 
pH (10% aqueous solution) 3.5–7.0 
Water 45.0% 
Residue on ignition 40.1% 
Selenium 40.003% 
Heavy metals 40.002% 
Organic volatile impurities . 
Assay (anhydrous basis) 97.0–101.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 3.5–7.0 (10% w/v aqueous solution) 
Boiling point: 1188C 
Flash point: 1108C 
Refractive index: nD
25 = 1.521–1.526 
Solubility: miscible with ethanol (95%); freely soluble in water; 
practically insoluble in ether. 
Specific gravity: 1.241–1.250 
11 Stability and Storage Conditions 
Monothioglycerol is unstable in alkaline solutions. Monothioglycerol 
should be stored in a well-closed container in a cool, 
dry place. 
12 Incompatibilities 
Monothioglycerol can react with oxidizing materials. 
13 Method of Manufacture 
Monothioglycerol is prepared by heating an ethanolic solution 
of 3-chloro-1,2-propanediol with potassium bisulfide. 
14 Safety 
Monothioglycerol is generally regarded as a relatively nontoxic 
and nonirritant material at the concentrations used as a 
pharmaceutical excipient. It is used in topical and injectable 
preparations. 
Undiluted monothioglycerol is considered a poison by the IP 
and IV routes; it has also been reported to be mutagenic.(5) 
LD50 (cat, IV): 0.22 g/kg(5) 
LD50 (mouse, IP): 0.34 g/kg 
LD50 (rabbit, IV): 0.25 g/kg 
LD50 (rat, IP): 0.39 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Monothioglycerol is 
flammable when exposed to heat or flame; when heated to 
decomposition it emits toxic fumes of SOx.

16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IM, IV and 
other injections). Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
—
18 Comments 
The EINECS number for monothioglycerol is 202-495-0. 
19 Specific References 
1 Kasraian K, Kuzniar AA, Wilson GG, Wood JA. Developing an 
injectable formula containing an oxygen sensitive drug: case study 
of danofloxacin injectable. Pharm Dev Technol 1999; 4(4): 475– 
480. 
2 Jensen KK, Javor GT. Inhibition of Escherichia coli by thioglycerol. 
Antimicrob Agents Chemother 1981; 19: 556–561. 
3 Javor GT. Depression of adenoslymethionine content of Escherichia 
coli by thioglycerol. Antimicrob Agents Chemother 1983; 24: 
860–867. 
4 Javor GT. Inhibition of respiration of Escherichia coli by 
thioglycerol. Antimicrob Agents Chemother 1983; 24: 868–870. 
5 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2574. 
20 General References 
Nealon DA, Pettit SM, Henderson AR. Diluent pH and the stability of 
the thiol group in monothioglycerol, N-acetyl-L-cysteine, and 2- 
mercaptoethanol. Clin Chem 1981; 27(3): 505–506. 
21 Authors 
PJ Sheskey, PJ Weller. 
22 Date of Revision 
14 August 2005. 
Monothioglycerol 483

Myristic Acid 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Edenor C14 98-100; n-tetradecanoic acid; 1-tridecanecarboxylic 
acid. 
3 Chemical Name and CAS Registry Number 
Tetradecanoic acid [544-63-8] 
4 Empirical Formula and Molecular Weight 
C14H28O2 228.37 
5 Structural Formula 
6 Functional Category 
Emulsifying agent; skin penetrant; tablet and capsule lubricant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Myristic acid is used in oral and topical pharmaceutical 
formulations. Myristic acid has been evaluated as a penetration 
enhancer in melatonin transdermal patches in rats(1) and 
bupropion formulations on human cadaver skin.(2) Further 
studies have assessed the suitability of myristic acid in 
oxymorphone formulations(3) and clobetasol 17-propionate 
topical applications.(4) 
8 Description 
Myristic acid occurs as an oily white crystalline solid with a 
faint odor. 
9 Pharmacopeial Specifications 
See Section 18. 
10 Typical Properties 
Boiling point: 326.28C 
Flash point: >1108C 
Melting point: 54.58C 
Solubility: soluble in acetone, benzene, chloroform, ethanol 
(95%), ether, and aromatic and chlorinated solvents; 
practically insoluble in water. 
Specific gravity: 0.860–0.870 
11 Stability and Storage Conditions 
The bulk material should be stored in a well-closed container in 
a cool, dry, place. 
12 Incompatibilities 
Myristic acid is incompatible with strong oxidizing agents and 
bases. 
13 Method of Manufacture 
Myristic acid occurs naturally in nutmeg butter and in most 
animal and vegetables fats. Synthetically, it may be prepared by 
electrolysis of methyl hydrogen adipate and decanoic acid or by 
Maurer oxidation of myristyl alcohol. 
14 Safety 
Myristic acid is used in oral and topical pharmaceutical 
formulations and is generally regarded as nontoxic and 
nonirritant at the levels employed as an excipient. However, 
myristic acid is reported to be an eye and skin irritant at high 
levels and is poisonous by intravenous administration. Mutation 
data have also been reported.(5) 
LD50 (mouse, IV): 43 mg/kg(5) 
LD50 (rat, oral): >10 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of the material handled. Acrid smoke and 
irritating fumes are emitted when myristic acid is heated to 
decomposition. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(oral capsules). Included in nonparenteral medicines licensed in 
the UK. 
17 Related Substances 
Lauric acid; myristyl alcohol; palmitic acid; potassium myristate; 
sodium myristate; stearic acid. 
Myristyl alcohol 
Empirical formula: C14H30O 
Molecular weight: 214.39 
CAS number: [112-72-1] 
Melting point: 37–398C 
Boiling point: 277–2888C 
Specific gravity: 0.8 
Solubility: practically insoluble in water. 
Potassium myristate 
Empirical formula: C14H28O2K 
Molecular weight: 267.52 
CAS number: [13429-27-1]

Comments: potassium myristate is used as surfactant and 
emulsifying agent in pharmaceutical formulations. The 
EINECS number for potassium myristate is 236-550-5. 
Sodium myristate 
Empirical formula: C14H28O2Na 
Molecular weight: 251.41 
CAS number: [822-12-8] 
Comments: sodium myristate is used as an emulsifying agent in 
pharmaceutical formulations. The EINECS number for 
sodium myristate is 212-487-9. 
18 Comments 
Although not included in any pharmacopeias, a specification 
for myristic acid is contained in the Food Chemicals Codex 
(FCC) and in the Japanese Pharmaceutical Excipients (JPE), see 
Table I. 
The EINECS number for myristic acid is 208-875-2. 
Table I: Food Chemicals Codex(6) and Japanese Pharmaceutical 
Excipients(7) specifications for myristic acid. 
Test FCC 1996 JPE 2004 
Identification — . 
Acid value 242–249 240–250 
Heavy metals 410 mg/kg . 
Iodine value 41.0 41.0 
Residue on ignition 40.1% 40.1% 
Saponification value 242–251 — 
Melting point 48–55.58C — 
Unsaponifiable matter 41% — 
Water 40.2% — 
Ester value — 43 
19 Specific References 
1 Kanikkannan N, Andega S, Burton S, et al. Formulation and in 
vitro evaluation of transdermal patches of melatonin. Drug Dev 
Ind Pharm 2004; 30: 205–212. 
2 Gondaliya D, Pundarikakshudu K. Studies in formulation and 
pharmacotechnical evaluation of controlled release transdermal 
delivery system of bupropion. AAPS PharmSci Tech 2003; 4: E3. 
3 Aungst BJ, Blake JA, Rogers NJ, Hussain MA. Transdermal 
oxymorphone formulation development and methods for evaluating 
flux and lag times for two skin permeation-enhancing vehicles. 
J Pharm Sci 1990; 79: 1072–1076. 
4 Fang JY, Shen KL, Huang YB, et al. Evaluation of topical 
application of clobetasol 17-propionate from various cream bases. 
Drug Dev Ind Pharm 1999; 25: 7–14. 
5 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2586. 
6 Food Chemicals Codex, 4th edn. Washington, DC: National 
Academy Press, 1996: 262. 
7 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004: 572. 
20 General References 
—
21 Authors 
LY Galichet. 
22 Date of Revision 
24 May 2005. 
Myristic Acid 485

Neohesperidin Dihydrochalcone 
1 Nonproprietary Names 
BP: Neohesperidin dihydrochalcone 
PhEur: Neohesperidin dihydrochalconum 
2 Synonyms 
Citrosa; 3,5-dihydroxy-4-(3-hydroxy-4-methoxyhydrocinnamoyl)
phenyl-2-O-(6-deoxy-a-L-mannopyranosyl)-b-D-glucopyranoside; 
3,5-dihydroxy-4-[3-(3-hydroxy-4-methoxyphenyl) 
propionyl]phenyl-2-O-(6-deoxy-a-L-mannopyranosyl)-b-Dglucopyranoside; 
E959; neohesperidin DC; neohesperidin 
DHC; neohesperidine dihydrochalcone; NHDC; 1-propanone, 
1-[4-[[2-O-6-deoxy-a-L-mannopyranosyl)-b-D-glycopyranosyl 
]oxy]-2,6-dihydroxyphenyl]-3-(3-hydroxy-4-methoxyphenyl); 
Sukor. 
3 Chemical Name and CAS Registry Number 
1-[4-[[2-O-(6-Deoxy-a-L-mannopyranosyl)-b-D-glucopyranosyl]
oxy]-2,6-dihydroxyphenyl]-3-(3-hydroxy-4-methoxyphenyl)
propan-1-one [20702-77-6] 
4 Empirical Formula and Molecular Weight 
C28H36O15 612.58 
5 Structural Formula 
6 Functional Category 
Flavor enhancer; sweetening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Neohesperidin dihydrochalcone is a synthetic intense sweetening 
agent approximately 1500–1800 times sweeter than 
sucrose and 20 times sweeter than saccharin. Structurally it is 
an analogue of neohesperidin, a flavanone that occurs naturally 
in Seville oranges (Citrus aurantium). Neohesperidin dihydrochalcone 
is used in pharmaceutical and food applications as a 
sweetening agent and flavor enhancer. The sweetness profile is 
characterized by a lingering sweet/menthol-like aftertaste.(1) 
The typical level used in foods is 1–5 ppm although much 
higher levels may be used in certain applications such as 
chewing gum. Synergistic effects occur with other intense and 
bulk sweeteners such as acesulfame K, aspartame, polyols, and 
saccharin.(2) 
In pharmaceutical applications, neohesperidin dihydrochalcone 
is useful in masking the unpleasant bitter taste of a number 
of drugs such as antacids, antibiotics, and vitamins. In antacid 
preparations levels of 10–30 ppm result in improved palatability. 
8 Description 
Neohesperidin dihydrochalcone occurs as a white or yellowishwhite 
powder with an intensely sweet taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for neohesperidin 
dihydrochalcone. 
Test PhEur 2005 
Identification . 
Characters . 
Appearance of solution . 
Related substances . 
Heavy metals 410 ppm 
Water 412.0% 
Sulfated ash 40.2% 
Assay (anhydrous substance) 96.0–101.0% 
10 Typical Properties 
Hygroscopicity: slightly hygroscopic; absorbs up to 15% of 
water. 
Melting point: 156–1588C 
Solubility: see Table II. 
Table II: Solubility of neohesperidin dihydrochalcone. 
Solvent Solubility at 258C unless otherwise 
stated 
Dichloromethane Practically insoluble 
Dimethyl sulfoxide Freely soluble 
Methanol Soluble 
Water 1 in 2000 at 228C 
1 in 1.54 at 808C 
11 Stability and Storage Conditions 
Neohesperidin dihydrochalcone is stable for over three years 
when stored at room temperature.(1) 
Accelerated stability studies on aqueous solutions stored 
at 30–608C and pH 1–7 for 140 days indicate that neohes

peridin dihydrochalcone solutions are likely to be stable for 12 
months at room temperature and pH 2–6.(3) Solutions 
formulated with some or all of the water replaced by solvents 
with a lower dielectric constant are reported to have longer 
shelf-lives.(4) 
The bulk material should be stored in a cool, dry, place 
protected from light. 
12 Incompatibilities 
—
13 Method of Manufacture 
Neohesperidin dihydrochalcone is synthesized commercially 
from either of the bitter-flavanones neohesperidin or naringin 
by catalytic hydrogenation under alkaline conditions in a 
process first described in the 1960s, in which neohesperidin 
is purified by recrystallization from water solutions.(5) Neohesperidin 
dihydrochalcone is obtained by the alkaline hydrogenation 
of neohesperidin.(6) 
14 Safety 
Neohesperidin dihydrochalcone is accepted for use in food 
products either as a sweetener or flavor modifier in a number of 
areas including Europe, US, Australia, New Zealand, and 
several countries in Africa and Asia. It is also used in a number 
of oral pharmaceutical formulations. 
Animal toxicity studies suggest that neohesperidin dihydrochalcone 
is a nontoxic, nonteratogenic, and noncarcinogenic 
material at the levels used in foods and 
pharmaceuticals.(7,8) In Europe, an acceptable daily intake of 
0–5 mg/kg bodyweight has been established.(9,10) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
17 Related Substances 
Hesperidin. 
Hesperidin 
Empirical formula: C28H34O15 
Molecular weight: 610.56 
CAS number: [520-26-3] 
Synonyms: (2S)-7-[[6-O-(6-Deoxy-a-L-mannopyranosyl)-b-Dglucopyranosyl]
oxy]-2,3-dihydro-5-hydroxy-2-(3-hydroxy- 
4-methoxyphenyl)-4H-1-benzopyran-4-one; hesperitin 7- 
rhamnoglucoside; hesperetin-7-rutinoside. 
Melting point: 258–2628C 
Solubility: freely soluble in diluted alkalis and pyridines; soluble 
in formamide; slightly soluble in methanol and hot glacial 
acetic acid. 
Comments: hesperedin is the predominant flavonoid in lemons 
and sweet oranges (Citrus sinensis). 
18 Comments 
Neohesperidin dihydrochalcone is sufficiently soluble in 
aqueous solutions for most pharmaceutical and food applications; 
however, solubility may be improved by dissolving in 
ethanol, glycerin, propylene glycol, or aqueous mixtures of 
these solvents.(10) Solubility may also be improved by mixing 
with other intense or bulk sweeteners.(2) 
Neohesperidin dihydrochalcone in weak concentrations has 
been shown not to enhance the taste of aqueous sucrose 
solutions.(6) 
The EINECS number for neohesperidin dihydrochalcone is 
243-978-6. 
19 Specific References 
1 Cano J, Montijano H, Lopez Cremades F. Masking the bitter taste 
of pharmaceuticals. Manuf Chem 2000; 71(7): 16–17. 
2 Benavente-Garcia O, Castillo J, Del Bano MJ, Lorente J. Improved 
water solubility of neohesperidin dihydrochalcone sweetener 
blends. J Agric Food Chem 2001; 49(1): 189–191. 
3 Canales I, Borrego F, Lindley MG. Neohesperidin dihydrochalcone 
stability in aqueous buffer solutions. J Food Sci 1993; 58: 589– 
591, 643. 
4 Montijano H, Borrego F. Hydrolysis of the intense sweetener 
neohesperidine dihydrochalcone in water–organic solvent mixtures. 
Int J Food Sci Technol 1999; 34: 291–294. 
5 Horowitz RM, Gentili B. Dihydrochalcone derivatives and their 
use as sweetening agents. US Patent No. 3,087,821; 1963. 
6 Kroeze JH. Neohesperidine dihydrochalcone is not a taste 
enhancer in aqueous solutions. Chem Senses 2000; 25(5): 555– 
559. 
7 Lina BAR, Dreef-van der Meulen HC, Leegwater DC. Subchronic 
(13-week) oral toxicity of neohesperidin dihydrochalcone in rats. 
Food Chem Toxicol 1990; 28(7): 507–513. 
8 Waalkens-Berendsen DH, Kuilman-Wahls ME, Bar A. Embryotoxicity 
and teratogenicity study with neohesperidin dihydrochalcone 
in rats. Regul Toxicol Pharmacol 2004; 40(1): 74–79. 
9 Horowitz RM, Gentili B. Dihydrochalcone sweeteners from citrus 
flavanones. In: O’Brien Nabors L, Gelardi RC, eds. Alternative 
Sweeteners, 2nd edn. New York: Marcel Dekker, 1991: 97–115. 
10 Borrego F, Montijano H. Neohesperidin dihydrochalcone. In: 
O’Brien Nabors L, ed. Alternative Sweeteners, 3rd edn. New York: 
Marcel Dekker, 2001: 87–104. 
20 General References 
Borrego F, Montijano H. Potential applications of the sweetener 
neohesperidin dihydrochalcone in drugs [in German]. Pharm Ind 
1995; 57: 880–882. 
Borrego F. Neohesperidine DC. In: Birch G, ed. Ingredients Handbook: 
Sweeteners, 2nd edn. Leatherhead: Leatherhead Publishing, 2000: 
205–220. 
Colaizzi JL. Synthetic sweeteners—toxicity problems and current 
status. J Am Pharm Assoc 1971; NS11(Mar): 135–138. 
DuBois GE, Crosby GA, Saffron P. Non-nutritive sweeteners: taste– 
structure relationships for some new simple dihydrochalcones. 
Science 1977; 195: 397–399. 
Lautenbacher L. Neohesperidin DC (PhEur): an exceptional sweetener 
from Spanish bitter oranges—application and approval in finished 
drugs [in German]. Pharm Ind 2003; 65: 82–83. 
Lindley MG. Neohesperidine dihydrochalcone: recent findings and 
technical advances. In: Grenby TH, ed. Advances in Sweeteners. 
Glasgow: Blackie Academic and Professional, 1996: 240–252. 
Nakazato M, Kobayashi C, Yamajima Y, et al. Determination of 
neohesperidin dihydrochalcone in foods [in Japanese]. Shokuhin 
Eiseigaku Zasshi 2001; 42(1): 40–44. 
21 Authors 
PJ Weller. 
22 Date of Revision 
23 May 2005. 
Neohesperidin Dihydrochalcone 487

Nitrogen 
1 Nonproprietary Names 
BP: Nitrogen 
JP: Nitrogen 
PhEur: Nitrogenium 
USPNF: Nitrogen 
2 Synonyms 
Azote; E941. 
3 Chemical Name and CAS Registry Number 
Nitrogen [7727-37-9] 
4 Empirical Formula and Molecular Weight 
N2 28.01 
5 Structural Formula 
N2 
6 Functional Category 
Aerosol propellant; air displacement. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Nitrogen and other compressed gases such as carbon dioxide 
and nitrous oxide are used as propellants for topical 
pharmaceutical aerosols. They are also used in other aerosol 
products that work satisfactorily with the coarse aerosol spray 
produced with compressed gases, e.g. furniture polish and 
window cleaner. Nitrogen is insoluble in water and other 
solvents, and therefore remains separated from the actual 
pharmaceutical formulation. 
Advantages of compressed gases as aerosol propellants are 
that they are inexpensive; of low toxicity; and practically 
odorless and tasteless. In contrast to liquefied gases, their 
pressures change relatively little with temperature. However, 
there is no reservoir of propellant in the aerosol and as a result 
the pressure decreases as the product is used, changing the 
spray characteristics. 
Misuse of a product by the consumer, such as using a 
product inverted, results in the discharge of the vapor phase 
instead of the liquid phase. Most of the propellant is contained 
in the vapor phase and therefore some of the propellant will be 
lost and the spray characteristics will be altered. Additionally, 
the sprays produced using compressed gases are very wet. 
However, recent developments in valve technology have 
reduced the risk of misuse by making available valves which 
will spray only the product (not propellant) regardless of the 
position of the container. Additionally, barrier systems will also 
prevent loss of propellant. 
Nitrogen is also used to displace air from solutions subject to 
oxidation, by sparging, and to replace air in the headspace 
above products in their final packaging, e.g. in parenteral 
products packaged in glass ampoules. Nitrogen is also used for 
the same purpose in many food products. 
8 Description 
Nitrogen occurs naturally as approximately 78% v/v of the 
atmosphere. It is a nonreactive, noncombustible, colorless, 
tasteless, and odorless gas. It is usually handled as a compressed 
gas, stored in metal cylinders. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for nitrogen. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters — . — 
Odor — — . 
Carbon monoxide — 45 ppm 40.001% 
Carbon dioxide . 4300 ppm — 
Water — 467 ppm — 
Oxygen — 450 ppm 41.0% 
Assay 599.5% 599.5% 599.0% 
10 Typical Properties 
Boiling point: 195.88C 
Critical pressure: 3.39 mPa (33.49 atm) 
Critical temperature: 147.28C 
Density: 0.967 g/cm3 for vapor at 218C. 
Flammability: nonflammable 
Melting point: 2108C 
Solubility: practically insoluble in water and most solvents; 
soluble in water under pressure. 
Vapor density (absolute): 1.25 g/cm3 at standard temperature 
and pressure. 
Vapor density (relative): 0.97 (air = 1) 
11 Stability and Storage Conditions 
Nitrogen is stable and chemically unreactive. It should be 
stored in tightly sealed metal cylinders in a cool, dry place. 
12 Incompatibilities 
Generally compatible with most materials encountered in 
pharmaceutical formulations and food products. 
13 Method of Manufacture 
Nitrogen is obtained commercially, in large quantities, by the 
fractional distillation of liquefied air.

14 Safety 
Nitrogen is generally regarded as a nontoxic and nonirritant 
material. However, it is an asphyxiant and inhalation of large 
quantities is therefore hazardous. See also Section 18. 
15 Handling Precautions 
Handle in accordance with procedures for handling metal 
cylinders containing liquefied or compressed gases. Eye 
protection, gloves, and protective clothing are recommended. 
Nitrogen is an asphyxiant and should be handled in a wellventilated 
environment. The oxygen content of air in the 
working environment should be monitored and should not be 
permitted to fall below 19% v/v at normal atmospheric 
pressure.(1) 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(injections; dental preparations; nasal sprays; oral solutions; 
rectal gels). Accepted for use as a food additive in Europe. 
Included in parenteral and nonparenteral medicines licensed in 
the UK and USA. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Carbon dioxide; nitrous oxide. 
18 Comments 
Different grades of nitrogen are commercially available that 
have, for example, especially low moisture levels. 
Nitrogen is commonly used as a component of the gas 
mixtures breathed by divers. Under high pressure, such as when 
diving at great depths, nitrogen will dissolve in blood and lipid. 
If decompression is too rapid, decompression sickness may 
occur when the nitrogen effervesces from body stores to form 
gas emboli. 
A specification for nitrogen is contained in the Food 
Chemicals Codex (FCC). The EINECS number for nitrogen is 
231-783-9. 
19 Specific References 
1 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
Johnson MA. The Aerosol Handbook, 2nd edn. New Jersey: WE 
Dorland, 1982: 361–372. 
Sanders PA. Handbook of Aerosol Technology, 2nd edn. New York: 
Van Nostrand Reinhold, 1979: 44–54. 
Sciarra JJ. Pharmaceutical aerosols. In: Banker GS, Rhodes CT, eds. 
Modern Pharmaceutics, 3rd edn. New York: Marcel Dekker, 1996: 
547–574. 
Sciarra JJ, Sciarra CJ. Aerosols. In: Gennaro AR, ed. Remington: The 
Science and Practice of Pharmacy, 20th edn. Baltimore: Lippincott 
Williams and Wilkins, 2000: 963–979. 
Sciarra JJ, Stoller L. The Science and Technology of Aerosol Packaging. 
New York: Wiley, 1974: 137–145. 
21 Authors 
CJ Sciarra, JJ Sciarra. 
22 Date of Revision 
23 August 2005. 
Nitrogen 489

Nitrous Oxide 
1 Nonproprietary Names 
BP: Nitrous oxide 
JP: Nitrous oxide 
PhEur: Dinitrogenii oxidum 
USP: Nitrous oxide 
2 Synonyms 
Dinitrogen monoxide; E942; laughing gas; nitrogen monoxide. 
3 Chemical Name and CAS Registry Number 
Dinitrogen oxide [10024-97-2] 
4 Empirical Formula and Molecular Weight 
N2O 44.01 
5 Structural Formula 
N2O 
6 Functional Category 
Aerosol propellant; therapeutic agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Nitrous oxide and other compressed gases such as carbon 
dioxide and nitrogen are used as propellants for topical 
pharmaceutical aerosols. They are also used in other aerosol 
products that work satisfactorily with the coarse aerosol spray 
that is produced with compressed gases, e.g. furniture polish 
and window cleaner. 
The advantages of compressed gases as aerosol propellants 
are that they are inexpensive, of low toxicity, and practically 
odorless and tasteless. In contrast to liquefied gases, their 
pressures change relatively little with temperature. However, 
there is no reservoir of propellant in the aerosol, and as a result 
the pressure decreases as the product is used, changing the 
spray characteristics. 
Misuse of a product by the consumer, such as using a 
product inverted, results in the discharge of the vapor phase 
instead of the liquid phase. Since most of the propellant is 
contained in the vapor phase, some of the propellant will be lost 
and the spray characteristics will be altered. Additionally, the 
sprays produced using compressed gases are very wet. 
However, recent developments in valve technology have 
reduced the risk of misuse by making available valves which 
will spray only the product (not propellant) regardless of the 
position of the container. Additionally, barrier systems will also 
prevent loss of propellant. 
Therapeutically, nitrous oxide is best known as an anesthetic 
administered by inhalation. When used as an anesthetic it has 
strong analgesic properties but produces little muscle relaxation. 
Nitrous oxide is always administered in conjunction with 
oxygen since on its own it is hypoxic. 
8 Description 
Nitrous oxide is a nonflammable, colorless and odorless, sweettasting 
gas. It is usually handled as a compressed gas, stored in 
metal cylinders. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for nitrous oxide. 
Test JP 2001 PhEur 2005 USP 28 
Production — . — 
Identification . . . 
Characters — . — 
Acidity or alkalinity . — — 
Carbon dioxide . 4300 ppm 40.03% 
Carbon monoxide . 45 ppm 40.001% 
Nitric oxide — — 41 ppm 
Nitrogen dioxide — — 41 ppm 
Nitric monoxide and 
nitrogen dioxide 
— 42 ppm — 
Halogens — — 41 ppm 
Oxidizing substances . — — 
Potassium permanganatereducing 
substances 
. — — 
Ammonia — — 40.0025% 
Chloride . — — 
Air — — 41.0% 
Water — 467 ppm <0.03% 
Assay 597.0% 598.0% 599.0% 
10 Typical Properties 
Boiling point: 88.58C 
Critical pressure: 7.27 mPa (71.7 atm) 
Critical temperature: 36.58C 
Density: 1.53 g/cm3 
Flammability: nonflammable, but supports combustion. 
Freezing point: 90.88C 
Solubility: freely soluble in chloroform, ethanol (95%), ether, 
and oils; soluble 1 in 1.5 volumes of water at 208C and 
101.3 kPa pressure. 
Vapor density (absolute): 1.97 g/cm3 at standard temperature 
and pressure. 
Vapor density (relative): 1.52 (air = 1) 
11 Stability and Storage Conditions 
Nitrous oxide is essentially nonreactive and stable except at 
high temperatures; at a temperature greater than 5008C nitrous 
oxide decomposes to nitrogen and oxygen. Explosive mixtures 
may be formed with other gases such as ammonia, hydrogen, 
and other fuels. Nitrous oxide should be stored in a tightly 
sealed metal cylinder in a cool, dry place.

12 Incompatibilities 
Nitrous oxide is generally compatible with most materials 
encountered in pharmaceutical formulations, although it may 
react as a mild oxidizing agent. 
13 Method of Manufacture 
Nitrous oxide is prepared by heating ammonium nitrate to 
about 1708C. This reaction also forms water. 
14 Safety 
Nitrous oxide is most commonly used therapeutically as an 
anesthetic and analgesic. Reports of adverse reactions to 
nitrous oxide therefore generally concern its therapeutic use, 
where relatively large quantities of the gas may be inhaled, 
rather than its use as an excipient. 
The main complications associated with nitrous oxide 
inhalation occur as a result of hypoxia. Prolonged administration 
may also be harmful. Nitrous oxide is rapidly absorbed on 
inhalation. 
15 Handling Precautions 
Handle in accordance with procedures for handling metal 
cylinders containing liquefied or compressed gases. Eye 
protection, gloves, and protective clothing are recommended. 
Nitrous oxide is an anesthetic gas and should be handled in a 
well-ventilated environment. In the UK, the recommended 
long-term (8-hour TWA) occupational exposure limit for 
nitrous oxide is 183 mg/m3 (100 ppm).(1) 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in nonparenteral medicines licensed in the UK and 
USA. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Carbon dioxide; nitrogen. 
18 Comments 
A mixture of 50% nitrous oxide and 50% oxygen (Entonox, 
BOC) is commonly used as an analgesic administered by 
inhalation. 
A specification for nitrous oxide is contained in the Food 
Chemicals Codex (FCC). The EINECS number for nitrous 
oxide is 233-032-0. 
19 Specific References 
1 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
Johnson MA. The Aerosol Handbook, 2nd edn. New Jersey: WE 
Dorland, 1982: 361–372. 
Sanders PA. Handbook of Aerosol Technology, 2nd edn. New York: 
Van Nostrand Reinhold, 1979: 44–54. 
Sciarra JJ. Aerosol suspensions and emulsions. In: Pharmaceutical 
Dosage Forms; Disperse Systems, 2nd edn, vol. 2. New York: 
Marcel Dekker, 1996: 319–356. 
Sciarra JJ. Pharmaceutical aerosols. In: Banker GS, Rhodes CT, eds. 
Modern Pharmaceutics, 3rd edn. New York: Marcel Dekker, 1996: 
547–574. 
Sciarra JJ, Sciarra CJ. Aerosols. In: Gennaro AR, ed. Remington: The 
Science and Practice of Pharmacy, 20th edn. Baltimore: Lippincott 
Williams and Wilkins, 2000: 963–979. 
Sciarra JJ, Stoller L. The Science and Technology of Aerosol Packaging. 
New York: Wiley, 1974: 137–145. 
21 Authors 
CJ Sciarra, JJ Sciarra. 
22 Date of Revision 
23 August 2005. 
Nitrous Oxide 491

Octyldodecanol 
1 Nonproprietary Names 
PhEur: Octyldodecanolum 
USPNF: Octyldodecanol 
2 Synonyms 
Eutanol G PH; isoarachidyl alcohol; isoeicosyl alcohol; Jarcol 
1-20; Jeecol ODD; octildodecanol; 2-octyldecyl alcohol; 2- 
octyl-1-dodecanol. 
3 Chemical Name and CAS Registry Number 
Octyldodecanol [5333-42-6] 
4 Empirical Formula and Molecular Weight 
C20H42O 298.62 
5 Structural Formula 
6 Functional Category 
Emollient; emulsifying agent; lubricant; solvent; thickening 
agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Octyldodecanol is widely used in cosmetics and pharmaceutical 
applications as an emulsifying and opacifying agent. It is 
primarily used in topical applications because of its lubricating 
and emollient properties. 
Octyldodecanol has been used in the preparation of oil/ 
water microemulsions investigated as the vehicle for the dermal 
administration of drugs having no or low skin penetration.(1) 
Octyldodecanol has also been evaluated as a solvent for 
naproxen when applied topically.(2) 
8 Description 
Octyldodecanol occurs as a clear, colorless, or yellowish, oily 
liquid. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for octyldodecanol. 
Test PhEur 2005 USPNF 23 
Characters . — 
Identification . . 
Acidity or alkalinity . — 
Relative density 0.840 — 
Refractive index 1.455 — 
Optical rotation 0.108 to .108 — 
Hydroxyl value 175–190 175–190 
Iodine value 48 48 
Saponification value 45 45 
Acid value — 40.5 
Peroxide value 40.5 — 
Heavy metals 410 ppm — 
Water 40.5% — 
Sulfated ash 40.1% — 
Organic volatile impurities — . 
Assay >90.0% >90.0% 
10 Typical Properties 
Flash point: 1808C2008C 
Melting point: < 208C 
Refractive index: nD
20 = 1.45–1.46 
Solubility: miscible with ethanol (95%); practically insoluble in 
water. 
Specific gravity: 0.83–0.85 at 208C 
Viscosity (dynamic): 58–64 mPa s (58–64 cP) at 208C 
11 Stability and Storage Conditions 
The bulk material should be stored in a well-closed container in 
a cool, dry, place protected from light. In the original unopened 
container, octyldodecanol can be stored for two years protected 
from moisture at below 308C. 
12 Incompatibilities 
Octyldodecanol is generally compatible with most materials 
encountered in cosmetic and pharmaceutical formulations. 
13 Method of Manufacture 
Octyldodecanol is produced by the condensation of two 
molecules of decyl alcohol. It also occurs naturally in small 
quantities in plants. 
14 Safety 
Octyldodecanol is widely used in cosmetics and topical 
pharmaceutical formulations and is generally regarded as 
nontoxic and nonirritant at the levels employed as an excipient. 
In acute oral toxicity studies in rats fed 5 g/kg of undiluted 
octyldodecanol, no deaths were observed.(3) In an acute dermal 
toxicity study, intact and abraded skin sites of guinea pigs were 
treated with 3 g/kg of undiluted octyldodecanol under occlusive

patches; no deaths occurred and no gross skin lesions were 
observed.(3) Octyldodecanol caused either no ocular irritation 
or minimal, transient irritation in the eyes of rabbits.(3) 
However, some sources describe undiluted octyldodecanol as 
an eye and severe skin irritant. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. When heated to decomposition, 
octyldodecanol emits acrid smoke and irritating fumes. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (topical, 
transdermal, and vaginal preparations). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian 
List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
—
18 Comments 
A specification for octyldodecanol is included in Japanese 
Pharmaceutical Excipients (JPE).(4) 
The EINECS number for octyldodecanol is 226-242-9. 
19 Specific References 
1 Shukla A, Janich M, Jahn K, et al. Investigation of pharmaceutical 
oil/water microemulsions by small-angle scattering. Pharm Res 
2002: 19(6): 881–886. 
2 Contreras Claramonte MD, Parera Vialard A, Girela Vilchez F. An 
application of regular solution theory in the study of the solubility 
of naproxen in some solvents used in topical preparations. Int J 
Pharm 1993: 94: 23–30. 
3 Elder RL. Final report on the safety assessment of stearyl alcohol, 
oleyl alcohol and octyl dodecanol. J Am Coll Toxicol 1985: 4: 1– 
29. 
4 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004: 583–585. 
20 General References 
Allen LV. Featured excipient: oligeanous vehicles. Int J Pharm 
Compound 2000; 4(6): 470–473, 484–485. 
Filippi U, Gibellini M, Guasani G, et al. Proposal for the pharmacopeia; 
octyl dodecanol. Bell Clin Form 1982; 121: 425–427. 
21 Authors 
RT Guest. 
22 Date of Revision 
22 August 2005. 
Octyldodecanol 493

Oleic Acid 
1 Nonproprietary Names 
BP: Oleic acid 
PhEur: Acidum oleicum 
USPNF: Oleic acid 
2 Synonyms 
Crodolene; Crossential 094; elaic acid; Emersol; Glycon; 
Groco; Hy-Phi; Industrene; Metaupon; Neo-Fat; cis-9-octadecenoic 
acid; 9,10-octadecenoic acid; oleinic acid; Priolene. 
3 Chemical Name and CAS Registry Number 
(Z)-9-Octadecenoic acid [112-80-1] 
4 Empirical Formula and Molecular Weight 
C18H34O2 282.47 
5 Structural Formula 
6 Functional Category 
Emulsifying agent; skin penetrant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Oleic acid is used as an emulsifying agent in foods and topical 
pharmaceutical formulations. It has also been used as a 
penetration enhancer in transdermal formulations,(1–14) to 
improve the bioavailability of poorly water-soluble drugs in 
tablet formulations,(15) and as part of a vehicle in soft gelatin 
capsules. 
Oleic acid has been reported to act as an ileal ’break’ that 
slows down the transit of luminal contents through the distal 
portion of the small bowel.(16) 
Oleic acid labeled with 131I and 3H is used in medical 
imaging. 
8 Description 
Ayellowish to pale brown, oily liquid with a characteristic lardlike 
odor and taste. 
Oleic acid consists chiefly of (Z)-9-octadecenoic acid 
together with varying amounts of saturated and other 
unsaturated acids. It may contain a suitable antioxidant. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for oleic acid. 
Test PhEur 2005 USPNF 23 
Identification . — 
Characters . — 
Specific gravity 0.892 0.889–0.895 
Residue on ignition — 41mg 
Total ash 40.1% — 
Mineral acids — . 
Neutral fat or mineral oil — . 
Fatty acid composition . — 
Myristic acid 45.0% — 
Palmitic acid 416.0% — 
Palmitoleic acid 48.0% — 
Stearic acid 46.0% — 
Oleic acid 65.0–88.0% — 
Linoleic acid 418.0% — 
Linolenic acid 44.0% — 
Fatty acids of chain length 
greater than C18 
44.0% — 
Acid value 195–204 196–204 
Iodine value 89–105 85–95 
Peroxide value 410.0 — 
Congealing temperature — . 
From animal sources — 3–108C 
From vegetable sources — 10–168C 
Margaric acid — — 
From animal sources 44.0% — 
From vegetable sources 40.2% — 
Color of solution . — 
Organic volatile impurities — . 
Assay 65–88% — 
10 Typical Properties 
Acidity/alkalinity: pH = 4.4 (saturated aqueous solution) 
Autoignition temperature: 3638C 
Boiling point: 2868C at 13.3 kPa (100 mmHg) (decomposition 
at 80–1008C) 
Density: 0.895 g/cm3 
Flash point: 1898C 
Melting point: 48C 
Refractive index: nD
26 = 1.4585 
Solubility: miscible with benzene, chloroform, ethanol (95%), 
ether, hexane, and fixed and volatile oils; practically 
insoluble in water. 
Vapor pressure: 133 Pa (1 mmHg) at 176.58C 
Viscosity (dynamic): 26 mPa s (26 cP) at 258C 
11 Stability and Storage Conditions 
On exposure to air, oleic acid gradually absorbs oxygen, 
darkens in color, and develops a more pronounced odor. At 
atmospheric pressure, it decomposes when heated at 
80–1008C. 
Oleic acid should be stored in a well-filled, well-closed 
container, protected from light, in a cool, dry place.

12 Incompatibilities 
Incompatible with aluminum, calcium, heavy metals, iodine 
solutions, perchloric acid, and oxidizing agents. Oleic acid 
reacts with alkalis to form soaps. 
13 Method of Manufacture 
Oleic acid is obtained by the hydrolysis of various animal and 
vegetable fats or oils, such as olive oil, followed by separation 
of the liquid acids. It consists chiefly of (Z)-9-octadecenoic acid. 
Oleic acid that is to be used systemically should be prepared 
from edible sources. 
14 Safety 
Oleic acid is used in oral and topical pharmaceutical formulations. 
In vitro tests have shown that oleic acid causes rupture of 
red blood cells (hemolysis), and intravenous injection or 
ingestion of a large quantity of oleic acid can therefore be 
harmful. The effects of oleic acid on alveolar(17) and buccal(18) 
epithelial cells in vitro have also been studied; the in vitro and in 
vivo effects of oleic acid on rat skin have been reported.(19) 
Oleic acid is a moderate skin irritant; it should not be used in 
eye preparations. 
An acceptable daily intake for the calcium, sodium, and 
potassium salts of oleic acid was not specified by the WHO 
since the total daily intake of these materials in foods was such 
that they did not pose a hazard to health.(20) 
LD50 (mouse, IV): 0.23 g/kg(21) 
LD50 (rat, IV): 2.4 mg/kg 
LD50 (rat, oral): 74 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Gloves and eye protection are 
recommended. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(inhalation and nasal aerosols, tablets, topical and transdermal 
preparations). Included in nonparenteral medicines licensed in 
the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Ethyl oleate. 
18 Comments 
Several grades of oleic acid are commercially available ranging 
in color from pale yellow to reddish brown. Different grades 
become turbid at varying temperatures depending upon the 
amount of saturated acid present. Usually, oleic acid contains 
7–12% saturated acids, such as stearic and palmitic acid, 
together with other unsaturated acids, such as linoleic acid. A 
specification for oleic acid is contained in the Food Chemicals 
Codex (FCC). The EINECS number for oleic acid is 204-007-1. 
19 Specific References 
1 Cooper ER, Merritt EW, Smith RL. Effect of fatty acids and 
alcohols on the penetration of acyclovir across human skin in vitro. 
J Pharm Sci 1985; 74: 688–689. 
2 Francoeur ML, Golden GM, Potts RO. Oleic acid: its effects on 
stratum corneum in relation to (trans)dermal drug delivery. Pharm 
Res 1990; 7: 621–627. 
3 Lewis D, Hadgraft J. Mixed monolayers of dipalmitoylphosphatidylcholine 
with azone or oleic acid at the air–water interface. 
Int J Pharm 1990; 65: 211–218. 
4 Niazy EM. Influence of oleic acid and other permeation promoters 
on transdermal delivery of dihydroergotamine through rabbit skin. 
Int J Pharm 1991; 67: 97–100. 
5 Ongpipattanakul B, Burnette RR, Potts RO, Francoeur ML. 
Evidence that oleic acid exists in a separate phase within stratum 
corneum lipids. Pharm Res 1991; 8: 350–354. 
6 Walker M, Hadgraft J. Oleic acid: membrane fluidiser or fluid 
within the membrane? Int J Pharm 1991; 71: R1–R4. 
7 Gao S, Singh J. Effect of oleic acid/ethanol and oleic acid/propylene 
glycol on the in vitro percutaneous absorption of 5-fluorouracil 
and tamoxifen and the macroscopic barrier property of porcine 
epidermis. Int J Pharm 1998; 165: 45–55. 
8 Murakami T, Yoshioka M, Yumoto R. Topical delivery of keloid 
therapeutic drug, tranilast, by combined use of oleic acid and 
propylene glycol as a penetration enhancer: evaluation by skin 
microdialysis in rats. J Pharm Pharmacol 1998; 50: 49–54. 
9 Santoyo S, Arellano A, Ygartua P, Mart..n C. Penetration enhancer 
effects on the in vitro percutaneous absorption of piroxicam 
through rat skin. Int J Pharm 1995; 117: 219–224. 
10 Kim D-D, Chien YW. Transdermal delivery of dideoxynucleosidetype 
anti-HIV drugs: 2. The effect of vehicle and enhancer on skin 
permeation. J Pharm Sci 1996; 85: 214–219. 
11 Singh SK, Roane DS, Reddy IK, et al. Effect of additives on the 
diffusion of ketoprofen through human skin. Drug Dev Ind Pharm 
1996; 22: 471–474. 
12 Bhatia KS, Gao S, Singh J. Effect of penetration enhancers and 
iontophoresis on the FT-IR spectroscopy and LHRH permeability 
through porcine skin. J Control Release 1997; 47: 81–89. 
13 Wang Y, Fan Q, Sang Y. Effects of fatty acids and iontophoresis on 
the delivery of midodrine hydrochloride and the structure of 
human skin. Pharm Res 2003; 20(10): 1612–1618. 
14 Gwak HS, Oh IS, Chun IK. Transdermal delivery of ondansetron 
hydrochloride: effects of vehicles and penetration enhancers. Drug 
Dev Ind Pharm 2004; 30(2): 187–194. 
15 Tokumura T, Tsushima Y, Tatsuishi K, et al. Enhancement of the 
oral bioavailability of cinnarizine in oleic acid in beagle dogs. J 
Pharm Sci 1987; 76: 286–288. 
16 Dobson CL, Davis SS, Chauhan S, et al. The effects of ileal brake 
activators on the oral bioavailability of atenolol in man. Int J 
Pharm 2002; 248(1–2): 61–70. 
17 Wang LY, Ma JKH, Pan WF, et al. Alveolar permeability 
enhancement by oleic acid and related fatty acids: evidence for a 
calcium-dependent mechanism. Pharm Res 1994; 11: 513–517. 
18 Turunen TM, Urtti A, Paronen P, et al. Effect of some penetration 
enhancers on epithelial membrane lipid domains: evidence from 
fluorescence spectroscopy studies. Pharm Res 1994; 11: 288–294. 
19 Fang JY, Hwang TL, Fang CL. In vitro and in vivo evaluations of 
the efficay and safety of skin permeation enhancers using 
flurbiprofen as a model. Int J Pharm 2003; 255(1–2): 153–166. 
20 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirty-third report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1989: 
No. 776. 
21 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2778. 
20 General References 
—
21 Authors 
CG Cable. 
22 Date of Revision 
23 August 2005. 
Oleic Acid 495

Oleyl Alcohol 
1 Nonproprietary Names 
PhEur: Alcohol oleicus 
USP: Oleyl alcohol 
2 Synonyms 
HD-Eutanol V PH; Ocenol; cis-9-octadecen-1-ol; oleic alcohol; 
oleo alcohol; oleol. 
3 Chemical Name and CAS Registry Number 
(Z)-9-Octadecen-1-ol [143-28-2] 
4 Empirical Formula and Molecular Weight 
C18H36O 268.48 
5 Structural Formula 
6 Functional Category 
Antifoaming agent; dissolution enhancer; emollient; emulsifying 
agent; skin penetrant; sustained-release agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Oleyl alcohol is mainly used in topical pharmaceutical 
formulations and has been used in transdermal delivery 
formulations.(1–6) It has been utilized in the development of 
biodegradable injectable thermoplastic oligomers,(7) and in 
aerosol formulations of insulin(8) and albuterol.(9) 
Therapeutically, it has been suggested that oleyl alcohol may 
exhibit antitumor properties via transmembrane permeation.(
10) 
8 Description 
Oleyl alcohol occurs as a pale yellow oily liquid that gives off 
acrid fumes when heated. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for oleyl alcohol. 
Test PhEur 2005 USPNF 23 
Appearance . — 
Cloud point <108C <108C 
Refractive index 1.458–1.460 1.458–1.460 
Acid value 41 41 
Hydroxyl value 205–215 205–215 
Iodine value — 85–95 
Saponification value 42 — 
Composition of fatty 
alcohols 
. — 
10 Typical Properties 
Boiling point: 182–1848C at 1.5 atm 
Density: 0.850 g/cm3 at 208C 
Flash point: 1708C 
Melting point: 13–198C 
Partition coefficient: log P (octanol/water) = 7.50. 
Refractive index: nD
25 = 1.4582 
Solubility: soluble in ethanol (95%), and ether; practically 
insoluble in water. 
11 Stability and Storage Conditions 
The bulk material should be stored in a well-closed container in 
a cool, dry, place. 
12 Incompatibilities 
—
13 Method of Manufacture 
Oleyl alcohol occurs naturally in fish oils. Synthetically, it can 
be prepared from butyl oleate by a Bouveault–Blanc reduction 
with sodium and butyl alcohol. An alternative method of 
manufacture is by the hydrogenation of triolein in the presence 
of zinc chromite. 
14 Safety 
Oleyl alcohol is mainly used in topical pharmaceutical 
formulations and is generally regarded as a nontoxic and 
nonirritant material at the levels employed as an excipient. 
However, contact dermatitis due to oleyl alcohol has been 
reported.(11) 
The results of acute oral toxicity and percutaneous studies in 
animals with products containing 8% oleyl alcohol indicate a 
very low toxicity.(12) Formulations containing 8% or 20% oleyl 
alcohol administered by gastric intubation, at doses up to 
10 g/kg body weight, caused no deaths and no toxic effects in 
rats.(12)

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (topical 
emulsions and ointments). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Oleic acid; oleyl oleate. 
Oleyl oleate 
Empirical formula: C36H68O2 
Molecular weight: 532.9 
CAS number: [3687-45-4] 
Refractive index: nD
25 = 1.464–1.468 
Specific gravity: 0.860–0.884 
Solubility: miscible with chloroform and with diethyl ether; 
slightly soluble in ethanol. 
18 Comments 
A specification for oleyl alcohol is included in the Japanese 
Pharmaceutical Excipients (JPE) 2004.(13) The EINECS number 
for oleyl alcohol is 205-597-3. 
19 Specific References 
1 Sudimack JJ, Guo W, Tjarks W, Lee RJ. A novel pH-sensitive 
liposome formulation containing oleyl alcohol. Biochim Biophys 
Acta 2002; 1564: 31–37. 
2 Agyralides GG, Dallas PP, Rekkas DM. Development and in vitro 
evaluation of furosemide transdermal formulations using experimental 
design techniques. Int J Pharm 2004; 281: 35–43. 
3 Cooper ER, Merritt EW, Smith RL. Effect of fatty acids and 
alcohols on the penetration of acyclovir across human skin in vitro. 
J Pharm Sci 1985; 74: 688–689. 
4 Gwak HS, Oh IS, Chun IK. Transdermal delivery of ondansetron 
hydrochloride: effects of vehicles and penetration enhancers. Drug 
Dev Ind Pharm 2004; 30: 187–194. 
5 Andega S, Kanikkannan N, Singh M. Comparison of the effect of 
fatty alcohols on the permeation of melatonin between porcine and 
human skin. J Control Release 2001; 77: 17–25. 
6 Monti D, Giannelli R, Chetoni P, Burgalassi S. Comparison of the 
effect of ultrasound and of chemical enhancers on transdermal 
permeation of caffeine and morphine through hairless mouse skin 
in vitro. Int J Pharm 2001; 229: 131–137. 
7 Amsden B, Hatefi A, Knight D, Bravo-Grimaldo E. Development 
of biodegradable injectable thermoplastic oligomers. Biomacromolecules 
2004; 5: 637–642. 
8 Lee SW, Sciarra JJ. Development of an aerosol dosage form 
containing insulin. J Pharm Sci 1976; 65: 567–572. 
9 Tiwari D, Goldman D, Malick WA, Madan PL. Formulation and 
evaluation of albuterol metered dose inhalers containing tetrafluoroethane 
(P132a), a non-CFC propellant. Pharm Dev Technol 
1998; 3: 163–174. 
10 Takada Y, Kageyama K, Yamada R, et al. Correlation of DNA 
synthesis-inhibiting activity and the extent of transmembrane 
permeation into tumor cells by unsaturated or saturated fatty 
alcohols of graded chain-length upon hyperthermia. Oncol Rep 
2001; 8: 547–551. 
11 Guidetti MS, Vincenzi C, Guerra L, Tosti A. Contact dermatitis 
due to oleyl alcohol. Contact Dermatitis 1994; 31: 260–261. 
12 CFTA. Final report on the safety assessment of stearyl alcohol, 
oleyl alcohol and octyl dodecanol. The Cosmetic Ingredient 
Review Program 1985: No. 4. 
13 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004: 593–595. 
20 General References 
Lee PJ, Langer R, Shastri VP. Novel microemulsion enhancer 
formulation for simultaneous transdermal delivery of hydrophilic 
and hydrophobic drugs. Pharm Res 2003; 20: 264–269. 
Malcolm RK, McCullagh S,Woolfson AD, et al. A dynamic mechanical 
method for determining the silicone elastomer solubility of drugs 
and pharmaceutical excipients in silicone intravaginal drug delivery 
rings. Biomaterials 2002; 23: 3589–3594. 
Murakami R, Takata Y, Ohta A, et al. Aggregate formation in oil and 
adsorption at oil/water interface: thermodynamics and its application 
to the oleyl alcohol system. J Colloid Interface Sci 2004; 270: 
262–269. 
Murota K, Kawada T, Matsui N, et al. Oleyl alcohol inhibits intestinal 
long-chain fatty acid absorption in rats. J Nutr Sci Vitaminol 
(Tokyo) 2000; 46: 302–308. 
Rang MJ, Miller CA. Spontaneous emulsification of oils containing 
hydrocarbon, nonionic surfactant, and oleyl alcohol. J Colloid 
Interface Sci 1999; 209: 179–192. 
21 Authors 
LY Galichet. 
22 Date of Revision 
17 August 2005. 
Oleyl Alcohol 497

Olive Oil 
1 Nonproprietary Names 
BP: Refined olive oil 
JP: Olive oil 
PhEur: Olivae oleum raffinatum 
USPNF: Olive oil 
2 Synonyms 
Gomenoleo oil; pure olive oil; olea europaea oil; oleum olivae. 
3 Chemical Name and CAS Registry Number 
Olive oil [8001-25-00] 
4 Empirical Formula and Molecular Weight 
Olive oil is a mixture of fatty acid glycerides. Analysis of olive 
oil shows a high proportion of unsaturated fatty acids, and a 
typical analysis shows that the composition of the fatty acids is 
as follows: 
Myristic acid (14 : 0), 40.5% 
Palmitic acid (16 : 0), 7.5–20.0% 
Palmitoleic acid (16 : 1), 0.3–5.0% 
Hepatodecenoic acid (17 : 1), 40.3% 
Stearic acid (18 : 0), 0.5–5.0% 
Oleic acid (18 : 1), 55.0–83.0% 
Linoleic acid (18 : 2), 3.5–21.0% 
Linoleic acid (18 : 3), 40.9% 
Arachidic acid (20 : 0), 40.6% 
Eicosaenoic acid (20 : 1), 40.4% 
Behenic acid (22:0), 40.2% 
Lignoceric acid (24:0), 41.0% 
Sterols are also present. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Oleaginous vehicle. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Olive oil has been used in enemas, liniments, ointments, 
plasters, and soap. It has also been used in oral capsules and 
solutions, and as a vehicle for oily injections. 
It has been used in topically applied lipogels of methyl 
nicotinate.(1) It has also been used to soften ear wax.(2) Olive oil 
has been used in combination with soybean oil to prepare lipid 
emulsion for use in pre-term infants.(3) 
Olive oil is used widely in the food industry as a cooking oil 
and for preparing salad dressings. In cosmetics, olive oil is used 
as a solvent, and also as a skin and hair conditioner. Types of 
products containing olive oil include shampoos and hair 
conditioners, cleansing products, topical creams and lotions, 
and sun-tan products. 
8 Description 
Olive oil is the fixed oil from the fruit of Olea europaea. It 
occurs as a clear, colorless or greenish-yellow, oily liquid. 
9 Pharmacopeial Specifications 
See Table I. 
10 Typical Properties 
Flash point: 2258C 
Refractive index: nD
25 = 1.4657–1.4893 
Smoke point: 160–1888C 
Solubility: slightly soluble in ethanol (95%); miscible with 
ether, chloroform, light petroleum (50–708C), and carbon 
disulfide. 
11 Stability and Storage Conditions 
When cooled, olive oil becomes cloudy at approximately 108C, 
and becomes a butterlike mass at 08C. 
Olive oil should be stored in a cool, dry place in a tight, wellfilled 
container, protected from light. 
For refined oil intended for use in the manufacture of 
parenteral dosage forms, the PhEur 2005 requires that the bulk 
oil be stored under an inert gas. 
12 Incompatibilities 
Olive oil may be saponified by alkali hydroxides. As it contains 
a high proportion of unsaturated fatty acids, olive oil is prone 
to oxidation and is incompatible with oxidizing agents. 
13 Method of Manufacture 
Virgin olive oil is produced by crushing olives (the fruit of Olea 
europaea), typically using an edge runner mill. The oil is then 
expressed from the crushed mass solely by mechanical or other 
physical methods under conditions that do not cause deterioration 
of the oil. Any further treatment that the oil undergoes is 
limited to washing, decantation, centrifugation, and filtration. 
Refined olive oil is obtained from virgin olive oil by refining 
methods that do not alter the initial glyceride content of the oil. 
14 Safety 
Olive oil is used widely as an edible oil and in food preparations 
and products such as cooking oils and salad dressings. It is used 
in cosmetics and topical pharmaceutical formulations. Olive oil 
is generally regarded as a relatively nonirritant and nontoxic 
material when used as an excipient. 
Olive oil is a demulcent and has mild laxative properties 
when taken orally. It has been used in topical formulations as 
an emollient and to sooth inflamed skin; to soften the skin and 
crusts in eczema; in massage oils; and to soften earwax.(2) 
There have been isolated reports that olive oil may cause a 
reaction in hypersensitive individuals. However, these incidences 
are relatively uncommon.(4–6) Olive oil is an infrequent

sensitizer and does not appear to be a significant allergen in the 
USA, possibly due to the development of oral tolerance. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Olive oil spills are slippery 
and an inert oil absorbent should be used to cover the oil, which 
can then be disposed of according to the appropriate legal 
regulations. 
16 Regulatory Status 
Olive oil is an edible oil. Included in the FDA Inactive 
Ingredients Guide (oral capsules and solution; topical solutions). 
Included in nonparenteral medicines licensed in Europe. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Crude olive-pomace oil; extra virgin olive oil; fine virgin olive 
oil; lampante virgin olive oil; olive-pomace oil; refined olivepomace 
oil; virgin olive oil. 
Crude olive-pomace oil 
Comments: crude olive-pomace oil is olive-pomace oil that is 
intended for refining prior to its use in food for human 
consumption, or that is intended for technical purposes. 
Extra virgin olive oil 
Comments: extra virgin oil is a virgin oil that has an 
organoleptic rating of not less than 6.5, and a free acidity 
(as oleic acid) of not more than 1.0 g per 100 g. 
Fine virgin olive oil 
Comments: fine virgin oil has an organoleptic rating of not less 
than 5.5, and a free acidity (as oleic acid) of not more than 
1.5 g per 100 g. 
Lampante virgin olive oil 
Comments: lampante virgin olive oil is virgin olive oil that is 
not fit for consumption unless it is further processed. This 
grade of oil is intended for refining or technical purposes. 
Olive-pomace oil 
Comments: olive-pomace oil is the oil obtained from the solvent 
extraction of olive pomace, but does not include oils 
obtained by reesterification processes or any mixture with 
oils of any kind. Olive-pomace oil of commerce is a blend of 
refined olive-pomace oil and virgin olive oil that is fit for 
human consumption. See also Section 18. 
Refined olive-pomace oil 
Comments: refined olive-pomace oil is obtained from crude 
olive-pomace oil by refining methods that do not alter the 
initial glyceride structure. It is intended for consumption, or 
blended with virgin olive oil. 
Virgin olive oil 
Comments: virgin olive oil has an organoleptic rating of not less 
than 3.5, and a free acidity (as oleic acid) of not more than 
3.3 g per 100 g. The PhEur 2005 contains a monograph on 
virgin olive oil as well as refined olive oil. 
18 Comments 
Olive oil is available in a variety of different grades; see Section 
17. All olive oils are graded according to the degree of acidity. 
Table I: Pharmacoepeial specifications for olive oil. 
Test JP 2001 PhEur 2005(a) USPNF 23 
Identification — . — 
Characters . . — 
Acid value 41.0 40.5 — 
Peroxide value — 45.0 — 
Saponification value 186–194 — 190–195 
Unsaponifiable matter 41.5% 41.5% — 
Iodine value 79–88 — 79–88 
Specific gravity — — 0.910–0.915 
Free fatty acids — — . 
Alkaline impurities — . — 
Absorbance at 
270nm 
— 0.20–1.20 — 
Composition of fatty 
acids 
— . — 
Saturated fatty acids 
of chain length less 
than C16 
— 40.1% — 
Palmitic acid — 7.5–20.0% — 
Palmitoleic acid — 43.5% — 
Stearic acid — 0.5–5.0% — 
Oleic acid — 56.0–85.0% — 
Linoleic acid — 3.5–20.0% — 
Linoleic acid 
(equivalent chain 
length on 
polyethyleneglycol 
adipate 
19.7) 
— 41.2% — 
Arachidic acid — 40.7% — 
Eicosenoic acid — 40.4% — 
Behenic acid — 40.2% — 
Lignoceric acid — 40.2% — 
Sterols — . — 
b-Sitostanol, 
5,24- 
stigmastadienol, 
clerosterol, 
sitostanol, 
5- 
avenasterol, and 

5,23- 
stigmastadienol 
— 593.0% — 
Cholesterol — 40.5% — 

7-stigmasterol — 40.5% — 
Campesterol — 44.0% — 
Stigmasterol — Not more than 
that of 
campesterol — 
Sesame oil — . . 
Water — . — 
Cottonseed oil — — . 
Drying oil . — — 
Peanut oil . — . 
Teaseed oil — — . 
Heavy metals — — 40.001% 
Organic volatile 
impurities 
— — . 
Solidification range of 
fatty acids 
— — 17–268C 
(a) The PhEur 2005 material refers to refined olive oil. 
Olive Oil 499

The flavor, color, and fragrance of olive oils may vary, 
depending on the region where the olives are grown, the 
condition of the crops, and the type of olive used. 
Olive-pomace oil is obtained from the olive pomace by 
solvent extraction. The use of solvent extraction causes small 
changes in the typical fatty acid composition of the oil, and 
changes in organoleptic properties and impurities. Other oils 
can be prepared by reesterification of the appropriate 
combination of fatty acids with glycerol. Olive-pomace oils or 
reesterified oils cannot be called olive oil. 
19 Specific References 
1 Realdon N, Ragazzi E, Ragazzi E. Effect of gelling conditions and 
mechanical treatment on drug availability from a lipogel. Drug 
Dev Ind Pharm 2001; 27(2): 165–170. 
2 Smythe O. Ear care. N Z Pharm 1998; 18: 25–26, 28. 
3 Koletzko B, Boehles HJ, Emgelberger I, et al. Parenteral fat 
emulsions based on olive and soybean oils: a randomized clinical 
trial in preterm infants. J Paed Gastroenterology Nutr 2003; 37(2): 
161–167. 
4 Kranke B, Komericki P, Aberer W. Olive oil – contact sensitizer or 
irritant. Contact Dermatitis 1997; 35(1): 5–10. 
5 Jung HD, Holzegel K. Contact allergy to olive oil. Derm Beruf 
Umwelt 1987; 35(4): 131–133. 
6 Van Joost T, Smitt JH, Van Ketel WG. Sensitization to olive oil 
(Olea europeae). Contact Dermatitis 1981; 7(6): 309–310. 
20 General References 
Allen LV. Featured excipient: oleaginous vehicles. Int J Pharm 
Compound 2000; 4(6): 470–473, 484–485. 
Croucher P. Olive oil as a functional food. NZ Pharm 2002; 22(8): 40– 
42. 
Garcia Del Pozo JA, Alvarez Martinez MO. Olive oil: attainment, 
composition and properties. Farm (El Farmaceutico) 2000; 241: 94, 
96, 98–100, 102, 104–105. 
21 Authors 
RC Moreton. 
22 Date of Revision 
31 August 2005. 
500 Olive Oil

Palmitic Acid 
1 Nonproprietary Names 
BP: Palmitic acid 
PhEur: Acidum palmiticum 
2 Synonyms 
Cetylic acid; Edenor C16 98-100; Emersol 140; Emersol 143; 
n-hexadecoic acid; hexadecylic acid; Hydrofol; Hystrene 9016; 
Industrene 4516; 1-pentadecanecarboxylic acid. 
3 Chemical Name and CAS Registry Number 
Hexadecanoic acid [57-10-3] 
4 Empirical Formula and Molecular Weight 
C16H32O2 256.42 
5 Structural Formula 
6 Functional Category 
Emulsifying agent; skin penetrant; tablet and capsule lubricant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Palmitic acid is used in oral and topical pharmaceutical 
formulations. Palmitic acid has been used in implants for 
sustained release of insulin in rats.(1,2) 
8 Description 
Palmitic acid occurs as white crystalline scales with a slight 
characteristic odor and taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for palmitic acid. 
Test PhEur 2005 
Appearance . 
Acidity . 
Freezing point 60–668C 
Iodine value <1 
Stearic acid <6% 
Nickel <1 ppm 
Assay >92.9% 
10 Typical Properties 
Boiling point: 271.58C at 100mmHg 
Flash point: >1108C 
Melting point: 63–648C 
Solubility: soluble in ethanol (95%); practically insoluble in 
water. 
Specific gravity: 0.849–0.851. 
11 Stability and Storage Conditions 
The bulk material should be stored in a well-closed container in 
a cool, dry, place. 
12 Incompatibilities 
Palmitic acid is incompatible with strong oxidizing agents and 
bases. 
13 Method of Manufacture 
Palmitic acid occurs naturally in all animal fats as the glyceride, 
palmitin, and in palm oil partly as the glyceride and partly 
uncombined. Palmitic acid is most conveniently obtained from 
olive oil after removal of oleic acid, or from Japanese beeswax. 
Synthetically, palmitic acid may be prepared by heating cetyl 
alcohol with soda lime to 2708C or by fusing oleic acid with 
potassium hydrate. 
14 Safety 
Palmitic acid is used in oral and topical pharmaceutical 
formulations and is generally regarded as nontoxic and 
nonirritant at the levels employed as an excipient. However, 
palmitic acid is reported to be an eye and skin irritant at high 
levels and is poisonous by intravenous administration. 
LD50 (mouse, IV): 57 mg/kg(3) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. When palmitic acid is heated 
to decomposition, carbon dioxide and carbon monoxide are 
formed. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(oral tablets). Included in nonparenteral medicines licensed in 
the UK. 
17 Related Substances 
Lauric acid; myristic acid; palmitin; sodium palmitate; stearic 
acid. 
Palmitin 
Empirical formula: C51H98O6 
Molecular weight: 807.29 
CAS number: [555-44-2] 
Refractive index: nD
25 = 1.4381

Specific gravity: 0.886 
Solubility: soluble in benzene, chloroform, and ether; practically 
insoluble in ethanol (95%) and in water. 
Sodium palmitate 
Synonyms: hexadecanoic acid sodium salt; palmitic acid 
sodium salt; sodium hexadecanoate. 
Empirical formula: C16H31O2Na 
Molecular weight: 278.47 
CAS number: [408-35-5] 
Melting point: 283–2908C 
Comments: sodium palmitate is used as a surfactant and 
emulsifying agent in pharmaceutical formulations. The 
EINECS number for sodium palmitate is 206-988-1. 
18 Comments 
A specification for palmitic acid is included in the Food 
Chemicals Codex(4) and in the Japanese Pharmaceutical 
Excipients 2004 (JPE).(5) The EINECS number for palmitic 
acid is 200-312-9. 
19 Specific References 
1 Wang PY. Palmitic acid as an excipient in implants for sustained 
release of insulin. Biomaterials 1991; 12: 57–62. 
2 Hashizume M, Douen T, Murakami M, et al. Improvement of 
large intestinal absorption of insulin by chemical modification with 
palmitic acid in rats. J Pharm Pharmacol 1992; 44: 555–559. 
3 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2813. 
4 Food Chemicals Codex, 4th edn. Washington, DC: National 
Academy Press, 1996: 278. 
5 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004, Tokyo: Yakuji Nippo, 2004: 601. 
20 General References 
Bhattacharya A, Ghosal SK. Permeation kinetics of ketotifen fumarate 
alone and in combination with hydrophobic permeation enhancers 
through human cadaver epidermis. Boll Chim Farm 2000; 139: 
177–181. 
Yagi S, Nakayama K, Kurosaki Y, et al. Factors determining drug 
residence in skin during transdermal absorption: studies on betablocking 
agents. Biol Pharm Bull 1998; 21: 1195–1201. 
21 Authors 
LY Galichet. 
22 Date of Revision 
17 August 2005. 
502 Palmitic Acid

Paraffin 
1 Nonproprietary Names 
BP: Hard paraffin 
JP: Paraffin 
PhEur: Paraffinum solidum 
USPNF: Paraffin 
2 Synonyms 
Hard wax; paraffinum durum; paraffin wax. 
3 Chemical Name and CAS Registry Number 
Paraffin [8002-74-2] 
4 Empirical Formula and Molecular Weight 
Paraffin is a purified mixture of solid saturated hydrocarbons 
having the general formula CnH2n.2, and is obtained from 
petroleum or shale oil. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Ointment base; stiffening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Paraffin is mainly used in topical pharmaceutical formulations 
as a component of creams and ointments. In ointments, it may 
be used to increase the melting point of a formulation or to add 
stiffness. Paraffin is additionally used as a coating agent for 
capsules and tablets, and is used in some food applications. 
Paraffin coatings can also be used to affect the release of drug 
from ion-exchange resin beads.(1) 
8 Description 
Paraffin is an odorless and tasteless, translucent, colorless, or 
white solid. It feels slightly greasy to the touch and may show a 
brittle fracture. Microscopically, it is a mixture of bundles of 
microcrystals. Paraffin burns with a luminous, sooty flame. 
When melted, paraffin is essentially without fluorescence in 
daylight; a slight odor may be apparent. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for paraffin. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters — . — 
Congealing range 50–758C — 47–658C 
Reaction — — . 
Heavy metals 410 ppm — — 
Arsenic 42 ppm — — 
Sulfates . . — 
Polycyclic aromatic 
hydrocarbons 
— . — 
Readily carbonizable 
substances 
. — . 
Acidity or alkalinity . . — 
10 Typical Properties 
Density: 0.84–0.89 g/cm3 at 208C 
Melting point: various grades with different specified melting 
ranges are commercially available. 
Solubility: soluble in chloroform, ether, volatile oils, and most 
warm fixed oils; slightly soluble in ethanol; practically 
insoluble in acetone, ethanol (95%), and water. Paraffin can 
be mixed with most waxes if melted and cooled. 
11 Stability and Storage Conditions 
Paraffin is stable, although repeated melting and congealing 
may alter its physical properties. Paraffin should be stored at a 
temperature not exceeding 408C in a well-closed container. 
12 Incompatibilities 
—
13 Method of Manufacture 
Paraffin is manufactured by the distillation of crude petroleum 
or shale oil, followed by purification by acid treatment and 
filtration. Paraffins with different properties may be produced 
by controlling the distillation and subsequent congealing 
conditions. 
Synthetic paraffin, synthesized from carbon monoxide and 
hydrogen is also available; see Section 17. 
14 Safety 
Paraffin is generally regarded as an essentially nontoxic and 
nonirritant material when used in topical ointments and as a 
coating agent for tablets and capsules. However, granulomatous 
reactions (paraffinomas) may occur following injection of 
paraffin into tissue for cosmetic purposes or to relieve pain. 
Long-term inhalation of aerosolized paraffin may lead to 
interstitial pulmonary disease. Ingestion of a substantial 
amount of white soft paraffin has led to intestinal obstruction 
in one instance.(2–6)

See also Mineral Oil for further information. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. In the UK, the recommended 
occupational exposure limits for paraffin wax fumes are 
2 mg/m3 long-term (8-hour TWA) and 6 mg/m3 short-term.(7) 
16 Regulatory Status 
Accepted in the UK for use in certain food applications. 
Included in the FDA Inactive Ingredients Guide (oral capsules 
and tablets, topical emulsions, and ointments). Included in 
nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Light mineral oil; microcrystalline wax; petrolatum; synthetic 
paraffin. 
Synthetic paraffin 
Molecular weight: 400–1400 
Appearance: a hard, odorless, white wax consisting of a 
mixture of mostly long-chain, unbranched, saturated 
hydrocarbons along with a small amount of branched 
hydrocarbons. 
Melting point: 96–1058C 
Viscosity (dynamic): 5–15 mPa s (5–15 cP) at 1358C. 
Comments: the USPNF 23 states that synthetic paraffin is 
synthesized by the Fischer–Tropsch process from carbon 
monoxide and hydrogen, which are catalytically converted 
to a mixture of paraffin hydrocarbons. The lower molecular 
weight fractions are removed by distillation and the residue 
is hydrogenated and further treated by percolation through 
activated charcoal. This mixture may be fractionated into its 
components by a solvent-separation method. Synthetic 
paraffin may contain not more than 0.005% w/w of a 
suitable antioxidant. 
18 Comments 
The more highly purified waxes are used in preference to 
paraffin in many applications because of their specifically 
controlled physical properties such as hardness, malleability, 
and melting range. A specification for synthetic paraffin is 
contained in the Food Chemicals Codex (FCC). The EINECS 
numbers for paraffin are 232-315-6 and 265-154-5. 
19 Specific References 
1 Motyckas S, Nairn J. Influence of wax coatings on release rate of 
anions form ion-exchange resin beads. J Pharm Sci 1978; 67: 500– 
503. 
2 Crosbie RB, Kaufman HD. Self-inflicted oleogranuloma of breast. 
Br Med J 1967; 3: 840–841. 
3 Bloem JJ, van derWaal I. Paraffinoma of the face: a diagnostic and 
therapeutic problem. Oral Surg 1974; 38: 675–680. 
4 Greaney MG, Jackson PR. Oleogranuloma of the rectum produced 
by Lasonil ointment. Br Med J 1977; 2: 997–998. 
5 Pujol J, Barneon G, Bousquet J, et al. Interstitial pulmonary disease 
induced by occupation exposure to paraffin. Chest 1990; 97: 234– 
236. 
6 Goh D, Buick R. Intestinal obstruction due to ingested Vaseline. 
Arch Dis Child 1987; 62: 1167–1168. 
7 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
—
21 Authors 
AH Kibbe. 
22 Date of Revision 
17 August 2005. 
504 Paraffin

Peanut Oil 
1 Nonproprietary Names 
BP: Arachis oil 
JP: Peanut oil 
PhEur: Arachidis oleum raffinatum 
USPNF: Peanut oil 
2 Synonyms 
Aextreff CT; earthnut oil; groundnut oil; katchung oil; nut oil. 
3 Chemical Name and CAS Registry Number 
Peanut oil [8002-03-7] 
4 Empirical Formula and Molecular Weight 
A typical analysis of refined peanut oil indicates the composition 
of the acids present as glycerides to be: arachidic acid 
2.4%; behenic acid 3.1%; palmitic acid 8.3%; stearic acid 
3.1%; lignoceric acid 1.1%; linoleic acid 26.0%, and oleic acid 
56.0%.(1) 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Oleaginous vehicle; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Peanut oil is used as an excipient in pharmaceutical formulations 
primarily as a solvent for sustained-release intramuscular 
injections. It is also used as a vehicle for topical preparations 
and as a solvent for vitamins and hormones. In addition, it has 
been part of sustained-release bead formulations,(2) nasal drug 
delivery systems,(3) and controlled-release injectables.(4) 
Therapeutically, emulsions containing peanut oil have been 
used in nutrition regimens, in enemas as a fecal softener, and in 
otic drops to soften ear wax. It is also administered orally, 
usually with sorbitol, as a gall bladder evacuant prior to 
cholecystography. 
Peanut oil is also widely used as an edible oil. 
8 Description 
Peanut oil is a colorless or pale yellow-colored liquid that has a 
faint nutty odor and a bland, nutty taste. At about 38C it 
becomes cloudy, and at lower temperatures it partially 
solidifies. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for peanut oil. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Solidification range 22–338C 28C 26–338C 
Acid value 40.2 40.5 — 
Peroxide value — 45.0 — 
Unsaponifiable matter 41.5% 41.0% 41.5% 
Specific gravity 0.909–0.916 0.915 0.912–0.920 
Alkaline impurities — . — 
Cottonseed oil — — . 
Rancidity — — . 
Iodine value 84–103 — 84–100 
Saponification value 188–196 — 185–195 
Refractive index at 
408C 
— — 1.462–4.464 
Heavy metals — — 40.001% 
Organic volatile 
impurities 
— — . 
Water — 40.3% — 
Composition of fatty 
acids 
— . — 
Saturated fatty 
acids 4C14 
— 40.4% — 
Palmitic acid — 7.0–16.0% — 
Stearic acid — 1.3–6.5% — 
Oleic acid — 35.0–72.0% — 
Linoleic acid — 13.0–43.0% — 
Linolenic acid — 40.6% — 
Lignoceric acid — 0.5–3.0% — 
Arachidic acid — 0.5–3.0% — 
Eicosenoic acid — 40.5–2.1% — 
Behenic acid — 1.0–5.0% — 
Erucic acid — 40.5% — 
10 Typical Properties 
Autoignition temperature: 4438C 
Density: 0.915 g/cm3 at 258C 
Flash point: 2838C 
Freezing point: 58C 
Hydroxyl value: 2.5–9.5 
Interfacial tension: 19.9mN/m at 258C(5) 
Refractive index: nD
25 = 1.466–1.470 
Solubility: very slightly soluble in ethanol (95%); soluble in 
benzene, carbon tetrachloride, and oils; miscible with 
carbon disulfide, chloroform, ether, and hexane. 
Surface tension: 37.5mN/m at 258C(5) 
Viscosity (dynamic): 35.2 mPa s (35.2 cP) at 378C(5) 
Viscosity (kinematic): 39.0mm2/s (39.0 cSt) at 378C(5) 
11 Stability and Storage Conditions 
Peanut oil is an essentially stable material.(6) However on 
exposure to air it can slowly thicken and may become rancid. 
Solidified peanut oil should be completely melted and mixed 
before use. Peanut oil may be sterilized by aseptic filtration or

by dry heat, for example, by maintaining it at 1508C for 1 
hour.(7) 
Peanut oil should be stored in a well-filled, airtight, lightresistant 
container, at a temperature not exceeding 408C. 
Material intended for use in parenteral dosage forms should be 
stored in a glass container. 
12 Incompatibilities 
Peanut oil may be saponified by alkali hydroxides. 
13 Method of Manufacture 
Refined peanut oil is obtained from the seeds of Arachis 
hypogaea Linne. (Fam. Leguminosae). The seeds are separated 
from the peanut shells and are expressed in a powerful 
hydraulic press. The crude oil has a light yellow to light brown 
color, and is then purified to make it suitable for food or 
pharmaceutical purposes. A suitable antioxidant may be added. 
14 Safety 
Peanut oil is mildly laxative at a dosage of 15–60mL orally or 
of 100–500mL rectally as an enema. 
Adverse reactions to peanut oil in foods and pharmaceutical 
formulations have been reported extensively.(8–18) These 
include severe allergic skin rashes(8,9) and anaphylactic shock 
following consumption of peanut butter.(10) Some workers have 
suggested that the use in infancy of preparations containing 
peanut oil, including infant formula and topical preparations, is 
associated with sensitization to peanut, with a subsequent risk 
of hypersensitivity reactions, and that such products should 
therefore be avoided or banned.(8–12) However, the role of 
pharmaceutical preparations in later development of hypersensitivity 
is disputed since such preparations contain highly 
refined peanut oil that should not contain the proteins 
associated with allergic reactions in susceptible individuals.(
13–15) 
Peanut oil is harmful if administered intravenously and it 
should not be used in such formulations.(16) 
See also Section 18. 
15 Handling Precautions 
Observe normal handling precautions appropriate to the 
circumstances and quantity of material handled. Spillages of 
peanut oil are slippery and should be covered with an inert 
absorbent material prior to disposal. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IM injections, 
topical preparations, oral capsules, and vaginal emulsions). 
Included in parenteral and nonparenteral medicines licensed in 
the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Almond oil; canola oil; corn oil; cottonseed oil; sesame oil; 
soybean oil; sunflower oil. 
18 Comments 
As a result of the potentially fatal reactions noted in Section 14, 
certain food products are now commonly labeled with a 
statement that they contain peanut oil. A specification for 
unhydrogenated peanut oil is contained in the Food Chemicals 
Codex (FCC). 
19 Specific References 
1 Allen A, Padley GH, Whalley GR. Fatty acid composition of some 
soapmaking fats and oils. Part 4: groundnut (peanut oil). Soap 
Perfum Cosmet 1969; 42: 725–726. 
2 Santucci E, Alhaique F, Carafa M, et al. Gellan for the formulation 
of sustained delivery beads. J Control Release 1996; 42: 157–164. 
3 Maitani Y, Yamamoto T, Takayama K, et al. Modelling analysis of 
drug absorption and administration from ocular, naso-lacrimal 
duct, and nasal routes in rabbits. Int J Pharm 1995; 126: 89–94. 
4 Matsubara K, Irie T, Uekama K. Controlled release of the LHRH 
agonist buserelin acetate from injectable suspensions containing 
triacetylated cyclodextrins in an oil vehicle. J Control Release 
1994; 31: 173–180. 
5 Howard JR, Hadgraft J. The clearance of oily vehicles following 
intramuscular and subcutaneous injections in rabbits. Int J Pharm 
1983; 16: 31–39. 
6 Selles E, Ruiz A. Study of the stability of peanut oil [in Spanish]. 
Ars Pharm 1981; 22: 421–427. 
7 Pasquale D, Jaconia D, Eisman P, Lachman L. A study of sterilizing 
conditions for injectable oils. Bull Parenter Drug Assoc 1964; 
18(3): 1–11. 
8 Moneret-Vautrin DA, Hatahet R, Kanny G, Ait-Djafer Z. 
Allergenic peanut oil in milk formulas [letter]. Lancet 1991; 338: 
1149. 
9 Brown HM. Allergenic peanut oil in milk formulas [letter]. Lancet 
1991; 338: 1523. 
10 De Montis G, Gendrel D, Chemillier-Truong M, Dupont C. 
Sensitization to peanut and vitamin D oily preparations [letter]. 
Lancet 1993; 341: 1411. 
11 Lever LR. Peanut and nut allergy: creams and ointments containing 
peanut oil may lead to sensitisation. Br Med J 1996; 313: 299. 
12 Wistow S, Bassan S. Peanut allergy. Pharm J 1999; 262: 709–710. 
13 Hourihane JO, Bedwani SJ, Dean TP, Warner JO. Randomized, 
double blind, crossover challenge study of allergenicity of peanut 
oils in subjects allergic to peanuts. Br Med J 1997; 314: 1084– 
1088. 
14 Committee on Toxicity of Chemicals in Food. Consumer Products 
and the Environment: Peanut Allergy. London: Department of 
Health, 1998. 
15 Anonymous. Questions raised over new advice following research 
into peanut oil. Pharm J 2001; 266: 773. 
16 Lynn KL. Acute rhabdomyolysis and acute renal failure after 
intravenous self-administration of peanut oil. Br Med J 1975; 4: 
385–386. 
17 Ewan PW. Clinical study of peanut and nut allergy in 62 
consecutive patients: new features and associations. Br Med J 
1996; 312: 1074–1078. 
18 Tariq SM, Stevens M, Matthews S, et al. Cohort study of peanut 
and tree nut sensitisation by age of 4 years. Br Med J 1996; 313: 
514–517. 
20 General References 
Strickley RG. Solubilizing excipients in oral and injectable formulations. 
Pharm Res 2004; 21(2): 201–230. 
21 Authors 
AH Kibbe. 
22 Date of Revision 
17 August 2005. 
506 Peanut Oil

Pectin 
1 Nonproprietary Names 
USP: Pectin 
2 Synonyms 
Citrus pectin; E440; methopectin; methyl pectin; methyl 
pectinate; mexpectin; pectina; pectinic acid. 
3 Chemical Name and CAS Registry Number 
Pectin [9000-65-5] 
4 Empirical Formula and Molecular Weight 
Pectin is a high-molecular-weight, carbohydrate-like plant 
constituent consisting primarily of chains of galacturonic acid 
units linked as 1,4-a-glucosides, with a molecular weight of 
30 000–100 000. 
5 Structural Formula 
Pectin is a complex polysaccharide comprising mainly 
esterified D-galacturonic acid residues in an a-(1–4) chain. 
The acid groups along the chain are largely esterified with 
methoxy groups in the natural product. The hydroxyl groups 
may also be acetylated. 
Pectin gelation characteristics can be divided into two types: 
high-methoxy and low-methoxy gelation, and sometimes the 
low-methoxy pectins may contain amine groups. Gelation of 
high-methoxy pectin usually occurs at pH <3.5. Low-methoxy 
pectin is gelled with calcium ions and is not dependent on the 
presence of acid or high solids content. Amidation may 
interfere with gelation, causing the process to be delayed. 
However, gels from amidated pectins have the ability to re-heal 
after shearing.(1) 
The USP 28 describes pectin as a purified carbohydrate 
product obtained from the dilute acid extract of the inner 
portion of the rind of citrus fruits or from apple pomace. It 
consists chiefly of partially methoxylated polygalacturonic 
acids. 
6 Functional Category 
Adsorbent; emulsifying agent; gelling agent; thickening agent; 
stabilizing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Pectin has been used as an adsorbent and bulk-forming agent, 
and is present in multi-ingredient preparations for the management 
of diarrhea, constipation, and obesity;(2) it has also been 
used as an emulsion stabilizer.(3) 
Experimentally, pectin has been used in gel formulations for 
the oral sustained delivery of ambroxol.(4) Pectin gel beads have 
been shown to be an effective medium for controlling the 
release of a drug within the gastrointestinal (GI) tract.(5) It has 
also been used in a colon-biodegradable pectin matrix with a 
pH-sensitive polymeric coating, which retards the onset of drug 
release, overcoming the problems of pectin solubility in the 
upper GI tract.(6–9) Amidated pectin matrix patches have been 
investigated for the transdermal delivery of chloroquine,(10) 
and gelling pectin formulations for the oral sustained delivery 
of paracetamol have been investigated in situ.(11) Pectin-based 
matrices with varying degrees of esterification have been 
evaluated as oral controlled-release tablets. Low-methoxy 
pectins were shown to have a release rate more sensitive to 
the calcium content of the formulation.(12) Pectins have been 
used as a component in the preparation of mixed polymer 
microsphere systems with the intention of producing controlled 
drug release.(13) 
8 Description 
Pectin occurs as a coarse or fine, yellowish-white, odorless 
powder that has a mucilaginous taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for pectin. 
Test USP 28 
Identification . 
Loss on drying 410.0% 
Arsenic 43 ppm 
Lead 45 mg/g 
Sugars and organic acids . 
Microbial limits . 
Assay 
Methoxy groups 46.7% 
Galacturonic acid 474.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 6.0–7.2 
Solubility: soluble in water; insoluble in ethanol (95%) and 
other organic solvents. 
11 Stability and Storage Conditions 
Pectin is a nonreactive and stable material; it should be stored in 
a cool, dry place.

12 Incompatibilities 
—
13 Method of Manufacture 
Pectin is obtained from the diluted acid extract from the inner 
portion of the rind of citrus fruits or from apple pomace. 
14 Safety 
Pectin is used in oral pharmaceutical formulations and food 
products and is generally regarded as an essentially nontoxic 
and nonirritant material. 
Low toxicity by the subcutaneous route has been 
reported.(14) 
LD50 (mouse, SC): 6.4 g/kg(14) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. When pectin is heated to 
decomposition, acrid smoke and irritating fumes are emitted. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (dental paste; 
oral powders; topical pastes). Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. Included in nonparenteral 
medicines licensed in the UK. 
17 Related Substances 
—
18 Comments 
Pectin has been used in film-coating formulations containing 
chitosan and hydroxypropylmethyl cellulose in the investigation 
of the biphasic drug-release properties of film-coated 
paracetamol tablets, both in vitro,(15,16) and in vivo.(17) It has 
been shown that chitosan acts as a crosslinking agent for 
concentrated pectin solutions.(18) 
Pectin gel systems have been used to show the partition and 
release of aroma compounds in foods during storage.(19) 
A specification for pectin is included in the Food Chemical 
Codex (FCC). In the food industry it is used as an emulsifying 
agent, gelling agent, thickener, and stabilizer. Cosmetically, it is 
used as a binder, emulsifying agent and viscosity-controlling 
agent. 
The EINECS number for pectin is 232-553-0. 
19 Specific References 
1 Cybercolloids Ltd. Introduction to pectins: properties. 
http://www.cybercolloids.net/library/pectin/properties.php 
(accessed 26 May 2005). 
2 Sweetman SC, ed. Martindale: the Complete Drug Reference, 34th 
edn. London: Pharmaceutical Press, 2005: 1580. 
3 LundW, ed. The Pharmaceutical Codex: Principles and Practice of 
Pharmaceutics, 12th edn. London: Pharmaceutical Press, 1994: 
88. 
4 Kubo W, Miyazaki S, Dairaku M, et al. Oral sustained delivery of 
ambroxol from in-situ gelling pectin formulations. Int J Pharm 
2004; 271(1–2): 233–240. 
5 Murata Y, Miyashita M, Kofuji K, et al. Drug release properties of 
a gel bead prepared with pectin and hydrolysate. J Control Release 
2004; 95(1): 61–66. 
6 Sriamornsak P, Nunthanid J, Wanchana S, Luangtana-Anan M. 
Composite film-coated tablets intended for colon-specific delivery 
of 5-aminosalicylic acid: using deesterified pectin. Pharm Dev 
Technol 2003; 8(3): 311–318. 
7 Liu L, Fishman ML, Kost J, Hicks KB. Pectin-based systems for 
colon-specific drug delivery via oral route. Biomaterials 2003; 
24(19): 3333–3343. 
8 Tho I, Sande SA, Kleinebudde P. Disintegrating pellets from a 
water-insoluble pectin derivative produced by extrusion/spheronisation. 
Eur J Pharm Biopharm 2003; 56(3): 371–380. 
9 Chourasia MK, Jain SK. Pharmaceutical approaches to colon 
targeted drug delivery systems. J Pharm Pharm Sci 2003; 6(1): 33– 
66. 
10 Musabayane CT, Munjeri O, Matavire TP. Transdermal delivery of 
chloroquine by amidated pectin hydrogel matrix patch in the rat. 
Ren Fail 2003; 25(4); 525–534. 
11 Kubo W, Konno Y, Miyazaki S, Attwood D. In situ gelling pectin 
formulations for oral sustained delivery of paracetamol. Drug Dev 
Ind Pharm 2004; 30(6): 593–599. 
12 Sungthongjeen S, Sriamornsak P, Pitaksuteepong T, et al. Effect of 
degree of esterification of pectin and calcium amount on drug 
release from pectin-based matrix tablets. AAPS Pharm Sci Tech 
2004; 5(1): E9. 
13 Pillay V, Danckwerts MP, Fassihi R. A crosslinked calciumalginate–
pectinate–cellulose acetophthalate gelisphere system for 
linear drug release. Drug Delivery 2002; 9(2): 77–86. 
14 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2825–2826. 
15 Ofori-Kwakye K, Fell JT. Biphasic drug release from film-coated 
tablets. Int J Pharm 2003; 250(2): 431–440. 
16 Ofori-Kwakye K, Fell JT. Leaching of pectin from mixed films 
containing pectin, chitosan and HPMC intended for biphasic drug 
delivery. Int J Pharm 2003; 250(1): 251–257. 
17 Ofori-Kwake K, Fell JT, Sharma HL, Smith AM. Gamma 
scintigraphic evaluation of film-coated tablets intended for colonic 
or biphasic release. Int J Pharm 2004; 270(1–2): 307–313. 
18 Marudova M, MacDougall AJ, Ring SG. Pectin–chitosan interactions 
and gel formation. Carbohydr Res 2004; 339(11): 1933– 
1939. 
19 Hansson A, Leufven A, van Ruth S. Partition and release of 21 
aroma compounds during storage of a pectin gel system. J Agric 
Food Chem 2003; 51(7): 2000–2005. 
20 General References 
Lofgren C, Walkenstrom P, Hermansson AM. Microstructure and 
rheological behavior of pure and mixed pectin gels. Biomacromolecules 
2002; 3(6): 1144–1153. 
21 Authors 
W Cook. 
22 Date of Revision 
26 August 2005. 
508 Pectin

Petrolatum 
1 Nonproprietary Names 
BP: Yellow soft paraffin 
JP: Yellow petrolatum 
PhEur: Vaselinum flavum 
USP: Petrolatum 
2 Synonyms 
Merkur; mineral jelly; petroleum jelly; Silkolene; Snow white; 
Soft white; yellow petrolatum; yellow petroleum jelly. 
3 Chemical Name and CAS Registry Number 
Petrolatum [8009-03-8] 
4 Empirical Formula and Molecular Weight 
Petrolatum is a purified mixture of semisolid saturated 
hydrocarbons having the general formula CnH2n.2, and is 
obtained from petroleum. The hydrocarbons consist mainly of 
branched and unbranched chains although some cyclic alkanes 
and aromatic molecules with paraffin side chains may also be 
present. The USP 28 and PhEur 2005 material may contain a 
suitable stabilizer (antioxidant) that must be stated on the label. 
The inclusion of a stabilizer is not discussed in the JP 2001 
monograph. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Emollient; ointment base. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Petrolatum is mainly used in topical pharmaceutical formulations 
as an emollient-ointment base; it is poorly absorbed by the 
skin. Petrolatum is also used in creams and transdermal 
formulations and as an ingredient in lubricant formulations 
for medicated confectionery together with mineral oil. 
Therapeutically, sterile gauze dressings containing petrolatum 
may be used for nonadherent wound dressings or as a 
packing material.(1) Petrolatum is additionally widely used in 
cosmetics and in some food applications. See Table I. 
Table I: Uses of petrolatum. 
Use Concentration (%) 
Emollient topical creams 10–30 
Topical emulsions 4–25 
Topical ointments Up to 100 
8 Description 
Petrolatum is a pale yellow to yellow-colored, translucent, soft 
unctuous mass. It is odorless, tasteless, and not more than 
slightly fluorescent by daylight, even when melted. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for petrolatum. 
Test JP 2001 PhEur 2005 USP 28 
Characters — . — 
Specific gravity at 608C — — 0.815–0.880 
Melting range 38–608C — 38–608C 
Drop point — 40–608C — 
Consistency — 100–300 100–300 
Alkalinity . . . 
Acidity . . . 
Residue on ignition 40.05% — 40.1% 
Sulfated ash — 40.05% — 
Organic acids . — . 
Polycyclic aromatic 
hydrocarbons 
— . — 
Fixed oils, fats and resins . — . 
Color . — . 
Light absorption — . — 
Heavy metals 430 ppm — — 
Arsenic 42 ppm — — 
Sulfur compounds . — — 
10 Typical Properties 
Refractive index: nD
60 = 1.460–1.474 
Solubility: practically insoluble in acetone, ethanol, hot or cold 
ethanol (95%), glycerin, and water; soluble in benzene, 
carbon disulfide, chloroform, ether, hexane, and most fixed 
and volatile oils. 
Viscosity (dynamic): the rheological properties of petrolatum 
are determined by the ratio of the unbranched chains to the 
branched chains and cyclic components of the mixture. 
Petrolatum contains relatively high amounts of branched 
and cyclic hydrocarbons, in contrast to paraffin, which 
accounts for its softer character and makes it an ideal 
ointment base.(2–5) 
11 Stability and Storage Conditions 
Petrolatum is an inherently stable material owing to the 
unreactive nature of its hydrocarbon components; most 
stability problems occur because of the presence of small 
quantities of impurities. On exposure to light, these impurities 
may be oxidized to discolor the petrolatum and produce an 
undesirable odor. The extent of the oxidation varies depending 
upon the source of the petrolatum and the degree of refinement. 
Oxidation may be inhibited by the inclusion of a suitable

antioxidant such as butylated hydroxyanisole, butylated 
hydroxytoluene, or alpha tocopherol. 
Petrolatum should not be heated for extended periods above 
the temperature necessary to achieve complete fluidity 
(approximately 708C). See also Section 18. 
Petrolatum may be sterilized by dry heat. Although 
petrolatum may also be sterilized by gamma irradiation, this 
process affects the physical properties of the petrolatum such as 
swelling, discoloration, odor, and rheological behavior.(6,7) 
Petrolatum should be stored in a well-closed container, 
protected from light, in a cool, dry place. 
12 Incompatibilities 
Petrolatum is an inert material with few incompatibilities. 
13 Method of Manufacture 
Petrolatum is manufactured from the semisolid residue that 
remains after the steam or vacuum distillation of petroleum.(8) 
This residue is dewaxed and/or blended with stock from other 
sources, along with lighter fractions, to give a product with the 
desired consistency. Final purification is performed by a 
combination of high-pressure hydrogenation or sulfuric acid 
treatment followed by filtration through adsorbents. A suitable 
antioxidant may be added. 
14 Safety 
Petrolatum is mainly used in topical pharmaceutical formulations 
and is generally considered to be a nonirritant and 
nontoxic material. 
Animal studies, in mice, have shown petrolatum to be 
nontoxic and noncarcinogenic following administration of a 
single subcutaneous 100mg dose. Similarly, no adverse effects 
were observed in a 2-year feeding study with rats fed a diet 
containing 5% of petrolatum blends.(9) 
Although petrolatum is generally nonirritant in humans 
following topical application, rare instances of allergic hypersensitivity 
reactions have been reported,(10–12) as have cases of 
acne, in susceptible individuals following repeated use on facial 
skin.(13) However, given the widespread use of petrolatum in 
topical products, there are few reports of irritant reactions. The 
allergic components of petrolatum appear to be polycyclic 
aromatic hydrocarbons present as impurities. The quantities of 
these materials found in petrolatum vary depending upon the 
source and degree of refining. Hypersensitivity appears to occur 
less with white petrolatum and it is therefore the preferred 
material for use in cosmetics and pharmaceuticals. 
Petrolatum has also been tentatively implicated in the 
formation of spherulosis of the upper respiratory tract 
following use of a petrolatum-based ointment packing after 
surgery,(14) and lipoid pneumonia following excessive use in the 
perinasal area.(15) Other adverse reactions to petrolatum 
include granulomas (paraffinomas) following injection into 
soft tissue.(16) Also, when taken orally, petrolatum acts as a 
mild laxative and may inhibit the absorption of lipids and lipidsoluble 
nutrients. 
Petrolatum is widely used in direct and indirect food 
applications. In the USA, the daily dietary exposure to 
petrolatum is estimated to be 0.404 mg/kg body-weight.(17) 
For further information see Mineral Oil and Paraffin. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. For recommended occupational 
exposure limits see Mineral Oil and Paraffin. 
16 Regulatory Status 
GRAS listed. Accepted for use in certain food applications in 
many countries worldwide. Included in the FDA Inactive 
Ingredients Guide (ophthalmic preparations, oral capsules and 
tablets, otic, topical, and transdermal preparations). Included 
in nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Mineral oil; mineral oil light; paraffin; petrolatum and lanolin 
alcohols; white petrolatum. 
White petrolatum 
Synonyms: vaselinum album; white petroleum jelly; white soft 
paraffin. 
Appearance: white petrolatum is a white to pale yellowcolored, 
translucent, soft unctuous mass. It is odorless and 
tasteless and not more than slightly fluorescent by daylight, 
even when melted. 
Method of manufacture: white petrolatum is petrolatum that 
has been highly refined so that it is wholly or nearly 
decolorized. 
Comments: white petrolatum is associated with fewer instances 
of hypersensitivity reactions and is the preferred petrolatum 
for use in cosmetics and pharmaceuticals, see Section 14. 
18 Comments 
Various grades of petrolatum are commercially available, 
which vary in their physical properties depending upon their 
source and refining process. Petrolatum obtained from different 
sources may therefore behave differently in a formulation.(18) 
Care is required in heating petrolatum because of its large 
coefficient of thermal expansion. It has been shown by both 
rheological and spectrophotometric methods that petrolatum 
undergoes phase transition at temperatures between 30–408C. 
Additives, such as microcrystalline wax, may be used to add 
body to petrolatum. A specification for petrolatum is contained 
in the Food Chemicals Codex (FCC). 
The EINECS number for petrolatum is 232-373-2. 
19 Specific References 
1 Smack DP, Harrington AC, Dunn C, et al. Infection and allergy 
incidence in ambulatory surgery patients using white petrolatum vs 
bacitracin ointment: randomized controlled trial. JAMA 1996; 
276: 972–977. 
2 Boylan JC. Rheological estimation of the spreading characteristics 
of pharmaceutical semisolids. J Pharm Sci 1967; 56: 1164–1169. 
3 Longworth AR, French JD. Quality control of white soft paraffin. J 
Pharm Pharmacol 1969; 21 (Suppl.): 1S–5S. 
4 Barry BW, Grace AJ. Grade variation in the rheology of white soft 
paraffin BP. J Pharm Pharmacol 1970; 22 (Suppl.): 147S–156S. 
5 Barry BW, Grace AJ. Structural, rheological and textural properties 
of soft paraffins. J Texture Studies 1971; 2: 259–279. 
6 Jacob BP, Leupin K. Sterilization of eye–nose ointments by gamma 
radiation [in German]. Pharm Acta Helv 1974; 49: 12–20. 
7 Davis SS, Khanderia MS, Adams I, et al. Effect of gamma radiation 
on rheological properties of pharmaceutical semisolids. J Texture 
Studies 1977; 8: 61–80. 
510 Petrolatum

8 Schindler H. Petrolatum for drugs and cosmetics. Drug Cosmet 
Ind 1961; 89(1): 36, 37, 76, 78–80, 82. 
9 Oser BL, Oser M, Carson S, Sternberg SS. Toxicologic studies of 
petrolatum in mice and rats. Toxicol Appl Pharmacol 1965; 7: 
382–401. 
10 Dooms-Goossens A, Degreef H. Contact allergy to petrolatums I: 
sensitivity capacity of different brands of yellow and white 
petrolatums. Contact Dermatitis 1983; 9: 175–185. 
11 Dooms-Goossens A, Degreef H. Contact allergy to petrolatums II: 
attempts to identify the nature of the allergens. Contact Dermatitis 
1983; 9: 247–256. 
12 Dooms-Goossens A, Dooms M. Contact allergy to petrolatums III: 
allergenicity prediction and pharmacopeial requirements. Contact 
Dermatitis 1983; 9: 352–359. 
13 Verhagen AR. Pomade acne in black skin [letter]. Arch Dermatol 
1974; 110: 465. 
14 Rosai J. The nature of myospherulosis of the upper respiratory 
tract. Am J Clin Pathol 1978; 69: 475–481. 
15 Cohen MA, Galbut B, Kerdel FA. Exogenous lipoid pneumonia 
caused by facial application of petrolatum. JAMA 2003; 49: 1128– 
1130. 
16 Crosbie RB, Kaufman HD. Self-inflicted oleogranuloma of breast. 
Br Med J 1967; 3: 840–841. 
17 Heimbach JT, Bodor AR, Douglass JS, et al. Dietary exposure to 
mineral hydrocarbons from food-use applications in the United 
States. Food Chem Toxicol 2002; 40: 555–571. 
18 Kneczke M, Landersjo. L, Lundgren P, Fu. hrer C. In vitro release of 
salicylic acid from two different qualities of white petrolatum. Acta 
Pharm Suec 1986; 23: 193–204. 
20 General References 
Bandelin FJ, Sheth BB. Semisolid preparations. In: Swarbrick J, Boylan 
JC, eds. Encyclopedia of Pharmaceutical Technology, vol. 14. New 
York: Marcel Dekker, 1996: 31–61. 
Barker G. New trends in formulating with mineral oil and petrolatum. 
Cosmet Toilet 1977; 92(1): 43–46. 
Davis SS. Viscoelastic properties of pharmaceutical semisolids I: 
ointment bases. J Pharm Sci 1969; 58: 412–418. 
De Muynck C, Lalljie SPD, Sandra P, et al. Chemical and physicochemical 
characterization of petrolatums used in eye ointment 
formulations. J Pharm Pharmacol 1993; 45: 500–503. 
De Rudder D, Remon JP, Van Aerde P. Structural stability of ophthalmic 
ointments containing soft paraffin. Drug Dev Ind Pharm 1987; 13: 
1799–1806. 
Morrison DS. Petrolatum: a useful classic. Cosmet Toilet 1996; 111(1): 
59–66, 69. 
Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 265–269. 
Sucker H. Petrolatums: technological properties and quality assessment. 
Cosmet Perfum 1974; 89(2): 37–43. 
21 Authors 
WJ Lambert. 
22 Date of Revision 
19 August 2005. 
Petrolatum 511

Petrolatum and Lanolin Alcohols 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Amerchol CAB; Forlan 500; petrolatum and wool alcohols; 
white soft paraffin and lanolin alcohols; yellow soft paraffin 
and lanolin alcohols. 
3 Chemical Name and CAS Registry Number 
Petrolatum [8009-03-8] and 
Lanolin alcohols [8027-33-6] 
4 Empirical Formula and Molecular Weight 
A mixture of petrolatum and lanolin alcohols. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Emollient; ointment base; plasticizer. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Petrolatum and lanolin alcohols is a soft solid used in topical 
pharmaceutical formulations and cosmetics as an ointment 
base with emollient properties. It is also used in the preparation 
of creams and lotions. Petrolatum and lanolin alcohols can be 
used to absorb wound exudates. See Table I. 
Table I: Uses of petrolatum and lanolin alcohols. 
Use Concentration (%) 
Absorption base component 10.0–50.0 
Emollient and plasticizer in ointments 5.0–50.0 
8 Description 
A pale ivory-colored, soft solid with a faint, characteristic sterol 
odor. 
9 Pharmacopeial Specifications 
—
10 Typical Properties 
Acid value: 41 
Arsenic: 42 ppm 
Ash: 40.2% 
Heavy metals: 420 ppm 
HLB value: 9 
Hydroxyl value: 11–15 
Melting range: 40–468C 
Microbiological count: the total bacterial count, when packaged, 
is less than 10 per gram of sample. 
Moisture content: 40.2% 
Saponification value: 42 
Solubility: soluble 1 in 20 parts of chloroform, and 1 in 100 
parts of mineral oil; precipitates at higher concentrations. 
Precipitation occurs in ethanol (95%), hexane, and water. 
May be dispersed in isopropyl palmitate. Forms a gel in 
castor oil and corn oil. 
11 Stability and Storage Conditions 
Petrolatum and lanolin alcohols is stable and should be stored 
in a well-closed container in a cool, dry place. 
12 Incompatibilities 
Lanolin alcohols is incompatible with coal tar, ichthammol, 
phenol, and resorcinol. 
13 Method of Manufacture 
Lanolin alcohols is blended with petrolatum. 
14 Safety 
Petrolatum and lanolin alcohols is generally regarded as an 
essentially nontoxic and nonirritant material. However, lanolin 
alcohols may be irritant to the skin and cause hypersensitivity 
in some individuals. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
Accepted for use in topical pharmaceutical formulations and 
cosmetics. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Lanolin alcohols; lanolin alcohols ointment; mineral oil and 
lanolin alcohols; petrolatum. 
Lanolin alcohols ointment 
Synonyms: Argobase EU; wool alcohols ointment. 
Appearance: white-colored ointment if prepared using white 
petrolatum, a yellow-colored ointment if yellow petrolatum 
is used in its preparation. 
Comments: the BP 2004 describes lanolin alcohols ointment 
(wool alcohols ointment BP) as a mixture consisting of: 
Lanolin alcohols 60 g 
Paraffin 240 g

Yellow or white petrolatum 100 g 
Mineral oil 600 g 
However, the proportions of paraffin, petrolatum, and 
mineral oil may be varied to produce an ointment of the 
desired physical properties. 
18 Comments 
See individual monographs on Lanolin Alcohols, and Petrolatum 
for further information. 
19 Specific References 
— 
20 General References 
Davis SS. Viscoelastic properties of pharmaceutical semisolids I: 
ointment bases. J Pharm Sci 1969; 58: 412–418. 
21 Authors 
SC Owen. 
22 Date of Revision 
12 August 2005. 
Petrolatum and Lanolin Alcohols 513

Phenol 
1 Nonproprietary Names 
BP: Phenol 
JP: Phenol 
PhEur: Phenolum 
USP: Phenol 
2 Synonyms 
Carbolic acid; hydroxybenzene; oxybenzene; phenic acid; 
phenyl hydrate; phenyl hydroxide; phenylic acid; phenylic 
alcohol. 
3 Chemical Name and CAS Registry Number 
Phenol [108-95-2] 
4 Empirical Formula and Molecular Weight 
C6H6O 94.11 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; disinfectant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Phenol is used mainly as an antimicrobial preservative in 
parenteral pharmaceutical products. It has also been used in 
topical pharmaceutical formulations and cosmetics; see Table I. 
Phenol is widely used as an antiseptic, disinfectant, and 
therapeutic agent, although it should not be used to preserve 
preparations that are to be freeze-dried.(1) 
Table I: Uses of phenol. 
Use Concentration (%) 
Disinfectant 5.0 
Injections (preservative) 0.5 
Local anesthetic 0.5–1.0 
Mouthwash 41.4 
8 Description 
Phenol occurs as colorless to light pink, caustic, deliquescent 
needle-shaped crystals or crystalline masses with a characteristic 
odor. When heated gently phenol melts to form a highly 
refractive liquid. The USP 28 permits the addition of a suitable 
stabilizer; the name and amount of substance used for this 
purpose must be clearly stated on the label. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for phenol. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Clarity of solution . . . 
Acidity . . — 
Congealing 
temperature 
— 539.58C 5398C 
Water — — 40.5% 
Nonvolatile 
residue 
40.05% 40.05% 40.05% 
Organic volatile 
impurities 
— — . 
Assay 598.0% 99.0–100.5% 99.0–100.5% 
10 Typical Properties 
Acidity/alkalinity: pH = 6.0 (saturated aqueous solution) 
Antimicrobial activity: phenol exhibits antimicrobial activity 
against a wide range of microorganisms such as Gramnegative 
and Gram-positive bacteria, mycobacteria and 
some fungi, and viruses; it is only very slowly effective 
against spores. Aqueous solutions of 1% w/v concentration 
are bacteriostatic, while stronger solutions are bactericidal. 
Phenol shows most activity in acidic solutions; increasing 
temperature also increases the antimicrobial activity. Phenol 
is inactivated by the presence of organic matter. 
Autoignition temperature: 7158C 
Boiling point: 181.88C 
Density: 1.071 g/cm3 
Dissociation constant: pKa = 10 at 258C 
Flash point: 798C (closed cup) 
Explosive limits: 2% lower limit; 9% upper limit. 
Freezing point: 40.98C 
Melting point: 438C 
Osmolarity: a 2.8% w/v solution is iso-osmotic with serum. 
Partition coefficient: octanol:water = 1.46 
Refractive index: nD
41 = 1.5425 
Solubility: see Table III. 
Vapor density (relative): 3.24 (air = 1) 
Vapor pressure: 133 Pa (1 mmHg) at 408C 
11 Stability and Storage Conditions 
When exposed to air and light, phenol turns a red or brown 
color, the color being influenced by the presence of metallic 
impurities. Oxidizing agents also hasten the color change. 
Aqueous solutions of phenol are stable. Oily solutions for

injection may be sterilized in hermetically sealed containers by 
dry heat. The bulk material should be stored in a well-closed, 
light-resistant container at a temperature not exceeding 158C. 
12 Incompatibilities 
Phenol undergoes a number of chemical reactions characteristic 
of alcohols; however, it possesses a tautomeric enol structure 
that is weakly acidic. It will form salts with sodium hydroxide 
or potassium hydroxide, but not with their carbonates or 
bicarbonates. 
Phenol is a reducing agent and is capable of reacting with 
ferric salts in neutral to acidic solutions to form a greenishcolored 
complex. Phenol decolorizes dilute iodine solutions, 
forming hydrogen iodide and iodophenol; stronger solutions of 
iodine react with phenol to form the insoluble 2,4,6-triiodophenol. 
Phenol is incompatible with albumin and gelatin as they are 
precipitated. It forms a liquid or soft mass when triturated with 
compounds such as camphor, menthol, thymol, acetaminophen, 
phenacetin, chloral hydrate, phenazone, ethyl aminobenzoate, 
methenamine, phenyl salicylate, resorcinol, terpin 
hydrate, sodium phosphate, or other eutectic formers. Phenol 
also softens cocoa butter in suppository mixtures. 
13 Method of Manufacture 
Historically, phenol was produced by the distillation of coal tar. 
Today, phenol is prepared by one of several synthetic methods, 
such as the fusion of sodium benzenesulfonate with sodium 
hydroxide followed by acidification; the hydrolysis of chlorobenzene 
by dilute sodium hydroxide at high temperature and 
pressure to give sodium phenate, which on acidification 
liberates phenol (Dow process); or the catalytic vapor-phase 
reaction of steam and chlorobenzene at 5008C (Raschig 
process). 
14 Safety 
Phenol is highly corrosive and toxic, the main effects being on 
the central nervous system. The lethal human oral dose is 
estimated to be 1 g for an adult. 
Phenol is absorbed from the gastrointestinal tract, skin, and 
mucous membranes and is metabolized to phenylglucuronide 
and phenyl sulfate, which are excreted in the urine. 
Although there are a number of reports describing the toxic 
effects of phenol, these largely concern instances of accidental 
poisoning(2,3) or adverse reactions during its use as a 
therapeutic agent.(4,5) Adverse reactions associated with phenol 
used as a preservative are less likely owing to the smaller 
quantities that are used; however, it has been suggested that the 
body burden of phenol should not exceed 50 mg in a 10-hour 
period.(6) This amount could be exceeded following administration 
of large volumes of phenol-preserved medicines. 
LD50 (mouse, IV): 0.11 g/kg(7) 
LD50 (mouse, oral): 0.3 g/kg 
LD50 (rabbit, skin): 0.85 g/kg 
LD50 (rat, skin): 0.67 g/kg 
LD50 (rat, oral): 0.32 g/kg 
LD50 (rat, SC): 0.46 g/kg 
15 Handling Precautions 
Phenol is toxic on contact with the skin or if swallowed or 
inhaled. Phenol is strongly corrosive, producing possibly 
irreversible damage to the cornea and severe skin burns, 
although the skin burns are painless owing to the anesthetic 
effects of phenol. 
Phenol should be handled with caution, particularly when 
hot, owing to the release of corrosive and toxic fumes. The use 
of fume cupboards, enclosed plants, or other environmental 
containment is recommended. Protective polyvinyl chloride or 
rubber clothing is recommended, together with gloves, eye 
protection, and respirators. Spillages on the skin or eyes should 
be washed with copious amounts of water. Affected areas of the 
skin should be washed with water followed by application of a 
vegetable oil. Medical attention should be sought. 
Phenol poses a slight fire hazard when cold and a moderate 
hazard when hot and exposed to heat or flame. 
In the UK, the occupational exposure limits for phenol are 
2 ppm long-term (8-hour TWA).(8) In the USA, the permissible 
exposure limit is 19 mg/m3 long-term and the recommended 
exposure limits are 20 mg/m3 long-term, and a maximum of 
60 mg/m3 short-term. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (injections). 
Included in medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Liquefied phenol. 
Liquefied phenol 
Appearance: liquefied phenol is phenol maintained as a liquid 
by the presence of approximately 10% water. It is a colorless 
liquid, with a characteristic aromatic odor, which may 
develop a red coloration on exposure to air and light. 
Specific gravity: 1.065 at 258C 
Comments: liquefied phenol is often more convenient to use in 
a formulation than the crystalline form. However, liquefied 
phenol should not be used with fixed or mineral oils, 
although the crystalline solid may be used. Caution should 
be observed when handling liquified phenol to avoid contact 
with skin, as this could cause serious burns. 
18 Comments 
Although phenol is soluble in approximately 12 parts of water 
at ambient temperatures, larger amounts of phenol in water 
produce a two-phase system of phenol solution floating on a 
lower layer of wet phenol. At 208C, 100 parts of phenol may be 
liquefied by the addition of 10 parts of water. At 848C phenol is 
miscible with water in all proportions. 
The EINECS number for phenol is 203-632-7. 
Table III: Solubility of phenol. 
Solvent Solubility at 208C 
Carbon disulfide Very soluble 
Chloroform Very soluble 
Ethanol (95%) Very soluble 
Ether Very soluble 
Fixed oils Very soluble 
Glycerin Very soluble 
Mineral oil 1 in 70 
Volatile oils Very soluble 
Water 1 in 15 
Phenol 515

19 Specific References 
1 FAO/WHO. WHO expert committee on biological standardization. 
Thirty-seventh report. World Health Organ Tech Rep Ser 
1987; No. 760. 
2 Foxall PJD, Bending MR, Gartland KPR, Nicholson JR. Acute 
renal failure following accidental cutaneous absorption of phenol: 
application of NMR urinalysis to monitor the disease process. 
Hum Toxicol 1989; 9: 491–496. 
3 Christiansen RG, Klaman JS. Successful treatment of phenol 
poisoning with charcoal hemoperfusion. Vet Hum Toxicol 1996; 
38: 27–28. 
4 Warner MA, Harper JV. Cardiac dysrhythmias associated with 
chemical peeling with phenol. Anesthesiology 1985; 62: 366–367. 
5 Ho SL, Hollinrake K. Acute epiglottitis and Chloraseptic. Br Med J 
1989; 298: 1584. 
6 Brancato DJ. Recognizing potential toxicity of phenol. Vet Hum 
Toxicol 1982; 24: 29–30. 
7 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2885. 
8 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
Karabit MS. Studies on the evaluation of preservative efficacy V. Effect 
of concentration of micro-organisms on the antimicrobial activity of 
phenol. Int J Pharm 1990; 60: 147–150. 
21 Authors 
RT Guest. 
22 Date of Revision 
23 August 2005. 
516 Phenol

Phenoxyethanol 
1 Nonproprietary Names 
BP: Phenoxyethanol 
PhEur: Phenoxyethanolum 
USPNF: Phenoxyethanol 
2 Synonyms 
Arosol; Emerescence 1160; ethyleneglycol monophenyl ether; 
b-hydroxyethyl phenyl ether; 1-hydroxy-2-phenoxyethane; 
Phenoxen; b-phenoxyethyl alcohol; phenyl cellulose. 
3 Chemical Name and CAS Registry Number 
2-Phenoxyethanol [122-99-6] 
4 Empirical Formula and Molecular Weight 
C8H10O2 138.16 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; disinfectant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Phenoxyethanol is an antimicrobial preservative used in 
cosmetics and topical pharmaceutical formulations at a 
concentration of 0.5–1.0%; it may also be used as a 
preservative and antimicrobial agent for vaccines.(1,2) Therapeutically, 
a 2.2% solution or 2.0% cream has been used as a 
disinfectant for superficial wounds, burns, and minor infections 
of the skin and mucous membranes.(3–5) 
Phenoxyethanol has a narrow spectrum of activity and is 
thus frequently used in combination with other preservatives, 
see Section 10. 
8 Description 
Phenoxyethanol is a colorless, slightly viscous liquid with a 
faint pleasant odor and burning taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for phenoxyethanol. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Refractive index 1.537–1.539 — 
Relative density 1.105–1.110 1.105–1.110 
Phenol . 40.1% 
Chromatographic purity — . 
Related substances . . 
Assay 99.0–100.5% 98.0–102.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 6.0 for a 1% v/v aqueous solution. 
Antimicrobial activity: phenoxyethanol is an antibacterial 
preservative effective over a wide pH range against strains 
of Pseudomonas aeruginosa and to a lesser extent against 
Proteus vulgaris and other Gram-negative organisms. It is 
most frequently used in combination with other preservatives, 
such as parabens, to obtain a wider spectrum of 
antimicrobial activity.(6–8) See also Section 12. For reported 
minimum inhibitory concentrations (MICs) see Table II.(9) 
Table II: Minimum inhibitory concentrations (MICs) of 
phenoxyethanol. 
Microorganism MIC (mg/mL) 
Aspergillus niger ATCC 16404 3300 
Candida albicans ATCC 10231 5400 
Escherichia coli ATCC 8739 3600 
Pseudomonas aeruginosa ATCC 9027 3200 
Staphylococcus aureus ATCC 6538 8500 
Autoignition temperature: 1358C 
Boiling point: 245.28C 
Flash point: 1218C (open cup) 
Melting point: 148C 
Partition coefficients: 
Isopropyl palmitate : water = 2.9; 
Mineral oil : water = 0.3; 
Peanut oil : water = 2.6. 
Refractive index: nD
20 = 1.537–1.539 
Solubility: see Table III. 
Specific gravity: 1.11 at 208C 
11 Stability and Storage Conditions 
Aqueous phenoxyethanol solutions are stable and may be 
sterilized by autoclaving. The bulk material is also stable and 
should be stored in a well-closed container in a cool, dry place. 
12 Incompatibilities 
The antimicrobial activity of phenoxyethanol may be reduced 
by interaction with nonionic surfactants and possibly by

Table III: Solubility of phenoxyethanol. 
Solvent Solubility at 208C 
Acetone Miscible 
Ethanol (95%) Miscible 
Glycerin Miscible 
Isopropyl palmitate 1 in 26 
Mineral oil 1 in 143 
Olive oil 1 in 50 
Peanut oil 1 in 50 
Water 1 in 43 
absorption by polyvinyl chloride.(10) The antimicrobial activity 
of phenoxyethanol against Pseudomonas aeruginosa may be 
reduced in the presence of cellulose derivatives (methylcellulose, 
sodium carboxymethylcellulose, and hypromellose 
(hydroxypropylmethylcellulose)).(11) 
13 Method of Manufacture 
Phenoxyethanol is prepared by treating phenol with ethylene 
oxide in an alkaline medium. 
14 Safety 
Phenoxyethanol produces a local anesthetic effect on the lips, 
tongue, and other mucous membranes. The pure material is a 
moderate irritant to the skin and eyes. In animal studies, a 10% 
v/v solution was not irritant to rabbit skin and a 2% v/v 
solution was not irritant to the rabbit eye.(12) Long-term 
exposure to phenoxyethanol may result in CNS toxic effects 
similar to other organic solvents.(13) 
LD50 (rabbit, skin): 5 g/kg(14) 
LD50 (rat, oral): 1.26 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Phenoxyethanol may be 
irritant to the skin and eyes; eye protection and gloves are 
recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (topical 
preparations). Included in nonparenteral medicines licensed in 
the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Chlorobutanol; chlorophenoxyethanol; phenoxypropanol. 
Chlorophenoxyethanol 
Empirical formula: C8H9ClO2 
Molecular weight: 172.60 
CAS number: [29533-21-9] 
Phenoxypropanol 
Empirical formula: C9H12O2 
Molecular weight: 152.18 
CAS number: [4169-04-4] 
Synonyms: 1-phenoxypropan-2-ol. 
18 Comments 
Aqueous solutions are best prepared by shaking phenoxyethanol 
with hot water until dissolved, followed by cooling and 
adjusting the volume to the required concentration. 
The EINECS number for phenoxyethanol is 204-589-7. 
19 Specific References 
1 Pivnick H, Tracy JM, Tosoni AL, Glass DG. Preservatives for 
poliomyelitis (Salk) vaccine III: 2-phenoxyethanol. J Pharm Sci 
1964; 53: 899–901. 
2 Lowe I, Southern J. The antimicrobial activity of phenoxyethanol 
in vaccines. Lett Appl Microbiol 1994; 18(2): 115–116. 
3 Thomas B, Sykes L, Stickler DJ. Sensitivity of urine-grown cells of 
Providencia stuartii to antiseptics. J Clin Pathol 1978; 31: 929– 
932. 
4 Lawrence JC, Cason JS, Kidson A. Evaluation of phenoxetolchlorhexidine 
cream as a prophylactic antibacterial agent in burns. 
Lancet 1982; i: 1037–1040. 
5 Bollag U. Phenoxetol–chlorhexidine cream as a prophylactic 
antibacterial agent in burns [letter]. Lancet 1982; ii: 106. 
6 Abdelaziz AA, El-Nakeeb MA. Sporicidal activity of local 
anaesthetics and their binary combinations with preservatives. J 
Clin Pharm Ther 1988; 13: 249–256. 
7 Denyer SP, Hugo WB, Harding VD. Synergy in preservative 
combinations. Int J Pharm 1985; 25: 245–253. 
8 Onawunmi GO. In vitro studies on the antibacterial activity of 
phenoxyethanol in combination with lemon grass oil. Pharmazie 
1988; 43: 42–44. 
9 Hall AL. Cosmetically acceptable phenoxyethanol. In: Kabara JJ, 
ed. Cosmetic and Drug Preservation Principles and Practice. New 
York: Marcel Dekker, 1984: 79–108. 
10 Lee MG. Phenoxyethanol absorption by polyvinyl chloride. J Clin 
Hosp Pharm 1984; 9: 353–355. 
11 Kurup TRR,Wan LSC, Chan LW. Interaction of preservatives with 
macromolecules part II: cellulose derivatives. Pharm Acta Helv 
1995; 70: 187–193. 
12 Nipa Laboratories Ltd. Technical literature: Phenoxetol, 1992. 
13 Morton WE. Occupational phenoxyethanol neurotoxicity: a 
report of three cases. J Occup Med 1990; 32(1): 42–45. 
14 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2904. 
20 General References 
Baird RM. A proposed alternative to calamine cream BPC. Pharm J 
1974; 213: 153–154. 
Denyer SP, Baird RM, eds. Guide to Microbiological Control in 
Pharmaceuticals. Chichester: Ellis Horwood, 1990. 
Fitzgerald KA, Davies A, Russell AD. Effect of chlorhexidine and 
phenoxyethanol, alone and in combination, on leakage from Gramnegative 
bacteria. J Pharm Pharmacol 1990; 42 (Suppl.): 104P. 
Gilbert P, Beveridge EG, Crone PB. The action of phenoxyethanol upon 
respiration and dehydrogenase enzyme systems in Escherichia coli. J 
Pharm Pharmacol 1976; 28 (Suppl.): 51P. 
Hall AL. Phenoxyethanol: a cosmetically acceptable preservative. 
Cosmet Toilet 1981; 96(3): 83–85. 
21 Authors 
SC Owen. 
22 Date of Revision 
17 August 2005. 
518 Phenoxyethanol

Phenylethyl Alcohol 
1 Nonproprietary Names 
USP: Phenylethyl alcohol 
2 Synonyms 
Benzeneethanol; benzyl carbinol; benzylmethanol; b-hydroxyethyl 
benzene; PEA; phenethanol; b-phenylethyl alcohol; 2- 
phenylethyl alcohol; phenylethanol. 
3 Chemical Name and CAS Registry Number 
2-Phenylethanol [60-12-8] 
4 Empirical Formula and Molecular Weight 
C8H10O 122.17 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Phenylethyl alcohol is used as an antimicrobial preservative in 
nasal, ophthalmic, and otic formulations at 0.25–0.5% v/v 
concentration; it is generally used in combination with other 
preservatives.(1–3) Phenylethyl alcohol has also been used on its 
own as an antimicrobial preservative at concentrations up to 
1% v/v in topical preparations. At this concentration, 
mycoplasmas are inactivated within 20 minutes, although 
enveloped viruses are resistant.(4) Phenylethyl alcohol is also 
used in flavors and as a perfumery component, especially in 
rose perfumes. 
8 Description 
Phenylethyl alcohol is a clear, colorless liquid with an odor of 
rose oil. It has a burning taste that irritates and then 
anesthetizes mucous membranes. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for phenylethyl alcohol. 
Test USP 28 
Identification . 
Specific gravity 1.017–1.020 
Refractive index 1.531–1.534 
Residue on ignition 40.005% 
Chlorinated compounds . 
Aldehyde . 
Organic volatile impurities . 
10 Typical Properties 
Antimicrobial activity: phenylethyl alcohol has moderate 
antimicrobial activity although it is relatively slow acting; 
it is not sufficiently active to be used alone.(5) Greatest 
activity occurs at less than pH 5; it is inactive above pH 8. 
Synergistic effects have been reported when combined with 
benzalkonium chloride, chlorhexidine gluconate or diacetate, 
polymyxin B sulfate, and phenylmercuric nitrate.(6–10) 
With either benzalkonium chloride or chlorhexidine, 
synergistic effects were observed against Pseudomonas 
aeruginosa and apparently additive effects against Grampositive 
organisms. With phenylmercuric nitrate, the effect 
was additive against Pseudomonas aeruginosa. Additive 
effects against Pseudomonas cepacia in combination with 
either benzalkonium chloride or chlorhexidine have also 
been reported.(11) See also Section 12. 
Bacteria: fair activity against Gram-positive bacteria; for 
Staphylococcus aureus, the minimum inhibitory concentration 
(MIC) may be more than 5 mg/mL. Greater activity is 
shown against Gram-negative organisms.(12) Typical MIC 
values are: Salmonella typhi 1.25 mg/mL; Pseudomonas 
aeruginosa 2.5 mg/mL; Escherichia coli 5.0 mg/mL. 
Fungi: poor activity against molds and fungi. 
Spores: inactive, e.g., at 0.6% v/v concentration, reported to 
be ineffective against spores of Bacillus stearothermophilus 
at 1008C for 30 minutes. 
Boiling point: 219–2218C 
Flash point: 1028C (open cup) 
Melting point: 278C 
Partition coefficients: 
Chloroform : water = 15.2; 
Heptane : water = 0.58; 
Octanol : water = 21.5. 
Solubility: see Table II. 
11 Stability and Storage Conditions 
Phenylethyl alcohol is stable in bulk, but is volatile and sensitive 
to light and oxidizing agents. It is reasonably stable in both 
acidic and alkaline solutions. Aqueous solutions may be 
sterilized by autoclaving. If stored in low-density polyethylene 
containers, phenylethyl alcohol may be absorbed by the 
containers. Losses to polypropylene containers have been 
reported to be insignificant over 12 weeks at 308C. Sorption 
to rubber closures is generally small.

Table II: Solubilty of phenylethyl alcohol. 
Solvent Solubility at 208C 
Benzyl benzoate Very soluble 
Chloroform Very soluble 
Diethyl phthalate Very soluble 
Ethanol (95%) Very soluble 
Ether Very soluble 
Fixed oils Very soluble 
Glycerin Very soluble 
Mineral oil Slightly soluble 
Propylene glycol Very soluble 
Water 1 in 60 
The bulk material should be stored in a well-closed 
container, protected from light, in a cool, dry place. 
12 Incompatibilities 
Incompatible with oxidizing agents and protein, e.g., serum. 
Phenylethyl alcohol is partially inactivated by polysorbates, 
although this is not as great as the reduction in antimicrobial 
activity that occurs with parabens and polysorbates.(13) 
13 Method of Manufacture 
Phenylethyl alcohol is prepared by reduction of ethyl phenylacetate 
with sodium in absolute alcohol; by hydrogenation of 
phenylacetaldehyde in the presence of a nickel catalyst; or by 
addition of ethylene oxide or ethylene chlorohydrin to 
phenylmagnesium bromide, followed by hydrolysis. Phenylethyl 
alcohol also occurs naturally in a number of essential oils, 
especially rose oil. 
14 Safety 
Phenylethyl alcohol is generally regarded as a nontoxic and 
nonirritant material. However, at the concentration used to 
preserve eye-drops (about 0.5% v/v) or above, eye irritation 
may occur.(14) 
LD50 (rabbit, skin): 0.79 g/kg(15) 
LD50 (rat, oral): 1.79 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Phenylethyl alcohol is 
combustible when exposed to heat or flame, and emits acrid 
smoke when heated to decomposition. Eye protection and 
gloves are recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (nasal, 
ophthalmic, and otic preparations). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Chlorobutanol. 
18 Comments 
The EINECS number for phenylethyl alcohol is 200-456-2. 
19 Specific References 
1 Goldstein SW. Antibacterial agents in compounded ophthalmic 
solutions. J Am Pharm Assoc (Pract Pharm) 1953; 14: 498–524. 
2 Heller WM, Foss NE, Shay DE, Ichniowski CT. Preservatives in 
solutions. J Am Pharm Assoc (Pract Pharm) 1955; 16: 29–36. 
3 Hodges NA, Denyer SP, Hanlon GW, Reynolds JP. Preservative 
efficacy tests on formulated nasal products: reproducibility and 
factors affecting preservative activity. J Pharm Pharmacol 1996; 
48: 1237–1242. 
4 Staal SP, Rowe WP. Differential effect of phenylethyl alcohol on 
mycoplasmas and enveloped viruses. J Virol 1974; 14: 1620–1622. 
5 Kohn SR, Gershenfeld L, Barr M. Effectiveness of antibacterial 
agents presently employed in ophthalmic preparations as preservatives 
against Pseudomonas aeruginosa. J Pharm Sci 1963; 52: 
967–974. 
6 Richards RME, McBride RJ. Cross-resistance in Pseudomonas 
aeruginosa resistant to phenylethanol. J Pharm Sci 1972; 61: 
1075–1077. 
7 Richards RME, McBride RJ. The preservation of ophthalmic 
solutions with antibacterial combinations. J Pharm Pharmacol 
1972; 24: 145–148. 
8 Richards RME, McBride RJ. Effect of 3-phenylpropan-1-ol, 2- 
phenylethanol, and benzyl alcohol on Pseudomonas aeruginosa. J 
Pharm Sci 1973; 62: 585–587. 
9 Richards RME, McBride RJ. Enhancement of benzalkonium 
chloride and chlorhexidine acetate activity against Pseudomonas 
aeruginosa by aromatic alcohols. J Pharm Sci 1973; 62: 2035– 
2037. 
10 Richards RME, McBride RJ. Antipseudomonal effect of polymyxin 
and phenylethanol. J Pharm Sci 1974; 63: 54–56. 
11 Richards RME, Richards JM. Pseudomonas cepacia resistance to 
antibacterials. J Pharm Sci 1979; 68: 1436–1438. 
12 Lilley BD, Brewer JH. The selective antibacterial action of 
phenylethyl alcohol. J Am Pharm Assoc (Sci) 1953; 42: 6–8. 
13 Bahal CK, Kostenbauder HB. Interaction of preservatives with 
macromolecules V: binding of chlorobutanol, benzyl alcohol, and 
phenylethyl alcohol by nonionic agents. J Pharm Sci 1964; 53: 
1027–1029. 
14 Boer Y. Irritation by eyedrops containing 2-phenylethanol. Pharm 
Weekbl (Sci) 1981; 3: 826–827. 
15 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2879. 
20 General References 
Silver S, Wendt L. Mechanism of action of phenylethyl alcohol: 
breakdown of the cellular permeability barrier. J Bacteriol 1967; 93: 
560–566. 
Sklubalova Z. Antimicrobial substances in ophthalmic drugs. Ceska 
Slov Farm 2004; 53(3): 107–116. 
21 Authors 
SC Owen. 
22 Date of Revision 
17 August 2005. 
520 Phenylethyl Alcohol

Phenylmercuric Acetate 
1 Nonproprietary Names 
BP: Phenylmercuric acetate 
PhEur: Phenyldriargyri acetas 
USPNF: Phenylmercuric acetate 
2 Synonyms 
(Acetato-O)phenylmercury; acetoxyphenylmercury; Gallotox; 
Liquiphene; phenylmercury acetate; PMA; PMAC; PMAS. 
3 Chemical Name and CAS Registry Number 
(Acetato)phenylmercury [62-38-4] 
4 Empirical Formula and Molecular Weight 
C8H8HgO2 336.74 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; antiseptic. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Phenylmercuric acetate is used as an alternative antimicrobial 
preservative to phenylmercuric borate or phenylmercuric 
nitrate in cosmetics (in concentrations not exceeeding 
0.0065% of mercury calculated as the metal) and pharmaceuticals. 
It may be used in preference to phenylmercuric nitrate 
owing to its greater solubility. 
Phenylmercuric acetate is also used as a spermicide, see 
Table I. 
See also Phenylmercuric Nitrate. 
Table I: Uses of phenylmercuric acetate. 
Use Concentration (%) 
Bactericide in parenterals and eye-drops 0.001–0.002 
Spermicide in vaginal suppositories and jellies 
(active ingredient) 
0.02 
8 Description 
Phenylmercuric acetate occurs as a white to creamy white, 
odorless or almost odorless, crystalline powder, or as small 
white prisms or leaflets. 
SEM: 1 
Excipient: Phenylmercuric acetate 
Manufacturer: Eastman Fine Chemicals 
Magnification: 600 
SEM: 2 
Excipient: Phenylmercuric acetate 
Manufacturer: Eastman Fine Chemicals 
Magnification: 1800 
9 Pharmacopeial Specifications 
See Table II.

Table II: Pharmacopeial specifications for phenylmercuric acetate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Appearance of solution . — 
Ionized mercury 40.2% . 
Loss on drying 40.5% — 
Polymercurated benzene 
compounds 
41.5% 41.5% 
Melting range — 149–1538C 
Residue on ignition — 40.2% 
Organic volatile impurities . . 
Assay 98.0–100.5% 98.0–100.5% 
10 Typical Properties 
Acidity/alkalinity: pH 4 for a saturated aqueous solution at 
208C. 
Antimicrobial activity: phenylmercuric acetate is a broadspectrum 
antimicrobial preservative with slow bactericidal 
and fungicidal activity similar to phenylmercuric nitrate; see 
Phenylmercuric Nitrate. 
Dissociation constant: pKa = 3.3 
Melting point: 1508C 
Partition coefficients: 
Mineral oil : water = 0.1 
Solubility: see Table III. 
Table III: Solubility of phenylmercuric acetate. 
Solvent Solubility at 208C(a) 
Acetone 1 in 19 
Chloroform 1 in 6.8 
Ethanol (95%) 1 in 225 
Ether 1 in 200 
Water 1 in 180 
(a) Compendial values for solubility vary considerably and in most instances do not show close 
agreement with laboratory-determined values, which also vary. 
11 Stability and Storage Conditions 
As for other phenylmercuric salts; see Phenylmercuric Nitrate. 
Phenylmercuric acetate should be stored in a well-closed 
container, protected from light, in a cool, dry place. 
12 Incompatibilities 
As for other phenylmercuric salts; see Phenylmercuric Nitrate. 
Incompatible with: halides; anionic emulsifying agents and 
suspending agents; tragacanth; starch; talc; sodium metabisulfite; 
sodium thiosulfate; disodium edetate; silicates; aluminum 
and other metals; amino acids; ammonia and ammonium salts; 
sulfur compounds; rubber; and some plastics. 
Phenylmercuric acetate is reported to be incompatible with 
cefuroxime and ceftazidime.(1) 
13 Method of Manufacture 
Phenylmercuric acetate is readily formed by heating benzene 
with mercuric acetate. 
14 Safety 
Phenylmercuric acetate is mainly used as an antimicrobial 
preservative in topical pharmaceutical formulations. A number 
of adverse reactions to mercury- containing preservatives have 
been reported; see Phenylmercuric Nitrate. 
LD50 (chicken, oral): 60 mg/kg(2) 
LD50 (mouse, IP): 13 mg/kg 
LD50 (mouse, IV): 18 mg/kg 
LD50 (mouse, oral): 13 mg/kg 
LD50 (mouse, SC): 12 mg/kg 
LD50 (rat, oral): 41 mg/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Phenylmercuric acetate may 
be irritant to the skin, eyes, and mucous membranes. Eye 
protection, gloves, and a respirator are recommended. Chronic 
exposure via any route can lead to central nervous system 
damage. In the UK, the occupational exposure limit for 
mercury-containing compounds, calculated as mercury, is 
0.01 mg/m3 long-term (8-hour TWA) and 0.03 mg/m3 shortterm.(
3) 
16 Regulatory Status 
Phenylmercuric acetate is no longer permitted to be used as a 
pesticide in the USA. It is, however, included in the FDA 
Inactive Ingredients Guide (ophthalmic preparations), and is 
also included in nonparenteral medicines licensed in the UK. In 
France, a maximum concentration of 0.01% is permitted for 
use in pharmaceuticals. The use of phenylmercuric acetate in 
cosmetics is restricted in the UK; see Phenylmercuric Nitrate. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients (however, there must be no other suitable preservatives 
available). 
17 Related Substances 
Phenylmercuric borate; phenylmercuric nitrate; thimerosal. 
18 Comments 
The EINECS number for phenylmercuric acetate is 200-532-5. 
19 Specific References 
1 Hill DB, Barnes AR. Compatibility of phenylmercuric acetate with 
cefuroxime and ceftazidime eye drops. Int J Pharm 1997; 147: 
127–129. 
2 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 33–34. 
3 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
Abdelaziz AA, El-Nakeeb MA. Sporicidal activity of local anaesthetics 
and their binary combinations with preservatives. J Clin Pharm 
Ther 1988; 13: 249–256. 
Barkman R, Germanis M, Karpe G, Malmborg AS. Preservatives in eye 
drops. Acta Ophthalmol 1969; 47: 461–475. 
Grier N. Mercurials inorganic and organic. In: Block SS, ed. 
Disinfection, Sterilization and Preservation, 3rd edn. Philadelphia: 
Lea and Febiger, 1983: 346–374. 
522 Phenylmercuric Acetate

Hecht G. Ophthalmic preparations. In: Gennaro AR, ed. Remington: 
The Science and Practice of Pharmacy, 20th edn. Baltimore: 
Lippincott Williams and Wilkins, 2000: 821–835. 
Parkin JE. The decomposition of phenylmercuric nitrate in sulphacetamide 
drops during heat sterilization. J Pharm Pharmacol 1993; 
45: 1024–1027. 
Parkin JE, Button KL, Maroudas PA. The decomposition of phenylmercuric 
nitrate caused by disodium edetate in neomycin eye drops 
during the process of heat sterilization. J Clin Pharm Ther 1992; 17: 
191–196. 
Parkin JE, Duffy MB, Loo CN. The chemical degradation of 
phenylmercuric nitrate by disodium edetate during heat sterilization 
at pH values commonly encountered in ophthalmic products. J Clin 
Pharm Ther 1992; 17: 307–314. 
21 Authors 
SE Hepburn. 
22 Date of Revision 
17 August 2005. 
Phenylmercuric Acetate 523

Phenylmercuric Borate 
1 Nonproprietary Names 
BP: Phenylmercuric borate 
PhEur: Phenylhydrargyri boras 
2 Synonyms 
(Dihydrogen borato)phenylmercury; phenylmercuriborate; 
phenylmercury borate; PMB. 
3 Chemical Name and CAS Registry Number 
[Orthoborato(3-)-O]-phenylmercurate(2-)dihydrogen [102- 
98-7] 
The CAS Registry Number, chemical name and synonyms 
all refer to phenylmercuric borate alone, rather than the 
compound. The name phenylmercuric borate and the synonyms 
may, however, be applied to the PhEur 2005 material, 
which is a compound or a mixture of compounds, see Section 4. 
Unique CAS Registry Numbers for phenylmercuric borate and 
the compounds are as follows: 
C6H7BHgO3 [102-98-7] 
C12H13BHg2O4 [8017-88-7] 
C12H11BHg2O3 [6273-99-0] 
4 Empirical Formula and Molecular Weight 
The PhEur 2005 material is a compound consisting of 
equimolecular proportions of phenylmercuric hydroxide and 
phenylmercuric orthoborate (C12H13BHg2O4) or of the dehydrated 
form (metaborate, C12H11BHg2O3), or a mixture of 
the two compounds. 
Phenylmercuric hydroxide and phenylmercuric orthoborate: 
C12H13BHg2O4 633.2 
Phenylmercuric hydroxide and phenylmercuric metaborate: 
C12H11BHg2O3 615.2 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; antiseptic. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Phenylmercuric borate is used as an alternative antimicrobial 
preservative to phenylmercuric acetate or phenylmercuric 
nitrate. It is more soluble than phenylmercuric nitrate and has 
also been reported to be less irritant than either phenylmercuric 
acetate or phenylmercuric nitrate.(1) See Table I. 
See also Phenylmercuric Nitrate. 
Table I: Uses of phenylmercuric borate. 
Use Concentration (%) 
Antimicrobial agent in ophthalmics 0.002–0.004 
Antimicrobial agent in parenterals 0.002 
8 Description 
Phenylmercuric borate occurs as colorless, shiny flakes or as a 
white or slightly yellow, odorless, crystalline powder. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for phenylmercuric borate. 
Test PhEur 2005 
Identification . 
Appearance of solution . 
Ionized mercury (as heavy metals) . 
Loss on drying (at 458C) 43.5% 
Assay (dried basis) of 
Mercury 64.5–66.0% 
Borates (as H3BO3) 9.8–10.3% 
10 Typical Properties 
Acidity/alkalinity: pH = 5.0–7.0 for 0.6% w/v aqueous 
solution at 208C. 
Antimicrobial activity: phenylmercuric borate is a broadspectrum 
antimicrobial preservative with slow bactericidal 
and fungicidal activity similar to that of phenylmercuric 
nitrate; see Phenylmercuric Nitrate. 
Dissociation constant: pKa = 3.3 
Melting point: 112–1138C 
Solubility: see Table III. 
11 Stability and Storage Conditions 
As for other phenylmercuric salts; see Phenylmercuric Nitrate. 
Solutions may be sterilized by autoclaving. 
Phenylmercuric borate should be stored in a well-closed 
container, protected from light, in a cool, dry place.

Table III: Solubility of phenylmercuric borate. 
Solvent Solubility at 208C(a) unless otherwise stated 
Ethanol (95%) 1 in 150 
Glycerin Soluble 
Propylene glycol Soluble 
Water 1 in 125 
1 in 100 at 1008C 
(a) Compendial values for solubility vary considerably. 
12 Incompatibilities 
As for other phenylmercuric salts; see Phenylmercuric Nitrate. 
Incompatible with: halides; anionic emulsifying agents and 
suspending agents; tragacanth; starch; talc; sodium metabisulfite; 
sodium thiosulfate; disodium edetate; silicates; aluminum 
and other metals; amino acids; ammonia and ammonium salts; 
sulfur compounds; rubber; and some plastics. 
13 Method of Manufacture 
Phenylmercuric borate may be prepared by heating mercuric 
borate with benzene or by evaporating to dryness, under 
vacuum, an alcoholic solution containing equimolar proportions 
of phenylmercuric hydroxide and boric acid. 
14 Safety 
Phenylmercuric borate is mainly used as an antimicrobial 
preservative in topical pharmaceutical formulations. A number 
of adverse reactions to mercury-containing preservatives have 
been reported; see Phenylmercuric Nitrate. 
Although phenylmercuric borate is an irritant, it has been 
reported to be less so than either phenylmercuric acetate or 
phenylmercuric nitrate.(1) There is, however, some crosssensitization 
potential with other mercurial preservatives. 
Systemic absorption has been reported following regular use 
of a hand disinfectant soap containing 0.04% phenylmercuric 
borate, resulting in an increase in the estimated total daily body 
load of mercury from 30–100 mg per 24 hours.(2) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Phenylmercuric borate may 
be irritant to the skin, eyes, and mucous membranes. Eye 
protection, gloves, and a respirator are recommended. In the 
UK, the occupational exposure limit for mercury-containing 
compounds, calculated as mercury, is 0.01 mg/m3 long-term (8- 
hour TWA) and 0.03 mg/m3 short-term.(3) 
16 Regulatory Status 
Included in nonparenteral medicines licensed in Europe. In 
France, a maximum concentration of up to 0.01% is permitted 
for use in pharmaceutical formulations. In the UK, the use of 
phenylmercuric borate in cosmetics is restricted;(4) see Phenylmercuric 
Nitrate. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients (ophthalmic, nasal and otic preparations; 
there must be no other suitable alternative preservative). 
17 Related Substances 
Phenylmercuric acetate; phenylmercuric nitrate; thimerosal. 
18 Comments 
The EINECS number for phenylmercuric borate is 203-068-1. 
19 Specific References 
1 Marzulli FN, Maibach HI. Antimicrobials: experimental contact 
sensitization in man. J Soc Cosmet Chem 1973; 24: 399–421. 
2 Peters-Haefeli L, Michod JJ, Aelhg A, et al. Urinary excretion of 
mercury after the use of an antiseptic soap containing 0.04% of 
phenylmercuric borate [in French]. Schweiz Med Wochenschr 
1976; 106(6): 171–178. 
3 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
4 Statutory Instrument (SI) 1989: No. 2233. Consumer Protection: 
The Consumer Products (Safety) Regulations 1989. London: 
HMSO, 1989. 
20 General References 
Abdelaziz AA, El-Nakeeb MA. Sporicidal activity of local anaesthetics 
and their binary combinations with preservatives. J Clin Pharm 
Ther 1988; 13: 249–256. 
Barkman R, Germanis M, Karpe G, Malmborg AS. Preservatives in eye 
drops. Acta Ophthalmol 1969; 47: 461–475. 
Grier N. Mercurials inorganic and organic. In: Block SS, ed. 
Disinfection, Sterilization and Preservation, 3rd edn. Philadelphia: 
Lea and Febiger, 1983: 346–374. 
Hecht G. Ophthalmic preparations. In: Gennaro AR, ed. Remington: 
The Science and Practice of Pharmacy, 20th edn. Baltimore: 
Lippincott Williams and Wilkins, 2000: 821–835. 
Parkin JE. The decomposition of phenylmercuric nitrate in sulphacetamide 
drops during heat sterilization. J Pharm Pharmacol 1993; 
45: 1024–1027. 
Parkin JE, Button KL, Maroudas PA. The decomposition of phenylmercuric 
nitrate caused by disodium edetate in neomycin eye drops 
during the process of heat sterilization. J Clin Pharm Ther 1992; 17: 
191–196. 
Parkin JE, Duffy MB, Loo CN. The chemical degradation of 
phenylmercuric nitrate by disodium edetate during heat sterilization 
at pH values commonly encountered in ophthalmic products. J Clin 
Pharm Ther 1992; 17: 307–314. 
21 Authors 
SE Hepburn. 
22 Date of Revision 
17 August 2005. 
Phenylmercuric Borate 525

Phenylmercuric Nitrate 
1 Nonproprietary Names 
BP: Phenylmercuric nitrate 
PhEur: Phenylhydrargyri nitras 
USPNF: Phenylmercuric nitrate 
2 Synonyms 
Basic phenylmercury nitrate; mercuriphenyl nitrate; merphenyl 
nitrate; nitratophenylmercury; phenylmercury nitrate; Phe- 
Mer-Nite; PMN. 
Note that the synonyms above are usually used to refer to 
phenylmercuric nitrate alone. However, confusion with nomenclature 
and CAS Registry Number has led to these synonyms 
also being applied to the PhEur 2005 and USPNF 23 material, 
which is a compound of phenylmercuric nitrate and phenylmercuric 
hydroxide. 
3 Chemical Name and CAS Registry Number 
There are two CAS Registry Numbers associated with 
phenylmercuric nitrate. One refers to the mixture of phenylmercuric 
nitrate and phenylmercuric hydroxide 
(C12H11Hg2NO4) while the other refers to phenylmercuric 
nitrate alone (C6H5HgNO3). The PhEur 2005, and USPNF 23 
use the name phenylmercuric nitrate to describe the mixture 
and use the CAS Registry Number [55-68-5]. 
Hydroxyphenylmercury mixture with (nitrato-O)phenylmercury: 
C12H11Hg2NO4 [8003-05-2] 
(Nitrato-O)phenylmercury: 
C6H5HgNO3 [55-68-5] 
4 Empirical Formula and Molecular Weight 
C12H11Hg2NO4 634.45 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; antiseptic. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Phenylmercuric salts are used as antimicrobial preservatives 
mainly in ophthalmic preparations, but are also used in 
cosmetics (see Section 16), parenteral, and topical pharmaceutical 
formulations; see Table I. 
Phenylmercuric salts are active over a wide pH range against 
bacteria and fungi and are usually used in neutral to alkaline 
solutions, although they have also been used effectively at 
slightly acid pH; see Section 10. In acidic formulations, 
phenylmercuric nitrate may be preferred to phenylmercuric 
acetate or phenylmercuric borate as it does not precipitate. 
Phenylmercuric nitrate is also an effective spermicide, 
although its use in vaginal contraceptives is no longer 
recommended; see Section 14. 
A number of adverse reactions to phenylmercuric salts have 
been reported and concern at the toxicity of mercury 
compounds may preclude the use of phenylmercuric salts 
under certain circumstances; see Section 14. 
Table I: Uses of phenylmercuric nitrate. 
Use Concentration (%) 
Bactericide in parenterals 0.001 
Bactericide in vaginal suppositories and jellies 0.02 
Preservative in eye drops 0.002 
8 Description 
Phenylmercuric nitrate PhEur 2005, and USPNF 23, is an 
equimolecular compound of phenylmercuric hydroxide and 
phenylmercuric nitrate; it occurs as a white, crystalline powder 
with a slight aromatic odor. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmcopeial specifications for phenylmercuric nitrate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Appearance of solution . — 
Loss on drying 41.0% — 
Residue on ignition — 40.1% 
Mercury ions — . 
Inorganic mercuric compounds . . 
Organic volatile impurities — . 
Assay (dried basis) of: 
Mercury 62.5–64.0% 62.75–63.50% 
Phenylmercuric ion — 87.0–87.9%

SEM: 1 
Excipient: Phenylmercuric nitrate 
Manufacturer: Eastman Fine Chemicals 
Magnification: 180 
SEM: 2 
Excipient: Phenylmercuric nitrate 
Manufacturer: Eastman Fine Chemicals 
Magnification: 1800 
10 Typical Properties 
Acidity/alkalinity: a saturated aqueous solution is acidic to 
litmus. 
Antimicrobial activity: phenylmercuric salts are broad-spectrum, 
growth-inhibiting agents at the concentrations normally 
used for the preservation of pharmaceuticals. They 
possess slow bactericidal and fungicidal activity. Antimicrobial 
activity tends to increase with increasing pH, although 
in solutions of pH 6 and below, activity against Pseudomonas 
aeruginosa has been demonstrated. Phenylmercuric salts 
are included in several compendial eye drop formulations of 
acid pH. 
Activity is also increased in the presence of phenylethyl 
alcohol, and in the presence of sodium metabisulfite at acid 
pH. Activity is decreased in the presence of sodium 
metabisulfite at alkaline pH.(1–3) When used as preservatives 
in topical creams, phenylmercuric salts are active at pH 
5–8.(4) 
Bacteria (Gram-positive): good inhibition, more moderate 
cidal activity. Minimum inhibitory concentration (MIC) 
against Staphylococcus aureus is 0.5 mg/mL. 
Bacteria (Gram-negative): inhibitory activity for most 
Gram-negative bacteria is similar to that for Gram-positive 
bacteria (MIC is approximately 0.3–0.5 mg/mL). Phenylmercuric 
salts are less active against some Pseudomonas 
species, and particularly Pseudomonas aeruginosa (MIC is 
approximately 12 mg/mL). 
Fungi: most fungi are inhibited by 0.3–1 mg/mL; phenylmercuric 
salts exhibit both inhibitory and fungicidal 
activity; e.g., for phenylmercuric acetate against Candida 
albicans, MIC is 0.8 mg/mL; for phenylmercuric acetate 
against Aspergillus niger, MIC is approximately 10 mg/mL. 
Spores: phenylmercuric salts may be active in conjunction 
with heat. The BP 1980 included heating at 1008C for 30 
minutes in the presence of 0.002% w/v phenylmercuric 
acetate or phenylmercuric nitrate as a sterilization method. 
However, in practice this may not be sufficient to kill spores 
and heating with a bactericide no longer appears as a 
sterilization method in the BP 2004. 
Dissociation constant: pKa = 3.3 
Melting point: 187–1908C with decomposition. 
Partition coefficients: 
Mineral oil : water = 0.58; 
Peanut oil : water = 0.4. 
Solubility: more soluble in the presence of either nitric acid or 
alkali hydroxides. See Table III. 
Table III: Solubility of phenylmercuric nitrate. 
Solvent Solubility at 208C(a) 
unless otherwise stated 
Ethanol (95%) 1 in 1000 
Fixed oils Soluble 
Glycerin Slightly soluble 
Water 1 in 600–1500 
1 in 160 at 1008C 
(a) Compendial values for solubility vary considerably. 
11 Stability and Storage Conditions 
All phenylmercuric compound solutions form a black residue of 
metallic mercury when exposed to light or after prolonged 
storage. Solutions may be sterilized by autoclaving, although 
significant amounts of phenylmercuric salts may be lost, hence 
reducing preservative efficacy, owing to incompatibilities with 
packaging components or other excipients, e.g., sodium 
metabisulfite.(5–7) See Section 12. 
Phenylmercuric nitrate should be stored in a well-closed 
container, protected from light, in a cool, dry place. 
12 Incompatibilities 
The antimicrobial activity of phenylmercuric salts may be 
reduced in the presence of anionic emulsifying agents and 
suspending agents, tragacanth, starch, talc, sodium metabisulfite,(
8) sodium thiosulfate,(2) disodium edetate,(2) and silicates 
Phenylmercuric Nitrate 527

(bentonite, aluminum magnesium silicate, magnesium trisilicate, 
and kaolin).(9,10) 
Phenylmercuric salts are incompatible with halides, particularly 
bromides and iodides, as they form less-soluble halogen 
compounds. At concentrations of 0.002% w/v precipitation 
may not occur in the presence of chlorides. Phenylmercuric salts 
are also incompatible with aluminum and other metals, 
ammonia and ammonium salts, amino acids, and with some 
sulfur compounds, e.g., in rubber. 
Phenylmercuric salts are absorbed by rubber stoppers and 
some types of plastic packaging components; uptake is usually 
greatest to natural rubbers and polyethylene and least to 
polypropylene.(11–16) 
Incompatibilities with some types of filter membranes may 
also result in loss of phenylmercuric salts following sterilization 
by filtration.(17) 
13 Method of Manufacture 
Phenylmercuric nitrate is readily formed by heating benzene 
with mercuric acetate, and treating the resulting acetate with an 
alkali nitrate.(18) 
14 Safety 
Phenylmercuric nitrate and other phenylmercuric salts are 
widely used as antimicrobial preservatives in parenteral and 
topical pharmaceutical formulations. However, concern over 
the use of phenylmercuric salts in pharmaceuticals has 
increased as a result of greater awareness of the toxicity of 
mercury and other mercury compounds. This concern must, 
however, be balanced by the effectiveness of these materials as 
antimicrobial preservatives and the low concentrations in 
which they are employed. 
Phenylmercuric salts are irritant to the skin at 0.1% w/w 
concentration in petrolatum.(19) In solution, they may give rise 
to erythema and blistering 6–12 hours after administration. In a 
modified repeated insult patch test, a 2% w/v solution was 
found to produce extreme sensitization of the skin.(20,21) 
Eye drops containing phenylmercuric nitrate as a preservative 
should not be used continuously for prolonged periods as 
mercurialentis, a brown pigmentation of the anterior capsule of 
the lens may occur. Incidence is 6% in patients using eye drops 
for greater than 6 years; however, the condition is not 
associated with visual impairment.(22,23) Cases of atypical 
band keratopathy have also been attributed to phenylmercuric 
nitrate preservative in eye drops.(24) 
Concern that the absorption of mercury from the vagina 
may be harmful has led to the recommendation that 
phenylmercuric nitrate should not be used in intravaginal 
formulations.(25) 
LD50 (mouse, IV): 27 mg/kg(26) 
LD50 (mouse, oral): 50 mg/kg 
LD50 (rat, SC): 63 mg/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Phenylmercuric nitrate may 
be irritant to the skin, eyes, and mucous membranes. Eye 
protection, gloves, and a respirator are recommended. In the 
UK, the occupational exposure limit for mercury-containing 
compounds, calculated as mercury, is 0.01 mg/m3 long-term (8- 
hour TWA) and 0.03 mg/m3 short-term.(27) 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IM and 
ophthalmic preparations). Included in nonparenteral medicines 
licensed in the UK. In the UK, the use of phenylmercuric salts in 
cosmetics is limited to 0.003% (calculated as mercury, 
equivalent to approximately 0.0047% of phenylmercuric 
nitrate) as a preservative in shampoos and hair creams, which 
contain nonionic emulsifiers that would render other preservatives 
ineffective. Total permitted concentration, as mercury, 
when mixed with other mercury compounds is 0.007% 
(equivalent up to approximately 0.011% of phenylmercuric 
nitrate).(28) Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients (ophthalmic, nasal and otic preparations 
only; there must be no other suitable alternative preservative). 
17 Related Substances 
Phenylmercuric acetate; phenylmercuric borate; thimerosal. 
18 Comments 
Phenylmercuric salts should be used in preference to benzalkonium 
chloride as a preservative for salicylates and nitrates 
and in solutions of salts of physostigmine and epinephrine that 
contain 0.1% sodium sulfite. 
19 Specific References 
1 Buckles J, Brown MW, Porter GS. The inactivation of phenylmercuric 
nitrate by sodium metabisulphite. J Pharm Pharmacol 1971; 
23 (Suppl.): 237S–238S. 
2 Richards RME, Reary JME. Changes in antibacterial activity of 
thiomersal and PMN on autoclaving with certain adjuvants. J 
Pharm Pharmacol 1972; 24(Suppl.): 84P–89P. 
3 Richards RME, Fell AF, Butchart JME. Interaction between 
sodium metabisulphite and PMN. J Pharm Pharmacol 1972; 24: 
999–1000. 
4 Parker MS. The preservation of pharmaceuticals and cosmetic 
products. In: Russell AD, Hugo WB, Ayliffe GAJ, eds. Principles 
and Practice of Disinfection, Preservation and Sterilization. 
Oxford: Blackwell Scientific, 1982: 287–305. 
5 Hart A. Antibacterial activity of phenylmercuric nitrate in zinc 
sulphate and adrenaline eye drops BPC 1968. J Pharm Pharmacol 
1973; 25: 507–508. 
6 Miezitis EO, Polack AE, Roberts MS. Concentration changes 
during autoclaving of aqueous solutions in polyethylene containers: 
an examination of some methods for reduction of solute loss. 
Aust J Pharm Sci 1979; 8(3): 72–76. 
7 Parkin JE, Marshall CA. The instability of phenylmercuric nitrate 
in APF ophthalmic products containing sodium metabisulfite. Aust 
J Hosp Pharm 1991; 20: 434–436. 
8 Collins AJ, Lingham P, Burbridge TA, Bain R. Incompatibility of 
phenylmercuric acetate with sodium metabisulphite in eye drop 
formulations. J Pharm Pharmacol 1985; 37(Suppl.): 123P. 
9 Yousef RT, El-Nakeeb MA, Salama S. Effect of some pharmaceutical 
materials on the bactericidal activities of preservatives. Can J 
Pharm Sci 1973; 8: 54–56. 
10 Horn NR, McCarthy TJ, Ramsted E. Interactions between powder 
suspensions and selected quaternary ammonium and organomercurial 
preservatives. Cosmet Toilet 1980; 95(2): 69–73. 
11 Ingversen J, Andersen VS. Transfer of phenylmercuric compounds 
from dilute aqueous solutions to vials and rubber closures. Dansk 
Tidsskr Farm 1968; 42: 264–271. 
12 Eriksson K. Loss of organomercurial preservatives from medicaments 
in different kinds of containers. Acta Pharm Suec 1967; 4: 
261–264. 
13 Christensen K, Dauv E. Absorption of preservatives by drip 
attachments in eye drop packages. J Mond Pharm 1969; 12(1): 5– 
11. 
528 Phenylmercuric Nitrate

14 Aspinall JA, Duffy TD, Saunders MB, Taylor CG. The effect of low 
density polyethylene containers on some hospital-manufactured 
eye drop formulations I: sorption of phenylmercuric acetate. J Clin 
Hosp Pharm 1980; 5: 21–29. 
15 McCarthy TJ. Interaction between aqueous preservative solutions 
and their plastic containers, III. Pharm Weekbl 1972; 107: 1–7. 
16 Aspinall JA, Duffy TD, Taylor CG. The effect of low density 
polyethylene containers on some hospital-manufactured eye drop 
formulations II: inhibition of the sorption of phenylmercuric 
acetate. J Clin Hosp Pharm 1983; 8: 223–240. 
17 Naido NT, Price CH, McCarthy TJ. Preservative loss from 
ophthalmic solutions during filtration sterilization. Aust J Pharm 
Sci 1972; 1(1): 16–18. 
18 Pyman FL, Stevenson HA. Phenylmercuric nitrate. Pharm J 1934; 
133: 269. 
19 Koby GA, Fisher AA. Phenylmercuric acetate as primary irritant. 
Arch Dermatol 1972; 106: 129. 
20 Kligman AM. The identification of contact allergens by human 
assay, III. The maximization test: a procedure for screening and 
rating contact sensitizers. J Invest Dermatol 1966; 47: 393–409. 
21 Galindo PA, Feo F, Garcia R, et al. Mercurochrome allergy: 
immediate and delayed hypersensitivity. Allergy 1997; 52(11): 
1138–1141. 
22 Garron LK,Wood IS, Spencer WH, et al. A clinical and pathologic 
study of mercurialentis medicamentosus. Trans Am Ophthalmol 
Soc 1977; 74: 295. 
23 Winder AF, Astbury NJ, Sheraidah GAK, Ruben M. Penetration of 
mercury from ophthalmic preservatives into the human eye. 
Lancet 1980; ii: 237–239. 
24 Brazier DJ, Hitchings RA. Atypical band keratopathy following 
long-term pilocarpine treatment. Br J Ophthalmol 1989; 73: 294– 
296. 
25 Lohr L. Mercury controversy heats up. Am Pharm 1978; 18(9): 
23. 
26 Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. 
Cincinnati: US Department of Health, 1987: 3060–3093. 
27 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
28 Statutory Instrument (SI) 1989: No. 2233. Consumer Protection: 
The Consumer Products (Safety) Regulations 1989. London: 
HMSO, 1989. 
20 General References 
Abdelaziz AA, El-Nakeeb MA. Sporicidal activity of local anaesthetics 
and their binary combinations with preservatives. J Clin Pharm 
Ther 1988; 13: 249–256. 
Barkman R, Germanis M, Karpe G, Malmborg AS. Preservatives in eye 
drops. Acta Ophthalmol 1969; 47: 461–475. 
Grier N. Mercurials inorganic and organic. In: Block SS, ed. 
Disinfection, Sterilization and Preservation, 3rd edn. Philadelphia: 
Lea and Febiger, 1983: 346–374. 
Hecht G. Ophthalmic preparations. In: Gennaro AR, ed. Remington: 
The Science and Practice of Pharmacy, 20th edn. Baltimore: 
Lippincott Williams and Wilkins, 2000: 821–835. 
Parkin JE. The decomposition of phenylmercuric nitrate in sulphacetamide 
drops during heat sterilization. J Pharm Pharmacol 1993; 
45: 1024–1027. 
Parkin JE, Button KL, Maroudas PA. The decomposition of phenylmercuric 
nitrate caused by disodium edetate in neomycin eye drops 
during the process of heat sterilization. J Clin Pharm Ther 1992; 17: 
191–196. 
Parkin JE, Duffy MB, Loo CN. The chemical degradation of 
phenylmercuric nitrate by disodium edetate during heat sterilization 
at pH values commonly encountered in ophthalmic products. J Clin 
Pharm Ther 1992; 17: 307–314. 
21 Authors 
SE Hepburn. 
22 Date of Revision 
17 August 2005. 
Phenylmercuric Nitrate 529

Phosphoric Acid 
1 Nonproprietary Names 
BP: Phosphoric acid 
PhEur: Acidum phosphoricum concentratum 
USPNF: Phosphoric acid 
See also Section 17. 
2 Synonyms 
Acid fosforico; acide phosphorique; E338; hydrogen phosphate; 
syrupy phosphoric acid. 
3 Chemical Name and CAS Registry Number 
Orthophosphoric acid [7664-38-2] 
4 Empirical Formula and Molecular Weight 
H3PO4 98.00 
5 Structural Formula 
H3PO4 
6 Functional Category 
Acidifying agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Phosphoric acid is widely used as an acidifying and buffering 
agent in a variety of pharmaceutical formulations. It is also 
widely used in food preparations as an acidulant, flavor, and 
synergistic antioxidant (0.001–0.005%) and sequestrant. 
Therapeutically, dilute phosphoric acid has been used welldiluted 
in preparations used in the treatment of nausea and 
vomiting. Phosphoric acid 35% gel has also been used in 
dentistry to etch tooth enamel. 
8 Description 
Concentrated phosphoric acid occurs as a colorless, odorless, 
syrupy liquid. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for phosphoric acid. 
PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Appearance of solution . — 
Relative density 1.7 — 
Sulfate 4100ppm . 
Chloride 450 ppm — 
Heavy metals 410 ppm 40.001% 
Substances precipitated with ammonia . — 
Arsenic 42 ppm — 
Iron 450 ppm — 
Alkali phosphates — . 
Limit of nitrate — . 
Phosphorous or hypophosphorous acid . . 
Assay (of H3PO4) 84.0–90.0% 85.0–88.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 1.6 (1% w/w aqueous solution) 
Boiling point: 117.878C 
Dissociation constant: 
pKa1 = 2.15; 
pKa2 = 7.09; 
pKa3 = 12.32. 
Melting point: 42.358C 
Refractive index: 
nD
17.5 = 1.35846 (30% w/w aqueous solution); 
nD
17.5 = 1.35032 (20% w/w aqueous solution); 
nD
17.5 = 1.3423 (10% w/w aqueous solution). 
Solubility: miscible with ethanol (95%) and water with the 
evolution of heat. 
Specific gravity: 
1.874 (100% w/w) at 258C; 
1.6850 (85% w/w aqueous solution) at 258C; 
1.3334 (50% w/w aqueous solution) at 258C; 
1.0523 (10% w/w aqueous solution) at 258C. 
11 Stability and Storage Conditions 
When stored at a low temperature, phosphoric acid may 
solidify, forming a mass of colorless crystals, comprised of the 
hemihydrate, which melt at 288C. Phosphoric acid should be 
stored in an airtight container in a cool, dry place. Stainless steel 
containers may be used. 
12 Incompatibilities 
Phosphoric acid is a strong acid and reacts with alkaline 
substances. Mixtures with nitromethane are explosive. 
13 Method of Manufacture 
The majority of phosphoric acid is made by digesting 
phosphate rock (essentially tricalcium phosphate) with sulfuric 
acid; the phosphoric acid is then separated by slurry filtration.

Purification is achieved via chemical precipitation, solvent 
extraction, crystallization, or ion exchange. 
14 Safety 
In the concentrated form, phosphoric acid is an extremely 
corrosive and harmful acid. However, when used in pharmaceutical 
formulations it is usually very diluted and is generally 
regarded as an essentially nontoxic and nonirritant material. 
The lowest lethal oral dose of concentrated phosphoric acid 
in humans is reported to be 1286 mL/kg.(1) 
LD50 (rabbit, skin): 2.74 g/kg(1) 
LD50 (rat, oral): 1.53 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Phosphoric acid is corrosive 
and can cause burns on contact with the skin, eyes and mucous 
membranes; contact should be avoided. Splashes should be 
washed with copious quantities of water. Protective clothing, 
gloves and eye protection are recommended. 
Phosphoric acid is also irritant on inhalation. In the UK, the 
occupational exposure limit for phosphoric acid is 8 mg/m3 
long-term (8-hour TWA) and 2 mg/m3 short-term (15-minutes).(
2) 
Phosphoric acid emits toxic fumes on heating. 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (infusions, injections, oral 
solutions, topical creams, lotions, ointments and solutions, and 
vaginal preparations). Included in nonparenteral and parenteral 
medicines licensed in the UK. Included in the Canadian List 
of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Dilute phosphoric acid. 
Dilute phosphoric acid 
Synonyms: acidum phosphoricum dilutum; diluted phosphoric 
acid. 
Comments: the PhEur 2005 states that dilute phosphoric acid 
contains 9.5–10.5% w/w H3PO4 and may be prepared by 
mixing phosphoric acid 115 g with 885 g of water. The 
USPNF 23 contains a monograph for diluted phosphoric 
acid and states that it contains 9.5–10.5% w/v H3PO4 and 
may be prepared by mixing phosphoric acid 69mL with 
water to 1000 mL. 
18 Comments 
In the UK, a 1 in 330 aqueous solution of phosphoric acid is 
approved as a disinfectant for foot-and-mouth disease. A 
specification for phosphoric acid is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for phosphoric acid is 231-633-2. 
19 Specific References 
1 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2948–2949. 
2 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
—
21 Authors 
WG Chambliss. 
22 Date of Revision 
8 August 2005. 
Phosphoric Acid 531

Polacrilin Potassium 
1 Nonproprietary Names 
USPNF: Polacrilin potassium 
2 Synonyms 
Amberlite IRP-88; methacrylic acid polymer with divinylbenzene, 
potassium salt; polacrilinum kalii. 
3 Chemical Name and CAS Registry Number 
2-Methyl-2-propenoic acid polymer with divinylbenzene, 
potassium salt [39394-76-5] 
4 Empirical Formula and Molecular Weight 
See Sections 5,13 and 18. 
5 Structural Formula 
6 Functional Category 
Tablet and capsule disintegrant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Polacrilin potassium is a cation-exchange resin used in oral 
pharmaceutical formulations as a tablet disintegrant.(1–3) 
Concentrations of 2–10% w/w have been used for this purpose 
although 2% w/w of polacrilin potassium is usually sufficient. 
Other polacrilin ion-exchange resins have been used as 
excipients to stabilize drugs, to mask or modify the taste of 
drugs, and in the preparation of sustained-release dosage 
forms(4) and drug carriers. 
Polacrilin resins are also used in the analysis and manufacture 
of pharmaceuticals and food products. 
8 Description 
Polacrilin potassium occurs as a cream-colored, odorless and 
tasteless, free-flowing powder. Aqueous dispersions have a 
bitter taste. 
9 Pharmacopeial Specifications 
See Table I. 
Figure 1: Particle size distribution of polacrilin potassium (Amberlite 
IRP-88). 
Table I: Pharmacopeial specifications for polacrilin potassium. 
Test USPNF 23 
Identification . 
Loss on drying 410.0% 
Powder fineness 41.0% on a #100 mesh 
430.0% on a #200 mesh 
Iron 40.01% 
Sodium 40.20% 
Heavy metals 40.002% 
Organic volatile impurities . 
Assay of potassium (dried basis) 20.6%–25.1% 
10 Typical Properties 
Density (bulk): 0.48 g/cm3 for Amberlite IRP-88.(3) 
Density (tapped): 0.62 g/cm3 for Amberlite IRP-88.(3) 
Particle size distribution: see Figure 1.(3) 
Solubility: practically insoluble in water and most other liquids, 
although polacrilin resins swell rapidly when wetted. 
11 Stability and Storage Conditions 
Polacrilin potassium and other polacrilin resins are stable to 
light, air, and heat up to their maximum operation temperature; 
see Table II. Excessive heating can cause thermal decomposition 
of the resins and may yield one or more oxides of carbon, 
nitrogen, sulfur, and/or amines.

Polacrilin resins should be stored in well-closed containers in 
a cool, dry place. 
12 Incompatibilities 
Incompatible with strong oxidizing agents, amines, particularly 
tertiary amines, and some other substances that interact with 
polacrilin resins.(5) 
13 Method of Manufacture 
Polacrilin resin (Amberlite IRP-64) is prepared by the 
copolymerization of methacrylic acid with divinylbenzene 
(DVB). Polacrilin potassium (Amberlite IRP-88) is then 
produced by neutralizing this resin with potassium hydroxide. 
Other resins are similarly produced by copolymerization 
between styrene and divinylbenzene (Amberlite IRP-69, 
Amberlite IRP-67, Amberlite IR-120, and Amberlite IRA- 
400). Phenolic-based polyamine condensates (Amberlite IRP- 
58) may also be produced. 
The homogeneity of the resin structure depends on the 
purity, nature, and properties of the copolymers used as well as 
the controls and conditions employed during the polymerization 
reaction. The nature and degree of crosslinking have 
significant influence on the physicochemical properties of the 
resin matrix. The functional groups introduced on the matrix 
confer the property of ion exchange. Depending upon the 
acidity or basicity of the functional groups, strongly acidic to 
strongly basic types of ion-exchange resins may be produced. 
14 Safety 
Polacrilin potassium and other polacrilin resins are used in oral 
pharmaceutical formulations and are generally regarded as 
nontoxic and nonirritant materials. However, excessive ingestion 
of polacrilin resins may disturb the electrolyte balance of 
the body. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Polacrilin potassium may be 
irritating to the eyes; eye protection and gloves are recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral capsules 
and tablets). Included in non-parenteral medicines licensed in 
the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Polacrilin. 
Polacrilin 
CAS number: [54182-62-6] 
Synonyms: Amberlite IRP-64; methacrylic acid polymer with 
divinylbenzene; 2-methyl-2-propenoic acid polymer with 
divinylbenzene. 
See also Section 18. 
18 Comments 
A number of other polacrilin (Amberlite) resins are commercially 
available that have a variety of industrial and pharmaceutical 
applications; see Table II. 
19 Specific References 
1 Van Abbe. NJ, Rees JT. Amberlite resin XE-88 as a tablet 
disintegrant. J Am Pharm Assoc (Sci) 1958; 47: 487–489. 
2 Khan KA, Rhodes CT. Effect of disintegrant concentration on 
disintegration and compression characteristics of two insoluble 
direct compression systems. Can J Pharm Sci 1973; 8: 77–80. 
3 Rudnic EM, Rhodes CT, Welch S, Bernardo P. Evaluation of the 
mechanism of disintegrant action. Drug Dev Ind Pharm 1982; 8: 
87–109. 
Table II: Summary of physicochemical properties of pharmaceutical grade Amberlite resins. 
Amberlite 
grade 
Copolymer Type Functional 
structure 
Ionic 
form 
Particle size 
(mesh) 
Parent 
resin 
Maximum 
moisture 
(%) 
pH 
range 
Maximum 
temperature 
(8C) 
Application 
Cation-exchange resins 
IRP-69 Styrene and 
DVB(a) 
Strongly 
acidic 
SO3 –
Na. Na. 100–500 IR-120 10 0–14 120 Carrier for cationic drugs 
that are bases or salts 
IRP-64 Methacrylic 
acid and 
DVB 
Weakly 
acidic 
COO–H. H. 100–500 IRC-50 10 5–14 120 Carrier for cationic drugs 
IRP-88 Methacrylic 
acid and 
DVB 
Weakly 
acidic 
COO–K. K. 100–500 IRC-50 10 5–14 120 Tablet disintegrant 
Anion-exchange resins 
IRP-58 Phenolic 
polyamine 
Weakly 
basic 
NH2NH2 Free base 100–500 IR-4B 10 0–7 60 Carrier for anionic drugs 
that are acids 
IRP-67 Styrene and 
DVB 
Strongly 
basic 
N(CH3)3.Cl– Cl– 100–500 IRA-400 10 0–12 60 Carrier for anionic drugs 
that are acids or salts 
Note that all of the above grades, with the exception of Amberlite IRP-88, are available in particle-size grades <325 mesh. 
(a) DVB: divinylbenzene. 
Polacrilin Potassium 533

4 Smith HA, Evanson RV, Sperandio GJ. The development of a 
liquid antihistaminic preparation with sustained release properties. 
J Am Pharm Assoc (Sci) 1960; 49: 94–97. 
5 Borodkin S, Yunker MH. Interaction of amine drugs with a 
polycarboxylic acid ion-exchange resin. J Pharm Sci 1970; 59: 
481–486. 
20 General References 
— 
21 Authors 
A Palmieri. 
22 Date of Revision 
8 August 2005. 
534 Polacrilin Potassium

Poloxamer 
1 Nonproprietary Names 
BP: Poloxamers 
PhEur: Poloxamera 
USPNF: Poloxamer 
2 Synonyms 
Lutrol; Monolan; Pluronic; poloxalkol; polyethylene–propylene 
glycol copolymer; polyoxyethylene–polyoxypropylene 
copolymer; Supronic; Synperonic. 
3 Chemical Name and CAS Registry Number 
a-Hydro-o-hydroxypoly(oxyethylene)poly(oxypropylene) 
poly(oxyethylene) block copolymer [9003-11-6] 
4 Empirical Formula and Molecular Weight 
The poloxamer polyols are a series of closely related block 
copolymers of ethylene oxide and propylene oxide conforming 
to the general formula HO(C2H4O)a(C3H6O)b(C2H4O)aH. 
The grades included in the PhEur 2005 and USPNF 23 are 
shown in Table I. The PhEur 2005 states that a suitable 
antioxidant may be added. 
Table I: Typical poloxamer grades. 
Poloxamer Physical form a b Average molecular weight 
124 Liquid 12 20 2 090–2 360 
188 Solid 80 27 7 680–9 510 
237 Solid 64 37 6 840–8 830 
338 Solid 141 44 12 700–17 400 
407 Solid 101 56 9 840–14 600 
5 Structural Formula 
6 Functional Category 
Dispersing agent; emulsifying and coemulsifying agent; solubilizing 
agent; tablet lubricant; wetting agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Poloxamers are nonionic polyoxyethylene–polyoxypropylene 
copolymers used primarily in pharmaceutical formulations as 
emulsifying or solubilizing agents.(1–8) The polyoxyethylene 
segment is hydrophilic while the polyoxypropylene segment is 
hydrophobic. All of the poloxamers are chemically similar in 
composition, differing only in the relative amounts of 
propylene and ethylene oxides added during manufacture. 
Their physical and surface-active properties vary over a wide 
range and a number of different types are commercially 
available; see Sections 4,9,10 and 18. 
Poloxamers are used as emulsifying agents in intravenous fat 
emulsions, and as solubilizing and stabilizing agents to 
maintain the clarity of elixirs and syrups. Poloxamers may 
also be used as wetting agents; in ointments, suppository bases, 
and gels; and as tablet binders and coatings. 
Poloxamer 188 has also been used as an emulsifying agent 
for fluorocarbons used as artificial blood substitutes and in the 
preparation of solid-dispersion systems. 
More recently, poloxamers have found use in drug-delivery 
systems.(9–14) 
Therapeutically, poloxamer 188 is administered orally as a 
wetting agent and stool lubricant in the treatment of constipation; 
it is usually used in combination with a laxative such as 
danthron. Poloxamers may also be used therapeutically as 
wetting agents in eye-drop formulations, in the treatment of 
kidney stones, and as skin-wound cleansers. 
Poloxamer 338 and 407 are used in solutions for contact 
lens care. See Table II. 
Table II: Uses of poloxamer. 
Use Concentration (%) 
Fat emulsifier 0.3 
Flavor solubilizer 0.3 
Fluorocarbon emulsifier 2.5 
Gelling agent 15–50 
Spreading agent 1 
Stabilizing agent 1–5 
Suppository base 4–6 or 90 
Tablet coating 10 
Tablet excipient 5–10 
Wetting agent 0.01–5 
8 Description 
Poloxamers generally occur as white, waxy, free-flowing prilled 
granules, or as cast solids. They are practically odorless and 
tasteless. At room temperature, poloxamer 124 occurs as a 
colorless liquid. 
9 Pharmacopeial Specifications 
See Table III. 
10 Typical Properties 
Acidity/alkalinity: pH = 5.0–7.4 for a 2.5% w/v aqueous 
solution. 
Cloud point: >1008C for a 1% w/v aqueous solution, and a 
10% w/v aqueous solution of poloxamer 188.

Table III: Pharmacopeial specifications for poloxamer. 
Test PhEur 2005 USPNF 23 
Identification . — 
Characters . — 
Appearance of solution . — 
Average molecular weight 
For poloxamer 124 2 090–2 360 2 090–2 360 
For poloxamer 188 7 680–9 510 7 680–9 510 
For poloxamer 237 6 840–8 830 6 840–8 830 
For poloxamer 338 12 700–17 400 12 700–17 400 
For poloxamer 407 9 840–14 600 9 840–14 600 
Weight percent oxyethylene 
For poloxamer 124 44.8–48.6 46.7 
 1.9 
For poloxamer 188 79.9–83.7 81.8 
 1.9 
For poloxamer 237 70.5–74.3 72.4 
 1.9 
For poloxamer 338 81.4–84.9 83.1 
 1.7 
For poloxamer 407 71.5–74.9 73.2 
 1.7 
pH (aqueous solution) 5.0–7.5 5.0–7.5 
Unsaturation (mEq/g) 
For poloxamer 124 — 0.020 
 0.008 
For poloxamer 188 — 0.026 
 0.008 
For poloxamer 237 — 0.034 
 0.008 
For poloxamer 338 — 0.031 
 0.008 
For poloxamer 407 — 0.048 
 0.017 
Oxypropylene:oxyethylene 
ratio 
. — 
Total ash 40.4% — 
Heavy metals — 40.002% 
Organic volatile impurities — . 
Water 41.0% — 
Free ethylene oxide, 
propylene oxide and 1,4- 
dioxane 
. . 
Ethylene oxide — 41 ppm 
Propylene oxide — 45 ppm 
1,4-Dioxane — 45 ppm 
Density: 1.06 g/cm3 at 258C 
Flash point: 2608C 
Flowability: solid poloxamers are free flowing. 
HLB value: 0.5–30; 29 for poloxamer 188. 
Melting point: 
168C for poloxamer 124; 
52–578C for poloxamer 188; 
498C for poloxamer 237; 
578C for poloxamer 338; 
52–578C for poloxamer 407. 
Moisture content: poloxamers generally contain less than 0.5% 
w/w water and are hygroscopic only at relative humidity 
greater than 80%. See also Figure 1. 
Solubility: solubility varies according to the poloxamer type; 
see also Table IV. 
Figure 1: Equilibrium moisture content of poloxamer 188 (Pluronic 
F-68). 
Surface tension: 
19.8mN/m (19.8 dynes/cm) for a 0.1% w/v aqueous 
poloxamer 188 solution at 258C; 
24.0mN/m (24.0 dynes/cm) for a 0.01% w/v aqueous 
poloxamer 188 solution at 258C; 
26.0mN/m (26.0 dynes/cm) for a 0.001% w/v aqueous 
poloxamer solution at 258C. 
Viscosity (dynamic): 1000 mPa s (1000 cP) as a melt at 778C for 
poloxamer 188. 
11 Stability and Storage Conditions 
Poloxamers are stable materials. Aqueous solutions are stable 
in the presence of acids, alkalis, and metal ions. However, 
aqueous solutions support mold growth. 
The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Depending on the relative concentrations, poloxamer 188 is 
incompatible with phenols and parabens. 
Table IV: Solubility at 208C for various types of poloxamer in different solvents. 
Type Solvent 
Ethanol (95%) Propan-2-ol Propylene glycol Water Xylene 
Poloxamer 124 Freely soluble Freely soluble Freely soluble Freely soluble Freely soluble 
Poloxamer 188 Freely soluble — — Freely soluble — 
Poloxamer 237 Freely soluble Sparingly soluble — Freely soluble Sparingly soluble 
Poloxamer 338 Freely soluble — Sparingly soluble Freely soluble — 
Poloxamer 407 Freely soluble Freely soluble — Freely soluble — 
536 Poloxamer

13 Method of Manufacture 
Poloxamer polymers are prepared by reacting propylene oxide 
with propylene glycol to form polyoxypropylene glycol. 
Ethylene oxide is then added to form the block copolymer. 
14 Safety 
Poloxamers are used in a variety of oral, parenteral, and topical 
pharmaceutical formulations and are generally regarded as 
nontoxic and nonirritant materials. Poloxamers are not 
metabolized in the body. 
Animal toxicity studies, with dogs and rabbits, have shown 
poloxamers to be nonirritating and nonsensitizing when 
applied in 5% w/v and 10% w/v concentration to the eyes, 
gums, and skin. 
In a 14-day study of intravenous administration at 
concentrations up to 0.5 g/kg/day to rabbits, no overt adverse 
effects were noted. A similar study with dogs also showed no 
adverse effects at dosage levels up to 0.5 g/kg/day. In a longerterm 
study, rats fed 3% w/w or 5% w/w of poloxamer in food 
for up to 2 years did not exhibit any significant symptoms of 
toxicity. However, rats receiving 7.5% w/w of poloxamer in 
their diet showed some decrease in growth rate. 
No hemolysis of human blood cells was observed over 18 
hours at 258C, with 0.001–10% w/v poloxamer solutions. 
Acute animal toxicity data for poloxamer 188:(15) 
LD50 (mouse, IV): 1 g/kg 
LD50 (mouse, oral): 15 g/kg 
LD50 (mouse, SC): 5.5 g/kg 
LD50 (rat, IV): 7.5 g/kg 
LD50 (rat, oral): 9.4 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IV injections; 
inhalations, ophthalmic preparations; oral powders, solutions, 
suspensions, and syrups; topical preparations). Included in 
nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
—
18 Comments 
Although the USPNF 23 contains specifications for five 
poloxamer grades, many more different poloxamers are 
commercially available that vary in their molecular weight 
and the proportion of oxyethylene present in the polymer. A 
series of poloxamers with greatly varying physical properties 
are thus available. 
The nonproprietary name ‘poloxamer’ is followed by a 
number, the first two digits of which, when multiplied by 100, 
correspond to the approximate average molecular weight of the 
polyoxypropylene portion of the copolymer and the third digit, 
when multiplied by 10, corresponds to the percentage by 
weight of the polyoxyethylene portion. 
Similarly, with many of the trade names used for poloxamers, 
e.g. Pluronic F-68 (BASF Corp), the first digit arbitrarily 
represents the molecular weight of the polyoxypropylene 
portion and the second digit represents the weight percent of 
the oxyethylene portion. The letters ‘L’, ‘P’, and ‘F’, stand for 
the physical form of the poloxamer: liquid, paste, or flakes; see 
also Table V. 
Table V: Nonproprietary name and corresponding commercial 
grade. 
Nonproprietary name Commercial grade 
Poloxamer 124 L-44 
Poloxamer 188 F-68 
Poloxamer 237 F-87 
Poloxamer 338 F-108 
Poloxamer 407 F-127 
Note that in the USA the trade name Pluronic is used by 
BASF Corp. for pharmaceutical-grade and industrial-grade 
poloxamers, while in Europe the trade name Lutrol is used by 
BASF Corp. for the pharmaceutical-grade material. 
Poloxamers for use in the cosmetic industry as oil-in-water 
emulsifiers, cleansers for mild facial products, and dispersing 
agents are marketed by BASF Corp. as Pluracare. The grades 
available are listed in Table VI. Poloxamer has been used in a 
poly(lactic-co-glycolic acid) (PLGA):poloxamer and PLGA:poloxamine 
blend nanoparticle composition as novel carriers for 
gene delivery.(16) A specification for poloxamer is contained in 
the Food Chemicals Codex (FCC). 
Table VI: Nonproprietary name and corresponding Pluracare grade 
(BASF Corp.). 
Nonproprietary 
name 
Commercial 
grade 
HLB 
value 
pH of 2.5% w/v aqueous 
solution 
Poloxamer 184 L-64 12–18 5–7.5 
Poloxamer 185 P-65 12–18 6–7.4 
Poloxamer 407 F-127 18–23 6–7.4 
19 Specific References 
1 Suh H, Jun HW. Physicochemical and release studies of naproxen 
in poloxamer gels. Int J Pharm 1996; 129: 13–20. 
2 Pandit NK,Wang D. Salt effects on the diffusion and release rate of 
propranolol from poloxamer 407 gels. Int J Pharm 1998; 167: 
183–189. 
3 Wanka G, Hoffman H, Ulbricht W. Phase diagrams and 
aggregation behaviour of poly(oxyethylene)-poly(oxypropylene)- 
poly(oxyethylene) triblock copolymers in aqueous solutions. 
Macromolecules 1994; 27: 4151–4159. 
4 Kabanov AV, Nazarova IR, Astafieva IV, et al. Micelle formation 
and solubilization of fluorescent probes in poly-(oxyethylene-boxypropylene-
b-oxyethylene) solutions. Macromolecules 1995; 
28: 2303–2314. 
5 Lee JW, Park ES, Chi SC. Solubilization of ibuprofen in aqueous 
solution. J Korean Pharm Sci 1997; 27(4): 279–286. 
6 Alakhov V, Pietrzynski G, Patel K, et al. Pluronic block copolymers 
and Pluronic poly(acrylic acid) microgels in oral delivery of 
megestrol acetate. J Pharm Pharmacol 2004; 56: 1233–1241. 
7 Cabana A, Ait-Kadi A, Juhasz J. Study of the gelation process of 
polyethylene oxide copolymer (Poloxamer 407) aqueous solutions. 
J Colloid Interface Sci 1997; 190: 307–312. 
Poloxamer 537

8 Bohorquez M, Koch C, Trygstad T, Pandit N. A study of the 
temperature-dependent micellizatin of Pluronic F127. J Colloid 
Interface Sci 1999; 216: 34–40. 
9 Lu G, Jun HW. Diffusion studies of methotrexate in carbopol and 
poloxamer gels. Int J Pharm 1998; 160: 1–9. 
10 Oh T, Bronich TK, Kabanov AV. Micellar formulations for drug 
delivery based on mixtures of hydrophobic and hydrophilic 
Pluronic (R) block copolymers. J Control Release 2004; 94(10): 
411–422. 
11 Bochot A, Fattal E, Gulik A, et al. Liposomes dispersed within a 
thermosensitive gel: a new dosage form for ocular delivery. Pharm 
Res 1998; 15: 1364–1369. 
12 Kim EK, Gao Z, Park J, et al. rhEGF/HP-b-CD complex in 
poloxamer gel for ophthalmic delivery. Int J Pharm 2002; 233: 
159–167. 
13 Anderson BC, Pandit NK, Mallapragada SK. Understanding drug 
release from poly(ethylene oxide)-b-(propylene oxide)-b-poly(ethlene 
oxide) gels. J Control Release 2001; 70: 157–167. 
14 Moore T, Croy S, Mallapragada SK, Pandit NK. Experimental 
investigation and mathematical modelling of Pluromic F127 gel 
dissolution: drug release in stirred systems. J Control Release 2000; 
67: 191–202. 
15 Sweet DV, ed. Registry of Toxic Effects of Chemical Substances, 
Cincinnati: US Department of Health, 1987. 
16 Csaba N, Caamaro P, Sanchez A, Dominguez F, Alonso MJ. 
PLGA:poloxamer and PLGA:poloxamine blend nanoparticles: 
new carriers for gene delivery. Biomacromolecules 2005; 6(1): 
271–278. 
20 General References 
—
21 Authors 
JH Collett. 
22 Date of Revision 
26 August 2005. 
538 Poloxamer

Polycarbophil 
1 Nonproprietary Names 
USP: Polycarbophil 
2 Synonyms 
Noveon AA-1. 
3 Chemical Name and CAS Registry Number 
Polycarbophil [9003-01-4] 
4 Empirical Formula and Molecular Weight 
Polycarbophils are polymers of acrylic acid crosslinked with 
divinyl glycol. The molecular weight of these polymers is 
theoretically estimated to range from 700 000 to 3–4 billion. 
However, there are no methods currently available to measure 
the actual molecular weight of a crosslinked (i.e. threedimensional) 
polymer of this type. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Adsorbent; bioadhesive; controlled-release tablet binder; emulsifying 
agent; thickening agent; suspending agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Conventionally, polycarbophil is used as a thickening agent at 
very low concentrations (less than 1%) to produce a wide range 
of viscosities and flow properties in topical lotions, creams, and 
gels, in oral suspensions, and in transdermal gel reservoirs. It is 
also used as an emulsifying agent in topical oil-in-water 
systems. 
Polycarbophil is an excellent bioadhesive in buccal, 
ophthalmic, intestinal, nasal, vaginal, and rectal applications. 
Buccal tablets prepared using polycarbophil have shown high 
bioadhesive force and prolonged residence time and proved to 
be nonirritative in in vivo trials with human buccal mucosa.(1) It 
is also useful in designing controlled-release formulations(2) and 
for drugs that undergo first-pass metabolism.(3) Polycarbophil 
buccoadhesive disks have also been developed in formulations 
increasing the bioavailability(4) and transmucosal absorption of 
poorly water-soluble drugs.(5) Sublingual tablets of buprenorphine 
formulated using polycarbophil have shown superior 
mucoadhesive strength when compared to those using carbomer.(
6) 
Polycarbophil gels have been used for delivering bioactive 
substances for local application to gingival,(7) oropharyngeal(8) 
and periodontal(9,10) areas and also for ocular drug delivery.(11) 
The nasal retention of plasmid DNA is highly prolonged with 
the use of polycarbophil as the gelling agent.(12) Polycarbophil 
has also been used to design an insulin liquid suppository for 
rectal application.(13,14) A vaginal gel of econazole has shown 
improved therapeutic benefit on topical application in vaginal 
candidiasis.(15) Mucoadhesive vaginal vaccine delivery systems 
using polycarbophil have proved to be effective in the induction 
of mucosal and systemic immune responses.(16) Polycarbophil 
gels have been used to deliver granulocyte-macrophage colonystimulating 
factor (GM-CSF) effectively to genital preneoplastic 
lesions.(17) Polycarbophil microspheres have been formulated 
for drug delivery to oral(18,19) and nasal(20) cavities. Floatingbioadhesive 
microspheres coated with polycarbophil have been 
found to be a useful gastroretentive drug delivery system for the 
treatment of Helicobacter pylori.(21) Conjugation with 
L-cysteine greatly enhances the mucoadhesive properties of 
polycarbophil(22) and can be used as a platform for oral 
polypeptide delivery(23) (e.g. heparin,(24) insulin,(25) antigens 
for oral protein vaccination(26)) and for ocular(27) and 
transdermal drug delivery systems.(28) Polycarbophil has been 
reported to act as a permeation enhancer by triggering the 
reversible opening of the tight junctions between the cells, 
thereby allowing the paracellular transport of peptides, in 
addition to locally deactivating the most important enzymes of 
the gastrointestinal tract.(29) Polycarbophil promotes bowel 
regularity and is used therapeutically for chronic constipation, 
diverticulosis, and irritable bowel syndrome. 
8 Description 
Polycarbophil occurs as fluffy, white to off-white, mildly acidic 
polymer powder with slightly acetic odor. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for polycarbophil. 
Test USP 28 
Identification . 
pH (1% dispersion) 44.0 
Loss on drying 41.5% 
Absorbing power 562 g/g 
Limit of acrylic acid 40.3% 
Limit of ethyl acetate 40.45% 
Organic volatile impurities . 
Residue on ignition 44.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 2.5–3.0 (1.0% w/v aqueous dispersion); 
pH = 2.7–3.5 (0.5% w/v aqueous dispersion). 
Ash content: 0.009 ppm 
Density (bulk): 0.19–0.24 g/cm3 
Dissociation constant: pKa = 6.0 
 0.5 
Equilibrium moisture content: 8–10% (at 50% relative 
humidity) 
Glass transition temperature: 100–1058C 
Moisture content: 2.0% maximum

Solubility: polycarbophil polymers can swell in water to around 
1000 times their original volume (and ten times their 
original diameter) to form gels when exposed to a pH 
environment above 4–6. Since the pKa of these polymers is 
6.0 
 0.5, the carboxylate groups on the polymer backbone 
ionize, resulting in electrostatic repulsion between the 
negative particles, which extends the molecule, adding to 
the swelling of the polymer. 
Particle size distribution: polycarbophils are produced from 
primary polymer particles of an average diameter of about 
0.2 mm. These polymers are then flocculated, resulting in 
powders averaging 2–7 mm in diameter. Once formed, the 
flocculated agglomerates cannot be broken down into their 
primary particles. 
Specific gravity: 1.41 
11 Stability and Storage Conditions 
Polycarbophil polymers are stable, hygroscopic materials. They 
do not undergo hydrolysis or oxidation under normal 
conditions. Heat aging at temperatures below 1048C for up 
to 2 hours does not affect the efficiency of the dry polymer. 
However, prolonged exposure to excessive temperatures can 
result in discoloration, reduced stability, and in some cases 
plasticization of the polymer. Complete decomposition occurs 
with heating for 30 minutes at 2608C. 
Polycarbophil polymers do not support bacteria, mold, or 
fungal growth in dry powder form. Microbial growth may 
occur in mucilages of the polymer solution. Although the gel 
properties are not affected by such growth, this phenomenon is 
usually unacceptable. The addition of appropriate preservatives 
prevents mold and bacterial growth in these mucilages. 
Exposure of polycarbophil mucilages to high temperatures 
results in a drop in viscosity. 
Polycarbophil polymers are very hygroscopic and should be 
packed in air-tight, corrosion-resistant containers. They should 
be stored in a cool, dry place, and the container should be kept 
closed when not in use. Moisture pickup does not affect the 
efficiency of the resins, but resin containing high levels of 
moisture is more difficult to disperse and weigh accurately. 
Glass, plastic, or resin-lined containers are recommended for 
products containing polycarbophil. Packaging in aluminum 
tubes usually requires formulations to have a pH less than 6.5, 
and packaging in other metallic tubes or containers necessitates 
a pH greater than 7.7 to prolong polycarbophil stability. 
12 Incompatibilities 
Heat may be generated if polycarbophil comes into contact 
with strong basic materials such as ammonia, sodium hydroxide, 
potassium hydroxide, or strongly basic amines. Polycarbophil 
polymers are not compatible with cationic polymers, 
strong acids, and high levels of electrolytes, as electrolytes tend 
to reduce the viscosity of polycarbophil-based gels. 
13 Method of Manufacture 
Polycarbophils are synthetic, high-molecular-weight, crosslinked 
polymers of acrylic acid. These poly(acrylic acid) 
polymers are crosslinked with divinyl glycol. They are 
synthesized via precipitation polymerization in ethyl acetate 
and then dried. 
14 Safety 
Polycarbophil polymers have a long history of safe and effective 
use in topical gels, creams, lotions, and ointments. They have 
been shown to have extremely low irritancy properties and are 
nonsensitizing with repeated usage. 
The use of these polymers is supported by extensive 
toxicological studies.(30) 
LD50 (guinea pig, oral): 2.0 g/kg 
LD50 (mouse, IP): 0.039 g/kg 
LD50 (mouse, IV): 0.070 g/kg 
LD50 (mouse, oral): 4.6 g/kg 
LD50 (rat, oral): >2.5 g/kg 
LD50 (rabbit, skin): >3.0 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Excessive dust generation 
should be minimized to avoid the risk of explosion (lowest 
explosive concentration is 130 g/m3). Polycarbophil dust is an 
irritant to eyes, mucous membranes, and the respiratory tract. 
Powder/dust eye irritation is a physical, not a chemical effect. 
Solid particles on the eye (powder/dust) may cause pain and be 
accompanied by irritation. Saline should be used for irrigation 
purposes. Dust inhalation may cause coughing, mucus production, 
and shortness of breath. Contact dermatitis may occur in 
individuals under extreme conditions of prolonged and 
repeated contact, high exposure, high temperature, and 
occlusion (being held onto the skin) by clothing. Gloves, eye 
protection, and a dust respirator are recommended during 
handling. Polycarbophil should be used in well-ventilated 
conditions. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(vaginal gel; oral, troche). Included in nonparenteral medicines 
licensed in the UK. 
17 Related Substances 
Calcium polycarbophil; carbomer. 
Calcium polycarbophil 
Empirical formula: calcium polycarbophil is the calcium salt of 
polyacrylic acid crosslinked with divinyl glycol. 
Molecular weight: the molecular weight of these polymers is 
theoretically estimated to range from 700 000 to 3–4 billion. 
There are, however, no methods currently available to 
measure the actual molecular weight of a crosslinked (i.e. 
three-dimensional) polymer of this type. 
CAS number: [9003-97-8] 
Synonyms: Noveon CA-1; Noveon CA-2. 
Appearance: white powder with slightly acetic odor. 
Acidity/alkalinity: pH = 6.0–8.0 (1% w/v aqueous dispersion). 
Density (bulk): 0.86 g/cm3 (Noveon CA-1); 0.55 g/cm3 
(Noveon CA-2). 
Moisture content: <10% 
Pharmacopeial specifications: see Table II. 
Comments: Noveon CA-1 is a coarsely ground grade of 
calcium polycarbophil and is ideally suited for formulating 
swallowable bulk laxative tablets, while Noveon CA-2 is a 
finely ground grade and is designed for formulating 
chewable or swallowable bulk laxative tablets. Both grades 
swell in the intestinal tract, taking advantage of the natural 
540 Polycarbophil

water absorbency of polycarbophil. The swollen polycarbophil 
gel then acts as a bulk laxative as it moves through the 
gastrointestinal tract. 
18 Comments 
—
19 Specific References 
1 Nafee NA, Ismail FA, Boraie NA, Mortada LM. Mucoadhesive 
delivery systems. I. Evaluation of mucoadhesive polymers for 
buccal tablet formulation. Drug Dev Ind Pharm 2004; 30(9): 985– 
993. 
2 Jain AC, Aungst BJ, Adeyeye MC. Development and in vivo 
evaluation of buccal tablets prepared using danazol–sulfobutylether 
7 beta-cyclodextrin (SBE 7) complexes. J Pharm Sci 2002; 
91(7): 1659–1668. 
3 Akbari J, Nokhodchi A, Farid D, et al. Development and 
evaluation of buccoadhesive propranolol hydrochloride tablet 
formulations: effect of fillers. Farmaco 2004; 59(2): 155–161. 
4 El-Samaligy MS, Yahia SA, Basalious EB. Formulation and 
evaluation of diclofenac sodium buccoadhesive discs. Int J Pharm 
2004; 286(1–2): 27–39. 
5 Jay S, Fountain W, Cui Z, Mumper RJ. Transmucosal delivery of 
testosterone in rabbits using novel bi-layer mucoadhesive wax-film 
composite disks. J Pharm Sci 2002; 91(9): 2016–2025. 
6 Das NG, Das SK. Development of mucoadhesive dosage forms of 
buprenorphine for sublingual drug delivery. Drug Deliv 2004; 
11(2): 89–95. 
7 Jones DS, Irwin CR, Woolfson AD, et al. Physicochemical 
characterization and preliminary in vivo efficacy of bioadhesive, 
semisolid formulations containing flurbiprofen for the treatment of 
gingivitis. J Pharm Sci 1999; 88(6): 592–598. 
8 Jones DS, Woolfson AD, Brown AF. Viscoelastic properties of 
bioadhesive, chlorhexidine-containing semi-solids for topical 
application to the oropharynx. Pharm Res 1998; 15(7): 1131– 
1136. 
9 Jones DS, Woolfson AD, Djokic J, Coulter WA. Development and 
mechanical characterization of bioadhesive semi-solid, polymeric 
systems containing tetracycline for the treatment of periodontal 
diseases. Pharm Res 1996; 13(11): 1734–1738. 
10 Jones DS,Woolfson AD, Brown AF, et al. Design, characterisation 
and preliminary clinical evaluation of a novel mucoadhesive 
topical formulation containing tetracycline for the treatment of 
periodontal disease. J Control Release 2000; 67(2–3): 357–368. 
11 Nagarsenker MS, Londhe VY, Nadkarni GD. Preparation and 
evaluation of liposomal formulations of tropicamide for ocular 
delivery. Int J Pharm 1999; 190(1): 63–71. 
12 Park JS, Oh YK, Yoon H, et al. In situ gelling and mucoadhesive 
polymer vehicles for controlled intranasal delivery of plasmid 
DNA. J Biomed Mater Res 2002; 59(1): 144–151. 
13 Yun M, Choi H, Jung J, Kim C. Development of a thermoreversible 
insulin liquid suppository with bioavailability enhancement. 
Int J Pharm 1999; 189(2): 137–145. 
14 Hosny EA. Relative hypoglycemia of rectal insulin suppositories 
containing deoxycholic acid, sodium taurocholate, polycarbophil, 
and their combinations in diabetic rabbits. Drug Dev Ind Pharm 
1999; 25(6): 745–752. 
15 Ghelardi E, Tavanti A, Lupetti A, et al. Control of Candida 
albicans murine vaginitis by topical administration of polycarbophil–
econazole complex. Antimicrob Agents Chemother 1998; 
42(9): 2434–2436. 
16 Oh YK, Park JS, Yoon H, Kim CK. Enhanced mucosal and 
systemic immune responses to a vaginal vaccine coadministered 
with RANTES-expressing plasmid DNA using in situ-gelling 
mucoadhesive delivery system. Vaccine 2003; 21(17–18): 1980– 
1988. 
17 Hubert P, Evrard B, Maillard C, et al. Delivery of granulocytemacrophage 
colony-stimulating factor in bioadhesive hydrogel 
stimulates migration of dendritic cells in models of human 
papillomavirus-associated (pre)neoplastic epithelial lesions. Antimicrob 
Agents Chemother 2004; 48(11): 4342–4348. 
18 Kockisch S, Rees GD, Young SA, et al. Polymeric microspheres for 
drug delivery to the oral cavity: an in vitro evaluation of 
mucoadhesive potential. J Pharm Sci 2003; 92(8): 1614–1623. 
19 Kockisch S, Rees GD, Young SA, et al. In situ evaluation of drugloaded 
microspheres on a mucosal surface under dynamic test 
conditions. Int J Pharm 2004; 276(1–2): 51–58. 
20 Leitner VM, Guggi D, Krauland AH, Bernkop-Schnurch A. Nasal 
delivery of human growth hormone: in vitro and in vivo evaluation 
of a thiomer/glutathione microparticulate delivery system. J 
Control Release 2004; 100(1): 87–95. 
21 Umamaheswari RB, Jain S, Tripathi PK, et al. Floating-bioadhesive 
microspheres containing acetohydroxamic acid for clearance of 
Helicobacter pylori. Drug Deliv 2002; 9(4): 223–231. 
22 Langoth N, Kalbe J, Bernkop-Schnurch A. Development of buccal 
drug delivery systems based on a thiolated polymer. Int J Pharm 
2003; 252(1–2): 141–148. 
23 Bernkop-Schnurch A, Thaler SC. Polycarbophil–cysteine conjugates 
as platforms for oral polypeptide delivery systems. J Pharm 
Sci 2000; 89(7): 901–909. 
24 Kast CE, Guggi D, Langoth N, Bernkop-Schnurch A. Development 
and in vivo evaluation of an oral delivery system for low molecular 
weight heparin based on thiolated polycarbophil. Pharm Res 
2003; 20(6): 931–936. 
25 Marschutz MK, Caliceti P, Bernkop-Schnurch A. Design and in 
vivo evaluation of an oral delivery system for insulin. Pharm Res 
2000; 17(12): 1468–1474. 
26 Marschutz MK, Puttipipatkhachorn S, Bernkop-Schnurch A. 
Design and in vitro evaluation of a mucoadhesive oral delivery 
system for a model polypeptide antigen. Pharmazie 2001; 56(9): 
724–729. 
27 Hornof MD, Bernkop-Schnurch A. In vitro evaluation of the 
permeation enhancing effect of polycarbophil–cysteine conjugates 
on the cornea of rabbits. J Pharm Sci 2002; 91(12): 2588–2592. 
28 Valenta C,Walzer A, Clausen AE, Bernkop-Schnurch A. Thiolated 
polymers: development and evaluation of transdermal delivery 
systems for progesterone. Pharm Res 2001; 18(2): 211–216. 
29 Junginger HE, Verhoef JC. Macromolecules as safe penetration 
enhancers for hydrophilic drugs—a fiction? Pharm Sci Tech Today 
1998; 1: 370–375. 
30 The Registry of Toxic Effects of Chemical Substances. Atlanta: 
National Institute for Occupational Safety and Health, 2004. 
20 General References 
Noveon Inc. Polycarbophil. http://www.pharma.noveon.com/ 
literature/msds/msdaa1.pdf (accessed 18 May 2005). 
21 Authors 
KK Singh. 
22 Date of Revision 
25 August 2005. 
Table II: Pharmacopeial specifications for calcium polycarbophil. 
Test USP 28 
Identification . 
Loss on drying 410% 
Absorbing power 535 g/g 
Organic volatile impurities . 
Calcium content (on dried basis) 18–22% 
Polycarbophil 541

Polydextrose 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
E1200; Litesse; polydextrose A; polydextrose K. 
3 Chemical Name and CAS Registry Number 
Polydextrose [68424-04-4] 
4 Empirical Formula and Molecular Weight 
(C6H12O6)x 1200–2000 (average) 
5 Structural Formula 
See Section 18. 
6 Functional Category 
Base for medicated confectionery; coating agent; granulation 
aid; tablet binder; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Polydextrose is used in pharmaceutical formulations and food 
products. In food products it is used as a bulking agent; it also 
has texturizing and humectant properties. 
Although polydextrose can be used in a wide range of 
pharmaceutical formulations, its primary use is in solid-dosage 
forms. 
In tableting, polydextrose solutions are used as binders in 
wet-granulation processes. Polydextrose is also used in the 
manufacture of directly compressible tableting excipients. 
Polydextrose solutions may also be used, in conjunction with 
other materials, as a film and tablet coating agent. 
Polydextrose acts as a bulking agent in the formulation of 
‘sugar-free’ confectionery-type dosage forms. In conjunction 
with isomalt, lactitol, or maltitol, polydextrose can be used in 
the manufacture of ‘sugar-free’ hard-boiled candies and acacia 
lozenges or pastilles. 
The combination of high water solubility and high viscosity 
of polydextrose facilitates the processing of sugar-free candies 
of excellent quality. Polydextrose is amorphous and does not 
crystallize at low temperatures or high concentrations, so it can 
be used to control the crystallization of polyols and sugars and 
therefore the structure and texture of the final product. 
8 Description 
Polydextrose occurs as an odorless, off-white to light tan 
powder with a bland, slightly tart taste. 
9 Pharmacopeial Specifications 
See Section 18. 
10 Typical Properties 
Acidity/alkalinity: pH = 2.5 minimum (10% w/v aqueous 
solution) 
Density (bulk): 0.625 g/cm3 
Density (tapped): 0.694 g/cm3 
Heat of solution: 8 kcal/g 
Melting point: polydextrose is an amorphous polymer that 
does not have a melting range. However, it can undergo a 
viscosity transition at a temperature as low as 150–1608C. 
Moisture content: at relative humidities above approximately 
60%, polydextrose absorbs significant amounts of moisture; 
see Section 11. See also Figure 1. 
Refractive index: nD
20= 1.3477 (10% w/v aqueous solution) 
Solubility: completely miscible in water. Sparingly soluble to 
insoluble in most organic solvents. Polydextrose has a 
higher water solubility than most carbohydrates and 
polyols, allowing the preparation of 80% w/v solutions at 
208C. Polydextrose is soluble in ethanol and only partially 
soluble in glycerin and propylene glycol. 
Viscosity (dynamic): polydextrose solutions behave as Newtonian 
fluids. Polydextrose has a higher viscosity than 
sucrose or sorbitol at equivalent temperatures. This 
characteristic enables polydextrose to provide the desirable 
mouthfeel and textural qualities that are important when 
formulating syrups and viscous solutions. See Figure 2. 
11 Stability and Storage Conditions 
Polydextrose is hygroscopic and absorbs significant amounts of 
moisture at relative humidities greater than 60%. Under dry 
storage conditions it has good stability. 
The bulk material should be stored in a cool, dry place in 
well-closed containers. 
12 Incompatibilities 
Incompatible with oxidizing agents, strong acids, and alkalis, 
forming a brown coloration and depolymerizing. 
13 Method of Manufacture 
Dextrose and sorbitol undergo a catalytic condensation 
reaction with an acid. Further purification may be performed to

Figure 1: Moisture content of polydextrose at 208C. 
Figure 2: Viscosity of polydextrose solutions at 258C at various 
concentrations. 
~: Sucrose 
&: Polydextrose 
&: Sorbitol 
remove acidity and flavor notes generated during the condensation. 
14 Safety 
Polydextrose is used in oral pharmaceutical applications, food 
products, and confectionery and is generally regarded as a 
relatively nontoxic and nonirritant material.(1,2) 
However, excessive consumption of non-digestible carbohydrates, 
such as polydextrose, can lead to gastrointestinal 
distress. After evaluating a series of clinical studies, the Joint 
FAO/WHO Expert Committee on Food Additives (JECFA) and 
the European Commission Scientific Committee for Food (EC/ 
SCF) concluded that polydextrose was better tolerated than 
other digestible carbohydrates such as polyols. The committee 
concluded that polydextrose has a mean laxative threshold of 
approximately 90 g/day (1.3 g/kg body-weight) or 50 g as a 
single dose.(3) See also Section 18. 
LD50 (mouse, oral): >30 g/kg 
LD50 (rat, oral): >15 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Polydextrose may be irritant 
to the eyes. Eye protection and gloves are recommended. 
Conventional dust-control practices should be employed. 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (oral tablets). Included in 
non-parenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Dextrose. 
18 Comments 
Polydextrose is a randomly bonded polymer prepared by the 
condensation of a melt that consists of approximately 90% 
w/w D-glucose, 10% w/w sorbitol, and 1% w/w citric acid or 
0.1% w/w phosphoric acid. 
The 1,6 glycosidic linkage predominates in the polymer, but 
other possible bonds are present. The product contains small 
quantities of free glucose, sorbitol, and D-anhydroglucoses 
(levoglucosan), with traces of citric or phosphoric acid. 
Polydextrose may be partially reduced by transition-metal 
catalytic hydrogenation in aqueous solution. It may be 
neutralized with any food-grade base and/or decolorized and 
deionized for further purification. 
Although not currently included in any pharmacopeias, a 
specification for polydextrose is contained in the Food 
Chemicals Codex (FCC). See Table I. 
Polydextrose is partially fermented by intestinal microorganisms 
to produce volatile fatty acids. The volatile fatty acids 
are absorbed in the large intestine. Because of the inefficient 
way the human body derives energy from volatile fatty acids, 
polydextrose contributes only one-quarter of the energy of the 
equivalent weight of sugar, i.e, 4 kJ/g (1 kcal/g).(4–6) 
When consumed, polydextrose has a negligible effect on 
blood glucose levels. Polydextrose is metabolized independently 
of insulin and contributes only one quarter of the energy 
of normal carbohydrate. 
A specification for polydextrose is contained in the Food 
Chemicals Codex (FCC). 
Polydextrose 543

Table I: Food Chemicals Codex specifications for polydextrose.(3) 
Test FCC 1996 (Suppl. 2) 
Identification . 
Heavy metals 45 ppm 
5-Hydroxymethylfurfural 40.1% 
Lead 40.5 ppm 
Molecular weight limit . 
Monomers 
1,6-Anhydro-D-glucose 44.0% 
Glucose and sorbitol 46.0% 
pH of a 10% solution 
Untreated 2.5–7.0 
Neutralized 5.0–6.0 
Residue on ignition 
Untreated 40.3% 
Neutralized 42.0% 
Water 44.0% 
Assay 590.0% 
19 Specific References 
1 Flood MT, Auerbach MH, Craig SA. A review of the clinical 
toleration studies of polydextrose in food. Food Chem Toxicol 
2004; 42(9): 1531–1542. 
2 Burdock GA, Flamm WG. A review of the studies of the safety of 
polydextrose in food. Food Chem Toxicol 1999; 37(2–3): 233– 
264. 
3 Committee on Food Chemicals Codex. Food Chemicals Codex, 
4th edn. Washington, DC: National Academy Press, 1996: 297– 
300. 
4 Figdor SK, Rennhard HH. Caloric utilization and disposition of 
[14C]polydextrose in the rat. J Agric Food Chem 1981; 29: 1181– 
1189. 
5 Juhr N, Franke J. A method for estimating the available energy of 
incompletely digested carbohydrates in rats. J Nutr 1992; 122: 
1425–1433. 
6 Achour L, Flourie B, Briet F, et al. Gastrointestinal effects and 
energy value of polydextrose in healthy non-obese men. Am J Clin 
Nutr 1994; 59: 1362–1368. 
20 General References 
Allingham RP. Chemistry of Foods and Beverages: Recent Developments. 
New York: Academic Press, 1982: 293–303. 
Murphy O. Non-polyol low-digestible carbohydrates: food applications 
and functional benefits. Br J Nutr 2001; 85 (Suppl. 1): S47– 
S53. 
Slade L, Levine H. Glass transitions and water–food interaction. 
Advances in Food and Nutrition Research. San Diego: Academic 
Press, 1994. 
21 Authors 
PJ Weller. 
22 Date of Revision 
19 April 2005. 
544 Polydextrose

Polyethylene Glycol 
1 Nonproprietary Names 
BP: Macrogols 
JP: Macrogol 400 
Macrogol 1500 
Macrogol 4000 
Macrogol 6000 
Macrogol 20000 
PhEur: Macrogola 
USPNF: Polyethylene glycol 
2 Synonyms 
Carbowax; Carbowax Sentry; Lipoxol; Lutrol E; PEG; Pluriol 
E; polyoxyethylene glycol. 
3 Chemical Name and CAS Registry Number 
a-Hydro-o-hydroxypoly(oxy-1,2-ethanediyl) [25322-68-3] 
4 Empirical Formula and Molecular Weight 
HOCH2(CH2OCH2)mCH2OH where m represents the average 
number of oxyethylene groups. 
Alternatively, the general formula H(OCH2CH2)nOH may 
be used to represent polyethylene glycol, where n is a number m 
in the previous formula . 1. 
See Table I for the average molecular weights of typical 
polyethylene glycols. Note that the number that follows PEG 
indicates the average molecular weight of the polymer. 
Table I: Structural formula and molecular weight of typical 
polyethylene glycol polymers. 
Grade m Average molecular weight 
PEG 200 4.2 190–210 
PEG 300 6.4 285–315 
PEG 400 8.7 380–420 
PEG 540 (blend) — 500–600 
PEG 600 13.2 570–613 
PEG 900 15.3 855–900 
PEG 1000 22.3 950–1 050 
PEG 1450 32.5 1 300–1 600 
PEG 1540 28.0–36.0 1 300–1 600 
PEG 2000 40.0–50.0 1 800–2 200 
PEG 3000 60.0–75.0 2 700–3 300 
PEG 3350 75.7 3 000–3 700 
PEG 4000 69.0–84.0 3 000–4 800 
PEG 4600 104.1 4 400–4 800 
PEG 8000 181.4 7 000–9 000 
5 Structural Formula 
6 Functional Category 
Ointment base; plasticizer; solvent; suppository base; tablet and 
capsule lubricant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Polyethylene glycols (PEGs) are widely used in a variety of 
pharmaceutical formulations including parenteral, topical, 
ophthalmic, oral, and rectal preparations. It has been used 
experimentally in biodegradable polymeric matrices used in 
controlled-release systems.(1) 
Polyethylene glycols are stable, hydrophilic substances that 
are essentially nonirritant to the skin; see Section 14. They do 
not readily penetrate the skin, although the polyethylene glycols 
are water-soluble and are easily removed from the skin by 
washing, making them useful as ointment bases.(2) Solid grades 
are generally employed in topical ointments, with the consistency 
of the base being adjusted by the addition of liquid grades 
of polyethylene glycol. 
Mixtures of polyethylene glycols can be used as suppository 
bases,(3) for which they have many advantages over fats. For 
example, the melting point of the suppository can be made 
higher to withstand exposure to warmer climates; release of the 
drug is not dependent upon melting point; the physical stability 
on storage is better; and suppositories are readily miscible with 
rectal fluids. Polyethylene glycols have the following disadvantages: 
they are chemically more reactive than fats; greater care is 
needed in processing to avoid inelegant contraction holes in the 
suppositories; the rate of release of water-soluble medications 
decreases with the increasing molecular weight of the polyethylene 
glycol; and polyethylene glycols tend to be more 
irritating to mucous membranes than fats. 
Aqueous polyethylene glycol solutions can be used either as 
suspending agents or to adjust the viscosity and consistency of 
other suspending vehicles. When used in conjunction with other 
emulsifiers, polyethylene glycols can act as emulsion stabilizers. 
Liquid polyethylene glycols are used as water-miscible 
solvents for the contents of soft gelatin capsules. However, 
they may cause hardening of the capsule shell by preferential 
absorption of moisture from gelatin in the shell. 
In concentrations up to approximately 30% v/v, PEG 300 
and PEG 400 have been used as the vehicle for parenteral 
dosage forms. 
In solid-dosage formulations, higher-molecular-weight polyethylene 
glycols can enhance the effectiveness of tablet binders 
and impart plasticity to granules.(4) However, they have only 
limited binding action when used alone, and can prolong 
disintegration if present in concentrations greater than 5%

w/w. When used for thermoplastic granulations,(5–7) a mixture 
of the powdered constituents with 10–15% w/w PEG 6000 is 
heated to 70–758C. The mass becomes pastelike and forms 
granules if stirred while cooling. This technique is useful for the 
preparation of dosage forms such as lozenges when prolonged 
disintegration is required. 
Polyethylene glycols can also be used to enhance the 
aqueous solubility or dissolution characteristics of poorly 
soluble compounds by making solid dispersions with an 
appropriate polyethylene glycol.(8) Animal studies have also 
been performed using polyethylene glycols as solvents for 
steroids in osmotic pumps. 
In film coatings, solid grades of polyethylene glycol can be 
used alone for the film-coating of tablets or can be useful as 
hydrophilic polishing materials. Solid grades are also widely 
used as plasticizers in conjunction with film-forming polymers.(
9) The presence of polyethylene glycols in film coats, 
especially of liquid grades, tends to increase their water 
permeability and may reduce protection against low pH in 
enteric-coating films. Polyethylene glycols are useful as 
plasticizers in microencapsulated products to avoid rupture of 
the coating film when the microcapsules are compressed into 
tablets. 
Polyethylene glycol grades with molecular weights of 6000 
and above can be used as lubricants, particularly for soluble 
tablets. The lubricant action is not as good as that of 
magnesium stearate, and stickiness may develop if the material 
becomes too warm during compression. An antiadherent effect 
is also exerted, again subject to the avoidance of overheating. 
Polyethylene glycols have been used in the preparation of 
urethane hydrogels, which are used as controlled-release 
agents. It has also been used in insulin-loaded microparticles 
for the oral delivery of insulin;(10,11) it has been used in 
inhalation preparations to improve aerosolization;(12) polyethylene 
glycol nanoparticles have been used to improve the 
oral bioavailability of cyclosporine;(13) it has been used in selfassembled 
polymeric nanoparticles as a drug carrier;(14) and 
copolymer networks of polyethylene glycol grafted with 
poly(methacrylic acid) have been used as bioadhesive controlled 
drug delivery formulations.(15) 
8 Description 
The USPNF 23 describes polyethylene glycol as being an 
addition polymer of ethylene oxide and water. Polyethylene 
glycol grades 200–600 are liquids; grades 1000 and above are 
solids at ambient temperatures. 
Liquid grades (PEG 200–600) occur as clear, colorless or 
slightly yellow-colored, viscous liquids. They have a slight but 
characteristic odor and a bitter, slightly burning taste. PEG 600 
can occur as a solid at ambient temperatures. 
Solid grades (PEG>1000) are white or off-white in color, 
and range in consistency from pastes to waxy flakes. They have 
a faint, sweet odor. Grades of PEG 6000 and above are 
available as free-flowing milled powders. 
9 Pharmacopeial Specifications 
See Table II. 
10 Typical Properties 
Density: 
1.11–1.14 g/cm3 at 258C for liquid PEGs; 
1.15–1.21 g/cm3 at 258C for solid PEGs. 
Flash point: 
1828C for PEG 200; 
2138C for PEG 300; 
2388C for PEG 400; 
2508C for PEG 600. 
Freezing point: 
<658C PEG 200 sets to a glass; 
15 to 88C for PEG 300; 
4–88C for PEG 400; 
15–258C for PEG 600. 
Melting point: 
37–408C for PEG 1000; 
44–488C for PEG 1500; 
40–488C for PEG 1540; 
45–508C for PEG 2000; 
48–548C for PEG 3000; 
50–588C for PEG 4000; 
55–638C for PEG 6000; 
60–638C for PEG 8000; 
60–638C for PEG 20000. 
Moisture content: liquid polyethylene glycols are very hygroscopic, 
although hygroscopicity decreases with increasing 
molecular weight. Solid grades, e.g. PEG 4000 and above, 
are not hygroscopic. See Figures 1, 2 and 3. 
Particle size distribution: see Figures 4 and 5. 
Refractive index: 
nD
25 = 1.459 for PEG 200; 
nD
25 = 1.463 for PEG 300; 
nD
25 = 1.465 for PEG 400; 
nD
25 = 1.467 for PEG 600. 
Solubility: all grades of polyethylene glycol are soluble in water 
and miscible in all proportions with other polyethylene 
glycols (after melting, if necessary). Aqueous solutions of 
higher-molecular-weight grades may form gels. Liquid 
polyethylene glycols are soluble in acetone, alcohols, 
benzene, glycerin, and glycols. Solid polyethylene glycols 
are soluble in acetone, dichloromethane, ethanol (95%), 
Table II: Pharmacopeial specifications for polyethylene glycol. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . — 
Characters — . — 
Acidity or alkalinity — . — 
Appearance of solution — . . 
Density — See Table IV — 
Freezing point See Table III See Table IV — 
Viscosity — See Table IV See Table V 
Average molecular weight See Table III — See Table V 
pH (5% w/v solution) See Table III — 4.5–7.5 
Hydroxyl value — See Table IV — 
Reducing substances — . — 
Residue on ignition See Table III — 40.1% 
Sulfated ash — 40.2% — 
Limit of ethylene glycol and 
diethylene glycol 
40.25% 40.4% 40.25% 
Ethylene oxide — 41 ppm 410 mg/g 
1,4-Dioxane — 410 ppm 410 mg/g 
Heavy metals — 420 ppm 45 mg/g 
Organic volatile impurities — — . 
Water 41.0% 42.0% — 
Formaldehyde — 415 ppm — 
546 Polyethylene Glycol

and methanol; they are slightly soluble in aliphatic hydrocarbons 
and ether, but insoluble in fats, fixed oils, and 
mineral oil. 
Surface tension: approximately 44mN/m (44 dynes/cm) for 
liquid polyethylene glycols; approximately 55mN/m 
(55 dynes/cm) for 10% w/v aqueous solution of solid 
polyethylene glycol. 
Viscosity (kinematic): see Tables IV, V, and VI. 
11 Stability and Storage Conditions 
Polyethylene glycols are chemically stable in air and in solution, 
although grades with a molecular weight less than 2000 are 
hygroscopic. Polyethylene glycols do not support microbial 
growth, and they do not become rancid. 
Polyethylene glycols and aqueous polyethylene glycol 
solutions can be sterilized by autoclaving, filtration, or gamma 
irradiation.(16) Sterilization of solid grades by dry heat at 1508C 
for 1 hour may induce oxidation, darkening, and the formation 
of acidic degradation products. Ideally, sterilization should be 
carried out in an inert atmosphere. Oxidation of polyethylene 
glycols may also be inhibited by the inclusion of a suitable 
antioxidant. 
If heated tanks are used to maintain normally solid 
polyethylene glycols in a molten state, care must be taken to 
avoid contamination with iron, which can lead to discoloration. 
The temperature must be kept to the minimum necessary 
to ensure fluidity; oxidation may occur if polyethylene glycols 
are exposed for long periods to temperatures exceeding 508C. 
However, storage under nitrogen reduces the possibility of 
oxidation. 
Polyethylene glycols should be stored in well-closed containers 
in a cool, dry place. Stainless steel, aluminum, glass, or lined 
steel containers are preferred for the storage of liquid grades. 
12 Incompatibilities 
The chemical reactivity of polyethylene glycols is mainly 
confined to the two terminal hydroxyl groups, which can be 
either esterified or etherified. However, all grades can exhibit 
some oxidizing activity owing to the presence of peroxide 
impurities and secondary products formed by autoxidation. 
Liquid and solid polyethylene glycol grades may be 
incompatible with some coloring agents. 
The antibacterial activity of certain antibiotics is reduced in 
polyethylene glycol bases, particularly that of penicillin and 
bacitracin. The preservative efficacy of the parabens may also 
be impaired owing to binding with polyethylene glycols. 
Physical effects caused by polyethylene glycol bases include 
softening and liquefaction in mixtures with phenol, tannic acid, 
and salicylic acid. Discoloration of sulfonamides and dithranol 
can also occur and sorbitol may be precipitated from mixtures. 
Plastics, such as polyethylene, phenolformaldehyde, polyvinyl 
chloride, and cellulose-ester membranes (in filters) may be 
softened or dissolved by polyethylene glycols. Migration of 
polyethylene glycol can occur from tablet film coatings, leading 
to interaction with core components. 
13 Method of Manufacture 
Polyethylene glycols are condensation polymers formed by the 
reaction of ethylene oxide and water under pressure in the 
presence of a catalyst. 
14 Safety 
Polyethylene glycols are widely used in a variety of pharmaceutical 
formulations. Generally, they are regarded as nontoxic 
and nonirritant materials.(17–19) 
Adverse reactions to polyethylene glycols have been 
reported, the greatest toxicity being with glycols of low 
molecular weight. However, the toxicity of glycols is relatively 
low. 
Polyethylene glycols administered topically may cause 
stinging, especially when applied to mucous membranes. 
Hypersensitivity reactions to polyethylene glycols applied 
topically have also been reported, including urticaria and 
delayed allergic reactions.(20) 
The most serious adverse effects associated with polyethylene 
glycols are hyperosmolarity, metabolic acidosis, and renal 
failure following the topical use of polyethylene glycols in burn 
patients.(21) Topical preparations containing polyethylene 
glycols should therefore be used cautiously in patients with 
renal failure, extensive burns, or open wounds. 
Table IV: Specifications from PhEur 2005. 
Type of PEG Density (g/cm3) Freezing point (8C) Hydroxyl value Viscosity (dynamic) [mPa s (cP)] Viscosity (kinematic) [mm2/s (cSt)] 
300 1.120 — 340–394 80–105 71–94 
400 1.120 — 264–300 105–130 94–116 
600 1.080 15–25 178–197 15–20 13.9–18.5 
1000 1.080 35–40 107–118 22–30 20.4–27.7 
1500 1.080 42–48 70–80 34–50 31–46 
3000 1.080 50–56 34–42 75–100 69–93 
3350 1.080 53–57 30–38 83–120 76–110 
4000 1.080 53–59 25–32 110–170 102–158 
6000 1.080 55–61 16–22 200–270 185–250 
8000 1.080 55–62 12–16 260–510 240–472 
20000 1.080 557 — 2 700–3 500 2 500–3 200 
35000 1.080 557 — 11 000–14 000 10 000–13 000 
Table III: Specifications from JP 2001. 
Type of 
PEG 
Average 
molecular 
weight 
Freezing 
point (8C) 
pH (5% 
w/v solution) 
Residue on 
ignition 
400 380–420 4–8 4.0–7.0 40.1% 
1500 — 37–41 4.0–7.0 40.1% 
4000 2 600–3 800 53–57 4.0–7.5 40.25% 
6000 7 300–9 300 56–61 4.5–7.5 40.25% 
20000 15 000–25 000 56–64 4.5–7.5 40.25% 
Polyethylene Glycol 547

Figure 1: Equilibrium moisture content of PEG 4000 
(McKesson, Lot No. B192–8209) at 258C. 
Figure 2: Equilibrium moisture content of PEG 4000 at 258C. 
*: PEG 4000 powder (Union Carbide Corp, Lot no. B- 
251) 
~: PEG E–4000 (BASF, Lot no. WPYA–575B) 
Figure 3: Equilibrium moisture content of PEG 6000 at 258C. 
*: PEG 6000 powder (Union Carbide Corp., 
Lot no. B–507) 
~: PEG E–6000 (BASF, Lot no. WPNA–124B) 
Figure 4: Particle size distribution of PEG 4000 and PEG 6000 
flakes. 
*: PEG 4000 flakes 
~: PEG 6000 flakes 
548 Polyethylene Glycol

Figure 5: Particle size distribution of PEG 4000 and PEG 6000 
powder. 
*: PEG 4000 powder 
~: PEG 6000 powder 
Oral administration of large quantities of polyethylene 
glycols can have a laxative effect. Therapeutically, up to 4 L of 
an aqueous mixture of electrolytes and high-molecular-weight 
polyethylene glycol is consumed by patients undergoing bowel 
cleansing.(22) 
Liquid polyethylene glycols may be absorbed when taken 
orally, but the higher-molecular-weight polyethylene glycols are 
not significantly absorbed from the gastrointestinal tract. 
Absorbed polyethylene glycol is excreted largely unchanged 
in the urine, although polyethylene glycols of low molecular 
weight may be partially metabolized. 
The WHO has set an estimated acceptable daily intake of 
polyethylene glycols at up to 10 mg/kg body-weight.(23) 
In parenteral products, the maximum recommended concentration 
of PEG 300 is approximately 30% v/v as hemolytic 
effects have been observed at concentrations greater than about 
40% v/v. 
For animal toxicity data, see Table VII.(24) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection is recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (dental 
preparations; IM and IV injections; ophthalmic preparations; 
oral capsules, solutions, syrups, and tablets; rectal, topical, and 
vaginal preparations). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
Table V: Specification for viscosity of polyethylene glycol of the given 
nominal molecular weight at 98.98C 
 0.38C from the USPNF 23. 
Type of PEG (nominal average 
molecular weight) 
Viscosity (kinematic) [mm2/s (cSt)] 
200 3.9–4.8 
300 5.4–6.4 
400 6.8–8.0 
500 8.3–9.6 
600 9.9–11.3 
700 11.5–13.0 
800 12.5–14.5 
900 15.0–17.0 
1000 16.0–19.0 
1100 18.0–22.0 
1200 20.0–24.5 
1300 22.0–27.5 
1400 24–30 
1450 25–32 
1500 26–33 
1600 28–36 
1700 31–39 
1800 33–42 
1900 35–45 
2000 38–49 
2100 40–53 
2200 43–56 
2300 46–60 
2400 49–65 
2500 51–70 
2600 54–74 
2700 57–78 
2800 60–83 
2900 64–88 
3000 67–93 
3250 73–105 
3350 76–110 
3500 87–123 
3750 99–140 
4000 110–158 
4250 123–177 
4500 140–200 
4750 155–228 
5000 170–250 
5500 206–315 
6000 250–390 
6500 295–480 
7000 350–590 
7500 405–735 
8000 470–900 
Table VI: Viscosity of selected polyethylene glycols at 258Cand 998C. 
Type of PEG Viscosity [mm2/s (cSt)] 
258C 998C 
PEG 200 39.9 4.4 
PEG 300 68.8 5.9 
PEG 400 90.0 7.4 
PEG 600 131 11.0 
PEG 1000 solid 19.5 — 
PEG 2000 solid 47 — 
PEG 4000 solid 180 — 
PEG 6000 solid 580 — 
PEG 20000 solid 6 900 — 
Polyethylene Glycol 549

17 Related Substances 
Polyoxyethylene alkyl ethers; polyethylene oxide; polyoxyethylene 
sorbitan fatty acid esters; polyoxyethylene stearates; 
suppository bases. 
18 Comments 
A specification for polyethylene glycol is contained in the Food 
Chemicals Codex (FCC). 
19 Specific References 
1 Mohl S, Winter G. Continuous release of rh-interferon alpha-2a 
from triglyceride matrices. J Control Release 2004; 97(1): 67–78. 
2 Hadia IA, Ugrine. HE, Farouk AM, Shayoub M. Formulation of 
polyethylene glycol ointment bases suitable for tropical and 
subtropical climates I. Acta Pharm Hung 1989; 59: 137–142. 
3 Kellaway IW, Marriott C. Correlations between physical and drug 
release characteristics of polyethylene glycol suppositories. 
J Pharm Sci 1975; 64: 1162–1166. 
4 Wells JI, Bhatt DA, Khan KA. Improved wet massed tableting 
using plasticized binder. J Pharm Pharmacol 1982; 34 (Suppl.): 
46P. 
5 Chiou WL, Riegelman S. Pharmaceutical applications of solid 
dispersion systems. J Pharm Sci 1971; 60: 1281–1302. 
6 Ford JL, Rubinstein MH. Formulation and ageing of tablets 
prepared from indomethacin–polyethylene glycol 6000 solid 
dispersions. Pharm Acta Helv 1980; 55: 1–7. 
7 Vila-Jato JL, Blanco J, Alonso MJ. The effect of the molecular 
weight of polyethylene glycol on the bioavailability of paracetamol–
polyethylene glycol solid dispersions. J Pharm Pharmacol 
1986; 38: 126–128. 
8 Miralles MJ, McGinity JW, Martin A. Combined water-soluble 
carriers for coprecipitates of tolbutamide. J Pharm Sci 1982; 71: 
302–304. 
9 Okhamafe AO, York P. Moisture permeation mechanism of some 
aqueous-based film coats. J Pharm Pharmacol 1982; 34 (Suppl.): 
53P. 
10 Marishita M, Goto T, Peppas NA, et al. Mucosal insulin delivery 
systems based on complexation polymer hydrogels: effect of 
particle size on insulin enteral absorption. J Control Release 2004; 
97(1): 67–78. 
11 Marcel T, Nagappan P, Nerenbaum L, et al. Calcium phosphate- 
PEG-insulin-casein (CAPIC) particles as oral delivery systems for 
insulin. Int J Pharm 2004; 277(1–2): 91–97. 
12 Fiegel J, Fu H, Hanes J. Poly(ether-anhydride) dry powder aerosols 
for sustained drug delivery in the lungs. J Control Release 2004; 
96(3): 411–423. 
13 Jaiswal J, Gupta SK, Kreuter J. Preparation of biodegradable 
cyclosporine nanoparticles by high-pressure emulsion-solvent 
evaporation process. J Control Release 2004; 96(1): 169–178. 
14 Jung SW, Jeong YI, Kim YH, Kim SH. Self-assembled polymeric 
nanoparticles of poly(ethylene glycol) grafted pullulan acetate as a 
novel drug carrier. Arch Pharmacal Res 2004; 27(5): 562–569. 
15 Peppas NA. Devices based on intelligent biopolymers for oral 
protein delivery. Int J Pharm 2004; 277(1–2): 11–17. 
16 Bhalla HL, Menon MR, Gopal NGS. Radiation sterilization of 
polyethylene glycols. Int J Pharm 1983; 17: 351–355. 
17 Smyth HF, Carpenter CP, Weil CS. The toxicology of the 
polyethylene glycols. J Am Pharm Assoc (Sci) 1950; 39: 349–354. 
18 Tusing TW, Elsea JR, Sauveur AB. The chronic dermal toxicity of a 
series of polyethylene glycols. J Am Pharm Assoc (Sci) 1954; 43: 
489–490. 
19 Smyth HF, Carpenter CP, Weil CS. The chronic oral toxicology of 
the polyethylene glycols. J Am Pharm Assoc (Sci) 1955; 44: 27–30. 
20 Fisher AA. Immediate and delayed allergic contact reactions to 
polyethylene glycol. Contact Dermatitis 1978; 4: 135–138. 
21 Anonymous. Topical PEG in burn ointments. FDA Drug Bull 
1982; 12: 25–26. 
22 Sweetman SC, ed. Martindale: The Complete Drug Reference, 
34th edn. London: Pharmaceutical Press, 2005: 1708–1709. 
23 FAO/WHO. Evaluation of certain food additives. Twenty-third 
report of the joint FAO/WHO expert committee on food additives. 
World Health Organ Tech Rep Ser 1980; No. 648. 
24 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3001. 
20 General References 
Donovan MD, Flynn GL, Amidon GL. Absorption of polyethylene 
glycols 600 through 2000: molecular weight dependence of 
gastrointestinal and nasal absorption. Pharm Res 1990; 7: 863– 
867. 
Mi YI,Wood J. The application and mechanisms of polyethylene glycol 
8000 on stabilizing lactate dehydrogenase during lyophilization. 
PDA J Pharm Sci Technol 2004; 58(4): 192–202. 
Union Carbide Corporation. Technical literature: Carbowax polyethylene 
glycols, 1986. 
Van Dam J, Daenens P. Molecular weight identification of polyethylene 
glycols in pharmaceutical preparations by gel permeation chromatography. 
J Pharm Sci 1993; 82: 938–941. 
Yamaoka T, Tabata Y, Ikada Y. Distribution and tissue uptake of 
poly(ethylene glycol) with different molecular weights after 
intravenous administration to mice. J Pharm Sci 1994; 83: 601– 
606. 
21 Authors 
JC Price. 
22 Date of Revision 
29 August 2005. 
Table VII: Animal toxicity data (LD50) for various grades of polyethylene glycol.(24) 
PEG grade LD50 (g/kg) 
Guinea pig (oral) Mouse (IP) Mouse (IV) Mouse (oral) Rabbit (oral) Rabbit (IV) Rat (IP) Rat (IV) Rat (oral) 
PEG 200 — 7.5 — 34 19.9 — — — 28.0 
PEG 300 19.6 — — — 17.3 — — — 27.5 
PEG 400 15.7 10.0 8.6 28.9 26.8 — 9.7 7.3 — 
PEG 600 — — — 47 — — — — 38.1 
PEG 1000 — 20 — — — — 15.6 — 32 
PEG 1500 28.9 — — — 28.9 8 17.7 — 44.2 
PEG 4000 50.9 — 16 — 76 — 11.6 — 50 
PEG 6000 50 — — — — — 6.8 — — 
550 Polyethylene Glycol

Polyethylene Oxide 
1 Nonproprietary Names 
USPNF: Polyethylene oxide 
2 Synonyms 
Polyox; polyoxirane; polyoxyethylene. 
3 Chemical Name and CAS Registry Number 
Polyethylene oxide [25322-68-3] 
4 Empirical Formula and Molecular Weight 
See Table I. 
5 Structural Formula 
The USPNF 23 describes polyethylene oxide as a nonionic 
homopolymer of ethylene oxide, represented by the formula 
(CH2CH2O)n, where n represents the average number of 
oxyethylene groups. It may contain up to 3% of silicon dioxide. 
6 Functional Category 
Mucoadhesive; tablet binder; thickening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Polyethylene oxide can be used as a tablet binder at 
concentrations of 5–85%. The higher molecular weight grades 
provide delayed drug release via the hydrophilic matrix 
approach; see Table I. 
The relationship between swelling capacity and molecular 
weight is a good guide when selecting products for use in 
immediate- or sustained-release matrix formulations; see Figure 
1. 
Polyethylene oxide has been shown to be an excellent 
mucoadhesive polymer.(1) Low levels of polyethylene oxide are 
effective thickeners, although alcohol is usually added to waterbased 
formulations to provide improved viscosity stability; see 
Table II. Polyethylene oxide films demonstrate good lubricity 
when wet. This property has been utilized in the development of 
coatings for medical devices. Polyethylene oxide can be 
radiation crosslinked in solution to produce a hydrogel that 
can be used in wound care applications. 
8 Description 
White to off-white, free-flowing powder. Slight ammoniacal 
odor. 
Figure 1: Swelling capacity of polyethylene oxide (Polyox WSR). 
Measured for four molecular weight grades; 28mm tablets 
in 300 mL of water. 
Table I: Number of repeat units and molecular weight as a function of 
polymer grade for polyethylene oxide. 
Polyox grade Approximate number 
of repeating units 
Approximate 
molecular weight 
WSR N-10 2 275 100 000 
WSR N-80 4 500 200 000 
WSR N-750 6 800 300 000 
WSR N-3000 9 100 400 000 
WSR 205 14 000 600 000 
WSR 1105 20 000 900 000 
WSR N-12K 23 000 1 000 000 
WSR N-60K 45 000 2 000 000 
WSR 301 90 000 4 000 000 
WSR Coagulant 114 000 5 000 000 
WSR 303 159 000 7 000 000 
Note: molecular weight based on dilute viscosity measurements. 
Table II: Polyethylene oxide viscosity at 258C (mPa s). 
Polyox grade 5% solution 2% solution 1% solution 
WSR N-10 30–50 — — 
WSR N-80 55–90 — — 
WSR N-750 600–1 200 — — 
WSR N-3000 2 250–4 500 — — 
WSR 205 4 500–8 800 — — 
WSR 1105 8 800–17 600 — — 
WSR N-12K — 400–800 — 
WSR N-60K — 2 000–4 000 — 
WSR 301 — — 1 650–5 500 
WSR coagulant — — 5 500–7 500 
WSR 303 — — 7 500–10 000 
Note: all solution concentrations are based on the water content of the hydro-alcoholic solutions.

9 Pharmacopeial Specifications 
See Table III. 
Table III: Pharmacopeial specifications for polyethylene oxide. 
Test USPNF 23 
Identification . 
Loss on drying 41.0% 
Silicon dioxide and nonsilicon 
dioxide residue on ignition 
42.0% 
Silicon dioxide 43.0% 
Heavy metals 40.001% 
Free ethylene oxide 40.001% 
Organic volatile impurities . 
Viscosity . 
10 Typical Properties 
Angle of repose: 348 
Density (true): 1.3 g/cm3 
Melting point: 65–708C 
Moisture content: <1% 
Solubility: polyethylene oxide is soluble in water and a number 
of common organic solvents such as acetonitrile, chloroform, 
and methylene chloride. It is insoluble in aliphatic 
hydrocarbons, ethylene glycol, and most alcohols.(2) 
Viscosity (dynamic): see Table II. 
11 Stability and Storage Conditions 
Store in tightly sealed containers in a cool, dry place. Avoid 
exposure to high temperatures since this can result in reduction 
in viscosity. 
12 Incompatibilities 
Polyethylene oxide is incompatible with strong oxidizing 
agents. 
13 Method of Manufacture 
Polyethylene oxide is prepared by the polymerization of 
ethylene oxide using a suitable catalyst.(1) 
14 Safety 
Animal studies suggest that polyethylene oxide has a low level 
of toxicity regardless of the route of administration. It is poorly 
absorbed from the gastrointestinal tract but appears to be 
completely and rapidly eliminated. The resins are neither skin 
irritants nor sensitizers, and they do not cause eye irritation. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (sustainedrelease 
tablets). Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Polyethylene glycol. 
18 Comments 
—
19 Specific References 
1 Bottenberg P, Cleymaet R, de Muynck C, et al. Development and 
testing of bioadhesive, fluoride-containing slow-release tablets for 
oral use. J Pharm Pharmacol 1991; 43: 457–464. 
2 Bailey FE, Kolesky JV. Poly(ethylene oxide). London: Academic 
Press: 1976. 
20 General References 
Dhawan S, Varma M, Sinha VR. High molecular weight poly(ethylene 
oxide)-based drug delivery systems. Part 1: hydrogels and hydrophilic 
matrix systems. Pharm Technol 2005; 29(5): 72–74, 76–80. 
Union Carbide Corp. Technical literature: Polyox water soluble resin, 
1998. 
Yu DM, Amidon GL, Weiner ND, Goldberg AH. Viscoelastic properties 
of poly(ethylene oxide) solution. J Pharm Sci 1994; 83: 1443– 
1449. 
21 Authors 
SC Owen. 
22 Date of Revision 
17 August 2005. 
552 Polyethylene Oxide

Polymethacrylates 
1 Nonproprietary Names 
BP: Methacrylic acid–ethyl acrylate copolymer (1 : 1) 
PhEur: Acidum methacrylicum et ethylis acrylas polymerisatum 
1 : 1 
Acidum methacrylicum et ethylis acrylas polymerisatum 
1 : 1 dispersio 30 per centum 
Acidum methacrylicum et methylis methacrylas 
polymerisatum 1 : 1 
Acidum methacrylicum et methylis methacrylas 
polymerisatum 1 : 2 
Copolymerum methacrylatis butylati basicum 
Polyacrylatis dispersion 30 per centum 
USPNF: Ammonio methacrylate copolymer 
Methacrylic acid copolymer 
Methacrylic acid copolymer dispersion 
Note that three separate monographs applicable to polymethacrylates 
are contained in the USPNF 23; see Section 9. Several 
different types of material are defined in the monographs. The 
PhEur 2005 contains four separate monographs applicable to 
polymethacrylates. 
2 Synonyms 
Acryl-EZE; Acryl-EZE MP; Eastacryl 30D; Eudragit; Kollicoat 
MAE 30 D; Kollicoat MAE 30 DP; polymeric methacrylates. 
See also Table I. 
3 Chemical Name and CAS Registry Number 
See Table I. 
4 Empirical Formula and Molecular Weight 
The PhEur 2005 describes methacrylic acid–ethyl acrylate 
copolymer (1 : 1) as a copolymer of methacrylic acid and ethyl 
acrylate having a mean relative molecular mass of about 
250 000. The ratio of carboxylic groups to ester groups is about 
1 : 1. It may contain suitable surfactants such as sodium dodecyl 
sulfate or polysorbate 80. An aqueous 30% w/v dispersion of 
this material is also defined in a separate monograph. 
Methacrylic acid–methyl methacrylate copolymer (1 : 1) is 
described in the PhEur 2005 as a copolymer of methacrylic 
acid and methyl methacrylate having a mean relative molecular 
mass of about 135 000. The ratio of carboxylic acid to ester 
groups is about 1 : 1. A further monograph in the PhEur 2005 
describes methacrylic acid–methyl methacrylate copolymer 
(1 : 2), where the ratio of carboxylic acid to ester groups is 
about 1 : 2. The PhEur 2005 describes basic butylated 
methyacrylate copolymer as a copolymer of (2-dimethylaminoethyl) 
methacrylate, butyl methyacrylate, and methyl methacrylate 
having a mean relative molecular mass of about 
150 000. The ratio of (2-dimethylaminoethyl) methacrylate 
groups to butyl methyacrylate and methyl methacrylate groups 
is about 2 : 1 : 1. Polyacrylate dispersion (30 per cent) is 
described in the PhEur 2005 as a dispersion in water of a 
copolymer of ethyl acrylate and methyl methacrylate having a 
mean relative molecular mass of about 800 000. It may contain 
a suitable emulsifier. 
The USPNF 23 describes methacrylic acid copolymer as a 
fully polymerized copolymer of methacrylic acid and an acrylic 
or methacrylic ester. Three types of copolymers, namely Type A, 
Type B, and Type C, are defined in the monograph. They vary in 
their methacrylic acid content and solution viscosity. Type C 
may contain suitable surface-active agents. Two additional 
polymers, Type A (Eudragit RL) and Type B (Eudragit RS), also 
referred to as ammonio methacrylate copolymers, consisting of 
fully polymerized copolymers of acrylic and methacrylic acid 
esters with a low content of quaternary ammonium groups, are 
also described in the USPNF 23. A further monograph for an 
aqueous dispersion of Type C methacrylic acid copolymer is 
also defined; see Section 9. 
Typically, the molecular weight of the polymer is5100 000. 
5 Structural Formula 
For Eudragit E: 
R1, R3 = CH3 
R2 = CH2CH2N(CH3)2 
R4 = CH3, C4H9 
For Eudragit L and Eudragit S: 
R1, R3 = CH3 
R2 = H 
R4 = CH3 
For Eudragit FS: 
R1 = H 
R2 = H, CH3 
R3 = CH3 
R 4 = CH3 
For Eudragit RL and Eudragit RS: 
R1 = H, CH3 
R2 = CH3, C2H5 
R3 = CH3 
R4 = CH2CH2N(CH3)3.Cl 
For Eudragit NE 30 D and Eudragit NE 40 D: 
R1, R3 = H, CH3 
R2, R4 = CH3, C2H5 
For Acryl-EZE and Acryl-EZE MP; Eudragit L 30 D-55 
and Eudragit L 100-55, Eastacryl 30D, Kollicoat MAE 30 
D and Kollicoat MAE 30 DP: 
R1, R3 = H, CH3 
R2 = H 
R4 = CH3, C2H5

6 Functional Category 
Film former; tablet binder; tablet diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Polymethacrylates are primarily used in oral capsule and tablet 
formulations as film-coating agents.(1–17) Depending on the 
type of polymer used, films of different solubility characteristics 
can be produced; see Table II. 
Eudragit E is used as a plain or insulating film former; it is 
soluble in gastric fluid below pH 5. In contrast, Eudragit L, S 
and FS types are used as enteric coating agents because they are 
resistant to gastric fluid. Different types are available that are 
soluble at different pH values: e.g. Eudragit L is soluble at pH 
> 6; Eudragit S and FS are soluble at pH > 7. 
Eudragit RL, RS, RD 100, NE 30 D and NE 40 D are used 
to form water-insoluble film coats for sustained-release 
products. Eudragit RL films are more permeable than those 
of Eudragit RS, and films of varying permeability can be 
obtained by mixing the two types together. 
Eudragit L 30 D-55 is used as an enteric coating film former 
for solid-dosage forms. The coating is resistant to gastric juice 
but dissolves readily at above pH 5.5. 
Eudragit L 100-55 is an alternative to Eudragit L 30 D-55. 
It is commercially available as a redispersible powder. 
Acryl-EZE and Acryl-EZE MP are also commercially 
available as redispersible powder forms, which are designed 
for enteric coating of tablets and beads, respectively. 
Eastacryl 30 D, Kollicoat MAE 30 D, and Kollicoat MAE 
30 DP, are aqueous dispersions of methacrylic acid–ethyl 
acrylate copolymers. They are also used as enteric coatings for 
solid-dosage forms. 
Polymethacrylates are also used as binders in both aqueous 
and organic wet-granulation processes. Larger quantities 
(5–20%) of dry polymer are used to control the release of an 
active substance from a tablet matrix. Solid polymers may be 
used in direct-compression processes in quantities of 10–50%. 
Polymethacrylate polymers may additionally be used to 
form the matrix layers of transdermal delivery systems and 
have also been used to prepare novel gel formulations for rectal 
administration.(18) 
See also Section 18. 
8 Description 
Polymethacrylates are synthetic cationic and anionic polymers 
of dimethylaminoethyl methacrylates, methacrylic acid, and 
methacrylic acid esters in varying ratios. Several different types 
are commercially available and may be obtained as the dry 
powder, as an aqueous dispersion, or as an organic solution. A 
(60 : 40) mixture of acetone and propan-2-ol is most commonly 
used as the organic solvent. See Tables I and III. 
Eudragit E is cationic polymer based on dimethylaminoethyl 
methacrylate and other neutral methacrylic acid esters. It 
Table I: Chemical name and CAS Registry Number of polymethacrylates. 
Chemical name Trade name Company name CAS number 
Poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl 
methacrylate) 1 : 2 : 1 
Eudragit E 100 Ro.hm GmbH [24938-16-7] 
Eudragit E 12.5 Ro.hm GmbH 
Eudragit E PO Ro.hm GmbH 
Poly(ethyl acrylate, methyl methacrylate) 2 : 1 Eudragit NE 30 D Ro.hm GmbH [9010-88-2] 
Eudragit NE 40 D Ro.hm GmbH 
Poly(methacrylic acid, methyl methacrylate) 1 : 1 Eudragit L 100 Ro.hm GmbH [25806-15-1] 
Eudragit L 12.5 Ro.hm GmbH 
Eudragit L 12.5 P Ro.hm GmbH 
Poly(methacrylic acid, ethyl acrylate) 1 : 1 Acryl-EZE Colorcon [25212-88-8] 
Acryl-EZE MP Colorcon 
Eudragit L 30 D-55 Ro.hm GmbH 
Eudragit L 100-55 Ro.hm GmbH 
Eastacryl 30D Eastman Chemical 
Kollicoat MAE 30 D BASF Fine Chemicals 
Kollicoat MAE 30 DP BASF Fine Chemicals 
Poly(methacrylic acid, methyl methacrylate) 1 : 2 Eudragit S 100 Ro.hm GmbH [25086-15-1] 
Eudragit S 12.5 Ro.hm GmbH 
Eudragit S 12.5 P Ro.hm GmbH 
Poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7: 3:1 Eudragit FS 30D Ro.hm GmbH [26936-24-3] 
Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl 
methacrylate chloride) 1 : 2 : 0.2 
Eudragit RL 100 Ro.hm GmbH [33434-24-1] 
Eudragit RL PO Ro.hm GmbH 
Eudragit RL 30 D Ro.hm GmbH 
Eudragit RL 12.5 Ro.hm GmbH 
Eudragit RD 100 Ro.hm GmbH 
Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl 
methacrylate chloride) 1 : 2 : 0.1 
Eudragit RS 100 Ro.hm GmbH [33434-24-1] 
Eudragit RS PO Ro.hm GmbH 
Eudragit RS 30 D Ro.hm GmbH 
Eudragit RS 12.5 Ro.hm GmbH 
554 Polymethacrylates

Table II: Summary of properties and uses of commercially available polymethacrylates. 
Type Supply form Polymer dry 
weight content 
Recommended solvents 
or diluents 
Solubility/permeability Applications 
Eudragit (Ro.hm GmbH) 
Eudragit E 12.5 Organic solution 12.5% Acetone, alcohols Soluble in gastric fluid to 
pH 5 
Film coating 
Eudragit E 100 Granules 98% Acetone, alcohols Soluble in gastric fluid to 
pH 5 
Film coating 
Eudragit E PO Powder 98% Acetone, alcohols Soluble in gastric fluid to 
pH 5 
Film coating 
Eudragit L 12.5 P Organic solution 12.5% Acetone, alcohols Soluble in intestinal fluid 
from pH 6 
Enteric coatings 
Eudragit L 12.5 Organic solution 12.5% Acetone, alcohols Soluble in intestinal fluid 
from pH 6 
Enteric coatings 
Eudragit L 100 Powder 95% Acetone, alcohols Soluble in intestinal fluid 
from pH 6 
Enteric coatings 
Eudragit L 100-55 Powder 95% Acetone, alcohols Soluble in intestinal fluid 
from pH 5.5 
Enteric coatings 
Eudragit L 30 D-55 Aqueous dispersion 30% Water Soluble in intestinal fluid 
from pH 5.5 
Enteric coatings 
Eudragit S 12.5 P Organic solution 12.5% Acetone, alcohols Soluble in intestinal fluid 
from pH 7 
Enteric coatings 
Eudragit S 12.5 Organic solution 12.5% Acetone, alcohols Soluble in intestinal fluid 
from pH 7 
Enteric coatings 
Eudragit S 100 Powder 95% Acetone, alcohols Soluble in intestinal fluid 
from pH 7 
Enteric coatings 
Eudragit FS 30D Aqueous dispersion 30% Water Soluble in intestinal fluid 
from pH 7 
Enteric coatings 
Eudragit RL 12.5 Organic solution 12.5% Acetone, alcohols High permeability Sustained release 
Eudragit RL 100 Granules 97% Acetone, alcohols High permeability Sustained release 
Eudragit RD 100 Powder 97% Acetone, alcohols High permeability Rapid disintegrating Film 
Eudragit RL PO Powder 97% Acetone, alcohols High permeability Sustained release 
Eudragit RL 30 D Aqueous dispersion 30% Water High permeability Sustained release 
Eudragit RS 12.5 Organic solution 12.5% Acetone, alcohols Low permeability Sustained release 
Eudragit RS 100 Granules 97% Acetone, alcohols Low permeability Sustained release 
Eudragit RS PO Powder 97% Acetone, alcohols Low permeability Sustained release 
Eudragit RS 30 D Aqueous dispersion 30% Water Low permeability Sustained release 
Eudragit NE 30 D Aqueous dispersion 30% Water Swellable, permeable Sustained release, tablet 
matrix 
Eudragit NE 40 D Aqueous dispersion 40% Water Swellable, permeable Sustained release, tablet 
matrix 
Eastacryl (Eastman 
Chemical) 
Eastacryl 30 D Aqueous dispersion 30% Water Soluble in intestinal fluid 
from pH 5.5 
Enteric coatings 
Kollicoat (BASF Fine 
Chemicals) 
Kollicoat 30 D Aqueous dispersion 30% Water Soluble in intestinal fluid 
from pH 5.5 
Enteric coatings 
Kollicoat 30 DP Aqueous dispersion 30% Water Soluble in intestinal fluid 
from pH 5.5 
Enteric coatings 
Acryl-EZE (Colorcon) 
Acryl-EZE Powder 95% Water Soluble in intestinal fluid 
from pH 5.5 
Enteric coatings 
Acryl-EZE MP Aqueous dispersion 95% Water Soluble in intestinal fluid 
from pH 5.5 
Enteric coatings 
Note: Recommended plasticizers for the above polymers include dibutyl phthalate, polyethylene glycols, triethyl citrate, triacetin, and 1,2-propylene glycol. The recommended concentration of the 
plasticizer is approximately 10–25% plasticizer (based on the dry polymer weight). A plasticizer is not necessary with Eudragit E 12.5, Eudragit E 100 and Eudragit NE 30 D. 
Polymethacrylates 555

is soluble in gastric fluid as well as in weakly acidic buffer 
solutions (up to pH  5). Eudragit E is available as a 12.5% 
ready-to-use solution in propan-2-ol–acetone (60 : 40). It is 
light yellow in color with the characteristic odor of the solvents. 
Solvent-free granules contain 98% dried weight content of 
Eudragit E. Eudragit E PO is a white free-flowing powder with 
at least 95% of dry polymer. 
Eudragit L and S, also referred to as methacrylic acid 
copolymers in the USPNF 23 monograph, are anionic 
copolymerization products of methacrylic acid and methyl 
methacrylate. The ratio of free carboxyl groups to the ester is 
approximately 1 : 1 in Eudragit L (Type A) and approximately 
1 : 2 in Eudragit S (Type B). Both polymers are readily soluble in 
neutral to weakly alkaline conditions (pH 6–7) and form salts 
with alkalis, thus affording film coats that are resistant to 
gastric media but soluble in intestinal fluid. They are available 
as a 12.5% solution in propan-2-ol without plasticizer 
(Eudragit L 12.5 and S 12.5); and as a 12.5% ready-to-use 
solution in propan-2-ol with 1.25% dibutyl phthalate as 
plasticizer (Eudragit L 12.5 P and S 12.5 P). Solutions are 
colorless, with the characteristic odor of the solvent. Eudragit 
L-100 and Eudragit S-100 are white free-flowing powders with 
at least 95% of dry polymers. 
Eudragit FS 30D is the aqueous dispersion of an anionic 
copolymer based on methyl acrylate, methyl methacrylate, and 
methacrylic acid. The ratio of free carboxyl groups to ester 
groups is approximately 1 : 10. It has been designed for the use 
in enteric-coated solid-dosage forms and dissolves in aqueous 
systems at pH >7. 
Eudragit RL and Eudragit RS, also referred to as ammonio 
methacrylate copolymers in the USPNF 23 monograph, are 
copolymers synthesized from acrylic acid and methacrylic acid 
esters, with Eudragit RL (Type A) having 10% of functional 
quaternary ammonium groups and Eudragit RS (Type B) 
having 5% of functional quaternary ammonium groups. The 
ammonium groups are present as salts and give rise to pHindependent 
permeability of the polymers. Both polymers are 
water-insoluble, and films prepared from Eudragit RL are 
freely permeable to water, whereas, films prepared from 
Eudragit RS are only slightly permeable to water. They are 
available as 12.5% ready-to-use solutions in propan-2-ol– 
acetone (60 : 40). Solutions are colorless or slightly yellow in 
color, and may be clear or slightly turbid; they have an odor 
characteristic of the solvents. Solvent-free granules (Eudragit 
RL 100 and Eudragit RS 100) contain 597% of the dried 
weight content of the polymer. 
Table III: Solubility of commercially available polymethacrylates in various solvents. 
Type Solvent 
Acetone and alcohols(a) Dichloromethane Ethyl acetate 1N HCl 1N NaOH Petroleum ether Water 
Eudragit (Ro.hm GmbH) 
Eudragit E 12.5 M M M M — M — 
Eudragit E 100 S S S — — I I 
Eudragit L 12.5 P M M M — M P P 
Eudragit L 12.5 M M M — M P P 
Eudragit L 100-55 S I I — S I I 
Eudragit L 100 S I I — S I I 
Eudragit L 30 D-55(b) M(c) — — M — M — 
Eudragit S 12.5 P M M M — M P P 
Eudragit S 12.5 M M M — M P P 
Eudragit S 100 S I I — S I I 
Eudragit RL 12.5 M M M — — P M 
Eudragit RL 100 S S S — — I I 
Eudragit RL PO S S S — I I I 
Eudragit RL 30 D(b) M(c) M M — I I M 
Eudragit RS 12.5 M M M — — P M 
Eudragit RS 100 S S S — — I I 
Eudragit RS PO S S S — I I I 
Eudragit RS 30 D(b) M(c) M M — I I M 
Eastacryl (Eastman 
Chemical Company) 
Eastacryl 30D(b) M(c) — — — M — M 
Kollicoat (BASF Fine Chemicals) 
Kollicoat MAE 30 D(b) M(c) — — — M — M 
Kollicoat MAE 30 DP(b) M(c) — — — M — M 
Acryl-EZE (Colorcon) 
Acryl-EZE S I I — S I I 
Acryl-EZE MP S I I — S I I 
S = soluble; M = miscible; I = insoluble or immiscible; P = precipitates. 
(a) Alcohols including ethanol (95%), methanol, and propan-2-ol. 
(b) Supplied as a milky-white aqueous dispersion. 
(c)A 1 : 5 mixture forms a clear, viscous, solution. 
1 part of Eudragit RL 30 D or of Eudragit RS 30 D dissolves completely in 5 parts acetone, ethanol (95%), or propan-2-ol to form a clear or slightly turbid solution. However, when mixed in a ratio of 1 : 5 
with methanol, Eudragit RL 30 D dissolves completely, whereas Eudragit RS 30 D dissolves only partially. 
556 Polymethacrylates

Eudragit RL PO and Eudragit RS PO are fine, white 
powders with a slight amine-like odor. They are characteristically 
the same polymers as Eudragit RL and RS. They 
contain 597% of dry polymer. 
Eudragit RL 30 D and Eudragit RS 30 D are aqueous 
dispersions of copolymers of acrylic acid and methacrylic acid 
esters with a low content of quaternary ammonium groups. The 
dispersions contain 30% polymer. The quaternary groups 
occur as salts and are responsible for the permeability of films 
made from these polymers. Films prepared from Eudragit RL 
30 D are readily permeable to water and to dissolved active 
substances, whereas films prepared from Eudragit RS 30 D are 
less permeable to water. Film coatings prepared from both 
polymers give pH-independent release of active substance. 
Plasticizers are usually added to improve film properties. 
Eudragit RD100 is in the powder form, which can be redispersed 
in water and used as rapid disintegrating films. The 
composition for Eudragit RD100 is Eudragit RL100 and 
carboxymethylcellulose sodium (90 : 10). 
Eudragit NE 30 D and Eudragit NE 40 D are aqueous 
dispersions of a neutral copolymer consisting of polymethacrylic 
acid esters. The dispersions are milky-white liquids 
of low viscosity and have a weak aromatic odor. Films prepared 
from the lacquer swell in water, to which they become 
permeable. Thus, films produced are insoluble in water, but 
give pH-independent drug release. 
Eudragit L 30 D-55, is an aqueous dispersion of an anionic 
copolymer based on methacrylic acid and ethyl acrylate. The 
copolymer corresponds to USPNF 23 methacrylic acid copolymer, 
Type C. The ratio of free-carboxyl groups to ester groups 
is 1 : 1. Films prepared from the copolymers dissolve above pH 
5.5, forming salts with alkalis, thus affording coatings that are 
insoluble in gastric media but soluble in the small intestine. 
Eastacryl 30D, Kollicoat MAE 30D, and Kollicoat MAE 30 
DP are also aqueous dispersions of the anionic copolymer 
based on methacrylic acid and ethyl acrylate. The copolymer 
also corresponds to USPNF 23 methacrylic acid copolymer, 
Type C. The ratio of free-carboxyl groups to ester groups is 
1 : 1. Films prepared from the copolymers dissolve above pH 
5.5, forming salts with alkalis, thus affording coatings that are 
insoluble in gastric media, but soluble in the small intestine. 
Eudragit L 100-55 (prepared by spray-drying Eudragit L 30 
D-55) is a white, free-flowing powder that is redispersible in 
water to form a latex that has properties similar to those of 
Eudragit L 30 D-55. 
Acryl-EZE and Acryl-EZE MP are also commercially 
available as redispersible powder forms, which are designed 
for enteric coating of tablets and beads, respectively. 
9 Pharmacopeial Specifications 
Specifications for polymethacrylates from the PhEur 2005 are 
shown in Table IV and those from the USPNF 23 in Table V. 
Table IV: Specifications from PhEur 2005. 
Test PhEur 2005 
Methacrylic 
acid–ethyl 
acrylate copolymer 
(1 : 1)(a) 
Methacrylic 
acid–ethyl 
acrylate 
copolymer 
(1 : 1) 
dispersion 
30%(b) 
Methacrylic 
acid–methyl 
methacrylate 
copolymer 
(1 : 1)(c) 
Methacrylic 
acid–methyl 
methacrylate 
copolymer 
(1 : 2)(d) 
Basic 
butylated 
methacrylate 
copolymer(e) 
Polyacrylate 
dispersion 30%(f) 
Identification . . . . . . 
Characters . . . . . . 
Appearance of a film . . . . . . 
Apparent viscosity 100–200 mPa s 415 mPa s 50–200 mPa s 50–200 mPa s 3–6 mPa s 450 mPa s 
Particulate matter — 41.0% — — — 40.5% 
Limit of monomers — — — — 40.3% 4100 ppm 
Ethyl acrylate and 
methacrylic acid 
40.1% 40.1% — — — — 
Methyl methacrylate and 
methacrylic acid 
— — 40.1% 40.1% — — 
Residue on evaporation — 0.285–0.315 g — — — 0.285–0.315 g 
Loss on drying 45.0% — 45.0% 45.0% 42.0% — 
Heavy metals — — — — 420 ppm 420 ppm 
Sulfated ash 40.4% 40.2% 40.1% 40.1% 40.1% 40.4% 
Microbial contamination — 4103/g — — — 4103/g 
Assay Methacrylic 
acid units 
46.0–50.6% 
Methacrylic 
acid units 
46.0–50.6% 
Methacrylic 
acid units 
46.0–50.6% 
Methacrylic 
acid units 
27.6–30.7% 
Dimethylaminoethyl 
units 
20.8–25.5% 
Residue on 
evaporation 
28.5%–31.5% 
(a) Corresponds to Eudragit L100-55. 
(b) Corresponds to Eudragit L 30D-55. 
(c) Corresponds to Eudragit L. 
(d) Corresponds to Eudragit S. 
(e) Corresponds to Eudragit E. 
(f) Corresponds to Eudragit NE 30D. 
Polymethacrylates 557

10 Typical Properties 
Acid value: 
300–330 for Eudragit L 12.5, L 12.5 P, L 100, L 30 D-55, L 
100-55, Eastacryl 30D, Kollicoat MAE 30 D, and Kollicoat 
MAE 30 DP. 
180–200 for Eudragit S 12.5, S 12.5 P, and S 100. 
Alkali value: 
162–198 for Eudragit E 12.5 and E 100; 
23.9–32.3 for Eudragit RL 12.5, RL 100, and RL PO; 
27.5–31.7 for Eudragit RL 30 D; 
12.1–18.3 for Eudragit RS 12.5, RS 100, and RS PO; 
16.5–22.3 for Eudragit RS 30 D. 
Density (bulk): 0.390 g/cm3 
Density (tapped): 0.424 g/cm3 
Density (true): 
0.811–0.821 g/cm3 for Eudragit E; 
0.83–0.85 g/cm3 for Eudragit L, S 12.5 and 12.5 P; 
1.058–1.068 g/cm3 for Eudragit FS 30D; 
0.831–0.852 g/cm3 for Eudragit L, S 100; 
1.062–1.072 g/cm3 for Eudragit L 30 D-55; 
0.821–0.841 g/cm3 for Eudragit L 100-55; 
0.816–0.836 g/cm3 for Eudragit RL and RS 12.5; 
0.816–0.836 g/cm3 for Eudragit RL and RS PO; 
1.047–1.057 g/cm3 for Eudragit RL and RS 30 D; 
1.037–1.047 g/cm3 for Eudragit NE 30D; 
1.062–1.072 g/cm3 for Eastacryl 30D; 
1.062–1.072 g/cm3 for Kollicoat MAE 30 D and Kollicoat 
MAE 30 DP. 
Refractive index: 
nD
20 = 1.38–1.385 for Eudragit E; 
nD
20 = 1.39–1.395 for Eudragit L and S; 
nD
20 = 1.387–1.392 for Eudragit L 100-55; 
nD
20 = 1.38–1.385 for Eudragit RL and RS. 
Solubility: see Table II. 
Viscosity (dynamic): 
3–12 mPa s for Eudragit E; 
450 mPa s for Eudragit NE 30D; 
50–200 mPa s for Eudragit L and S; 
420 mPa s for Eudragit FS 30D; 
415 mPa s for Eudragit L 30 D-55; 
100–200 mPa s for Eudragit L 100-55; 
415 mPa s for Eudragit RL and RS; 
4200 mPa s for Eudragit RL and RS 30D; 
415 mPa s for Kollicoat MAE 30 D and Kollicoat MAE 30 
DP; 
145 mPa s for Eastacryl 30D. 
11 Stability and Storage Conditions 
Dry powder polymer forms are stable at temperatures less than 
308C. Above this temperature, powders tend to form clumps, 
although this does not affect the quality of the substance and 
the clumps can readily be broken up. Dry powders are stable 
for at least 3 years if stored in a tightly closed container at less 
than 308C. 
Dispersions are sensitive to extreme temperatures and phase 
separation occurs below 08C. Dispersions should therefore be 
stored at temperatures between 5 and 258C and are stable for at 
least 18 months after shipping from the manufacturer’s 
warehouse if stored in a tightly closed container at the above 
conditions. 
12 Incompatibilities 
Incompatibilities occur with certain polymethacrylate dispersions 
depending upon the ionic and physical properties of the 
polymer and solvent. For example, coagulation may be caused 
by soluble electrolytes, pH changes, some organic solvents, and 
extremes of temperature; see Table II. For example, dispersions 
of Eudragit L 30 D, RL 30 D, L 100-55, and RS 30 D are 
incompatible with magnesium stearate. Eastacryl 30D, Kollicoat 
MAE 30 D, and Kollicoat MAE 30 DP are also 
incompatible with magnesium stearate. 
Interactions between polymethacrylates and some drugs can 
occur, although solid polymethacrylates and organic solutions 
are generally more compatible than aqueous dispersions. 
13 Method of Manufacture 
Prepared by the polymerization of acrylic and methacrylic acids 
or their esters, e.g. butyl ester or dimethylaminoethyl ester. 
14 Safety 
Polymethacrylate copolymers are widely used as film-coating 
materials in oral pharmaceutical formulations. They are also 
used in topical formulations and are generally regarded as 
nontoxic and nonirritant materials. 
A daily intake of 2 mg/kg body-weight of Eudragit 
(equivalent to approximately 150mg for an average adult) 
may be regarded as essentially safe in humans. 
See also Section 15. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Additional measures should 
be taken when handling organic solutions of polymethacrylates. 
Eye protection, gloves, and a dust mask or respirator are 
recommended. Polymethacrylates should be handled in wellventilated 
environment and measures should be taken to 
prevent dust formation. 
Acute and chronic adverse effects have been observed in 
workers handling the related substances methyl methacrylate 
and poly(methyl methacrylate) (PMMA).(19,20) In the UK, the 
occupational exposure limit for methyl methacrylate has been 
set at 208 mg/m3 (50 ppm) long-term (8-hour TWA), and 
416 mg/m3 (100 ppm) short-term.(21) 
See also Section 17. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral capsules 
and tablets). Included in nonparenteral medicines licensed in 
the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Methyl methacrylate; poly(methyl methacrylate). 
Methyl methacrylate 
Empirical formula: C5H8O2 
Molecular weight: 100.13 
CAS number: [80-62-6] 
Synonyms: methacrylic acid, methyl ester; methyl 2-methacrylate; 
methyl 2-methylpropenoate; MME. 
Safety:
LD50 (dog, SC): 4.5 g/kg 
LD50 (mouse, IP): 1 g/kg 
LD50 (mouse, oral): 5.2 g/kg 
558 Polymethacrylates

LD50 (mouse, SC): 6.3 g/kg 
LD50 (rat, IP): 1.33 g/kg 
LD50 (rat, SC): 7.5 g/kg 
Comments: methyl methacrylate forms the basis of acrylic bone 
cements used in orthopedic surgery. 
Poly(methyl methacrylate) 
Empirical formula: (C5H8O2)n 
Synonyms: methyl methacrylate polymer; PMMA. 
Comments: poly(methyl methacrylate) has been used as a 
material for intraocular lenses, for denture bases, and as a 
cement for dental prostheses. 
18 Comments 
A number of different polymethacrylates are commercially 
available that have different applications and properties; see 
Table II. 
For spray coating, polymer solutions and dispersions should 
be diluted with suitable solvents. Some products need the 
addition of a plasticizer such as dibutyl sebacate, dibutyl 
phthalate, glyceryl triacetate, or polyethylene glycol. Different 
types of plasticizer may be mixed to optimize the polymer 
properties for special requirements. 
19 Specific References 
1 Lehmann K, Dreher D. The use of aqueous synthetic-polymer 
dispersions for coating pharmaceutical dosage forms. Drugs Made 
Ger 1973; 16: 126, 131, 132, 134, 136. 
2 Lehmann K. Acrylic coatings in controlled release tablet manufacture 
I. Manuf Chem Aerosol News 1973; 44(5): 36–38. 
3 Lehmann K. Acrylic coatings in controlled release tablet manufacture 
II. Manuf Chem Aerosol News 1973; 44(6): 39–41. 
4 Lehmann K. Polymer coating of tablets – a versatile technique. 
Manuf Chem Aerosol News 1974; 45(5): 48, 50. 
5 Gurny R, Guitard P, Buri P, Sucker H. Realization and theoretical 
development of controlled-release drug forms using methacrylate 
films 3: preparation and characterization of controlled-release 
drug forms [in French]. Pharm Acta Helv 1977; 52: 182–187. 
6 Lehmann K, Dreher D. Coating of tablets and small particles with 
acrylic resins by fluid bed technology. Int J Pharm Technol Prod 
Manuf 1981; 2(4): 31–43. 
7 Dew MJ, Hughes PJ, Lee MG, et al. An oral preparation to release 
drugs in the human colon. Br J Clin Pharmacol 1982; 14: 405– 
408. 
8 Lehmann K. Formulation of controlled release tablets with acrylic 
resins. Acta Pharm Fenn 1984; 93: 55–74. 
9 Lehmann K. Acrylic latices from redispersible powders for peroral 
and transdermal drug formulations. Drug Dev Ind Pharm 1986; 
12: 265–287. 
10 Lehmann K, Dreher D. Mixtures of aqueous polymethacrylate 
dispersions for drug coating. Drugs Made Ger 1988; 31: 101–102. 
11 Beckert TE, Lehmann K, Schmidt PC. Compression of enteric 
coated pellets to disintegrating tablets. Int J Pharm 1996; 143: 13– 
23. 
12 Vecchio C, Fabiani F, Gazzaniga A. Use of colloidal silica as a 
separating agent in film forming processes performed with 
aqueous dispersion of acrylic resins. Drug Dev Ind Pharm 1995; 
21(15): 1781–1787. 
13 Okor RS, Obi CE. Drug release through aqueous-based film 
coatings of acrylate-methacrylate, a water-insoluble copolymer. Int 
J Pharm 1990; 58: 89–91. 
14 Caneron CG, McGinity JW. Controlled-release theophylline tablet 
formulations containing acrylic resins, part 3: influence of filler 
excipient. Drug Dev Ind Pharm 1987; 13(2): 303–318. 
Table V: Specifications from USPNF 23 
Test USPNF 23 
Ammonio methacrylate copolymer(a) Methacrylic acid copolymer(b) Methacrylic acid copolymer dispersion(c) 
Identification . . . 
Viscosity 
Type A 415 mPa s 50–200 mPa s — 
Type B 415 mPa s 50–200 mPa s — 
Type C — 100–200 mPa s 415 mPa s 
Loss on drying 
Type A 43.0% 45.0% — 
Type B 43.0% 45.0% — 
Type C — 45.0% 68.5–71.5%(d) 
Residue on ignition 
Type A 40.1% 40.1% — 
Type B 40.1% 40.1% — 
Type C — 40.4% 40.2%(d) 
Heavy metals 40.002% 40.002% 40.002%(d) 
Organic volatile impurities — . — 
Limit of monomers — 40.05% 40.01% 
Limit of methyl methacrylate 40.005% — — 
Limit of ethyl acrylate 40.025% — — 
Coagulum content — — 41%(d) 
Assay (dried basis) Ammonio methacrylate units Methacrylic acid units Methacrylic acid units 
Type A 8.85–11.96% 46.0–50.6% — 
Type B 4.48–6.77% 27.6–30.7% — 
Type C — 46.0–50.6% 46.0–50.6% 
(a) Corresponds to Eudragit RL and RS. 
(b) Corresponds to Eudragit L, S and L100-55. 
(c) Corresponds to Eudragit L 30D-55. 
(d) Calculated based on undried dispersion basis. 
Polymethacrylates 559

15 Jovanovic M, Jovicic G, Duvic Z, et al. Effect of fillers and 
lubricants on acetylsalicylic acid release kinetics from eudragit 
matrix tablets. Drug Dev Ind Pharm 1997; 23(6): 595–602. 
16 Gupta VK, Beckert TE, Price JC. A novel pH- and time-based 
multi-unit potential colonic drug delivery system. I. Development. 
Int J Pharm 2001; 213: 83–91. 
17 Gupta VK, Assmus MW, Beckert TE, Price JC. A novel pH- and 
time-based multi-unit potential colonic drug delivery system. II 
Optimization of multiple response variables. Int J Pharm 2001; 
213: 93–102. 
18 Umejima H, Kim N-S, Ito T, et al. Preparation and evaluation of 
Eudragit gels VI: in vivo evaluation of Eudispert rectal hydrogel 
and Xerogel containing salicylamide. J Pharm Sci 1993; 82: 195– 
199. 
19 Routledge R. Possible hazard of contact lens manufacture [letter]. 
Br Med J 1973; 1: 487–488. 
20 Burchman S, Wheater RH. Hazard of methyl methacrylate to 
operating room personnel. J Am Med Assoc 1976; 235: 2652. 
21 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
McGinity JW. Aqueous Polymeric Coatings for Pharmaceutical Dosage 
Forms, 2nd edn. New York: Marcel Dekker, 1997. 
Ro.hm Pharma GmbH. Eudragit. http://www.roehm.com/en/ 
pharmapolymers (accessed 20 May 2005). 
21 Authors 
RK Chang, Y Peng, AJ Shukla. 
22 Date of Revision 
20 May 2005. 
560 Polymethacrylates

Poly(methyl vinyl ether/maleic anhydride) 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Butyl ester of poly(methylvinyl ether–co-maleic anhydride); 
calcium and sodium salts of poly(methylvinyl ether–co-maleic 
anhydride); Gantrez AN-119; Gantrez AN-139; Gantrez AN- 
149; Gantrez AN-169; Gantrez AN-179; Gantrez AN-903; 
Gantrez ES-225; Gantrez ES-425; Gantrez S-95; Gantrez S-96; 
Gantrez S-97; Gantrez MS-955. 
3 Chemical Name and CAS Registry Number 
See Table I. 
4 Empirical Formula and Molecular Weight 
(C4H2O3C3H6O)x See Table II. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Bioadhesive; color dispersant; complexing agent; emulsion 
stabilizer; film former; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Poly(methylvinyl ether/maleic anhydride) copolymers and 
derivatives are used in denture adhesive bases,(1) controlledrelease 
coatings, enteric coatings, ostomy adhesives,(2) transdermal 
patches,(3) toothpastes,(4) mouthwashes,(5) and transdermal 
gels.(6,7) Gantrez AN-119 has been used to manufacture 
Table II: Molecular weights of selected commercially available 
copolymers of poly(methylvinyl ether/maleic anhydride) 
Grade Approximate molecular weight 
Gantrez AN-119 200 000 
Gantrez AN-903 800 000 
Gantrez AN-139 1 000 000 
Gantrez AN-169 2 000 000 
Gantrez S-96 700 000 
Gantrez S-97 (powder) 1 200 000 
Gantrez S-97 (solution) 1 500 000 
Gantrez MS-995 1 000 000 
Gantrez ES-225 100 000–150 000 
Gantrez ES-425 90 000–150 000 
specific bioadhesive ligand-nanoparticle conjugates(8) to aid 
gastrointestinal retention for oral drug delivery applications. 
More recently Gantrez has been utilized to develop novel 
polyethylene surface-modified medical devices with enhanced 
hydrophilicity and wettability.(9) 
8 Description 
In the solid state, poly(methylvinyl ether/maleic anhydride) 
copolymers are a white to off-white free flowing, odorless, 
hygroscopic powders. In solution, poly(methylvinyl ether/ 
maleic anhydride) is a slightly hazy, odorless, viscous liquid. 
9 Pharmacopeial Specifications 
—
10 Typical Properties 
See Table III. 
Table I: Chemical name and CAS registry number for poly(methylvinyl ether/maleic anhydride) copolymers and derivatives. 
Chemical name Trade name CAS number 
Poly(methylvinyl ether/maleic anhydride) Gantrez AN-119 [9011-16-9] 
Gantrez AN-903 
Gantrez AN-139 
Gantrez AN-149 
Gantrez AN-169 
Gantrez AN-179 
Poly(methylvinyl ether/maleic acid) Gantrez S-95 [25153-40-6] 
Gantrez S-96 
Gantrez S-97 
Monoethyl ester of poly(methylvinyl ether/maleic acid) (48–52%) in 
ethanol (48–52%) 
Gantrez ES-225 50% Alcoholic Solution [25087-06-3] [64-17-5] 
Mixture of monoethyl ester of poly(methylvinyl ether/maleic acid) and 
monobutyl ester of poly(methylvinyl ether/maleic acid) (48–52%) in 
ethanol (43–47%) and n-butyl alcohol (5%) 
Gantrez ES-425 50% Alcoholic Solution [25087-06-3] [25119-68-0] 
[64-17-5] 
[200-751-6] 
Mixed sodium/calcium salts of poly(methylvinyl ether/maleic anhydride) Gantrez MS-955 [62386-95-2]

11 Stability and Storage Conditions 
Poly(methylvinyl ether/maleic anhydride) and related free acids 
are hygroscopic powders and therefore excessive exposure to 
moisture should be avoided. Aqueous solutions exhibit 
decreases in viscosity upon exposure to UV light. Poly(methylvinyl 
ether/maleic anhydride) should be stored in a cool, dry 
place out of direct sunlight. 
12 Incompatibilities 
Poly(methylvinyl ether/maleic anhydride) and copolymers are 
incompatible with strong oxidizing agents and reducing agents, 
concentrated nitric acid, sulfuric acid, nitrofoam, oleum, 
potassium t-butoxide, aluminum, aluminum triisopropoxide, 
and crotonaldehyde. In addition, the anhydride will hydrolyze 
in water to form a water-soluble free acid that can subsequently 
be ionized to form salts in the presence of cations (Na., Zn2., 
Ca2., and Al3.). Excessive addition of bivalent and trivalent 
metal ions to aqueous solution will result in precipitation, 
particularly in solutions containing high polymer concentrations. 
13 Method of Manufacture 
Poly(methylvinyl ether/maleic anhydride) and copolymers are 
manufactured from methylvinyl ether and maleic anhydride. 
The S, ES, and MS grades of Gantrez are manufactured by 
dispersing AN copolymers in a number of different solvents or 
salt solutions.(10) 
14 Safety 
Poly(methylvinyl ether/maleic anhydride) and copolymers are 
widely used in a diverse range of topical and oral pharmaceutical 
formulations.(11) These copolymers are generally regarded 
as nontoxic and nonirritant. Moreover, the dry powders and 
aqueous solutions are nonirritating with the exception of ES, 
MS, and A grades, which are irritating to the eye and may cause 
tissue damage. 
LD50 (rat, oral): 8 g/kg (Gantrez AN-130 Powder)(10) 
LD50 (rat, oral): 40 ml/kg (Gantrez AN-139 20% w/w 
aqueous solution) 
LD50 (rat, oral): <25.6 g/kg (Gantrez ES-225) 
LD50 (rat, oral): 25.6 g/kg (Gantrez ES-425 40% w/v 
corn oil solution) 
LD50 (rat, oral): 25.6 g/kg (Gantrez MS-955 20% 
aqueous solution) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Excessive dust generation 
should be avoided when using powders, and an appropriate 
ventilation area and dust mask are recommended. Hand and 
eye protection is also recommended. The A, ES, and MS 
copolymers are extremely irritating to the eyes and a NIOSHapproved 
respirator and suitable eye protection are recommended 
when using Gantrez ES-435, Gantrez ES-225, and 
Gantrez A-425. 
16 Regulatory Status 
GRAS listed. Included in nonparenteral medicines licensed in 
the UK. 
17 Related Substances 
—
18 Comments 
—
19 Specific References 
1 Shay K. The retention of complete dentures. In: Zarb GA, Bolender 
CL, Carlsson GE, Boucher CO, eds. Boucher’s Prosthodontic 
Table III: Typical physical properties of selected commercially available copolymers of poly(methylvinyl ether/maleic anhydride) 
Grade Specific viscosity 
(1% in MEK) 
Tg (8C) Specific 
gravity (258C, 
5% solids) 
Bulk 
density 
(g/cm3) 
Polydispersity 
(Mn/Mw) 
Moisture 
content 
(% w/w) 
Viscosity (mPa s) 
of 5% w/w 
solution at 258C 
Dissociation 
constant 
Gantrez AN copolymers 
AN-119 0.1–0.5 152 1.018 0.34 2.74 <1 15 — 
AN-903 0.8–1.2 156 1.017 0.33 — — 30 — 
AN-139 1.0–1.5 151 1.016 0.33 3.47 <1 40 — 
AN-149 1.5–2.5 153 1.017 0.35 2.58 <1 45 — 
AN-169 2.5–3.5 154 1.017 0.32 2.06 <1 85 — 
AN-179 3.5–5.0 154 1.017 0.33 2.12 <1 135 — 
Gantrez S copolymers 
S-95 1.0–2.0 139 1.015 — 2.71 417 20 3.51–6.41 
S-96 Solution 4.0 — — — — 86–88 150 3.51–6.41 
S-97 4.0–10.0 143 1.015 — 2.06 46 70 3.47–6.47 
S-97 Solution 4.0–10.0 — — — — 86–88 1000 3.50–6.50 
Gantrez ES and MS copolymers 
ES-225 0.36–0.45 102 0.983 — 2.5–3.0 40.5 18,800 5.33 
ES-425 0.37–0.45 96 0.977 — 2.5–3.4 40.5 14,400 5.28 
MS-955 — — 1.061(a) — 2.3 415 700–3000(b) — 
(a)13% solids at 308C. 
(b) Viscosity of 11.1% solids aqueous solution. 
562 Poly(methyl vinyl ether/maleic anhydride)

Treatment for Edentulous Patients. Toronto, Ontario: Mosby, 
1997: 400–411. 
2 Scalf BS, Fowler JF. Peristomal allergic contact dermatitis due to 
Gantrez in stomadhesive paste. J Am Acad Dermatol 2000; 42: 
355–356. 
3 Woolfson AD, McCafferty DF, Moss GP. Development and 
characterization of a moisture-activated bioadhesive drug delivery 
system for percutaneous local anesthesia. Int J Pharm 1998; 169: 
83–94. 
4 Busscher HJ, White DJ, Kamminga-Rasker HJ, Van der Mei HC. A 
surface physicochemical rationale for calculus formation in the 
oral cavity. J Cryst Growth 2004; 261: 87–92. 
5 Kockisch S, Rees GD, Young SA, et al. A direct-staining method to 
evaluate the mucoadhesion of polymers from aqueous dispersion. J 
Control Release 2001; 77: 1–6. 
6 Jones DS, Lawlor MS, Woolfson AD. Examination of the flow 
rheological and textural properties of polymer gels composed of 
poly(methylvinylether–co-maleic anhydride) and poly(vinylpyrrolidone): 
rheological and mathematical interpretation of textural 
parameters. J Pharm Sci 2002; 91(9): 2090–2101. 
7 Jones DS, Lawlor MS, Woolson AD. Rheological and mucoadhesive 
characterization of polymeric systems composed of poly(- 
methylvinylether–co-maleic anhydride) and 
poly(vinylpyrrolidone) designed as platforms for topical drug 
delivery. J Pharm Sci 2003; 92(5): 995–1007. 
8 Arbos P, Wirth M, Arangoa MA, et al. Gantrez1 AN as a new 
polymer for the preparation of ligand-nanoparticle conjugates. J 
Control Release 2002; 83: 321–330. 
9 Kuzuya M, Sawa T, Mouri M, et al. Plasma technique for the 
fabrication of a durable functional surface on organic polymers. 
Surf Coat Tech 2003; 169: 587–591. 
10 ISP. Technical literature: Gantrez1 Copolymers, 2003. 
11 Sharma NC, Galaustians HJ, Qaquish J, et al. The clinical 
effectiveness of a dentrifice containing triclosan and a copolymer 
for controlling breath odor measured organoleptically twelve 
hours after toothbrushing. J Clin Dent 1999; 10: 131–134. 
20 General References 
—
21 Authors 
GP Andrews, DS Jones. 
22 Date of Revision 
26 August 2005. 
Poly(methyl vinyl ether/maleic anhydride) 563

Polyoxyethylene Alkyl Ethers 
1 Nonproprietary Names 
The polyoxyethylene alkyl ethers are a series of polyoxyethylene 
glycol ethers of n-alcohols (lauryl, oleyl, myristyl, cetyl, 
and stearyl alcohol). Of the large number of different materials 
commercially available, four types are listed in the USPNF 23, 
one type in the JP 2001, and four types in the PhEur 2005. 
BP: Macrogol cetostearyl ether 
Macrogol lauryl ether 
Macrogol oleyl ether 
Macrogol stearyl ether 
JP: Lauromacrogol 
PhEur: Macrogoli aether cetostearylicus 
Macrogoli aether laurilicum 
Macrogoli aether oleicum 
Macrogoli aether stearylicus 
USPNF: Polyoxyl 20 cetostearyl ether 
Polyoxyl 10 oleyl ether 
Polyoxyl lauryl ether 
Polyoxyl stearyl ether 
Polyoxyethylene alkyl ethers are employed extensively in 
cosmetics, where the CTFA names laureth-N, myreth-N, 
ceteth-N, and steareth-N are commonly used. In this nomenclature, 
N is the number of ethylene oxide groups, e.g. steareth- 
20.
See also Sections 2–5. 
2 Synonyms 
Polyoxyethylene alkyl ethers are nonionic surfactants produced 
by the polyethoxylation of linear fatty alcohols. Products tend 
to be mixtures of polymers of slightly varying molecular 
weights and the numbers used to describe polymer lengths are 
average values. 
Two systems of nomenclature are used to describe these 
materials. The number ‘10’ in the name Texofor A10 refers to 
the approximate polymer length in oxyethylene units (i.e. y, see 
Section 5). The number ‘1000’ in the name ‘cetomacrogol 
1000’ refers to the average molecular weight of the polymer 
chain. 
Synonyms applicable to polyoxyethylene alkyl ethers are 
shown below. 
Brij; Cremophor A; Cyclogol 1000; Empilan KB; Empilan 
KM; Emulgen; Ethylan C; macrogol ethers; Marlowet; 
Plurafac; Procol; Ritoleth; Ritox; Texofor A; Volpo. 
Table I shows synonyms for specific materials. 
3 Chemical Name and CAS Registry Number 
Polyethylene glycol monocetyl ether [9004-95-9] 
Polyethylene glycol monolauryl ether [9002-92-0] 
Polyethylene glycol monooleyl ether [9004-98-2] 
Polyethylene glycol monostearyl ether [9005-00-9] 
4 Empirical Formula and Molecular Weight 
See Sections 1, 2, and 5. 
5 Structural Formula 
CH3(CH2)x(OCH2CH2)yOH 
In the formula, (x . 1) is the number of carbon atoms in the 
alkyl chain, typically: 
12 lauryl (dodecyl) 
14 myristyl (tetradecyl) 
16 cetyl (hexadecyl) 
18 stearyl (octadecyl) 
and y is the number of ethylene oxide groups in the hydrophilic 
chain, typically 10–60. 
The polyoxyethylene alkyl ethers tend to be mixtures of 
polymers of slightly varying molecular weights, and the 
Table I: Synonyms of selected polyoxyethylene alkyl ethers. 
Name Synonym 
Cetomacrogol 1000 Polyethylene glycol 1000; macrocetyl ether; polyoxyethylene glycol 1000 monocetyl ether; Cresmer 1000. 
Polyoxyl 6 cetostearyl ether Ceteareth 6; Cremophor A6; Volpo CS6. 
Polyoxyl 20 cetostearyl ether Atlas G-3713; Ceteareth 20; Cremophor A 20 polyether; Volpo CS20. 
Polyoxyl 25 cetostearyl ether Ceteareth 25; Cremophor A25; Volpo CS25. 
Polyoxyl 2 cetyl ether Brij 52; ceteth-2; Lipocol C-2; Procol CA-2. 
Polyoxyl 10 cetyl ether Brij 56; ceteth-10; Lipocol C-10; Procol CA-10. 
Polyoxyl 20 cetyl ether Brij 58; ceteth-20; Lipocol C-20; Volpo C20. 
Polyoxyl 4 lauryl ether Brij 30; laureth-4; Lipocol L-4; Procol LA-4; Tego Alkanol L4; Volpo L4. 
Polyoxyl 9 lauryl ether Laureth-9; lauromacrogol 400; polidocanol; Volpo L9. 
Polyoxyl 23 lauryl ether Brij 35; laureth-23; Lipocol L-23; Procol LA-23; Ritox 35; Tego Alkanol L23 P. 
Polyoxyl 2 oleyl ether Brij 92; Brij 93; oleth-2; Lipocol O-2; Procol 0A-2; Ritoleth 2;Volpo N2. 
Polyoxyl 10 oleyl ether Brij 96; Brij 97; oleth-10; polyethylene glycol monooleyl ether; Lipocol O-10; Procol OA-10; Ritoleth 10; Volpo N 10. 
Polyoxyl 20 oleyl ether Brij 98; Brij 99; Lipocol O-20; oleth-20; Procol OA-20; Ritoleth 20; Volpo N 20. 
Polyoxyl 2 stearyl ether Brij 72; Lipocol S-2; Procol SA-2; steareth-2; Tego Alkanol S2; Volpo S-2. 
Polyoxyl 10 stearyl ether Brij 76; Lipocol S-10; Procol SA-10; steareth-10; Tego Alkanol S10; Volpo S-10. 
Polyoxyl 21 stearyl ether Brij 721; Ritox 721; steareth-21. 
Polyoxyl 100 stearyl ether Brij 700; steareth-100.

numbers quoted are average values. In cetomacrogol 1000, for 
example, x is 15 or 17, and y is 20–24. 
6 Functional Category 
Emulsifying agent; penetration enhancer; solubilizing agent; 
wetting agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Polyoxyethylene alkyl ethers are nonionic surfactants widely 
used in topical pharmaceutical formulations and cosmetics, 
primarily as emulsifying agents for water-in-oil and oil-in-water 
emulsions; and the stabilization of microemulsions and multiple 
emulsions. 
Polyoxyethylene alkyl ethers are used as solubilizing agents 
for essential oils, perfumery chemicals, vitamin oils, and 
drugs of low-water solubility such as cortisone acetate, 
griseofulvin, menadione,(1) chlordiazepoxide(2) and cholesterol.(
3) They have applications as antidusting agents for 
powders; wetting and dispersing agents for coarse-particle 
liquid dispersions; and detergents, especially in shampoos, face 
washes and similar cosmetic cleaning preparations. They are 
used as gelling and foaming agents (e.g. Brij 72 gives a quickbreaking 
foam, while Brij 97 (15–20%), Volpo N series and 
Cremophor A25 (21–30%) give clear gels). 
Polyoxyethylene alkyl ethers have been used in formulation 
of oleosomes, hydrosomes, phosphosomes, vesicles(4) and 
niosomes.(5,6) An increased flux of estradiol niosomes through 
human stratum corneum in vitro has been demonstrated.(7) 
Polyoxyethylene alkyl ethers have been found to have an 
enhancing effect on the skin permeation of drugs such as 
ibuprofen,(8) methyl nicotinate,(9) and clotrimazole.(10) 
Enhanced ocular absorption of insulin from eye drops,(11) 
and an ocular insert device,(12) have been observed using 
polyoxyethylene alkyl ethers in the formulation systems. 
Increased buccal absorption of verapamil through porcine 
esophageal mucosa has also been reported.(13) 
Polyoxyethylene alkyl ethers have also been used in 
suppository formulations to increase the drug release from 
the suppository bases.(14–16) 
Polyoxyethylene alkyl ethers (especially laureth-23) have 
been used as a solubilizer and coating agent to provide 
hydrophilicity to polymeric nanoparticles.(17–19) 
Polyoxyethylene alkyl ethers such as polidocanol are 
suitable for use in injectable formulations as a solubilizer or 
dispersant.(20) 
8 Description 
Polyoxyethylene alkyl ethers vary considerably in their physical 
appearance from liquids, to pastes, to solid waxy substances. 
They are colorless, white, cream-colored or pale yellow 
materials with a slight odor. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for polyoxyethylene alkyl ethers. 
Test JP 2001 PhEur 2005 PhEur 2005 PhEur 2005 PhEur 2005 USPNF 23 USPNF 23 USPNF 23 USPNF 23 
Lauromacrogol 
Macrogol 
cetostearyl 
ether 
Macrogol 
stearyl 
ether 
Macrogol 
lauryl ether 
Macrogol 
oleyl ether 
Polyoxyl 20 
cetostearyl 
ether 
Polyoxyl 10 
oleyl ether 
Polyoxyl 
lauryl ether 
Polyoxyl 
stearyl 
ether 
Appearance of 
solution 
— . . . . — — . . 
Identification . . . . . . . . . 
Characters . . . . . — — — — 
Water — 43.0% 43.0% 43.0% 43.0% 41.0% 43.0% 43.0% 43.0% 
pH (10% solution) — — — — — 4.5–7.5 — — — 
Alkalinity — . . . . — — . . 
Acidity . — — — — — — — — 
Residue on 
ignition 
40.20% — — — — 40.4% 40.4% — — 
Heavy metals — — — — — 40.002% 40.002% — — 
Acid value — 41.0 41.0 41.0 41.0 40.5 41.0 41.0 41.0 
Hydroxyl value — . . . . 42–60 75–95 . . 
Iodine value — 42.0 42.0 42.0 . — 23–40 42.0 42.0 
Saponification 
value 
— 43.0 43.0 43.0 43.0 42.0 43.0 43.0 43.0 
Free polyethylene 
glycols 
— — — — — 47.5% 47.5% — — 
Free ethylene 
oxide 
— 41 ppm 41 ppm 41 ppm 41 ppm 40.01% 40.01% 41 mg/g 41 mg/g 
Dioxan — 410 ppm 410 ppm 410 ppm 410 ppm — — 410 mg/g 410 mg/g 
Peroxide value — — — — 410.0 — — — — 
Average polymer 
length 
— — — — — 17.2–25.0 8.6–10.4 3.0–23.0 2.0–20.0 
Organic volatile 
impurities 
— — — — — . . — — 
Total ash — 40.2% — 40.2% 40.2% — — 40.2% — 
Polyoxyethylene Alkyl Ethers 565

10 Typical Properties 
See Tables III and IV. 
11 Stability and Storage Conditions 
Polyoxyethylene alkyl ethers are chemically stable in strongly 
acidic or alkaline conditions. The presence of strong electrolytes 
may, however, adversely affect the physical stability of 
emulsions containing polyoxyethylene alkyl ethers. 
On storage, polyoxyethylene alkyl ethers can undergo 
autoxidation, resulting in the formation of peroxides with an 
increase in acidity. Many commercially available grades are 
thus supplied with added antioxidants. Typically, a mixture of 
0.01% butylated hydroxyanisole and 0.005% citric acid is used 
for this purpose. 
Polyoxyethylene alkyl ethers should be stored in an airtight 
container, in a cool, dry place. 
12 Incompatibilities 
Discoloration or precipitation may occur with iodides, mercury 
salts, phenolic substances, salicylates, sulfonamides, and 
tannins. Polyoxyethylene alkyl ethers are also incompatible 
with benzocaine, tretinoin(21) and oxidizable drugs.(22) 
The antimicrobial efficacy of some phenolic preservatives, 
such as the parabens, is reduced owing to hydrogen bonding. 
Cloud points are similarly depressed by phenols owing to 
hydrogen bonding between ether oxygen atoms and phenolic 
hydroxyl groups. Salts, other than nitrates, iodides, and 
thiocyanates (which cause an increase) can also depress cloud 
points.(23) 
13 Method of Manufacture 
Polyoxyethylene alkyl ethers are prepared by the condensation 
of linear fatty alcohols with ethylene oxide. The reaction is 
controlled so that the required ether is formed with the 
polyethylene glycol of the desired molecular weight. 
14 Safety 
Polyoxyethylene alkyl ethers are used as nonionic surfactants in 
a variety of topical pharmaceutical formulations and cosmetics. 
The polyoxyethylene alkyl ethers form a series of materials with 
varying physical properties and manufacturers’ literature 
should be consulted for information on the applications and 
safety of specific materials. 
Although generally regarded as essentially nontoxic and 
nonirritant materials, some polyoxyethylene alkyl ethers, 
particularly when used in high concentration (>20%), appear 
to have a greater irritant potential than others. 
Animal toxicity studies suggest that polyoxyethylene alkyl 
ethers have a similar oral toxicity to other surfactants and can 
be regarded as being moderately toxic. 
Polyoxyethylene cetyl ether:(24) 
LD50 (mouse, oral): 2.60 g/kg 
LD50 (rabbit, skin): 40 g/kg/4 week intermittent 
LD50 (rat, oral): 2.50 g/kg 
Polyoxyethylene lauryl ether:(24) 
LD50 (mouse, IP): 0.16 g/kg 
LD50 (mouse, IV): 0.10 g/kg 
LD50 (mouse, oral): 4.94 g/kg 
LD50 (mouse, SC): 0.79 g/kg 
LD50 (rat, IV): 0.027 g/kg 
LD50 (rat, oral): 8.60 g/kg 
LD50 (rat, SC): 0.95 g/kg 
Polyoxyethylene oleyl ether:(24) 
LD50 (rat, oral): 25.8 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. 
16 Regulatory Status 
Included in nonparenteral medicines licensed in the USA and 
UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Nonionic emulsifying wax. 
18 Comments 
Many other polyoxyethylene ethers are commercially available 
and are also used as surfactants. In addition to their surfactant 
properties, the series of polyoxyethylene ethers with lauryl side 
chains, e.g. nonoxynol 10, are also widely used as spermicides. 
19 Specific References 
1 Elworthy PH, Patel MS. Demonstration of maximum solubilization 
in a polyoxyethylene alkyl ether series of non-ionic 
surfactants. J Pharm Pharmacol 1982; 34: 543–546. 
2 Abdel Rahman AA, Aboutaleb AE, Samy EM. Factors affecting 
chlordiazepoxide solubilization by non-ionic surfactants. Bull 
Pharm Sci 1991; 14(1–2): 35–45. 
3 Mueller-Goymann CC, Usselmann B. Solubilization of cholesterol 
in liquid crystals of aqueous systems of polyoxyethylene cetyl 
ethers. Acta Pharm Jugosl 1988; 38(4): 327–329. 
4 Friberg SE, Yang H, Fei L, Sadasivan S, et al. Preparation of 
vesicles from hydrotope solutions. J Dispersion Sci Technol 1998; 
19(1): 19–30. 
5 Arunothayanun P, Uchegbu IF, Craig DQ, et al. In vitro/in vivo 
characterization of polyhedral niosomes. Int J Pharm. 1999; 
183(1): 57–61. 
6 Parthasarathi G, Udupa N, Pillai GK. Formulations and in vitro 
evaluation of vincristine encapsulated niosomes. Int J Pharm 1994; 
56(3): 90–94. 
7 Van Hal D, Van Rensen A, De Vringer T, et al. Diffusion of 
estradiol from non-ionic surfactant vesicles through human 
stratum corneum in vitro. STP Pharm Sci 1996; 6(1): 72–78. 
8 Park ES, Chang SY, Hahn M, Chi SC. Enhancing effect of 
polyoxyethylene alkyl ethers on the skin permeation of ibuprofen. 
Int J Pharm 2001; 218(1–2): 167–168. 
9 Ashton P, Walters KA, Brain KR, Hadgraft J. Surfactant effects in 
percutaneous absorption. Part 1. Effects on the transdermal flux of 
methyl nicotinate. Int J Pharm 1992; 87(10): 261–264. 
10 Ibrahim SA, Hafez E, El-Shanawany SM, et al. Formulation and 
evaluation of some topical anti mycotics. Part 3. Effect of 
promoters on the in vitro and in vivo efficacy of clotrimazole 
ointment. Bull Pharm Sci 1991; 14(1–2): 82–94. 
11 Zhang WY, Zhang LH. Study of absorption enhancers of insulin 
eye drops. J China Pharm Univ 1997; 28(5): 275–277. 
566 Polyoxyethylene Alkyl Ethers

Table III: Typical properties of selected commercially available grades of polyoxyethylene alkyl ethers. 
Name Physical form Acid 
value 
HLB 
value 
Hydroxyl 
value 
Iodine 
number 
Saponification 
value 
Density (g/cm3) 
at 208C unless 
otherwise stated 
Water 
content 
(%) 
Boiling 
point 
(8C) 
Melting point 
or pour point 
(8C) 
Cloud point 
(8C) for 
1% aqueous 
solution 
pH 
aqueous 
solution 
Brij 30 Colorless to pale 
yellow liquid 
42 9.7 145–165 — — 0.95 at 258C 41.0 >100 2 — — 
Brij 35 White waxy solid 45 16.9 40–60 — — 1.05 at 258C 43.0 >100 33 — — 
Brij 52 White waxy solid 41 5.3 160–180 — — 0.95 41.0 — 33 — 5–8 (10% in 1 : 1 
IPA: water) 
Brij 56 White waxy solid 41 12.9 75–90 — — 1.06 at 258C 43.0 — 31 — — 
Brij 58 White solid 41 15.7 45–60 — — 1.02 at 258C 43.0 — 38 — — 
Brij 72 White waxy solid 41 4.9 150–170 — — 0.97 at 258C 41.0 — 43 — — 
Brij 76 White waxy solid 41 12.4 75–90 — — 1.05 at 258C 43.0 >100 38 — 5–8 (10% in 1 : 1 
IPA: water) 
Brij 78 White solid pellets 41 15.3 45–60 — — 1.09 at 258C 43.0 — 38 — 5–8 (10% in 1 : 4 
IPA: water) 
Brij 721 White to ivory solid 
pellets or flakes 
<2 15.5 44–61 — — 1.0 at 258C 42.0 — 45 — — 
Brij 93Veg Pale yellow liquid 41 4.9 160–180 — — 0.9 at 258C 41.0 >100 10 — 5–8 (10% in 1 : 1 
IPA: water) 
Brij 97 White to pale yellow 
liquid to semi-solid 
41 12.4 80–95 — — 1.0 at 258C 43.0 >100 16 >100 >100 
Brij 98 Cream soft waxy solid 41 15.3 50–65 — — 1.07 at 258C 43.0 >100 33 — 5–8 (10% in 1 : 4 
IPA: water) 
Cremophor A6 White waxy 
substance 
41 10–12 115–134 41 43 0.896–0.906 
at 608C 
41.0 — 41–45 — — 
Cremophor A 20 
polyether 
White flakes — — — — — 0.98% at 708C — >149 56 — — 
Cremophor A25 White to off-white 
micro beads 
41 15–17 36–45 41 43 1.020–1.028 
at 608C 
41.0 — 44–48 — 5–7 (10%) 
Emulgen 104P Clear liquid — 9.6 — — — — — — — — — 
Emulgen 123P White solid — 16.9 — — — — — — — >100 — 
Emulgen 210P Light yellow solid — 10.7 — — — — — — — — — 
Emulgen 220 Light yellow solid — 14.2 — — — — — — — 98 — 
Emulgen 320P White solid — 13.9 — — — — — — — 91 — 
Emulgen 409P Light yellow liquid — 12.0 — — — — — — — 55 — 
Ethosperse 1A4 — 42 — 145–160 — — 0.95 40.5 — — — — 
Ethosperse 1A12 — 42 — 72–82 — — 1.10 41.0 — — — — 
Ethosperse TDA6 — 41 — 118–133 — — 0.98 41.0 — — — — 
Ethosperse S120 — 40.5 — 385–430 — — 1.16 41.0 — — — — 
Ethosperse G26 — 42 — 133–142 — — 1.12 at 388C 40.5 — — — — 
Ethylan D252 Liquid — 5.6 — — — 0.903 40.5 — 5 Insoluble — 
Ethylan 253 Liquid — 7.8 — — — 0.930 40.5 — 3 Insoluble — 
Ethylan 254 Liquid — 9.8 — — — 0.948 43.0 — 5 Insoluble — 
Ethylan 256 Liquid — 11.4 — — — 0.972 40.5 — 15 43 — 
Ethylan 257 Liquid — 12.2 — — — 0.974 at 408C 40.5 — 21 49 — 
Ethylan 2512 Solid — 14.2 — — — 1.001 40.5 — 29 92 — 
Polyoxyethylene Alkyl Ethers 567

Name Physical form Acid 
value 
HLB 
value 
Hydroxyl 
value 
Iodine 
number 
Saponification 
value 
Density (g/cm3) 
at 208C unless 
otherwise stated 
Water 
content 
(%) 
Boiling 
point 
(8C) 
Melting point 
or pour point 
(8C) 
Cloud point 
(8C) for 
1% aqueous 
solution 
pH 
aqueous 
solution 
Ethylan 2560 Solid — 18.6 — — — — 40.5 — 45 >100 — 
Plurafac RA20 Colorless hazy liquid — 10.0 69–78 — 0.9965 0.988 at 258C 40.2 — — 45 5.0–6.5 (1%) 
Plurafac RA30 Colorless liquid — 9.0 85–95 — — 0.971 at 258C 40.2 — 10 36 5.0–6.5 (1%) 
Plurafac RA40 Clear liquid — 7.0 65–75 — — 0.974 at 258C 40.2 — –26 25 5.0–6.5 (1%) 
Plurafac RA43 White opaque liquid — 7.0 — — — 0.974 at 258C 40.4 — 6 — — 
Plurafac RA340 — — — 73 — — 0.977 — 0.974 at 
258C 
–23 — — 
Renex 30 Colorless to pale 
yellow cloudy 
liquid 
41 14.5 75–85 — — 1.0 at 258C 43.0 0.974 at 
258C 
14 84 6.0 (1%) 
Renex 31 Liquid 41 15.4 60–74 — — 1.0 at 258C 43.0 — 16 99 — 
Renex 36 Colorless to pale 
yellow hazy liquid 
41 11.4 118–133 — — 1.0 at 258C 41.0 >100 0.6 <0 6.0 (1%) 
Ritoleth 2 Clear to slightly 
yellow liquid 
<0.5 4.9 150–180 — — 0.92 at 258C <1.0 149 — — — 
Ritoleth 5 Clear to slightly 
yellow liquid 
<2.0 8.8 120–133 — — 0.94 at 258C <3.0 149 — — — 
Ritoleth 10 White semi-solid 
paste 
<10.0 12.3 80–90 32–40 <2.0 0.94 at 258C <3.0 149 — 47–55 4.5–7.5 (10%) 
Ritoleth 20 White to light yellow 
liquid 
— — — — — 1.01 at 258C — 149 — — — 
Ritox 35 White waxy solid — — — — — 1.05 at 258C — — — — — 
Ritox 721 White waxy flakes <2.0 — 44–61 — — 1.02 at 258C <2.0 — 358C — 6.0–8.0 (0.5%) 
Texofor A1P Solid — 16.2 — — — 1.025 at 608C — — 40 >100 — 
Texofor AP — — — — — — 0.875 — — 31 Insoluble — 
Texofor A6 Solid — — — — — 0.140 — — 26 Insoluble — 
Texofor A10 Solid — — — — — 0.970 — — 30 75 — 
Texofor A14 Solid — — — — — 0.995 — — 35 100 — 
Texofor A30 Solid — — — — — 1.035 — — 43 >100 — 
Texofor A45 Solid — — — — — 1.055 — — 47 >100 — 
Texofor A60 Solid — — — — — 1.065 — — 48 >100 — 
Volpo N 10 Hazy liquid <2 — 79–91 31–37 — — <1.0 — — >55 — 
Volpo N 20 Soft solid <2 15.5 50–58 18–25 — — <1.0 — — >100 — 
Volpo S2 White translucent 
plastic wax 
<1 4.9 150–165 <2.0 <3.0 — <1.0 — 41–45 — 6.0–7.5 (3%) 
Volpo S10 White waxy solid <1 12.4 78–86 <2.0 <3.0 — <1.0 — 35–38 — 6.0–7.5 (3%) 
Volpo S20 White to off- white 
waxy pastilles 
<1 15.3 45–55 <2.0 <3.0 — <1.0 — 42–48 — 6.0–7.5 (3%) 
Volpo C2 White, waxy solid <1 — 160–180 — — — — — — — 6.0–7.5 (3%) 
Volpo C20 White, waxy solid — 15.7 — — — — — — 40–45 — 6.0–7.5 (3%) 
Volpo CS10 White soft solid — — — — — — — — 35–38 — 6.0–7.5 (3%) 
Volpo CS20 White waxy pastilles <1 15.7 45–55 <2.0 <3.0 — <1.0 — 44 — 6.0–7.5 (3%) 
Volpo L4 Clear colorless liquid <1 9.5 145–160 <2.0 <3.0 — <1.0 — — — — 
Volpo L23 White waxy solid <1 16.7 42–52 — — 1.049 at 258C 1–3 — 37 — 6.0–7.5 (3%) 
568 Polyoxyethylene Alkyl Ethers

Table IV: Typical properties of selected commercially available grades of polyoxyethylene alkyl ethers. 
Name Critical micelle 
concentration (%) 
Surface tension of aqueous 
solution at 258C (mN/m) 
Dynamic viscosity 
at 258C or pour 
point (mPa s) 
Refractive index 
at 608C 
Solubility 
(0.05%) (0.1%) (0.2%) Ethanol Fixed oils Mineral 
oil 
Propylene 
glycol 
Water Flash 
point (8C) 
Brij 30 — — — — 30 — S D D S I >149 
Brij 35 0.013 — — — — — S I I S S >149 
Brij 52 — — — — — — S S H I I >149 
Brij 56 — — — — — — H D I D H >149 
Brij 58 — — — — — — S D I I S >149 
Brij 72 — — — — — — S S I I I >149 
Brij 76 — — — — — — S I I D D >149 
Brij 78 — — — — — — S D I I D >149 
Brij 721 — — — — — — I I D I D >110 
Brij 93Veg — — — — 30 — S S S S I — 
Brij 97 — — — — 100 — S D H S S — 
Brij 98 — — — — — — S I I S S >149 
Cremophor A6 — — — — 13.5 at 608C 1.4420–1.4424 S I — — S 190 
Cremophor A20 polyether — — — — — — — — — — D >149 
Cremophor A25 — — — — — 1.4512–1.4520 S I — — S — 
Ethosperse 1A4 — — — — 30 — S S — — S — 
Ethosperse 1A12 — — — — 1000 — S SH — — S — 
Ethosperse TDA6 — — — — 80 — S I — — D — 
Ethosperse S120 — — — — 460 — S I — — S — 
Ethosperse G26 — — — — 150 at 388C — S I — — S — 
Ethylan D252 — — — — — — — — — — I — 
Ethylan 253 — — — — — — — — — — I — 
Ethylan 254 — — — — — — — — — — I — 
Ethylan 256 — — — — — — — — — — S — 
Ethylan 257 — — — — — — — — — — S — 
Ethylan 2512 — — — — — — — — — — S — 
Ethylan 2560 — — — — — — — — — — S — 
Plurafac RA20 — — 30.7 — 80 — — — — — >10% at 258C 246 
Plurafac RA30 — — 28.6 — 65 — — — — — >10% at 258C 235 
Plurafac RA40 — — 30.3 — 80 — — — — — >10% at 258C 256 
Plurafac RA43 — — — — 200 — — — — — >1% at 258C 225 
Plurafac RA340 — — 30.5 — — — — — — — — — 
Renex 30 — — — — 60 — S I I — S — 
Renex 31 — — — — 130 — S I — — S — 
Renex 36 — — — — 80 — S I I — D >93 
Ritoleth 2 — — — — — — — — — — I >149 
Ritoleth 5 — — — — — — — — — — I >149 
Ritoleth 10 — — — — — — — — — — I >149 
Ritoleth 20 — — — — — — — — — — I >149 
Ritox 35 — — — — — — — — — — S >149 
Ritox 721 — — — — — — — — — — S >149 
Texofor A1P 0.006 42.9 — 42.3 — — S — — — S — 
Polyoxyethylene Alkyl Ethers 569

Name Critical micelle 
concentration (%) 
Surface tension of aqueous 
solution at 258C (mN/m) 
Dynamic viscosity 
at 258C or pour 
point (mPa s) 
Refractive index 
at 608C 
Solubility 
(0.05%) (0.1%) (0.2%) Ethanol Fixed oils Mineral 
oil 
Propylene 
glycol 
Water Flash 
point (8C) 
Texofor AP — — — — — — S — — — I — 
Texofor A6 — — — — — — S — — — I — 
Texofor A10 0.004 36.5 — 36.7 — — S — — — S — 
Texofor A14 — 36.9 — 36.6 — — S — — — S — 
Texofor A30 0.003 46.0 — 46.0 — — S — — — S — 
Texofor A45 0.004 47.5 — 47.0 — — S — — — S — 
Texofor A60 0.003 48.3 — 48.3 — — S — — — S — 
Volpo S2 — — — — — — S — — — D >100 
Volpo S10 — — — — — — S — — — S >100 
Volpo S20 — — — — — — S — — — S >100 
Volpo C2 — — — — — — S — — — D >100 
Volpo C20 — — — — — — S — — — S >100 
Volpo CS10 — — — — — — S — — — S >100 
Volpo CS20 — — — — — — S — — — S >100 
Volpo L4 — — — — — — S — — — S — 
Volpo L23 — — — — — — S — — — S 274 
S = Soluble; H = Soluble with haze; I = Insoluble; D = Dispersible; SH = Soluble on heating. 
Suppliers: ICI Surfactants (Brij, Pharma grades of Brij 30, 35, 72, 76 and 78P are also available); Croda Chemicals (Volpo); BASF Corporation (Cremophor, Plurafac); Rita Corporation (Ritoleth, Ritox). 
570 Polyoxyethylene Alkyl Ethers

12 Lee YC, Simamora P, Yalkowsky SH. Effect of Brij-78 on systemic 
delivery of insulin from an ocular device. J Pharm Sci 1997; 86(4): 
430–433. 
13 Sawicki W, Janicki S. Influence of polyoxyethylene-10-oleylether 
on in vitro verapamil hydrochloride penetration through mucous 
membrane from model buccal drug formulation. STP Pharma Sci 
1998; 8(2): 107–111. 
14 Al Gohary OM, Foda NH. Pharmaceutical and microbiological 
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37(1–6): 273–284. 
15 El Assasy AH, Foda NH, Badawi SS, Abd-El-Rehim RT. 
Formulation of flurbiprofen suppositories. Egyptian J Pharm Sci 
1995; 36(1–6): 31–53. 
16 El Assasy AH, Foda NH, Badawi SS, Abd-El-Rehim RT. Release 
characteristics and bioavailability of pirprofen from suppository 
bases. Egyptian J Pharm Sci 1995; 36(1–6): 15–29. 
17 Harmia-Pulkkinen T, Ojantakanen S. In vitro release kinetics of 
timolol and timol oleate from polyethylcyanoacrylate nanoparticles. 
Part 2. Nanoparticles manufacture with timolol maleate using 
different surfactants and organic solvents. Acta Pharm Fenn 1992; 
101(2): 57–63. 
18 Muller RH, Wallis KH, Troster SD, Kreuter J. In vitro 
characterization of poly(methyl-methacrylate) nanoparticles and 
correlation to their in vivo fate. J Control Release 1992; 20: 237– 
246. 
19 Troster SD, Muller U, Kreuter J. Modification of the body 
distribution of poly(methylmethacrylate) nanoparticles in rats by 
coating with surfactants. Int J Pharm 1990; 61: 85–100. 
20 Cabrera J, Redondo P, Becerra A, et al. Ultrasound-guided 
injection of polidocanol microfoam in the management of venous 
leg ulcers. Arch Dermatol 2004; 140(6): 667–673. 
21 Brisaert MG, Everaerts I, Plaizier-Vercammen JA. Chemical 
stability of tretinoin in dermatological preparations. Pharm Acta 
Helv 1995; 70(2): 161–166. 
22 Azaz E, Donbrow M, Hamburger R. Incompatibility of non-ionic 
surfactants with oxidizable drugs. Pharm J 1973; 211: 15. 
23 McDonald C, Richardson C. The effect of added salts on 
solubilization by a non-ionic surfactant. J Pharm Pharmacol 
1981; 33: 38–39. 
24 The Registry of Toxic Effects of Chemical Substances. Atlanta, 
GA: National Institute for Occupational Safety and Health, 2000. 
20 General References 
Ammar HO, Khali RM. Solubilization of certain analgesics by 
Cetomacrogol 1000. Egypt J Pharm Sci 1996; 37: 261–271. 
Elworthy PH, Guthrie WG. Adsorption of non-ionic surfactants at the 
griseofulvin-solution interface. J Pharm Pharmacol 1970; 22 
(Suppl.): 114S–120S. 
Guveli D, Davis SS, Kayes JB. Viscometric studies on surface agent 
solutions and the examination of hydrophobic interactions. J Pharm 
Pharmacol 1974; 26 (Suppl.): 127P–128P. 
Malcolmson C, Satra C, Kantaria S, et al. Effect of oil on the level of 
solubilization of testosterone propionate into non-ionic oil-in-water 
microemulsions. J Pharm Sci 1998; 87: 109–116. 
Vasiljevic D, Vuleta G, Dakovic LJ, Primorac M. Influence of emulsifier 
concentration on the rheological behavior of w/o/w multiple 
emulsions. Pharmazie 1994; 49: 933–934. 
Walters KA, Dugard PH, Florence AT. Non-ionic surfactants and 
gastric mucosal transport of paraquat. J Pharm Pharmacol 1981; 
33: 207–213. 
21 Authors 
RR Gupta, KK Singh. 
22 Date of Revision 
5 August 2005. 
Polyoxyethylene Alkyl Ethers 571

Polyoxyethylene Castor Oil Derivatives 
1 Nonproprietary Names 
BP: Polyoxyl castor oil 
Hydrogenated polyoxyl castor oil 
PhEur: Macrogolglyceroli ricinoleas 
Macrogolglyceroli hydroxystearas 
USPNF: Polyoxyl 35 castor oil 
Polyoxyl 40 hydrogenated castor oil 
Polyoxyethylene castor oil derivatives are a series of materials 
obtained by reacting varying amounts of ethylene oxide with 
either castor oil or hydrogenated castor oil. Several different 
types of material are commercially available, the best-known 
being the Cremophor series (BASF Corp.). Of these, two castor 
oil derivatives are listed in the PhEur 2005 and USPNF 23. 
See also Sections 2, 3 and 4. 
2 Synonyms 
Synonyms applicable to polyoxyethylene castor oil derivatives 
are shown below. See Table I for information on specific 
materials. 
Acconon; Arlatone; Cremophor; Etocas; Eumulgin; Jeechem; 
Lipocol; Mapeg; Marlowet; Nikkol; Protachem; Simulsol. 
3 Chemical Name and CAS Registry Number 
Polyethoxylated castor oil [61791-12-6] 
4 Empirical Formula and Molecular Weight 
Polyoxyethylene castor oil derivatives are complex mixtures of 
various hydrophobic and hydrophilic components. Members 
within each range have different degrees of ethoxylation 
(moles)/PEG units as indicated by their numerical sufffix (n). 
The chemical structures of the polyethoxylated hydrogenated 
castor oils are analogous to polyethoxylated castor oils with the 
exception that the double bond in the fatty chain has been 
saturated by hydrogenation. 
The PhEur 2005 states that polyoxyl castor oil contains 
mainly ricinoleyl glycerol ethoxylated with 30–50 molecules of 
ethylene oxide (nominal value), with small amounts of 
macrogol ricinoleate, and of the corresponding free glycols. 
The PhEur 2005 also states that polyoxyl hydrogenated castor 
oil contains mainly trihydroxystearyl glycerol ethoxylated with 
7–60 molecules of ethylene oxide (nominal value). 
In polyoxyl 35 castor oil (Cremophor EL), the relatively 
hydrophobic constituents comprise about 83% of the total 
mixture, the main component being glycerol polyethylene 
glycol ricinoleate. Other hydrophobic constituents include fatty 
acid esters of polyethylene glycol along with some unchanged 
castor oil. The hydrophilic part (17%) consists of polyethylene 
glycols and glycerol ethoxylates. Cremophor ELP, a ‘purified’ 
grade of Cremophor EL is also a polyoxyl 35 castor oil; it has a 
lower content of water, potassium, and free fatty acids and 
hence is claimed to have improved stability. 
In polyoxyl 40 hydrogenated castor oil (Cremophor RH 
40), approximately 75% of the components of the mixture are 
hydrophobic. These comprise mainly fatty acid esters of 
Table I: Synonyms of selected polyoxyethylene castor oil derivatives. 
Name Synonym 
Polyoxyl 5 castor oil Acconon CA-5; castor oil POE-5; Etocas 5; 
Hetoxide C-5; Jeechem CA-5; PEG-5 
castor oil; polyoxyethylene 5 castor oil. 
Polyoxyl 9 castor oil Acconon CA-9; castor oil POE-9; Jeechem CA- 
9; PEG-9 castor oil; polyoxyethylene 9 
castor oil; Protachem CA-9. 
Polyoxyl 15 castor oil Acconon CA-15; castor oil POE-15; Jeechem 
CA-15; PEG-15 castor oil; 
polyoxyethylene 15 castor oil; Protachem 
CA-15. 
Polyoxyl 35 castor oil Castor oil POE-35; Cremophor EL; Cremophor 
ELP; Etocas 35; glycerol 
polyethyleneglycol ricinoleate; PEG-35 
castor oil; polyethoxylated castor oil; 
polyoxyethylene 35 castor oil. 
Polyoxyl 40 castor oil Castor oil POE-40; Cirrasol G-1284; Croduret 
40; Etocas 40; Eumulgin RO; Hetoxide 
C40; Jeechem CA-40; Marlowet R40; 
Nikkol CO 40TX; Nonionic GR-40; PEG- 
40 castor oil; polyoxyethylene 40 castor 
oil; Protachem CA-40. 
Polyoxyl 40 
hydrogenated 
castor oil 
Cremophor RH 40; Croduret 40; Eumulgin 
HRE 40; glycerol polyethyleneglycol 
oxystearate; Hetoxide HC40; 
hydrogenated castor oil POE-40; Jeechem 
CAH-40; PEG-40 hydrogenated castor oil; 
polyethoxylated hydrogenated castor oil; 
polyoxyethylene 40 hydrogenated castor 
oil; Lipocol HCO-40; Lipocol LAV HCO 
40; Nikkol HCO 40 Pharma; Nonionic 
GRH-40; Protachem CAH-40. 
Polyoxyl 60 castor oil Castor oil POE-60;Jeechem CA-60; Nikkol 
CO 60TX; PEG-60 castor oil; 
polyoxyethylene 60 castor oil. 
Polyoxyl 60 
hydrogenated 
castor oil 
Croduret 60; Eumulgin HRE 60; Hetoxide 
HC60; hydrogenated castor oil POE-60; 
Jeechem CAH-60; PEG-60 hydrogenated 
castor oil; polyoxyethylene 60 
hydrogenated castor oil; Lipocol HCO-60; 
Nikkol HCO 60 Pharma; Protachem CAH- 
60. 
Polyoxyl 100 castor oil Hydrogenated castor oil POE-100; Jeechem 
CA-100; PEG-100 hydrogenated castor 
oil; polyoxyethylene 100 hydrogenated 
castor oil. 
Polyoxyl 100 
hydrogenated 
castor oil 
Cirrasol G-1300; Jeechem CA-100; Nikkol 
HCO 100; polyoxyethylene 100 
hydrogenated castor oil. 
Polyoxyl 200 castor oil Hetoxide C200; Jeechem CA-200; 
polyoxyethylene 200 castor oil; PEG-200 
castor oil; castor oil POE-200. 
Polyoxyl 200 
hydrogenated 
castor oil 
Hydrogenated castor oil POE-200; Jeechem 
CAH-200; PEG-200 hydrogenated castor 
oil; polyoxyethylene 200 hydrogenated 
castor oil.

glycerol polyethylene glycol and fatty acid esters of polyethylene 
glycol. The hydrophilic portion consists of polyethylene 
glycols and glycerol ethoxylates. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Emulsifying agent; solubilizing agent; wetting agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Polyoxyethylene castor oil derivatives are nonionic surfactants 
used in oral, topical, and parenteral pharmaceutical formulations. 
Polyoxyl 35 castor oil is mainly used as an emulsifing and 
solubilizing agent, and is particularly suitable for the production 
of aqueous liquid preparations containing volatile oils, fatsoluble 
vitamins, and other hydrophobic substances.(1,2) 
Cremophor EL emulsifies or solubilizes the fat-soluble vitamins 
A, D, E, and K in aqueous solutions for oral and topical 
administration. In 1mL of a 25% v/v aqueous polyoxyl 35 
castor oil (Cremophor EL) solution it is possible to incorporate 
approximately 10 mg of vitamin A palmitate; approximately 
10 mg of vitamin D; approximately 120mg of vitamin E 
acetate; or approximately 120 mg of vitamin K1. 
In aqueous alcoholic solutions, it very readily solubilizes 
essential oils. Aqueous solutions of hydrophobic drugs (e.g. 
miconazole, hexetidine, clotrimazole, benzocaine) can also be 
prepared with Cremophor EL. Cremophor EL has also been 
used as a solubilizing agent for drugs like cyclosporin A,(3) 
paclitaxel,(4) and cisplatin.(5) Cremophor ELP is manufactured 
by purifying Cremophor EL and is therefore suitable for 
parenteral applications, e.g. Taxol preparations. In oral 
formulations, the taste of polyoxyl 35 castor oil (Cremophor 
EL) can be masked by a banana flavor. 
Polyoxyl 35 castor oil (Cremophor EL) has also been used 
as a solvent in proprietary injections of diazepam, propanidid, 
and alfaxalone with alfadolone acetate; see Section 14. A selfmicroemulsifying 
drug delivery system (SMEDDS) for oral 
bioavailability, and the enhancement of halofantrine,(6) and 
simvastatin,(7) has been prepared using Cremophor EL. 
Cremophor EL has also been used as a buffering agent for 
aqueous tropicamide eyedrops.(8) It has also been used in an 
aqueous mixture together with caprylic/capric glyceride for 
mucosal vaccination, providing a potential alternative to 
parenteral vaccination.(9) It has also been used to enhance the 
permeability of peptides across monolayers of Caco-2 cells by 
inhibiting the apically polarized efflux system, enhancing 
intestinal absorption of some drugs.(10) Cremophor has been 
used as a vehicle for boron neutron-capture therapy in mice; 
which is a form of radiation therapy used in the treatment of 
glioblastoma multiforme.(11) Polyoxyl 35 castor oil is also used 
in the production of glycerin suppositories. 
In veterinary practice, polyoxyl 35 castor oil can be used to 
emulsify cod liver oil, and oils and fats incorporated into animal 
feeding stuffs. 
In cosmetics, polyoxyl 35 castor oil is mainly used as a 
solubilizing agent for perfume bases and volatile oils in vehicles 
containing 30–50% v/v alcohol (ethanol or propan-2-ol). In 
hand lotions, it can be used to replace castor oil. 
Polyoxyl 40 hydrogenated castor oil may be used in 
preference to polyoxyl 35 castor oil in oral formulations since 
it is almost tasteless. In aqueous alcoholic or completely 
aqueous solutions, polyoxyl 40 hydrogenated castor oil can be 
used to solubilize vitamins, essential oils, and certain drugs. 
Using 1mL of a 25% v/v aqueous solution of polyoxyl 40 
hydrogenated castor oil, it is possible to solubilize approximately 
88 mg of vitamin A palmitate, or approximately 160mg 
of vitamin A propionate. Other materials that can be 
solubilized are alfadolone, alfaxalone, hexachlorophene, hexetidine, 
levomepromazine, miconazole, propanidid, and thiopental. 
In aerosol vehicles that include water, the addition of 
polyoxyl 40 hydrogenated castor oil improves the solubility of 
the propellant in the aqueous phase. This enhancement applies 
both to dichlorodifluoromethane and to propane/butane 
mixtures. 
Foam formation in aqueous ethanol solutions containing 
polyoxyl 40 hydrogenated castor oil can be suppressed by the 
addition of small amounts of polypropylene glycol 2000. 
Polyoxyl 40 hydrogenated castor oil is also used as an 
emulsifier of fatty acids and alcohols. 
Polyoxyethylene castor oil derivatives have been used 
experimentally as a surfactant for the controlled release matrix 
pellet formulation containing nanocrystalline ketoprofen,(12) 
and for the transdermal delivery of vinpocetin.(13) 
Hydrogenated castor oil (HCO) derivatives containing more 
than 20 oxyethylene units were found to prolong the plasma 
circulation times of menatetrenone incorporated in lipid 
emulsions.(14) Polyoxl 60 hydrogenated castor oil has been 
reported to provide a self-microemulsifying system with 
enhanced oral absorption,(15) and a drastic reduction in plasma 
clearance of lipid emulsions.(16) It has been used in the 
formulation of liposomes,(17) and it has been suggested that 
more than 60% aids in the targeting of liposomes to the 
liver.(18) Also, polyoxyl 60 hydrogenated castor oil micellar 
solutions of cyclosporin A delivered the drug via the GI tract to 
the lymphatics with an extremely high selectivity.(19,20) 
Cremophor RH 40 and RH 60 have been used as additives 
to enhance the drug release from suppository formulations.(
21,22) 
8 Description 
Polyoxyl 35 castor oil occurs as a pale yellow, viscous liquid 
that is clear at temperatures above 268C. It has a slight but 
characteristic odor and can be completely liquefied by heating 
to 268C. 
Polyoxyl 40 hydrogenated castor oil occurs as a white to 
yellowish, semisolid paste at 208C that liquefies at 308C. It has 
a very faint characteristic odor and is almost tasteless in 
aqueous solution. 
Polyoxyl 60 hydrogenated castor oil occurs as a white paste 
at room temperature. It has little taste or odor in aqueous 
solution. 
9 Pharmacopeial Specifications 
See Table II. 
10 Typical Properties 
See Tables III, IV, and V. 
11 Stability and Storage Conditions 
Polyoxyl 35 castor oil (Cremophor EL and Cremophor ELP) 
forms stable solutions in many organic solvents such as 
Polyoxyethylene Castor Oil Derivatives 573

chloroform, ethanol, and propan-2-ol; it also forms clear, 
stable, aqueous solutions. Polyoxyl 35 castor oil (Cremophor 
EL and Cremophor ELP) is miscible with other polyoxyethylene 
castor oil derivatives and on heating with fatty acids, fatty 
alcohols, and some animal and vegetable oils. Solutions of 
polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) in 
aqueous alcohols are also stable. 
On heating of an aqueous solution, the solubility of 
polyoxyl 35 castor oil (Cremophor EL and Cremophor ELP) 
is reduced and the solution becomes turbid. Aqueous solutions 
of polyoxyl hydrogenated castor oil (Cremophor RH grades) 
heated for prolonged periods may separate into solid and liquid 
phases on cooling. However, the product can be restored to its 
original form by homogenization. 
Aqueous solutions of polyoxyl 35 castor oil (Cremophor EL 
and Cremophor ELP) are stable in the presence of low 
concentrations of electrolytes such as acids or salts, with the 
exception of mercuric chloride; see Section 12. 
Aqueous solutions of polyoxyl 35 castor oil (Cremophor EL 
and Cremophor ELP) can be sterilized by autoclaving for 20 
minutes at 1218C. In this process, a product may acquire a 
deeper color but this has no significance for product stability. 
Aqueous solutions of polyoxyl hydrogenated castor oil 
(Cremophor RH) can similarly be sterilized by autoclaving at 
1218C, but this may cause a slight decrease in the pH value. 
Although the method of manufacture used for polyoxyethylene 
castor oil derivatives ensures that they are near-sterile, 
microbial contamination can occur on storage. 
Polyoxyethylene castor oil derivatives should be stored in a 
well-filled, airtight container, protected from light, in a cool, 
dry place. 
12 Incompatibilities 
In strongly acidic or alkaline solutions, the ester components of 
polyoxyethylene hydrogenated castor oil are liable to saponify. 
In aqueous solution, polyoxyl 35 castor oil (Cremophor EL 
and Cremophor ELP) is stable toward most electrolytes in the 
concentrations normally employed. However, it is incompatible 
with mercuric chloride since precipitation occurs. 
Some organic substances may cause precipitation at certain 
concentrations, especially compounds containing phenolic 
hydroxyl groups, e.g. phenol, resorcinol, and tannins. 
Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) 
and polyoxyl 60 hydrogenated castor oil are largely unaffected 
by the salts that cause hardness in water. Cremophor RH 40 
was found to prolong the dissolution time of digoxin tablets.(23) 
13 Method of Manufacture 
Polyoxyethylene castor oil derivatives are prepared by reacting 
varying amounts of ethylene oxide with either castor oil or 
hydrogenated castor oil under controlled conditions. 
Polyoxyl 35 castor oil is produced in this way by reacting 1 
mole of castor oil with 35–40 moles of ethylene oxide. 
Polyoxyl 40 hydrogenated castor oil is produced by reacting 
1 mole of hydrogenated castor oil with 40–45 moles of ethylene 
oxide. Polyoxyl 60 hydrogenated castor oil is similarly 
produced by reacting 1 mole of hydrogenated castor oil with 
60 moles of ethylene oxide. 
14 Safety 
Polyoxyethylene castor oil derivatives are used in a variety of 
oral, topical, and parenteral pharmaceutical formulations. 
Acute and chronic toxicity tests in animals have shown 
polyoxyethylene castor oil derivatives to be essentially nontoxic 
and nonirritant materials; see Table VI.(24,25) However, there 
are reports of cardiovascular changes and nephrotoxicity in 
various species of animals.(26) Several serious anaphylactic 
reactions,(27–38) cardiotoxicity,(39–41) nephrotoxicity,(42,43) neurotoxicity,(
44) and pulmonary toxicty(45) have also been 
observed in humans and animals following parenteral administration 
of formulations containing polyoxyethylene castor oil 
derivatives. The precise mechanism of the reaction is not 
known. 
Table II: Pharmacopeial specifications for polyoxyethylene castor oil derivatives. 
Test PhEur 2005 USPNF 23 
Polyoxyl castor oil Polyoxyl hydrogenated castor oil Polyoxyl 35 castor oil Polyoxyl 40 hydrogenated castor oil 
Identification . . . . 
Characters . . — — 
Appearance of solution . . — — 
Alkalinity . . — — 
Relative density 1.05 — — — 
Specific gravity — — 1.05–1.06 — 
Congealing temperature — — — 16–268C 
Viscosity at 258C 500–800 mPa s — 650–850 cP s — 
Water 43.0% 43.0% 43.0% 43.0% 
Total ash 40.3% 40.3% — — 
Residue on ignition — — 40.3% 40.3% 
Heavy metals 410 ppm 410 ppm 40.001% 40.001% 
Acid value 42.0 42.0 42.0 42.0 
Hydroxyl value . . 65–80 60–80 
Dioxan 410 ppm 410 ppm — — 
Free ethylene oxide 41 ppm 41 ppm — — 
Organic volatile impurities — — . . 
574 Polyoxyethylene Castor Oil Derivatives

Table III: Typical physical properties of selected commercially available polyoxyethylene castor oil derivatives. 
Name Acid value HLB value Hydroxyl 
value 
Iodine 
number 
Saponification 
value 
Water 
content (%) 
Melting 
point (8C) 
Solidification 
point (8C) 
Cloud point for a 
1% aqueous solution 
(8C) 
Polyoxyl 35 castor oil (Cremophor EL) 42.0 12–14 65–78 25–35 65–70 2.80 19–20 — 72.5 
Poloxyl 35 castor oil, purified (Cremophor ELP) 42.0 12–14 65–78 25–35 65–70 40.5 — — — 
Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) 41.0 14–16 60–80 41 50–60 42.0 30 20–28 95.6 
Polyoxyl 60 hydrogenated castor oil 41.0 15–17 50–70 41 40–50 42 40 — — 
Etocas 29 — 11.7 — — — — — — — 
Etocas 35 — 12.7 — — — — — — — 
Etocas 40 — 13 — — — — — — — 
Croduret 7 Special — 4.9 — — — — — — — 
Croduret 40 — 13 — — — — — — — 
Croduret 50 Special — 14.1 — — — — — — — 
Croduret 60 — 14.7 — — — — — — — 
Eumulgin HRE 40 41.0 — 60–75 42 50–60 41.0 — — 76–82 
Eumulgin HRE 60 41.0 — 50–67 — 40–50 41 — <22 80–86 
Arlatone G Pharma — 10.8 — — — — 7 — — 
Cirrasol G-1284 — 13.1 — — — — — — — 
Hetoxide C5 — 4 — — — — — — — 
Hetoxide C-16 — 8.6 — — — — — — — 
Hetoxide C-25 — 10.8 — — — — — — — 
Hetoxide HC-16 — 8.6 — — — — — — — 
Hetoxide HC-40 — 13.1 — — — — — — — 
Hetoxide HC-60 — 14.8 — — — — — — — 
Jeechem CA-5 41.5 — 128–140 63–73 138–153 41.0 — — — 
Jeechem CA-15 41.0 — — — 95–100 41.0 — — — 
Jeechem CA-25 — — 75–85 — 77–85 41.0 — — — 
Jeechem CA-40 42.0 — 77–89 24–30 57–64 43.0 — — — 
Jeechem CA-60 42.0 — 42–55 — 28–38 412.0 — — — 
Jeechem CA-100 42.0 — — — 27–37 41.0 — — — 
Jeechem CA-200 42.0 — 20–34 — 14–20 41.0 125 — — 
Jeechem CAH-25 42.0 — 73–84 41.0 77–87 42.0 — — — 
Jeechem CAH-40 43.0 — 59–68 42.0 50–65 41.0 — — — 
Jeechem CAH-60 41.5 — 39–49 — 41–51 41.0 — — — 
Jeechem CAH-200 42.0 — 20–33 — 14–22 41.0 125 — — 
Lipocol HCO-40 43.0 — — 42.0 60–67 — — — — 
Lipocol LAV HCO-40 41.0 — 60–80 42.0 45–69 43.0 — — — 
Lipocol HCO-60 41.0 — 50–70 41.0 40–50 421.0 — — — 
Nikkol CO-3 — 3 — — — — — — — 
Nikkol CO-10 — 6.5 — — — — — — — 
Nikkol HCO-50 — 13.5 — — — — — — — 
Nikkol HCO-80 — 15 — — — — — — — 
Nikkol HCO-100 — 16.5 — — — — — — — 
Polyoxyethylene Castor Oil Derivatives 575

Table IV: Typical physical properties of selected commercially available polyoxyethylene castor oil derivatives. 
Name Density (g/cm3) pH Refractive index at 
208C 
Surface tension of 
0.1% w/v aqueous 
solution (mN/m) 
Viscosity at 258C (mPa s) Critical micelle 
concentration (%) 
Polyoxyl 35 castor oil 
(Cremophor EL) 
1.05–1.06 6–8 1.471 40.9 650–800 0.009 
Poloxyl 35 castor oil, purified 
(Cremophor ELP) 
1.05–1.06 5–7 — — 600–750 0.009 
Polyoxyl 40 hydrogenated 
castor oil (Cremophor RH 
40) 
— 6–7 1.453–1.457 43.0 20–40(a) 0.039 
Polyoxyl 60 hydrogenated 
castor oil 
— 6–7 — — — — 
Eumulgin HRE 40 1.0220–1.0260 at 708C 6–7 — — — — 
Eumulgin HRE 60 1.0340–1.0380 at 708C 6–7 — — — — 
Arlacel 989 — — — — 1200 — 
Arlatone G Pharma 1.0 — — — 1400 — 
Cirrasol G-1284 1.10 7–9 — — 1500 — 
Jeechem CA-5 1.0 6–8 — — — — 
Jeechem CA-9 1.02 5.5–7.5 — — — — 
Jeechem CA-15 1.021 6.0–7.5 — — — — 
Jeechem CA-25 1.04 6.0–7.5 — — — — 
Jeechem CA-30 1.01 6.5–7.5 — — — — 
Jeechem CA-40 1.1 5.0–8.0 — — — — 
Jeechem CA-60 1.068 5.0–7.0 — — — — 
Jeechem CA-100 — 5.5–7.0 — — — — 
Jeechem CA-200 1.08 5.0–7.0 — — — — 
Jeechem CAH-16 1.02 6.0–7.5 1.4665–1.4685 — — — 
Jeechem CAH-25 1.03 5.0–7.5 — — — — 
Jeechem CAH-40 1.1 5.5–7.5 — — — — 
Jeechem CAH-60 — 3.5–6.1 — — — — 
Jeechem CAH-100 1.1 3.5–6.1 — — — — 
Jeechem CAH-200 1.1 — — — — — 
Lipocol HCO-40 1.0 — — — — — 
Lipocol HCO-60 1.05 — — — — — 
(a)30% w/v aqueous solution. 
576 Polyoxyethylene Castor Oil Derivatives

Table V: Solubility of selected commercially available polyoxyethylene castor oil derivatives. 
Name Solubility 
Castor oil Chloroform Ethanol Fatty acids Fatty alcohols Olive oil Mineral oil Water 
Polyoxyl 35 castor oil (Cremophor EL) S S S S S S — S 
Poloxyl 35 castor oil, purified (Cremophor ELP) S S S S S S — S 
Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) S S S S S S — S 
Polyoxyl 60 hydrogenated castor oil S — S(a) S S S — S 
Etocas 5 S — S — S — I I 
Etocas 29 S — S — S — I S 
Etocas 35 S — S — S — I S 
Etocas 40 S — S — PS — I S 
Croduret 7 Special S — PS — S — I I 
Croduret 40 D — S — D — I S 
Croduret 50 Special D — S — I — I S 
Croduret 60 D — S — D — I S 
Arlacet 989 — — S — — — — I 
Arlatone G Pharma — — S — — — I S 
Cirrasol G-1284 — — — — — — I D 
Jeechem CA-5 — — — — — — — D 
Jeechem CA-9 — — — — — — — D 
Jeechem CA-15 — — — — — — — PS 
Jeechem CA-25 — — — — — — — S 
Jeechem CA-30 — — — — — — — S 
Jeechem CA-40 — — — — — — — S 
Jeechem CA-60 — — — — — — — PS 
Jeechem CA-200 — — — — — — — S 
Jeechem CAH-16 — — — — — — — D 
Jeechem CAH-25 — — — — — — — D 
Jeechem CAH-40 — — — — — — — S 
Jeechem CAH-60 — — — — — — — S 
Jeechem CAH-100 — — — — — — — S 
Jeechem CAH-200 — — — — — — — S 
Lipocol LAV HCO-40 — — — — — — — S 
Lipocol HCO-40 — — — — — — — S 
Lipocol HCO-60 — — — — — — — S 
S = soluble, PS = partially soluble, I = insoluble, D = dispersible. 
(a) Need to add 0.5–1.0% water to maintain a clear solution. 
Polyoxyethylene Castor Oil Derivatives 577

Table VI: LD50 values of selected polyoxyethylene castor oil 
derivatives.(24,25) 
Name Animal and 
route 
LD50 (g/kg 
body-weight) 
Polyoxyl 35 castor oil (Cremophor EL) Cat (oral) >10 
Dog (IV) 0.64 
Mouse (IV) 2.5 
Rabbit (oral) >10 
Rat (oral) >6.4 
Polyoxyl 40 hydrogenated castor oil 
(Cremophor RH 40) 
Mouse (IP) >12.5 
Mouse (IV) >12.0 
Rat (oral) >16.0 
Polyoxyl 60 hydrogenated castor oil Mouse (IP) >12.5 
Rat (oral) >16.0 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IV injections 
and ophthalmic solutions). Included in parenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Polyoxyethylene alkyl ethers; polyoxyethylene stearates. 
18 Comments 
Note that the trade name Cremophor (BASF Corp.) is also used 
for other polyoxyethylene derivatives, e.g., the Cremophor A 
series are polyoxyethylene alkyl ethers of cetostearyl alcohol. 
19 Specific References 
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11 Miura M, Micca PL, Fisher CD, et al. Synthesis of a nickel 
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12 Vergote GJ, Vervaet C, Van Driessche I, et al. An oral controlled 
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14 Ueda K, Yamazaki Y, Noto H, et al. Effect of oxyethylene moieties 
in hydrogenated castor oil on the pharmacokinetics of menatetrenone 
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18 Kato Y, Watanabe K, Hosokawa T, et al. Modification of 
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19 Takada K, Furuya Y, Yoshikawa H, Muranishi S. Biological and 
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1988; 11: 80–87. 
20 Takada K, Shibata N, Yoshimura H, et al. Promotion of the 
selective lymphatic delivery of cyclosporin A by lipid-surfactant 
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21 Berko S, Regdon GJr, Eros I. Solutol and cremophor products as 
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22 Berko S, Regdon GJr, Ducza E, et al. In vitro and in vivo study in 
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23 Tayrouz Y, Ding R, Burhenne J, et al. Pharmacokinetic and 
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24 BASF Corporation. Technical literature: Cremophor EL, 2004. 
25 BASF Corporation. Technical literature: Cremophor RH grades, 
2004. 
26 Final report on the safety assessment of PEG-30, 33, 35, 36, and 40 
castor oil and PEG-30 and 40 hydrogenated castor oil. Int J 
Toxicol 1997; 16(3): 269–306. 
27 Forrest ARW, Watrasiewicz K, Moore CJ. Long-term althesin 
infusion and hyperlipidaemia. Br Med J 1977; 2: 1357–1358. 
28 Dye D, Watkins J. Suspected anaphylactic reaction to cremophor 
EL. Br Med J 1980; 280: 1353. 
29 Knell AJ, Turner P, Chalmers EPD. Potential hazard of steroid 
anaesthesia for prolonged sedation [letter]. Lancet 1983; i: 526. 
30 Lawler PGP, McHutchon A, Bamber PA. Potential hazards of 
prolonged steroid anaesthesia [letter]. Lancet 1983; i: 1270–1271. 
31 Moneret-Vautrin DA, Laxenaire MC, Viry-Babel F. Anaphylaxis 
caused by anti-cremophor EL IgG STS antibodies in a case of 
reaction to althesin. Br J Anaesth 1983; 55: 469–471. 
32 Chapuis B, Helg C, Jeannet M, et al. Anaphylactic reaction to 
intravenous cyclosporine. N Engl J Med 1985; 312: 1259. 
578 Polyoxyethylene Castor Oil Derivatives

33 Howrie DL, Ptachcinski RJ, Griffith BP, et al. Anaphylactoid 
reactions associated with parenteral cyclosporine use: possible role 
of cremophor EL. Drug Intell Clin Pharm 1985; 19: 425–427. 
34 van Hooff JP, Bessems P, Beuman GH, Leunissen KML. Absence of 
allergic reaction to cyclosporin capsules in patient allergic to 
standard oral and intravenous solution of cyclosporin [letter]. 
Lancet 1987; ii: 1456. 
35 Siddall SJ, Martin J, Nunn AJ. Anaphylactic reactions to teniposide. 
Lancet 1989; i: 394. 
36 McCormick PA, Hughes JE, Burroughs AK, McIntyre N. 
Reformulation of injectable vitamin A: potential problems. Br 
Med J 1990; 301: 924. 
37 Fja. llskog M-L, Frii L, Bergh J. Is cremophor EL, solvent for 
paclitaxel, cytotoxic? Lancet 1993; 342: 873. 
38 Liebmann J, Cook JA, Mitchell JB. Cremophor EL, solvent for 
paclitaxel, and toxicity. Lancet 1993; 342: 1428. 
39 Badary OA, Al-Shabanah OA, Al-Gharably NM, Elmazar MM. 
Effect of Cremophor EL on the pharmacokinetics, antitumor 
activity and toxicity of doxorubicin in mice. Anticancer Drugs 
1998; 9: 809–815. 
40 Sanchez H, Bigard X, Veksler V, et al. Immunosuppressive 
treatment affects cardiac and skeletal muscle mitochondria by 
the toxic effect of vehicle. J Mol Cell Cardiol 2000; 32: 323–331. 
41 Bowers VD, Locker S, Ames S, et al. The hemodynamic effects of 
Cremophor-EL. Transplantation 1991; 51: 847–850. 
42 Verani R. Cyclosporin nephrotoxicity in the Fischer rat. Clin 
Nephrol 1986; 25( Suppl 1): S9–13. 
43 Thiel G, Hermle M, Brunner FP. Acutely impaired renal function 
during the intravenous administration of cyclosporin A: a 
cremophore side-effect. Clin Nephrol 1986; 25( Suppl 1): S40–42. 
44 Windebank AJ, Blexrud MD, de Groen PC. Potential neurotoxicity 
of the solvent vehicle for cyclosporin. J Pharmacol Exp Ther 1994; 
268: 1051–1056. 
45 Kiorpes AL, Keith IM, Dubielzig RR. Pulmonary changes in rats 
following the administration of 3-methylindole in Cremophor EL. 
Histol Histopathol 1988; 3: 125–132. 
20 General References 
Rischin D, Webster LK, Millward MJ, et al. Cremophor pharmacokinetics 
in patients receiving 3, 6, and 24 hour infusions of 
paclitaxel. J Natl Cancer Inst 1996; 88: 1297–1301. 
21 Authors 
KK Singh. 
22 Date of Revision 
30 August 2005. 
Polyoxyethylene Castor Oil Derivatives 579

Polyoxyethylene Sorbitan Fatty Acid Esters 
1 Nonproprietary Names 
BP: Polysorbate 20, Polysorbate 40, Polysorbate 60, 
and Polysorbate 80 
JP: Polysorbate 80 
PhEur: Polysorbatum 20, Polysorbatum 40, Polysorbatum 
60, and Polysorbatum 80 
USPNF: Polysorbate 20, Polysorbate 40, Polysorbate 60, 
and Polysorbate 80 
2 Synonyms 
For synonyms of selected polysorbates, see Table I; see also 
Section 3. 
3 Chemical Names and CAS Registry Numbers 
See Table II. 
4 Empirical Formula and Molecular Weight 
Approximate molecular weights for selected polysorbates are 
shown in Table III. 
Table II: Chemical names and CAS Registry Numbers of selected 
polysorbates. 
Polysorbate Chemical name CAS number 
Polysorbate 20 Polyoxyethylene 20 sorbitan 
monolaurate 
[9005-64-5] 
Polysorbate 21 Polyoxyethylene (4) sorbitan 
monolaurate 
[9005-64-5] 
Polysorbate 40 Polyoxyethylene 20 sorbitan 
monopalmitate 
[9005-66-7] 
Polysorbate 60 Polyoxyethylene 20 sorbitan 
monostearate 
[9005-67-8] 
Polysorbate 61 Polyoxyethylene (4) sorbitan 
monostearate 
[9005-67-8] 
Polysorbate 65 Polyoxyethylene 20 sorbitan 
tristearate 
[9005-71-4] 
Polysorbate 80 Polyoxyethylene 20 sorbitan 
monooleate 
[9005-65-6] 
Polysorbate 81 Polyoxyethylene (5) sorbitan 
monooleate 
[9005-65-6] 
Polysorbate 85 Polyoxyethylene 20 sorbitan 
trioleate 
[9005-70-3] 
Polysorbate 120 Polyoxyethylene 20 sorbitan 
monoisostearate 
[66794-58-9] 
Table I: Synonyms of selected polysorbates. 
Polysorbate Synonym 
Polysorbate 20 Armotan PML 20; Capmul POE-L; Campul POE-L Low PV; Crillet 1; Drewmulse; E432; Durfax 20; E432; Eumulgin SML; 
Glycosperse L-20; Hodag PSML-20; Lamesorb SML-20; Liposorb L-20; Liposorb L-20K; Montanox 20; Nissan Nonion LT-221; 
Norfox Sorbo T-20; POE-SML; Ritabate 20; Sorbax PML-20; sorbitan monododecanoate; Sorgen TW-20; T-Maz 20; T-Maz 
20K; poly(oxy-1,2-ethanediyl) derivatives; polyoxyethylene 20 laurate; Protasorb L-20; Tego SML 20; Tween 20. 
Polysorbate 21 Crillet 11; Hodag PSML-4; Protasorb L-5; Tween 21. 
Polysorbate 40 Crillet 2; E434; Eumulgin SMP; Glycosperse S-20; Hodag PSMP-20; Lamesorb SMP-20; Liposorb P-20; Lonzest SMP-20; 
Montanox 40; poly(oxy-1,2-ethanediyl) derivatives; Protasorb P-20; Ritabate 40; sorbitan monohexadecanoate; Sorbax PMP- 
20; Tween 40. 
Polysorbate 60 Atlas 70K; Atlas Armotan PMS 20; Capmul POE-S; Cremophor PS 60; Crillet 3; Drewpone 60K; Durfax 60; Durfax 60K; E435; 
Emrite 6125; Eumulgin SMS; Glycosperse S-20; Glycosperse S-20FG; Glycosperse S-20FKG; Hodag PSMS-20; Hodag SVS- 
18; Lamsorb SMS-20; Liposorb S-20; Liposorb S-20K; Lonzest SMS-20; Nikkol TS-10; Norfox SorboT-60 Montanox 60; 
Polycon T 60 K; polyoxyethylene 20 stearate; Ritabate 60; Protasorb S-20; Sorbax PMS-20; sorbitan monooctadecanoate 
poly(oxy-1,2-ethanediyl) derivatives; T-Maz 60; T-Max 60KHS; Tween 60; Tween 60K; Tween 60 VS. 
Polysorbate 61 Crillet 31; Hodag PSMS-4; Liposorb S-4; Protasorb S-4; Tween 61. 
Polysorbate 65 Alkamuls PSTS-20; Crillet 35; E436; Glycosperse TS-20; Glycosperse TS-20 FG; Glycosperse TS-20 KFG; Hodag PSTS-20; 
Lamesorb STS-20; Lanzet STS-20; Liposorb TS-20; Liposorb TS-20A; Liposorb TS-20K; Montanox 65; Protasorb STS-20; 
Sorbax PTS-20; sorbitan trioctadecanoate poly(oxy-1,2-ethanediyl) derivatives; T-Maz 65K; Tween 65; Tween 65K; Tween 
65V. 
Polysorbate 80 Atlas E; Armotan PMO 20; Capmul POE-O; Cremophor PS 80; Crillet 4; Crillet 50; Drewmulse POE-SMO; Drewpone 80K; Durfax 
80; Durfax 80K; E433; Emrite 6120; Eumulgin SMO; Glycosperse O-20; Hodag PSMO-20; Liposorb O-20; Liposorb O-20K; 
Montanox 80; polyoxyethylene 20 oleate; Protasorb O-20; Ritabate 80; (Z)-sorbitan mono-9-octadecenoate poly(oxy1,2- 
ethanediyl) derivatives; Tego SMO 80; Tego SMO 80V; Tween 80. 
Polysorbate 81 Crillet 41; Hetsorb O-5; Hodag PSMO-5; Protasorb O-5; Sorbax PMO-5; sorbitan mono-9-octadecenoate poly(oxy-1,2- 
ethanediyl) derivatives; T-Maz 81; Tego SMO 81; Tween 81. 
Polysorbate 85 Alkamuls PSTO-20; Crillet 45; Glycosperse TO-20; Hodag PSTO-20; Lonzest STO-20; Liposorb TO-20; Montanox 85; Protasorb 
TO-20; Sorbax PTO-20; sorbitan tri-9-octadecenoate poly(oxy1,2-ethanediyl) derivatives; Tego STO 85; Tween 85. 
Polysorbate 120 Crillet 6.

Table III: Empirical formula and molecular weight of selected 
polysorbates. 
Polysorbate Formula Molecular weight 
Polysorbate 20 C58H114O26 1128 
Polysorbate 21 C26H50O10 523 
Polysorbate 40 C62H122O26 1284 
Polysorbate 60 C64H126O26 1312 
Polysorbate 61 C32H62O10 607 
Polysorbate 65 C100H194O28 1845 
Polysorbate 80 C64H124O26 1310 
Polysorbate 81 C34H64O11 649 
Polysorbate 85 C100H188O28 1839 
Polysorbate 120 C64H126O26 1312 
5 Structural Formula 
w . x . y . z = 20 (Polysorbates 20, 40, 60, 65, 80, and 85) 
w . x . y . z = 5 (Polysorbates 81) 
w . x . y . z = 4 (Polysorbates 21 and 61) 
R = fatty acid 
6 Functional Category 
Emulsifying agent; nonionic surfactant; solubilizing agent; 
wetting, dispersing/suspending agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Polyoxyethylene sorbitan fatty acid esters (polysorbates) are a 
series of partial fatty acid esters of sorbitol and its anhydrides 
copolymerized with approximately 20, 5, or 4 moles of 
ethylene oxide for each mole of sorbitol and its anhydrides. 
The resulting product is therefore a mixture of molecules of 
varying sizes rather than a single uniform compound. 
Polysorbates containing 20 units of oxyethylene are hydrophilic 
nonionic surfactants that are used widely as emulsifying 
agents in the preparation of stable oil-in-water pharmaceutical 
emulsions. They may also be used as solubilizing agents for a 
variety of substances including essential oils and oil-soluble 
vitamins, and as wetting agents in the formulation of oral and 
parenteral suspensions. They have been found to be useful in 
improving the oral bioavailability of drug molecules that are 
substrates for p-glycoprotein.(1) 
Polysorbates are also widely used in cosmetics and food 
products. See Table IV. 
Table IV: Uses of polysorbates. 
Use Concentration (%) 
Emulsifying agent 
Used alone in oil-in-water emulsions 1–15 
Used in combination with hydrophilic 
emulsifiers in oil-in-water emulsions 
1–10 
Used to increase the water-holding properties of 
ointments 
1–10 
Solubilizing agent 
For poorly soluble active constituents in 
lipophilic bases 
1–10 
Wetting agent 
For insoluble active constituents in lipophilic 
bases 
0.1–3 
8 Description 
Polysorbates have a characteristic odor and a warm, somewhat 
bitter taste. Their colors and physical forms at 258C are shown 
in Table V, although it should be noted that the absolute color 
intensity of the products may vary from batch to batch and 
from manufacturer to manufacturer. 
Table V: Colors and physical forms of selected polysorbates at 258C. 
Polysorbate Color and form at 258C 
Polysorbate 20 Yellow oily liquid 
Polysorbate 21 Yellow oily liquid 
Polysorbate 40 Yellow oily liquid 
Polysorbate 60 Yellow oily liquid 
Polysorbate 61 Tan solid 
Polysorbate 65 Tan solid 
Polysorbate 80 Yellow oily liquid 
Polysorbate 81 Amber liquid 
Polysorbate 85 Amber liquid 
Polysorbate 120 Yellow liquid 
9 Pharmacopeial Specifications 
See Table VI. 
Polyoxyethylene Sorbitan Fatty Acid Esters 581

Table VI: Pharmacopeial specifications for polysorbates. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification 
Polysorbate 20 — . . 
Polysorbate 40 — . . 
Polysorbate 60 — . . 
Polysorbate 80 . . . 
Saponification value 
Polysorbate 20 — 40–50 40–50 
Polysorbate 40 — 41–52 41–52 
Polysorbate 60 — 45–55 45–55 
Polysorbate 80 45–55 45–55 45–55 
Composition of fatty acids — see Table VII — 
Hydroxyl value 
Polysorbate 20 — 96–108 96–108 
Polysorbate 40 — 89–105 89–105 
Polysorbate 60 — 81–96 81–96 
Polysorbate 80 — 65–80 65–80 
Water 
Polysorbate 20 — 43.0% 43.0% 
Polysorbate 40 — 43.0% 43.0% 
Polysorbate 60 — 43.0% 43.0% 
Polysorbate 80 43.0% 43.0% 43.0% 
Residue on ignition 
Polysorbate 20 — 40.25% 40.25% 
Polysorbate 40 — 40.25% 40.25% 
Polysorbate 60 — 40.25% 40.25% 
Polysorbate 80 40.15% 40.25% 40.25% 
Arsenic 
Polysorbate 80 42 ppm — — 
Heavy metals 
Polysorbate 20 — 410 ppm 40.001% 
Polysorbate 40 — 410 ppm 40.001% 
Polysorbate 60 — 410 ppm 40.001% 
Polysorbate 80 420 ppm 410 ppm 40.001% 
Acid value 
Polysorbate 20 — 42.0 42.2 
Polysorbate 40 — 42.0 42.2 
Polysorbate 60 — 42.0 42.2 
Polysorbate 80 42.0 42.0 42.2 
Iodine value 
Polysorbate 80 19–24 — — 
Specific gravity 
Polysorbate 20 — 1.10 — 
Polysorbate 40 — 1.10 — 
Polysorbate 60 — 1.10 — 
Polysorbate 80 1.065–1.095 1.10 1.06–1.09 
Viscosity at 258C 
Polysorbate 20 — 400 mPa s — 
Polysorbate 40 — 400 mPa s — 
Polysorbate 60 — 400 mPa s — 
Polysorbate 80 345–445mm2 400 mPa s 300–500mm2/s 
Organic volatile impurities — — . 
Peroxide value 
Polysorbate 20 — 410 — 
Polysorbate 40 — 410 — 
Polysorbate 60 — 410 — 
Polysorbate 80 — 410 — 
Residual ethylene oxide 
Polysorbate 20 — 41 ppm — 
Polysorbate 40 — 41 ppm — 
Polysorbate 60 — 41 ppm — 
Polysorbate 80 — 41 ppm — 
Residual dioxan 
Continued 
582 Polyoxyethylene Sorbitan Fatty Acid Esters

Table VII: Fatty acid composition of polysorbate 20, 40, 60, 80 from 
PhEur 2005. 
Fatty acid Polysorbate 
20 
Polysorbate 
40 
Polysorbate 
60 
Polysorbate 
80 
Caproic acid 41.0% — — — 
Caprylic acid 410.0% — — — 
Capric acid 410.0% — — — 
Lauric acid 40.0–60.0% — — — 
Myristic acid 14.0–25.0% — — 45.0% 
Palmitic acid 7.0–15.0% 592.0% .(a) 416.0% 
Palmitoleic acid — — — 48.0% 
Stearic acid 47.0% — 40.0–60.0% 46.0% 
Oleic acid 411.0% — — 58.0– 
85.0% 
Linolenic acid — — — 44.0% 
Linoleic acid 43.0% — — — 
(a) Sum of the contents of palmitic and stearic acids 590.0%. 
10 Typical Properties 
Acid value: see Table VIII. 
Acidity/alkalinity: pH = 6.0–8.0 for a 5% w/v aqueous 
solution. 
Flash point: 1498C 
HLB value: see Table IX. 
Hydroxyl value: see Table VIII. 
Moisture content: see Table VIII. 
Saponification value: see Table VIII. 
Solubility: see Table X. 
Specific gravity: see Table IX. 
Surface tension: for 0.1% w/v solutions, see Table XI. 
Viscosity (dynamic): see Table IX. 
Table VIII: Typical properties of selected polysorbates. 
Polysorbate Acid 
value (%) 
Hydroxyl 
value 
Moisture 
content 
Saponification 
value 
Polysorbate 20 2.0 96–108 3.0 40–50 
Polysorbate 21 3.0 225–255 3.0 100–115 
Polysorbate 40 2.0 90–105 3.0 41–52 
Polysorbate 60 2.0 81–96 3.0 45–55 
Polysorbate 61 2.0 170–200 3.0 95–115 
Polysorbate 65 2.0 44–60 3.0 88–98 
Polysorbate 80 2.0 65–80 3.0 45–55 
Polysorbate 81 2.0 134–150 3.0 96–104 
Polysorbate 85 2.0 39–52 3.0 80–95 
Polysorbate 120 2.0 65–85 5.0 40–50 
Table IX: Typical properties of selected polysorbates. 
Polysorbate HLB value Specific gravity 
at 258C 
Viscosity 
(mPa s) 
Polysorbate 20 16.7 1.1 400 
Polysorbate 21 13.3 1.1 500 
Polysorbate 40 15.6 1.08 500 
Polysorbate 60 14.9 1.1 600 
Polysorbate 61 9.6 1.06 Solid 
Polysorbate 65 10.5 1.05 Solid 
Polysorbate 80 15.0 1.08 425 
Polysorbate 81 10.0 — 450 
Polysorbate 85 11.0 1.00 300 
Polysorbate 120 14.9 — — 
Table X: Solubilities of selected polysorbates in various solvents. 
Polysorbate Solvent 
Ethanol Mineral oil Vegetable oil Water 
Polysorbate 20 S I I S 
Polysorbate 21 S I I D 
Polysorbate 40 S I I S 
Polysorbate 60 S I I S 
Polysorbate 61 SW SW SWT D 
Polysorbate 65 SW SW DW D 
Polysorbate 80 S I I S 
Polysorbate 81 S S ST D 
Polysorbate 85 S I ST D 
Polysorbate 120 S I I S 
D = dispersible; I = insoluble; S = soluble; T = turbid; W = on warming. 
Table XI: Surface tension of related polysorbates. 
Polysorbate Surface tension at 208C (mN/m) 
Polysorbate 21 34.7 
Polysorbate 40 41.5 
Polysorbate 60 42.5 
Polysorbate 61 41.5 
Polysorbate 80 42.5 
Polysorbate 85 41.0 
11 Stability and Storage Conditions 
Polysorbates are stable to electrolytes and weak acids and 
bases; gradual saponification occurs with strong acids and 
bases. The oleic acid esters are sensitive to oxidation. 
Polysorbates are hygroscopic and should be examined for 
water content prior to use and dried if necessary. Also, in 
common with other polyoxyethylene surfactants, prolonged 
storage can lead to the formation of peroxides. 
Test JP 2001 PhEur 2005 USPNF 23 
Polysorbate 20 — 410 ppm — 
Polysorbate 40 — 410 ppm — 
Polysorbate 60 — 410 ppm — 
Polysorbate 80 — 410 ppm — 
Table VI: Continued 
Polyoxyethylene Sorbitan Fatty Acid Esters 583

Polysorbates should be stored in a well-closed container, 
protected from light, in a cool, dry place. 
12 Incompatibilities 
Discoloration and/or precipitation occur with various substances, 
especially phenols, tannins, tars, and tarlike materials. 
The antimicrobial activity of paraben preservatives is reduced 
in the presence of polysorbates.(2) See Methylparaben. 
13 Method of Manufacture 
Polysorbates are prepared from sorbitol in a three-step process. 
Water is initially removed from the sorbitol to form a sorbitan 
(a cyclic sorbitol anhydride). The sorbitan is then partially 
esterified with a fatty acid, such as oleic or stearic acid, to yield 
a hexitan ester. Finally, ethylene oxide is chemically added in 
the presence of a catalyst to yield the polysorbate. 
14 Safety 
Polysorbates are widely used in cosmetics, food products, and 
oral, parenteral, and topical pharmaceutical formulations and 
are generally regarded as nontoxic and nonirritant materials. 
There have, however, been occasional reports of hypersensitivity 
to polysorbates following their topical and intramuscular 
use.(3) Polysorbates have also been associated with serious 
adverse effects, including some deaths, in low-birthweight 
infants intravenously administered a vitamin E preparation 
containing a mixture of polysorbates 20 and 80.(4,5) When 
heated to decomposition, the polysorbates emit acrid smoke 
and irritating fumes. 
The WHO has set an estimated acceptable daily intake for 
polysorbates 20, 40, 60, 65, and 80, calculated as total 
polysorbate esters, at up to 25 mg/kg body-weight.(6) 
Polysorbate 20: moderate toxicity by IP and IV routes. 
Moderately toxic by ingestion. Human skin irritant. 
LD50 (hamster, oral): 18 g/kg(7) 
LD50 (mouse, IV): 1.42 g/kg 
LD50 (rat, oral): 37 g/kg 
Polysorbate 21: moderately toxic by IV route. 
Polysorbate 40: LD50 (rat, IV): 1.58 g/kg.(7) Moderately 
toxic by IV route. 
Polysorbate 60: LD50 (rat, IV): 1.22 g/kg.(7) Moderately 
toxic by IV route. Experimental tumorigen; reproductive 
effects. 
Polysorbate 61: moderately toxic by IV route. 
Polysorbate 80: moderately toxic by IV route. Mildly toxic 
by ingestion. Eye irritation. Experimental tumorigen, 
reproductive effects. Mutogenic data. 
LD50 (mouse, IP): 7.6 g/kg(7) 
LD50 (mouse, IV): 4.5 g/kg 
LD50 (mouse, oral): 25 g/kg 
LD50 (rat, IP): 6.8 g/kg 
LD50 (rat, IV): 1.8 g/kg 
Polysorbate 85: skin irritant. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. 
16 Regulatory Status 
Polysorbates 60, 65, and 80 are GRAS listed. Polysorbates 20, 
40, 60, 65, and 80 are accepted as food additives in Europe. 
Polysorbates 20, 40, 60, and 80 are included in the FDA 
Inactive Ingredients Guide (IM, IV, oral, rectal, topical, and 
vaginal preparations). Polysorbates are included in parenteral 
and nonparenteral medicines licensed in the UK. Polysorbates 
20, 21, 40, 60, 61, 65, 80, 81, 85, and 120 are included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Polyethylene glycol; sorbitan esters (sorbitan fatty acid esters). 
18 Comments 
—
19 Specific References 
1 Nerurkar MM, Burton PS, Borchardt RT. The use of surfactants to 
enhance the permeability of peptides through Caco-2 cells by 
inhibition of an apically polarized efflux system. Pharm Res 1996; 
13(4): 528–534. 
2 Blanchard J. Effect of polyols on interaction of paraben 
preservatives with polysorbate 80. J Pharm Sci 1980; 69: 169–173. 
3 Shelley WB, Talanin N, Shelley ED. Polysorbate 80 hypersensitivity 
[letter]. Lancet 1995; 345: 1312–1313. 
4 Alade SL, Brown RE, Paquet A. Polysorbate 80 and E-Ferol 
toxicity. Pediatrics 1986; 77: 593–597. 
5 Balistreri WF, Farrell MK, Bove KE. Lessons from the E-Ferol 
tragedy. Pediatrics 1986; 78: 503–506. 
6 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications, 
Seventeenth report of the joint FAO/WHO expert committee on 
food additives.World Health Organ Tech Rep Ser 1974; No. 539. 
7 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3013. 
20 General References 
Allen LV, Levinson RS, Robinson C, Lau A. Effect of surfactant on 
tetracycline absorption across everted rat intestine. J Pharm Sci 
1981; 70: 269–271. 
Chowhan ZT, Pritchard R. Effect of surfactants on percutaneous 
absorption of naproxen I: comparisons of rabbit, rat, and human 
excised skin. J Pharm Sci 1978; 67: 1272–1274. 
Donbrow M, Azaz E, Pillersdorf A. Autoxidation of polysorbates. 
J Pharm Sci 1978; 67: 1676–1681. 
Khossravi M, Kao Y-H, Mrsny RJ, Sweeney TD. Analysis methods of 
polysorbate 20: a new method to assess the stability of polysorbate 
20 and established methods that may overlook degraded polysorbate 
20. Pharm Res 2002; 19(5): 634–639. 
Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 295–301. 
21 Authors 
MJ Lawrence. 
22 Date of Revision 
22 August 2005. 
584 Polyoxyethylene Sorbitan Fatty Acid Esters

Polyoxyethylene Stearates 
1 Nonproprietary Names 
The polyoxyethylene stearates are a series of polyethoxylated 
derivatives of stearic acid. Of the large number of different 
materials commercially available, one type is listed in the 
USPNF 23. 
JP: Polyoxyl 40 stearate 
USPNF: Polyoxyl 40 stearate 
See also Sections 2, 3, 4, and 5. 
2 Synonyms 
Ethoxylated fatty acid esters; macrogol stearates; Marlosol; 
PEG fatty acid esters; PEG stearates; polyethylene glycol 
stearates; poly(oxy-1,2-ethanediyl) a-hydro-o-hydroxyoctadecanoate; 
polyoxyethylene glycol stearates. 
Polyoxyethylene stearates are nonionic surfactants produced 
by polyethoxylation of stearic acid. Two systems of 
nomenclature are used for these materials. The number ‘8’ in 
the names ‘poloxyl 8 stearate’ or ‘polyoxyethylene 8 stearate’ 
refers to the approximate polymer length in oxyethylene units. 
The same material may also be designated ‘polyoxyethylene 
glycol 400 stearate’ or ‘macrogol stearate 400’ in which case, 
the number ‘400’ refers to the average molecular weight of the 
polymer chain. 
For synonyms applicable to specific polyoxyethylene 
stearates, see Table I. 
3 Chemical Name and CAS Registry Number 
Polyethylene glycol stearate [9004-99-3] 
Polyethylene glycol distearate [9005-08-7] 
4 Empirical Formula and Molecular Weight 
See Table II. 
Table I: Synonyms of selected polyoxyethylene stearates and distearates. 
Name Synonym 
Polyoxyl 2 
stearate 
Hodag DGS; Lipo DGS; PEG-2 stearate. 
Polyoxyl 4 
stearate 
Acconon 200-MS; Hodag 20-S; PEG-4 stearate; polyethylene glycol 200 monostearate; polyoxyethylene (4) monostearate; 
Protamate 200-DPS. 
Polyoxyl 6 
stearate 
Cerasynt 616; Kessco PEG 300 Monostearate; Lipal 300S; Lipo PEG 3-S; PEG-6 stearate; polyethylene glycol 300 monostearate; 
polyoxyethylene (6) monostearate; Polystate C; Protamate 300-DPS. 
Polyoxyl 8 
stearate 
Acconon 400-MS; Cerasynt 660; Cithrol 4MS; Crodet S8; Emerest 2640; Grocor 400; Hodag 40-S; Kessco PEG-400 
Monostearate; Lipo-PEG 4-S; macrogol stearate 400; Myrj 45; PEG-8 stearate; Pegosperse 400 MS; polyethylene glycol 400 
monostearate; polyoxyethylene (8) monostearate; Protamate 400-DPS; Ritapeg 400 MS. 
Polyoxyl 12 
stearate 
Hodag 60-S; Kessco PEG 600 Monostearate; Lipo-PEG 6-S; PEG-12 stearate; Pegosperse 600 MS; polyethylene glycol 600 
monostearate; polyoxyethylene (12) monostearate; Protamate 600-DPS. 
Polyoxyl 20 
stearate 
Cerasynt 840; Hodag 100-S; Kessco PEG 1000 Monostearate; Lipo-PEG 10-S; Myrj 49; Pegosperse 1000 MS; PEG-20 stearate; 
polyethylene glycol 1000 monostearate; polyoxyethylene (20) monostearate; Protamate 1000-DPS. 
Polyoxyl 30 
stearate 
Myrj 51; PEG-30 stearate; polyoxyethylene (30) stearate. 
Polyoxyl 40 
stearate 
Crodet S40; E431; Emerest 2672; Hodag POE (40) MS; Lipal 395; Lipo-PEG 39-S; macrogol stearate 2000; Myrj 52; PEG-40 
stearate; polyoxyethylene glycol 2000 monostearate; polyoxyethylene (40) monostearate; Protamate 2000-DPS; Ritox 52. 
Polyoxyl 50 
stearate 
Atlas G-2153; Crodet S50; Lipal 505; Myrj 53; PEG-50 stearate; polyoxyethylene (50) monostearate. 
Polyoxyl 100 
stearate 
Lipo-PEG 100-S; Myrj 59; PEG-100 stearate; polyethylene glycol 4400 monostearate; polyoxyethylene (100) monostearate; 
Protamate 4400-DPS; Ritox 53. 
Polyoxyl 150 
stearate 
Hodag 600-S; PEG-150 stearate; Ritox 59. 
Polyoxyl 4 
distearate 
Hodag 22-S; PEG-4 distearate. 
Polyoxyl 8 
distearate 
Hodag 42-S; Kessco PEG 400 DS; PEG-8 distearate; polyethylene glycol 400 distearate; Protamate 400-DS. 
Polyoxyl 12 
distearate 
Hodag 62-S; Kessco PEG 600 Distearate; PEG-12 distearate; polyethylene (12) distearate; polyethylene glycol 600 distearate; 
Protamate 600-DS. 
Polyoxyl 32 
distearate 
Hodag 154-S; Kessco PEG 1540 Distearate; PEG-32 distearate; polyethylene glycol 1540 distearate; polyoxyethylene (32) 
distearate. 
Polyoxyl 150 
distearate 
Hodag 602-S; Kessco PEG 6000 DS; Lipo-PEG 6000-DS; PEG-150 distearate; polyethylene glycol 6000 distearate; 
polyoxyethylene (150) distearate; Protamate 6000-DS.

Table II: Empirical formulas and molecular weights of selected 
polyoxyethylene stearates. 
Name Empirical formula Molecular weight 
Polyoxyl 6 stearate C30H60O8 548.80 
Polyoxyl 8 stearate C34H68O10 636.91 
Polyoxyl 12 stearate C42H84O14 813.12 
Polyoxyl 20 stearate C58H116O22 1165.55 
Polyoxyl 40 stearate C98H196O42 2046.61 
Polyoxyl 50 stearate C118H236O52 2487.15 
Polyoxyl 100 stearate C218H436O102 4689.80 
5 Structural Formula 
Structure A applies to the monostearate; where the average 
value of n is 6 for polyoxyl 6 stearate, 8 for polyoxyl 8 stearate, 
and so on. 
Structure B applies to the distearate; where the average value 
of n is 12 for polyoxyl 12 distearate, 32 for polyoxyl 32 
distearate, and so on. 
In both structures, R represents the alkyl group of the parent 
fatty acid. With stearic acid, R is CH3(CH2)16. However, it 
should be noted that stearic acid usually contains other fatty 
acids, primarily palmitic acid, and consequently a polyoxyethylene 
stearate may also contain varying amounts of other 
fatty acid derivatives such as palmitates. 
6 Functional Category 
Emulsifying agent; solubilizing agent; wetting agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Polyoxyethylene stearates are generally used as emulsifiers in 
oil-in-water-type creams and lotions. Their hydrophilicity or 
lipophilicity depends on the number of ethylene oxide units 
present: the larger the number, the greater the hydrophilic 
properties. Polyoxyl 40 stearate has been used as an emulsifying 
agent in intravenous infusions.(1) 
Polyoxyethylene stearates are particularly useful as emulsifying 
agents when astringent salts or other strong electrolytes 
are present. They can also be blended with other surfactants to 
obtain any hydrophilic–lipophilic balance for lotions or 
ointment formulations. See Table III. 
Table III: Uses of polyoxyethylene stearates. 
Use Concentration (%) 
Auxiliary emulsifier for o/w intravenous fat 
emulsion 
0.5–5 
Emulsifier for o/w creams or lotions 0.5–10 
Ophthalmic ointment 7 
Suppository component 1–10 
Tablet lubricant 1–2 
8 Description 
See Table IV. 
Table IV: Description of various polyoxyethylene stearates. 

Name Description 
Polyoxyl 6 stearate Soft solid 
Polyoxyl 8 stearate Waxy cream 
Polyoxyl 12 stearate Pasty solid 
Polyoxyl 20 stearate Waxy solid 
Polyoxyl 40 stearate Waxy solid, with a faint, bland, fat-like 
odor, off-white to light tan in color 
Polyoxyl 50 stearate Solid, with a bland, fat-like odor or 
odorless 
Polyoxyl 100 stearate Solid 
Polyoxyl 12 distearate Paste 
Polyoxyl 32 distearate Solid 
Polyoxyl 150 distearate Solid 
9 Pharmacopeial Specifications 
See Table V. 
Table V: Pharmacopeial specifications for polyoxyethylene stearates. 
Test JP 2001 USPNF 23 
Polyoxyl 40 stearate Polyoxyl 40 stearate 
Identification . . 
Clarity and color of 
solution 
. — 
Congealing range 39–448C 37–478C 
Congealing point of the 
fatty acid 
5538C — 
Residue on ignition 40.10% — 
Water — 43.0% 
Arsenic 43 ppm — 
Heavy metals 410 ppm 40.001% 
Acid value 41 42 
Hydroxyl value — 25–40 
Saponification value 25–35 25–35 
Free polyethylene 
glycols 
— 17–27% 
Organic volatile 
impurities 
— . 
10 Typical Properties 
Flash point: >1498C for poloxyl 8 stearate (Myrj 45). 
Solubility: see Table VI. See also Table VII. 
586 Polyoxyethylene Stearates

Table VI: Solubility of polyoxyethylene stearates. 
Name Solvent 
Ethanol (95%) Mineral oil Water 
Polyoxyl 6 stearate S S DH 
Polyoxyl 8 stearate S I D 
Polyoxyl 12 stearate S I S 
Polyoxyl 20 stearate S I S 
Polyoxyl 40 stearate S I S 
Polyoxyl 50 stearate S I S 
Polyoxyl 100 stearate S I S 
Polyoxyl 12 distearate S — DH 
Polyoxyl 32 distearate S — S 
Polyoxyl 150 distearate I — S 
D = dispersible; I = insoluble; S = soluble; DH = dispersible (with heat). 
11 Stability and Storage Conditions 
Polyoxyethylene stearates are generally stable in the presence of 
electrolytes and weak acids or bases. Strong acids and bases can 
cause gradual hydrolysis and saponification. 
The bulk material should be stored in a well-closed 
container, in a dry place, at room temperature. 
12 Incompatibilities 
Polyoxyethylene stearates are unstable in hot alkaline solutions 
owing to hydrolysis, and will also saponify with strong acids or 
bases. Discoloration or precipitation can occur with salicylates, 
phenolic substances, iodine salts, and salts of bismuth, silver, 
and tannins.(2–4) Complex formation with preservatives may 
also occur.(5) The antimicrobial activity of some materials such 
as bacitracin, chloramphenicol, phenoxymethylpenicillin, 
sodium penicillin, and tetracycline may be reduced in the 
presence of polyoxyethylene stearate concentrations greater 
than 5% w/w.(6,7) 
13 Method of Manufacture 
Polyoxyethylene stearates are prepared by the direct reaction of 
fatty acids, particularly stearic acid, with ethylene oxide. 
14 Safety 
Although polyoxyethylene stearates are primarily used as 
emulsifying agents in topical pharmaceutical formulations, 
certain materials, particularly polyoxyl 40 stearate, have also 
been used in intravenous injections and oral preparations.(1,4) 
Polyoxyethylene stearates have been tested extensively for 
toxicity in animals(8–13) and are widely used in pharmaceutical 
formulations and cosmetics. They are generally regarded as 
essentially nontoxic and nonirritant materials. 
Polyoxyl 8 stearate: 
LD50 (hamster, oral): 27 g/kg 
LD50 (rat, oral): 64 g/kg 
Polyoxyl 20 stearate: 
LD50 (mouse, IP): 0.2 g/kg 
LD50 (mouse, IV): 0.87 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
Polyoxyethylene stearates that contain greater than 
100 ppm of free ethylene oxide may present an explosion 
hazard when stored in a closed container. This is due to the 
release of ethylene oxide into the container headspace, where it 
can accumulate and so exceed the explosion limit. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (dental 
solutions; IV injections; ophthalmic preparations; oral capsules 
and tablets; otic suspensions; topical creams, emulsions, 
lotions, ointments, and solutions; and vaginal preparations). 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Polyethylene glycol; stearic acid. 
18 Comments 
— 
Table VII: Typical properties of polyoxyethylene stearates. 
Name Acid 
value 
Free ethylene oxide HLB value Hydroxyl 
value 
Iodine 
number 
Melting 
point (8C) 
Saponification 
value 
Water 
content (%) 
Polyoxyl 6 stearate 45.0 4100 ppm 9.7 — 40.5 28–32 95–110 — 
Polyoxyl 8 stearate 42.0 4100 ppm 11.1 87–105 41.0 28–33 82–95 43.0 
Polyoxyl 12 stearate 48.5 4100 ppm 13.6 55–75 41.0  37 62–78 41.0 
Polyoxyl 20 stearate 41.0 4100 ppm 14 50–62 41.0  28 46–56 41.0 
Polyoxyl 30 stearate 42.0 — 16 35–50 — — 30–45 43.0 
Polyoxyl 40 stearate 41.0 — 16.9 27–40 —  38 25–35 43.0 
Polyoxyl 50 stearate 42.0 — 17.9 23–35 —  42 20–28 43.0 
Polyoxyl 100 stearate 41.0 4100 ppm 18.8 15–30 —  46 9–20 43.0 
Polyoxyl 8 distearate 410.0 — — 415 40.5  36 115–124 — 
Polyoxyl 12 distearate 410.0 4100 ppm 10.6 420 41.0  39 93–102 41.0 
Polyoxyl 32 distearate 410.0 4100 ppm 14.8 420 40.25  45 50–62 41.0 
Polyoxyl 150 distearate 7–9 4100 ppm 18.4 415 40.1 53–57 14–20 41.0 
Polyoxyethylene Stearates 587

19 Specific References 
1 Cohn I, Singleton S, Hartwig QL, Atik M. New intravenous fat 
emulsion. J Am Med Assoc 1963; 183: 755–757. 
2 Thoma K, Ullmann E, Fickel O. The antibacterial activity of 
phenols in the presence of polyoxyethylene stearates and 
polyethylene glycols [in German]. Arch Pharm 1970; 303: 289– 
296. 
3 Thoma K, Ullmann E, Fickel O. Dimensions and cause of the 
reaction between phenols and polyoxyethylene stearates [in 
German]. Arch Pharm 1970; 303: 297–304. 
4 Duchene D, Djiane A, Puisieux F. Tablet study III: influence of 
nonionic surfactants with ester linkage on the quality of 
sulfanilamide grains and tablets [in French]. Ann Pharm Fr 
1970; 28: 289–298. 
5 Chakravarty D, Lach JL, Blaug SM. Study of complex formation 
between polyoxyl 40 stearate and some pharmaceuticals. Drug 
Standards 1957; 25: 137–140. 
6 Ullmann E, Moser B. Effect of polyoxyethylene stearates on the 
antibacterial activity of antibiotics [in German]. Arch Pharm 1962; 
295: 136–143. 
7 Thoma K, Ullmann E, Zelfel G. Investigation of the stability of 
penicillin G sodium in the presence of nonionic surface active 
agents (polyethylene glycol derivatives) [in German]. Arch Pharm 
1962; 295: 670–678. 
8 Culver PJ, Wilcox CS, Jones CM, Rose RS. Intermediary 
metabolism of certain polyoxyethylene derivatives in man I: 
recovery of the polyoxyethylene moiety from urine and feces 
following ingestion of polyoxyethylene (20) sorbitan monooleate 
and of polyoxyethylene (40) mono-stearate. J Pharmacol Exp Ther 
1951; 103: 377–381. 
9 Oser BL, Oser M. Nutritional studies on rats on diets containing 
high levels of partial ester emulsifiers I: general plan and 
procedures; growth and food utilization. J Nutr 1956; 60: 367– 
390. 
10 Oser BL, Oser M. Nutritional studies on rats on diets containing 
high levels of partial ester emulsifiers II: reproduction and 
lactation. J Nutr 1956; 60: 489–505. 
11 Oser BL, Oser M. Nutritional studies on rats on diets containing 
high levels of partial ester emulsifiers III: clinical and metabolic 
observations. J Nutr 1957; 61: 149–166. 
12 Oser BL, Oser M. Nutritional studies on rats on diets containing 
high levels of partial ester emulsifiers IV: mortality and postmortem 
pathology; general conclusions. J Nutr 1957; 61: 235– 
252. 
13 Fitzhugh OG, Bourke AR, Nelson AA, Frawley JP. Chronic oral 
toxicities of four stearic acid emulsifiers. Toxicol Appl Pharmacol 
1959; 1: 315–331. 
20 General References 
Satkowski WB, Huang SK, Liss RL. Polyoxyethylene esters of fatty 
acids. In: Schick MJ, ed. Nonionic Surfactants. New York: Marcel 
Dekker, 1967: 142–174. 
21 Authors 
SC Owen. 
22 Date of Revision 
31 August 2005. 
588 Polyoxyethylene Stearates

Polyvinyl Acetate Phthalate 
1 Nonproprietary Names 
USPNF: Polyvinyl acetate phthalate 
2 Synonyms 
Phthalavin; PVAP; Opaseal; Sureteric. 
3 Chemical Name and CAS Registry Number 
Polyvinyl acetate phthalate [34481-48-6] 
4 Empirical Formula and Molecular Weight 
The USPNF 23 describes polyvinyl acetate phthalate as a 
reaction product of phthalic anhydride and a partially 
hydrolyzed polyvinyl acetate. It contains not less than 55.0% 
and not more than 62.0% of phthalyl (o-carboxybenzoyl, 
C8H5O3) groups, calculated on an anhydrous acid-free basis. 
It has been reported that the free phthalic acid content is 
dependent on the source of the material.(1) 
5 Structural Formula 
Depending on the phthalyl content, a will vary with b in 
mole percent. The acetyl content c remains constant depending 
on the starting material. 
6 Functional Category 
Coating agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Polyvinyl acetate phthalate is a viscosity-modifying agent that is 
used in pharmaceutical formulations to produce enteric coatings 
for products and for the core sealing of tablets prior to a 
sugar-coating process. Polyvinyl acetate phthalate does not 
exhibit tackiness during coating and produces strong robust 
films. 
Plasticizers are often included in polyvinyl acetate phthalate 
coating formulations to enable a continuous, homogeneous, 
noncracking film to be produced. Polyvinyl acetate phthalate 
has been shown to be compatible with several plasticizers such 
as glyceryl triacetate, triethyl citrate, acetyl triethylcitrate, 
diethyl phthalate and polyethylene glycol 400. 
For enteric coating applications, polyvinyl acetate phthalate 
is dissolved in a solvent system together with other additives 
such as diethyl phthalate and stearic acid. Methanol may be 
used as the solvent if a colorless film is required; for a colored 
film, methanol or ethanol/water may be used depending on the 
amount of pigment to be incorporated. A weight increase of up 
to 8% is necessary for nonpigmented systems, whereas for 
pigmented systems a weight increase of 6% is usually required. 
A formulated, aqueous-based coating solution (Sureteric, 
Colorcon) is available commercially for the enteric coating of 
tablets, hard and soft gelatin capsules and granules. 
Polyvinyl acetate phthalate has superseded materials such as 
shellac in producing the initial layers of coating (the sealing 
coat) in the sugar coating process for tablets. The sealing 
coating should be kept as thin as possible while providing an 
adequate barrier to moisture, a balance that is often difficult to 
achieve in practice. A solvent system containing a high 
proportion of industrial methylated spirits and other additives 
can be used. Two coats are usually sufficient to seal most 
tablets, although up to five may be necessary for tablets 
containing alkaline ingredients. If an enteric coating is also 
required, between six and 12 coats may be necessary, see Table 
I. 
The properties of polyvinyl acetate phthalate enteric coating 
have been compared with those of other enteric polymers such 
as cellulose acetate phthalate(2,3) and Eudragit L 30D.(3) The 
factors that affect the release kinetics from polyvinyl acetate 
phthalate enteric-coated tablets have also been described.(4) A 
method for enteric coating hypromellose capsules which avoids 
the sealing step prior to coating has been developed. The 
properties of several enteric coating polymers, including 
polyvinyl acetate phthalate, were assessed.(5) 
Table I: Uses of polyvinyl acetate phthalate. 
Use Concentration (%) 
Tablet enteric film coating 9–10 
Tablet sealant (sugar-coating) 28–29 
8 Description 
Polyvinyl acetate phthalate is a free-flowing white to off-white 
powder and may have a slight odor of acetic acid. The material 
is essentially amorphous.(6) 
9 Pharmacopeial Specifications 
See Table II.

Table II: Pharmacopeial specifications for polyvinyl acetate 
phthalate. 
Test USPNF 23 
Identification . 
Apparent viscosity at 258C 7–11 mPa s 

Water 45.0% 
Residue on ignition 41.0% 
Free phthalic acid 40.6% 
Free acid other than phthalic 40.6% 
Organic volatile impurities . 
Phthalyl content 55.0–62.0% 
10 Typical Properties 
The characteristics of polyvinyl acetate phthalate from two 
sources have been compared; values for molecular weight 
(60 700; 47 000), moisture content (3.74%; 2.20%) and 
density (1.31 g/cm3; 1.37 g/cm3) have been reported. The 
solubility of each polyvinyl acetate phthalate in a range of 
different solvents was described and scanning electron photomicrographs 
were produced to give evidence of the different 
polymer morphology.(7) 
Glass transition temperature: a glass transition temperature of 
42.58C has been reported for polyvinyl acetate phthalate; 
the glass transition temperature was shown to fall with the 
addition of increasing amounts of the plasticizer diethyl 
phthalate.(6) 
Solubility: soluble in ethanol and methanol; sparingly soluble in 
acetone and propan-2-ol; practically insoluble in chloroform, 
dichloromethane, and water. In buffer solutions, 
polyvinyl acetate phthalate (200 mg/L) is insoluble below 
pH 5 and becomes soluble at pH values above 5. Polyvinyl 
acetate pththalate shows a sharp solubility response with 
pH; this occurs at pH 4.5–5.0, which is lower than for most 
other polymers used for enteric coatings. Solubility is also 
influenced by ionic strength. See Table III. 
Table III: Solubility of polyvinyl acetate phthalate. 
Solvent Solubility at 258C 
Acetone/ethanol (1 : 1 w/w) 1 in 3 
Acetone/methanol (1 : 1 w/w) 1 in 4 
Ethanol (95%) 1 in 4 
Methanol 1 in 2 
Methanol/dichloromethane (1 : 1 w/w) 1 in 3 
Viscosity (dynamic): the viscosity of a solution of polyvinyl 
acetate phthalate:methanol (1 : 1) is 5000 mPa s. In methanol/
dichloromethane systems, viscosity increases as the 
concentration of methanol in the system increases. 
11 Stability and Storage Conditions 
Polyvinyl acetate phthalate should be stored in airtight 
containers. It is relatively stable to temperature and humidity 
and does not age, giving predictable release profiles even after 
prolonged storage. 
At high temperature and humidity, polyvinyl acetate 
phthalate undergoes less hydrolysis than other commonly 
used enteric coating polymers. In aqueous colloidal dispersions 
of polyvinyl acetate phthalate, the formation of free phthalic 
acid through hydrolysis was found to adversely affect physical 
stability.(1) 
Following storage at room temperature for 9 months, 
capsules coated with a commercial polyvinyl acetate phthalate 
formulation (Coateric) were found to retain gastroresistant 
properties and showed no apparent physical change; however, a 
delayed drug dissolution profile was observed after storage. 
Storage at 378C, or 378C and 80% relative humidity, for 3 
months resulted in capsules having an unsatisfactory appearance.(
3) 
12 Incompatibilities 
Polyvinyl acetate phthalate reacts with povidone to form an 
insoluble complex that precipitates out of solution;(8) benzocaine 
is also incompatible with polyvinyl acetate phthalate.(9) 
Erythromycin disperses in polyvinyl acetate phthalate and has 
been shown to be physically stable(10) while omeprazole exists 
in the amorphous form in polyvinyl acetate phthalate coatings 
with no evidence of interaction.(11) 
13 Method of Manufacture 
Polyvinyl acetate phthalate is a reaction product of phthalic 
anhydride, sodium acetate, and a partially hydrolyzed polyvinyl 
alcohol. The polyvinyl alcohol is a low molecular weight 
grade, and 87–89 mole percent is hydrolyzed. Therefore, the 
polyvinyl acetate phthalate polymer is a partial esterification of 
a partially hydrolyzed polyvinyl acetate. 
See also Section 4. 
14 Safety 
Polyvinyl acetate phthalate is used in oral pharmaceutical 
formulations and is generally regarded as an essentially 
nonirritant and nontoxic material when used as an excipient. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Gloves and eye protection are 
recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (sustainedaction 
oral tablet). Included in nonparenteral medicines 
licensed in Europe. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Cellulose acetate phthalate; hypromellose phthalate; polymethacrylates; 
shellac. 
18 Comments 
Polyvinyl acetate phthalate dissolves along the whole length of 
the duodenum. 
19 Specific References 
1 Davis MB. Preparation and stability of aqueous-based enteric 
polymer dispersions. Drug Dev Ind Pharm 1986; 12(10): 1419– 
1448. 
590 Polyvinyl Acetate Phthalate

2 Porter SC, Ridgway K. The permeability of enteric coatings and the 
dissolution rates of coated tablets. J Pharm Pharmacol 1982; 34: 
5–8. 
3 Murthy KS, Enders NA, Mahjour M, Fawzi MB. A comparative 
evaluation of aqueous enteric polymers in capsule coatings. Pharm 
Technol 1986; 10(10): 36, 38, 40, 42, 44. 
4 Ozturk SS, Palsson BO, Donohoe B, Dressman JB. Kinetics of 
release from enteric-coated tablets. Pharm Res 1988; 5(9): 550– 
565. 
5 Huyghebaert N, Vermeire A, Remon JP. Alternative method for 
enteric coating of HPMC capsules resulting in ready-to-use entericcoated 
capsules. Eur J Pharm Sci 2004; 21(5): 617–623. 
6 Porter SC, Ridgway K. An evaluation of the properties of enteric 
coating polymers: measurement of glass transition temperature. J 
Pharm Pharmacol 1983; 35: 341–344. 
7 Nesbitt RU, Goodhart FW, Gordon RH. Evaluation of polyvinyl 
acetate phthalate as an enteric coating material. Int J Pharm 1985; 
26: 215–226. 
8 Kumar V, Yang T, Yang Y. Interpolymer complexation I: 
preparation and characterization of a polyvinyl acetate phthalate–
polyvinylpyrrolidone (PVAP-PVP) complex. Int J Pharm 
1999; 188: 221–232. 
9 Kumar V, Banker GS. Incompatibility of polyvinyl acetate 
phthalate with benzocaine: isolation and characterization of 4- 
phthalimidobenzoic acid ethyl ester. Int J Pharm 1992; 79: 61–65. 
10 Sarisuta N, Kumpugdee M, Mu. ller BW, Puttipipatkhachorn S. 
Physico-chemical characterization of interactions between 
erythromycin and various film polymers. Int J Pharm 1999; 186: 
109–118. 
11 Sarisuta N, Kumpugdee M. Crystallinity of omeprazole in various 
film polymers. Pharm Pharmacol Commun 2000; 6: 7–11. 
20 General References 
—
21 Authors 
CG Cable. 
22 Date of Revision 
23 August 2005. 
Polyvinyl Acetate Phthalate 591

Polyvinyl Alcohol 
1 Nonproprietary Names 
PhEur: Poly(vinylis acetas) 
USP: Polyvinyl alcohol 
2 Synonyms 
Airvol; Alcotex; Elvanol; Gelvatol; Gohsenol; Lemol; Mowiol; 
Polyvinol; PVA; vinyl alcohol polymer. 
3 Chemical Name and CAS Registry Number 
Ethenol, homopolymer [9002-89-5] 
4 Empirical Formula and Molecular Weight 
(C2H4O)n 20 000–200 000 
Polyvinyl alcohol is a water-soluble synthetic polymer 
represented by the formula (C2H4O)n. The value of n for 
commercially available materials lies between 500 and 5000, 
equivalent to a molecular weight range of approximately 
20 000–200 000, see Table I. 
Table I: Commercially available grades of polyvinyl acohol. 
Grade Molecular weight 
High viscosity 200 000 
Medium viscosity 130 000 
Low viscosity 20 000 
5 Structural Formula 
6 Functional Category 
Coating agent; lubricant; stabilizing agent; viscosity-increasing 
agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Polyvinyl alcohol is used primarily in topical pharmaceutical 
and ophthalmic formulations; see Table II.(1–3) It is used as a 
stabilizing agent for emulsions (0.25–3.0% w/v). Polyvinyl 
alcohol is also used as a viscosity-increasing agent for viscous 
formulations such as ophthalmic products. It is used in artificial 
tears and contact lens solutions for lubrication purposes, in 
sustained-release formulations for oral administration,(4) and in 
transdermal patches.(5) Polyvinyl alcohol may be made into 
microspheres when mixed with a glutaraldehyde solution.(6) 
Table II: Uses of polyvinyl alcohol. 
Use Concentration (%) 
Emulsions 0.5 
Ophthalmic formulations 0.25–3.00 
Topical lotions 2.5 
8 Description 
Polyvinyl alcohol occurs as an odorless, white to cream-colored 
granular powder. 
9 Pharmacopeial Specifications 
See Table III. 
Table III: Pharmacopeial specifications for polyvinyl alcohol. 
Test PhEur 2005 USP 28 
Viscosity — . 
pH 4.5–6.5 5.0–8.0 
Loss on drying 45.0% 45.0% 
Residue on ignition 41.0% 42.0% 
Water-soluble substances — 40.1% 
Degree of hydrolysis — 40.1% 
Organic volatile impurities — . 
Assay — 85.0–115.0% 
10 Typical Properties 
Melting point: 
2288C for fully hydrolyzed grades; 
180–1908C for partially hydrolyzed grades. 
Refractive index: nD
25 = 1.49–1.53 
Solubility: soluble in water; slightly soluble in ethanol (95%); 
insoluble in organic solvents. Dissolution requires dispersion 
(wetting) of the solid in water at room temperature 
followed by heating the mixture to about 908C for 
approximately 5 minutes. Mixing should be continued 
while the heated solution is cooled to room temperature. 
Specific gravity: 
1.19–1.31 for solid at 258C; 
1.02 for 10% w/v aqueous solution at 258C. 
Specific heat: 1.67 J/g (0.4 cal/g) 
Viscosity (dynamic): see Table IV. 
Table IV: Viscosity of commercial grades of polyvinyl alcohol. 
Grade Dynamic viscosity of 4% w/v aqueous 
solution at 208C (mPa s) 
High viscosity 40.0–65.0 
Medium viscosity 21.0–33.0 
Low viscosity 4.0–7.0

11 Stability and Storage Conditions 
Polyvinyl alcohol is stable when stored in a tightly sealed 
container in a cool, dry place. Aqueous solutions are stable in 
corrosion-resistant sealed containers. Preservatives may be 
added to the solution if extended storage is required. Polyvinyl 
alcohol undergoes slow degradation at 1008C and rapid 
degradation at 2008C; it is stable on exposure to light. 
12 Incompatibilities 
Polyvinyl alcohol undergoes reactions typical of a compound 
with secondary hydroxy groups, such as esterification. It 
decomposes in strong acids, and softens or dissolves in weak 
acids and alkalis. It is incompatible at high concentration with 
inorganic salts, especially sulfates and phosphates; precipitation 
of polyvinyl alcohol 5% w/v can be caused by phosphates. 
Gelling of polyvinyl alcohol solution may occur if borax is 
present. 
13 Method of Manufacture 
Polyvinyl alcohol is produced through the hydrolysis of 
polyvinyl acetate. The repeating unit of vinyl alcohol is not 
used as the starting material because it cannot be obtained in 
the quantities and purity required for polymerization purposes. 
The hydrolysis proceeds rapidly in methanol, ethanol, or a 
mixture of alcohol and methyl acetate, using alkalis or mineral 
acids as catalysts. 
14 Safety 
Polyvinyl alcohol is generally considered a nontoxic material. It 
is nonirritant to the skin and eyes at concentrations up to 10%; 
concentrations up to 7% are used in cosmetics. 
Studies in rats have shown that polyvinyl alcohol 5% w/v 
aqueous solution injected subcutaneously can cause anemia 
and infiltrate various organs and tissues.(7) 
LD50 (mouse, oral): 14.7 g/kg 
LD50 (rat, oral): >20 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. Polyvinyl alcohol dust may be an irritant on 
inhalation. Handle in a well-ventilated environment. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (ophthalmic 
preparations and oral tablets). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian List 
of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
—
18 Comments 
Various grades of polyvinyl alcohol are commercially available. 
The degree of polymerization and the degree of hydrolysis are 
the two determinants of their physical properties. Pharmaceutical 
grades are partially hydrolyzed materials and are named 
according to a coding system. The first number following a 
trade name refers to the degree of hydrolysis and the second set 
of numbers indicates the approximate viscosity (dynamic), in 
mPa s, of a 4% w/v aqueous solution at 208C. 
19 Specific References 
1 Krishna N, Brow F. Polyvinyl alcohol as an ophthalmic vehicle: 
effect on regeneration of corneal epithelium. Am J Ophthalmol 
1964; 57: 99–106. 
2 Patton TF, Robinson JR. Ocular evaluation of polyvinyl alcohol 
vehicle in rabbits. J Pharm Sci 1975; 64: 1312–1316. 
3 Anonymous. New method of ocular drug delivery launched. 
Pharm J 1993; 250: 174. 
4 Carstensen JT, Marty JP, Puisieux F, Fessi H. Bonding mechanisms 
and hysteresis areas in compression cycle plots. J Pharm Sci 1981; 
70: 222–223. 
5 Wan LSC, Lim LY. Drug release from heat-treated polyvinyl 
alcohol films. Drug Dev Ind Pharm 1992; 18: 1895–1906. 
6 Thanoo BC, Sunny MC, Jayakrishnan A. Controlled release of 
oral drugs from crosslinked polyvinyl alcohol microspheres. J 
Pharm Pharmacol 1993; 45: 16–20. 
7 Hall CE, Hall O. Polyvinyl alcohol: relationship of physicochemical 
properties to hypertension and other pathophysiologic 
sequelae. Lab Invest 1963; 12: 721–736. 
20 General References 
Chudzikowski R. Polyvinyl alcohol. Manuf Chem Aerosol News 1970; 
41(7): 31–37. 
Finch CA, ed. Polyvinyl Alcohol Developments. Chichester: Wiley, 
1992. 
21 Authors 
O AbuBaker. 
22 Date of Revision 
12 August 2005. 
Polyvinyl Alcohol 593

Potassium Alginate 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Alginic acid, potassium salt; E402; Improved Kelmar; potassium 
polymannuronate. 
3 Chemical Name and CAS Registry Number 
Potassium alginate [9005-36-1] 
4 Empirical Formula and Molecular Weight 
(C6H7O6K)n 
Potassium alginate is the potassium salt of alginic acid, a 
polyuronide made up of a sequence of two hexuronic acid 
residues, namely D-mannuronic acid and L-guluronic acid. The 
two sugars form blocks of up to 20 units along the chain with 
the proportion of the blocks dependent on the species of 
seaweed and also the part of the seaweed used. The number and 
length of the blocks is important in determining the physical 
properties of the alginate produced; the number and sequence 
of the mannuronate and guluronate residues varies in the 
naturally occurring alginate. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Emulsifying agent; stabilizing agent; suspending agent; thickening 
agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Potassium alginate is widely used in foods as a stabilizer, 
thickener, and emulsifier; however, its use as a pharmaceutical 
excipient is currently limited to experimental hydrogel systems. 
The viscosity, adhesiveness, elasticity, stiffness, and cohesiveness 
of potassium alginate hydrogels has been determined and 
compared with values from a range of other hydrogel-forming 
materials.(1) The effect of calcium ions on the rheological 
properties of procyanidin hydrogels containing potassium 
alginate and intended for oral administration has also been 
investigated.(2) 
8 Description 
Potassium alginate occurs as a white to yellowish, fibrous or 
granular powder; it is almost odorless and tasteless. 
9 Pharmacopeial Specifications 
See Section 18. 
10 Typical Properties 
Particle size distribution: average particle size 150 mm 
(Improved Kelmar) 
Solubility: potassium alginate is soluble in water, dissolving to 
form a viscous hydrophilic colloidal solution. It is insoluble 
in ethanol (95%) and in hydroalcoholic solutions in which 
the alcohol content is greater than 30% by weight; also 
insoluble in chloroform, ether, and acids having a pH lower 
than about 3. When preparing solutions of potassium 
alginate it is important to ensure proper dispersion of the 
particles, as poor dispersion will lead to the formation of 
large lumps of unhydrated powder and significantly 
extended hydration times. 
Viscosity (dynamic): 400 mPa s (for a 1% dispersion of 
Improved Kelmar). Vicosities of 4.32103 mPa s (2.5% 
dispersion) and 31.1103 mPa s (4% dispersion) have been 
reported.(1) 
Potassium alginate hydrates readily in hot or cold water; 
in solution, the acid groups of the alginate become ionized 
and a viscous solution is obtained. The viscosity is 
proportional to the concentration and molecular weight of 
the material used. As the temperature rises, a reversible 
decrease in viscosity occurs. The addition of calcium ions to 
potassium alginate solutions results in crosslinking and in 
the formation of gels; where the crosslinks formed are strong 
and numerous, the gel becomes thermally irreversible. 
11 Stability and Storage Conditions 
In the solid state, potassium alginate is a stable material that is 
not prone to microbial spoilage. Over time, a slow reduction in 
the degree of polymerization can occur, which may be reflected 
in a reduction in the viscosity of solutions. As both temperature 
and moisture can impair the performance of potassium 
alginate, storage below 258C is recommended. 
Potassium alginate solutions are stable at pH 4–10; longterm 
storage outside this range can result in depolymerization 
of the polymer through hydrolysis. Gelation or precipitation of 
the alginate can occur at pH values less than 4. Liquid or 
semisolid alginate formulations should be preserved: suitable 
preservatives are sodium benzoate, potassium sorbate, or 
parabens. 
Potassium alginate should be stored under cool, dry 
conditions in a well-closed container. 
12 Incompatibilities 
Incompatible with strong oxidizers. 
13 Method of Manufacture 
Alginate obtained from brown seaweed is subjected to 
demineralization, extraction, and precipitation of alginic acid. 
Following neutralization, the potassium alginate obtained is 
dried and milled.

14 Safety 
Potassium alginate is widely used in food products. It is 
currently used as an excipient only in experimental pharmaceutical 
formulations. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. When heated to decomposition, 
potassium alginate emits acrid smoke and irritating fumes. 
16 Regulatory Status 
GRAS listed. Accepted for use in foods in the USA and Europe. 
17 Related Substances 
Alginic acid; ammonium alginate; calcium alginate; propylene 
glycol alginate; sodium alginate. 
18 Comments 
Although not included in any pharmacopeias, a specification 
for potassium alginate is contained in the Food Chemicals 
Codex (FCC); see Table I. 
Table I: Food Chemicals Codex specifications for potassium 
alginate.(3) 
Test FCC 1996 
Arsenic 43 mg/kg 
Heavy metals 40.002% (as lead) 
Lead 45 mg/kg 
Loss on drying 15.00% 
Assay 89.2–105.5% 
19 Specific References 
1 Vennat B, Lardy F, Arvouey-Grand A, Pourrat A. Comparative 
texturometric analysis of hydrogels based on cellulose derivatives, 
carraghenates and alginates. Evaluation of adhesiveness. Drug 
Dev Ind Pharm 1998; 24(1): 27–35. 
2 Vennat B, Quan ZQ, Pouget MP, Pourrat A. Procyanidin 
hydrogels. Influence of calcium on the gelling of alginate solutions. 
Drug Dev Ind Pharm 2003; 20(17): 2707–2714. 
3 Food Chemicals Codex, 4th edn. Washington, DC: National 
Academy Press, 1996: 312 
20 General References 
—
21 Authors 
CG Cable. 
22 Date of Revision 
22 August 2005. 
Potassium Alginate 595

Potassium Benzoate 
1 Nonproprietary Names 
USPNF: Potassium benzoate 
2 Synonyms 
Benzoate of potash; benzoic acid potassium salt; E212; kalium 
benzoat; potassium salt trihydrate; ProBenz PG. 
3 Chemical Name and CAS Registry Number 
Potassium benzoate [582-25-2] 
4 Empirical Formula and Molecular Weight 
C7H5KO2 160.21 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; tablet and capsule lubricant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Potassium benzoate is predominantly used as an antimicrobial 
preservative in a wide range of beverages, foods and some 
pharmaceutical formulations. Preservative efficacy increases 
with decreasing pH; it is most effective at pH 4.5 or below. 
However, at low pH undissociated benzoic acid may produce a 
slight though discernible taste in food products. 
Increasingly, potassium benzoate is used as an alternative to 
sodium benzoate in applications where a low sodium content is 
desirable. 
Therapeutically, potassium benzoate has also been used in 
the management of hypokalemia. See also Table I. 
Table I: Uses of potassium benzoate. 
Use Concentration (%) 
Carbonated beverages 0.03–0.08 
Food products 40.1 
8 Description 
Potassium benzoate occurs as a slightly hygroscopic, white, 
odorless or nearly odorless crystalline powder or granules. 
Aqueous solutions are slightly alkaline and have a sweetish 
astringent taste. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for potassium benzoate. 
Test USPNF 23 
Identification . 
Alkalinity . 
Water 41.5% 
Heavy metals 40.001% 
Organic volatile impurities . 
Assay (anhydrous basis) 99.0–100.5% 
10 Typical Properties 
Acidity/alkalinity: aqueous solutions are slightly alkaline. 
Melting point: >3008C 
Solubility: see Table III. 
Table III: Solubility of potassium benzoate. 
Solvent Solubility at 208C 
unless otherwise stated 
Ethanol (95%) 1 in 75 
Ethanol (90%) 1 in 50 
Ether Practically insoluble 
Methanol Very slightly soluble 
Water 1 in 2.46 at 138C 
1 in 2.43 at 17.58C 
1 in 2.36 
1 in 2.27 at 33.38C 
1 in 2.23 at 418C 
1 in 2.15 at 508C 
Specific gravity: 1.5 
11 Stability and Storage Conditions 
Potassium benzoate is stable at room temperature under 
normal storage conditions. Since it is slightly hygroscopic, 
potassium benzoate should be stored in sealed containers. 
Exposure to conditions of high humidity and elevated 
temperatures should be avoided. 
12 Incompatibilities 
Potassium benzoate is incompatible with strong acids and 
strong oxidizing agents.

13 Method of Manufacture 
Potassium benzoate is prepared from the acid–base reaction 
between benzoic acid and potassium hydroxide. 
14 Safety 
Potassium benzoate is widely used in food products and is 
generally regarded as a nontoxic and nonirritant material. 
However, people with a history of allergies may show allergic 
reactions when exposed to potassium benzoate. Ingestion is 
inadvisable for asthmatics. Higher concentrations of potassium 
benzoate have been reported to cause irritation to mucous 
membranes. 
The WHO acceptable daily intake of total benzoates 
including potassium benzoate, calculated as benzoic acid, has 
been estimated at up to 5 mg/kg of body-weight.(1,2) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Potassium benzoate may be 
irritant to the eyes and skin. Eye protection and gloves are 
recommended. When exposed to heat, and when heated to 
decomposition, potassium benzoate emits acrid smoke and 
irritating fumes. 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Benzoic acid; sodium benzoate. 
18 Comments 
The EINECS number for potassium benzoate is 209-481-3. 
19 Specific References 
1 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications. 
Seventeenth report of the joint FAO/WHO expert committee on 
food additives.World Health Organ Tech Rep Ser 1974; No. 539. 
2 FAO/WHO. Evaluation of certain food additives and contaminants. 
Twenty-seventh report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1983; No. 696. 
20 General References 
—
21 Authors 
CP McCoy. 
22 Date of Revision 
17 August 2005. 
Potassium Benzoate 597

Potassium Bicarbonate 
1 Nonproprietary Names 
BP: Potassium bicarbonate 
PhEur: Kalii hydrogenocarbonas 
USP: Potassium bicarbonate 
2 Synonyms 
Carbonic acid monopotassium salt; E501; monopotassium 
carbonate; potassium acid carbonate; potassium hydrogen 
carbonate. 
3 Chemical Name and CAS Registry Number 
Potassium bicarbonate [298-14-6] 
4 Empirical Formula and Molecular Weight 
KHCO3 100.11 
5 Structural Formula 
KHCO3 
6 Functional Category 
Alkalizing agent; therapeutic agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
As an excipient, potassium bicarbonate is generally used in 
formulations as a source of carbon dioxide in effervescent 
preparations, at concentrations of 25–50% w/w. It is of 
particular use in formulations where sodium bicarbonate is 
unsuitable, for example, when the presence of sodium ions in a 
formulation needs to be limited or is undesirable. Potassium 
bicarbonate is often formulated with citric acid or tartaric acid 
in effervescent tablets or granules; on contact with water, 
carbon dioxide is released through chemical reaction, and the 
product disintegrates. On occasion, the presence of potassium 
bicarbonate alone may be sufficient in tablet formulations, as 
reaction with gastric acid can be sufficient to cause effervescence 
and product disintegration. 
Potassium bicarbonate has also been investigated as a gasforming 
agent in alginate raft systems.(1,2) 
Potassium bicarbonate is also used in food applications as 
an alkali and a leavening agent, and is a component of baking 
powder. 
Therapeutically, potassium bicarbonate is used as an 
alternative to sodium bicarbonate in the treatment of certain 
types of metabolic acidosis. It is also used as an antacid to 
neutralize acid secretions in the gastrointestinal tract and as a 
potassium supplement. 
8 Description 
Potassium bicarbonate occurs as colorless, transparent crystals 
or as a white granular or crystalline powder. It is odorless, with 
a saline or weakly alkaline taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for potassium bicarbonate. 
Test PhEur 2005 USP 28 
Identification . . 
Characters . — 
Appearance . — 
Normal carbonates — 42.5% 
Chloride 4150 ppm — 
Sulfate 4150 ppm — 
Ammonium 420 ppm — 
Calcium 4100 ppm — 
Heavy metals 410 ppm 40.001% 
Iron 420 ppm — 
Sodium 40.5% — 
Loss on drying — 40.3% 
Organic volatile impurities — . 
Assay 99.0–101.0% 99.5–101.5% 
10 Typical Properties 
Acidity/alkalinity: pH = 8.2 (for a 0.1M aqueous solution) 
Solubility: soluble 1 in 4.5 of water at 08C, 1 in 2.8 of water at 
208C, 1 in 2 of water at 508C; practically insoluble in 
ethanol (95%). 
Specific gravity: 2.17 
11 Stability and Storage Conditions 
Potassium bicarbonate should be stored in a well-closed 
container in a cool, dry location. Potassium bicarbonate is 
stable in air at normal temperatures, but when heated to 
100–2008C in the dry state, or in solution, it is gradually 
converted to potassium carbonate. 
12 Incompatibilities 
Potassium bicarbonate reacts with acids and acidic salts with 
the evolution of carbon dioxide. 
13 Method of Manufacture 
Potassium bicarbonate can be made by passing carbon dioxide 
into a concentrated solution of potassium carbonate, or by 
exposing moist potassium carbonate to carbon dioxide, 
preferably under moderate pressure. 
Potassium bicarbonate also occurs naturally in the mineral 
calcinite.

14 Safety 
Potassium bicarbonate is used in cosmetics, foods, and oral 
pharmaceutical formulations, where it is generally regarded as 
a relatively nontoxic and nonirritant material when used as an 
excipient. However, excessive consumption of potassium 
bicarbonate or other potassium salts may produce toxic 
manifestations of hyperkalemia. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe (the E 
number E501 refers to potassium carbonates). Included in 
nonparenteral medicines licensed in the UK and USA (chewable 
tablets; effervescent granules; effervescent tablets; lozenges; 
oral granules; oral suspensions). Included in the Canadian List 
of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Sodium bicarbonate. 
18 Comments 
One gram of potassium bicarbonate represents approximately 
10 mmol of potassium and of bicarbonate; 2.56 g of potassium 
bicarbonate is approximately equivalent to 1 g of potassium. A 
specification for potassium bicarbonate is contained in the 
Food Chemicals Codex (FCC). 
The EINECS number for potassium bicarbonate is 206- 
059-0. 
19 Specific References 
1 Johnson FA, Craig DQM, Mercer AD, Chauhan S. The effects of 
alginate molecular structure and formulation variables on the 
physical characteristics of alginate raft systems. Int J Pharm 1997; 
159: 35–42. 
2 Johnson FA, Craig DQM, Mercer A, Chauhan S. The use of image 
analysis as a means of monitoring bubble formation in alginate 
rafts. Int J Pharm 1998; 170: 179–185. 
20 General References 
—
21 Authors 
CG Cable. 
22 Date of Revision 
22 August 2005. 
Potassium Bicarbonate 599

Potassium Chloride 
1 Nonproprietary Names 
BP: Potassium chloride 
JP: Potassium chloride 
PhEur: Kalii chloridum 
USP: Potassium chloride 
2 Synonyms 
Chloride of potash; chloropotassuril; dipotassium dichloride; 
E508; potassium monochloride. 
3 Chemical Name and CAS Registry Number 
Potassium chloride [7447-40-7] 
4 Empirical Formula and Molecular Weight 
KCl 74.55 
5 Structural Formula 
KCl 
6 Functional Category 
Therapeutic agent; tonicity agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Potassium chloride is widely used in a variety of parenteral and 
nonparenteral pharmaceutical formulations. Its primary use, in 
parenteral and ophthalmic preparations, is to produce isotonic 
solutions. 
Potassium chloride is also used therapeutically in the 
treatment of hypokalemia. 
Many solid-dosage forms of potassium chloride exist 
including: tablets prepared by direct compression(1–4) and 
granulation;(5,6) effervescent tablets; coated, sustained-release 
tablets;(7–10) sustained-release wax matrix tablets;(11) microcapsules;(
12) pellets; and osmotic pump formulations.(13,14) 
Experimentally, potassium chloride is frequently used as a 
model drug in the development of new solid-dosage forms, 
particularly for sustained-release or modified-release products. 
Potassium chloride is also used widely in the food industry 
as a dietary supplement, pH control agent, stabilizer, thickener, 
and gelling agent. It can also be used in infant formulations. 
8 Description 
Potassium chloride occurs as odorless, colorless crystals or a 
white crystalline powder, with an unpleasant, saline taste. The 
crystal lattice is a face-centered cubic structure. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for potassium chloride. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Acidity or alkalinity . . . 
Appearance of solution. . — 
Loss on drying 40.5% 41.0% 41.0% 
Iodide or bromide . . . 
Aluminum — 41 ppm 41 mg/g 
Arsenic 42 ppm — — 
Barium — . — 
Calcium and 
magnesium 
. 4200 ppm . 
Heavy metals 45 ppm 410 ppm 40.001% 
Iron — 420 ppm — 
Sodium . 40.1% . 
Sulfates — 4300 ppm — 
Organic volatile 
impurities 
— — . 
Assay (dried basis) 599.0% 99.0–100.5% 99.0–100.5% 
10 Typical Properties 
Acidity/alkalinity: pH 7 for a saturated aqueous solution at 
158C. 
Boiling point: sublimes at 15008C 
Compressibility: see Figure 1.(3,4) 
Density: 1.99 g/cm3; 1.17 g/cm3 for a saturated aqueous 
solution at 158C. 
Melting point: 7908C 
Osmolarity: a 1.19% w/v solution is iso-osmotic with serum. 
Particle size distribution: typical distribution(5) is 10% less than 
30 mm, 50% less than 94 mm, and 90% less than 149 mm in 
size. Mean particle diameter is 108 mm. Finer powders may 
be obtained by milling. 
Solubility: see Table II. 
Table II: Solubility of potassium chloride. 
Solvent Solubility at 208C 
unless otherwise stated 
Acetone Practically insoluble 
Ethanol (95%) 1 in 250 
Ether Practically insoluble 
Glycerin 1 in 14 
Water 1 in 2.8 
1 in 1.8 at 1008C 
Specific surface area: 0.084m2/g (BET method)(5)

Figure 1: Compression characteristics of potassium chloride.(3) Tablet 
diameter = 10 mm. 
11 Stability and Storage Conditions 
Potassium chloride tablets become increasingly hard on storage 
at low humidities. However, tablets stored at 76% relative 
humidity showed no increase or only a slight increase in 
hardness.(2) The addition of lubricants, such as 2% w/w 
magnesium stearate,(1) reduces tablet hardness and hardness on 
aging.(2) Aqueous potassium chloride solutions may be 
sterilized by autoclaving or by filtration. 
Potassium chloride is stable and should be stored in a wellclosed 
container in a cool, dry place. 
12 Incompatibilities 
Potassium chloride reacts violently with bromine trifluoride 
and with a mixture of sulfuric acid and potassium permanganate. 
The presence of hydrochloric acid, sodium chloride, and 
magnesium chloride decreases the solubility of potassium 
chloride in water. Aqueous solutions of potassium chloride 
form precipitates with lead and silver salts. 
Intravenous aqueous potassium chloride solutions are 
incompatible with protein hydrolysate. 
13 Method of Manufacture 
Potassium chloride occurs naturally as the mineral sylvite or 
sylvine; it also occurs in other minerals such as sylvinite, 
carnallite, and kainite. Commercially, potassium chloride is 
obtained by the solar evaporation of brine or by the mining of 
mineral deposits. 
14 Safety 
Potassium chloride is used in a large number of pharmaceutical 
formulations including oral, parenteral, and topical preparations 
both as an excipient and as a therapeutic agent. 
Potassium ions play an important role in cellular metabolism 
and imbalances can result in serious clinical effects. Orally 
ingested potassium chloride is rapidly absorbed from the 
gastrointestinal tract and excreted by the kidneys. Potassium 
chloride is more irritant than sodium chloride when adminstered 
orally, and ingestion of large quantities of potassium 
chloride can cause effects such as gastrointestinal irritation, 
nausea, vomiting, and diarrhea. 
High localized concentrations of potassium chloride in the 
gastrointestinal tract can cause ulceration, hence the development 
of the many enteric-coated and wax matrix sustainedrelease 
preparations that are available.(15) Although it is 
claimed that some formulations cause less ulceration than 
others, it is often preferred to administer potassium chloride as 
an aqueous solution. However, solutions have also been 
associated with problems, mainly due to their unpleasant taste. 
Parenterally, rapid injection of strong potassium chloride 
solutions can cause cardiac arrest; in the adult, solutions should 
be infused at a rate not greater than 750 mg/hour. 
Therapeutically, in adults, up to 10 g orally, in divided doses 
has been administered daily, while intravenously up to 6 g daily 
has been used. 
LD50 (guinea pig, oral): 2.5 g/kg(16) 
LD50 (mouse, IP): 1.18 g/kg 
LD50 (mouse, IV): 0.12 g/kg 
LD50 (mouse, oral): 0.38 g/kg 
LD50 (rat, IP): 0.66 g/kg 
LD50 (rat, IV): 0.14 g/kg 
LD50 (rat, oral): 2.6 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (injections, ophthalmic 
preparations, oral capsules, and tablets). Included in nonparenteral 
and parenteral medicines licensed in the UK. Included in 
the Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Sodium chloride. 
18 Comments 
Each gram of potassium chloride represents approximately 
13.4 mmol of potassium; 1.91 g of potassium chloride is 
approximately equivalent to 1 g of potassium. 
For diets where the intake of sodium chloride is restricted, 
salt substitutes for use in cooking or as table salt are available 
and contain mainly potassium chloride, e.g. LoSalt (Klinge 
Chemicals Ltd) is a blend of 2/3 potassium chloride and 1/3 
sodium chloride with magnesium carbonate added as a flowpromoting 
agent. A specification for potassium chloride is 
contained in the Food Chemicals Codex (FCC). 
The EINECS number for potassium chloride is 231-211-8. 
19 Specific References 
1 Hirai Y, Okada J. Calculated stress and strain conditions of 
lubricated potassium chloride powders during die-compression. 
Chem Pharm Bull 1982; 30: 2202–2207. 
2 Lordi N, Shiromani P. Mechanism of hardness of aged compacts. 
Drug Dev Ind Pharm 1984; 10: 729–752. 
Potassium Chloride 601

3 Pintye-Hodi K, Sohajda-Szu. cs E. Study on the compressibility of 
potassium chloride part 1: direct pressing without auxiliary 
products [in German]. Pharm Ind 1984; 46: 767–769. 
4 Pintye-Hodi K, Sohajda-Szu. cs E. Study on the compressibility of 
potassium chloride part 2: direct compressing with microgranulous 
celluloses [in German]. Pharm Ind 1984; 46: 1080–1083. 
5 Niskanen T, Yliruusi J, Niskanen M, Kontro O. Granulation of 
potassium chloride in instrumental fluidized bed granulator part 1: 
effect of flow rate. Acta Pharm Fenn 1990; 99: 13–22. 
6 Niskanen T, Yliruusi J, Niskanen M, Kontro O. Granulation of 
potassium chloride in instrumental fluidized bed granulator part 2: 
evaluation of the effects of two independent process variables using 
32-factorial design. Acta Pharm Fenn 1990; 99: 23–30. 
7 Fee JV, Grant DJW, Newton JM. The effect of surface coatings on 
the dissolution rate of a non-disintegrating solid (potassium 
chloride). J Pharm Pharmacol 1973; 25 (Suppl.): 149P–150P. 
8 Thomas WH. Measurement of dissolution rates of potassium 
chloride from various slow release potassium chloride tablets using 
a specific ion electrode. J Pharm Pharmacol 1973; 25: 27–34. 
9 Cartwright AC, Shah C. An in vitro dissolution test for slow 
release potassium chloride tablets. J Pharm Pharmacol 1977; 29: 
367–369. 
10 Beckett AH, Samaan SS. Sustained release potassium chloride 
products in vitro–in vivo correlations. J Pharm Pharmacol 1978; 
30 (Suppl.): 69P. 
11 Flanders P, Dyer GA, Jordan D. The control of drug release from 
conventional melt granulation matrices. Drug Dev Ind Pharm 
1987; 13: 1001–1022. 
12 Harris MS. Preparation and release characteristics of potassium 
chloride microcapsules. J Pharm Sci 1981; 70: 391–394. 
13 Ramadan MA, Tawashi R. The effect of hydrodynamic conditions 
and delivery orifice size on the rate of drug release from the 
elementary osmotic pump system (EOP). Drug Dev Ind Pharm 
1987; 13: 235–248. 
14 Lindstedt B, Sjo. berg M, Hja. rtstam J. Osmotic pumping release 
from KCl tablets coated with porous and non-porous ethylcellulose. 
Int J Pharm 1991; 67: 21–27. 
15 McMahon FG, Ryan JR, Akdamar K, Ertan A. Effect of potassium 
chloride supplements on upper gastrointestinal mucosa. Clin 
Pharmacol Ther 1984; 35: 852–855. 
16 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3025–3026. 
20 General References 
Love DW, Foster TS, Bradley DL. Comparison of the taste and 
acceptance of three potassium chloride preparations. Am J Hosp 
Pharm 1978; 35(5): 586–588. 
Staniforth JN, Rees JE. Segregation of vibrated powder mixes containing 
different concentrations of fine potassium chloride and tablet 
excipients. J Pharm Pharmacol 1983; 35: 549–554. 
21 Authors 
SC Owen. 
22 Date of Revision 
9 August 2005. 
602 Potassium Chloride

Potassium Citrate 
1 Nonproprietary Names 
BP: Potassium citrate 
PhEur: Kalii citras 
USP: Potassium citrate 
2 Synonyms 
Citrate of potash; citric acid potassium salt; E332; tripotassium 
citrate monohydrate. 
3 Chemical Name and CAS Registry Number 
2-Hydroxy-1,2,3-propanetricarboxylic acid tripotassium salt 
monohydrate [6100-05-6] 
2-Hydroxy-1,2,3-propanetricarboxylic acid tripotassium salt 
anhydrous [866-84-2] 
4 Empirical Formula and Molecular Weight 
C6H5K3O7H2O 324.41 (for monohydrate) 
C6H5K3O7 306.40 (for anhydrous) 
5 Structural Formula 
6 Functional Category 
Alkalizing agent; buffering agent; sequestering agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Potassium citrate is used in beverages, foods, and oral 
pharmaceutical formulations as a buffering and alkalizing 
agent. It is also used as a sequestering agent and as a therapeutic 
agent to alkalinize the urine and to relieve the painful irritation 
caused by cystitis.(1–5) See Table I. 
Table I: Uses of potassium citrate. 
Use Concentration (%) 
Buffer for solutions 0.3–2.0 
Sequestering agent 0.3–2.0 
8 Description 
Transparent prismatic crystals or a white, granular powder. 
Potassium citrate is hygroscopic and odorless, and has a 
cooling, saline taste. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for potassium citrate. 
Test PhEur 2005 USP 28 
Identification . . 
Characters . — 
Acidity or alkalinity . . 
Loss on drying 4.0–7.0% 3.0–6.0% 
Appearance of solution . — 
Tartrate — . 
Heavy metals 410 ppm 40.001% 
Sodium 40.3% — 
Chlorides 450 ppm — 
Oxalates 4300 ppm — 
Sulfates 4150 ppm — 
Organic volatile impurities — . 
Readily carbonizable substances . — 
Assay (dried basis) 99.0–101.0% 99.0–100.5% 
10 Typical Properties 
Acidity/alkalinity: pH = 8.5 (saturated aqueous solution). 
Density: 1.98 g/cm3 
Melting point: 2308C (loses water of crystallization at 1808C). 
Solubility: see Table III. 
Table III: Solubility of potassium citrate. 
Solvent Solubility at 208C 
Ethanol (95%) Practically insoluble 
Glycerin 1 in 2.5 
Water 1 in 0.65 
11 Stability and Storage Conditions 
Potassium citrate is a stable, though hygroscopic material, and 
should be stored in an airtight container in a cool, dry place.

12 Incompatibilities 
Aqueous potassium citrate solutions are slightly alkaline and 
will react with acidic substances. Potassium citrate may also 
precipitate alkaloidal salts from their aqueous or alcoholic 
solutions. Calcium and strontium salts will cause precipitation 
of the corresponding citrates. 
13 Method of Manufacture 
Potassium citrate is prepared by adding either potassium 
bicarbonate or potassium carbonate to a solution of citric 
acid until effervescence ceases. The resulting solution is then 
filtered and evaporated to dryness to obtain potassium citrate. 
14 Safety 
Potassium citrate is used in oral pharmaceutical formulations 
and is generally regarded as a nontoxic and nonirritant material 
by this route of administration. 
Most potassium citrate safety data relate to its use as a 
therapeutic agent, for which up to 10 g may be administered 
daily, in divided doses, as a treatment for cystitis. Although 
there are adverse effects associated with excessive ingestion of 
potassium salts, the quantities of potassium citrate used as a 
pharmaceutical excipient are insignificant in comparison to 
those used therapeutically. 
LD50 (IV, dog): 0.17 g/kg(6) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Potassium citrate may be 
irritant to the skin and eyes and should be handled in a wellventilated 
environment. Eye protection and gloves are recommended. 
When heated to decomposition, potassium citrate 
emits toxic fumes of potassium oxide.(6) 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (oral solutions and 
suspensions; topical emulsions and aerosol foams). Included 
in nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
—
18 Comments 
Each gram of potassium citrate monohydrate represents 
approximately 9.25 mmol of potassium and 3.08 mmol of 
citrate. Each gram of potassium citrate anhydrous represents 
approximately 9.79 mmol of potassium and 3.26 mmol of 
citrate. A specification for potassium citrate is contained in the 
Food Chemicals Codex (FCC). The EINECS number for 
potassium citrate is 212-755-5. 
19 Specific References 
1 Elizabeth JE, Carter NJ. Potassium citrate mixture: soothing but 
not harmless? Br Med J 1987; 295: 993. 
2 Gabriel R. Potassium sorbate mixture: soothing but not harmless? 
[letter] Br Med J 1987; 295: 1487. 
3 Liak TL, Li Wan Po A, Irwin WJ. The effects of drug therapy on 
urinary pH: excipient effects and bioactivation of methenamine. 
Int J Pharm 1987; 36: 233–242. 
4 Fjellstedt E, Denneberg T, Jeppsson JO, Tiselins HG. A comparison 
of the effects of potassium citrate and sodium bicarbonate in the 
alkalinization of urine in homozygous cystinuria. Urol Res 2001; 
29(5): 295–302. 
5 Domrongkitchaiporn S, Khositseth S, Stitchantrokul W, et al. 
Dosage of potassium citrate in the correction of urinary 
abnormalities in pediatric distal renal tubular acidosis patients. 
Am J Kidney Dis 2002; 39(2): 383–391. 
6 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3026. 
20 General References 
Cole ET, Rees JE, Hersey JA. Relations between compaction data for 
some crystalline pharmaceutical materials. Pharm Acta Helv 1975; 
50: 28–32. 
21 Authors 
SC Owen. 
22 Date of Revision 
9 August 2005. 
604 Potassium Citrate

Potassium Hydroxide 
1 Nonproprietary Names 
BP: Potassium hydroxide 
JP: Potassium hydroxide 
PhEur: Kalii hydroxidum 
USPNF: Potassium hydroxide 
2 Synonyms 
Caustic potash; E525; kalium hydroxydatum; potash lye; 
potassium hydrate. 
3 Chemical Name and CAS Registry Number 
Potassium hydroxide [1310-58-3] 
4 Empirical Formula and Molecular Weight 
KOH 56.11 
5 Structural Formula 
KOH 
6 Functional Category 
Alkalizing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Potassium hydroxide is widely used in pharmaceutical formulations 
to adjust the pH of solutions. It can also be used to 
react with weak acids to form salts. 
Therapeutically, potassium hydroxide is used in various 
dermatological applications. 
8 Description 
Potassium hydroxide occurs as a white or nearly white fused 
mass. It is available in small pellets, flakes, sticks and other 
shapes or forms. It is hard and brittle and shows a crystalline 
fracture. Potassium hydroxide is hygroscopic and deliquescent; 
on exposure to air, it rapidly absorbs carbon dioxide and water 
with the formation of potassium carbonate. 
9 Pharmacopeial Specifications 
See Table I. 
10 Typical Properties 
Acidity/alkalinity: pH = 13.5 (0.1M aqueous solution) 
Melting point: 3608C; 3808C when anhydrous 
Solubility: see Table II. 
Table I: Pharmacopeial specifications for potassium hydroxide. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Appearance of solution . . — 
Aluminum — 40.2 ppm — 
Characters — . — 
Chloride 40.05% 450 ppm — 
Heavy metals 430 ppm 410 ppm 40.003% 
Insoluble substances — — . 
Iron — 410 ppm — 
Phosphates — 420 ppm — 
Potassium carbonate 42.0% 42.0% — 
Sodium . 41.0% — 
Sulfates — 450 ppm — 
Assay 585.0% 85.0–100.5% 585.0% 
Table II: Solubility of potassium hydroxide. 
Solvent Solubility at 208C unless otherwise stated 
Ethanol (95%) 1 in 3 
Ether Practically insoluble 
Glycerin 1 in 2.5 
Water 1 in 0.9 
1 in 0.6 at 1008C 
11 Stability and Storage Conditions 
Potassium hydroxide should be stored in an airtight, nonmetallic 
container in a cool, dry place. 
12 Incompatibilities 
Potassium hydroxide is a strong base and is incompatible with 
any compound that readily undergoes hydrolysis or oxidation. 
It should not be stored in glass or aluminum containers and will 
react with acids, esters, and ethers, especially in aqueous 
solution. 
13 Method of Manufacture 
Potassium hydroxide is made by the electrolysis of potassium 
chloride. Commercial grades may contain chlorides as well as 
other impurities. 
14 Safety 
Potassium hydroxide is widely used in the pharmaceutical and 
food industries and is generally regarded as a nontoxic material 
at low concentrations. At high concentrations it is a corrosive 
irritant to the skin, eyes, and mucous membranes. 
LD50 (rat, oral): 0.273 g/kg(1)

15 Handling Precautions 
Potassium hydroxide is a corrosive irritant to the skin, eyes, and 
mucous membranes. The solid and solutions cause burns, often 
with deep ulceration. It is very toxic on ingestion and harmful 
on inhalation. Observe normal handling precautions appropriate 
to the quantity and concentration of material handled. 
Gloves, eye protection, respirator, and other protective clothing 
should be worn. 
Potassium hydroxide is strongly exothermic when dissolved 
in ethanol (95%) or water and considerable heat is generated. 
The reaction between potassium hydroxide solutions and acids 
is also strongly exothermic. 
In the UK, the occupational exposure limit for potassium 
hydroxide has been set at 2 mg/m3 short-term.(2) 
16 Regulatory Status 
GRAS listed. Accepted for use in Europe in certain food 
applications. Included in the FDA Inactive Ingredients Guide 
(injections, infusions, and oral capsules and solutions). 
Included in nonparenteral and parenteral medicines licensed 
in the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Sodium hydroxide. 
18 Comments 
A specification for potassium hydroxide is contained in the 
Food Chemicals Codex (FCC). The EINECS number for 
potassium hydroxide is 215-181-3. 
19 Specific References 
1 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3033–3034. 
2 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: HSE Books, 2002. 
20 General References 
—
21 Authors 
AH Kibbe. 
22 Date of Revision 
3 August 2005. 
606 Potassium Hydroxide

Potassium Metabisulfite 
1 Nonproprietary Names 
USPNF: Potassium metabisulfite 
2 Synonyms 
Disulfurous acid; dipotassium pyrosulfite; dipotassium salt; 
E224; kali disulfis; potassium pyrosulfite. 
3 Chemical Name and CAS Registry Number 
Dipotassium pyrosulfite [16731-55-8] 
4 Empirical Formula and Molecular Weight 
K2S2O5 222.32 
5 Structural Formula 
K2S2O5 
6 Functional Category 
Antimicrobial preservative; antioxidant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Potassium metabisulfite is used in applications similar to those 
of sodium metabisulfite in pharmaceuticals and in the food, 
brewing, and wine making industries. It is used as an 
antioxidant, antimicrobial preservative and sterilizing agent. 
8 Description 
Potassium metabisulfite occurs as white or colorless freeflowing 
crystals, crystalline powder, or granules, usually with 
an odor of sulfur dioxide. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for potassium metabisulfite. 
Test USPNF 23 
Identification . 
Iron 40.001% 
Heavy metals 40.001% 
Organic volatile impurities . 
Assay (as SO2) 51.8–57.6% 
10 Typical Properties 
Acidity/alkalinity: 3.5–4.5 (5% w/v aqueous solution) 
Density (bulk): 1.1–1.3 g/cm3 
Density (tapped): 1.2–1.5 g/cm3 
Melting point: 1908C although potassium metabisulfite decomposes 
at temperatures above 1508C. 
Solubility: soluble 1 in 2.2 of water; practically insoluble in 
ethanol (95%). 
11 Stability and Storage Conditions 
Potassium metabisulfite should be stored in a cool, dark place. 
When stored at a maximum temperature of 258C and 
maximum relative humidity of 45%, the shelf-life is 6 months. 
Potassium metabisulfite decomposes at temperatures above 
1508C. In the air, it oxidizes to the sulfate, more readily in the 
presence of moisture. 
In aqueous solution, potassium metabisulfite forms potassium 
bisulfite (KHSO3) which exerts a strong reducing effect. 
12 Incompatibilities 
Potassium metabisulfite is incompatible with strong acids, 
water, and most common metals. It reacts with nitrites and 
sodium nitrate at room temperature, which occasionally results 
in the formation of flame. The reaction may be explosive if 
water is present. Potassium metabisulfite liberates SO2 with 
acids. 
Sulfites, including potassium metabisulfite, can react with 
various pharmaceutical compounds including sympathomimetics 
such as epinephrine (adrenaline),(1) chloramphenicol,(1) 
cisplatin,(2) and amino acids(3), which can result in their 
pharmacological inactivation. Sulfites are also reported to 
react with phenylmercuric nitrate,(4,5) and may adsorb onto 
rubber closures. 
See also Section 18. 
13 Method of Manufacture 
—
14 Safety 
Potassium metabisulfite is used in a variety of foods and 
pharmaceutical preparations, including oral, otic, rectal, and 
parenteral preparations. Potassium metabisulfite is considered 
a very irritating material, and may cause dermatitis on exposed 
skin.(6,7) 
Hypersensitivity reactions to potassium metabisulfite and 
other sulfites, mainly used as preservatives in food products, 
have been reported. Reactions include bronchospasm and 
anaphylaxis; some deaths have also been reported, especially in 
those with a history of asthma or atopic allergy.(8–11) These 
reactions have led to restrictions by the FDA on the use of 
sulfites in food applications.(12) However, this restriction has 
not been extended to their use in pharmaceutical applications. 
Indeed, epinephrine (adrenaline) injections used to treat severe 
allergic reactions may contain sulfites.(11,12) 
The WHO has set an acceptable daily intake of sulfites, as 
SO2, at up to 0.35 mg/kg body-weight.(13)

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Protective gloves and safety 
goggles are recommended, and precautions should be taken to 
minimize exposure to the mucous membranes and respiratory 
tract. When heated to decomposition, it emits toxic fumes of 
SO2. See also Section 12. 
16 Regulatory Status 
GRAS listed. Accepted in Europe for use as a food additive in 
certain applications. Included in the FDA Inactive Ingredients 
Guide (IM and IV injections, otic and rectal solutions and 
suspensions). Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Potassium bisulfite; sodium metabisulfite. 
Potassium bisulfite 
Empirical formula: KHSO3 
Molecular weight: 120.2 
CAS number: [7773-03-7] 
Synonyms: E228; potassium acid sulfite; potassium bisulphite; 
potassium hydrogen sulfite. 
Comments: accepted in Europe as a food additive in certain 
applications. Included in food and pharmaceutical applications 
similarly to potassium metabisulfite. 
18 Comments 
Like all sulfites, potassium metabisulfite is not recommended 
for use in foods that are a source of thiamin, owing to the 
instability of the vitamin in their presence. Such foods include 
meat, raw fruits and vegetables, fresh potatoes, and foods that 
are a source of vitamin B12. A specification for potassium 
metabisulfite is contained in the Food Chemicals Codex (FCC). 
The EINECS number for potassium metabisulfite is 240- 
795-3. 
19 Specific References 
1 Higuchi T, Schroeter LC. Reactivity of bisulfite with a number of 
pharmaceuticals. J Am Pharm Assoc (Sci) 1959; 48: 535–540. 
2 Garren KW, Repta AJ. Incompatibility of cisplatin and Reglan 
Injectable. Int J Pharm 1985; 24: 91–99. 
3 Brawley V, Bhatia J, Karp WB. Effect of sodium metabisulphite on 
hydrogen peroxide production in light-exposed pediatric parenteral 
amino acid solutions. Am J Health Syst Pharm 1998; 55: 
1288–1292. 
4 Richards RME, Reary JME. Changes in antibacterial activity of 
thiomersal and PMN on autoclaving with certain adjuvants. J 
Pharm Pharmacol 1972; 24 (Suppl.): 84P–89P. 
5 Collins AJ, Lingham P, Burbridge TA, Bain R. Incompatibility of 
phenylmercuric acetate with sodium metabisulfite in eye drop 
formulations. J Pharm Pharmacol 1985; 37 (Suppl.): 123P. 
6 Nater JP. Allergic contact dermatitis caused by potassium 
metabisulfite. Dermatologica 1968; 136(6): 477–478. 
7 Vena GA, Foti C, Angelini G. Sulfite contact allergy. Contact 
Dermatitis 1994; 31(3): 172–175. 
8 Mathison DA, Stevenson DD, Simon RA. Precipitating factors in 
asthma: aspirin, sulfites, and other drugs and chemicals. Chest 
1985; 87 (Suppl.): 50S–54S. 
9 Anonymous. Sulfites in drugs and food. Med Lett Drugs Ther 
1986; 28: 74–75. 
10 Belchi-Hernandez J, Florido-Lopez JF, Estrada-Rodriguez JL, et al. 
Sulfite-induced urticaria. Ann Allergy 1993; 71(3): 230–232. 
11 Sweetman SC, ed. Martindale: The Complete Drug Reference, 
34th edn. London: Pharmaceutical Press, 2005: 1193. 
12 Anonymous. Warning for prescription drugs containing sulfites. 
FDA Drug Bull 1987; 17: 2–3. 
13 FAO/WHO. Evaluation of the toxicity of a number of antimicrobials 
and antioxidants. Sixth report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1962; No. 228. 
20 General References 
Smolinske SC. Handbook of Food, Drug and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 393–406. 
Valade J-P, Le Bras G. Sulfur dioxide release from effervescent tablets. 
Rev Fr Oenol 1998; 171: 22–25. 
21 Authors 
PJ Sheskey. 
22 Date of Revision 
23 August 2005. 
608 Potassium Metabisulfite

Potassium Sorbate 
1 Nonproprietary Names 
BP: Potassium sorbate 
PhEur: Kalii sorbas 
USPNF: Potassium sorbate 
2 Synonyms 
E202; 2,4-hexadienoic acid (E,E)-potassium salt; potassium 
(E,E)-hexa-2,4-dienoate; potassium (E,E)-sorbate; sorbic acid 
potassium salt. 
3 Chemical Name and CAS Registry Number 
2,4-Hexadienoic acid potassium salt [24634-61-5] 
4 Empirical Formula and Molecular Weight 
C6H7O2K 150.22 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Potassium sorbate is an antimicrobial preservative, with 
antibacterial and antifungal properties used in pharmaceuticals, 
foods, enteral preparations, and cosmetics. Generally, it is 
used at concentrations of 0.1–0.2% in oral and topical 
formulations, especially those containing nonionic surfactants. 
Potassium sorbate has been used to enhance the ocular 
bioavailability of timolol.(1) 
Potassium sorbate is used in approximately twice as many 
pharmaceutical formulations as is sorbic acid owing to its 
greater solubility and stability in water. Like sorbic acid, 
potassium sorbate has minimal antibacterial properties in 
formulations above pH 6. 
8 Description 
Potassium sorbate occurs as a white crystalline powder with a 
faint, characteristic odor. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for potassium sorbate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Appearance of solution . — 
Acidity or alkalinity . . 
Loss on drying 41.0% 41.0% 
Heavy metals 410 ppm 40.001% 
Organic volatile impurities — . 
Aldehydes (as C2H4O) 40.15% — 
Assay (dried basis) 99.0–101.0% 98.0–101.0% 
10 Typical Properties 
Antimicrobial activity: potassium sorbate is predominantly 
used as an antifungal preservative although it also has 
antibacterial properties. Similarly to sorbic acid, the 
antimicrobial activity is dependent on the degree of 
dissociation; there is practically no antibacterial activity 
above pH 6. Preservative efficacy is increased with increasing 
temperature,(2) and increasing concentration of potassium 
sorbate.(2) The efficacy of potassium sorbate is also 
increased when used in combination with other antimicrobial 
preservatives or glycols since synergistic effects occur.(3) 
Reported minimum inhibitory concentrations (MICs) at the 
pH values indicated are shown in Table II.(3) 
Table II: Minimum inhibitory concentrations (MIC) of potassium 
sorbate. 
Microorganism MIC (mg/mL) at the stated pH 
5.5 6.0 7.0 
Escherichia coli 1400 1500 3800 
Pseudomonas 
aeruginosa 
1600–2300 1900–2500 5600–9000 
Staphylococcus aureus 1200 1000 3800 
Density: 1.363 g/cm3 
Melting point: 2708C with decomposition. 
Solubility: see Table III. 
11 Stability and Storage Conditions 
Potassium sorbate is more stable in aqueous solution than 
sorbic acid; aqueous solutions may be sterilized by autoclaving. 
The bulk material should be stored in a well-closed 
container, protected from light, at a temperature not exceeding 
408C. 
12 Incompatibilities 
Some loss of antimicrobial activity occurs in the presence of 
nonionic surfactants and some plastics. See also Sorbic Acid.

Table III: Solubility of potassium sorbate. 
Solvent Solubility at 208C unless otherwise stated 
Acetone 1 in 1000 
Benzene Practically insoluble 
Chloroform Very slightly soluble 
Corn oil Very slightly soluble 
Ethanol 1 in 50 
Ethanol (95%) 1 in 35 
Ethanol (5%) 1 in 1.7 
Ether Very slightly soluble 
Propylene glycol 1 in 1.8 
1 in 2.1 at 508C 
1 in 5 at 1008C 
Water 1 in 1.72 
1 in 1.64 at 508C 
1 in 1.56 at 1008C 
13 Method of Manufacture 
Potassium sorbate is prepared from sorbic acid and potassium 
hydroxide. 
14 Safety 
Potassium sorbate is used as an antimicrobial preservative in 
oral and topical pharmaceutical formulations and is generally 
regarded as a relatively nontoxic material. However, some 
adverse reactions to potassium sorbate have been reported, 
including irritant skin reactions which may be of the allergic, 
hypersensitive type. There have been no reports of adverse 
systemic reactions following oral consumption of potassium 
sorbate. 
The WHO has set an estimated total acceptable daily intake 
for sorbic acid, calcium sorbate, potassium sorbate, and sodium 
sorbate expressed as sorbic acid at up to 25 mg/kg bodyweight.(
4,5) 
LD50 (mouse, IP): 1.3 g/kg(6) 
LD50 (rat, oral): 4.92 g/kg 
See also Sorbic Acid. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Potassium sorbate is irritant 
to the skin, eyes, and mucous membranes; eye, protection and 
gloves are recommended. In areas of limited ventilation, a 
respirator is also recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (nasal sprays; 
oral capsules, solutions, suspensions, syrups, tablets; topical 
creams and lotions). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Sorbic acid. 
18 Comments 
Much of the information contained in the sorbic acid 
monograph on safety, incompatibilities, and references also 
applies to potassium, calcium, and sodium sorbates. See Sorbic 
Acid for further information. 
Potassium sorbate has less antimicrobial activity than sorbic 
acid, but is more water soluble. Most potassium sorbate 
compounds will contain sorbic acid. A specification for 
potassium sorbate is contained in the Food Chemicals Codex 
(FCC). 
The EINECS number for potassium sorbate is 246-376-1. 
19 Specific References 
1 Mandorf TK, Ogawa T, Naka H, et al. A 12 month, multicentre, 
randomized, double-masked, parallel group comparison of timolol-
LA once daily and timolol maleate ophthalmic solution twice 
daily in the treatment of adults with glaucoma or ocular 
hypertension. Clin Ther 2004; 26(4): 541–551. 
2 Lusher P, Denyer SP, Hugo WB. A note on the effect of dilution and 
temperature on the bactericidal activity of potassium sorbate. J 
Appl Bacteriol 1984; 57: 179–181. 
3 Woodford R, Adams E. Sorbic acid. Am Perfum Cosmet 1970; 
85(3): 25–30. 
4 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications. 
Seventeenth report of the joint FAO/WHO expert committee on 
food additives.World Health Organ Tech Rep Ser 1974; No. 539. 
5 FAO/WHO. Evaluation of certain food additives and contaminants. 
Twenty-ninth report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1986; No. 733. 
6 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3043. 
20 General References 
Smolinske SC, ed. Handbook of Food, Drug, and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 363–367. 
Sofos JN, Busta FF. Sorbates. In: Branen AL, Davidson PM, eds. 
Antimicrobials in Foods. New York: Marcel Dekker, 1983: 141– 
175. 
Walker R. Toxicology of sorbic acid and sorbates. Food Add Contam 
1990; 7(5): 671–676. 
21 Authors 
SC Owen. 
22 Date of Revision 
9 August 2005. 
610 Potassium Sorbate

Povidone 
1 Nonproprietary Names 
BP: Povidone 
JP: Povidone 
PhEur: Povidonum 
USP: Povidone 
2 Synonyms 
E1201; Kollidon; Plasdone; poly[1-(2-oxo-1-pyrrolidinyl)ethylene]; 
polyvidone; polyvinylpyrrolidone; PVP; 1-vinyl-2-pyrrolidinone 
polymer. 
3 Chemical Name and CAS Registry Number 
1-Ethenyl-2-pyrrolidinone homopolymer [9003-39-8] 
4 Empirical Formula and Molecular Weight 
(C6H9NO)n 2500–3 000 000 
The USP 28 describes povidone as a synthetic polymer 
consisting essentially of linear 1-vinyl-2-pyrrolidinone groups, 
the differing degree of polymerization of which results in 
polymers of various molecular weights. It is characterized by its 
viscosity in aqueous solution, relative to that of water, 
expressed as a K-value, in the range 10–120. The K-value is 
calculated using Fikentscher’s equation:(1) 
where z is the relative viscosity of the solution of concentration 
c (in % w/v), and k is the K-value  10–3. 
Alternatively, the K-value may be determined from the 
following equation: 
where z is the relative viscosity of the solution of concentration 
c (in % w/v). 
Approximate molecular weights for different povidone 
grades are shown in Table I. 
Table I: Approximate molecular weights for different grades of 
povidone. 
K-value Approximate molecular weight 
12 2 500 
15 8 000 
17 10 000 
25 30 000 
30 50 000 
60 400 000 
90 1 000 000 
120 3 000 000 
See also Section 8. 
5 Structural Formula 
6 Functional Category 
Disintegrant; dissolution aid; suspending agent; tablet binder. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Although povidone is used in a variety of pharmaceutical 
formulations, it is primarily used in solid-dosage forms. In 
tableting, povidone solutions are used as binders in wetgranulation 
processes.(2,3) Povidone is also added to powder 
blends in the dry form and granulated in situ by the addition of 
water, alcohol, or hydroalcoholic solutions. Povidone is used as 
a solubilizer in oral and parenteral formulations and has been 
shown to enhance dissolution of poorly soluble drugs from 
solid-dosage forms.(4–6) Povidone solutions may also be used as 
coating agents. 
Povidone is additionally used as a suspending, stabilizing, or 
viscosity-increasing agent in a number of topical and oral 
suspensions and solutions. The solubility of a number of poorly 
soluble active drugs may be increased by mixing with povidone. 
See Table II. 
Special grades of pyrogen-free povidone are available and 
have been used in parenteral formulations; see Section 14. 
Table II: Uses of povidone. 
Use Concentration (%) 
Carrier for drugs 10–25 
Dispersing agent Up to 5 
Eye drops 2–10 
Suspending agent Up to 5 
Tablet binder, tablet diluent, or coating agent 0.5–5 
8 Description 
Povidone occurs as a fine, white to creamy-white colored, 
odorless or almost odorless, hygroscopic powder. Povidones 
with K-values equal to or lower than 30 are manufactured by 
spray-drying and occur as spheres. Povidone K-90 and higher 
K-value povidones are manufactured by drum drying and occur 
as plates. 
9 Pharmacopeial Specifications 
See Table III.

Table III: Pharmacopeial specifications for povidone. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters — . — 
pH — . 3.0–7.0 
K 4 30 3.0–5.0 3.0–5.0 — 
K > 30 4.0–7.0 4.0–7.0 — 
Appearance of solution . . — 
Viscosity — . — 
Water 45.0% 45.0% 45.0% 
Residue on ignition 40.1% 40.1% 40.1% 
Lead — — 410 ppm 
Aldehydes 4500 ppm(a) 4500 ppm(a) 40.05% 
Hydrazine 41 ppm 41 ppm 41 ppm 
Vinylpyrrolidinone 410 ppm 410 ppm 40.2% 
Peroxides 4400 ppm(b) 4400 ppm(b) — 
K-value 25–90 — 10–120 
415 90.0–108.0% 85.0–115.0% 85.0–115.0% 
>15 90.0–108.0% 90.0–108.0% 90.0–108.0% 
Heavy metals 410 ppm 410 ppm — 
Assay (nitrogen content) 11.5–12.8% 11.5–12.8% 11.5–12.8% 
(a) Expressed as acetaldehyde. 
(b) Expressed as hydrogen peroxide. 
10 Typical Properties 
Acidity/alkalinity: pH = 3.0–7.0 (5% w/v aqueous solution). 
Density (bulk): 0.29–0.39 g/cm3 for Plasdone. 
Density (tapped): 0.39–0.54 g/cm3 for Plasdone. 
Density (true): 1.180 g/cm3 
Flowability: 
20 g/s for povidone K-15; 
16 g/s for povidone K-29/32. 
Melting point: softens at 1508C. 
Moisture content: povidone is very hygroscopic, significant 
amounts of moisture being absorbed at low relative 
humidities. See Figures 1 and 2. 
Figure 1: Sorption–desorption isotherm of povidone K-15 (Plasdone 
K-15). 
Figure 2: Sorption–desorption isotherm of povidone K-29/32 
(Plasdone K-29/32). 
Particle size distribution: 
Kollidon 25/30: 90% >50 mm, 50% >100 mm, 5% 
>200 mm; 
Kollidon 90: 90% >200 mm, 95% >250 mm.(7) 
Solubility: freely soluble in acids, chloroform, ethanol (95%), 
ketones, methanol, and water; practically insoluble in ether, 
hydrocarbons, and mineral oil. In water, the concentration 
of a solution is limited only by the viscosity of the resulting 
solution, which is a function of the K-value. 
Viscosity (dynamic): the viscosity of aqueous povidone solutions 
depends on both the concentration and the molecular 
weight of the polymer employed. See Tables IV and V.(7) 
Table IV: Dynamic viscosity of 10% w/v aqueous povidone (Kollidon) 
solutions at 208C.(7) 
Grade Dynamic viscosity (mPa s) 
K-11/14 1.3–2.3 
K-16/18 1.5–3.5 
K-24/27 3.5–5.5 
K-28/32 5.5–8.5 
K-85/95 300–700 
Table V: Dynamic viscosity of 5% w/v povidone (Kollidon) solutions 
in ethanol (95%) and propan-2-ol at 258C.(7) 
Grade Dynamic viscosity (mPa s) 
Ethanol (95%) Propan-2-ol 
K-12PF 1.4 2.7 
K-17PF 1.9 3.1 
K-25 2.7 4.7 
K-30 3.4 5.8 
K-90 53.0 90.0 
612 Povidone

SEM: 1 
Excipient: Povidone K-15 (Plasdone K-15) 
Manufacturer: ISP 
Lot No.: 82A-1 
Magnification: 60 Voltage: 5kV 
SEM: 2 
Excipient: Povidone K-15 (Plasdone K-15) 
Manufacturer: ISP 
Lot No.: 82A-1 
Magnification: 600 Voltage: 5kV 
SEM: 3 
Excipient: Povidone K-26/28 (Plasdone K-26/28) 
Manufacturer: ISP 
Lot No.: 82A-2 
Magnification: 60 Voltage: 5kV 
SEM: 4 
Excipient: Povidone K-26/28 (Plasdone K-26/28) 
Manufacturer: ISP 
Lot No.: 82A-2 
Magnification: 600 Voltage: 10 kV 
Povidone 613

SEM: 5 
Excipient: Povidone K-30 (Plasdone K-30) 
Manufacturer: ISP 
Lot No.: 82A-4 
Magnification: 60 Voltage: 10 kV 
SEM: 6 
Excipient: Povidone K-30 (Plasdone K-30) 
Manufacturer: ISP 
Lot No.: 82A-4 
Magnification: 600 Voltage: 10 kV 
SEM: 7 
Excipient: Povidone K-29/32 (Plasdone K-29/32) 
Manufacturer: ISP 
Lot No.: 82A-3 
Magnification: 60 Voltage: 5kV 
SEM: 8 
Excipient: Povidone K-29/32 (Plasdone K-29/32) 
Manufacturer: ISP 
Lot No.: 82A-3 
Magnification: 600 Voltage: 10 kV 
11 Stability and Storage Conditions 
Povidone darkens to some extent on heating at 1508C, with a 
reduction in aqueous solubility. It is stable to a short cycle of 
heat exposure around 110–1308C; steam sterilization of an 
614 Povidone

aqueous solution does not alter its properties. Aqueous 
solutions are susceptible to mold growth and consequently 
require the addition of suitable preservatives. 
Povidone may be stored under ordinary conditions without 
undergoing decomposition or degradation. However, since the 
powder is hygroscopic, it should be stored in an airtight 
container in a cool, dry place. 
12 Incompatibilities 
Povidone is compatible in solution with a wide range of 
inorganic salts, natural and synthetic resins, and other 
chemicals. It forms molecular adducts in solution with 
sulfathiazole, sodium salicylate, salicylic acid, phenobarbital, 
tannin, and other compounds; see Section 18. The efficacy of 
some preservatives, e.g. thimerosal, may be adversely affected 
by the formation of complexes with povidone. 
13 Method of Manufacture 
Povidone is manufactured by the Reppe process. Acetylene and 
formaldehyde are reacted in the presence of a highly active 
copper acetylide catalyst to form butynediol, which is hydrogenated 
to butanediol and then cyclodehydrogenated to form 
butyrolactone. Pyrrolidone is produced by reacting butyrolactone 
with ammonia. This is followed by a vinylation reaction in 
which pyrrolidone and acetylene are reacted under pressure. 
The monomer, vinylpyrrolidone, is then polymerized in the 
presence of a combination of catalysts to produce povidone. 
14 Safety 
Povidone has been used in pharmaceutical formulations for 
many years, being first used in the 1940s as a plasma expander, 
although it has now been superseded for this purpose by 
dextran.(8) 
Povidone is widely used as an excipient, particularly in oral 
tablets and solutions. When consumed orally, povidone may be 
regarded as essentially nontoxic since it is not absorbed from 
the gastrointestinal tract or mucous membranes.(8) Povidone 
additionally has no irritant effect on the skin and causes no 
sensitization. 
Reports of adverse reactions to povidone primarily concern 
the formation of subcutaneous granulomas at the injection site 
of intramuscular injections formulated with povidone.(9) 
Evidence also exists that povidone may accumulate in the 
organs of the body following intramuscular injection.(10) 
A temporary acceptable daily intake for povidone has been 
set by the WHO at up to 25 mg/kg body-weight.(11) 
LD50 (mouse, IP): 12 g/kg(12) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection, gloves, and a 
dust mask are recommended. 
16 Regulatory Status 
Accepted for use in Europe as a food additive. Included in the 
FDA Inactive Ingredients Guide (IM and IV injections; 
ophthalmic preparations; oral capsules, drops, granules, 
suspensions, and tablets; sublingual tablets; topical and vaginal 
preparations). Included in nonparenteral medicines licensed in 
the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Crospovidone. 
18 Comments 
The molecular adduct formation properties of povidone may be 
used advantageously in solutions, slow-release solid-dosage 
forms, and parenteral formulations. Perhaps the best-known 
example of povidone complex formation is povidone–iodine, 
which is used as a topical disinfectant. 
For accurate standardization of solutions, the water content 
of the solid povidone must be determined before use and taken 
into account for any calculations. A specification for povidone 
is contained in the Food Chemicals Codex (FCC). 
19 Specific References 
1 Fikentscher H, Herrle K. Polyvinylpyrrolidone. Modern Plastics 
1945; 23(3): 157–161, 212, 214, 216, 218. 
2 Becker D, Rigassi T, Bauer-Brandl A. Effectiveness of binders in 
wet granulation: comparison using model formulations of different 
tabletability. Drug Dev Ind Pharm 1997; 23(8): 791–808. 
3 Stubberud L, Arwidsson HG, Hjortsberg V, Graffner C. Water– 
solid interactions. Part 3. Effect of glass transition temperature, Tg 
and processing on tensile strength of compacts of lactose and 
lactose/polyvinyl pyrrolidone. Pharm Dev Technol 1996; 1(2): 
195–204. 
4 Iwata M, Ueda H. Dissolution properties of glibenclamide in 
combinations with polyvinylpyrrolidone. Drug Dev Ind Pharm 
1996; 22: 1161–1165. 
5 Lu WG, Zhang Y, Xiong QM, et al. Development of nifedipine 
(NE) pellets with a high bioavailability. Chin Pharm J Zhongguo 
Yaoxue Zazhi 1995; 30(Nov Suppl): 24–26. 
6 Chowdary KP, Ramesh KV. Microencapsulation of solid dispersions 
of nifedipine-novel approach for controlling drug release. 
Indian Drugs 1995; 32(Oct): 477–483. 
7 BASF Corporation. Technical literature: Soluble Kollidon Grades, 
Soluble Polyvinylpyrrolidone for the Pharmaceutical Industry, 
1997. 
8 Wessel W, Schoog M, Winkler E. Polyvinylpyrrolidone (PVP), its 
diagnostic, therapeutic and technical application and consequences 
thereof. Arzneimittelforschung 1971; 21: 1468–1482. 
9 Hizawa K, Otsuka H, Inaba H, et al. Subcutaneous pseudosarcomatous 
polyvinylpyrrolidone granuloma. Am J Surg Pathol 1984; 
8: 393–398. 
10 Christensen M, Johansen P, Hau C. Storage of polyvinylpyrrolidone 
(PVP) in tissues following long-term treatment with a PVP 
containing vasopressin preparation. Acta Med Scand 1978; 204: 
295–298. 
11 FAO/WHO. Evaluation of certain food additives and contaminants. 
Twenty-seventh report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1983; No. 696. 
12 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3016–3017. 
20 General References 
Adeyeye CM, Barabas E. Povidone. In: Brittain HG, ed. Analytical 
Profiles of Drug Substances and Excipients, vol. 22. London: 
Academic Press, 1993: 555–685. 
Genovesi A, Spadoni A, Funaro C, Vecchio C. Binder evaluation in 
tabletting. Manuf Chem 2004; 175(6): 29–30. 
Horn D, Ditter W. Chromatographic study of interactions between 
polyvinylpyrrolidone and drugs. J Pharm Sci 1982; 71: 1021–1026. 
Povidone 615

Hsiao CH, Rhodes HJ, Blake MI. Fluorescent probe study of 
sulfonamide binding to povidone. J Pharm Sci 1977; 66: 1157– 
1159. 
ISP. Technical literature: Plasdone povidone USP, 1999. 
Jager KF, Bauer KH. Polymer blends from PVP as a means to optimize 
properties of fluidized bed granulates and tablets. Acta Pharm 
Technol 1984; 30(1): 85–92. 
Plaizier-Vercammen JA, DeNe`ve RE. Interaction of povidone with 
aromatic compounds III: thermodynamics of the binding equilibria 
and interaction forces in buffer solutions at varying pH values and 
varying dielectric constant. J Pharm Sci 1982; 71: 552–556. 
Robinson BV, Sullivan FM, Borzelleca JF, Schwartz SL. PVP: A Critical 
Review of the Kinetics and Toxicology of Polyvinylpyrrolidone 
(Povidone). Chelsea, MI: Lewis Publishers, 1990. 
Shefter E, Cheng KC. Drug–polyvinylpyrrolidone (PVP) dispersions. A 
differential scanning calorimetric study. Int J Pharm 1980; 6: 179– 
182. 
Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 303–305. 
21 Authors 
AH Kibbe. 
22 Date of Revision 
30 August 2005. 
616 Povidone

Propionic Acid 
1 Nonproprietary Names 
USPNF: Propionic acid 
2 Synonyms 
Carboxyethane; ethanecarboxylic acid; E280; ethylformic acid; 
metacetonic acid; methylacetic acid; propanoic acid; pseudoacetic 
acid. 
3 Chemical Name and CAS Registry Number 
Propionic acid [79-09-4] 
4 Empirical Formula and Molecular Weight 
C3H6O2 74.08 
5 Structural Formula 
6 Functional Category 
Acidifying agent; antimicrobial preservative; antioxidant; 
esterifying agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Propionic acid is primarily used as an antioxidant and 
antimicrobial preservative in foods, and in oral and topical 
pharmaceutical applications. It is also used as an esterifying 
agent. 
8 Description 
Propionic acid occurs as a corrosive, oily liquid having a 
slightly pungent, disagreeable, rancid odor. It is flammable. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for propionic acid. 
Test USPNF 23 
Specific gravity 0.988–0.993 
Distilling range 138.5–142.58C 
Heavy metals 40.001% 
Limit of nonvolatile residue 40.01% 
Readily oxidizable substances . 
Limit of aldehydes . 
Organic volatile impurities . 
Assay 99.5–100.5% 
10 Typical Properties 
Antimicrobial activity: see Table II. 
Table II: Typical minimum inhibitory concentrations (MICs) for 
propionic acid at pH 3.9.(1) 
Microorganism MIC (mg/mL) 
Aspergillus niger 2000 
Candida albicans 2000 
Escherichia coli 2000 
Klebsiella pneumoniae 1250 
Penicillium notatum 2000 
Pseudomonas aeruginosa 3000 
Pseudomonas cepacia 3000 
Pseudomonas fluorescens 1250 
Staphylococcus aureus 2000 
Autoignition temperature: 9558C 
Boiling point: 141.18C 
Dissociation constant: pKa = 4.874 
Flash point: 52–588C (open cup) 
Melting point: 21.58C 
Partition coefficients: Octanol : water = 0.33. 
Refractive index: nD
25 = 1.3848 
Solubility: miscible with chloroform, ethanol (95%), ether, and 
water. 
Specific gravity: 0.9934 
Surface tension: 27.21mN/m (27.21 dynes/cm) at 158C 
Vapor density (relative): 2.56 (air = 1) 
Vapor pressure: 320 Pa (2.4 mmHg) at 208C 
Viscosity (dynamic): see Table III. 
Table III: Dynamic viscosity of propionic acid. 
Viscosity (dynamic)/mPa s Temperature 
1.175 158C 
1.02 258C 
0.956 308C 
0.668 608C 
0.495 908C

11 Stability and Storage Conditions 
Although stable, propionic acid is flammable. It should be 
stored in an airtight container away from heat and flames. 
12 Incompatibilities 
Propionic acid is incompatible with alkalis, ammonia, amines, 
and halogens. It can be salted out of aqueous solutions by the 
addition of calcium chloride or other salts. 
13 Method of Manufacture 
Propionic acid can be obtained from wood pulp waste liquor by 
fermentation. It can also be prepared from ethylene, carbon 
monoxide and steam; from ethanol and carbon monoxide using 
boron trifluoride catalyst; from natural gas; or as a by-product 
in the pyrolysis of wood. Very pure propionic acid can be 
obtained from propionitrile. Propionic acid can be found in 
dairy products in small amounts. 
14 Safety 
Propionic acid is generally regarded as a nontoxic and 
nonirritant material when used as an excipient. Up to 1% 
may be used in food applications (up to 0.3% in flour and 
cheese products). See also Sodium Propionate. 
LD50 (mouse, IV): 0.63 g/kg(2) 
LD50 (rabbit, skin): 0.5 g/kg 
LD50 (rat, oral): 2.6 g/kg 
15 Handling Precautions 
Propionic acid is corrosive and can cause eye and skin burns. It 
may be harmful if swallowed, inhaled or absorbed through the 
skin as a result of prolonged or widespread contact. Eye 
protection, PVC gloves, and suitable protective clothing should 
be worn. Propionic acid should be handled in a well-ventilated 
environment away from heat and flames. In the UK, the 
occupational exposure limits for propionic acid are 31 mg/m3 
(10 ppm) long-term (8-hour TWA) and 46 mg/m3 (15 ppm) 
short-term.(3) 
16 Regulatory Status 
GRAS listed. Accepted for use in Europe as a food additive. In 
Japan, propionic acid is restricted to use as a flavoring agent. 
17 Related Substances 
Sodium propionate. 
18 Comments 
A specification for propionic acid is contained in the Food 
Chemicals Codex (FCC). The EINECS number for propionic 
acid is 201-176-3. 
19 Specific References 
1 Wallha. usser KH. Propionic acid. In: Kabara JJ, ed. Cosmetic and 
Drug Preservation: Principles and Practice. New York: Marcel 
Dekker, 1984: 665–666. 
2 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3069–3070. 
3 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
—
21 Authors 
GE Amidon. 
22 Date of Revision 
24 August 2005. 
618 Propionic Acid

Propyl Gallate 
1 Nonproprietary Names 
BP: Propyl gallate 
PhEur: Propylis gallas 
USPNF: Propyl gallate 
2 Synonyms 
E310; gallic acid propyl ester; n-propyl gallate; Progallin P; 
propyl 3,4,5-trihydroxybenzoate; Tenox PG. 
3 Chemical Name and CAS Registry Number 
3,4,5-Trihydroxybenzoic acid propyl ester [121-79-9] 
4 Empirical Formula and Molecular Weight 
C10H12O5 212.20 
5 Structural Formula 
6 Functional Category 
Antioxidant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Propyl gallate has become widely used as an antioxidant in 
cosmetics, perfumes, foods, and pharmaceuticals since its use in 
preventing autoxidation of oils was first described in 1943.(1,2) 
It is primarily used, in concentrations up to 0.1% w/v, to 
prevent the rancidity of oils and fats;(3) it may also be used at 
concentrations of 0.002% w/v to prevent peroxide formation in 
ether, and at 0.01% w/v to prevent the oxidation of 
paraldehyde. Synergistic effects with other antioxidants such 
as butylated hydroxyanisole and butylated hydroxytoluene 
have been reported. Propyl gallate is also said to possess some 
antimicrobial properties; see Section 10. 
Studies have shown that, when added to powder blends 
containing ketorolac, propyl gallate significantly increases the 
drug stability in the preparation.(4) 
Other alkyl gallates are also used as antioxidants and have 
approximately equivalent antioxidant properties when used in 
equimolar concentration; however, solubilities vary, see 
Section 17. 
8 Description 
Propyl gallate is a white, odorless or almost odorless crystalline 
powder, with a bitter astringent taste that is not normally 
noticeable at the concentrations employed as an antioxidant. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for propyl gallate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Melting range — 146–1508C 
Appearance of solution . — 
Gallic acid . — 
Loss on drying 40.5% 40.5% 
Residue on ignition — 40.1% 
Sulfated ash 40.1% 40.1% 
Total chlorine 4200 ppm — 
Chloride 4100 ppm — 
Heavy metals 410 ppm 40.001% 
Zinc 425 ppm — 
Organic volatile impurities — . 
Assay (dried basis) 97.0–103.0% 98.0–102.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 5.9 (0.1% w/v aqueous solution) 
Antimicrobial activity: propyl gallate has been reported to 
possess some antimicrobial activity against Gram-negative, 
Gram-positive, and fungal species.(5) Its effectiveness as a 
preservative may be improved when used in combination 
with zinc salts, such as zinc sulfate, owing to synergistic 
effects.(6) For reported minimum inhibitory concentrations 
(MICs) for aqueous solutions containing 4% v/v ethanol as 
cosolvent, see Table II.(5) 
Table II: Minimum inhibitory concentrations (MICs) for aqueous 
solutions containing propyl gallate and 4% v/v ethanol. 
Microorganism MIC (mg/mL) 
Candida albicans 1500 
Escherichia coli 330 
Staphylococcus aureus 600 
Dissociation constant: pKa = 8.11 
Melting point: 1508C 
Partition coefficients: 
Octanol : water = 32; 
Oleyl alcohol : water = 17. 
Solubility: see Table III.

Table III: Solubility of propyl gallate. 
Solvent Solubility at 208C 
unless otherwise stated 
Almond oil 1 in 44 
Castor oil 1 in 4.5 
Cottonseed oil 1 in 81 at 308C 
Ethanol (95%) 1 in 3 
1 in 0.98 at 258C 
Ether 1 in 3 
1 in 1.2 at 258C 
Lanolin 1 in 16.7 at 258C 
Lard 1 in 88 at 458C 
Mineral oil 1 in 200 
Peanut oil 1 in 2000 
Propylene glycol 1 in 2.5 at 258C 
Soybean oil 1 in 100 at 258C 
Water 1 in 1000 
1 in 286 at 258C 
11 Stability and Storage Conditions 
Propyl gallate is unstable at high temperatures and is rapidly 
destroyed in oils that are used for frying purposes. 
The bulk material should be stored in a well-closed, 
nonmetallic container, protected from light, in a cool, dry place. 
12 Incompatibilities 
The alkyl gallates are incompatible with metals, e.g. sodium, 
potassium, and iron, forming intensely colored complexes. 
Complex formation may be prevented, under some circumstances, 
by the addition of a sequestering agent, typically citric 
acid. Propyl gallate may also react with oxidizing materials. 
13 Method of Manufacture 
Propyl gallate is prepared by the esterification of 3,4,5- 
trihydroxybenzoic acid (gallic acid) with n-propanol. Other 
alkyl gallates are prepared similarly using an appropriate 
alcohol of the desired alkyl chain length. 
14 Safety 
It has been reported, following animal studies, that propyl 
gallate has a strong contact sensitization potential.(7) Propyl 
gallate has also produced cytogenic effects in CHO-K1 cells.(8) 
However, despite this, there have been few reports of adverse 
reactions to propyl gallate.(9) Those that have been described 
include contact dermatitis; allergic contact dermatitis;(9–11) and 
methemoglobinemia in neonates.(12) 
The WHO has set an estimated acceptable daily intake for 
propyl gallate at up to 1.4 mg/kg body-weight.(13) 
LD50 (cat, oral): 0.4 g/kg(14) 
LD50 (mouse, oral): 1.7 g/kg 
LD50 (rat, oral): 2.1 g/kg 
LD50 (rat, IP): 0.38 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. When heated to decomposition, propyl gallate 
may emit toxic fumes and smoke. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (IM injections, 
oral, and topical preparations). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Dodecyl gallate; ethyl gallate; octyl gallate. 
Dodecyl gallate 
Empirical formula: C19H30O5 
Molecular weight: 338.44 
CAS number: [1166-52-5] 
Synonyms: dodecyl 3,4,5-trihydroxybenzoate; dodecylis gallas; 
E312; lauryl gallate. 
Appearance: white, odorless or almost odorless, crystalline 
powder. 
Melting point: 96–97.58C 
Solubility: see Table IV. 
Table IV: Solubility of dodecyl gallate. 
Solvent Solubility at 208C 
Acetone 1 in 2 
Chloroform 1 in 60 
Ethanol (95%) 1 in 3.5 
Ether 1 in 4 
Methanol 1 in 1.5 
Peanut oil 1 in 30 
Propylene glycol 1 in 60 
Water Practically insoluble 
Safety: the WHO has established a temporary estimated 
acceptable daily intake for dodecyl gallate at up to 
0.05 mg/kg body-weight.(13) 
Comments: the EINECS number for dodecyl gallate is 214- 
620-6. 
Ethyl gallate 
Empirical formula: C9H10O5 
Molecular weight: 198.17 
CAS number: [831-61-8] 
Synonyms: ethyl 3,4,5-trihydroxybenzoate. 
Appearance: white, odorless or almost odorless, crystalline 
powder. 
Melting point: 151–1548C 
Solubility: see Table V. 
Table V: Solubility of ethyl gallate. 
Solvent Solubility at 208C 
Ethanol (95%) 1 in 3 
Ether 1 in 3 
Peanut oil Practically insoluble 
Water Slightly soluble 
Octyl gallate 
Empirical formula: C15H22O5 
Molecular weight: 282.34 
CAS number: [1034-01-1] 
620 Propyl Gallate

Synonyms: E311; octyl 3,4,5-trihydroxybenzoate. 
Appearance: white, odorless or almost odorless, crystalline 
powder. 
Melting point: 100–1028C 
Solubility: see Table VI. 
Table VI: Solubility of octyl gallate. 
Solvent Solubility at 208C 
Acetone 1 in 1 
Chloroform 1 in 30 
Ethanol (95%) 1 in 2.5 
Ether 1 in 3 
Methanol 1 in 0.7 
Peanut oil 1 in 33 
Propylene glycol 1 in 7 
Water Practically insoluble 
Safety: the WHO has established a temporary estimated 
acceptable daily intake for octyl gallate at up to 0.1 mg/kg 
body-weight.(13) 
Comments: the EINECS number for octyl gallate is 252-073-5. 
18 Comments 
Propyl gallate has been reported to impart an ‘off’ flavor to 
corn and cottonseed oils when used as an antioxidant.(15) A 
specification for propyl gallate is contained in the Food 
Chemicals Codex (FCC). The EINECS number for propyl 
gallate is 204-498-2. 
19 Specific References 
1 Boehm E, Williams R. The action of propyl gallate on the 
autoxidation of oils. Pharm J 1943; 151: 53. 
2 Boehm E, Williams R. A study of the inhibiting actions of propyl 
gallate (normal propyl trihydroxy benzoate) and certain other 
trihydric phenols on the autoxidation of animal and vegetable oils. 
Chemist Drug 1943; 140: 146–147. 
3 Okide GB, Adikwu MU. Kinetic study of the auto-oxidation of 
arachis oil. Boll Chim Farm 1998; 137: 277–280. 
4 Brandl M, Magill A, Rudrarajn V, Gordon MS. Approaches for 
improving the stability of ketorolac in powder blends. J Pharm Sci 
1995; 84: 1151–1153. 
5 Zeelie JJ, McCarthy TJ. The potential antimicrobial properties of 
antioxidants in pharmaceutical systems. S Afr Pharm J 1982; 49: 
552–554. 
6 McCarthy TJ, Zeelie JJ, Krause DJ. The antimicrobial action of 
zinc ion/antioxidant combinations. J Clin Pharm Ther 1992; 17: 
51–54. 
7 Kahn G, Phanuphak P, Claman HN. Propyl gallate contact 
sensitization and orally induced tolerance. Arch Dermatol 1974; 
109: 506–509. 
8 Tayama S, Nakagawa Y. Cytogenetic effects of propyl gallate in 
CHO-K1 cells. Mutat Res 2001; 498(1–2): 117–127. 
9 Golightly LK, Smolinske SS, Bennett ML, Sutherland EW, Rumack 
BH. Pharmaceutical excipients: adverse effects associated with 
‘inactive’ ingredients in drug products (part II). Med Toxicol 1988; 
3: 209–240. 
10 Cusano F, Capozzi M, Errico G. Safety of propyl gallate in topical 
products. J Am Acad Dermatol 1987; 17: 308–309. 
11 Bojs G, Nicklasson B, Svensson A. Allergic contact dermatitis to 
propyl gallate. Contact Dermatitis 1987; 17: 294–298. 
12 Nitzan M, Volovitz B, Topper E. Infantile methemoglobinemia 
caused by food additives. Clin Toxicol 1979; 15(3): 273–280. 
13 FAO/WHO. Evaluation of certain food additives and contaminants. 
Forty-sixth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1997; No. 
868. 
14 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3084. 
15 McConnell JEW, Esselen WB. Effect of storage conditions and 
antioxidants on the keeping quality of packaged oils. J Am Oil 
Chem Soc 1947; 24: 6–14. 
20 General References 
Johnson DM, Gu LC. Autoxidation and antioxidants. In: Swarbrick J, 
Boylan JC, eds. Encyclopedia of Pharmaceutical Technology, 
volume 1. New York: Marcel Dekker, 1988: 415–449. 
21 Authors 
PJ Weller. 
22 Date of Revision 
9 August 2005. 
Propyl Gallate 621

Propylene Carbonate 
1 Nonproprietary Names 
USPNF: Propylene carbonate 
2 Synonyms 
Carbonic acid, cyclic propylene ester; cyclic methylethylene 
carbonate; cyclic propylene carbonate; 4-methyl-2-oxo-1,3- 
dioxolane; 1,2-propanediol cyclic carbonate; 1,2-propylene 
carbonate. 
3 Chemical Name and CAS Registry Number 

-4-Methyl-1,3-dioxolan-2-one [108-32-7] 
4 Empirical Formula and Molecular Weight 
C4H6O3 102.09 
5 Structural Formula 
6 Functional Category 
Gelling agent; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Propylene carbonate is used mainly as a solvent in oral and 
topical pharmaceutical formulations. 
In topical applications, propylene carbonate has been used 
in combination with propylene glycol as a solvent for 
corticosteroids. The corticosteroid is dissolved in the solvent 
mixture to yield microdroplets that can then be dispersed in 
petrolatum.(1) Propylene carbonate has been used as a 
dispensing solvent in topical preparations.(2) 
Propylene carbonate has also been used in hard gelatin 
capsules as a nonvolatile, stabilizing, liquid carrier. For 
formulations with a low dosage of active drug, a uniform 
drug content may be obtained by dissolving the drug in 
propylene carbonate then spraying this solution on to a solid 
carrier such as compressible sugar; the sugar may then be filled 
into hard gelatin capsules.(3) 
Propylene carbonate may additionally be used as a solvent, 
at room and elevated temperatures, for many cellulose-based 
polymers and plasticizers. Propylene carbonate is also used in 
cosmetics. 
8 Description 
Propylene carbonate is a clear, colorless, mobile liquid, with a 
faint odor. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for propylene carbonate. 
Test USPNF 23 
Identification . 
Specific gravity 1.203–1.210 
pH (10% v/v aqueous solution) 6.0–7.5 
Residue on ignition 40.01% 
Organic volatile impurities . 
Assay 99.0–100.5% 
10 Typical Properties 
Boiling point: 2428C 
Flash point: 1328C 
Freezing point: 49.28C 
Heat of combustion: 14.21 kJ/mol (3.40 kcal/mol) 
Heat of vaporization: 55.2 kJ/mol (13.2 kcal/mol) at 1508C 
Refractive index: nD
20 = 1.420–1.422 
Solubility: practically insoluble in hexane; freely soluble in 
water. Miscible with acetone, benzene, chloroform, ethanol, 
ethanol (95%), and ether. 
Specific heat: 2.57 J/g/8C (0.62 cal/g/8C) at 208C 
Vapor pressure: 4 Pa (0.03 mmHg) at 208C. 
Viscosity (dynamic): 2.5 mPa s (2.5 cP) at 258C. 
11 Stability and Storage Conditions 
Propylene carbonate and its aqueous solutions are stable but 
may degrade in the presence of acids or bases, or upon heating; 
see also Section 12. 
Store in a well-closed container in a cool, dry place. 
12 Incompatibilities 
Propylene carbonate hydrolyzes rapidly in the presence of 
strong acids and bases, forming mainly propylene oxide and 
carbon dioxide. Propylene carbonate can also react with 
primary and secondary amines to yield carbamates. 
13 Method of Manufacture 
Propylene carbonate may be prepared by the reaction of 
sodium bicarbonate with propylene chlorohydrin.(4) 
14 Safety 
Propylene carbonate is used as a solvent in oral and topical 
pharmaceutical formulations and is generally regarded as an 
essentially nontoxic and nonirritant material.

In animal studies, propylene carbonate was found to cause 
tissue necrosis after parenteral administration.(5) 
LD50 (mouse, oral): 20.7 g/kg 
LD50 (mouse, SC): 15.8 g/kg 
LD50 (rat, oral): 29 g/kg 
LD50 (rat, SC): 11.1 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Propylene carbonate may be 
irritant to the eyes and mucous membranes. Eye protection and 
gloves are recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (topical 
ointments). Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
(S)-Propylene carbonate. 
(S)-Propylene carbonate 
Empirical formula: C4H6O3 
Molecular weight: 102.09 
CAS number: [51260-39-0] 
Specific rotation: [a]D
25 = 1.78 (0.92% v/v solution in ethanol) 
Comments: the (S)-enantiomer of 
-propylene carbonate.(6) 
18 Comments 
The EINECS number for propylene carbonate is 203-572-1. 
19 Specific References 
1 Burdick KH, Haleblian JK, Poulsen BJ, Cobner SE. Corticosteroid 
ointments: comparison by two human bioassays. Curr Ther Res 
1973; 15: 233–242. 
2 Yoshida H, Tamura S, Toyoda T, et al. In vitro release of 
tacrolimus from tacrolimus ointment and its speculated mechanism. 
Int J Pharm 2004; 270(1–2): 55–64. 
3 Dahl TC, Burke G. Feasibility of manufacturing a solid dosage 
form using a liquid nonvolatile drug carrier: a physicochemical 
characterization. Drug Dev Ind Pharm 1990; 16: 1881–1891. 
4 Najer H, Chabrier P, Giudicelli R. Study of organic cyclic 
carbonates and their derivatives [in French]. Bull Soc Chim Fr 
1954: 1142–1148. 
5 Hem SL, Bright DR, Banker GS, Pogue JP. Tissue irritation 
evaluation of potential parenteral vehicles. Drug Dev Commun 
1974–75 1: 471–477. 
6 Usieli V, Pilersdorf A, Shor S, et al. Chiroptical properties of cyclic 
esters and ketals derived from (S)-1,2-propylene glycol and (S,S)- 
and (R,R)-2,3-butylene glycol. J Org Chem 1974; 39: 2073–2079. 
20 General References 
Cheng H, Gadde RR. Determination of propylene carbonate in 
pharmaceutical formulations using liquid chromatography. J Pharm 
Sci 1985; 74: 695–696. 
Ursin C, Hansen CM, Van Dyk JW, et al. Permeability of commercial 
solvents through living human skin. Am Ind Hyg J 1995; 56: 651– 
660. 
21 Authors 
PJ Weller. 
22 Date of Revision 
9 August 2005. 
Propylene Carbonate 623

Propylene Glycol 
1 Nonproprietary Names 
BP: Propylene glycol 
JP: Propylene glycol 
PhEur: Propylenglycolum 
USP: Propylene glycol 
2 Synonyms 
1,2-Dihydroxypropane; E1520; 2-hydroxypropanol; methyl 
ethylene glycol; methyl glycol; propane-1,2-diol. 
3 Chemical Name and CAS Registry Number 
1,2-Propanediol [57-55-6] 
()-1,2-Propanediol [4254-14-2] 
(.)-1,2-Propanediol [4254-15-3] 
4 Empirical Formula and Molecular Weight 
C3H8O2 76.09 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; disinfectant; humectant; plasticizer; 
solvent; stabilizer for vitamins; water-miscible cosolvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Propylene glycol has become widely used as a solvent, 
extractant, and preservative in a variety of parenteral and 
nonparenteral pharmaceutical formulations. It is a better 
general solvent than glycerin and dissolves a wide variety of 
materials, such as corticosteroids, phenols, sulfa drugs, 
barbiturates, vitamins (A and D), most alkaloids, and many 
local anesthetics. 
As an antiseptic it is similar to ethanol, and against molds it 
is similar to glycerin and only slightly less effective than 
ethanol. 
Propylene glycol is commonly used as a plasticizer in 
aqueous film-coating formulations. 
Propylene glycol is also used in cosmetics and in the food 
industry as a carrier for emulsifiers and as a vehicle for flavors 
in preference to ethanol, since its lack of volatility provides a 
more uniform flavor. See Table I. 
Table I: Uses of propylene glycol. 
Use Dosage form Concentration (%) 
Humectant Topicals 15 
Preservative Solutions, semisolids 15–30 
Solvent or cosolvent Aerosol solutions 10–30 
Oral solutions 10–25 
Parenterals 10–60 
Topicals 5–80 
8 Description 
Propylene glycol is a clear, colorless, viscous, practically 
odorless liquid with a sweet, slightly acrid taste resembling 
that of glycerin. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for propylene glycol. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Appearance — . — 
Specific gravity 1.035–1.040 1.035–1.040 1.035–1.037 
Acidity . . . 
Water 40.5% 40.2% 40.2% 
Residue on ignition 40.005% — 43.5 mg 
Sulfated ash — 40.01% — 
Chloride 40.007% — 40.007% 
Sulfate 40.002% — 40.006% 
Heavy metals 45 ppm 45 ppm 45 ppm 
Organic volatile 
impurities 
— — . 
Refractive index — 1.431–1.433 — 
Oxidizing 
substances 
— . — 
Reducing substances — . — 
Arsenic 42 ppm — — 
Glycerin . — — 
Distilling range 184–1898C — — 
Assay — — 599.5% 
10 Typical Properties 
Autoignition temperature: 3718C 
Boiling point: 1888C 
Density: 1.038 g/cm3 at 208C 
Flammability: upper limit, 12.6% v/v in air; lower limit, 2.6% 
v/v in air. 
Flash point: 998C (open cup) 
Heat of combustion: 1803.3 kJ/mol (431.0 kcal/mol) 
Heat of vaporization: 705.4 J/g (168.6 cal/g) at b.p. 
Melting point: 598C

Osmolarity: a 2.0% v/v aqueous solution is iso-osmotic with 
serum. 
Refractive index: nD
20 = 1.4324 
Specific rotation [a]D
20: 
15.08 (neat) for (R)-form; 
.15.88 (neat) for (S)-form. 
Solubility: miscible with acetone, chloroform, ethanol (95%), 
glycerin, and water; soluble at 1 in 6 parts of ether; not 
miscible with light mineral oil or fixed oils, but will dissolve 
some essential oils. 
Specific heat: 2.47 J/g (0.590 cal/g) at 208C 
Surface tension: 40.1mN/m (40.1 dynes/cm) at 258C 
Vapor density (relative): 2.62 (air = 1) 
Vapor pressure: 9.33 Pa (0.07 mmHg) at 208C 
Viscosity (dynamic): 58.1 mPa s (58.1 cP) at 208C 
11 Stability and Storage Conditions 
At cool temperatures, propylene glycol is stable in a well-closed 
container, but at high temperatures, in the open, it tends to 
oxidize, giving rise to products such as propionaldehyde, lactic 
acid, pyruvic acid, and acetic acid. Propylene glycol is 
chemically stable when mixed with ethanol (95%), glycerin, 
or water; aqueous solutions may be sterilized by autoclaving. 
Propylene glycol is hygroscopic and should be stored in a 
well-closed container, protected from light, in a cool, dry place. 
12 Incompatibilities 
Propylene glycol is incompatible with oxidizing reagents such 
as potassium permanganate. 
13 Method of Manufacture 
Propylene is converted to chlorohydrin by chlorine water and 
hydrolyzed to 1,2-propylene oxide. With further hydrolysis, 
1,2-propylene oxide is converted to propylene glycol. 
14 Safety 
Propylene glycol is used in a wide variety of pharmaceutical 
formulations and is generally regarded as a relatively nontoxic 
material. It is also used extensively in foods and cosmetics. 
Probably as a consequence of its metabolism and excretion, 
propylene glycol is less toxic than other glycols. Propylene 
glycol is rapidly absorbed from the gastrointestinal tract; there 
is also evidence that it is absorbed topically when applied to 
damaged skin. It is extensively metabolized in the liver, mainly 
to lactic and pyruvic acids and is also excreted unchanged in the 
urine.(1,2) 
In topical preparations, propylene glycol is regarded as 
minimally irritant, although it is more irritant than glycerin. 
Some local irritation is produced upon application to mucous 
membranes or when it is used under occlusive conditions.(3) 
Parenteral administration may cause pain or irritation when 
used in high concentration. 
Propylene glycol is estimated to be one-third as intoxicating 
as ethanol, with administration of large volumes being 
associated with adverse effects most commonly on the central 
nervous system, especially in neonates and children.(4–6) Other 
adverse reactions reported, though generally isolated, include: 
ototoxicity;(7) cardiovascular effects; seizures; and hyperosmolarity(
8) and lactic acidosis, both of which occur most frequently 
in patients with renal impairment. Adverse effects are more 
likely to occur following consumption of large quantities of 
propylene glycol or on adminstration to neonates, children 
under 4 years of age, pregnant women, and patients with 
hepatic or renal failure. Adverse events may also occur in 
patients treated with disulfiram or metronidazole.(9) 
On the basis of metabolic and toxicological data, the WHO 
has set an acceptable daily intake of propylene glycol at up to 
25 mg/kg body-weight.(10) Formulations containing 35% propylene 
glycol can cause hemolysis in humans. 
In animal studies, there has been no evidence that propylene 
glycol is teratogenic or mutagenic. Rats can tolerate a repeated 
oral daily dose of up to 30 mL/kg in the diet over 6 months, 
while the dog is unaffected by a repeated oral daily dose of 
2 g/kg in the diet for 2 years.(11) 
LD50 (mouse, IP): 9.72 g/kg(12) 
LD50 (mouse, IV): 6.63 g/kg 
LD50 (mouse, oral): 22.0 g/kg 
LD50 (mouse, SC): 17.34 g/kg 
LD50 (rat, IM): 0.01 g/kg 
LD50 (rat, IP): 6.66 g/kg 
LD50 (rat, IV): 6.42 g/kg 
LD50 (rat, oral): 0.02 g/kg 
LD50 (rat, SC): 22.5 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Propylene glycol should be 
handled in a well-ventilated environment; eye protection is 
recommended. In the UK, the long-term (8-hour TWA) 
occupational exposure limit for propylene glycol vapor and 
particulates is 474 mg/m3 (150 ppm) and 10 mg/m3 for 
particulates.(13) 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (dental 
preparations, IM and IV injections, inhalations, ophthalmic, 
oral, otic, percutaneous, rectal, topical, and vaginal preparations). 
Included in nonparenteral and parenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Propylene glycol alginate. 
18 Comments 
In addition to its uses as an excipient, propylene glycol is used 
in veterinary medicine as an oral glucogenic in ruminants.(14) A 
specification for potassium glycol is contained in the Food 
Chemicals Codex (FCC). The EINECS number for propylene 
glycol is 200-338-0. 
19 Specific References 
1 Yu DK, Elmquist WF, Sawchuk RJ. Pharmacokinetics of propylene 
glycol in humans during multiple dosing regimens. J Pharm Sci 
1985; 74: 876–879. 
2 Speth PAJ, Vree TB, Neilen NF, et al. Propylene glycol 
pharmacokinetics and effects after intravenous infusion in 
humans. Ther Drug Monit 1987; 9: 255–258. 
3 Motoyoshi K, Nozawa S, Yoshimura M, Matsuda K. The safety of 
propylene glycol and other humectants. Cosmet Toilet 1984; 
99(10): 83–91. 
Propylene Glycol 625

4 Arulanantham K, Genel M. Central nervous system toxicity 
associated with ingestion of propylene glycol. J Pediatr 1978; 93: 
515–516. 
5 MacDonald MG, Getson PR, Glasgow AM, et al. Propylene 
glycol: increased incidence of seizures in low birth weight infants. 
Pediatrics 1987; 79: 622–625. 
6 Martin G, Finberg L. Propylene glycol: a potentially toxic vehicle 
in liquid dosage form. J Pediatr 1970; 77: 877–878. 
7 Morizono T, Johnstone BM. Ototoxicity of chloramphenicol ear 
drops with propylene glycol as solvent. Med J Aust 1975; 2: 634– 
638. 
8 Fligner CL, Jack R, Twiggs GA, Raisys VA. Hyperosmolality 
induced by propylene glycol: a complication of silver sulfadiazine 
therapy. J Am Med Assoc 1985; 253: 1606–1609. 
9 Anonymous. US warning on HIV drug excipient. Pharm J 2000; 
264: 685. 
10 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications. 
Seventeenth report of the FAO/WHO expert committee on food 
additives. World Health Organ Tech Rep Ser 1974: No. 539. 
11 Clayton GD, Clayton FE, eds. Patty’s Industrial Hygiene and 
Toxicology, 3rd edn. Chichester: Wiley, 1987. 
12 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3061. 
13 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
14 Bishop Y, ed. The Veterinary Formulary, 6th edn. London: 
Pharmaceutical Press, 2005: 420. 
20 General References 
Doenicke A, Nebauer AE, Hoernecke R, et al. Osmolalities of 
propylene glycol-containing drug formulations for parenteral use: 
should propylene glycol be used as a solvent? Anesth Analg 1992; 
75(3): 431–435. 
Krzyzaniak JF, Raymond DM, Yalkowsky SH. Lysis of human red 
blood cells 2: effect of contact time on cosolvent induced hemolysis. 
Int J Pharm 1997; 152: 193–200. 
Strickley RG. Solubilizing excipients in oral and injectable formulations. 
Pharm Res 2004; 21(2): 201–230. 
Wells JI, Bhatt DA, Khan KA. Improved wet massed tableting using 
plasticized binder. J Pharm Pharmacol 1982; 34 (Suppl.): 46P. 
Williams AC, Barry BW. Penetration enhancers. Adv Drug Delivery 
Rev 2004; 56(5): 603–618. 
Yu CD, Kent JS. Effect of propylene glycol on subcutaneous absorption 
of a benzimidazole hydrochloride. J Pharm Sci 1982; 71: 476–478. 
21 Authors 
SC Owen, PJ Weller. 
22 Date of Revision 
9 August 2005. 
626 Propylene Glycol

Propylene Glycol Alginate 
1 Nonproprietary Names 
USPNF: Propylene glycol alginate 
2 Synonyms 
Alginic acid, propylene glycol ester; E405; hydroxypropyl 
alginate; Kelcoloid; Manucol ester; Pronova; propane-1,2-diol 
alginate; Protanal; TIC Pretested. 
3 Chemical Name and CAS Registry Number 
Propylene glycol alginate [9005-37-2] 
4 Empirical Formula and Molecular Weight 
Propylene glycol alginate is a propylene glycol ester of alginic 
acid, a linear glycuronan polymer consisting of a mixture of b- 
(1!4)-D-mannosyluronic acid and a-(1!4)-L-gulosyluronic 
acid residues. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Antifoaming agent; emulsifying agent; flavoring agent; stabilizing 
agent; suspending agent; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Propylene glycol alginate is used as a stabilizing, suspending, 
gelling, and emulsifying agent in oral and topical pharmaceutical 
formulations. Typically, a concentration of 0.3–5% w/v is 
used, although this may vary depending upon the specific 
application and the grade of propylene glycol alginate used. 
Propylene glycol alginate is also used in cosmetics and food 
products. 
8 Description 
Propylene glycol alginate occurs as a white to yellowish 
colored, practically odorless and tasteless, fibrous or granular 
powder. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for propylene glycol alginate. 
Test USPNF 23 
Identification . 
Microbial limits 4200/g 
Loss on drying 420.0% 
Ash 410.0% 
Arsenic 43 ppm 
Lead 40.001% 
Heavy metals 40.004% 
Free carboxyl groups . 
Esterified carboxyl groups . 
Assay (of alginates) . 
10 Typical Properties 
Solubility: soluble in dilute organic acids and water, forming 
stable, viscous, colloidal solutions at pH 3. Depending upon 
the degree of esterification, propylene glycol alginate is also 
soluble in aqueous ethanol/water mixtures containing up to 
60% w/w of ethanol (95%). 
Viscosity (dynamic): the viscosity of aqueous solutions depends 
upon the grade of material used. Typically, a 1% w/v 
aqueous solution has a viscosity of 20–400 mPa s 
(20–400 cP). Viscosity may vary depending upon concentration, 
pH, temperature, or the presence of metal ions. See 
also Sodium Alginate. 
11 Stability and Storage Conditions 
Propylene glycol alginate is a stable material, although it will 
gradually become less soluble if stored at elevated temperatures 
for extended periods. 
Propylene glycol alginate solutions are most stable at pH 
3–6. In alkaline solutions, propylene glycol alginate is rapidly 
saponified. Alginate solutions are susceptible to microbial 
spoilage and should be sterilized or preserved with an 
antimicrobial preservative. However, sterilization processes 
may adversely affect the viscosity of propylene glycol alginate 
solutions, see Sodium Alginate. 
The bulk material should be stored in an airtight container 
in a cool, dry place. 
12 Incompatibilities 
—
13 Method of Manufacture 
Alginic acid, extracted from brown seaweed, is reacted with 
propylene oxide to form propylene glycol alginate. Various 
grades may be obtained that differ in composition according to 
the degree of esterification and the percentage of free and 
neutralized carboxyl groups present in the molecule; complete 
esterification of alginic acid is impractical.

14 Safety 
Propylene glycol alginate is used in oral and topical pharmaceutical 
formulations, cosmetics, and food products. It is 
generally regarded as a nontoxic and nonirritant material, 
although excessive oral consumption may be harmful. A study 
in five healthy male volunteers fed a daily intake of 175 mg/kg 
body-weight of propylene glycol alginate for 7 days, followed 
by a daily intake of 200 mg/kg body-weight of propylene glycol 
alginate for a further 16 days, showed no significant adverse 
effects.(1) 
Inhalation of alginate dust may be irritant and has been 
associated with industrially related asthma in workers involved 
in alginate production. However, it appears that the cases of 
asthma were linked to exposure to seaweed dust rather than 
pure alginate dust.(2) 
LD50 (hamster, oral): 7.0 g/kg(3) 
LD50 (mouse, oral): 7.8 g/kg 
LD50 (rabbit, oral): 7.6 g/kg 
LD50 (rat, oral): 7.2 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Propylene glycol alginate 
may be irritant to the eyes or respiratory system if inhaled as 
dust; see Section 14. Eye protection, gloves, and a dust 
respirator are recommended. Propylene glycol alginate should 
be handled in a well-ventilated environment. 
16 Regulatory Status 
GRAS listed. Accepted in Europe for use as a food additive. 
Included in the FDA Inactive Ingredients Guide (oral preparations). 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Alginic acid; propylene glycol; sodium alginate. 
18 Comments 
A specification for propylene glycol alginate is contained in the 
Food Chemicals Codex (FCC). 
See Alginic Acid and Sodium Alginate for further information. 
19 Specific References 
1 Anderson DM, Brydon WG, Eastwood MA, Sedgwick DM. 
Dietary effects of propylene glycol alginate in humans. Food Addit 
Contam 1991; 8(3): 225–236. 
2 Henderson AK, Ranger AF, Lloyd J, et al. Pulmonary hypersensitivity 
in the alginate industry. Scott Med J 1984; 29(2): 90–95. 
3 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3080–3081. 
20 General References 
McDowell RH. New reactions of propylene glycol alginate. J Soc 
Cosmet Chem 1970; 21: 441–457. 
21 Authors 
CK Tye. 
22 Date of Revision 
28 June 2005. 
628 Propylene Glycol Alginate

Propylparaben 
1 Nonproprietary Names 
BP: Propyl hydroxybenzoate 
JP: Propyl parahydroxybenzoate 
PhEur: Propylis parahydroxybenzoas 
USPNF: Propylparaben 
2 Synonyms 
E216; 4-hydroxybenzoic acid propyl ester; Nipasol M; 
propagin; propyl p-hydroxybenzoate; Propyl parasept; Solbrol 
P; Uniphen P-23. 
3 Chemical Name and CAS Registry Number 
Propyl 4-hydroxybenzoate [94-13-3] 
4 Empirical Formula and Molecular Weight 
C10H12O3 180.20 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Propylparaben is widely used as an antimicrobial preservative 
in cosmetics, food products, and pharmaceutical formulations; 
see Table I. 
It may be used alone, in combination with other paraben 
esters, or with other antimicrobial agents. It is one of the most 
frequently used preservatives in cosmetics.(1) 
The parabens are effective over a wide pH range and have a 
broad spectrum of antimicrobial activity, although they are 
most effective against yeasts and molds; see Section 10. 
Owing to the poor solubility of the parabens, the paraben 
salts, particularly the sodium salt, are frequently used in 
formulations. This may cause the pH of poorly buffered 
formulations to become more alkaline. 
Propylparaben (0.02% w/v) together with methylparaben 
(0.18% w/v) has been used for the preservation of various 
parenteral pharmaceutical formulations; see Section 14. 
See Methylparaben for further information. 
Table I: Uses of propylparaben in pharmaceutical preparations. 
Use Concentration (%) 
IM, IV, SC injections 0.005–0.2 
Inhalation solutions 0.015 
Intradermal injections 0.02–0.26 
Nasal solutions 0.017 
Ophthalmic preparations 0.005–0.01 
Oral solutions and suspensions 0.01–0.02 
Rectal preparations 0.02–0.01 
Topical preparations 0.01–0.6 
Vaginal preparations 0.02–0.1 
8 Description 
Propylparaben occurs as a white, crystalline, odorless, and 
tasteless powder. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for propylparaben. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Melting range 96.0–99.08C — 95.0–98.08C 
Acidity — . — 
Loss on drying 40.5% — 40.5% 
Residue on ignition 40.1% — 40.05% 
Sulfated ash — 40.1% — 
Appearance of 
solution 
— . — 
Chloride 40.035% — — 
Sulfate 40.024% — — 
Parahydroxy benzoic 
acid and salicylic 
acid 
. — — 
Heavy metals 420 ppm — — 
Related substances — . — 
Readily carbonizable 
substances 
. — — 
Organic volatile 
impurities 
— — . 
Assay (dried basis) 599.0% 98.0–102.0% 99.0–100.5% 
10 Typical Properties 
Antimicrobial activity: propylparaben exhibits antimicrobial 
activity between pH 4–8. Preservative efficacy decreases 
with increasing pH owing to the formation of the phenolate 
anion. Parabens are more active against yeasts and molds 
than against bacteria. They are also more active against 
Gram-positive than against Gram-negative bacteria. The 
activity of the parabens increases with increasing chain 
length of the alkyl moiety; however, solubility decreases.

Activity may be improved by using combinations of 
parabens, as additive effects occur. Propylparaben has been 
used with methylparaben in parenteral preparations, and is 
used in combination with other parabens in topical and oral 
formulations. Activity has also been reported to be 
improved by the addition of other excipients; see Methylparaben. 
Reported minimum inhibitory concentrations (MICs) for 
propylparaben are provided in Table III.(2) 
Table III: Minimum inhibitory concentrations (MICs) for 
propylparaben in aqueous solution.(2) 
Microorganism MIC (mg/mL) 
Aerobacter aerogenes ATCC 8308 1000 
Aspergillus niger ATCC 9642 500 
Aspergillus niger ATCC 10254 200 
Bacillus cereus var. mycoides ATCC 6462 125 
Bacillus subtilis ATCC 6633 500 
Candida albicans ATCC 10231 250 
Enterobacter cloacae ATCC 23355 1000 
Escherichia coli ATCC 8739 500 
Escherichia coli ATCC 9637 100 
Klebsiella pneumoniae ATCC 8308 500 
Penicillium chrysogenum ATCC 9480 125 
Penicillium digitatum ATCC 10030 63 
Proteus vulgaris ATCC 13315 250 
Pseudomonas aeruginosa ATCC 9027 >1000 
Pseudomonas aeruginosa ATCC 15442 >1000 
Pseudomonas stutzeri 500 
Rhizopus nigricans ATCC 6227A 125 
Saccharomyces cerevisiae ATCC 9763 125 
Salmonella typhosa ATCC 6539 500 
Serratia marcescens ATCC 8100 500 
Staphylococcus aureus ATCC 6538P 500 
Staphylococcus epidermidis ATCC 12228 500 
Trichophyton mentagrophytes 65 
Boiling point: 2958C 
Density (bulk): 0.426 g/cm3 
Density (tapped): 0.706 g/cm3 
Density(true): 1.288 g/cm3 
Dissociation constant: pKa = 8.4 at 228C 
Flash point: 1408C 
Partition coefficients: values for different vegetable oils vary 
considerably and are affected by the purity of the oil; see 
Table IV. 
Table IV: Partition coefficients for propylparaben in vegetable oil and 
water.(3) 
Solvent Partition coefficient oil : water 
Corn oil 58.0 
Mineral oil 0.5 
Peanut oil 51.8 
Soybean oil 65.9 
Refractive index: nD
14 = 1.5049 
Solubility: see Table V. 
Table V: Solubility of propylparaben in various solvents.(2) 
Solvent Solubility at 208C 
unless otherwise stated 
Acetone Freely soluble 
Ethanol (95%) 1 in 1.1 
Ethanol (50%) 1 in 5.6 
Ether Freely soluble 
Glycerin 1 in 250 
Mineral oil 1 in 3330 
Peanut oil 1 in 70 
Propylene glycol 1 in 3.9 
Propylene glycol (50%) 1 in 110 
Water 1 in 4350 at 158C 
1 in 2500 
1 in 225 at 808C 
11 Stability and Storage Conditions 
Aqueous propylparaben solutions at pH 3–6 can be sterilized 
by autoclaving, without decomposition.(4) At pH 3–6, aqueous 
solutions are stable (less than 10% decomposition) for up to 
about 4 years at room temperature, while solutions at pH 8 or 
above are subject to rapid hydrolysis (10% or more after about 
60 days at room temperature).(5) 
See Table VI, for the predicted rate constants and half-lives 
at 258C for propylparaben.(5) 
Propylparaben should be stored in a well-closed container in 
a cool, dry place. 
Table VI: Predicted rate constants and half-lives at 258C for 
propylparaben dissolved in hydrochloric acid solution. 
Initial pH 
of solution 
Rate constant 
k 
 s(a) (h1) 
Half-life 
t1/2 
 s(a) (day) 
1 (1.255 
 0.042)  10–4 230 
 7.6 
2 (1.083 
 0.081)  10–5 2670 
 200 
3 (8.41 
 0.96)  10–7 34 300 
 3900 
4 (2.23 
 0.37)  10–7 130 000 
 22 000 
(a)s indicates the standard error. 
The predicted amount of propylparaben remaining after 
autoclaving is given in Table VII.(5) 
Table VII: Predicted amount of propylparaben dissolved in 
hydrochloric acid, after autoclaving. 
Initial pH of solution Rate constant 
k 
 s(a) (h1) 
Predicted residual 
amount after 
sterilization (%) 
1 (4.42 
 0.10)  101 86.30 
 0.30 
2 (4.67 
 0.19)  10–2 98.46 
 0.06 
3 (2.96 
 0.24)  10–3 99.90 
 0.01 
4 (7.8 
 1.1)  10–4 99.97 
 0.004 
(a)s indicates the standard error. 
12 Incompatibilities 
The antimicrobial activity of propylparaben is reduced 
considerably in the presence of nonionic surfactants as a result 
of micellization.(6) Absorption of propylparaben by plastics has 
been reported, with the amount absorbed dependent upon the 
630 Propylparaben

type of plastic and the vehicle.(7) Magnesium aluminum silicate, 
magnesium trisilicate, yellow iron oxide, and ultramarine blue 
have also been reported to absorb propylparaben, thereby 
reducing preservative efficacy.(8,9) 
Propylparaben is discolored in the presence of iron and is 
subject to hydrolysis by weak alkalis and strong acids. 
See also Methylparaben. 
13 Method of Manufacture 
Propylparaben is prepared by the esterification of p-hydroxybenzoic 
acid with n-propanol. 
14 Safety 
Propylparaben and other parabens are widely used as 
antimicrobial preservatives in cosmetics, food products, and 
oral and topical pharmaceutical formulations. 
Propylparaben and methylparaben have been used as 
preservatives in injections and ophthalmic preparations; however 
they are now generally regarded as being unsuitable for 
these types of formulations owing to the irritant potential of the 
parabens. 
Systemically, no adverse reactions to parabens have been 
reported, although they have been associated with hypersensitivity 
reactions. TheWHOhas set an estimated acceptable total 
daily intake for methyl, ethyl, and propyl parabens at up to 
10 mg/kg body-weight.(10) 
LD50 (mouse, IP): 0.2 g/kg(11) 
LD50 (mouse, oral): 6.33 g/kg 
LD50 (mouse, SC): 1.65 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Propylparaben may be 
irritant to the skin, eyes, and mucous membranes and should be 
handled in a well-ventilated environment. Eye protection, 
gloves, and a dust mask or respirator are recommended. 
16 Regulatory Status 
Propylparaben and methylparaben are affirmed GRAS direct 
food substances in the USA at levels up to 0.1%. All esters 
except the benzyl ester are allowed for injection in Japan. 
In cosmetics, the EU and Brazil allow use of each paraben at 
0.4%, but the total of all parabens may not exceed 0.8%. The 
upper limit in Japan is 1.0%. 
Accepted as a food additive in Europe. Included in the FDA 
Inactive Ingredients Guide (IM, IV, and SC injections; inhalations; 
ophthalmic preparations; oral capsules, solutions, 
suspensions, and tablets; otic, rectal, topical, and vaginal 
preparations). Included in parenteral and nonparenteral 
medicines licensed in the UK. Included in the Canadian List 
of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Butylparaben; ethylparaben; methylparaben; propylparaben 
potassium; propylparaben sodium. 
Propylparaben potassium 
Empirical formula: C10H11KO3 
Molecular weight: 218.30 
CAS number: [84930-16-5] 
Synonyms: potassium propyl hydroxybenzoate; propyl 
4-hydroxybenzoate potassium salt. 
Propylparaben sodium 
Empirical formula: C10H11NaO3 
Molecular weight: 202.20 
CAS number: [35285-69-9] 
Synonyms: E217; propyl 4-hydroxybenzoate sodium salt; 
sodium propyl hydroxybenzoate; soluble propyl hydroxybenzoate. 
Appearance: white, odorless or almost odorless, hygroscopic 
crystalline powder. 
Acidity/alkalinity: pH = 9.5–10.5 (0.1% w/v aqueous solution). 
Solubility: 1 in 50 of ethanol (95%); 1 in 2 ethanol (50%); 1 in 
1 of water; practically insoluble in fixed oils. 
Comments: propylparaben sodium may be used instead of 
propylparaben because of its greater aqueous solubility. 
However, it may cause the pH of a formulation to become 
more alkaline. 
18 Comments 
A specification for propylparaben is contained in the Food 
Chemicals Codex (FCC). The EINECS number for propylparaben 
is 202-307-7. 
See Methylparaben for further information and references. 
19 Specific References 
1 Decker RL, Wenninger JA. Frequency of preservative use in 
cosmetic formulas as disclosed to FDA—1987. Cosmet Toilet 
1987; 102(12): 21–24. 
2 Haag TE, Loncrini DF. Esters of para-hydroxybenzoic acid. In: 
Kabara JJ, ed. Cosmetic and Drug Preservation. New York: 
Marcel Dekker, 1984: 63–77. 
3 Wan LSC, Kurup TRR, Chan LW. Partition of preservatives in oil/ 
water systems. Pharm Acta Helv 1986; 61: 308–313. 
4 Aalto TR, Firman MC, Rigler NE. p-Hydroxybenzoic acid esters 
as preservatives I: uses, antibacterial and antifungal studies, 
properties and determination. J Am Pharm Assoc (Sci) 1953; 42: 
449–457. 
5 Kamada A, Yata N, Kubo K, Arakawa M. Stability of phydroxybenzoic 
acid esters in acidic medium. Chem Pharm Bull 
1973; 21: 2073–2076. 
6 Aoki M, Kameta A, Yoshioka I, Matsuzaki T. Application of 
surface active agents to pharmaceutical preparations I: effect of 
Tween 20 upon the antifungal activities of p-hydroxybenzoic acid 
esters in solubilized preparations [in Japanese]. J Pharm Soc Jpn 
1956; 76: 939–943. 
7 Kakemi K, Sezaki H, Arakawa E, et al. Interactions of parabens 
and other pharmaceutical adjuvants with plastic containers. Chem 
Pharm Bull 1971; 19: 2523–2529. 
8 Allwood MC. The adsorption of esters of p-hydroxybenzoic acid 
by magnesium trisilicate. Int J Pharm 1982; 11: 101–107. 
9 Sakamoto T, Yanagi M, Fukushima S, Mitsui T. Effects of some 
cosmetic pigments on the bactericidal activities of preservatives. J 
Soc Cosmet Chem 1987; 38: 83–98. 
10 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications. 
Seventeenth report of the joint FAO/WHO expert committee on 
food additives.World Health Organ Tech Rep Ser 1974; No. 539. 
11 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2053. 
Propylparaben 631

20 General References 
Golightly LK, Smolinske SS, Bennett ML, et al. Pharmaceutical 
excipients: adverse effects associated with inactive ingredients in 
drug products (part I). Med Toxicol 1988; 3: 128–165. 
Jian L, Li Wan Po A. Ciliotoxicity of methyl- and propyl-phydroxybenzoates: 
a dose-response and surface-response study. J 
Pharm Pharmacol 1993; 45: 925–927. 
21 Authors 
R Johnson, R Steer. 
22 Date of Revision 
23 August 2005. 
632 Propylparaben

2-Pyrrolidone 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
g-Aminobutyric acid lactam; 4-aminobutyric acid lactam; gaminobutyric 
lactam; g-aminobutyrolactam; g-butyrolactam; 
butyrolactam; 2-oxopyrrolidine; 2-Pyrol; a-pyrrolidinone; pyrrolidone; 
a-pyrrolidone; Soluphor P. 
3 Chemical Name and CAS Registry Number 
2-Pyrrolidinone [616-45-5] 
4 Empirical Formula and Molecular Weight 
C4H7NO 85.11 
5 Structural Formula 
6 Functional Category 
Penetration enhancer; plasticizer; solvent; solubilizing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Pyrrolidones such as 2-pyrrolidone and N-methylpyrrolidone 
(see Section 17) are mainly used as solvents in veterinary 
injections.(1,2) They have also been suggested for use in human 
pharmaceutical formulations as solvents in parenteral, oral, 
and topical applications. In topical applications, pyrrolidones 
appear to be effective penetration enhancers.(1–7) Pyrrolidones 
have also been investigated for their application in controlledrelease 
depot formulations.(8) 
8 Description 
2-Pyrrolidone occurs as a colorless or slightly colored liquid 
that solidifies at room temperature and has a characteristic 
odor. 
9 Pharmacopeial Specifications 
—
10 Typical Properties 
Acidity/alkalinity: pH = 8.210.8 for a 10% v/v aqueous 
solution. 
Boiling point: 2458C 
Dipole moment: 2.3 Debye at 258C 
Enthalpy of vaporization: 48.21 
 3.0 kJ/mol 
Flash point (open cup): 548C 
Melting point: 2.68C 
Refractive index: nD
25 = 1.480–1.490 
Solubility: miscible with ethanol (95%), propan-2-ol, and 
water. Also miscible with other organic solvents such as 
aromatic hydrocarbons. 
Specific gravity: 1.11 at 258C 
Viscosity (dynamic): 13.3 mPa s (13.3 cP) at 258C 
11 Stability and Storage Conditions 
2-Pyrrolidone is chemically stable and, if it is kept in unopened 
original containers, the shelf-life is approximately one year. 2- 
Pyrrolidone should be stored in a well-closed container 
protected from light and oxidation, at temperatures below 
208C. 
12 Incompatibilities 
2-Pyrrolidone is incompatible with oxidizing agents and strong 
acids. 
13 Method of Manufacture 
2-Pyrrolidone is prepared from butyrolactone by a Reppe 
process, in which acetylene is reacted with formaldehyde. 
14 Safety 
Pyrrolidones are mainly used in veterinary injections and have 
also been suggested for use in human oral, topical, and 
parenteral pharmaceutical formulations. In mammalian species, 
pyrrolidones are biotransformed to polar metabolites that 
are excreted via the urine.(9,10) 2-Pyrrolidone is mildly toxic by 
ingestion and subcutaneous routes; mutagenicity data have 
been reported.(11) 2-Pyrrolidone appears to be nonirritant when 
applied to skin and mucous membranes.(1) 
LD50 (guinea pig, oral): 6.5 g/kg(11) 
LD50 (rat, oral): 6.5 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Some pyrrolidones in their 
pure state are considered toxic, corrosive, and flammable; 
contact with skin and eyes should be avoided. Vapors or sprays 
should not be inhaled. Suitable eye and skin protection and a 
respirator are recommended. When heated to decomposition, 
2-pyrrolidone emits toxic fumes of NOx. 
16 Regulatory Status 
—

17 Related Substances 
N-Methylpyrrolidone. 
N-Methylpyrrolidone 
Synonyms: 1-methyl-2-pyrrolidinone; 1-methyl-5-pyrrolidinone; 
N-methyl-2-pyrrolidinone; methylpyrrolidone; Nmethylpyrrolidonum; 
NMP; Pharmasolve; m-Pyrol. 
Empirical formula: C5H9NO 
Molecular weight: 99.14 
CAS number: [872-50-4] 
Description: N-methylpyrrolidone occurs as a clear, hygroscopic 
liquid with a mild amine odor. 
Typical properties: Boiling point: 2028C 
Dielectric constant: 32.2 at 258C 
Dipole moment: 4.9 Debye at 258C 
Enthalpy of evaporation: 43.82 
 3.0 kJ/mol 
Flash point (closed cup): 938C 
Flash point (open cup): 968C 
Freezing point: 248C 
Heat of combustion: 719 kcal/mol 
Melting point: 178C 
Refractive index: nD
25 = 1.4690 
Solubility: miscible with ethanol (95%), water, and most 
other organic solvents. 
Specific gravity: 1.028 at 258C 
Surface tension: 40.7mN/m (40.7 dyne/cm) at 258C 
Vapor pressure: 0.33mmHg at 23.28C; 5.00mmHg at 
65.08C. 
Viscosity: 1.65 mPa s (1.65 cP) at 258C 
Safety: N-methylpyrrolidone is considered a poison by the 
intravenous route. It is moderately toxic by ingestion, skin 
contact, and intraperitoneal routes. It is an experimental 
teratogen; mutagenicity data have been reported.(12) 
LD50 (mouse, IP): 3.05 g/kg(12) 
LD50 (mouse, IV): 0.155 g/kg 
LD50 (mouse, oral): 5.13 g/kg 
LD50 (rabbit, SC): 8.0 g/kg 
LD50 (rat, IP): 2.472 g/kg 
LD50 (rat, IV): 0.0805 g/kg 
LD50 (rat, oral): 3.914 g/kg 
Handling precautions: in the UK, the occupational exposure 
limits for N-methylpyrrolidone are 103 mg/m3 (25 ppm) 
long-term (8-hour TWA) and 309 mg/m3 (75 ppm) shortterm 
(15 minutes).(13) 
Comments: N-methylpyrrolidone is produced by the condensation 
of butyrolactone with methylamine. The EINECS 
number for N-methylpyrrolidone is 212-828-1. A specification 
for N-methylpyrrolidone is included in the PhEur 2005 
and Japanese Pharmaceutical Excipients (JPE) 2004.(14) 
18 Comments 
The EINECS number for 2-pyrrolidone is 204-648-7. 
19 Specific References 
1 BASF. Soluphor P. http://www.pharma-solutions.basf.com 
(accessed 31 May 2005). 
2 International Specialty Products. http://www.ispcorp.com/ 
products/pharma/index.html (accessed 31 May 2005). 
3 Bhatia KS, Singh J. Percutaneous absorption of LHRH through 
porcine skin: effect of N-methyl 2-pyrrolidone and isopropyl 
myristate. Drug Dev Ind Pharm 1997; 23: 1111–1114. 
4 Bhatia KS, Singh J. Effect of dimethylacetamide and 2-pyrrolidone 
on the iontophoretic permeability of LHRJ through porcine skin. 
Drug Dev Ind Pharm 1997; 23: 1215–1218. 
5 Ryatt KS, Stevenson JM, Maibach RH, Guy RH. Pharmacodynamic 
measurement of percutaneous enhancement in vivo. J 
Pharm Sci 1986; 75: 374–377. 
6 Southwell D, Barry BW. Penetration enhancement in human skin: 
effect of 2-pyrrolidone, dimethylformamide and increased hydration 
on finite dose permeation of aspirin and caffeine. Int J Pharm 
1984; 22: 291–298. 
7 Alberti I, Kalia YN, Naik A, et al. In vivo assessment of 
enhancement topical delivery of terbinafine to human stratum 
corneum. J Control Release 2001; 71: 319–327. 
8 Ravivarapu HB, Dunn RL. Parameters affecting the efficacy of a 
sustained release polymeric implant of leuprolide. Int J Pharm 
2000; 194: 181–191. 
9 Bandle EF, Wendt G, Ranalder UB, Trautmann KH. 2-Pyrrolidinone 
and succinimide endogenously present in several mammalian 
species. Life Sci 1984; 35: 2205–2212. 
10 Akesson B, Jonsson BA. Major metabolic pathway for N-methyl- 
2-pyrrolidone in humans. Drug Metab Dispos 1997; 25: 267–269. 
11 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3122. 
12 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2523. 
13 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
14 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004: 547–548. 
20 General References 
—
21 Authors 
RK Chang, AJ Shukla, Y Sun. 
22 Date of Revision 
26 August 2005. 
634 2-Pyrrolidone

Raffinose 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Gossypose; melitose; melitriose; D-raffinose; D-(.)-raffinose. 
3 Chemical Name and CAS Registry Number 
b-D-Fructofuranosyl-O-a-D-galactopyranosyl-(1!6)-a-Dglucopyranoside, 
anhydrous [512-69-6] 
b-D-Fructofuranosyl-O-a-D-galactopyranosyl-(1!6)-a-Dglucopyranoside 
pentahydrate [17629-30-0] 
4 Empirical Formula and Molecular Weight 
C18H32O16 504.44 (for anhydrous) 
C18H32O165H2O 594.52 (for pentahydrate) 
5 Structural Formula 
D-Raffinose anhydrous 
6 Functional Category 
Blood substitute stabilizer; stabilizer for freeze-dried formulations; 
sucrose crystallization modifier. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Raffinose is a trisaccharide carbohydrate that is used as a 
bulking agent, stabilizer, and water scavenger in freezedrying.(
1,2) It is also used as a crystallization inhibitor in 
sucrose solutions.(3–5) 
8 Description 
Raffinose is a white crystalline powder. It is odorless and has a 
sweet taste approximately 10% that of sucrose.(6) 
9 Pharmacopeial Specifications 
— 
10 Typical Properties 
Collapse temperature: –268C(2) 
Decomposition temperature: 1308C (pentahydrate)(7) 
Density (bulk): 0.67 g/cm3 (pentahydrate) 
Density (tapped): 0.98 g/cm3 (pentahydrate) 
Density (true): 1.465 g/cm3 (anhydrous) 
Diffusion coefficient (infinite dilution): 0.33  105 cm2/s 
(water at 158C)(8) 
Glass transition temperature: 1148C (amorphous)(9) 
Heat of solution at infinite dilution (258C): 52 kJ/mol (crystalline 
pentahydrate); –38 kJ/mol (amorphous)(1) 
Melting point: 808C (pentahydrate);(7) 1188C (anhydrous)(10) 
Optical rotation: 1058 (pentahydrate); 1238 (anhydrous)(11) 
Specific gravity: 1.465 (pentahydrate)(7) 
Solubility in methanol: 0.10 g/mL(11) 
Solubility in water: 0.14 g/mL(7) 
Solubility: soluble 1 in 10 of methanol, in pyridine and 1 in 7.1 
of water; slightly soluble in ethanol (95%); insoluble in 
diethyl ether. 
The data for the crystal structure,(12,13) NMR structure,(
14) powder x-ray diffraction pattern,(15) water vapor 
sorption isotherms, (15,16) glass transition temperature as a 
function of water,(15) heat capacity,(1) heat of solution 
properties,(1) vapor pressure,(17) and osmotic pressure(18) 
are described in the literature. 
SEM: 1 
Excipient: D-(.)-Raffinose pentahydrate 
Manufacturer: Sigma-Aldrich (Lot No. 092K01211) 
Magnification: 100 
11 Stability and Storage Conditions 
Raffinose is stable under ordinary conditions of use and 
storage. Excessive heat should be avoided to prevent degradation. 
Thermal decomposition products are carbon monoxide 
and carbon dioxide.(19,20)

SEM: 2 
Excipient: D-(.)-Raffinose pentahydrate 
Manufacturer: Sigma-Aldrich (Lot No. 092K01211) 
Magnification: 500 
12 Incompatibilities 
Raffinose is incompatible with strong oxidizers.(21) 
13 Method of Manufacture 
Raffinose occurs naturally in Australian manna, cottonseed 
meal, and seeds of various food legumes. It can be isolated from 
beet sugar molasses through sucrose separation, seed-crystallization, 
and filtration.(13,22) 
14 Safety 
Raffinose is a naturally occurring trisaccharide investigated for 
use in freeze-dried pharmaceutical formulations. It occurs in a 
number of plants that are consumed widely (see Section 13). 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Gloves and safety glasses are 
recommended. Dust generation should be kept to reasonable 
levels to avoid ignition or explosion. Short-term exposure has 
caused respiratory and eye irritation. Long-term exposure has 
shown adverse reproductive effects in animals. No occupational 
exposure limits have been established. Dust or air 
mixtures may ignite or explode.(19,20) 
16 Regulatory Status 
Raffinose is a naturally occurring trisaccharide and is 
consumed as part of a normal diet. 
17 Related Substances 
Raffinose is composed of three monosaccharides: galactose, 
glucose, and fructose. It shares related structures with sucrose 
and melibiose. It is also related to stachyose, which possesses an 
additional (1!6)-linked a-D-galactopyranosyl unit. 
Two solvated forms(22) and an amorphous form(14,23,24) of 
raffinose can be synthesized. 
18 Comments 
Raffinose has been shown to accumulate in organisms that can 
survive extreme desiccation, and has therefore been examined 
as an excipient in stabilizing co-lyophilized protein and labile 
preparations during storage at elevated temperatures.(25,26) 
When exposed to elevated relative humidity (RH) of 75% at 
258C, raffinose has been shown to form different hydrate 
levels.(27) 
Raffinose is indigestible by humans because of a lack of an 
a-galactosidase and undergoes fermentation in the colon, 
causing production of carbon dioxide, hydrogen, and 
methane gases.(10) 
19 Specific References 
1 Miller DP, de Pablo JJ. Calorimetric solution properties of simple 
saccharides and their significance for the stabilization of biological 
structure and function. J Phys Chem 2000; B104: 8876–8883. 
2 Mackenzie AP. Basic principles of freeze-drying for pharmaceuticals. 
Bull Parenter Drug Assoc 1966; 20(4): 101–129. 
3 Caffrey M, Fonseca V, Leopold AC. Lipid–sugar interactions: 
relevance to anhydrous biology. Plant Physiol 1988; 86: 754–758. 
4 Liang B, Hartel RW, Berglund KA. Effects of raffinose to 
anhydrous biology. AIChE J 1989; 35(12): 2053–2057. 
5 Van Scoik KG, Carstensen JT. Nucleation phenomena in amorphous 
sucrose systems. Int J Pharm 1990; 58: 185–196. 
6 Halsam E, ed. Comprehensive Organic Chemistry: The Synthesis 
and Reactions of Organic Compounds, vol. 5. Oxford: Pergamon 
Press, 1979; 749. 
7 Perry RH, Green DW. Perry’s Chemical Engineer’s Handbook, 7th 
edn. New York: McGraw Hill, 1997. 
8 Lide DR. Handbook of Chemistry and Physics, 83rd edn. Boca 
Raton, FL: CRC Press, 2002. 
9 Taylor LS, Zografi G. Sugar–polymer hydrogen bond interactions 
in lyophilized amorphous mixtures. J Pharm Sci 1998; 87(12): 
1615–1621. 
10 Kirk-Othmer Encyclopedia of Chemical Technology, vol. 22, 4th 
edn. New York: Wiley, 1992; 903. 
11 O’Neil MJ, ed. Merck Index, 13th edn. Whitehouse Station, NJ: 
Merck, 2001: 1452. 
12 Van Alsenoy C, French AD, Cao M, et al. Ab initio-MIA and 
molecular mechanics studies of the distorted sucrose linkage of 
raffinose. J Am Chem Soc 1994; 116: 9590–9595. 
13 Berman, HM. The crystal structure of a trisaccharaide, raffinose 
pentahydrate. Acta Crystallogr 1970; B26: 290–299. 
14 Neubauer H, Meiler J, Peti W, Griesinger C. NMR structure 
determination of saccharose and raffinose by means of homo- and 
heteronuclear dipolar couplings. Helv Chim Acta 2001; 84(1): 
243–258. 
15 Saleki-Gerhardt A, Stowell JG, Burn SR, Zografi G. Hydration and 
dehydration of crystalline and amorphous forms of raffinose. J 
Pharm Sci 1995; 84(3): 318–323. 
16 Saleki-Gerhardt A. Role of water in the solid state properties of 
crystalline and amorphous form of sugars. Doctor of Philosophy 
Thesis, University of Wisconsin-Madison 1993; 104–108. 
17 Cooke SA, Jonsdottir SO. The vapour pressure of water as a 
function of solute concentration above aqeous solutions of 
fructose, sucrose, raffinose, erythitol, xylitol, and sorbitol. J 
Chem Thermodynam 2002; 34(10): 1545–1555. 
18 Kiyosawa K. The volumes of hydrated glucose, sucrose and 
raffinose molecules, and the osmotic pressures of these aqueous 
saccharide solutions as measured by the freezing-point-of-depression 
method. Bull Chem Soc Jpn 1988; 61: 633–642. 
19 Mallinckrodt Baker, Inc. Material Safety Data Sheet. No R0300: 
Raffinose, 5-hydrate, 29 October 2001. 
20 Acros Organics N.V. Material Safety Data Sheet. No 93702: 
D-Raffinose pentahydrate, 2 August 2000. 
636 Raffinose

21 MDL Information Systems, Inc. Material Safety Data Sheet: 
D-Raffinose pentahydrate, 22 March 2001. 
22 Hungerford EH, Nees AR. Raffinose preparation and properties. 
Ind Eng Chem 1934; 26(4): 462–464. 
23 Collins PM, ed. Carbohydrates. London: Chapman and Hall, 
1997: 431. 
24 Jeffrey GA, Huang D. The hydrogen bonding in the crystal 
structure of raffinose pentahydrate. Carbohydr Res 1990; 206: 
173–182. 
25 Davidson P, SunQW. Effect of sucrose/raffinose mass ratios on the 
stability of co-lyophilized protein during storage above the Tg. 
Pharm Res 2001; 18(4): 474–479. 
26 Kazuhito K, Franks F, Echlin P, Greer AL. Structural and dynamic 
properties of crystalline and amorphous phases in raffinose–water 
mixtures. Pharm Res 1999; 16(9): 1441–1448. 
27 Hogan SE, Buckton G. Water sorption/desorption—near IR and 
calorimetric study of crystalline and amorphous raffinose. Int J 
Pharm 2001; 227: 57–69. 
20 General References 
—
21 Authors 
BC Hancock, MP Mullarney. 
22 Date of Revision 
25 August 2005. 
Raffinose 637

Saccharin 
1 Nonproprietary Names 
BP: Saccharin 
PhEur: Saccharinum 
USPNF: Saccharin 
2 Synonyms 
1,2-Benzisothiazolin-3-one 1,1-dioxide; benzoic sulfimide; 
benzosulfimide; 1,2-dihydro-2-ketobenzisosulfonazole; 2,3- 
dihydro-3-oxobenzisosulfonazole; E954; Garantose; gluside; 
Hermesetas; sacarina; saccharin insoluble; o-sulfobenzimide; 
o-sulfobenzoic acid imide. 
3 Chemical Name and CAS Registry Number 
1,2-Benzisothiazol-3(2H)-one 1,1-dioxide [81-07-2] 
4 Empirical Formula and Molecular Weight 
C7H5NO3S 183.18 
5 Structural Formula 
6 Functional Category 
Sweetening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Saccharin is an intense sweetening agent used in beverages, 
food products, table-top sweeteners, and oral hygiene products 
such as toothpastes and mouthwashes. In oral pharmaceutical 
formulations, it is used at a concentration of 0.02–0.5% w/w. It 
has been used in chewable tablet formulations as a sweetening 
agent.(1,2) 
Saccharin can be used to mask some unpleasant taste 
characteristics or to enhance flavor systems. Its sweetening 
power is approximately 500 times that of sucrose. 
8 Description 
Saccharin occurs as odorless white crystals or a white crystalline 
powder. It has an intensely sweet taste, with a metallic 
aftertaste that at normal levels of use can be detected by 
approximately 25% of the population. 
SEM: 1 
Excipient: Saccharin 
Magnification: 600 
SEM: 2 
Excipient: Saccharin 
Magnification: 2400 
9 Pharmacopeial Specifications 
See Table I.

Table I: Pharmacopeial specifications for saccharin. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Appearance of solution . — 
Melting range 226–2308C 226–2308C 
Loss on drying 41.0% 41.0% 
Residue on ignition — 40.2% 
Sulfated ash 40.1% — 
Toluenesulfonamides . 40.0025% 
Selenium — 40.003% 
Heavy metals 420 ppm 40.001% 
Readily carbonizable substances — . 
Benzoic and salicylic acids — . 
Organic volatile impurities — . 
Related substances — — 
Assay (dried basis) 98.0–101.0% 98.0–101.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 2.0 (0.35% w/v aqueous solution) 
Density (bulk): 0.7–1.0 g/cm3 
Density (tapped): 0.9–1.2 g/cm3 
Dissociation constant: pKa = 1.6 at 258C 
Heat of combustion: 3644.3 kJ/mol (871 kcal/mol) 
Moisture content: 0.1% 
Solubility: readily dissolved by dilute ammonia solutions, alkali 
hydroxide solutions, or alkali carbonate solutions (with the 
evolution of carbon dioxide). See Table II. 
Table II: Solubility of saccharin. 
Solvent Solubility at 208C 
unless otherwise stated 
Acetone 1 in 12 
Chloroform Slightly soluble 
Ethanol (95%) 1 in 31 
Ether Slightly soluble 
Glycerin 1 in 50 
Water 1 in 290 
1 in 25 at 1008C 
11 Stability and Storage Conditions 
Saccharin is stable under the normal range of conditions 

employed in formulations. In the bulk form it shows no 
detectable decomposition and only when it is exposed to a high 
temperature (1258C) at a low pH (pH 2) for over 1 hour does 
significant decomposition occur. The decomposition product 
formed is (ammonium-o-sulfo)benzoic acid.(3) 
Saccharin should be stored in a well-closed container in a 
cool, dry place. 
12 Incompatibilities 
Saccharin can react with large molecules, resulting in a 
precipitate being formed. 
13 Method of Manufacture 
Saccharin is prepared from toluene by a series of reactions 
known as the Remsen–Fahlberg method. Toluene is first 
reacted with chlorosulfonic acid to form o-toluenesulfonyl 
chloride, which is reacted with ammonia to form the 
sulfonamide. The methyl group is then oxidized with dichromate, 
yielding o-sulfamoylbenzoic acid, which forms the cyclic 
imide saccharin when heated. 
An alternative method involves a refined version of the 
Maumee process. Methyl anthranilate is initially diazotized to 
form 2-carbomethoxybenzenediazonium chloride; sulfonation 
followed by oxidation then yields 2-carbomethoxybenzenesulfonyl 
chloride. Amidation of this material, followed by 
acidification, forms insoluble acid saccharin. 
14 Safety 
There has been considerable controversy concerning the safety 
of saccharin, which has led to extensive studies since the mid- 
1970s. 
Two-generation studies in rats exposed to diets containing 
5.0–7.5% total saccharin (equivalent to 175 g daily in humans) 
suggested that the incidence of bladder tumors was significantly 
greater in saccharin-treated males of the second generation than 
in controls.(4,5) Further experiments in rats suggested that a 
contaminant of commercial saccharin, o-toluene sulfonamide, 
might also account for carcinogenic effects. In view of these 
studies, a ban on the use of saccharin was proposed in several 
countries. However, in 1977 a ban by the FDA led to a 
Congressional moratorium that permitted the continued use of 
saccharin in the USA. 
From the available data it now appears that the development 
of tumors is a sex-, species-, and organ-specific phenomenon 
and extensive epidemiological studies have shown that 
saccharin intake is not related to bladder cancer in humans.(6,7) 
The WHO has set a temporary acceptable daily intake for 
saccharin, including its calcium, potassium, and sodium salts, 
at up to 2.5 mg/kg body-weight.(8) In the UK, the Committee on 
Toxicity of Chemicals in Food, Consumer Products, and the 
Environment (COT) has set an acceptable daily intake for 
saccharin and its calcium, potassium, and sodium salts 
(expressed as saccharin sodium) at up to 5 mg/kg bodyweight.(
9) 
Adverse reactions to saccharin, although relatively few in 
relation to its widespread use, include: urticaria with pruritus 
following ingestion of saccharin-sweetened beverages(10) and 
photosensitization reactions.(11) 
LD50 (mouse, oral): 17.5 g/kg(12) 
LD50 (rat, IP): 7.10 g/kg 
LD50 (rat, oral): 14.2 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and a dust 
mask are recommended. 
16 Regulatory Status 
Accepted for use as a food additive in Europe. Note that the EU 
number ‘E954’ is applied to both saccharin and saccharin salts. 
Included in the FDA Inactive Ingredients Guide (oral solutions, 
syrups, tablets, and topical preparations). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian 
List of Acceptable Non-medicinal Ingredients. 
Saccharin 639

17 Related Substances 
Alitame; saccharin ammonium; saccharin calcium; saccharin 
sodium. 
Saccharin ammonium 
Empirical formula: C7H8N2O3S 
Molecular weight: 200.2 
CAS number: [6381-61-9] 
Saccharin calcium 
Empirical formula: C14H8CaN2O6S23H2O 
Molecular weight: 467.48 
CAS number: 
[6381-91-5] for the hydrated form 
[6485-34-3] for the anhydrous form 
Synonyms: Syncal CAS. 
Appearance: white, odorless crystals or crystalline powder with 
an intensely sweet taste. 
Solubility: 1 in 4.7 ethanol (95%); 1 in 2.6 of water. 
18 Comments 
The perceived intensity of sweeteners relative to sucrose 
depends upon their concentration, temperature of tasting, and 
pH, and on the flavor and texture of the product concerned. 
Intense sweetening agents will not replace bulk, textural, or 
preservative characteristics of sucrose if sucrose is removed 
from a formulation. 
Synergistic effects for combinations of sweeteners have been 
reported. Saccharin is often used in combination with 
cyclamates and aspartame since the saccharin content may be 
reduced to minimize any aftertaste. A specification for 
saccharin is contained in the Food Chemicals Codex (FCC). 
The EINECS number for saccharin is 201-321-0. 
19 Specific References 
1 Suzuki H, Onishi H, Hisamatsu S, et al. Acetaminophen-containing 
chewable tablets with suppressed bitterness and improved oral 
feeling. Int J Pharm 2004; 278(1): 57–61. 
2 Mullarney MP, Hancock BC, Carlson GT, et al. The powder flow 
and compact mechanical properties of sucrose and three highdensity 
sweetners used in chewable tablets. Int J Pharm 2003; 
257(1–2): 227–236. 
3 DeGarmo O, Ashworth GW, Eaker CM, Munch RH. Hydrolytic 
stability of saccharin. J Am Pharm Assoc (Sci) 1952; 41: 17–18. 
4 Arnold DL, Moodie CA, Grice HC, et al. Long-term toxicity of 
ortho-toluenesulfonamide and sodium saccharin in the rat. Toxicol 
Appl Pharmacol 1980; 52: 113–152. 
5 Arnold DL. Two-generation saccharin bioassays. Environ Health 
Perspect 1983; 50: 27–36. 
6 Council on Scientific Affairs. Saccharin: review of safety issues. J 
Am Med Assoc 1985; 254: 2622–2624. 
7 Morgan RW, Wong O. A review of epidemiological studies on 
artificial sweeteners and bladder cancer. Food Chem Toxicol 1985; 
23: 529–533. 
8 FAO/WHO. Evaluation of certain food additives and contaminants. 
Twenty-eighth report of the FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1984; No. 
710. 
9 Food Advisory Committee. FAC further advice on saccharin. 
FdAC/REP/9. London: MAFF, 1990. 
10 Miller R, White LW, Schwartz HJ. A case of episodic urticaria due 
to saccharin ingestion. J Allergy Clin Immunol 1974; 53: 240–242. 
11 Gordon HH. Photosensitivity to saccharin. J Am Acad Dermatol 
1983; 8: 565. 
12 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3277. 
20 General References 
Anonymous. Saccharin is safe. Chem Br 2001; 37(4): 18. 
Lindley MG. Sweetener markets, marketing and product development. 
In: Marie S, Piggott JR, eds. Handbook of Sweeteners. Glasgow: 
Blackie, 1991: 186. 
Zubair MU, Hassan MMA. Saccharin. In: Florey K, ed. Analytical 
Profiles of Drug Substances, vol. 13. Orlando, FL: Academic Press, 
1984: 487–519. 
21 Authors 
SC Owen. 
22 Date of Revision 
11 August 2005. 
640 Saccharin

Saccharin Sodium 
1 Nonproprietary Names 
BP: Saccharin sodium 
JP: Saccharin sodium 
PhEur: Saccharinum natricum 
USP: Saccharin sodium 
2 Synonyms 
1,2-Benzisothiazolin-3-one 1,1-dioxide, sodium salt; Crystallose; 
E954; sodium o-benzosulfimide; soluble gluside; soluble 
saccharin; sucaryl sodium. 
3 Chemical Name and CAS Registry Number 
1,2-Benzisothiazol-3(2H)-one 1,1-dioxide, sodium salt 
[6155-57-3] for the dihydrate 
[128-44-9] for the anhydrous material 
See also Section 8. 
4 Empirical Formula and Molecular Weight 
C7H4NNaO3S 205.16 
C7H4NNaO3S2=3H2O (84%) 217.24 
C7H4NNaO3S2H2O (76%) 241.19 
5 Structural Formula 
6 Functional Category 
Sweetening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Saccharin sodium is an intense sweetening agent used in 
beverages, food products, table-top sweeteners,(1) and pharmaceutical 
formulations such as tablets, powders, medicated 
confectionery, gels, suspensions, liquids, and mouthwashes;(2) 
see Table I. It is also used in vitamin preparations. 
Saccharin sodium is considerably more soluble in water than 
saccharin, and is more frequently used in pharmaceutical 
formulations. Its sweetening power is approximately 300 times 
that of sucrose. Saccharin sodium enhances flavor systems and 
may be used to mask some unpleasant taste characteristics. 
Injection of saccharin sodium has been used to measure the 
arm-to-tongue circulation time. 
Table I: Uses of saccharin sodium. 
Use Concentration (%) 
Dental paste/gel 0.12–0.3 
IM/IV injections 0.9 
Oral solution 0.075–0.6 
Oral syrup 0.04–0.25 
8 Description 
Saccharin sodium occurs as a white, odorless or faintly 
aromatic, efflorescent, crystalline powder. It has an intensely 
sweet taste, with a metallic aftertaste that at normal levels of use 
can be detected by approximately 25% of the population. 
Saccharin sodium can contain variable amounts of water. 
SEM: 1 
Excipient: Saccharin sodium 
Magnification: 35 Voltage: 5kV 
9 Pharmacopeial Specifications 
See Table II.

Table II: Pharmacopeial specifications for saccharin sodium. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters . . — 
Clarity and color of 
solution 
. . — 
Acidity or alkalinity . . . 
Water 415.0% 415.0% 415.0% 
Benzoate and salicylate . — . 
Arsenic 42 ppm — — 
Selenium — — 40.003% 
Acidity or alkalinity . . . 
Toluenesulfonamides . . . 
Heavy metals 420 ppm 420 ppm 
40.001% 
Readily carbonizable 
substances 
. — . 
Organic volatile 
impurities 
— — . 
Assay (anhydrous basis) 598.0% 99.0–101.0% 98.0–101.0% 
10 Typical Properties 
Unless stated, data refer to either 76% or 84% saccharin 
sodium. 
Acidity/alkalinity: pH = 6.6 (10% w/v aqueous solution) 
Density (bulk): 
0.8–1.1 g/cm3 (76% saccharin sodium); 
0.86 g/cm3 (84% saccharin sodium). 
Density (particle): 1.70 g/cm3 (84% saccharin sodium) 
Density (tapped): 
0.9–1.2 g/cm3 (76% saccharin sodium); 
0.96 g/cm3 (84% saccharin sodium). 
Melting point: decomposes upon heating. 
Moisture content: saccharin sodium 76% contains 14.5% w/w 
water; saccharin sodium 84% contains 5.5% w/w water. 
During drying, water evolution occurs in two distinct 
phases. The 76% material dries under ambient conditions 
to approximately 5.5% moisture (84% saccharin sodium); 
the remaining moisture is then removed only by heating. 
Solubility: see Table III. 
Table III: Solubility of saccharin sodium. 
Solvent Solubility at 208C 
unless otherwise stated 
Buffer solutions: 
pH 2.2 (phthalate) 1 in 1.15 
1 in 0.66 at 608C 
pH 4.0 (citrate–phosphate) 1 in 1.21 
1 in 0.69 at 608C 
pH 7.0 (citrate–phosphate) 1 in 1.21 
1 in 0.66 at 608C 
pH 9.0 (borate) 1 in 1.21 
1 in 0.69 at 608C 
Ethanol 1 in 102 
Ethanol (95%) 1 in 50 
Propylene glycol 1 in 3.5 
Propan-2-ol Practically insoluble 
Water 1 in 1.2 
Specific surface area: 0.25m2/g 
11 Stability and Storage Conditions 
Saccharin sodium is stable under the normal range of 
conditions employed in formulations. Only when it is exposed 
to a high temperature (1258C) at a low pH (pH 2) for over 1 
hour does significant decomposition occur. The 84% grade is 
the most stable form of saccharin sodium since the 76% form 
will dry further under ambient conditions. 
Saccharin sodium should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
—
13 Method of Manufacture 
Saccharin is produced by the oxidation of o-toluene sulfonamide 
by potassium permanganate in a solution of sodium 
hydroxide. Acidification of the solution precipitates saccharin, 
which is then dissolved in water at 508C and neutralized by 
addition of sodium hydroxide. Rapid cooling of the solution 
initiates crystallization of saccharin sodium from the liquors. 
14 Safety 
There has been considerable controversy concerning the safety 
of saccharin and saccharin sodium in recent years; however, it is 
now generally regarded as a safe, intense sweetener. See 
Saccharin for further information. 
The WHO has set a temporary acceptable daily intake of up 
to 2.5 mg/kg body-weight for saccharin, including its salts.(3) In 
the UK, the Committee on Toxicity of Chemicals in Food, 
Consumer Products, and the Environment (COT) has set an 
acceptable daily intake for saccharin and its salts (expressed as 
saccharin sodium) at up to 5 mg/kg body-weight.(4) 
LD50 (mouse, oral): 17.5 g/kg(5) 
LD50 (rat, IP): 7.1 g/kg 
LD50 (rat, oral): 14.2 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and a dust 
mask are recommended. 
16 Regulatory Status 
Accepted for use as a food additive in Europe; ‘E954’ is applied 
to both saccharin and saccharin salts. Included in the FDA 
Inactive Ingredients Guide (buccal and dental preparations; IM 
and IV injections; oral and topical preparations). Included in 
nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Alitame; saccharin. 
18 Comments 
The perceived intensity of sweeteners relative to sucrose 
depends upon their concentration, temperature of tasting, and 
pH, and on the flavor and texture of the product concerned. 
642 Saccharin Sodium

Intense sweetening agents will not replace bulk, textural, or 
preservative characteristics of sugar if sugar is removed from a 
formulation. 
Synergistic effects for combinations of sweeteners have been 
reported. Saccharin sodium is often used in combination with 
cyclamates and aspartame since the saccharin sodium content 
may be reduced to minimize any aftertaste. 
19 Specific References 
1 Kloesel L. Sugar substitutes. Int J Pharm Compound 2000; 4(2): 
86–87. 
2 Ungphaiboon S, Maitani Y. In vitro permeation studies of 
triamcinolone acetonide mouthwashes. Int J Pharm 2001; 
220(1–2): 111–117. 
3 FAO/WHO. Evaluation of certain food additives and contaminants. 
Twenty-eighth report of the FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1984; No. 
710. 
4 Food Advisory Committee. FAC further advice on saccharin. 
FdAC/REP/9. London: MAFF, 1990. 
5 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3277. 
See Saccharin for further references. 
20 General References 
Anonymous. Saccharin is safe. Chem Br 2001; 37(4): 18. 
Lindley MG. Sweetener markets, marketing and product developments. 
In: Marie S, Piggott JR, eds. Handbook of Sweeteners. Glasgow: 
Blackie, 1991: 186. 
21 Authors 
SC Owen. 
22 Date of Revision 
11 August 2005. 
Saccharin Sodium 643

Saponite 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Afrodit; aluminum-saponite; auxite; cathkinite; ferroan saponite; 
griffithite; licianite; lucianite. 
3 Chemical Name and CAS Registry Number 
Saponite [1319-41-1] 
4 Empirical Formula and Molecular Weight 
(Ca0.5Na)0.3(Mg,Fe2.)3(Si,Al)4O10(OH)24H2O 480 
Saponite is a naturally occurring phyllosilicate clay of the 
smectite (montmorillonite) group. It is a magnesium-rich 
hydrated aluminum silicate and is present as a component of 
some commercial magnesium aluminum silicate clays. Saponite 
is a mineral with an approximate empirical formula owing to 
the variability in cation substitution; see Table I. 
Table I: Approximate composition of saponite based on chemical 
analysis. 
Component Wt % 
SiO2 37.5 
Al2O3 10.6 
MgO 18.9 
CaO 1.2 
Na2O 0.65 
FeO 11.2 
H2O 18.8 
5 Structural Formula 
Saponite is a natural mineral clay that is a hydrous silicate of 
aluminum and magnesium. It occurs in soft, amorphous masses 
in the cavities of certain rocks. 
Saponite is composed of two tetrahedral layers formed by 
phylosilicate sheets and one octahedral layer. Common 
impurities include manganese, nickel, phosphorus, potassium, 
and titanium. 
See Section 4. 
6 Functional Category 
Adsorbent; emulsifying agent; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Saponite is a colloidal material present in various naturally 
occurring clays such as magnesium aluminum silicates(1) and is 
therefore suitable for use in pharmaceutical formulation 
applications as an adsorbent, viscosity-increasing agent, 
suspending agent, or as an oil-in-water emulsifying agent. It is 
a swelling clay with a low cation exchange capacity, and when 
mixed with water it displays thixotropic properties. Saponite is 
similar to bentonite, and has the capacity to adsorb drugs 
through cationic exchange.(2) Drug–saponite adsorbates show 
a slight reduction in dissolution rate.(2) Saponite is useful in the 
formulation of gastrointestinal X-ray contrast agents(3) and 
formulations designed for sustained drug delivery to the 
gastrointestinal tract.(4) 
8 Description 
Saponite occurs as a white to off-white, dull powder composed 
of fine-grained crystals of colloidal size. The material is greasy 
or soapy to the touch and swells on the addition of water. 
9 Pharmacopeial Specifications 
—
10 Typical Properties 
Density (true): 2.67 g/cm3 
Crystal data: monoclinic; a = 5.3, b = 9.14, c = 16.9, b  978. 
Hardness (Mohs): 1–2 
11 Stability and Storage Conditions 
Saponite is a stable material and should be stored in a cool, dry 
place. 
12 Incompatibilities 
—
13 Method of Manufacture 
Naturally occurring saponite is mined from deposits in various 
localities around the world. 
14 Safety 
Saponite is a natural clay mineral that is not acutely toxic; 
therefore, no toxicity values have been established. However, it 
may contain small amounts of crystalline silica in the form of 
quartz. Chronic exposure to crystalline silica can have adverse 
effects on the respiratory system. EU labeling states the material 
is not classified as dangerous. 
Saponite dust can be irritating to the respiratory tract and 
eyes. Contact with this material may cause drying of the skin. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material being handled. Avoid generating and 
breathing dust and use eye protection. For dusty conditions, eye 
protection, gloves, and a dust mask are recommended. The 
occupational exposure limits for saponite are 5 mg/m3 (respirable) 
PEL-TWA, 3 mg/m3 (respirable) TLV-TWA, and 10 mg/m3 
(inhalable) dust TLV-TWA.

16 Regulatory Status 
Reported in the EPA TSCA Inventory. 
17 Related Substances 
Attapulgite; bentonite; kaolin; hectorite; magnesium aluminum 
silicate; talc. 
18 Comments 
The EINECS number for saponite is 215-289-0. 
19 Specific References 
1 Browne JE, Feldkamp JR, White JL, Hem SL. Characterization and 
adsorptive properties of pharmaceutical grade clays. J Pharm Sci 
1980; 69(7): 816–823. 
2 El-Gindy GA, Ali AS, El-Shinnawi OM. Preparation and formulation 
of sustained-release terbutaline sulphate microcapsules. Bull 
Pharm Sci Assiut Univ 2000; 23(1): 55–63. 
3 Ruddy SB, Eickhoff WM, Liversidge G, Cooper ER. Formulations 
of oral gastrointestinal therapeutic agents in combination with 
pharmaceutically acceptable clays. International Patent WO96/ 
2096; 1996. 
4 Ruddy SB, McIntire GL, Roberts ME, Caulifield TJ, Cooper ER. 
X-ray contrast compositions containing iodoaniline derivatives 
and pharmaceutically acceptable clays. United States Patent No. 
5,424,056; 1995. 
20 General References 
Cormleyu I, Addison J. The in vitro cytotoxicity of some standard clay 
mineral dusts of respirable size. Clay Miner 1983; 18(2): 153–163. 
Polon JA. Mechanisms of thickening by inorganic agents. J Soc Cosmet 
Chem 1970; 21: 347–363. 
Post JL. Saponite from near Ballarat, California. Clays Clay Miner 
1984; 32: 147–153. 
Viseras C, Lopez-Galindo A. Characteristics of pharmaceutical grade 
phylosilicate powders. Pharm Dev Technol 2000; 5(1): 47–52. 
21 Authors 
PE Luner. 
22 Date of Revision 
18 August 2005. 
Saponite 645

Sesame Oil 
1 Nonproprietary Names 
BP: Refined sesame oil 
JP: Sesame oil 
PhEur: Sesami oleum raffinatum 
USPNF: Sesame oil 
2 Synonyms 
Benne oil; gingelly oil; gingili oil; jinjili oil; Lipovol SES; teel oil. 
3 Chemical Name and CAS Registry Number 
Sesame oil [8008-74-0] 
4 Empirical Formula and Molecular Weight 
A typical analysis of refined sesame oil indicates the composition 
of the acids, present as glycerides, to be: arachidic acid 
0.8%; linoleic acid 40.4%; oleic acid 45.4%; palmitic acid 
9.1%; and stearic acid 4.3%. Sesamin, a complex cyclic ether, 
and sesamolin, a glycoside, are also present in small amounts. 
Note that other reported analyses may vary slightly from 
that above.(1) 
The monographs for Sesame Oil in the USPNF 23 and 
Refined Sesame Oil in the PhEur 2005 specify the acceptable 
range of eight triglycerides found in sesame oil. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Oleaginous vehicle; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
The major use of sesame oil in pharmaceutical formulations is 
as a solvent in the preparation of sustained-release intramuscular 
injections of steroids, such as estradiol valerate, hydroxyprogesterone 
caproate, testosterone enanthate, and nandrolone 
decanoate,(2) or other oil-soluble drug substances, such as, the 
decanoates or enanthate esters of fluphenazine. The disappearance 
of sesame oil from the injection site, following 
subcutaneous or intramuscular administration to pigs, has 
been reported to have a half-life of about 23 days.(3) 
Sesame oil may be used as a solvent in the preparation of 
subcutaneous injections,(4) oral capsules,(5,6) rectal suppositories,(
7) and ophthalmic preparations;(8) it may also be used in 
the formulation of suspensions(9) and emulsions.(9–11) Multipleemulsion 
formulations, in which sesame oil was one of the oil 
phases incorporated, have been investigated as a prolongedrelease 
system for rifampicin;(12) microemulsions containing 
sesame oil have been prepared for the transdermal delivery of 
ketoprofen.(13) Sesame oil has also been used in the preparation 
of liniments, pastes, ointments, and soaps. A sesame paste 
(tahini), composed of crushed sesame seeds in sesame oil, has 
been investigated as a novel suspending agent.(14) 
Sesame oil is additionally used as an edible oil and in the 
preparation of oleomargarine. 
8 Description 
Refined sesame oil is a clear, pale-yellow colored liquid with a 
slight, pleasant odor and a bland taste. It solidifies to a soft 
mass at about 48C. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for sesame oil. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Specific gravity 0.914–0.921 0.919 0.916–0.921 
Refractive index at 
208C 
— 1.470–1.476 — 
Heavy metals — — 40.001% 
Cottonseed oil — . . 
Solidification range 
of fatty acids 
— — 20–258C 
Free fatty acids — — . 
Acid value 40.2 40.6 — 
— 40.3(a) — 
Iodine value 103–118 103–116 
Peroxide value — 410.0 — 
— 45.0(a) — 
Saponification value 187–194 — 188–195 
Unsaponifiable 
matter 
42.0% 42.0% 41.5% 
Composition of 
triglycerides 
— . . 
Alkaline impurities — . — 
Organic volatile 
impurities 
— — . 
Water — 40.05%(a) — 
(a) In sesame oil intended for parenteral use. 
10 Typical Properties 
Density: 0.916–0.920 g/cm3 
Flash point: 3388C (open cup) 
Freezing point: 58C 
Refractive index: nD
40 = 1.4650–1.4665 
Solubility: insoluble in water; practically insoluble in ethanol 
(95%); miscible with carbon disulfide, chloroform, ether, 
hexane, and light petroleum. 
Specific rotation [a]D
25: .18 to .98 
Viscosity (dynamic): 43 mPa s (43 cP)

11 Stability and Storage Conditions 
Sesame oil is more stable than most other fixed oils and does 
not readily become rancid; this has been attributed to the 
antioxidant effect of some of its characteristic constituents. The 
PhEur 2005 permits the addition of a suitable antioxidant to 
sesame oil. 
Sesame oil may be sterilized by aseptic filtration or dry heat. 
It has been reported that suitable conditions for the sterilization 
of injections containing sesame oil are a temperature of 1708C 
for 2 hours; it has been suggested that 1508C for 1 hour is 
inadequate.(15) However, it has been demonstrated that dry 
heat sterilization of sesame oil at 1508C for 1 hour was 
sufficient to kill all added Bacillus subtilis spores.(16) 
Sesame oil should be stored in a well-filled, airtight, lightresistant 
container, at a temperature not exceeding 408C. 
Sesame oil intended for use in the manufacture of parenteral 
dosage forms should be stored under an inert gas in an airtight 
glass container. 
12 Incompatibilities 
Sesame oil may be saponified by alkali hydroxides. 
13 Method of Manufacture 
Sesame oil is obtained from the ripe seeds of one or more 
cultivated varieties of Sesamum indicum Linne. (Fam. Pedaliaceae) 
by expression in a hydraulic press or by solvent 
extraction. The crude oil thus obtained is refined to obtain an 
oil suitable for food or pharmaceutical use. Improved color and 
odor may be obtained by further refining. 
14 Safety 
Sesame oil is mainly used in intramuscular and subcutaneous 
injections; it should not be administered intravenously. It is also 
used in topical pharmaceutical formulations and consumed as 
an edible oil. 
Although it is generally regarded as an essentially nontoxic 
and nonirritant material,(17) there have been rare reports of 
hypersensitivity to sesame oil, with sesamin suspected as being 
the primary allergen.(18–21) Anaphylactic reactions to sesame 
seeds have also been reported. However, it is thought that the 
allergens in the seeds may be inactivated or destroyed by 
heating as heat-extracted sesame seed oil or baked sesame seeds 
do not cause anaphylactic reactions in sesame seed-allergic 
individuals.(22) 
LD50 (rabbit, IV): 678 mg/kg(23) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Spillages of sesame oil are 
slippery and should be covered with an inert absorbent material 
prior to disposal. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IM and SC 
injections, oral capsules, emulsions, and tablets, also topical 
preparations). Included in parenteral (IM injections) and 
nonparenteral (oral capsules and sprays) medicines licensed in 
the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Almond oil; canola oil; corn oil; cottonseed oil; peanut oil; 
soybean oil; sunflower oil. 
18 Comments 
—
19 Specific References 
1 British Standards Institute. Specification for Crude Vegetable Fats, 
BS 7207. London: BSI, 1990. 
2 Williams JS, Stein JH, Ferris TH. Nandrolone decanoate therapy 
for patients receiving hemodialysis. Arch Intern Med 1974; 134: 
289–292. 
3 Larsen SW, Rinvar E, Svendsen O, et al. Determination of the 
disappearance rate of iodine-125 labelled oils from the injection 
site after intramuscular and subcutaneous administration to pigs. 
Int J Pharm 2001; 230(1–2): 67–75. 
4 Hirano K, Ichihashi T, Yamada H. Studies on the absorption of 
practically water-insoluble drugs following injection V: subcutaneous 
absorption in rats from solutions in water immiscible oils. J 
Pharm Sci 1982; 71: 495–500. 
5 Perez-Reyes M, Lipton MA, Timmons MC, et al. Pharmacology of 
orally administered 
9-tetrahydrocannabinol. Clin Pharmacol 
Ther 1973; 14: 48–55. 
6 Sallan SE, Zinberg NE, Frei E. Antiemetic effect of delta-9- 
tetrahydrocannabinol in patients receiving cancer chemotherapy. 
N Engl J Med 1975; 293: 795–797. 
7 Tanabe K, Sawanoi M, Yamazaki M, Kamada A. Effect of different 
suppository bases on release of indomethacin [in Japanese]. 
Yakuzaigaku 1984; 44: 115–120. 
8 Chien DS, Schoenwald RD. Ocular pharmacokinetics and 
pharmacodynamics of phenylephrine and phenylephrine oxazolidine 
in rabbit eyes. Pharm Res 1990; 7: 476–483. 
9 Shinkuma D, Hamaguchi T, Muro C, et al. Bioavailability of 
phenytoin from oil suspension and emulsion in dogs. Int J Pharm 
1981; 9: 17–28. 
10 Rosenkrantz H, Thompson GR, Braude MC. Oral and parenteral 
formulations of marijuana constituents. J Pharm Sci 1972; 61: 
1106–1112. 
11 Unno K, Goto A, Kagaya S, et al. Preparation and tissue 
distribution of 5-fluorouracil emulsion [in Japanese]. J Nippon 
Hosp Pharm Assoc 1980; 6(1): 14–20. 
12 Nakhare S, Vyas SP. Prolonged release of rifampicin from internal 
phase of multiple w/o/w emulsion systems. Indian J Pharm Sci 
1995; 57(2): 71–77. 
13 Rhee Y-S, Choi J-G, Park E-S, Chi S-C. Transdermal delivery of 
ketoprofen using microemulsions. Int J Pharm 2001; 228(1–2): 
161–170. 
14 Al-Achi A, Greenwood R, Akin-Isijola A, Bullard J. Calamine 
lotion: experimenting with a new suspending agent. Int J Pharm 
Compound 1999; 3(6): 490–492. 
15 Pasquale D, Jaconia D, Eisman P, Lachman L. A study of sterilizing 
conditions for injectable oils. Bull Parenter Drug Assoc 1964; 
18(3): 1–11. 
16 Kupiec TC, Matthews P, Ahmad R. Dry-heat sterilisation of 
parenteral oil vehicles. Int J Pharm Compound 2000; 4(3): 223– 
224. 
17 Hem SL, Bright DR, Banker GS, Pogue JP. Tissue irritation 
evaluation of potential parenteral vehicles. Drug Dev Commun 
1974–75 1: 471–477. 
18 Neering H, Vitanyi BE, Malten KE, et al. Allergens in sesame oil 
contact dermatitis. Acta Dermatol Venerol 1975; 55: 31–34. 
19 Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation 
Agents: A Handbook of Excipients. New York: Marcel Dekker, 
1989: 212–213. 
20 Perkins MS. Sesame allergy is also a problem [letter]. Br Med J 
1996; 313: 300. 
21 Perkins MS. Raising awareness of sesame allergy. Pharm J 2001; 
267: 757–758. 
Sesame Oil 647

22 Ka. gi MK, Wu. thrich B. Falafel-burger anaphylaxis due to sesame 
seed allergy [letter]. Lancet 1991; 338: 582. 
23 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3203. 
20 General References 
— 
21 Authors 
CG Cable. 
22 Date of Revision 
23 August 2005. 
648 Sesame Oil

Shellac 
1 Nonproprietary Names 
BP: Shellac 
JP: Purified shellac, White shellac 
PhEur: Lacca 
USPNF: Shellac 
2 Synonyms 
Bleached shellac; CertiSeal; dewaxed orange shellac; E904; lac; 
Mantrolac R-49; orange shellac; refined bleached shellac; 
regular bleached shellac; Swanlac. 
3 Chemical Name and CAS Registry Number 
Shellac [9000-59-3] 
4 Empirical Formula and Molecular Weight 
Shellac is a naturally occurring material consisting of a complex 
mixture of constituents that may be obtained in various refined 
or modified forms; see Section 13. 
The PhEur 2005 defines four types of shellac depending on 
the nature of the treatment of the crude shellac (seed lac): waxcontaining 
shellac; bleached shellac; dewaxed shellac; and 
bleached dewaxed shellac. The USPNF 23 similarly defines four 
types of shellac: orange shellac; dewaxed orange shellac; 
regular bleached (white) shellac; and refined bleached shellac. 
The JP 2001 defines two types: purified shellac and white 
shellac (bleached). 
Elementary analysis reveals that shellac contains carbon, 
hydrogen, oxygen, and a negligible amount of ash. A formula 
of C60H90O15 and an average molecular weight of 1000 is 
assigned to shellac. Although its composition has not been fully 
elucidated, the main component of shellac (about 95%) is a 
resin that gives a mixture of aliphatic and alicyclic hydroxy 
acids and polyesters on mild basic hydrolysis. Some of the 
compounds identified and named include aleuritic, butolic, 
kerrolic, and shellolic acids. The major component of the 
aliphatic fraction is aleuritic acid, while the major component 
of the alicyclic fraction is shellolic acid. 
Shellac also contains about 5–6% wax along with gluten, 
other impurities, and a small amount of pigment. The exact 
composition of shellac may vary depending upon the country of 
origin and method of manufacture.(1,2) 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Coating agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Shellac has been used in pharmaceutical formulations for the 
enteric coating of tablets and beads,(3) the material usually 
being applied as a 35% w/v alcoholic solution; see also Section 
18.
It is a primary ingredient of pharmaceutical printing inks for 
monogramming capsules and tablets, and can be applied as a 
40% w/v alcoholic solution. It has also been used to apply one 
or two sealing coats to tablet cores to protect them from 
moisture before being film- or sugar-coated. 
Shellac may also be used in food products and cosmetics. 
8 Description 
Shellac is a naturally occurring material that may be obtained in 
a variety of refined or modified forms; see Sections 4 and 13. 
Generally, shellac occurs as hard, brittle, transparent, pale 
lemon-yellow to brownish orange-colored flakes of varying size 
and shape; it is also available as a powder. Shellac is tasteless 
and odorless, or may have a faint odor. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for shellac. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification — . . 
Characters — . — 
Heavy metals 410 ppm 410 ppm 40.001% 
Arsenic 45 ppm 43 ppm — 
Ethanol-insoluble substances 42.0% — — 
Rosin . — . 
Total ash 41.0% — — 
Acid value (on dried basis) 60–80 65–95 . 
Dewaxed orange shellac — — 71–79 
Orange shellac — — 68–76 
Refined bleached shellac — — 75–91 
Regular bleached shellac — — 73–89 
Loss on drying 42.0% . . 
Dewaxed orange shellac — — 42.0% 
Orange shellac — — 42.0% 
Refined bleached shellac — — 46.0% 
Regular bleached shellac — 46.0% 46.0% 
Unbleached shellac — 42.0% — 
Wax 420mg — . 
Dewaxed orange shellac — — 40.2% 
Orange shellac — — 45.5% 
Refined bleached shellac — — 40.2% 
Regular bleached shellac — — 45.5% 
10 Typical Properties 
Alcohol-insoluble matter: 41.0% 
Ash: 41.0% 
Density: 1.035–1.140 g/cm3 
Hydroxyl value: 230–280 
Iodine number: 10–18 
Melting point: 115–1208C

Refractive index: nD
20 = 1.5210–1.5272 
Saponification value: 185–210 
Solubility: see Table II. 
Table II: Solubility of shellac. 
Solvent Solubility at 208C 
Alkalis Soluble 
Aqueous ethanolamine solution Soluble 
Benzene 1 in 10 
Ethanol 1 in 2 
Ethanol (95%) 1 in 1.2 (very slowly soluble) 
Ether 1 in 8 
Hexane Practically insoluble 
Propylene glycol 1 in 10 
Water Practically insoluble 
11 Stability and Storage Conditions 
After long periods of storage, shellac becomes less readily 
soluble in alcohol, less fluid on heating, and darker in color. 
Shellac-coated tablets may have increased disintegration times 
following prolonged storage owing to changes in the physical 
characteristics of the coating; see Section 18.(4) 
Shellac should be stored in a well-closed container at 
temperatures below 278C. Wax-containing grades should be 
mixed before use to ensure uniform distribution of the wax. 
12 Incompatibilities 
Shellac is chemically reactive with aqueous alkalis, organic 
bases, alcohols, and agents that esterify hydroxyl groups. 
Therefore, shellac should be used with caution in the presence 
of such compounds. 
13 Method of Manufacture 
Shellac or lac is obtained by purification of the resinous 
secretion of the insect Laccifero (Tachardia) lacca Kerr 
(Homoptera, Coccidae). The insect lives on the sap of the 
stems of various trees; secretions are found most abundantly on 
the smaller branches and twigs, which are broken off and 
constitute sticklac. After scraping of the twigs and soaking in 
water, the water-soluble components are removed by treatment 
with dilute alkali. The resulting water-insoluble material is 
called seed lac. 
Historically, seed lac was processed into shellac by melting 
the seed lac in a muslin bag suspended over a fire. Shellac could 
then be squeezed from the bag by hand and poured into molds 
to produce button shellac. Alternatively, the molten shellac was 
collected and allowed to cool as discs or wafer-thin sheets. 
Today, most shellac is produced on a commercial scale using 
machine processes involving extraction from seed lac using 
steam heat or solvent extraction with hot ethanol. Shellac 
produced by the heat and solvent extraction processes cannot 
usually be differentiated by chemical tests. 
Various different grades of modified or refined shellac are 
available, which may be broadly defined as either bleached or 
orange shellac. Orange shellac is essentially the crude shellac 
obtained from seed lac, as described above. It may retain most 
of its wax or be dewaxed, and may contain less of the natural 
color than was originally present. The quantities of wax, 
coloring material, and other impurities present may vary; the 
physical properties of orange shellac may therefore also vary 
depending upon its source or the processing methods used. 
Bleached or white shellac is obtained by dissolving shellac in 
aqueous sodium carbonate, bleaching the solution with sodium 
hypochlorite, and precipitating the bleached shellac with 2N 
sulfuric acid. Removal of wax by filtration results in a refined 
bleached shellac. 
Most commercial shellac is produced in India and Thailand; 
smaller amounts come from Burma and Malaysia. 
14 Safety 
Shellac is used in oral pharmaceutical formulations, food 
products, and cosmetics. It is generally regarded as an 
essentially nonirritant and nontoxic material at the levels 
employed as an excipient. However, excessive consumption of 
shellac may be harmful. 
15 Handling Precautions 
Shellac may be harmful if ingested in large quantities. It is 
irritating to the eyes, and to the respiratory system if inhaled as 
dust. Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection, 
gloves, and a dust respirator are recommended. Shellac should 
be handled in a well-ventilated environment. 
16 Regulatory Status 
Accepted as a food additive in Europe. Included in the FDA 
Inactive Ingredients Guide (oral capsules and tablets). Included 
in nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Aleuritic acid; pharmaceutical glaze; polyvinyl acetate phthalate; 
shellolic acid. 
Aleuritic acid 
Empirical formula: C16H32O5 
Molecular weight: 304.42 
CAS number: [533-87-9] 
Synonyms: DL-erythro-9,10,16,-trihydroxyhexadecanoic acid; 
9,10,16-trihydroxypalmitic acid; 8,9,15-trihydroxypentadecane-
1-carboxylic acid. 
Melting point: 100–1018C 
Solubility: soluble in methanol. 
Comments: component of shellac. The EINECS number for 
aleuritic acid is 208-578-8. 
Pharmaceutical glaze 
Comments: pharmaceutical glaze is a specially denatured 
alcoholic solution of shellac containing between 20% and 
57% of anhydrous shellac. It may be prepared using either 
ethanol or ethanol 95% and may contain waxes and 
titanium dioxide as an opacifing agent. 
Shellolic acid 
Empirical formula: C15H20O6 
Molecular weight: 296.33 
CAS number: [4448-95-7] 
Synonyms: 10b,13-dihydroxycedr-8-ene-12,15-dioic acid; 
2,3,4,7,8,8a-hexahydro-4-hydroxy-8-(hydroxymethyl)-8- 
methyl-1H-3a,7-methanoazulene-3,6-dicarboxylic acid. 
Melting point: 204–2078C 
Comments: component of shellac. 
650 Shellac

18 Comments 
Shellac is insoluble in acidic conditions but is soluble at higher 
pH; it therefore appears to be a suitable enteric-coating 
material. However, in practice, delayed disintegration and 
drug release may occur in vivo as shellac is insoluble in the 
slightly acidic environment of the upper intestine. Additives 
such as lauric acid may be added to plasticize and improve 
disintegration of shellac films, although shellac tends not to be 
used in new drug formulations as an enteric-coating agent. 
Studies using the USP disintegration test for enteric-coated 
tablets have indicated that there is a marked increase in the 
disintegration time over a 6-month storage period for shellaccoated 
tablets.(4) It is likely that this effect is due to the 
polymerization of shellac, which occurs over storage periods of 
this duration. A specification for shellac is contained in the 
Food Chemicals Codex (FCC). 
The EINECS number for shellac is 232-549-9. 
19 Specific References 
1 Yates P, Field GF. Lac—I: the structure of shellolic acid. 
Tetrahedron 1970; 26: 3135–3158. 
2 Yates P, Burke PM, Field GF. Lac—II: the stereochemistry of 
shellolic and epishellolic acids. Tetrahedron 1970; 26: 3159–3170. 
3 Specht F, Saugestad M, Waaler T, Muller BW. The application of 
shellac acidic polymer for enteric coating. Pharm Technol Eur 
1998; 10(9): 20, 22, 24, 27, 28. 
4 Luce GT. Disintegration of tablets enteric coated with CAP. Manuf 
Chem Aerosol News 1978; 49(7): 50, 52, 67. 
20 General References 
Chang RK, Iturrioz G, Luo CW. Preparation and evaluation of shellac 
pseudolatex as an aqueous enteric coating system for pellets. Int J 
Pharm 1990; 60: 171–173. 
Cockeram HS, Levine SA. The physical and chemical properties of 
shellac. J Soc Cosmet Chem 1961; 12: 316–323. 
Labhasetwar VD, Puranik PK, Dorle AK. Study of shellac-glycerol 
esters as anhydrous binding agents in tablet formulations. Indian J 
Pharm Sci 1988; 50: 343–345. 
Limmatrapirat S, Limmatrapirat C, Luangtana-Anan M, et al. 
Modification of physicochemical and mechanical properties of 
shellac by partial hydrolysis. Int J Pharm 2004; 278(1): 41–49. 
21 Authors 
X Li, BR Jasti. 
22 Date of Revision 
18 August 2005. 
Shellac 651

Simethicone 
1 Nonproprietary Names 
BP: Simeticone 
PhEur: Simeticonum 
USP: Simethicone 
2 Synonyms 
Dow Corning Q7-2243 LVA; Dow Corning Q7-2587; polydimethylsiloxane–
silicon dioxide mixture; Sentry Simethicone; 
simeticone. 
3 Chemical Name and CAS Registry Number 
a-(Trimethysilyl-o-methylpoly[oxy(dimethylsilylene)], mixture 
with silicon dioxide [8050-81-5] 
4 Empirical Formula and Molecular Weight 
See Section 8. 
5 Structural Formula 
where n = 200–350 
6 Functional Category 
Antifoaming agent; tablet diluent; water-repelling agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
The main use of simethicone as an excipient is as an 
antifoaming agent in pharmaceutical manufacturing processes, 
for which 1–50 ppm is used. 
Therapeutically, simethicone is included in a number of oral 
pharmaceutical formulations as an antiflatulent, although its 
therapeutic benefit is questionable.(1) It is also included in 
antacid products such as tablets or capsules.(2–6) In some types 
of surgical or gastroscopic procedures where gas is used to 
inflate the body cavity, a defoaming preparation containing 
simethicone may be used in the area to control foaming of the 
fluids. 
When simethicone is used in aqueous formulations, it 
should be emulsified to ensure compatibility with the aqueous 
system and components. 
In the USA, up to 10 ppm of simethicone may be used in 
food products. 
8 Description 
The PhEur 2005 and USP 28 describe simethicone as a mixture 
of fully methylated linear siloxane polymers containing 
repeating units of the formula [–(CH3)2SiO–]n, stabilized with 
trimethylsiloxy end-blocking units of the formula [(CH3)3 SiO– 
], and silicon dioxide. It contains not less than 90.5% and not 
more than 99.0% of the polydimethylsiloxane [–(CH3)2SiO–]n, 
and not less than 4.0% and not more than 7.0% of silicon 
dioxide. The PhEur 2005 additionally states that the degree of 
polymerization is between 20–400. 
Simethicone occurs as a translucent, gray-colored, viscous 
fluid. It has a molecular weight of 14 000–21 000. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for simethicone. 
Test PhEur 2005 USP 28 
Identification . . 
Characters . — 
Acidity . — 
Defoaming activity 415 seconds 415 seconds 
Loss on heating — 418% 
Volatile matter 41.0% — 
Heavy metals 45 ppm 45 mg/g 
Organic volatile impurities — . 
Mineral oils . — 
Phenylated compounds . — 
Assay (dimethicone) . — 
Assay (silicon dioxide) — 4.0–7.0% 
Assay (silica) 47.0% — 
Assay (polydimethylsiloxane) 90.5–99.0% 90.5–99.0% 
10 Typical Properties 
Boiling point: 358C 
Refractive index: nD
20 = 0.965–0.970 
Solubility: practically insoluble in ethanol (95%) and water. 
The liquid phase is soluble in benzene, chloroform, and 
ether, but silicon dioxide remains as a residue in these 
solvents. 
Specific gravity: 0.95–0.98 at 258C 
Viscosity (kinematic): 370mm2/s at 258C for Dow Corning 
Q7-2243 LVA. 
11 Stability and Storage Conditions 
Simethicone is generally regarded as a stable material when 
stored in the original unopened container. A shelf-life of 18 
months from the date of manufacture is typical. However, some 
simethicone products have a tendency for the silicon dioxide to 
settle slightly and containers of simethicone should therefore be 
shaken thoroughly to ensure uniformity of contents before 
sampling or use. Simethicone should be stored in a cool, dry, 
location away from oxidizing materials.

Simethicone can be sterilized by dry heating or autoclaving. 
With dry heating, a minimum of 4 hours at 1608C is required. 
12 Incompatibilities 
Simethicone as supplied is not generally compatible with 
aqueous systems and will float like an oil on a formulation 
unless it is first emulsified. It should not be used in formulations 
or processing conditions that are very acidic (below pH 3) or 
highly alkaline (above pH 10), since these conditions may have 
some tendency to break the polydimethylsiloxane polymer. 
Simethicone cannot normally be mixed with polar solvents of 
any kind because it is very minimally soluble. Simethicone is 
incompatible with oxidizing agents. 
13 Method of Manufacture 
Silicon dioxide is initially rendered hydrophobic in one of a 
variety of proprietary processes specific to a particular 
manufacturer. It is then slowly mixed with the silicone fluids 
in a formulation. After mixing, the simethicone is milled to 
ensure uniformity. 
14 Safety 
Simethicone is used in cosmetics, foods, and oral and topical 
pharmaceutical formulations and is generally regarded as a 
relatively nontoxic and nonirritant material when used as an 
excipient. Direct contact with the eye may cause irritation. 
Therapeutically, oral doses of 125–250mg of simethicone, 
three or four times daily, have been given as an antiflatulent. 
Doses of 20–40 mg of simethicone have been given with feeds 
to relieve colic in infants.(7) 
LD50 (dog, IV): 0.9 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. Simethicone should be handled in areas with 
adequate ventilation. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(oral emulsions, powders, solutions, suspensions, tablets, and 
rectal and topical preparations). Included in nonparenteral 
medicines licensed in the UK. 
17 Related Substances 
Cyclomethicone; dimethicone. 
18 Comments 
—
19 Specific References 
1 Anonymous. Simethicone for gastrointestinal gas. Med Lett Drugs 
Ther 1996; 38: 57–58. 
2 Sox T. Simethicone and sulfasalazine for treatment of ulcerative 
colitis. United States Patent 6,100,245; 1999. 
3 Holtman G, Gschossmann J, Karaus M, et al. Randomized doubleblind 
comparison of simethicone with cisapride in functional 
dyspepsia. Aliment Pharmacol Ther 1999; 13(11): 1459–1465. 
4 Tiongson A. Process of making an aqueous calcium carbonate 
suspension. International Patent WO 9945937; 1999. 
5 Luber J, Madison G, McNally G. Antifoam oral solid dosage 
forms comprising simethicone and anhydrous calcium phosphate. 
European Patent 891776; 1999. 
6 Devlin BT, Hoy MR. Semisolid composition containing an 
antiflatulent agent. European Patent 815864; 1998. 
7 Metcalf TJ, Irons TG, Sher LD, Young PC. Simethicone in the 
treatment of infant colic: randomized, placebo-controlled, multicenter 
trial. Pediatrics 1994; 84: 29–34. 
20 General References 
Daher L. Lubricants for use in tabletting. United States Patent 
5,922,351; 1999. 
Rider JA, Roorda AK, Rider DL. Further analysis of standards for 
antacid simethicone defoaming properties. Curr Ther Res 1997; 
58(12): 955–963. 
21 Authors 
RT Guest. 
22 Date of Revision 
22 August 2005. 
Simethicone 653

Sodium Acetate 
1 Nonproprietary Names 
BP: Sodium acetate 
JP: Sodium acetate 
PhEur: Natrii acetas trihydricus 
USP: Sodium acetate 
2 Synonyms 
Acetic acid, sodium salt; E262; sodium ethanoate. 
3 Chemical Name and CAS Registry Number 
Sodium acetate anhydrous [127-09-3] 
Sodium acetate trihydrate [6131-90-4] 
4 Empirical Formula and Molecular Weight 
C2H3NaO2 82.0 (for anhydrous) 
C2H3NaO23H2O 136.1 (for trihydrate) 
Note that the trihydrate is the material described in the 
JP2001, PhEur 2005 and USP 28, although the PhEur 2005 is 
the only pharmacopeia that makes this explicit with the title of 
the monograph. 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; buffering agent; flavoring agent, 
stabilizing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sodium acetate is used as a buffering agent in various 
intramuscular, intravenous, topical, ophthalmic, nasal, oral, 
otic, and subcutaneous formulations. It may be used to reduce 
the bitterness of oral pharmaceuticals.(1) It can be used to 
enhance the antimicrobial properties of formulations; it has 
been shown to inhibit the growth of S. aureus and E. coli, but 
not C. albicans in protein hydrolysate solutions.(2) It is widely 
used in the food industry as a preservative.(3) Sodium acetate 
has also been used therapeutically for the treatment of 
metabolic acidosis in premature infants,(4,5) and in hemodialysis 
solutions.(6,7) 
8 Description 
Sodium acetate occurs as colorless, transparent crystals or a 
granular crystalline powder with a slight acetic acid odor. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for sodium acetate. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Description . — — 
Characters — . — 
Appearance of 
solution 
. . — 
Acid or alkali . — — 
pH — 7.5–9.0 7.5–9.2 
Insoluble matter — — 40.05% 
Chloride 40.011% 4200 ppm 40.035% 
Sulfate 40.017% 4200 ppm 40.005% 
Heavy metals 410 ppm 410 ppm 40.001% 
Calcium and 
magnesium 
. 450 ppm . 
Potassium — — . 
Arsenic 42 ppm 42 ppm — 
Iron — 410 ppm — 
Reducing substances . . — 
Aluminum — 40.2 ppm 40.2 mg/g 
Loss on drying 
anhydrous — — 41.0% 
trihydrate 39.0–40.5% 39.0–40.5% 38.0–41.0% 
Organic volatile 
impurities 
— — . 
Assay (dried basis) 599.5% 99.0–101.0% 99.0–101.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 7.5–9.0 (5% w/v aqueous solution) 
Hygroscopicity: the anhydrous and trihydrate sodium acetate 
are hygroscopic. 
Solubility: soluble 1 in 0.8 in water, 1 in 20 in ethanol (95%). 
Melting point: 588C for trihydrate; 3248C for anhydrous.(8) 
Specific gravity: 1.53 
11 Stability and Storage Conditions 
Sodium acetate should be stored in airtight containers. 
12 Incompatibilities 
Sodium acetate reacts with acidic and basic components. It will 
react violently with fluorine, potassium nitrate, and diketene. 
13 Method of Manufacture 
Sodium acetate is prepared by neutralization of acetic acid with 
sodium carbonate.

14 Safety 
Sodium acetate is widely used in cosmetics, foods, and 
pharmaceutical formulations (see Section 18), and is generally 
regarded as a nontoxic and nonirritant material. 
A short-term feeding study in chickens with a diet 
supplemented with 5.44% sodium acetate showed reduced 
growth rates that were attributed to the sodium content.(9) 
Sodium acetate is poisonous if injected intravenously, is 
moderately toxic by ingestion, and is an irritant to the skin 
and eyes.(10) 
LD50 (rat, oral): 3.53 g/kg(10) 
LD50 (mouse, IV): 0.38 g/kg(11) 
LD50 (mouse, SC): 8.0 g/kg(10) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Sodium acetate is a mild skin 
and eye irritant; gloves and eye protection are recommended. 
On exposure, wash eyes and skin with large amounts of water. 
Inhalation of dust may cause pulmonary tract problems. When 
heated to decomposition, sodium acetate emits toxic fumes of 
NaO2.(10) 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (injections, nasal, otic, 
ophthalmic, and oral preparations). 
17 Related Substances 
—
18 Comments 
Sodium acetate was shown to enhance aqueous humor to 
plasma concentration ratio of timolol by about 20-fold in an 
ophthalmic monoisopropyl PVM-MA matrix system, presumably 
by decreasing systemic absorption.(12) 
Sodium acetate has also been used experimentally in matrix 
tablet formulations, where it increased the effect of carbomer as 
a sustained release matrix.(13) 
A specification for sodium acetate is contained within the 
Food Chemicals Codex (FCC). The PhEur 2005 also contains a 
monograph on sodium acetate [1-11C] injection under Radiopharmaceutical 
Preparations. 
The EINECS number for sodium acetate is 204-823-8. 
19 Specific References 
1 Keast RS, Breslin PA. Modifying the bitterness of selected oral 
pharmaceuticals with cation and anion series of salts. Pharm Res 
2002; 19(7): 1019–1026. 
2 Frech G, Allen LV. Sodium acetate as a preservative in protein 
hydrolysate solutions. Am J Hosp Pharm 1979; 36: 1672–1675. 
3 Bedie GK, Smaelis J, Sofos JN. Antimicrobials in the formulation 
to control Listeria monocytogenes postprocessing contamination 
on frankfurters stored at 48C in vacuum packages. J Food Prot 
2001; 64(12): 1949–1955. 
4 Ekblad H, Kero P, Takala J. Slow sodium acetate infusion in the 
correction of metabolic acidosis in premature infants. Am J Dis 
Child 1985; 139(7): 708–710. 
5 Kasik JW, Vafai J, Goodrich P. Sodium acetate infusion to correct 
acidosis in premature infants. Am J Dis Child 1986; 140(1): 9–10. 
6 Katiuchi T, Mabuchi H, et al. Hemodynamic change during 
hemodialysis, especially on cardiovascular effects of sodium 
acetate. Jpn J Artif Organs 1982; 11(2): 456–459. 
7 Jackson JK, Derleth DP. Effects of various arterial infusion 
solutions on red blood cells in the newborn. Arch Dis Child Fetal 
Neonatal Ed 2000; 83(2): F130–F134. 
8 Ash M, Ash I. Handbook of Pharmaceutical Additives, 2nd edn. 
Endicott, NY: Synapse Information Resources, 2002: 706. 
9 Waterhouse HN, Scott HM. Effect of sex, feathering, rate of 
growth and acetates on chicks need for glycine. Poultry Sci 1962; 
41: 1957–1962. 
10 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3225. 
11 Spector WS. Handbook of Toxicology. Philadelphia: WB Saunders, 
1956: 268. 
12 Finne U, Salivirta J, Urtti A. Sodium acetate improves the ocular/ 
systemic absorption ratio of timolol applied ocularly in monoisopropyl 
PVM-MA matrices. Int J Pharm 1991; 75; R1–R4. 
13 Meshali MM, El-Sayed GM, El-Helw A. Effect of added 
substances on theophylline release from carbopol 934P matrix. 
STP Pharma Sci 1997; 7(3): 195–198. 
20 General References 
—
21 Authors 
WG Chambliss. 
22 Date of Revision 
8 August 2005. 
Sodium Acetate 655

Sodium Alginate 
1 Nonproprietary Names 
BP: Sodium alginate 
PhEur: Natrii alginas 
USPNF: Sodium alginate 
2 Synonyms 
Algin; alginic acid, sodium salt; E401; Kelcosol; Keltone; 
Protanal; sodium polymannuronate. 
3 Chemical Name and CAS Registry Number 
Sodium alginate [9005-38-3] 
4 Empirical Formula and Molecular Weight 
Sodium alginate consists chiefly of the sodium salt of alginic 
acid, which is a mixture of polyuronic acids composed of 
residues of D-mannuronic acid and L-guluronic acid. 
The block structure and molecular weight of sodium 
alginate samples has been investigated.(1) 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Stabilizing agent; suspending agent; tablet and capsule disintegrant; 
tablet binder; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sodium alginate is used in a variety of oral and topical 
pharmaceutical formulations.(2) In tablet formulations, sodium 
alginate may be used as both a binder and disintegrant;(3) it has 
been used as a diluent in capsule formulations.(4) Sodium 
alginate has also been used in the preparation of sustainedrelease 
oral formulations since it can delay the dissolution of a 
drug from tablets,(5–7) capsules,(8) and aqueous suspensions.(9) 
In topical formulations, sodium alginate is widely used as a 
thickening and suspending agent in a variety of pastes, creams, 
and gels, and as a stabilizing agent for oil-in-water emulsions. 
Recently, sodium alginate has been used for the aqueous 
microencapsulation of drugs,(10) in contrast with the more 
conventional microencapsulation techniques which use 
organic-solvent systems. It has also been used in the formation 
of nanoparticles.(11) 
The adhesiveness of hydrogels prepared from sodium alginate 
has been investigated(12) and drug release from oral mucosal 
adhesive tablets,(13) and buccal gels,(14,15) based on sodium 
alginate have been reported. Other novel delivery systems 
containing sodium alginate include ophthalmic solutions that 
form a gel in situ when administered to the eye;(16,17) an in situ 
forming gel containing paracetamol for oral administration;(18) 
and a freeze-dried device intended for the delivery of bonegrowth 
factors.(19) 
Hydrogel systems containing alginates have also been 
investigated for delivery of proteins and peptides.(20) 
Therapeutically, sodium alginate has been used in combination 
with an H2-receptor antagonist in the management of 
gastroesophageal reflux,(21) and as a hemostatic agent in 
surgical dressings.(22,23) Alginate dressings, used to treat 
exuding wounds, often contain significant amounts of sodium 
alginate as this improves the gelling properties.(24) Sponges 
composed of sodium alginate and chitosan produce a sustained 
drug release and may be useful as wound dressings or as tissue 
engineering matrices.(25) 
Sodium alginate is also used in cosmetics and food products; 
see Table I. 
Table I: Uses of sodium alginate. 
Use Concentration (%) 
Pastes and creams 5–10 
Stabilizer in emulsions 1–3 
Suspending agent 1–5 
Tablet binder 1–3 
Tablet disintegrant 2.5–10 
8 Description 
Sodium alginate occurs as an odorless and tasteless, white to 
pale yellowish-brown colored powder. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for sodium alginate. 
Test PhEur 2005 USPNF 23 
Characters . . 
Identification . . 
Appearance of solution . — 
Microbial limits 41000/g 4200/g 
Loss on drying 415.0% 415.0% 
Ash — 18.0–27.0% 
Sulfated ash 30.0–36.0% — 
Arsenic — 41.5 ppm 
Calcium 41.5% — 
Chlorides 41.0% — 
Lead — 40.001% 
Heavy metals 420 ppm 40.004% 
Assay (dried basis) — 90.8–106.0% 
10 Typical Properties 
Acidity/alkalinity: pH 7.2 for a 1% w/v aqueous solution. 
Solubility: practically insoluble in ethanol (95%), ether, chloroform, 
and ethanol/water mixtures in which the ethanol 
content is greater than 30%. Also, practically insoluble in 
other organic solvents and aqueous acidic solutions in which

the pH is less than 3. Slowly soluble in water, forming a 
viscous colloidal solution. 
Viscosity (dynamic): various grades of sodium alginate are 
commercially available that yield aqueous solutions of 
varying viscosity. Typically, a 1% w/v aqueous solution, at 
208C, will have a viscosity of 20–400 mPa s (20–400 cP). 
Viscosity may vary depending upon concentration, pH, 
temperature, or the presence of metal ions.(26–28) Above pH 
10, viscosity decreases, see also Alginic Acid and Section 11. 
11 Stability and Storage Conditions 
Sodium alginate is a hygroscopic material, although it is stable 
if stored at low relative humidities and a cool temperature. 
Aqueous solutions of sodium alginate are most stable at pH 
4–10. Below pH 3, alginic acid is precipitated. A 1% w/v 
aqueous solution of sodium alginate exposed to differing 
temperatures had a viscosity 60–80% of its original value after 
storage for 2 years.(29) Solutions should not be stored in metal 
containers. 
Sodium alginate solutions are susceptible on storage to 
microbial spoilage, which may affect solution viscosity. 
Solutions are ideally sterilized using ethylene oxide, although 
filtration using a 0.45 mm filter also has only a slight adverse 
effect on solution viscosity.(30) Heating sodium alginate 
solutions to temperatures above 708C causes depolymerization 
with a subsequent loss of viscosity. Autoclaving of solutions can 
cause a decrease in viscosity, which may vary depending upon 
the nature of any other substances present.(30,31) Gamma 
irradiation should not be used to sterilize sodium alginate 
solutions since this process severely reduces solution viscosity.(
30,32) 
Preparations for external use may be preserved by the 
addition of 0.1% chlorocresol, 0.1% chloroxylenol, or 
parabens. If the medium is acidic, benzoic acid may also be 
used. 
The bulk material should be stored in an airtight container 
in a cool, dry place. 
12 Incompatibilities 
Sodium alginate is incompatible with acridine derivatives, 
crystal violet, phenylmercuric acetate and nitrate, calcium salts, 
heavy metals, and ethanol in concentrations greater than 5%. 
Low concentrations of electrolytes cause an increase in viscosity 
but high electrolyte concentrations cause salting-out of sodium 
alginate; salting-out occurs if more than 4% of sodium chloride 
is present. 
13 Method of Manufacture 
Alginic acid is extracted from brown seaweed and is neutralized 
with sodium bicarbonate to form sodium alginate. 
14 Safety 
Sodium alginate is widely used in cosmetics, food products, and 
pharmaceutical formulations, such as tablets and topical 
products, including wound dressings. It is generally regarded 
as a nontoxic and nonirritant material, although excessive oral 
consumption may be harmful. A study in five healthy male 
volunteers fed a daily intake of 175 mg/kg body-weight of 
sodium alginate for 7 days, followed by a daily intake of 
200 mg/kg body-weight of sodium alginate for a further 16 
days, showed no significant adverse effects.(33) 
The WHO has not specified an acceptable daily intake for 
alginic acid and alginate salts as the levels used in food do not 
represent a hazard to health.(34) 
Inhalation of alginate dust may be irritant and has been 
associated with industrial-related asthma in workers involved 
in alginate production. However, it appears that the cases of 
asthma were linked to exposure to seaweed dust rather than 
pure alginate dust.(35) 
LD50 (cat, IP): 0.25 g/kg(36) 
LD50 (mouse, IV): 0.2 g/kg 
LD50 (rabbit, IV): 0.1 g/kg 
LD50 (rat, IV): 1 g/kg 
LD50 (rat, oral): >5 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Sodium alginate may be 
irritant to the eyes or respiratory system if inhaled as dust; see 
Section 14. Eye protection, gloves, and a dust respirator are 
recommended. Sodium alginate should be handled in a wellventilated 
environment. 
16 Regulatory Status 
GRAS listed. Accepted in Europe for use as a food additive. 
Included in the FDA Inactive Ingredients Guide (oral suspensions 
and tablets). Included in nonparenteral medicines licensed 
in the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Alginic acid; calcium alginate; potassium alginate; propylene 
glycol alginate. 
18 Comments 
A number of different grades of sodium alginate, which have 
different solution viscosities, are commercially available. Many 
different alginate salts and derivatives are also commercially 
available including ammonium alginate; calcium alginate; 
magnesium alginate, and potassium alginate. 
To assist in the preparation of dispersions of sodium 
alginate, the material may be mixed with a dispersing agent 
such as sucrose, ethanol, glycerol, or propylene glycol. A 
specification for sodium alginate is contained in the Food 
Chemicals Codex (FCC). 
See also Alginic Acid for further information. 
19 Specific References 
1 Johnson FA, Craig DQM, Mercer AD. Characterization of the 
block structure and molecular weight of sodium alginates. J Pharm 
Pharmacol 1997; 49: 639–643. 
2 Tonnesen HH, Karlsen J. Alginate in drug delivery systems. Drug 
Dev Ind Pharm 2002; 28(6): 621–630. 
3 Sakr AM, Elsabbagh HM, Shalaby AH. Effect of the technique of 
incorporating sodium alginate on its binding and/or disintegrating 
effectiveness in sulfathiazole tablets. Pharm Ind 1978; 40(10): 
1080–1086. 
4 Veski P, Marvola M. Sodium alginates as diluents in hard gelatin 
capsules containing ibuprofen as a model drug. Pharmazie 1993; 
48(10): 757–760. 
5 Klaudianos S. Alginate sustained-action tablets [in German]. Dtsch 
Apoth Ztg 1978; 118: 683–684. 
Sodium Alginate 657

6 Holte O, Onsoven E, Myrvold R. Sustained release of watersoluble 
drug from directly compressed alginate tablets. Eur J 
Pharm Sci 2003; 20(4–5): 403–407. 
7 Azarmi S, Valizadeh H, Barzegar JM, Loebenberg R. ’In situ’ crosslinking 
of polyanionic polymers to sustain the drug-release of 
acetazolamide tablets. Pharm Ind 2003; 63(9): 877–881. 
8 Veski P, Marvola M, Smal J, et al. Biopharmaceutical evaluation of 
pseudoephedrine hydrochloride capsules containing different 
grades of sodium alginate. Int J Pharm 1994; 111: 171–179. 
9 Zatz JL, Woodford DW. Prolonged release of theophylline from 
aqueous suspensions. Drug Dev Ind Pharm 1987; 13: 2159–2178. 
10 Bodmeier R, Wang J. Microencapsulation of drugs with aqueous 
colloidal polymer dispersions. J Pharm Sci 1993; 82: 191–194. 
11 Rajaonarivony M, Vauthier C, Couarraze G, et al. Development of 
a new drug carrier made from alginate. J Pharm Sci 1993; 82(9): 
912–917. 
12 Vennat B, Lardy F, Arvouet-Grand A, Pourrat A. Comparative 
texturometric analysis of hydrogels based on cellulose derivatives, 
carraghenates, and alginates: evaluation of adhesiveness. Drug 
Dev Ind Pharm 1998; 24(1): 27–35. 
13 Miyazaki S, Nakayama A, Oda M, et al. Drug release from oral 
mucosal adhesive tablets of chitosan and sodium alginate. Int J 
Pharm 1995; 118: 257–263. 
14 Attia MA, ElGibaly I, Slialtout SE. Transbuccal permeation, antiinflammatory 
and clinical efficacy of piroxicam formulated in 
different gels. Int J Pharm 2004; 276: 11–28. 
15 Mohammed FA, Kheder H. Preparation and in vitro/in vivo 
evaluations of the buccal bioadhesive properties of slow-release 
tablets containing miconazole nitrate. Drug Dev Ind Pharm 2003; 
29(3): 321–337. 
16 Cohen S, Lobel E, Trevgoda A, Peled Y. A novel in situ-forming 
ophthalmic drug delivery system from alginates undergoing 
gelation in the eye. J Control Release 1997; 44: 201–208. 
17 Balasubramaniam J, Pandit JK. Ion-activated in situ gelling 
systems for sustained release ophthalmic delivery of ciprofloxacin 
hydrochloride. Drug Delivery 2003; 10(3): 185–191. 
18 Kubo W, Miyazaki S, Attwood D. Oral sustained delivery of 
paracetamol from in-situ gelling gellan and sodium alginate 
formulations. Int J Pharm 2003; 258(1–2): 55–64. 
19 Duggirala S, DeLuca PP. Buffer uptake and mass loss characteristics 
of freeze-dried cellulosic and alginate devices. PDA J Pharm 
Sci Technol 1996; 50(5): 297–305. 
20 Gombotz WR, Pettit DK. Biodegradable polymers for protein and 
peptide drug delivery. Bioconjug Chem 1995; 6: 332–351. 
21 Stanciu C, Bennett JR. Alginate/antacid in the reduction of gastrooesophageal 
reflux. Lancet 1974; i: 109–111. 
22 Thomas S. Wound Management and Dressings. London: Pharmaceutical 
Press, 1990: 43–49. 
23 Qin Y, Gilding DK. Alginate fibres and wound dressings. Med 
Device Technol 1996; Nov: 32–41. 
24 Thomas S. Alginate dressings in surgery and wound management—
Part 1. J Wound Care 2000; 9(2): 56–60. 
25 Lai HL, Abu Khalil A, Craig DQM. The preparation and 
characteristics of drug-loaded alginate and chitosan sponges. Int 
J Pharm 2003; 251: 175–181. 
26 Bugaj J, Go. recki M. Kinetics of dynamic viscosity changes of 
aqueous sodium carboxymethylcellulose and sodium alginate 
solutions. Pharmazie 1995; 50(11): 750–752. 
27 Duggirala S, DeLuca PP. Rheological characterization of cellulosic 
and alginate polymers. PDA J Pharm Sci Technol 1996; 50(5): 
290–296. 
28 Bugaj J, Go. recki M. Rheometrical estimation of physical properties 
of sodium alginate and sodium carboxymethylcellulose 
aqueous solutions. Acta Pol Pharm Drug Res 1996; 53(2): 141– 
146. 
29 Pa. vics L. Comparison of rheological properties of mucilages [in 
Hungarian]. Acta Pharm Hung 1970; 40: 52–59. 
30 Coates D, Richardson G. A note on the production of sterile 
solutions of sodium alginate. Can J Pharm Sci 1974; 9: 60–61. 
31 Vandenbossche GMR, Remon J-P. Influence of the sterilization 
process on alginate dispersions. J Pharm Pharmacol 1993; 45: 
484–486. 
32 Hartman AW, Nesbitt RU, Smith FM, Nuessle NO. Viscosities of 
acacia and sodium alginate after sterilization by cobalt-60. J 
Pharm Sci 1975; 64: 802–805. 
33 Anderson DM, Brydon WG, Eastwood MA, Sedgwick DM. 
Dietary effects of sodium alginate in humans. Food Addit Contam 
1991; 8(3): 237–248. 
34 FAO/WHO. Evaluation of certain food additives and naturally 
occurring toxicants. Thirty-ninth report of the joint FAO/WHO 
expert committee on food additives. World Health Organ Tech 
Rep Ser 1992; No. 828. 
35 Henderson AK, Ranger AF, Lloyd J, et al. Pulmonary hypersensitivity 
in the alginate industry. Scott Med J 1984; 29(2): 90–95. 
36 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3225–3226. 
20 General References 
—
21 Authors 
CG Cable. 
22 Date of Revision 
20 August 2005. 
658 Sodium Alginate

Sodium Ascorbate 
1 Nonproprietary Names 
PhEur: Natrii ascorbas 
USP: Sodium ascorbate 
2 Synonyms 
L-Ascorbic acid monosodium salt; E301; 3-oxo-L-gulofuranolactone 
sodium enolate; SA-99; vitamin C sodium. 
3 Chemical Name and CAS Registry Number 
Monosodium L-(.)-ascorbate [134-03-2] 
4 Empirical Formula and Molecular Weight 
C6H7NaO6 198.11 
5 Structural Formula 
6 Functional Category 
Antioxidant; therapeutic agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sodium ascorbate is used as an antioxidant in pharmaceutical 
formulations, and also in food products where it increases the 
effectiveness of sodium nitrite against growth of Listeria 
monocytogenes in cooked meats. It improves gel cohesiveness 
and sensory firmness of fiberized products regardless of 
vacuum treatment. 
It is also used therapeutically as a source of vitamin C in 
tablets and parenteral preparations. 
8 Description 
Sodium ascorbate occurs as a white or slightly yellow-colored, 
practically odorless, crystalline powder with a pleasant saline 
taste. 
SEM: 1 
Excipient: Sodium ascorbate USP 
Manufacturer: Pfizer Ltd. 
Lot No: 9B-1 (C92220-C4025) 
Magnification: 120 Voltage: 20 kV 
SEM: 2 
Excipient: Sodium ascorbate USP 
Manufacturer: Pfizer Ltd. 
Lot No: 9B-1 (C92220-C4025) 
Magnification: 600 Voltage: 20 kV

9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for sodium ascorbate. 
Test PhEur 2005 USP 28 
Identification . . 
Characters . — 
Appearance of solution . — 
pH 7.0–8.0 7.0–8.0 
Specific optical rotation 
(10% w/v aqueous solution) 
.1038 to .1088 .1038 to .1088 
Oxalic acid 40.30% — 
Benzene 42 ppm — 
Sulfates 4150 ppm — 
Copper 45 ppm — 
Iron 42 ppm — 
Nickel 41 ppm — 
Heavy metals 410 ppm 40.002% 
Loss on drying 40.25% 40.25% 
Organic volatile impurities — . 
Assay (dried basis) 99.0–101.0% 99.0–101.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 7–8 (10% w/v aqueous solution) 
Density (tapped): 
0.6–1.1 g/cm3 for fine powder; 
0.8–1.1 g/cm3 for fine granular grade. 
Density (true): 1.826 g/cm3 
Hygroscopicity: not hygroscopic. Sodium ascorbate adsorbs 
practically no water up to 80% relative humidity at 208C 
and less than 1% w/w of water at 90% relative humidity. 
Melting point: 2188C (with decomposition) 
Particle size distribution: various grades of sodium ascorbate 
with different particle-size distributions are commercially 
available, e.g., approximately 98% passes through a 149 mm 
mesh for a fine powder grade (Takeda), and approximately 
95% passes through a 840 mm mesh for a standard grade 
(Takeda). 
Solubility: see Table II. 
Table II: Solubility of sodium ascorbate. 
Solvent Solubility at 208C 
unless otherwise stated 
Chloroform Practically insoluble 
Ethanol (95%) Very slightly soluble 
Ether Practically insoluble 
Water 1 in 1.6 
1 in 1.3 at 758C 
Specific gravity: 
1.782 for powder at 208C; 
1.005 for 1% w/v aqueous solution at 258C; 
1.026 for 5% w/v aqueous solution at 258C. 
Specific rotation [a]D
20: .104.48(10% w/v aqueous solution) 
11 Stability and Storage Conditions 
Sodium ascorbate is relatively stable in air, although it 
gradually darkens on exposure to light. Aqueous solutions 
are unstable and subject to rapid oxidation in air at pH > 6.0. 
The bulk material should be stored in a well-closed 
nonmetallic container, protected from light, in a cool, dry place. 
12 Incompatibilities 
Incompatible with oxidizing agents, heavy metal ions, especially 
copper and iron, methenamine, sodium nitrite, sodium 
salicylate, and theobromine salicylate. The aqueous solution is 
reported to be incompatible with stainless steel filters.(1) 
13 Method of Manufacture 
An equivalent amount of sodium bicarbonate is added to a 
solution of ascorbic acid in water. Following the cessation of 
effervescence, the addition of propan-2-ol precipitates sodium 
ascorbate. 
14 Safety 
The parenteral administration of 0.251.00 g of sodium 
ascorbate, given daily in divided doses, is recommended in 
the treatment of vitamin C deficiencies. Various adverse 
reactions have been reported following the administration of 
1 g or more of sodium ascorbate, although ascorbic acid and 
sodium ascorbate are usually well tolerated; see Ascorbic acid. 
There have been no reports of adverse effects associated with 
the much lower concentrations of sodium ascorbate and 
ascorbic acid, which are employed as antioxidants. 
The WHO has set an acceptable daily intake of ascorbic 
acid, potassium ascorbate, and sodium ascorbate, as antioxidants 
in food, at up to 15 mg/kg body-weight in addition to 
that naturally present in food.(2) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Sodium ascorbate may be 
irritant to the eyes. Eye protection and rubber or plastic gloves 
are recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (IV preparations; 
oral tablets). Included in nonparenteral and parenteral 
medicines licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Ascorbic acid; ascorbyl palmitate; calcium ascorbate. 
Calcium ascorbate 
Empirical formula: C12H14O12Ca 
Molecular weight: 390.31 
CAS number: [5743-27-1] 
Synonyms: calcium L-(.)-ascorbate; CCal-97; E302. 
18 Comments 
1mg of sodium ascorbate is equivalent to 0.8890mg of 
ascorbic acid (1 mg of ascorbic acid is equivalent to 
1.1248 mg of sodium ascorbate); 1 g of sodium ascorbate 
contains approximately 5 mmol of sodium. A specification for 
sodium ascorbate is contained in the Food Chemicals Codex 
(FCC). 
The EINECS number for sodium ascorbate is 205-126-1. 
660 Sodium Ascorbate

19 Specific References 
1 Buck GW, Wolfe KR. Interaction of sodium ascorbate with 
stainless steel particulate filter needles [letter]. Am J Hosp Pharm 
1991; 48: 1191. 
2 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications. 
Seventeenth report of the FAO/WHO expert committee on food 
additives. World Health Organ Tech Rep Ser 1974; No. 539. 
20 General References 
Dahl GB, Jeppsson RI, Tengborn HJ. Vitamin stability in a TPN 
mixture stored in an EVA plastic bag. J Clin Hosp Pharm 1986; 11: 
271–279. 
DeRitter E, Magid L, Osadca M, Rubin SH. Effect of silica gel on 
stability and biological availability of ascorbic acid. J Pharm Sci 
1970; 59: 229–232. 
Dettman IC. Sterilization of ascorbates by heat and absolute ethanol. 
United States Patent No. 4,816,223; 1989. 
Iida S, Kita K, Ootsuki H. Stable ascorbic acid solutions. Japanese 
Patent No. 61,130,205; 1986. 
Kitamori N, Hemmi K, Maeno M, Mima H. Direct compression of 
chewable vitamin C tablets. Pharm Technol 1982; 6(10): 56–64. 
Pfeifer HJ, Webb JW. Compatibility of penicillin and ascorbic acid 
injection. Am J Hosp Pharm 1976; 33: 448–450. 
Sekine K, Araki D, Suzuki Y. Powdery pharmaceutical compositions 
containing ascorbic acids for intranasal administration. Japanese 
Patent No. 63,115,820; 1988. 
Thielemann AM, Arata R, Morasso MI, Arancibia A. Biopharmaceutical 
study of a vitamin C controlled-release formulation. Farmaco 
(Prat) 1988; 43: 387–395. 
21 Authors 
CP McCoy. 
22 Date of Revision 
17 August 2005. 
Sodium Ascorbate 661

Sodium Benzoate 
1 Nonproprietary Names 
BP: Sodium benzoate 
JP: Sodium benzoate 
PhEur: Natrii benzoas 
USPNF : Sodium benzoate 
2 Synonyms 
Benzoic acid sodium salt; benzoate of soda; E211; natrium 
benzoicum; sobenate; sodii benzoas; sodium benzoic acid. 
3 Chemical Name and CAS Registry Number 
Sodium benzoate [532-32-1] 
4 Empirical Formula and Molecular Weight 
C7H5NaO2 144.11 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; tablet and capsule lubricant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sodium benzoate is used primarily as an antimicrobial 
preservative in cosmetics, foods, and pharmaceuticals. It is 
used in concentrations of 0.02–0.5% in oral medicines, 0.5% in 
parenteral products, and 0.1–0.5% in cosmetics. The usefulness 
of sodium benzoate as a preservative is limited by its 
effectiveness over a narrow pH range; see Section 10. 
Sodium benzoate is used in preference to benzoic acid in 
some circumstances, owing to its greater solubility. However, in 
some applications it may impart an unpleasant flavor to a 
product. Sodium benzoate has also been used as a tablet 
lubricant(1) at 2–5% w/w concentrations. Solutions of sodium 
benzoate have also been administered, orally or intravenously, 
in order to determine liver function. 
8 Description 
Sodium benzoate occurs as a white granular or crystalline, 
slightly hygroscopic powder. It is odorless, or with faint odor of 
benzoin and has an unpleasant sweet and saline taste. 
SEM: 1 
Excipient: Sodium benzoate 
Manufacturer: Bush Boake Allen Corp. 
Magnification: 60 
SEM: 2 
Excipient: Sodium benzoate 
Manufacturer: Bush Boake Allen Corp. 
Magnification: 2400 
9 Pharmacopeial Specifications 
See Table I.

Table I: Pharmacopeial specifications for sodium benzoate. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters . . — 
Acidity or alkalinity . . . 
Appearance of solution. . — 
Arsenic 42 ppm — — 
Chloride . 4200 ppm — 
Heavy metals 420 ppm 410 ppm 40.001% 
Organic volatile 
impurities 
— — . 
Loss on drying 41.5% 42.0% 41.5% 
Phthalic acid . — — 
Sulfate 40.120% — — 
Total chlorine — 4300 ppm — 
Assay (dried basis) 599.0% 99.0–100.5% 99.0–100.5% 
10 Typical Properties 
Acidity/alkalinity: pH = 8.0 (saturated aqueous solution at 
258C). It is relatively inactive above approximately pH 5. 
Antimicrobial activity: sodium benzoate has both bacteriostatic 
and antifungal properties attributed to undissociated 
benzoic acid, hence preservative efficacy is best seen in 
acidic solutions (pH 2–5). In alkaline conditions it is almost 
without effect. 
Density: 1.497–1.527 g/cm3 at 248C 
Freezing point depression: 0.248C (1.0% w/v) 
Osmolarity: a 2.25% w/v aqueous solution is iso-osmotic with 
serum. 
Partition coefficients: 
Vegetable oil : water = 3–6 
Solubility: see Table II. 
Table II: Solubility for sodium benzoate. 
Solvent Solubility at 208C 
unless otherwise stated 
Ethanol (95%) 1 in 75 
Ethanol (90%) 1 in 50 
Water 1 in 1.8 
1 in 1.4 at 1008C 
11 Stability and Storage Conditions 
Aqueous solutions may be sterilized by autoclaving or 
filtration. 
The bulk material should be stored in a well-closed 
container, in a cool, dry place. 
12 Incompatibilities 
Incompatible with quaternary compounds, gelatin, ferric salts, 
calcium salts, and salts of heavy metals, including silver, lead, 
and mercury. Preservative activity may be reduced by interactions 
with kaolin(2) or nonionic surfactants. 
13 Method of Manufacture 
Prepared by the treatment of benzoic acid with either sodium 
carbonate or sodium bicarbonate. 
14 Safety 
Ingested sodium benzoate is conjugated with glycine in the liver 
to yield hippuric acid, which is excreted in the urine. Symptoms 
of systemic benzoate toxicity resemble those of salicylates.(3) 
Whereas oral administration of the free-acid form may cause 
severe gastric irritation, benzoate salts are well tolerated in 
large quantities: e.g. 6 g of sodium benzoate in 200mL of water 
is administered orally as a liver function test. 
Clinical data have indicated that sodium benzoate can 
produce nonimmunological contact uricartia and nonimmunological 
immediate contact reactions.(4) However, it is also 
recognized that these reactions are strictly cutaneous, and can 
therefore be used safely at concentrations up to 5%. However, 
this nonimmunological phenomenon should be considered 
when designing formulations for infants and children. 
Other adverse effects include anaphylaxis(5–7) and urticarial 
reactions, although a controlled study has shown that the 
incidence of urticaria in patients given benzoic acid is no greater 
than that with a lactose placebo.(8) 
It has been recommended that caffeine and sodium benzoate 
injection should not be used in neonates;(9) however, sodium 
benzoate has been used by others in the treatment of some 
neonatal metabolic disorders.(10) It has been suggested that 
there is a general adverse effect of benzoate preservatives on the 
behavior of 3-year-old children, which is detectable by parents, 
but not by a simple clinical assessment.(11) 
The WHO acceptable daily intake of total benzoates, 
calculated as benzoic acid, has been estimated at up to 
5 mg/kg of body-weight.(12,13) 
LD50 (mouse, IM): 2.3 g/kg(13,14) 
LD50 (mouse, IV): 1.4 g/kg 
LD50 (mouse, oral): 1.6 g/kg 
LD50 (rabbit, oral): 2.0 g/kg 
LD50 (rat, IV): 1.7 mg/kg 
LD50 (rat, oral): 4.1 g/kg 
See also Benzoic Acid. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Sodium benzoate may be 
irritant to the eyes and skin. Eye protection and rubber or 
plastic gloves are recommended. 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (dental preparations; IM 
and IV injections; oral capsules, solutions and tablets; rectal; 
and topical preparations). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Benzoic acid; potassium benzoate. 
18 Comments 
Sodium benzoate has been used as an antimicrobial agent used 
in polymeric films in food packaging.(15) A specification for 
sodium benzoate is contained in the Food Chemicals Codex 
(FCC). The EINECS number for sodium benzoate is 208-534-8. 
Sodium Benzoate 663

19 Specific References 
1 Saleh SI, Wehrle. P, Stamm A. Improvement of lubrication capacity 
of sodium benzoate: effects of milling and spray drying. Int J 
Pharm 1988; 48: 149–157. 
2 Clarke CD, Armstrong NA. Influence of pH on the adsorption of 
benzoic acid by kaolin. Pharm J 1972; 209: 44–45. 
3 Michils A, Vandermoten G, Duchateau J, Yernault J-C. Anaphylaxis 
with sodium benzoate [letter]. Lancet 1991; 337: 1424–1425. 
4 Nair B. Final report on the safety assessment of benzyl alcohol, 
benzoic acid, and sodium benzoate. Int J Toxicol 2001; 20 (Suppl. 
3): 23–50. 
5 Rosenhall L. Evaluation of intolerance to analgesics, preservatives 
and food colorants with challenge tests. Eur J Respir Dis 1982; 63: 
410–419. 
6 Michae.lsson G, Juhlin L. Urticaria induced by preservatives and 
dye additives in food and drugs. Br J Dermatol 1973; 88: 525–532. 
7 Warin RP, Smith RJ. Challenge test battery in chronic urticaria. Br 
J Dermatol 1976; 94: 401–406. 
8 Lahti A, Hannuksela M. Is benzoic acid really harmful in cases of 
atopy and urticaria? Lancet 1981; ii: 1055. 
9 Edwards RC, Voegeli CJ. Inadvisability of using caffeine and 
sodium benzoate in neonates. Am J Hosp Pharm 1984; 41: 658. 
10 Brusilow SW, Danney M, Waber LJ, et al. Treatment of episodic 
hyperammonemia in children with inborn errors of urea synthesis. 
N Engl J Med 1984; 310: 1630–1634. 
11 Anonymous. The effects of a double blind, placebo controlled, 
artificial food colorings and benzoate preservative challenge on 
hyperactivity in a general population sample of preschool children. 
Child Care Health Dev 2004; 30(5): 561. 
12 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications. 
Seventeenth report of the joint FAO/WHO expert committee on 
food additives.World Health Organ Tech Rep Ser 1974; No. 539. 
13 FAO/WHO. Evaluation of certain food additives and contaminants. 
Twenty-seventh report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1983; No. 696. 
14 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3232. 
15 Buonocore GG, Del-Nobile MA, Panizza A, et al. A general 
approach to describe the antimicrobial agent release from highly 
swellable films intended for food packaging applications. J 
Controlled Release 2003; 90(1): 97–107. 
20 General References 
Nishijo J, Yonetani I. Interaction of theobromine with sodium 
benzoate. J Pharm Sci 1982; 71: 354–356. 
21 Authors 
SC Owen. 
22 Date of Revision 
16 August 2005. 
664 Sodium Benzoate

Sodium Bicarbonate 
1 Nonproprietary Names 
BP: Sodium bicarbonate 
JP: Sodium bicarbonate 
PhEur: Natrii hydrogenocarbonas 
USP: Sodium bicarbonate 
2 Synonyms 
Baking soda; E500; Effer-Soda; monosodium carbonate; Sal de 
Vichy; sodium acid carbonate; sodium hydrogen carbonate. 
3 Chemical Name and CAS Registry Number 
Carbonic acid monosodium salt [144-55-8] 
4 Empirical Formula and Molecular Weight 
NaHCO3 84.01 
5 Structural Formula 
NaHCO3 
6 Functional Category 
Alkalizing agent; therapeutic agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sodium bicarbonate is generally used in pharmaceutical 
formulations as a source of carbon dioxide in effervescent 
tablets and granules. It is also widely used to produce or 
maintain an alkaline pH in a preparation. 
In effervescent tablets and granules, sodium bicarbonate is 
usually formulated with citric and/or tartaric acid;(1) combinations 
of citric and tartaric acid are often preferred in 
formulations as citric acid alone produces a sticky mixture 
that is difficult to granulate, while if tartaric acid is used alone, 
granules lose firmness. When the tablets or granules come into 
contact with water, a chemical reaction occurs, carbon dioxide 
is evolved, and the product disintegrates.(2,3) Melt granulation 
in a fluidized bed dryer has been suggested as a one-step method 
for the manufacture of effervescent granules composed of 
anhydrous citric acid and sodium bicarbonate, for subsequent 
compression into tablets.(4) 
Tablets may also be prepared with sodium bicarbonate 
alone since the acid of gastric fluid is sufficient to cause 
effervescence and disintegration. Sodium bicarbonate is also 
used in tablet formulations to buffer drug molecules that are 
weak acids, thereby increasing the rate of tablet dissolution and 
reducing gastric irritation.(5–7) 
The effects of tablet binders, such as polyethylene glycols, 
microcrystalline cellulose, silicified microcrystalline cellulose, 
pregelatinized starch, and povidone, on the physical and 
mechanical properties of sodium bicarbonate tablets have 
also been investigated.(8,9) 
Additionally, sodium bicarbonate is used in solutions as a 
buffering agent for erythromycin,(10) lidocaine,(11) local anesthetic 
solutions,(12) and total parenteral nutrition (TPN) 
solutions.(13) In some parenteral formulations, e.g., niacin, 
sodium bicarbonate is used to produce a sodium salt of the 
active ingredient that has enhanced solubility. Sodium bicarbonate 
has also been used as a freeze-drying stabilizer(14) and in 
toothpastes. 
Recently, sodium bicarbonate has been used as a gasforming 
agent in alginate raft systems(15–17) and in floating, 
controlled-release oral dosage forms of furosemide(18) and 
cisapride.(19) Tablet formulations containing sodium bicarbonate 
have been shown to increase the absorption of paracetamol,(
20,21) and improve the stability of levothyroxine.(22) 
Therapeutically, sodium bicarbonate may be used as an 
antacid, and as a source of the bicarbonate anion in the 
treatment of metabolic acidosis. Sodium bicarbonate may also 
be used as a component of oral rehydration salts and as a 
source of bicarbonate in dialysis fluids. 
Sodium bicarbonate is used in food products as an alkali or 
as a leavening agent, e.g. baking soda. See Table I. 
Table I: Uses of sodium bicarbonate. 
Use Concentration (%) 
Buffer in tablets 10–40 
Effervescent tablets 25–50 
Isotonic injection/infusion 1.39 
8 Description 
Sodium bicarbonate occurs as an odorless, white, crystalline 
powder with a saline, slightly alkaline taste. The crystal 
structure is monoclinic prisms. Grades with different particle 
sizes, from a fine powder to free-flowing uniform granules, are 
commercially available. 
9 Pharmacopeial Specifications 
See Table II. 
10 Typical Properties 
Acidity/alkalinity: pH = 8.3 for a freshly prepared 0.1M 
aqueous solution at 258C; alkalinity increases on standing, 
agitation, or heating. 
Density (bulk): 0.869 g/cm3 
Density (tapped): 1.369 g/cm3 
Density(true): 2.173 g/cm3 
Freezing point depression: 0.3818C (1% w/v solution) 
Melting point: 2708C (with decomposition) 
Moisture content: below 80% relative humidity, the moisture 
content is less than 1% w/w. Above 85% relative humidity, 
sodium bicarbonate rapidly absorbs excessive amounts of 
water and may start to decompose with loss of carbon 
dioxide.

SEM: 1 
Excipient: Sodium bicarbonate 
Manufacturer: Merck Ltd. 
Magnification: 120 
Osmolarity: a 1.39% w/v aqueous solution is isoosmotic with 
serum. 
Refractive index: nD
20 = 1.3344 (1% w/v aqueous solution) 
Solubility: see Table III. 
Table II: Pharmacopeial specifications for sodium bicarbonate. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters — . — 
Loss on drying — — 40.25% 
Insoluble substances — — . 
pH (5% w/v aqueous 
solution) 
7.9–8.4 — — 
Appearance . . — 
Carbonate . . 40.23%(a) 
Normal carbonate — — . 
Chloride 40.04% 4150 ppm 40.015% 
Sulfate — 4150 ppm 40.015% 
Ammonia — — . 
Ammonium . 420 ppm — 
Aluminum — — 42 mg/g(a) 
Arsenic 42 ppm 42 ppm 42 mg/g 
Calcium — 4100 ppm 40.01%(a) 
Magnesium — — 40.004%(a) 
Copper — — 41 mg/g(a) 
Iron — 420 ppm 45 mg/g(a) 
Heavy metals 45 ppm 410 ppm 45 mg/g 
Limit of organics — — .(a) 
Organic volatile 
impurities 
— — . 
Assay (dried basis) 599.0% 99.0–101.0% 99.0–100.5% 
(a) Where it is labeled as intended for use in hemodialysis. 
SEM: 2 
Excipient: Sodium bicarbonate 
Manufacturer: Merck Ltd. 
Magnification: 600 
Table III: Solubility of sodium bicarbonate. 
Solvent Solubility at 208C unless otherwise stated 
Ethanol (95%) Practically insoluble 
Ether Practically insoluble 
Water 1 in 11 
1 in 4 at 1008C(a) 
1 in 10 at 258C 
1 in 12 at 188C 
(a) Note that in hot water, sodium bicarbonate is converted to the carbonate. 
11 Stability and Storage Conditions 
When heated to about 508C, sodium bicarbonate begins to 
dissociate into carbon dioxide, sodium carbonate, and water; 
on heating to 250–3008C, for a short time, sodium bicarbonate 
is completely converted into anhydrous sodium carbonate. 
However, the process is both time- and temperature-dependent, 
with conversion 90% complete within 75 minutes at 938C. The 
reaction proceeds via surface-controlled kinetics; when sodium 
bicarbonate crystals are heated for a short period of time, very 
fine needle-shaped crystals of anhydrous sodium carbonate are 
formed on the sodium bicarbonate surface.(23) 
The effects of relative humidity and temperature on the 
moisture sorption and stability of sodium bicarbonate powder 
have been investigated. Sodium bicarbonate powder is stable 
below 76% relative humidity at 258C and below 48% relative 
humidity at 408C.(24) At 54% relative humidity, the degree of 
pyrolytic decarboxylation of sodium bicarbonate should not 
exceed 4.5% in order to avoid detrimental effects on 
stability.(25) 
At ambient temperatures, aqueous solutions slowly decompose 
with partial conversion into the carbonate; the decomposition 
is accelerated by agitation or heat. 
Aqueous solutions of sodium bicarbonate may be sterilized 
by filtration or autoclaving. To minimize decomposition of 
666 Sodium Bicarbonate

sodium bicarbonate by decarboxylation on autoclaving, 
carbon dioxide is passed through the solution in its final 
container, which is then hermetically sealed and autoclaved. 
The sealed container should not be opened for at least 2 hours 
after it has returned to ambient temperature, to allow time for 
the complete reformation of the bicarbonate from the 
carbonate produced during the heating process. 
Aqueous solutions of sodium bicarbonate stored in glass 
containers may develop deposits of small glass particles. 
Sediments of calcium carbonate with traces of magnesium or 
other metal carbonates have been found in injections sterilized 
by autoclaving; these are due to impurities in the bicarbonate or 
to extraction of calcium and magnesium ions from the glass 
container. Sedimentation may be retarded by the inclusion of 
0.01–0.02% disodium edetate.(26–28) 
Sodium bicarbonate is stable in dry air but slowly 
decomposes in moist air and should therefore be stored in a 
well-closed container in a cool, dry place. 
12 Incompatibilities 
Sodium bicarbonate reacts with acids, acidic salts, and many 
alkaloidal salts, with the evolution of carbon dioxide. Sodium 
bicarbonate can also intensify the darkening of salicylates. 
In powder mixtures, atmospheric moisture or water of 
crystallization from another ingredient is sufficient for sodium 
bicarbonate to react with compounds such as boric acid or 
alum. In liquid mixtures containing bismuth subnitrate, sodium 
bicarbonate reacts with the acid formed by hydrolysis of the 
bismuth salt. 
In solution, sodium bicarbonate has been reported to be 
incompatible with many drug substances such as ciprofloxacin,(
29,30) amiodarone,(31) nicardipine,(32) and levofloxacin.(33) 
13 Method of Manufacture 
Sodium bicarbonate is manufactured either by passing carbon 
dioxide into a cold saturated solution of sodium carbonate, or 
by the ammonia–soda (Solvay) process, in which first ammonia 
and then carbon dioxide is passed into a sodium chloride 
solution to precipitate sodium bicarbonate while the moresoluble 
ammonium chloride remains in solution. 
14 Safety 
Sodium bicarbonate is used in a number of pharmaceutical 
formulations including injections and ophthalmic, otic, topical, 
and oral preparations. 
Sodium bicarbonate is metabolized to the sodium cation, 
which is eliminated from the body by renal excretion, and the 
bicarbonate anion, which becomes part of the body’s bicarbonate 
store. Any carbon dioxide formed is eliminated via the 
lungs. Administration of excessive amounts of sodium bicarbonate 
may thus disturb the body’s electrolyte balance, leading 
to metabolic alkalosis or possibly sodium overload with 
potentially serious consequences. The amount of sodium 
present in antacids and effervescent formulations has been 
sufficient to exacerbate chronic heart failure, especially in 
elderly patients.(34) 
Orally ingested sodium bicarbonate neutralizes gastric acid 
with the evolution of carbon dioxide and may cause stomach 
cramps and flatulence. 
When used as an excipient, sodium bicarbonate is generally 
regarded as an essentially nontoxic and nonirritant material. 
LD50 (mouse, oral): 3.36 g/kg(35) 
LD50 (rat, oral): 4.22 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (injections; 
ophthalmic preparations; oral capsules, solutions, and tablets). 
Included in parenteral (intravenous infusions and injections) 
and nonparenteral medicines (ear drops; eye lotions; oral 
capsules, chewable tablets, effervescent powders, effervescent 
tablets, granules, and tablets; suppositories and suspensions) 
licensed in the UK. 
17 Related Substances 
Potassium bicarbonate. 
18 Comments 
Each gram of sodium bicarbonate represents approximately 
11.9 mmol of sodium and of bicarbonate. Each gram of sodium 
bicarbonate will neutralize 12 mEq of gastric acid in 60 
minutes. 
The yield of carbon dioxide from sodium bicarbonate is 
approximately 52% by weight. 
Three molecules of sodium bicarbonate are required to 
neutralize one molecule of citric acid, and two molecules of 
sodium bicarbonate to neutralize one molecule of tartaric acid. 
A specification for sodium bicarbonate is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for sodium bicarbonate is 205-633-8. 
19 Specific References 
1 Usui F, Carstensen JT. Interactions in the solid state I: interactions 
of sodium bicarbonate and tartaric acid under compressed 
conditions. J Pharm Sci 1985; 74(12): 1293–1297. 
2 Anderson NR, Banker GS, Peck GE. Quantitative evaluation of 
pharmaceutical effervescent systems I: design of testing apparatus. 
J Pharm Sci 1982; 71(1): 3–6. 
3 Anderson NR, Banker GS, Peck GE. Quantitative evaluation of 
pharmaceutical effervescent systems II: stability monitoring by 
reactivity and porosity measurements. J Pharm Sci 1982; 71(1): 7– 
13. 
4 Yanze FM, Duru C, Jacob M. A process to produce effervescent 
tablets: fluidised bed dryer melt granulation. Drug Dev Ind Pharm 
2000; 26(11): 1167–1176. 
5 Javaid KA, Cadwallader DE. Dissolution of aspirin from tablets 
containing various buffering agents. J Pharm Sci 1972; 61(9): 
1370–1373. 
6 Rainsford KD. Gastric mucosal ulceration induced in pigs by 
tablets but not suspensions or solutions of aspirin. J Pharm 
Pharmacol 1978; 30: 129–131. 
7 Mason WD, Winer N. Kinetics of aspirin, salicylic acid and 
salicyluric acid following oral administration of aspirin as a tablet 
and two buffered solutions. J Pharm Sci 1981; 70(3): 262–265. 
8 Olsson H, Mattsson S, Nystro.m C. Evaluation of the effects of 
polyethylene glycols of differing molecular weights on the 
mechanical strength of sodium chloride and sodium bicarbonate 
tablets. Int J Pharm 1998; 171(1): 31–44. 
9 Mattsson S, Nystro.m C. Evaluation of critical binder properties 
affecting the compactibility of binary mixtures. Drug Dev Ind 
Pharm 2001; 27(3): 181–194. 
10 Allwood MC. The influence of buffering on the stability of 
erythromycin injection in small-volume infusions. Int J Pharm 
1992; 80 (Suppl.): R7–R9.
Sodium Bicarbonate 667

11 Doolan KL. Buffering lidocaine with sodium bicarbonate. Am J 
Hosp Pharm 1994; 51: 2564–2565. 
12 Erramouspe J. Buffering local anesthetic solutions with sodium 
bicarbonate: literature review and commentary. Hosp Pharm 
1996; 31(10): 1275–1282. 
13 MacKayMW, Fitzgerald KA, Jackson D. The solubility of calcium 
and phosphate in two specialty amino acid solutions. J Parenter 
Enteral Nutr 1996; 20: 63–66. 
14 Connolly M, Debenedetti PG, Tung H-H. Freeze crystallization of 
imipenem. J Pharm Sci 1996; 85(2): 174–177. 
15 Johnson FA, Craig DQM, Mercer AD, Chauhan S. The effects of 
alginate molecular structure and formulation variables on the 
physical characteristics of alginate raft systems. Int J Pharm 1997; 
159(1): 35–42. 
16 Johnson FA, Craig DQ, Mercer A, Chauhan S. The use of image 
analysis as a means of monitoring bubble formation in alginate 
rafts. Int J Pharm 1998; 170(2): 179–185. 
17 Choi BY, Park HJ, Hwang SJ. Preparation of alginate beads for 
floating drug delivery system: effects of carbon dioxide gasforming 
agents. Int J Pharm 2002; 239(1–2): 81–91. 
18 O.
zdemir N, Ordu S, O.
zkan Y. Studies of floating dosage forms of 
furosemide: in vitro and in vivo evaluations of bilayer tablet 
formulations. Drug Dev Ind Pharm 2000; 26(8): 857–866. 
19 Wei Z, Yu Z, Bi D. Design and evaluation of a two-layer floating 
tablet for gastric retention using cisapride as a model drug. Drug 
Dev Ind Pharm 2001; 27(5): 469–474. 
20 Rostami-Hodjegan A, Shiran MR, Ayesh R, et al. A new rapidly 
absorbed paracetamol tablet containing sodium bicarbonate. I. A 
four-way crossover study to compare the concentration-time 
profile of paracetamol from the new paracetamol/sodium bicarbonate 
tablet and a conventional paracetamol tablet in fed and 
fasted volunteers. Drug Dev Ind Pharm 2002; 28(5): 523–531. 
21 Rostami-Hodjegan A, Shiran MR, Tucker GT, et al. A new rapidly 
absorbed paracetamol tablet containing sodium bicarbonate. II. 
Dissolution studies and in vitro/in vivo correlation. Drug Dev Ind 
Pharm 2002; 28(5): 533–543. 
22 Patel H, Stalcup A, Dansereau R, Sakr A. The effect of excipients 
on the stability of levothyroxine pentahydrate tablets. Int J Pharm 
2003; 264(1–2): 35–43. 
23 Shefter E, Lo A, Ramalingam S. A kinetic study of the solid state 
transformation of sodium bicarbonate to sodium carbonate. Drug 
Dev Commun 1974; 1: 29–38. 
24 Kuu WY, Chilamkurti R, Chen C. Effect of humidity and 
temperature on moisture sorption and stability of sodium 
bicarbonate powder. Int J Pharm 1998; 166(2): 167–175. 
25 Ljunggren L, Volkova N, Hansson H. Calorimetry a method to be 
used to characterise pyrolytically decarboxylated bicarbonate and 
assess its stability at elevated humidities. Int J Pharm 2000; 
202(1–2): 71–77. 
26 Hadgraft JW, Hewer BD. Molar injection of sodium bicarbonate 
[letter]. Pharm J 1964; 192: 544. 
27 Hadgraft JW. Unsatisfactory infusions of sodium bicarbonate 
[letter]. Lancet 1966; i: 603. 
28 Smith G. Unsatisfactory infusions of sodium bicarbonate [letter]. 
Lancet 1966; i: 658. 
29 Gilbert DL, Trissel LA, Martinez JF. Compatibility of ciprofloxacin 
lactate with sodium bicarbonate during simulated Y- site administration. 
Am J Health Syst Pharm 1997; 54: 1193–1195. 
30 Trissel LA. Concentration-dependent precipitation of sodium 
bicarbonate with ciprofloxacin lactate [letter]. Am J Health Syst 
Pharm 1996; 53: 84–85. 
31 Korth-Bradley JM, Ludwig S, Callaghan C. Incompatibility of 
amiodarone hydrochloride and sodium bicarbonate injections 
[letter]. Am J Health Syst Pharm 1995; 52: 2340. 
32 Baaske DM, DeMay JF, Latona CA, et al. Stability of nicardipine 
hydrochloride in intravenous solutions. Am J Health Syst Pharm 
1996; 53: 1701–1705. 
33 Williams NA, Bornstein M, Johnson K. Stability of levofloxacin in 
intravenous solutions in polyvinyl chloride bags. Am J Health Syst 
Pharm 1996; 53: 2309–2313. 
34 Panchmatia K, Jolobe OM. Contra-indications of Solpadol [letter]. 
Pharm J 1993; 251: 73. 
35 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3233. 
20 General References 
Hannula A-M, Marvola M, Aho E. Release of ibuprofen from hard 
gelatin capsule formulations: effect of sodium bicarbonate as a 
disintegrant. Acta Pharm Fenn 1989; 98: 131–134. 
Sendall FEJ, Staniforth JN, Rees JE, Leatham MJ. Effervescent tablets. 
Pharm J 1983; 230: 289–294. 
Travers DN, White RC. The mixing of micronized sodium bicarbonate 
with sucrose crystals. J Pharm Pharmacol 1971; 23: 260S–261S. 
21 Authors 
CG Cable. 
22 Date of Revision 
23 August 2005. 
668 Sodium Bicarbonate

Sodium Borate 
1 Nonproprietary Names 
BP: Borax 
JP: Sodium borate 
PhEur: Borax 
USPNF: Sodium borate 
2 Synonyms 
Borax decahydrate; boric acid disodium salt; E285; natrii 
tetraboras; sodium biborate decahydrate; sodium pyroborate 
decahydrate; sodium tetraborate decahydrate. 
3 Chemical Name and CAS Registry Number 
Disodium tetraborate decahydrate [1303-96-4] 
4 Empirical Formula and Molecular Weight 
Na2B4O710H2O 381.37 
5 Structural Formula 
Na2B4O710H2O 
6 Functional Category 
Alkalizing agent; antimicrobial preservative; buffering agent; 
disinfectant; emulsifying agent; stabilizing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sodium borate is used in pharmaceutical applications similarly 
to boric acid (see Boric Acid). It has been used externally as a 
mild astringent and as an emulsifying agent in creams.(1) It has 
also been used in lozenges, mouthwashes, otic preparations 
(0.3% w/v), and ophthalmic solutions (0.03–1.0% w/v). 
Sodium borate has additionally been investigated in the 
prevention of crystal formation in freeze-dried solutions.(2) 
Preparations of sodium borate in honey have historically 
been used as paints for the throat, tongue, and mouth, but such 
use is now inadvisable because of concerns about toxicity in 
such applications, see Section 14. Sodium borate is also used in 
cosmetics such as moisturizers, deodorants, and shampoos. 
8 Description 
Sodium borate occurs as white, hard crystals, granules, or 
crystalline powder. It is odorless and efflorescent. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for sodium borate. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters — . — 
Carbonate and 
bicarbonate 
. — . 
Color of solution . . — 
pH 9.1–9.6 9.0–9.6 — 
Heavy metals 420 ppm 425 ppm 40.002% 
Arsenic 45 ppm 45 ppm — 
Calcium — 4100 ppm — 
Ammonium — 410 ppm — 
Sulfates — 450 ppm — 
Organic volatile 
impurities 
— — . 
Assay 99.0–103.0% 99.0–103.0% 99.0–105.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 9.0–9.6 (4% w/v aqueous solution) 
Density: 1.73 g/cm3 
Melting point: 758C when rapidly heated. At 1008C it loses 
5H2O; at 1508C it loses 9H2O; and at 3208C it becomes 
anhydrous. At about 8808C the substance melts into a glassy 
state: ‘borax beads.’ 
Solubility: 1 in 1 of glycerin; 1 in 1 of boiling water; 1 in 16 of 
water; practically insoluble in ethanol (95%), ethanol 
(99.5%), and diethyl ether. 
11 Stability and Storage Conditions 
Sodium borate should be stored in a well-closed container in a 
cool, dry, place. See also Section 18. 
12 Incompatibilities 
Sodium borate is incompatible with acids and with metallic and 
alkaloidal salts. 
13 Method of Manufacture 
Sodium borate can be prepared from minerals such as 
borosodium calcite, pandermite, or tinkal; these are natural 
sodium or calcium borates. Treatment of the mineral with 
sodium carbonate and sodium hydrogencarbonate yields the 
sodium borate decahydrate. In the USA, brine from salt lakes is 
also an important source of sodium borate.(3) 
14 Safety 
Sodium borate has weak bacteriostatic and astringent properties. 
Historically, sodium borate has been used as a disinfectant 
in skin lotions and eye-, nose-, and mouthwashes. However, 
boric acid is easily absorbed via mucous membranes and 
damaged skin, and severe toxicity has been observed, especially 
in babies and children.(4) Consequently, the use of sodium

borate as a disinfectant is now considered somewhat obsolete 
and careful use is recommended. The toxic effects of sodium 
borate include vomiting, diarrhea, erythema, CNS depression, 
and kidney damage. The lethal oral intake is approximately 
20 g in adults and 5 g in children.(5) 
LD50 (guinea pig, oral): 5.33 g/kg(5,6) 
LD50 (mouse, IP): 2.711 g/kg 
LD50 (mouse, IV): 1.320 g/kg 
LD50 (mouse, oral): 2.0 g/kg 
LD50 (rat, oral): 2.66 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 

and the quantity of material handled; do not combine with 
acids. 
16 Regulatory Status 
Accepted for use as a food additive in Europe. Included in the 
FDA Inactive Ingredients Guide (otic preparations; ophthalmic 
solutions and suspensions). Included in nonparenteral medicines 
licensed in the UK, Italy, France, Germany, and Japan. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Boric acid; sodium borate anhydrous. 
Sodium borate anhydrous 
Synonyms: borax glass; disodium tetraborate anhydrous; fused 
borax; fused sodium borate; sodium pyroborate; sodium 
tetraborate anhydrous. 
Empirical formula: Na2B4O7 
Molecular weight: 201.2 
CAS number: [1330-43-4] 
Boiling point: 15758C (decomposes) 
Melting point: 7418C 
Solubility: slightly soluble in glycerin, and water; practically 
insoluble in ethanol (95%). 
Specific gravity: 2.367 
Comments: the EINECS number for sodium borate anhydrous 
is 215-540-4. 
18 Comments 
Commercially available sodium borate decahydrate is usually 
present as monoclinic prismatic crystals that become opaque on 
the surface in dry air. In addition to the decahydrate, a 
pentahydrate exists; this is also known as ‘jeweller’s borax.’ The 
anhydrous substance is also available and is called ‘pyroborax.’ 
The EINECS number for sodium borate is 271-536-2. 
19 Specific References 
1 Prince LM. Beeswax/borax reaction in cold creams. Cosmet 
Perfum 1974; 89(May): 47–49. 
2 Izutsu K, Ocheda SO, Aoyagi N, Kojima S. Effects of sodium 
tetraborate and boric acid on nonisothermal mannitol crystallization 
in frozen solutions and freeze-dried solids. Int J Pharm 
2004; 273(1): 85–93. 
3 Lyday PA. Boron. In: Mineral Yearbook, Vol. 1. Washington DC: 
US Department of the Interior US Geological Survey, 1992: 249. 
4 Gordon AS, Prichard JS, Freedman MH. Seizure disorders and 
anemia associated with chronic borax intoxication. Can Med 
Assoc J 1973; 108: 719–721, 724. 
5 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3234. 
6 Smyth HF, Carpenter CP, Weil CS, et al. Range-finding toxicity 
data: list VII. Am Ind Hyg Assoc J 1969; 30(5): 470–476. 
20 General References 
—
21 Authors 
HJ de Jong. 
22 Date of Revision 
24 August 2005. 
670 Sodium Borate

Sodium Chloride 
1 Nonproprietary Names 
BP: Sodium chloride 
JP: Sodium chloride 
PhEur: Natrii chloridum 
USP: Sodium chloride 
2 Synonyms 
Alberger; chlorure de sodium; common salt; hopper salt; 
natural halite; rock salt; saline; salt; sea salt; table salt. 
3 Chemical Name and CAS Registry Number 
Sodium chloride [7647-14-5] 
4 Empirical Formula and Molecular Weight 
NaCl 58.44 
5 Structural Formula 
NaCl 
6 Functional Category 
Tablet and capsule diluent; tonicity agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sodium chloride is widely used in a variety of parenteral and 
nonparenteral pharmaceutical formulations, where the primary 
use is to produce isotonic solutions. 
Sodium chloride has been used as a lubricant and diluent in 
capsules and direct-compression tablet formulations in the 
past,(1–5) although this practice is no longer common. Sodium 
chloride has also been used as a channeling agent(6,7) and as an 
osmotic agent(8,9) in the cores of controlled-release tablets. It 
has been used as a porosity modifier in tablet coatings,(10) and 
to control drug release from microcapsules.(11,12) 
The addition of sodium chloride to aqueous spray-coating 
solutions containing hydroxypropyl cellulose or hypromellose 
suppresses the agglomeration of crystalline cellulose particles.(
13) Sodium chloride can also be used to modify drug 
release from gels(14) and from emulsions.(15) It can be used to 
control micelle size,(16–18) and to adjust the viscosity of polymer 
dispersions by altering the ionic character of a formulation.(
19,20) 
See Table I. 
Table I: Uses of sodium chloride. 
Use Concentration (%) 
Capsule diluent 10–80 
Controlled flocculation of suspensions 41 
Direct compression tablet diluent 10–80 
To produce isotonic solutions in 
intravenous or ophthalmic preparations 
40.9 
Water-soluble tablet lubricant 5–20 
SEM: 1 
Excipient: Sodium chloride, powder 
Manufacturer: Mallinckrodt Speciality Chemicals Co. 
Magnification: 600 
8 Description 
Sodium chloride occurs as a white crystalline powder or 
colorless crystals; it has a saline taste. The crystal lattice is a 
face-centered cubic structure. Solid sodium chloride contains 
no water of crystallization although, below 08C, salt may 
crystallize as a dihydrate. 
9 Pharmacopeial Specifications 
See Table II.

Table II: Pharmacopeial specifications for sodium chloride. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters . . — 
Appearance of 
solution 
. . . 
Acidity or 
alkalinity 
. . . 
Loss on drying 40.5% 40.5% 0.5% 
Arsenic 42 ppm 41 ppm 1 mg/g 
Bromides . 4100 ppm 40.01% 
Chloride — — . 
Barium . . . 
Nitrites — . . 
Aluminum — 40.2 ppm(a) 40.2 mg/g(a) 
Calcium and 
magnesium 
. — — 
Magnesium and 
alkaline earth 
metals 
. 4100 ppm 40.01% 
Iodide . . . 
Iron . 42 ppm 42 mg/g 
Sulfate . 4200 ppm 40.020% 
Ferrocyanides . . . 
Heavy metals 43 ppm 45 ppm 45 ppm 
Phosphate . 425 ppm 40.0025% 
Potassium — 4500 ppm(a)(b) 40.05%(a)(b) 
Organic volatile 
impurities 
— — — 
Sterility — — . 
Bacterial 
endotoxins 
— 45 IU/g(b) — 
Assay (dried basis) 99.0–100.5% 99.0–100.5% 99.5–100.5% 
(a) If for use in peritoneal dialysis, hemodialysis or hemofiltration solutions. 
(b) If for parenteral use. 
SEM: 2 
Excipient: Sodium chloride, granular 
Manufacturer: Van Waters & Rogers, Inc. 
Magnification: 120 
10 Typical Properties 
Acidity/alkalinity: pH = 6.7–7.3 (saturated aqueous solution) 
Angle of repose: 388 for cubic crystals 
Boiling point: 14138C 
Compressibility: with sodium chloride powder of less than 
30 mm particle size, tablets are formed by plastic deformation; 
above this size, both plastic deformation and fracture 
occur.(1,3,4) See also Figure 1. 
Density: 
2.17 g/cm3; 
1.20 g/cm3 for saturated aqueous solution. 
Density (bulk): 0.93 g/cm3 
Density (tapped): 1.09 g/cm3 
Dielectric constant: 5.9 at 1MHz 
Freezing point depression: see Table III. 
Table III: Freezing point depression values of aqueous sodium 
chloride. 
Aqueous sodium chloride 
solution (% w/v) 
Freezing point depression (8C) 
11.69 6.90 
17.53 10.82 
23.38 15.14 
30.39 21.12 
Hardness (Mohs): 2–2.5 
Hygroscopicity: hygroscopic above 75% relative humidity. 
Melting point: 8048C 
Osmolarity: a 0.9% w/v aqueous solution is iso-osmotic with 
serum. 
Refractive index: nD
20 = 1.343 for a 1M aqueous solution. 
Solubility: see Table IV. 
Table IV: Solubility of sodium chloride. 
Solvent Solubility at 208C 
unless otherwise stated 
Ethanol Slightly soluble 
Ethanol (95%) 1 in 250 
Glycerin 1 in 10 
Water 1 in 2.8 
1 in 2.6 at 1008C 
Thermal conductivity: 1.15Wm/K at 273K 
Specific heat capacity: 854 J/kg/K 
Vapor pressure: 
133.3 Pa at 8658C for solid; 
1759.6 Pa at 208C for a saturated aqueous solution 
(equivalent to 75.3% relative humidity). 
Viscosity: a 10% w/v solution has a viscosity of 1.19 mPa s 
(1.19 cP). 
11 Stability and Storage Conditions 
Aqueous sodium chloride solutions are stable but may cause the 
separation of glass particles from certain types of glass 
containers. Aqueous solutions may be sterilized by autoclaving 
or filtration. The solid material is stable and should be stored in 
a well-closed container, in a cool, dry place. 
It has been shown that the compaction characteristics and 
the mechanical properties of tablets are influenced by the 
relative humidity of the storage conditions under which sodium 
chloride was stored.(21,22) 
672 Sodium Chloride

SEM: 3 
Excipient: Sodium chloride, granular 
Manufacturer: Van Waters & Rogers, Inc. 
Magnification: 600 
Figure 1: Compression characteristics of sodium chloride (cubic 
crystals).(3) Tablet diameter = 12 mm. 
12 Incompatibilities 
Aqueous sodium chloride solutions are corrosive to iron. They 
also react to form precipitates with silver, lead, and mercury 
salts. Strong oxidizing agents liberate chlorine from acidified 
solutions of sodium chloride. The solubility of the antimicrobial 
preservative methylparaben is decreased in aqueous 
sodium chloride solutions(23) and the viscosity of carbomer 
gels and solutions of hydroxyethyl cellulose or hydroxypropyl 
cellulose is reduced by the addition of sodium chloride. 
13 Method of Manufacture 
Sodium chloride occurs naturally as the mineral halite. 
Commercially, it is obtained by the solar evaporation of sea 
water, by mining, or by the evaporation of brine from 
underground salt deposits. 
14 Safety 
Sodium chloride is the most important salt in the body for 
maintaining the osmotic tension of blood and tissues. About 
5–12 g of sodium chloride is consumed daily, in the normal 
adult diet, and a corresponding amount is excreted in the urine. 
As an excipient, sodium chloride may be regarded as an 
essentially nontoxic and nonirritant material. However, toxic 
effects following the oral ingestion of 0.5–1.0 g/kg body-weight 
in adults may occur. The oral ingestion of larger quantities of 
sodium chloride, e.g. 1000 g in 600mL of water,(24) is harmful 
and can induce irritation of the gastrointestinal tract, vomiting, 
hypernatremia, respiratory distress, convulsions, or death. 
In rats, the minimum lethal intravenous dose is 2.5 g/kg 
body-weight. 
LD50 (mouse, IP): 6.61 g/kg(25) 
LD50 (mouse, IV): 0.65 g/kg 
LD50 (mouse, oral): 4.0 g/kg 
LD50 (mouse, SC): 3.0 g/kg 
LD50 (rat, oral): 3.0 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. If heated to high temperatures, 
sodium chloride evolves a vapor irritating to the eyes. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(injections; inhalations; nasal, ophthalmic, oral, otic, rectal, 
and topical preparations). Included in nonparenteral and 
parenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Potassium chloride. 
18 Comments 
Domestic table salt may contain sodium iodide (as a 
prophylactic substance against goiter) and agents such as 
magnesium carbonate, calcium phosphate, or starch, which 
reduce the hygroscopic characteristics of the salt and maintain 
the powder in a free-flowing state. 
Food-grade dendritic salt, which is porous, can be used as an 
absorbent for liquid medications, and as a tablet diluent in 
specific formulations. 
Each gram of sodium chloride represents approximately 
17.1 mmol of sodium and 17.1 mmol of chloride; 2.54 g of 
sodium chloride is approximately equivalent to 1 g of sodium. 
A saturated solution of sodium chloride can be used as a 
constant-humidity solution; at 258C, a relative humidity of 
75% is produced. A specification for sodium chloride is 
contained in the Food Chemicals Codex (FCC). 
The EINECS number for sodium chloride is 231-598-3. 
Sodium Chloride 673

19 Specific References 
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pharmaceutical materials. J Pharm Sci 1967; 56: 888–892. 
2 Rees JE, Shotton E. Some observations on the ageing of sodium 
chloride compacts. J Pharm Pharmacol 1970; 22: 17S–23S. 
3 Shotton E, Obiorah BA. The effect of particle shape and crystal 
habit on the properties of sodium chloride. J Pharm Pharmacol 
1973; 25: 37P–43P. 
4 Roberts RJ, Rowe RC, Kendall K. Brittle-ductile transitions in die 
compaction of sodium chloride. Chem Eng Sci 1989; 44: 1647– 
1651. 
5 Hammouda Y, Eshra AG, El-Banna HM. The use of sodium 
chloride as a directly compressible filler. Part III: Drug-to-filler 
ratio. Pharm Ind 1978; 40(9): 987–992. 
6 Gonza. lez-Rodriguez ML, Ferna.ndez-Herva. s MJ, Caraballo I, 
Rabasco AM. Design and evaluation of a new central core matrix 
tablet. Int J Pharm 1997; 146: 175–180. 
7 Korsatko-Wabnegg B. Development of press-coated tablets with 
controlled release effect using poly-D-(–)-3-hydroxybutyric acid [in 
German]. Pharmazie 1990; 45: 842–844. 
8 Moussa IS, Cartilier LH. Evaluation of crosslinked amylose presscoated 
tablets for sustained drug delivery. Int J Pharm 1997; 149: 
139–149. 
9 O. zdemir N, Sahin J. Design of a controlled release osmotic pump 
system of ibuprofen. Int J Pharm 1997; 158: 91–97. 
10 Shivanand P, Sprockel OL. A controlled porosity drug delivery 
system. Int J Pharm 1998; 167: 83–96. 
11 Tirkkonen S, Paronen P. Enhancement of drug release from 
ethylcellulose microcapsules using solid sodium chloride in the 
wall. Int J Pharm 1992; 88: 39–51. 
12 Tirkkonen S, Paronen P. Release of indomethacin from tabletted 
ethylcellulose microcapsules. Int J Pharm 1993; 92: 55–62. 
13 Yuasa H, Nakano T, Kanaya Y. Suppression of agglomeration in 
fluidized bed coating I. Suppression of agglomeration by adding 
sodium chloride. Int J Pharm 1997; 158: 195–201. 
14 Pandit NK,Wang D. Salt effects on the diffusion and release rate of 
propranolol from poloxamer 407 gels. Int J Pharm 1998; 167: 
183–189. 
15 Mishra B, Pandit JK. Multiple water-oil-water emulsions as 
prolonged release formulations of pentazocine. J Control Release 
1990; 14: 53–60. 
16 Shah D, Ecanow B, Balagot R. Coacervate formation by inorganic 
salts with benzalkonium chloride. J Pharm Sci 1973; 62: 1741– 
1742. 
17 Richard AJ. Ultracentrifugal study of effect of sodium chloride on 
micelle size of fusidate sodium. J Pharm Sci 1975; 64: 873–875. 
18 McDonald C, Richardson C. The effect of added salts on 
solubilization by a non-ionic surfactant. J Pharm Pharmacol 
1981; 33: 38–39. 
19 Mattha AG. Rheological studies on Plantago albicans (Psyllium) 
seed gum dispersions II: effect of some pharmaceutical additives. 
Pharm Acta Helv 1977; 52: 214–217. 
20 Okor RS. The effect of phenol on the electrolyte flocculation of 
certain polymeric dispersions to thixotropic gels. Pharm Res 1993; 
10: 220–222. 
21 Elamin AA, Alderborn G, Ahlneck C. The effect of pre-compaction 
processing and storage conditions on powder and compaction 
properties of some crystalline materials. Int J Pharm 1994; 108: 
213–224. 
22 Ahlneck C, Alderborn G. Moisure adsorption and tabletting. II. 
The effect on tensile strength and air permeability of the relative 
humidity during storage of tablets of 3 crystalline materials. Int J 
Pharm 1989; 56: 143–150. 
23 McDonald C, Lindstrom RE. The effect of urea on the solubility of 
methyl p-hydroxybenzoate in aqueous sodium chloride solution. J 
Pharm Pharmacol 1974; 26: 39–45. 
24 Calam J, Krasner N, Haqqani M. Extensive gastrointestinal 
damage following a saline emetic. Dig Dis Sci 1982; 27: 936–940. 
25 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3238–3239. 
20 General References 
Heng PW, Hao JS, Chan LW, Chen SH. Influence of osmotic agents in 
diffusion layer on drug release from multilayer coated pellets. Drug 
Dev Ind Pharm 2004; 30(2): 213–220. 
21 Authors 
SC Owen. 
22 Date of Revision 
8 June 2005. 
674 Sodium Chloride

Sodium Citrate Dihydrate 
1 Nonproprietary Names 
BP: Sodium citrate 
JP: Sodium citrate 
PhEur: Natrii citras 
USP: Sodium citrate 
2 Synonyms 
Citric acid trisodium salt; E331; sodium citrate tertiary; 
trisodium citrate. 
3 Chemical Name and CAS Registry Number 
Trisodium 2-hydroxypropane-1,2,3-tricarboxylate dihydrate 
[6132-04-3] 
4 Empirical Formula and Molecular Weight 
C6H5Na3O72H2O 294.10 
5 Structural Formula 
6 Functional Category 
Alkalizing agent; buffering agent; emulsifier; sequestering 
agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sodium citrate, as either the dihydrate or anhydrous material, is 
widely used in pharmaceutical formulations; see Table I. 
It is used in food products, primarily to adjust the pH of 
solutions. It is also used as a sequestering agent. The anhydrous 
material is used in effervescent tablet formulations.(1) Sodium 
citrate is additionally used as a blood anticoagulant either alone 
or in combination with other citrates such as disodium 
hydrogen citrate. 
Therapeutically, sodium citrate is used to relieve the painful 
irritation caused by cystitis, and also to treat dehydration and 
acidosis due to diarrhea; see Section 14. 
Table I: Uses of sodium citrate dihydrate. 
Use Concentration (%) 
Buffering agent 0.3–2.0 
Injections 0.02–4.0 
Ophthalmic solutions 0.1–2.0 
Sequestering agent 0.3–2.0 
8 Description 
Sodium citrate dihydrate consists of odorless, colorless, 
monoclinic crystals, or a white crystalline powder with a 
cooling, saline taste. It is slightly deliquescent in moist air, and 
in warm dry air it is efflorescent. Although most pharmacopeias 
specify that sodium citrate is the dihydrate, the USP 28 states 
that sodium citrate may be either the dihydrate or anhydrous 
material. 
9 Pharmacopeial Specifications 
See Table II. 
10 Typical Properties 
Acidity/alkalinity: pH = 7.0–9.0 (5% w/v aqueous solution) 
Density (bulk): 1.12 g/cm3 
Density (tapped): 0.99 g/cm3 
Density (true): 1.19 g/cm3 
Melting point: converts to the anhydrous form at 1508C. 
SEM: 1 
Excipient: Sodium citrate dihydrate (granular) 
Manufacturer: Pfizer Ltd 
Magnification: 60

SEM: 2 
Excipient: Sodium citrate dihydrate (granular) 
Manufacturer: Pfizer Ltd 
Magnification: 600 
Table II: Pharmacopeial specifications for sodium citrate dihydrate. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters — . — 
pH 7.5–8.5 — — 
Appearance of 
solution 
. . — 
Acidity or alkalinity . . . 
Loss on drying 10.0–13.0% — — 
Water — 11.0–13.0% 10.0–13.0% 
Oxalate . 4300 ppm — 
Sulfate 40.048% 4150 ppm — 
Heavy metals 410 ppm 410 ppm 40.001% 
Arsenic 42 ppm — — 
Chloride 40.015% 450 ppm — 
Tartrate . — . 
Readily carbonizable 
substances 
. . — 
Pyrogens — .(a) — 
Assay (anhydrous 
basis) 
599.0% 99.0–101.0% 99.0–100.5% 
(a) If intended for use in large-volume preparations for parenteral use, compliance with a test for 
pyrogens may be required. 
Osmolarity: a 3.02% w/v aqueous solution is iso-osmotic with 
serum. 
Particle size distribution: various grades of sodium citrate 
dihydrate with different particle sizes are commercially 
available. 
Solubility: soluble 1 in 1.5 of water, 1 in 0.6 of boiling water; 
practically insoluble in ethanol (95%). 
11 Stability and Storage Conditions 
Sodium citrate dihydrate is a stable material. Aqueous solutions 
may be sterilized by autoclaving. On storage, aqueous solutions 
may cause the separation of small, solid particles from glass 
containers. 
The bulk material should be stored in an airtight container 
in a cool, dry place. 
12 Incompatibilities 
Aqueous solutions are slightly alkaline and will react with 
acidic substances. Alkaloidal salts may be precipitated from 
their aqueous or hydro-alcohol solutions. Calcium and 
strontium salts will cause precipitation of the corresponding 
citrates. Other incompatibilities include bases, reducing agents, 
and oxidizing agents. 
13 Method of Manufacture 
Sodium citrate is prepared by adding sodium carbonate to a 
solution of citric acid until effervescence ceases. The resulting 
solution is filtered and evaporated to dryness. 
14 Safety 
After ingestion, sodium citrate is absorbed and metabolized to 
bicarbonate. Although it is generally regarded as a nontoxic 
and nonirritant excipient, excessive consumption may cause 
gastrointestinal discomfort or diarrhea. Therapeutically, in 
adults, up to 15 g daily of sodium citrate dihydrate may be 
administered orally, in divided doses, as an aqueous solution to 
relieve the painful irritation caused by cystitis. 
Citrates and citric acid enhance intestinal aluminum 
absorption in renal patients, which may lead to increased, 
harmful serum aluminum levels. It has therefore been suggested 
that patients with renal failure taking aluminum compounds to 
control phosphate absorption should not be prescribed citrateor 
citric acid-containing products.(2) 
See Section 17 for anhydrous sodium citrate animal toxicity 
data. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Sodium citrate dihydrate dust 
may be irritant to the eyes and respiratory tract. Eye protection 
and gloves are recommended. Sodium citrate should be handled 
in a well-ventilated environment or a dust mask should be 
worn. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (inhalations, 
injections, ophthalmic products, oral solutions, suspensions, 
syrups and tablets, nasal, otic, rectal, topical, transdermal, and 
vaginal preparations). Included in nonparenteral and parenteral 
medicines licensed in the UK. Included in the Canadian List 
of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Anhydrous sodium citrate; citric acid monohydrate. 
676 Sodium Citrate Dihydrate

Anhydrous sodium citrate 
Empirical formula: C6H5Na3O7 
Molecular weight: 258.07 
CAS number: [68-04-2] 
Synonyms: anhydrous trisodium citrate; citric acid trisodium 
salt anhydrous; trisodium 2-hydroxy-1,2,3-propanetricarboxylic 
acid. 
Appearance: colorless crystals or a white crystalline powder. 
Safety:
LD50 (mouse, IP): 1.36 g/kg(3) 
LD50 (mouse, IV): 0.17 g/kg 
LD50 (rabbit, IV): 0.45 g/kg 
LD50 (rat, IP): 1.55 g/kg 
18 Comments 
Each gram of sodium citrate dihydrate represents approximately 
10.2 mmol of sodium and 3.4 mmol of citrate. Each 
gram of anhydrous sodium citrate represents approximately 
11.6 mmol of sodium and 3.9 mmol of citrate. 
The EINECS number for sodium citrate is 200-675-3. 
19 Specific References 
1 Anderson NR, Banker GS, Peck GE. Quantitative evaluation of 
pharmaceutical effervescent systems II: stability monitoring of 
reactivity and porosity measurements. J Pharm Sci 1982; 71: 7–13. 
2 Main J, Ward MK. Potentiation of aluminum absorption by 
effervescent analgesic tablets in a haemodialysis patient. Br Med J 
1992; 304: 1686. 
3 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2572. 
20 General References 
—
21 Authors 
GE Amidon. 
22 Date of Revision 
19 August 2005. 
Sodium Citrate Dihydrate 677

Sodium Cyclamate 
1 Nonproprietary Names 
BP: Sodium cyclamate 
PhEur: Natrii cyclamas 
2 Synonyms 
Cyclohexylsulfamic acid monosodium salt; E952; sodium 
cyclohexanesulfamate. 
3 Chemical Name and CAS Registry Number 
Sodium N-cyclohexylsulfamate [139-05-9] 
4 Empirical Formula and Molecular Weight 
C6H12NNaO3S 201.22 
5 Structural Formula 
6 Functional Category 
Sweetening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sodium cyclamate is used as an intense sweetening agent in 
pharmaceutical formulations, foods, beverages, and table-top 
sweeteners. In dilute solution, up to about 0.17% w/v, the 
sweetening power is approximately 30 times that of sucrose. 
However, at higher concentrations this is reduced and at a 
concentration of 0.5% w/v a bitter taste becomes noticeable. 
Sodium cyclamate enhances flavor systems and can be used to 
mask some unpleasant taste characteristics. In most applications, 
sodium cyclamate is used in combination with saccharin. 
8 Description 
Sodium cyclamate occurs as white, odorless or almost odorless 
crystals or as a crystalline powder with an intensely sweet taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for sodium cyclamate. 
Test PhEur 2005 
Identification . 
Characters . 
Appearance of solution . 
pH (10% w/v aqueous solution) 5.5–7.5 
Absorbance at 270 nm 40.10 
Sulfamic acid . 
Aniline 41 ppm 
Cyclohexylamine 410 ppm 
Dicyclohexylamine 41 ppm 
Sulfates 40.1% 
Heavy metals 410 ppm 
Loss on drying 41.0% 
Assay (dried basis) 98.5–101.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 5.5–7.5 for a 10% w/v aqueous 
solution. 
Solubility: see Table II. 
Table II: Solubility of sodium cyclamate. 
Solvent Solubility at 208C 
unless otherwise stated 
Benzene Practically insoluble 
Chloroform Practically insoluble 
Ethanol (95%) 1 in 250 
Ether Practically insoluble 
Propylene glycol 1 in 25 
Water 1 in 5 
1 in 2 at 458C 
11 Stability and Storage Conditions 
Sodium cyclamate is hydrolyzed by sulfuric acid and cyclohexylamine 
at a very slow rate that is proportional to the 
hydrogen ion concentration. Therefore, for all practical 
considerations, it can be regarded as stable. Solutions are also 
stable to heat, light, and air over a wide pH range. 
Samples of tablets containing sodium cyclamate and 
saccharin have shown no loss in sweetening power following 
storage for up to 20 years. 
The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
—
13 Method of Manufacture 
Cyclamates are prepared by the sulfonation of cyclohexylamine 
in the presence of a base. Commercially, the sulfonation can

involve sulfamic acid, a sulfate salt, or sulfur trioxide. Tertiary 
bases such as triethylamine or trimethylamine may be used as 
the condensing agent. The amine salts of cyclamate that are 
produced are converted to the sodium, calcium, potassium, or 
magnesium salt by treatment with the appropriate metal oxide. 
14 Safety 
There has been considerable controversy concerning the safety 
of cyclamate following the FDA decision in 1970 to ban its use 
in the USA.(1–3) This decision resulted from a feeding study in 
rats that suggested that cyclamate could cause an unusual form 
of bladder cancer. However, that study has been criticized 
because it involved very high doses of cyclamate administered 
with saccharin, which has itself been the subject of controversy 
concerning its safety; see Saccharin. Although excreted almost 
entirely unchanged in the urine, a potentially harmful 
metabolite of sodium cyclamate, cyclohexylamine, has been 
detected in humans.(4) 
Extensive long-term animal feeding studies and epidemiological 
studies in humans have failed to show any evidence that 
cyclamate is carcinogenic or mutagenic.(5,6) As a result, sodium 
cyclamate is now accepted in many countries for use in foods 
and pharmaceutical formulations. See also Section 16. 
Few adverse reactions to cyclamate have been reported, 
although its use has been associated with instances of 
photosensitive dermatitis.(7) 
The WHO has set an estimated acceptable daily intake for 
sodium and calcium cyclamate, expressed as cyclamic acid, at 
up to 11 mg/kg body-weight.(8) In Europe, a temporary 
acceptable daily intake for sodium and calcium cyclamate, 
expressed as cyclamic acid, has been set at up to 1.5 mg/kg 
body-weight. 
LD50 (mouse, IP): 1.15 g/kg(9) 
LD50 (mouse, IV): 4.8 g/kg 
LD50 (mouse, oral): 17 g/kg 
LD50 (rat, IP): 1.35 g/kg 
LD50 (rat, IV): 3.5 g/kg 
LD50 (rat, oral): 15.25 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection is recommended. 
16 Regulatory Status 
The use of cyclamates as artificial sweetners in food, soft 
drinks, and artificial sweetening tablets was at one time 
prohibited in the UK and some other countries owing to 
concern about the metabolite cyclohexylamine. However, this is 
no longer the case, and cyclamates are now permitted for use as 
a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral 
powder, solutions and suspensions). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Alitame; calcium cyclamate; cyclamic acid. 
Calcium cyclamate 
Empirical formula: C12H24CaN2O6S22H2O 
Molecular weight: 432.57 
CAS number: 
[5897-16-5] for the dihydrate; 
[139-06-0] for the anhydrous form. 
Synonyms: calcium N-cyclohexylsulfamate dihydrate; Cyclan; 
cyclohexanesulfamic acid calcium salt; cyclohexylsulfamic 
acid calcium salt; E952; Sucaryl calcium. 
Appearance: white, odorless or almost odorless crystals or a 
crystalline powder with an intensely sweet taste. 
Acidity/alkalinity: pH = 5.5–7.5 for a 10% w/v aqueous 
solution. 
Solubility: freely soluble in water; practically insoluble in 
benzene, chloroform, ethanol (95%), and ether. 
Cyclamic acid 
Empirical formula: C6H13NO3S 
Molecular weight: 179.23 
CAS number: [100-88-9] 
Synonyms: cyclamate; cyclohexanesulfamic acid; N-cyclohexylsulfamic 
acid; E952; hexamic acid; Sucaryl. 
Appearance: white, odorless or almost odorless crystals or a 
crystalline powder with an intensely sweet taste. 
Melting point: 169–1708C 
Solubility: slightly soluble in water. 
18 Comments 
The perceived intensity of sweeteners relative to sucrose 
depends upon their concentration, temperature of tasting, and 
pH, and on the flavor and texture of the product concerned. 
Intense sweetening agents will not replace the bulk, textural, 
or preservative characteristics of sucrose if sucrose is removed 
from a formulation. 
Synergistic effects for combinations of sweeteners have been 
reported, e.g., sodium cyclamate with saccharin sodium or 
acesulfame potassium. 
Sodium cyclamate has also been used to increase the 
solubility of neohesperidin dihydrochalcone in sweetener 
blends.(10) 
19 Specific References 
1 Nabors LO, Miller WT. Cyclamate: a toxicological review. 
Commen Toxicol 1989; 3(4): 307–315. 
2 Lecos C. The sweet and sour history of saccharin, cyclamate and 
aspartame. FDA Consumer 1981; 15(7): 8–11. 
3 Anonymous. Cyclamate alone not a carcinogen. Am Pharm 1985; 
NS25(9): 11. 
4 Kojima S, Ichibagase H. Studies on synthetic sweetening agents 
VIII. Cyclohexylamine, a metabolite of sodium cyclamate. Chem 
Pharm Bull 1966; 14: 971–974. 
5 D’Arcy PF. Adverse reactions to excipients in pharmaceutical 
formulations. In: Florence AT, Salole EG, eds. Formulation Factors 
in Adverse Reactions. London: Wright, 1990: 1–22. 
6 Schma. hl D, Habs M. Investigations on the carcinogenicity of the 
artificial sweeteners sodium cyclamate and sodium saccharin in 
rats in a two-generation experiment. Arzneimittelforschung 1984; 
34: 604–606. 
7 Yong JM, Sanderson KV. Photosensitive dermatitis and renal 
tubular acidosis after ingestion of calcium cyclamate. Lancet 1969; 
ii: 1273–1274. 
8 FAO/WHO. Evaluation of certain food additives and contaminants. 
Twenty-sixth report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1982; No. 683. 
9 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3243. 
Sodium Cyclamate 679

10 Benavente-Garcia O, Castillo J, Del Bano MJ, Lorente J. Improved 
water solubility of neohesperidin dihydrochalcone in sweetener 
blends. J Agric Food Chem 2001; 49(1): 189–191. 
20 General References 
Anonymous. Saccharin is safe. Chem Br 2001; 37(4): 18. 
Schiffman SS, Sattely-Miller EA, Graham BG, et al. Effect of 
temperature, pH, and ions on sweet taste. Physiol Behav 2000; 
68(4): 469–481. 
21 Authors 
SC Owen. 
22 Date of Revision 
11 August 2005. 
680 Sodium Cyclamate

Sodium Hyaluronate 
1 Nonproprietary Names 
BP: Sodium hyaluronate 
PhEur: Natrii hyaluronas 
2 Synonyms 
Hyaluronan; hyaluronate sodium; RITA HA C-1-C. 
3 Chemical Name and CAS Registry Number 
Sodium hyaluronate [9067-32-7] 
4 Empirical Formula and Molecular Weight 
(C14H20NO11Na)n (401.3)n 
5 Structural Formula 
6 Functional Category 
Humectant; lubricant; matrix for sustained release. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sodium hyaluronate is the predominant form of hyaluronic 
acid at physiological pH. The name hyaluronan is used when 
the polysaccharide is mentioned in general terms, and in the 
literature the terms hyaluronic acid and sodium hyaluronate 
are used interchangeably. 
Hyaluronan is used therapeutically to treat osteoarthritis in 
the knee, and is an effective treatment for arthritic pain.(1) 
Crosslinked hyaluronan gels are used as drug delivery 
systems.(2) 
Hyaluronan is the most common negatively charged 
glycosaminoglycan in the human vitreous humor, and is known 
to interact with polymeric and liposomal DNA complexes,(3) 
where hyaluronan solutions have been shown to decrease the 
cellular uptake of complexes.(4) This is useful for enhancing the 
availability and retention time of drugs administered to the eye. 
It is immunoneutral, which makes it useful for the attachment 
of biomaterials for use in tissue engineering and drug delivery 
systems;(5) it also has important applications in the fields of 
vascosurgery and vascosupplementation.(6) 
8 Description 
The PhEur 2005 describes sodium hyaluronate as the sodium 
salt of hyaluronic acid, a glycosaminoglycan consisting of Dglucuronic 
acid andN-acetyl-D-glucosamine disaccharide units. 
Sodium hyaluronate occurs as white to off-white powder or 
granules. It is very hygroscopic. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specification for sodium hyaluronate. 
Test PhEur 2005 
Characters . 
Identification . 
Appearance of solution . 
pH 5.0–8.5 
Intrinsic viscosity . 
Sulfated glycosaminoglycans 41% 
Nucleic acids 40.5 
Protein 40.3%(a) 
Chlorides 40.5% 
Iron 480 ppm 
Loss on drying 420.0% 
Microbial contamination 4102/g 
Bacterial endotoxins 40.05 IU/mg(b) 
Assay 95.0–105.0% 
(a)<0.1% for parenteral dosage forms. 
(b)40.5 IU/mg for parenteral dosage forms. 
10 Typical Properties 
Acidity/alkalinity: pH = 5.0–8.5 (0.5% w/v aqueous solution) 
Solubility: soluble in water, although speed of dissolution 
depends upon molecular weight (higher molecular weights 
are slower to dissolve, although this process can be increased 
by gentle agitation). Slightly soluble in mixtures of organic 
solvents with water.(7) 
11 Stability and Storage Conditions 
Sodium hyaluronate should be stored in a cool, dry place in 
tightly sealed containers. The powder is stable for three years if 
stored in unopened containers. 
12 Incompatibilities 
—

13 Method of Manufacture 
Sodium hyaluronate occurs naturally in vitreous humor, serum, 
chicken combs, shark skin, and whale cartilage; it is usually 
extracted and purified from chicken combs. It may also be 
manufactured by fermentation of selected Streptococcus 
zooepidemicus bacterial strains; sodium hyaluronate is 
removed from the fermentation medium by filtration and 
purified by ultrafiltration. It is then precipitated with an organic 
solvent and dried. 
14 Safety 
Sodium hyaluronate is used in cosmetics and in topical, 
parenteral, and ophthalmic pharmaceutical formulations. It is 
generally regarded as a relatively nontoxic and nonirritant 
material. Sodium hyaluronate has been reported to be an 
experimental teratogen.(8) 
LD50 (mouse, IP): 1.5 g/kg(8) 
LD50 (rabbit, IP): 1.82 g/kg 
LD50 (rat, IP): 1.77 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. When heated to decomposition, 
sodium hyaluronate emits toxic fumes of Na2O. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (topical gel 
preparation). 
17 Related Substances 
Hyaluronic acid. 
Hyaluronic acid 
Molecular weight: hyaluronic acid molecules have a molecular 
weight of 300–2000 kDa as the number of repeating 
disaccharide units in each molecule is variable. In its natural 
form, hyaluronic acid exists as a high-molecular-weight 
polymer of 106–107 Da. 
CAS number: [9067-32-7] 
Appearance: hyaluronic acid appears as a white to off-white 
powder or granules. 
Comments: hyaluronic acid is used as an adjuvant for 
ophthalmic drug delivery,(9) and has been found to enhance 
the absorption of drugs and proteins via mucosal tissue.(10) 
It has also been used experimentally in controlled-release 
films that are suitable for application to surgical sites for the 
prevention of adhesion formation,(11) and in matrix 
formulations used in gene delivery systems.(12) The EINECS 
number for hyaluronic acid is 232-678-0. 
18 Comments 
Microspheres prepared from hyaluronan esters have been 
evaluated for the vaginal administration of calcitonin in the 
treatment of postmenopausal osteoporosis.(13) Microspheres 
prepared from hyaluronan esters have also been used experimentally 
as delivery devices for nerve growth factors,(14) and as 
a nasal delivery system for insulin.(15) 
An N-(2-hydroxypropyl)methacrylamide (HPMA)–hyaluronan 
polymeric drug delivery system has been used for the 
targeted delivery of doxorubicin to cancer cells. This copolymer 
exhibited increased toxicity due to hyaluronan receptormediated 
uptake of the macromolecular drug.(16) 
The EINECS number for sodium hyaluronate is232-678-0. 
19 Specific References 
1 Castellacci E, Polieri T. Antalgesic effect and clinical tolerability of 
hyaluronic acid in patients with degenerative diseases of knee 
cartilage: an outpatient treatment survey. Drugs Exp Clin Res 
2004; 30(2): 67–73. 
2 Dehayza P, Cheng L. Sodium hyaluronate microspheres. US Patent 
No. 2,004,127,459; 2004. 
3 Pitka.nen L, Ruponen M, Nieminen J, Urtti A. Vitreous is a barrier 
in nonviral gene transfer by cationic lipids and polymers. Pharm 
Res 2003; 20(4): 576–583. 
4 Ruponen M, Yla. -Herttuala S, Urtti A. Interactions of polymeric 
and liposomal gene delivery systems with extracellular glycosaminoglycans: 
physicochemical and transfection studies. Biochim 
Biophys Acta 1999; 1415: 331–341. 
5 Vercruysse KP, Prestwich GD. Hyaluronate derivatives in drug 
delivery. Crit Rev Ther Carrier Syst 1998; 15: 513–555. 
6 Balazs EA, Denlinger JL. Clinical uses of hyaluronan. In: Evered D, 
Whelan J, eds: The Biology of Hyaluronan. Chichester: Wiley, 
1989: 265–280. 
7 ContiproCa.s. Sodium hyaluronate. http://www.cpn-contipro.com 
(accessed 26 May 2005). 
8 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1970. 
9 Saettone MF, Monti D,Tarracca MT, Chetoni P. Mucoadhesive 
ophthalmic vehicles: evaluation of polymeric low-viscosity formulations. 
J Ocul Pharm 1994; 10: 83–92. 
10 Cho KY, Chung TW, Kim BC, et al. Release of ciprofloxacin from 
polymer-graft-hyaluronic acid hydrogels in vitro. Int J Pharm 
2003; 260(1): 83–91. 
11 Jackson JK, Skinner KC, Burgess L, et al. Paclitaxel-loaded 
crosslinked hyaluronic acid films for the prevention of postsurgical 
adhesions. Pharm Res 2002; 19(4): 411–417. 
12 Kim A, Checkla DM, Dehazya P, et al. Characterization of DNAhyaluronan 
matrix for sustained gene transfer. J Control Release 
2003; 90(1): 81–75. 
13 Rochira M, Miglietta MR, Richardson JL, et al. Novel vaginal 
delivery systems for calcitonin II. Preparation and characterisation 
of HYAFF1 microspheres containing calcitonin. Int J Pharm 1996; 
144: 19–26. 
14 Ghezzo E, Beredetti LM, Rochira M, et al. Hyaluronan derivative 
microspheres as NGF delivery devices: preparation methods and in 
vitro release characterization. Int J Pharm 1992; 29: 133–141. 
15 Illum L, Farray NF, Fisher AN, et al. Hyaluronic acid ester 
microspheres as a nasal delivery system for insulin. J Control 
Release 1994; 29: 133–141. 
16 Luo Y, Bernshaw NJ, Lu ZR, et al. Targetted delivery of 
doxorubicin by HPMA copolymer–hyaluronan bioconjugates. 
Pharm Res 2002; 19(4): 396–402. 
20 General References 
—
21 Authors 
SC Owen. 
22 Date of Revision 
26 May 2005. 
682 Sodium Hyaluronate

Sodium Hydroxide 
1 Nonproprietary Names 
BP: Sodium hydroxide 
JP: Sodium hydroxide 
PhEur: Natrii hydroxidum 
USPNF: Sodium hydroxide 
2 Synonyms 
Caustic soda; E524; lye; soda lye; sodium hydrate. 
3 Chemical Name and CAS Registry Number 
Sodium hydroxide [1310-73-2] 
4 Empirical Formula and Molecular Weight 
NaOH 40.00 
5 Structural Formula 
NaOH 
6 Functional Category 
Alkalizing agent; buffering agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sodium hydroxide is widely used in pharmaceutical formulations 
to adjust the pH of solutions.(1) It can also be used to react 
with weak acids to form salts. 
8 Description 
Sodium hydroxide occurs as a white or nearly white fused mass. 
It is available in small pellets, flakes, sticks, and other shapes or 
forms. It is hard and brittle and shows a crystalline fracture. 
Sodium hydroxide is very deliquescent and on exposure to air it 
rapidly absorbs carbon dioxide and water. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for sodium hydroxide. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters — . — 
Appearance of 
solution 
. . — 
Insoluble substances 
and organic matter 
— — . 
Sodium carbonate 42.0% 42.0% — 
Sulfates — 450 ppm — 
Chlorides 40.05% 450 ppm — 
Iron — 410 ppm — 
Mercury . — — 
Heavy metals 430 ppm 420 ppm 40.003% 
Potassium . — . 
Assay (total alkali 
calculated as 
NaOH) 
595.0% 97.0–100.5% 95.0–100.5% 
10 Typical Properties 
Acidity/alkalinity: 
pH  12 (0.05% w/w aqueous solution); 
pH  13 (0.5% w/w aqueous solution); 
pH  14 (5% w/w aqueous solution). 
Melting point: 3188C 
Solubility: see Table II. 
Table II: Solubility of sodium hydroxide. 
Solvent Solubility at 208C 
unless otherwise stated 
Ethanol 1 in 7.2 
Ether Practically insoluble 
Glycerin Soluble 
Methanol 1 in 4.2 
Water 1 in 0.9 
1 in 0.3 at 1008C 
11 Stability and Storage Conditions 
Sodium hydroxide should be stored in an airtight nonmetallic 
container in a cool, dry place. When exposed to air, sodium 
hydroxide rapidly absorbs moisture and liquefies, but subsequently 
becomes solid again owing to absorption of carbon 
dioxide and formation of sodium carbonate. 
12 Incompatibilities 
Sodium hydroxide is a strong base and is incompatible with any 
compound that readily undergoes hydrolysis or oxidation. It 
will react with acids, esters, and ethers, especially in aqueous 
solution.

13 Method of Manufacture 
Sodium hydroxide is manufactured by electrolysis of brine 
using inert electrodes. Chlorine is evolved as a gas at the anode 
and hydrogen is evolved as a gas at the cathode. The removal of 
chloride and hydrogen ions leaves sodium and hydroxide ions 
in solution. The solution is dried to produce the solid sodium 
hydroxide. 
A second method uses the Kellner–Solvay cell. Saturated 
sodium chloride solution is electrolyzed between a carbon 
anode and a flowing mercury cathode. In this case the sodium is 
produced at the cathode rather than the hydrogen because of 
the readiness of sodium to dissolve in the mercury. The sodium– 
mercury amalgam is then exposed to water and a sodium 
hydroxide solution is produced. 
14 Safety 
Sodium hydroxide is widely used in the pharmaceutical and 
food industries and is generally regarded as a nontoxic material 
at low concentrations. At high concentrations it is a corrosive 
irritant to the skin, eyes, and mucous membranes. 
LD50 (mouse, IP): 0.04 g/kg(2) 
LD50 (rabbit, oral): 0.5 g/kg 
15 Handling Precautions 
Observe normal handling precautions appropriate to the 
quantity and concentration of material handled. Gloves, eye 
protection, a respirator, and other protective clothing should be 
worn. 
Sodium hydroxide is a corrosive irritant to the skin, eyes, 
and mucous membranes. The solid and solutions cause burns, 
often with deep ulceration. It is moderately toxic on ingestion 
and harmful on inhalation. 
In the UK, the occupational exposure limit for sodium 
hydroxide has been set at 2 mg/m3 short-term.(3) 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (dental 
preparations; injections; inhalations; nasal, ophthalmic, oral, 
otic, rectal, topical, and vaginal preparations). Included in 
nonparenteral and parenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Potassium hydroxide. 
18 Comments 
Sodium hydroxide is most commonly used in solutions of fixed 
concentration. Sodium hydroxide has some antibacterial and 
antiviral properties and is used as a disinfectant in some 
applications.(4–6) A specification for sodium hydroxide is 
contained in the Food Chemicals Codex (FCC). 
The EINECS number for sodium hydroxide is 215-185-5. 
19 Specific References 
1 Zhan X, Yin G, Ma B. Improved stability of 25% vitamin C 
parenteral formulation. Int J Pharm 1998; 173: 43–49. 
2 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3254–3255. 
3 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002, Sudbury: Health and Safety Executive, 2002. 
4 Brown P, Rohmer RG, Gajduseck DC. Sodium hydroxide 
decontamination of Creutzfeldt–Jakob disease virus. N Engl J 
Med 1984; 320: 727. 
5 Gasser G. Creutzfeldt–Jakob disease [letter]. Br Med J 1990; 300: 
1523. 
6 Perkowski CA. Operational aspects of bioreactor contamination 
control. J Parenter Sci Technol 1990; 44: 113–117. 
20 General References 
—
21 Authors 
AH Kibbe. 
22 Date of Revision 
12 August 2005. 
684 Sodium Hydroxide

Sodium Lactate 
1 Nonproprietary Names 
BP: Sodium lactate solution 
PhEur: Natrii lactatis solutio 
USP: Sodium lactate solution 
2 Synonyms 
E325; 2-hydroxypropanoic acid monosodium salt; Lacolin; 
lactic acid monosodium salt; lactic acid sodium salt; sodium 
a-hydroxypropionate. 
3 Chemical Name and CAS Registry Number 
Sodium lactate [72-17-3] 
4 Empirical Formula and Molecular Weight 
C3H5NaO3 112.06 
5 Structural Formula 
The PhEur 2005 and USP 28 describe sodium lactate solution 
as a mixture of the enantiomers of sodium 2-hydroxypropanoate 
in approximately equal proportions. 
6 Functional Category 
Antimicrobial preservative; buffering agent; emulsifying agent; 
flavoring agent; humectant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sodium lactate is widely used in cosmetics,(1,2) food products 
and pharmaceutical applications including parenteral and 
topical formulations. 
Therapeutically, sodium lactate is used in infusions as a 
component of Ringer-lactate solution; as an alternative for 
sodium hydrogencarbonate in light acidosis; as a rehydrating 
agent; and as a carrier for electrolyte concentrates or medicines 
in perfusion/infusion solutions. 
8 Description 
Sodium lactate occurs as a clear, colorless, slightly syrupy 
liquid. It is odorless, or has a slight odor with a characteristic 
saline taste. It is hygroscopic. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for sodium lactate. 
Test PhEur 2005 USP 28 
Characters . — 
Identification . . 
Appearance of solution . — 
pH 6.5–9.0 5.0–9.0 
Reducing sugars and sucrose . . 
Methanol 450 ppm(a) . 
Chlorides 450 ppm 40.05% 
Oxalates and phosphates . . 
Sulfates 4100 ppm . 
Aluminum 40.1 ppm(a) — 
Barium . — 
Iron 410 ppm — 
Heavy metals 410 ppm 40.001% 
Bacterial endotoxins .(b) — 
Assay 96.0–104.0% 98.0–102.0% 
(a) If intended for use in the manufacture of parenteral dosage forms, hemodialysis, or 
hemofiltration solutions. 
(b) If intended for use in the manufacture of parenteral dosage forms without a further 
appropriate procedure for the removal of bacterial endotoxins. 
10 Typical Properties 
Acidity/alkalinity: pH = 7 for an aqueous solution. 
Boiling point: 1128C 
Hygroscopicity: very hygroscopic. 
Melting point: 178C with decomposition at 1408C. 
Solubility: miscible with ethanol (95%), and with water. 
Specific gravity: 1.311.34 
11 Stability and Storage Conditions 
Sodium lactate should be stored in a well-closed container in a 
cool, dry, place. Sodium lactate is combustible and decomposes 
upon heating. 
12 Incompatibilities 
See Lactic Acid. 
13 Method of Manufacture 
See Lactic Acid. 
14 Safety 
Sodium lactate occurs naturally in the body and is involved in 
physiological processes. It is generally regarded as a relatively 
nontoxic and nonirritant material when used as an excipient. 
Low concentrations are well tolerated by skin and eye mucosa, 
although higher concentrations should be avoided. 
LD50 (rat, IP): 2 g/kg(3) 
Sodium Lactate 685

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Sodium lactate may cause eye 
irritation. When heated to decomposition, sodium lactate emits 
toxic fumes of Na2O.(3) 
16 Regulatory Status 
GRAS listed (not for infant formulas). Included in the FDA 
Inactive Ingredient Guide (epidural, IM, IV, and SC injections; 
oral suspensions; topical gels and solutions). Included in 
nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Lactic Acid. 
18 Comments 
Generally, the commercially available product is a mixture with 
water containing 70–80% sodium lactate. The EINECS 
number for sodium lactate is 200-772-0. 
19 Specific References 
1 Suomela A, Kristoffersson E. Dry skin and moisturizing agents. 
Acta Pharm Fenn 1983; 92(2): 67–76. 
2 Middleton JD. Sodium lactate as a moisturizer. Cosmet Toiletries 
1978; 93(Mar): 85–86. 
3 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2197–2198. 
20 General References 
—
21 Authors 
HJ de Jong. 
22 Date of Revision 
17 August 2005. 
686 Sodium Lactate

Sodium Lauryl Sulfate 
1 Nonproprietary Names 
BP: Sodium lauryl sulfate 
JP: Sodium lauryl sulfate 
PhEur: Natrii laurilsulfas 
USPNF: Sodium lauryl sulfate 
2 Synonyms 
Dodecyl sodium sulfate; Elfan 240; sodium dodecyl sulfate; 
sodium laurilsulfate; sodium monododecyl sulfate; sodium 
monolauryl sulfate; Texapon K12P. 
3 Chemical Name and CAS Registry Number 
Sulfuric acid monododecyl ester sodium salt [151-21-3] 
4 Empirical Formula and Molecular Weight 
C12H25NaO4S 288.38 
The USPNF 23 describes sodium lauryl sulfate as a mixture 
of sodium alkyl sulfates consisting chiefly of sodium lauryl 
sulfate (C12H25NaO4S). The PhEur 2005 states that sodium 
lauryl sulfate should contain not less than 85% of sodium alkyl 
sulfates calculated as C12H25NaO4S. 
5 Structural Formula 
6 Functional Category 
Anionic surfactant; detergent; emulsifying agent; skin penetrant; 
tablet and capsule lubricant; wetting agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sodium lauryl sulfate is an anionic surfactant employed in a 
wide range of nonparenteral pharmaceutical formulations and 
cosmetics; see Table I. 
It is a detergent and wetting agent effective in both alkaline 
and acidic conditions. In recent years it has found application in 
analytical electrophoretic techniques: SDS (sodium dodecyl 
sulfate) polyacrylamide gel electrophoresis is one of the more 
widely used techniques for the analysis of proteins;(1) and 
sodium lauryl sulfate has been used to enhance the selectivity of 
micellar electrokinetic chromatography (MEKC).(2) 
Table I: Uses of sodium lauryl sulfate. 
Use Concentration (%) 
Anionic emulsifier, forms self-emulsifying bases with 
fatty alcohols 
0.5–2.5 
Detergent in medicated shampoos 10 
Skin cleanser in topical applications 1 
Solubilizer in concentrations greater than critical 
micelle concentration 
>0.0025 
Tablet lubricant 1.0–2.0 
Wetting agent in dentrifices 1.0–2.0 
SEM: 1 
Excipient: Sodium lauryl sulfate 
Manufacturer: Canadian Alcolac Ltd. 
Magnification: 120 
8 Description 
Sodium lauryl sulfate consists of white or cream to pale yellowcolored 
crystals, flakes, or powder having a smooth feel, a 
soapy, bitter taste, and a faint odor of fatty substances. 
9 Pharmacopeial Specifications 
See Table II. 
10 Typical Properties 
Acidity/alkalinity: pH = 7.0–9.5 (1% w/v aqueous solution) 
Acid value: 0 
Antimicrobial activity: sodium lauryl sulfate has some bacteriostatic 
action against Gram-positive bacteria but is

ineffective against many Gram-negative microorganisms. It 
potentiates the fungicidal activity of certain substances such 
as sulfanilamide and sulfathiazole. 
Critical micelle concentration: 8.2 mmol/L (0.23 g/L) at 208C 
Density: 1.07 g/cm3 at 208C 
HLB value: 40 
Interfacial tension: 11.8mN/m (11.8 dynes/cm) for a 0.05% 
w/v solution (unspecified nonaqueous liquid) at 308C. 
Melting point: 204–2078C (for pure substance) 
Moisture content: 45%; sodium lauryl sulfate is not hygroscopic. 
Solubility: freely soluble in water, giving an opalescent solution; 
practically insoluble in chloroform and ether. 
Spreading coefficient: 7.0 (0.05% w/v aqueous solution) at 
308C 
Surface tension: 25.2mN/m (25.2 dynes/cm) for a 0.05% w/v 
aqueous solution at 308C 
Wetting time (Draize test): 118 seconds (0.05% w/v aqueous 
solution) at 308C 
SEM: 2 
Excipient: Sodium lauryl sulfate 
Manufacturer: Canadian Alcolac Ltd. 
Magnification: 600 
Table II: Pharmacopeial specifications for sodium lauryl sulfate. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Alkalinity . . . 
Heavy metals — — 40.002% 
Sodium chloride 48.0% . . 
Sodium sulfate . . . 
Unsulfated alcohols 44.0% — 44.0% 
Nonesterified alcohols — 44.0% — 
Total alcohols 559.0% — 559.0% 
Organic volatile impurities — — . 
Water 45.0% — — 
Assay (as C12H25NaO4S) — 585.0% — 
11 Stability and Storage Conditions 
Sodium lauryl sulfate is stable under normal storage conditions. 
However, in solution, under extreme conditions, i.e., pH 2.5 or 
below, it undergoes hydrolysis to lauryl alcohol and sodium 
bisulfate. 
The bulk material should be stored in a well-closed 
container away from strong oxidizing agents in a cool, dry 
place. 
12 Incompatibilities 
Sodium lauryl sulfate reacts with cationic surfactants, causing 
loss of activity even in concentrations too low to cause 
precipitation. Unlike soaps, it is compatible with dilute acids 
and calcium and magnesium ions. 
Solutions of sodium lauryl sulfate (pH 9.5–10.0) are mildly 
corrosive to mild steel, copper, brass, bronze, and aluminum. 
Sodium lauryl sulfate is also incompatible with some alkaloidal 
salts and precipitates with lead and potassium salts. 
13 Method of Manufacture 
Sodium lauryl sulfate is prepared by sulfation of lauryl alcohol, 
followed by neutralization with sodium carbonate. 
14 Safety 
Sodium lauryl sulfate is widely used in cosmetics and oral and 
topical pharmaceutical formulations. It is a moderately toxic 
material with acute toxic effects including irritation to the skin, 
eyes, mucous membranes, upper respiratory tract, and stomach. 
Repeated, prolonged exposure to dilute solutions may 
cause drying and cracking of the skin; contact dermatitis may 
develop.(3) Prolonged inhalation of sodium lauryl sulfate will 
damage the lungs. Pulmonary sensitization is possible, resulting 
in hyperactive airway dysfunction and pulmonary allergy. 
Animal studies have shown intravenous administration to 
cause marked toxic effects to the lung, kidney, and liver. 
Mutagenic testing in bacterial systems has proved negative.(4) 
Adverse reactions to sodium lauryl sulfate in cosmetics and 
pharmaceutical formulations mainly concern reports of irritation 
to the skin(3,5–7) or eyes(8) following topical application. 
Sodium lauryl sulfate should not be used in intravenous 
preparations for humans. The probable human lethal oral dose 
is 0.5–5.0 g/kg. 
LD50 (mouse, IP): 0.25 g/kg(9) 
LD50 (mouse, IV): 0.12 g/kg 
LD50 (rat, oral): 1.29 g/kg 
LD50 (rat, IP): 0.21 g/kg 
LD50 (rat, IV): 0.12 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Inhalation and contact with 
the skin and eyes should be avoided; eye protection, gloves, and 
other protective clothing, depending on the circumstances, are 
recommended. Adequate ventilation should be provided or a 
dust respirator should be worn. Prolonged or repeated 
exposure should be avoided. Sodium lauryl sulfate emits toxic 
fumes on combustion. 
688 Sodium Lauryl Sulfate

16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(dental preparations; oral capsules, suspensions, and tablets; 
topical and vaginal preparations). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Cetostearyl alcohol; cetyl alcohol; magnesium lauryl sulfate; 
wax, anionic emulsifying. 
Magnesium lauryl sulfate 
Empirical formula: C12H26O4SHMg 
CAS number: [3097-08-3] 
Comments: a soluble tablet lubricant.(10) The EINECS number 
for magnesium lauryl sulfate is 221-450-6. 
18 Comments 
A specification for sodium lauryl sulfate is contained in the 
Food Chemicals Codex (FCC). The EINECS number for 
sodium lauryl sulfate is 205-788-1. 
19 Specific References 
1 Smith BJ. SDS polyacrylamide gel electrophoresis of proteins. 
Methods Mol Biol 1994; 32: 23–34. 
2 Riekkola ML, Wiedmar SK, Valko IE, Siren H. Selectivity in 
capillary electrophoresis in the presence of micelles, chiral selectors 
and non-aqueous media. J Chromatogr 1997; 792A: 13–35. 
3 Wigger-AlbertiW, Krebs A, Elsner P. Experimental irritant contact 
dermatitis due to cumulative epicutaneous exposure to sodium 
lauryl sulphate and toluene: single and concurrent application. Br J 
Dermatol 2000; 143: 551–556. 
4 Mortelmans K, Haworth S, Lawlor T, et al. Salmonella mutagenicity 
tests II: results from the testing of 270 chemicals. Environ 
Mutagen 1986; 8 (Suppl. 7): 1–119. 
5 Blondeel A, Oleffe J, Achten G. Contact allergy in 330 
dermatological patients. Contact Dermatitis 1978; 4(5): 270–276. 
6 Bruynzeel DP, van Ketel WG, Scheper RJ, von Blomberg-van der 
Flier BME. Delayed time course of irritation by sodium lauryl 
sulfate: observations on threshold reactions. Contact Dermatitis 
1982; 8(4): 236–239. 
7 Eubanks SW, Patterson JW. Dermatitis from sodium lauryl sulfate 
in hydrocortisone cream. Contact Dermatitis 1984; 11(4): 250– 
251. 
8 Grant WM. Toxicology of the Eye, 2nd edn. Springfield, IL: 
Charles C Thomas, 1974: 964. 
9 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3258–3259. 
10 Caldwell HC, Westlake WJ. Magnesium lauryl sulfate–soluble 
lubricant [letter]. J Pharm Sci 1972; 61: 984–985. 
20 General References 
Hadgraft J, Ashton P. The effect of sodium lauryl sulfate on topical drug 
bioavailability. J Pharm Pharmacol 1985; 37 (Suppl.): 85P. 
Nakagaki M, Yokoyama S. Acid-catalyzed hydrolysis of sodium 
dodecyl sulfate. J Pharm Sci 1985; 74: 1047–1052. 
Vold RD, Mittal KL. Determination of sodium dodecyl sulfate in the 
presence of lauryl alcohol. Anal Chem 1972; 44(4): 849–850. 
Wan LSC, Poon PKC. The interfacial activity of sodium lauryl sulfate in 
the presence of alcohols. Can J Pharm Sci 1970; 5: 104–107. 
Wang L-H, Chowhan ZT. Drug–excipient interactions resulting from 
powder mixing V: role of sodium lauryl sulfate. Int J Pharm 1990; 
60: 61–78. 
21 Authors 
S Behn. 
22 Date of Revision 
15 August 2005. 
Sodium Lauryl Sulfate 689

Sodium Metabisulfite 
1 Nonproprietary Names 
BP: Sodium metabisulphite 
JP: Sodium metabisulfite 
PhEur: Natrii metabisulfis 
USPNF: Sodium metabisulfite 
2 Synonyms 
Disodium disulfite; disodium pyrosulfite; disulfurous acid, 
disodium salt; E223; natrii disulfis; sodium acid sulfite; sodium 
pyrosulfite. 
3 Chemical Name and CAS Registry Number 
Sodium pyrosulfite [7681-57-4] 
4 Empirical Formula and Molecular Weight 
Na2S2O5 190.1 
5 Structural Formula 
Na2S2O5 
6 Functional Category 
Antioxidant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sodium metabisulfite is used as an antioxidant in oral, 
parenteral, and topical pharmaceutical formulations, at concentrations 
of 0.01–1.0% w/v. Primarily, sodium metabisulfite 
is used in acidic preparations; for alkaline preparations, sodium 
sulfite is usually preferred; see Section 18. Sodium metabisulfite 
also has some antimicrobial activity, which is greatest at acid 
pH, and may be used as a preservative in oral preparations such 
as syrups. 
In the food industry and in wine production, sodium 
metabisulfite is similarly used as an antioxidant, antimicrobial 
preservative, and antibrowning agent. However, at concentrations 
above about 550 ppm it imparts a noticeable flavor to 
preparations. 
Sodium metabisulfite usually contains small amounts of 
sodium sulfite and sodium sulfate. 
8 Description 
Sodium metabisulfite occurs as colorless, prismatic crystals or 
as a white to creamy-white crystalline powder that has the odor 
of sulfur dioxide and an acidic, saline taste. Sodium metabisulfite 
crystallizes from water as a hydrate containing seven 
water molecules. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for sodium metabisulfite. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters — . — 
Appearance of solution. . — 
pH (5% w/v solution) — 3.5–5.0 — 
Chloride — — 40.05% 
Thiosulfate . . 40.05% 
Arsenic 44 ppm 45 ppm 43 ppm 
Heavy metals 420 ppm 420 ppm 40.002% 
Selenium — — <0.005% 
Iron 420 ppm 420 ppm 40.002% 
Assay (as Na2S2O5) — 95.0–100.5% — 
Assay (as SO2) — — 65.0–67.4% 
10 Typical Properties 
Acidity/alkalinity: pH = 3.5–5.0 for a 5%w/v aqueous solution 
at 208C. 
Melting point: sodium metabisulfite melts with decomposition 
at less than 1508C. 
Osmolarity: a 1.38% w/v aqueous solution is isoosmotic with 
serum. 
Solubility: see Table II. 
Table II: Solubility of sodium metabisulfite. 
Solvent Solubility at 208C 
unless otherwise stated 
Ethanol (95%) Slightly soluble 
Glycerin Freely soluble 
Water 1 in 1.9 
1 in 1.2 at 1008C 
11 Stability and Storage Conditions 
On exposure to air and moisture, sodium metabisulfite is 
slowly oxidized to sodium sulfate with disintegration of the 
crystals.(1) Addition of strong acids to the solid liberates sulfur 
dioxide. 
In water, sodium metabisulfite is immediately converted to 
sodium (Na.) and bisulfite (HSO3) ions. Aqueous sodium 
metabisulfite solutions also decompose in air, especially on 
heating. Solutions that are to be sterilized by autoclaving 
should be filled into containers in which the air has been 
replaced with an inert gas, such as nitrogen. The addition of 
dextrose to aqueous sodium metabisulfite solutions results in a 
decrease in the stability of the metabisulfite.(2) 
The bulk material should be stored in a well-closed 
container, protected from light, in a cool, dry place. 
12 Incompatibilities 
Sodium metabisulfite reacts with sympathomimetics and other 
drugs that are ortho- or para-hydroxybenzyl alcohol deriva

tives to form sulfonic acid derivatives possessing little or no 
pharmacological activity. The most important drugs subject to 
this inactivation are epinephrine (adrenaline) and its derivatives.(
3) In addition, sodium metabisulfite is incompatible with 
chloramphenicol owing to a more complex reaction;(3) it also 
inactivates cisplatin in solution.(4,5) 
It is incompatible with phenylmercuric acetate when 
autoclaved in eye drop preparations.(6) 
Sodium metabisulfite may react with the rubber caps of 
multidose vials, which should therefore be pretreated with 
sodium metabisulfite solution.(7) 
13 Method of Manufacture 
Sodium metabisulfite is prepared by saturating a solution of 
sodium hydroxide with sulfur dioxide and allowing crystallization 
to occur; hydrogen is passed through the solution to 
exclude air. Sodium metabisulfite may also be prepared by 
saturating a solution of sodium carbonate with sulfur dioxide 
and allowing crystallization to occur, or by thermally dehydrating 
sodium bisulfite. 
14 Safety 
Sodium metabisulfite is widely used as an antioxidant in oral, 
topical, and parenteral pharmaceutical formulations; it is also 
widely used in food products. 
Although it is extensively used in a variety of preparations, 
sodium metabisulfite and other sulfites have been associated 
with a number of severe to fatal adverse reactions.(8–19) These 
are usually hypersensitivity-type reactions and include bronchospasm 

and anaphylaxis. Allergy to sulfite antioxidants is 
estimated to occur in 5–10% of asthmatics, although adverse 
reactions may also occur in nonasthmatics with no history of 
allergy. 
Following oral ingestion, sodium metabisulfite is oxidized to 
sulfate and is excreted in urine. Ingestion may result in gastric 
irritation, owing to the liberation of sulfurous acid, while 
ingestion of large amounts of sodium metabisulfite can cause 
colic, diarrhea, circulatory disturbances, CNS depression, and 
death. 
In Europe, the acceptable daily intake of sodium metabisulfite 
and other sulfites used in foodstuffs has been set at up to 
3.5 mg/kg body-weight, calculated as sulfur dioxide (SO2). The 
WHO has similarly also set an acceptable daily intake of 
sodium metabisulfite, and other sulfites, at up to 7.0 mg/kg 
body-weight, calculated as sulfur dioxide (SO2).(20) 
LD50 (rat, IV): 0.12 g/kg(21) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Sodium metabisulfite may be 
irritant to the skin and eyes; eye protection and gloves are 
recommended. In the UK, the long-term (8-hour TWA) 
occupational exposure limit for sodium metabisulfite is 
5 mg/m3.(22) 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (epidural, 
inhalation; IM, and IV injections; ophthalmic solutions; oral 
preparations, rectal, topical, and vaginal preparations). 
Included in nonparenteral and parenteral medicines licensed 
in the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Potassium metabisulfite; sodium bisulfite; sodium sulfite. 
Sodium bisulfite 
Empirical formula: NaHSO3 
Molecular weight: 104.07 
CAS number: [7631-90-5] 
Synonyms: E222; sodium hydrogen sulfite. 
Appearance: white crystalline powder. 
Density: 1.48 g/cm3 
Solubility: soluble 1 in 3.5 parts of water at 208C; 1 in 2 parts of 
water at 1008C; and 1 in 70 parts of ethanol (95%). 
Comments: most substances sold as sodium bisulfite contain 
significant, variable, amounts of sodium metabisulfite, as 
the latter is less hygroscopic and more stable during storage 
and shipment. See Section 18. 
18 Comments 
Sodium metabisulfite is used as an antioxidant at low pH, 
sodium bisulfite at intermediate pH, and sodium sulfite at 
higher pH values. A specification for sodium metabisulfite is 
contained in the Food Chemicals Codex (FCC). 
The EINECS number for sodium metabisulfite is 231-673-0. 
19 Specific References 
1 Schroeter LC. Oxidation of sulfurous acid salts in pharmaceutical 
systems. J Pharm Sci 1963; 52: 888–892. 
2 Schumacher GE, Hull RL. Some factors influencing the degradation 
of sodium bisulfite in dextrose solutions. Am J Hosp Pharm 
1966; 23: 245–249. 
3 Higuchi T, Schroeter LC. Reactivity of bisulfite with a number of 
pharmaceuticals. J Am Pharm Assoc (Sci) 1959; 48: 535–540. 
4 Hussain AA, Haddadin M, Iga K. Reaction of cis-platinum with 
sodium bisulfite. J Pharm Sci 1980; 69(3): 364–365. 
5 Garren KW, Repta AJ. Incompatibility of cisplatin and Reglan 
injectable. Int J Pharm 1985; 24: 91–99. 
6 Collins AJ, Lingham P, Burbridge TA, Bain R. Incompatibility of 
phenylmercuric acetate with sodium metabisulphite in eye drop 
formulations. J Pharm Pharmacol 1985; 37 (Suppl.): 123P. 
7 Schroeter LC. Sulfurous acid salts as pharmaceutical antioxidants. 
J Pharm Sci 1961; 50(11): 891–901. 
8 Jamieson DM, Guill MF, Wray BB, May JR. Metabisulfite 
sensitivity: case report and literature review. Ann Allergy 1985; 
54(4): 115–121. 
9 Anonymous. Possible allergic-type reactions. FDA Drug Bull 
1987; 17: 2. 
10 Tsevat J, Gross GN, Dowling GP. Fatal asthma after ingestion of 
sulfite-containing wine [letter]. Ann Intern Med 1987; 107(2): 263. 
11 Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation 
Agents: a Handbook of Excipients. New York: Marcel Dekker, 
1989: 314–320. 
12 Fitzharris P. What advances if any, have been made in treating 
sulfite allergy? Br Med J 1992; 305: 1478. 
13 Smolinske SC. Handbook of Food, Drug and Cosmetic Excipients. 
Boca Raton, FL: CRC Press Inc, 1992: 393–406. 
14 Anonymous. Sulfites in drugs and food. Med Lett Drugs Ther 
1986; 28: 74–75. 
15 Baker GJ. Bronchospasm induced by bisulfite containing food and 
drugs. Med J Aust 1981; ii: 614–617. 
16 Fwarog FJ, Leung DYM. Anaphylaxis to a component of 
isoethane. J Am Med Assoc 1982; 248: 2030–2031. 
Sodium Metabisulfite 691

17 Koephe JW. Dose dependent bronchospasm from sulfites in 
isoethane. J Am Med Assoc 1984; 251: 2982–2983. 
18 Mikolich DJ, McCloskeyWW. Suspected gentamicin allergy could 
be sulfite sensitivity. Clin Pharm 1988; 7: 269. 
19 Deziel-Evans LM, Hussey WJ. Possible sulfite sensitivity with 
gentamicin infusion. DICP Ann Pharmacother 1989; 23: 1032– 
1033. 
20 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirtieth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1987: No. 
751. 
21 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3261. 
22 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
Halsby SF, Mattocks AM. Absorption of sodium bisulfite from 
peritoneal dialysis solutions. J Pharm Sci 1965; 54: 52–55. 
Wilkins JW, Greene JA,Weller JM. Toxicity of intraperitoneal bisulfite. 
Clin Pharmacol Ther 1968; 9: 328–332. 
21 Authors 
JT Stewart. 
22 Date of Revision 
17 August 2005. 
692 Sodium Metabisulfite

Sodium Phosphate, Dibasic 
1 Nonproprietary Names 
BP: Anhydrous disodium hydrogen phosphate 
Disodium hydrogen phosphate 
Disodium hydrogen phosphate dodecahydrate 
JP: Dibasic sodium phosphate 
PhEur: Dinatrii phosphas anhydricus 
Dinatrii phosphas dihydricus 
Dinatrii phosphas dodecahydricus 
USP: Dibasic sodium phosphate 
Note that the BP 2004 and PhEur 2005 contain three separate 
monographs for the anhydrous, the dihydrate, and the 
dodecahydrate; the JP 2001 contains one monograph for the 
dodecahydrate; and the USP 28 contains one monograph for 
the anhydrous, the monohydrate, the dihydrate, the heptahydrate, 
and the dodecahydrate. See also Section 8. 
2 Synonyms 
Disodium hydrogen phosphate; disodium phosphate; E339; 
phosphoric acid, disodium salt; secondary sodium phosphate; 
sodium orthophosphate. 
3 Chemical Name and CAS Registry Number 
Anhydrous dibasic sodium phosphate [7558-79-4] 
Dibasic sodium phosphate dihydrate [10028-24-7] 
Dibasic sodium phosphate dodecahydrate [10039-32-4] 
Dibasic sodium phosphate heptahydrate [7782-85-6] 
Dibasic sodium phosphate hydrate [10140-65-5] 
Dibasic sodium phosphate monohydrate [118830-14-1] 
4 Empirical Formula and Molecular Weight 
Na2HPO4 141.96 
Na2HPO4H2O 159.94 
Na2HPO42H2O 177.98 
Na2HPO47H2O 268.03 
Na2HPO412H2O 358.08 
5 Structural Formula 
Na2HPO4xH2O where x = 0, 1, 2, 7, or 12. 
6 Functional Category 
Buffering agent; sequestering agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dibasic sodium phosphate is used in a wide variety of 
pharmaceutical formulations as a buffering agent and as a 
sequestering agent. Therapeutically, dibasic sodium phosphate 
is used as a mild laxative and in the treatment of hypophosphatemia.(
1,2) 
Dibasic sodium phosphate is also used in food products; for 
example as an emulsifier in processed cheese. 
8 Description 
The USP 28 states that dibasic sodium phosphate is dried or 
contains, 1, 2, 7, or 12 molecules of water of hydration. 
Anhydrous dibasic sodium phosphate occurs as a white 
powder. The dihydrate occurs as white or almost white, 
odorless crystals. The heptahydrate occurs as colorless crystals 
or as a white granular or caked salt that effloresces in warm, 
dry air. The dodecahydrate occurs as strongly efflorescent, 
colorless or transparent crystals. 
9 Pharmacopeial Specifications 

See Table I. 
Table I: Pharmacopeial specifications for sodium phosphate, 
dibasic(a). 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters . . — 
Appearance of solution . . — 
pH 9.0–9.4 — — 
Reducing substances — . — 
Insoluble substances — — 40.4% 
Monosodium phosphate — 40.025 — 
Carbonate . — — 
Chloride 40.014% . 40.06% 
Anhydrous — 4200 ppm — 
Dihydrate — 4400 ppm — 
Dodecahydrate — 4200 ppm — 
Water — . — 
Anhydrous — — — 
Dihydrate — — — 
Dodecahydrate — 57.0–61.0% — 
Sulfates 40.038% . 40.2% 
Anhydrous — 4500 ppm — 
Dihydrate — 40.1% — 
Dodecahydrate — 4500 ppm — 
Arsenic 42 ppm . 416 ppm 
Anhydrous — 42 ppm — 
Dihydrate — 44 ppm — 
Dodecahydrate — 42 ppm — 
Heavy metals 410 ppm . 40.002% 
Anhydrous — 410 ppm — 
Dihydrate — 420 ppm — 
Dodecahydrate — 410 ppm — 
Iron — . — 
Anhydrous — 420 ppm — 
Dihydrate — 440 ppm — 
Dodecahydrate — 420 ppm — 
Loss on drying 57.0–61.0%. . 
Anhydrous — 41.0% 45.0% 
Monohydrate — — 10.3–12.0% 
Dihydrate — 19.5–21.0% 18.5–21.5% 
Heptahydrate — — 43.0–50.0% 
Dodecahydrate — — 55.0–64.0% 
Assay (dried basis) 598.0% 98.0–101.0% 98.0–100.5% 
(a) PhEur 2005 (Suppl. 5.1) for the dodecahydrate.

10 Typical Properties 
Acidity/alkalinity: pH = 9.1 for a 1% w/v aqueous solution of 
the anhydrous material at 258C. A saturated aqueous 
solution of the dodecahydrate has a pH of about 9.5. 
Ionization constants: 
pKa1 = 2.15 at 258C;(3) 
pKa2 = 7.20 at 258C; 
pKa3 = 12.38 at 258C. 
Moisture content: the anhydrous form is hygroscopic and will 
absorb water on exposure to air, whereas the heptahydrate 
is stable in air. 
Osmolarity: a 2.23% w/v aqueous solution of the dihydrate is 
isoosmotic with serum; a 4.45% w/v aqueous solution of the 
dodecahydrate is isoosmotic with serum. 
Solubility: very soluble in water, more so in hot or boiling 
water; practically insoluble in ethanol (95%). The anhydrous 
material is soluble 1 in 8 parts of water, the 
heptahydrate 1 in 4 parts of water, and the dodecahydrate 1 
in 3 parts of water. 
11 Stability and Storage Conditions 
The anhydrous form of dibasic sodium phosphate is hygroscopic. 
When heated to 408C, the dodecahydrate fuses; at 
1008C it loses its water of crystallization; and at a dull-red heat 
(about 2408C) it is converted into the pyrophosphate, 
Na4P2O7. Aqueous solutions of dibasic sodium phosphate are 
stable and may be sterilized by autoclaving. 
The bulk material should be stored in an airtight container, 
in a cool, dry place. 
12 Incompatibilities 
Dibasic sodium phosphate is incompatible with alkaloids, 
antipyrine, chloral hydrate, lead acetate, pyrogallol, resorcinol 
and calcium gluconate, and ciprofloxacin.(4) Interaction 
between calcium and phosphate, leading to the formation of 
insoluble calcium–phosphate precipitates, is possible in parenteral 
admixtures. 
13 Method of Manufacture 
Either bone phosphate (bone ash), obtained by heating bones to 
whiteness, or the mineral phosphorite is used as a source of 
tribasic calcium phosphate, which is the starting material in the 
industrial production of dibasic sodium phosphate. 
Tribasic calcium phosphate is finely ground and digested 
with sulfuric acid. This mixture is then leached with hot water 
and neutralized with sodium carbonate, and dibasic sodium 
phosphate is crystallized from the filtrate. 
14 Safety 
Dibasic sodium phosphate is widely used as an excipient in 
parenteral, oral, and topical pharmaceutical formulations. 
Phosphate occurs extensively in the body and is involved in 
many physiological processes since it is the principal anion of 
intracellular fluid. Most foods contain adequate amounts of 
phosphate, making hypophosphatemia (phosphate deficiency)(
1) virtually unknown except for certain disease states(2) 
or in patients receiving total parenteral nutrition. Treatment is 
usually by the oral administration of up to 100 mmol of 
phosphate daily. 
Approximately two-thirds of ingested phosphate is 
absorbed from the gastrointestinal tract, virtually all of it being 
excreted in the urine, and the remainder is excreted in the feces. 
Excessive administration of phosphate, particularly intravenously, 
rectally, or in patients with renal failure, can cause 
hyperphosphatemia that may lead to hypocalcemia or other 
severe electrolyte imbalances.(5,6) Adverse effects occur less 
frequently following oral consumption, although phosphates 
act as mild saline laxatives when administered orally or rectally. 
Consequently, gastrointestinal disturbances including diarrhea, 
nausea, and vomiting may occur following the use of dibasic 
sodium phosphate as an excipient in oral formulations. 
However, the level of dibasic sodium phosphate used as an 
excipient in a pharmaceutical formulation is not usually 
associated with adverse effects. 
LD50 (rat, oral): 17 g/kg(7) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Dibasic sodium phosphate 
may be irritating to the skin, eyes, and mucous membranes. Eye 
protection and gloves are recommended. 
16 Regulatory Status 
GRAS listed. Accepted in Europe for use as a food additive. 
Included in the FDA Inactive Ingredients Guide (injections; 
infusions; nasal, ophthalmic, oral, otic, topical, and vaginal 
preparations). Included in nonparenteral and parenteral 
medicines licensed in the UK. Included in the Canadian List 
of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Dibasic potassium phosphate; sodium phosphate, monobasic; 
tribasic sodium phosphate. 
Dibasic potassium phosphate 
Empirical formula: K2HPO4 
Molecular weight: 174.15 
CAS number: [7758-11-4] 
Synonyms: dipotassium hydrogen orthophosphate; dipotassium 
hydrogen phosphate; dipotassium phosphate; E340; 
potassium phosphate. 
Appearance: colorless or white, granular, hygroscopic powder. 
Acidity/alkalinity: pH = 8.5–9.6 for a 5%w/v aqueous solution 
at 258C. 
Osmolarity: a 2.08% w/v aqueous solution of dibasic 
potassium phosphate is isoosmotic with serum. 
Solubility: freely soluble in water; very slightly soluble in 
ethanol (95%). 
Comments: one gram of dibasic potassium phosphate contains 
approximately 11.5 mmol of potassium and 5.7 mmol of 
phosphate. 
Tribasic sodium phosphate 
Empirical formula: Na3PO4xH2O 
Molecular weight: 163.94 for the anhydrous material 
380.06 for the dodecahydrate (12H2O) 
CAS number: [7601-54-9] for the anhydrous material. 
694 Sodium Phosphate, Dibasic

Synonyms: E339; trisodium orthophosphate; trisodium phosphate; 
TSP. 
Acidity/alkalinity: pH = 12.1 for a 1%w/v aqueous solution of 
the anhydrous material at 258C. A 1%w/v aqueous solution 
of the dodecahydrate at 258C has a pH of 12.0–12.2. 
Density: 
1.3 g/cm3 for the anhydrous material; 
0.9 g/cm3 for the dodecahydrate. 
Solubility: the anhydrous material is soluble 1 in 8 parts of 
water, while the dodecahydrate is soluble 1 in 5 parts of 
water at 208C. 
18 Comments 
One gram of anhydrous dibasic sodium phosphate represents 
approximately 14.1 mmol of sodium and 7.0 mmol of phosphate. 
One gram of dibasic sodium phosphate dihydrate represents 
approximately 11.2 mmol of sodium and 5.6 mmol of phosphate. 
One gram of dibasic sodium phosphate heptahydrate 
represents approximately 7.5 mmol of sodium and 3.7 mmol 
of phosphate. 
One gram of dibasic sodium phosphate dodecahydrate 
represents approximately 5.6 mmol of sodium and 2.8 mmol of 
phosphate. 
A specification for sodium phosphate, dibasic is contained in 
the Food Chemicals Codex (FCC). 
19 Specific References 
1 Lloyd CW, Johnson CE. Management of hypophosphatemia. Clin 
Pharm 1988; 7: 123–128. 
2 Holland PC, Wilkinson AR, Diez J, Lindsell DRM. Prenatal 
deficiency of phosphate, phosphate supplementation, and rickets 
in very-low-birthweight infants. Lancet 1990; 335: 697–701. 
3 Albert A, Serjearnt EP. Ionization Constants of Acids and Bases, 
2nd edn. Edinburgh: Chapman and Hall, 1971. 
4 Benjamin BE. Ciprofloxacin and sodium phosphates not compatible 

during actual Y-site injection [letter]. Am J Health Syst Pharm 
1996; 53: 1850–1851. 
5 Haskell LP. Hypocalcaemic tetany induced by hypertonic-phosphate 
enema [letter]. Lancet 1985; ii: 1433. 
6 Martin RR, Lisehora GR, Braxton M, Barcia PJ. Fatal poisoning 
from sodium phosphate enema: case report and experimental 
study. J Am Med Assoc 1987; 257: 2190–2192. 
7 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3273. 
20 General References 
Sweetman SC, ed. Martindale: The Complete Drug Reference, 34th 
edn. London: Pharmaceutical Press, 2005: 1231. 
21 Authors 
AS Kearney. 
22 Date of Revision 
20 August 2005. 
Sodium Phosphate, Dibasic 695

Sodium Phosphate, Monobasic 
1 Nonproprietary Names 
BP: Anhydrous sodium dihydrogen phosphate 
Sodium dihydrogen phosphate monohydrate 
Sodium dihydrogen phosphate dihydrate 
PhEur: Natrii dihydrogenophosphas dihydricus 
USP: Monobasic sodium phosphate 
Note that the BP 2004 contains three separate monographs for 
the anhydrous, the monohydrate, and the dihydrate; the PhEur 
2005 contains a single monograph for the dihydrate; and the 
USP 28 contains one monograph for the anhydrous, the 
monohydrate and the dihydrate. See also Section 8. 
2 Synonyms 
Acid sodium phosphate; E339; Kalipol 32; monosodium 
orthophosphate; monosodium phosphate; phosphoric acid, 
monosodium salt; primary sodium phosphate; sodium biphosphate; 
sodium dihydrogen orthophosphate; sodium dihydrogen 
phosphate. 
3 Chemical Name and CAS Registry Number 
Anhydrous monobasic sodium phosphate [7558-80-7] 
Monobasic sodium phosphate monohydrate [10049-21-5] 
Monobasic sodium phosphate dihydrate [13472-35-0] 
4 Empirical Formula and Molecular Weight 
NaH2PO4 119.98 
NaH2PO4H2O 137.99 
NaH2PO42H2O 156.01 
5 Structural Formula 
NaH2PO4xH2O where x = 0, 1, or 2. 
6 Functional Category 
Buffering agent; emulsifying agent; sequestering agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Monobasic sodium phosphate is used in a wide variety of 
pharmaceutical formulations as a buffering agent and as a 
sequestering agent. Therapeutically, monobasic sodium phosphate 
is used as a mild saline laxative and in the treatment of 
hypophosphatemia.(1–3) 
Monobasic sodium phosphate is also used in food products, 
for example, in baking powders, and as a dry acidulant and 
sequestrant. 
8 Description 
The USP 28 states that monobasic sodium phosphate contains 
one or two molecules of water of hydration or is anhydrous. 
The hydrated forms of monobasic sodium phosphate occur 
as odorless, colorless or white, slightly deliquescent crystals. 
The anhydrous form occurs as a white crystalline powder or 
granules. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for sodium phosphate, 
monobasic. 
Test PhEur 2005 USP 28 
Identification . . 
Characters . — 
Appearance of solution . — 
Aluminum, calcium and related 
elements 
— . 
Arsenic 42 ppm 48 ppm 
Chloride 4200 ppm 40.014% 
Insoluble substances — 40.2% 
Heavy metals 410 ppm 40.002% 
Insoluble substances — 40.2% 
Iron 410 ppm — 
Organic volatile impurities — . 
pH 4.2–4.5 4.1–4.5 
Reducing substances . — 
Sulfate 4300 ppm 40.15% 
Water . . 
Anhydrous — 42.0% 
Monohydrate — 10.0–15.0% 
Dihydrate 21.5–24.0% 18.0–26.5% 
Assay (dried basis) 98.0–100.5% 98.0–103.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 4.1–4.5 for a 5%w/v aqueous solution 
of the monohydrate at 258C. 
Density: 1.915 g/cm3 for the dihydrate. 
Dissociation constant: pKa = 2.15 at 258C 
Solubility: soluble 1 in 1 of water; very slightly soluble in 
ethanol (95%). 
11 Stability and Storage Conditions 
Monobasic sodium phosphate is chemically stable, although it 
is slightly deliquescent. On heating at 1008C, the dihydrate 
loses all of its water of crystallization. On further heating, it 
melts with decomposition at 2058C, forming sodium hydrogen 
pyrophosphate, Na2H2P2O7. At 2508C it leaves a final residue 
of sodium metaphosphate, NaPO3. 
Aqueous solutions are stable and may be sterilized by 
autoclaving. 
Monobasic sodium phosphate should be stored in an 
airtight container in a cool, dry place.

12 Incompatibilities 
Monobasic sodium phosphate is an acid salt and is therefore 
generally incompatible with alkaline materials and carbonates; 
aqueous solutions of monobasic sodium phosphate are acidic 
and will cause carbonates to effervesce. 
Monobasic sodium phosphate should not be administered 
concomitantly with aluminum, calcium, or magnesium salts 
since they bind phosphate and could impair its absorption from 
the gastrointestinal tract. Interaction between calcium and 
phosphate, leading to the formation of insoluble calcium 
phosphate precipitates, is possible in parenteral admixtures.(
4–6) 
13 Method of Manufacture 
Monobasic sodium phosphate is prepared by adding phosphoric 
acid to a hot, concentrated solution of disodium phosphate 
until the liquid ceases to form a precipitate with barium 
chloride. This solution is then concentrated and the monobasic 
sodium phosphate is crystallized. 
14 Safety 
Monobasic sodium phosphate is widely used as an excipient in 
parenteral, oral, and topical pharmaceutical formulations. 
Phosphate occurs extensively in the body and is involved in 
many physiological processes since it is the principal anion of 
intracellular fluid. Most foods contain adequate amounts of 
phosphate, making hypophosphatemia(1) virtually unknown 
except for in certain disease states(2) or in patients receiving 
total parenteral nutrition. Treatment is usually by the oral 
administration of up to 100 mmol of phosphate daily. 
Approximately two-thirds of ingested phosphate is 
absorbed from the gastrointestinal tract, virtually all of it being 
excreted in the urine, and the remainder is excreted in the feces. 
Excessive administration of phosphate, particularly intravenously, 
rectally, or in patients with renal failure, can cause 
hyperphosphatemia that may lead to hypocalcemia or other 
severe electrolyte imbalances.(7–9) Adverse effects occur less 
frequently following oral consumption, although phosphates 
act as mild saline laxatives when administered orally or rectally 
(2–4 g of monobasic sodium phosphate in an aqueous solution 
is used as a laxative). Consequently, gastrointestinal disturbances 
including diarrhea, nausea, and vomiting may occur 
following the use of monobasic sodium phosphate as an 
excipient in oral formulations. However, the level of monobasic 
sodium phosphate used as an excipient in a pharmaceutical 
formulation is not usually associated with adverse effects. 
LD50 (rat, IM): 0.25 g/kg(10) 
LD50 (rat, oral): 8.29 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Monobasic sodium phosphate 
may be irritant to the skin, eyes, and mucous membranes. 
Eye protection and gloves are recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (injections; 
infusions; ophthalmic, oral, topical, and vaginal preparations). 
Included in nonparenteral and parenteral medicines licensed in 
the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Dibasic sodium phosphate; monobasic potassium phosphate. 
Monobasic potassium phosphate 
Empirical formula: KH2PO4 
Molecular weight: 136.09 
CAS number: [7778-77-0] 
Synonyms: E340; monopotassium phosphate; potassium acid 
phosphate; potassium biphosphate; potassium dihydrogen 
orthophosphate. 
Appearance: colorless crystals or a white, odorless, granular or 
crystalline powder. 
Acidity/alkalinity: pH  4.5 for a 1% w/v aqueous solution at 
258C. 
Solubility: freely soluble in water; practically insoluble in 
ethanol (95%). 
Comments: 1 g of monobasic potassium phosphate represents 
approximately 7.3 mmol of potassium and of phosphate. 
The EINECS number for monobasic potassium phosphate 
is 231-913-4. 
18 Comments 
One gram of anhydrous monobasic sodium phosphate 
represents approximately 8.3 mmol of sodium and of phosphate. 
One gram of monobasic sodium phosphate monohydrate 
represents approximately 7.2 mmol of sodium and of phosphate. 
One gram of monobasic sodium phosphate dihydrate 
represents approximately 6.4 mmol of sodium and of phosphate. 
A specification for sodium phosphate monobasic is contained 
in the Food Chemicals Codex (FCC). The EINECS 
number for monobasic sodium phosphate is 231-449-2. 
19 Specific References 
1 Lloyd CW, Johnson CE. Management of hypophosphatemia. Clin 
Pharm 1988; 7: 123–128. 
2 Holland PC, Wilkinson AR, Diez J, Lindsell DRM. Prenatal 
deficiency of phosphate, phosphate supplementation, and rickets 
in very-low-birthweight infants. Lancet 1990; 335: 697–701. 
3 Rosen GH, Boullata JI, O’Rangers EA, et al. Intravenous 
phosphate repletion regimen for critically ill patients with 
moderate hypophosphatemia. Crit Care Med 1995; 23: 1204– 
1210. 
4 Eggert LD, Rusho WJ, Mackay MW, Chan GM. Calcium and 
phosphorus compatibility in parenteral nutrition solutions for 
neonates. Am J Hosp Pharm 1982; 39: 49–53. 
5 Niemiec PW, Vanderveen TW. Compatibility considerations in 
parenteral nutrient solutions. Am J Hosp Pharm 1984; 41: 893– 
911. 
6 Pereira-da-Silva L, Nurmamodo A, Amaral JM, et al. Compatibility 
of calcium and phosphate in four parenteral nutrition 
solutions for preterm neonates. Am J Health Syst Pharm 2003; 60: 
1041–1044. 
7 Haskell LP. Hypocalcaemic tetany induced by hypertonicphosphate 
enema [letter]. Lancet 1985; ii: 1433. 
8 Larson JE, Swigart SA, Angle CR. Laxative phosphate poisoning: 
pharmacokinetics of serum phosphorus. Hum Toxicol 1986; 5: 
45–49. 
Sodium Phosphate, Monobasic 697

9 Martin RR, Lisehora GR, Braxton M, Barcia PJ. Fatal poisoning 
from sodium phosphate enema: case report and experimental 
study. J Am Med Assoc 1987; 257: 2190–2192. 
10 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3274. 
20 General References 
Sweetman SC, ed. Martindale: The Complete Drug Reference, 34th 
edn. London: Pharmaceutical Press, 2005: 1230. 
21 Authors 
LY Galichet. 
22 Date of Revision 
17 August 2005. 
698 Sodium Phosphate, Monobasic

Sodium Propionate 
1 Nonproprietary Names 
PhEur: Natrii propionas 
USPNF: Sodium propionate 
2 Synonyms 
E281; ethylformic acid, sodium salt, hydrate; methylacetic acid, 
sodium salt, hydrate; sodium propanoate hydrate; sodium 
propionate hydrate. 
3 Chemical Name and CAS Registry Number 
Propionic acid, sodium salt, hydrate [6700-17-0] 
Propionic acid, sodium salt, anhydrous [137-40-6] 
4 Empirical Formula and Molecular Weight 
C3H5NaO2xH2O 114.06 (for monohydrate) 
C3H5NaO2 96.06 (for anhydrous) 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative. 
7 Applications in Pharmaceutical Formulation 
or Technology 
As an excipient, sodium propionate is used in oral pharmaceutical 
formulations as an antimicrobial preservative. Like 
propionic acid, sodium propionate and other propionic acid 
salts are fungistatic and bacteriostatic against a number of 
Gram-positive cocci. Propionates are more active against molds 
than is sodium benzoate, but have essentially no activity against 
yeasts; see Section 10. 
Therapeutically, sodium propionate has been used topically 
in concentrations up to 10% w/w alone or in combination with 
other propionates, caprylates, or other antifungal agents, in the 
form of ointments or solutions for the treatment of dermatophyte 
infections. Eye drops containing 5% w/v sodium 
propionate have also been used. See Section 18. 
In food processes, particularly baking, sodium propionate is 
used as an antifungal agent; it may also be used as a flavoring 
agent in food products. In veterinary medicine, sodium 
propionate is used therapeutically as a glucogenic substance 
in ruminants.(1) 
8 Description 
Sodium propionate occurs as colorless transparent crystals or 
as a granular, free-flowing, crystalline powder. It is odorless, or 
with a slight characteristic odor, and is deliquescent in moist air. 
Sodium propionate has a characteristic, slightly cheeselike 
taste, although by itself it is unpalatable. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for sodium propionate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Appearance of solution . — 
Alkalinity — . 
pH 7.8–9.2 — 
Water — 41.0% 
Heavy metals 410 ppm 40.001% 
Related substances . — 
Readily oxidizable substances . — 
Iron 410 ppm — 
Organic volatile impurities — . 
Loss on drying 0.50% — 
Assay (dried basis) 99.0–101.0% 99.0–100.5% 
10 Typical Properties 
Antimicrobial activity: sodium propionate, propionic acid, and 
other propionates possess mainly antifungal activity and are 
used as preservatives primarily against molds; they exhibit 
essentially no activity against yeasts. Although, in general, 
propionates exhibit little activity against bacteria, sodium 
propionate is effective against Bacillus mesenterium, the 
organism that causes ‘rope’ in bread. Antimicrobial activity 
is largely dependent upon the presence of the free acid and 
hence propionates exhibit optimum activity at acid pH, 
notably at less than pH 5. Synergistic effects occur between 
propionates and carbon dioxide or sorbic acid. See also 
Propionic acid. 
Solubility: soluble 1 in 24 of ethanol (95%), 1 in 1 of water, and 
1 in 0.65 of boiling water; practically insoluble in chloroform 
and ether. 
11 Stability and Storage Conditions 
Sodium propionate is deliquescent and should therefore be 
stored in an airtight container in a cool, dry place. 
12 Incompatibilities 
Incompatibilities for sodium propionate are similar to those of 
other weak organic acids.

13 Method of Manufacture 
Sodium propionate is prepared by the reaction of propionic 
acid with sodium carbonate or sodium hydroxide. 
14 Safety 
Sodium propionate and other propionates are used in oral 
pharmaceutical formulations, food products, and cosmetics. 
The free acid, propionic acid, occurs naturally at levels up to 
1% w/w in certain cheeses. 
Following oral consumption, propionate is metabolized in 
mammals in a manner similar to that of fatty acids. Toxicity 
studies in animals have shown sodium propionate and other 
propionates to be relatively nontoxic materials.(2,3) In veterinary 
medicine, sodium propionate is used as a therapeutic 
agent for cattle and sheep.(1) 
In humans, 6 g of sodium propionate has been administered 
daily without harm.(2) However, allergic reactions to propionates 
can occur. 
LD50 (mouse, oral): 6.33 g/kg(4) 
LD50 (mouse, SC): 2.1 g/kg 
LD50 (rabbit, skin): 1.64 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Sodium propionate may be 
irritant to the eyes and skin. Gloves, eye protection, and a dustmask 
are recommended. When heated to decomposition, 
sodium propionate emits toxic fumes of sodium monoxide, 
Na2O. 
In the UK, the occupational exposure limits for propionic 
acid are 31 mg/m3 (10 ppm) long-term (8-hour TWA) and 
46 mg/m3 (15 ppm) short-term.(5) 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. In 
cheese products, propionates are limited to 0.3% w/w 
concentration; a limit of 0.32% w/w is applied in flour and 
white bread rolls, while a limit of 0.38% w/w is applied in 
whole wheat products. 
Included in the FDA Inactive Ingredients Guide (oral 
capsules, powder, suspensions, and syrups). Included in 
nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Anhydrous sodium propionate; calcium propionate; potassium 
propionate; propionic acid; zinc propionate. 
Anhydrous sodium propionate 
Empirical formula: C3H5O2Na 
Molecular weight: 96.06 
CAS number: [137-40-6] 
Synonyms: E281; propanoic acid, sodium salt, anhydrous. 
Safety:
LD50 (mouse, oral): 2.35 g/kg(4) 
LD50 (rat, oral): 3.92 g/kg 
Calcium propionate 
Empirical formula: C6H10O4Ca 
Molecular weight: 186.22 
CAS number: [4075-81-4] 
Synonyms: calcium dipropionate; E282; propanoic acid, 
calcium salt; propionic acid, calcium salt. 
Appearance: white crystalline powder. 
Solubility: soluble in water; slightly soluble in ethanol (95%) 
and methanol; practically insoluble in acetone and benzene. 
Method of manufacture: prepared by the reaction of propionic 
acid and calcium hydroxide. 
Comments: occurs as the monohydrate or trihydrate. 
Potassium propionate 
Empirical formula: C3H5O2K 
Molecular weight: 112.17 
CAS number: [327-62-8] 
Synonyms: E283; propanoic acid, potassium salt; propionic 
acid, potassium salt. 
Appearance: white crystalline powder. 
Comments: occurs as the anhydrous form and the monohydrate. 
Decomposes in moist air to give off propionic acid. 
Zinc propionate 
Empirical formula: C6H10O4Zn 
Molecular weight: 211.52 
CAS number: [557-28-8] 
Synonyms: propanoic acid, zinc salt; propionic acid, zinc salt. 
Appearance: white platelets or needlelike crystals (for the 
monohydrate). 
Solubility: the anhydrous form is soluble 1 in 36 of ethanol 
(95%) at 158C, 1 in 6 of boiling ethanol (95%), and 1 in 3 of 
water at 158C. 
Method of manufacture: prepared by dissolving zinc oxide in 
dilute propionic acid solution. 
Comments: occurs as the anhydrous form and the monohydrate. 
Decomposes in moist air to give off propionic acid. 
18 Comments 
Propionates are used as antimicrobial preservatives in preference 
to propionic acid since they are less corrosive. 
The therapeutic use of sodium propionate in topical 
antifungal preparations has largely been superseded by a new 
generation of antifungal drugs. A specification for sodium 
propionate is contained in the Food Chemicals Codex (FCC). 
The EINECS number for sodium propionate is 205-290-4. 
19 Specific References 
1 Bishop Y, ed. The Veterinary Formulary, 6th edn. London: 
Pharmaceutical Press, 2005: 419–420. 
2 Heseltine WW. A note on sodium propionate. J Pharm Pharmacol 
1952; 4: 120–122. 
3 Graham WD, Teed H, Grice HC. Chronic toxicity of bread 
additives to rats. J Pharm Pharmacol 1954; 6: 534–545. 
4 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3276. 
5 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
Doores S. Organic acids. In: Branen AL, Davidson PM, eds. 
Antimicrobials in Foods. New York: Marcel Dekker, 1983: 85–87. 
Furia TE, ed. CRC Handbook of Food Additives. Cleveland, OH: CRC 
Press, 1972: 137–141. 
21 Authors 
SC Owen. 
22 Date of Revision 
9 August 2005. 
700 Sodium Propionate

Sodium Starch Glycolate 
1 Nonproprietary Names 
BP: Sodium starch glycollate 
PhEur:Carboxymethylamylum natricum 
USPNF: Sodium starch glycolate 
2 Synonyms 
Carboxymethyl starch, sodium salt; Explosol; Explotab; 
Glycolys; Primojel; starch carboxymethyl ether, sodium salt; 
Tablo; Vivastar P. 
3 Chemical Name and CAS Registry Number 
Sodium carboxymethyl starch [9063-38-1] 
4 Empirical Formula and Molecular Weight 
The USPNF 23 states that sodium starch glycolate is the sodium 
salt of a carboxymethyl ether of starch, containing 2.8–4.2% 
sodium. 
The PhEur 2005 describes three types of material: Types A 
and B occur as the sodium salt of a cross-linked partly Ocarboxymethylated 
potato starch, containing 2.8–4.2% and 
2.0–3.4% of sodium respectively. Type C is the sodium salt of a 
cross-linked by physical dehydration, partly O-carboxymethylated 
starch containing 2.8–5.0% sodium. 
The JP, PhEur and USPNF monographs have been 
harmonised for Type A and Type B variants. 
Sodium starch glycolate may be characterized by the degree 
of substitution and crosslinking. The molecular weight is 
typically 5105–1106. 
5 Structural Formula 
6 Functional Category 
Tablet and capsule disintegrant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sodium starch glycolate is widely used in oral pharmaceuticals 
as a disintegrant in capsule(1–6) and tablet formulations.(7–10) It 
is commonly used in tablets prepared by either directcompression(
11–13) or wet-granulation processes.(14–16) The 
usual concentration employed in a formulation is between 
2% and 8%, with the optimum concentration about 4%, 
although in many cases 2% is sufficient. Disintegration occurs 
by rapid uptake of water followed by rapid and enormous 
swelling.(17–20) 
Although the effectiveness of many disintegrants is affected 
by the presence of hydrophobic excipients such as lubricants, 
the disintegrant efficiency of sodium starch glycolate is 
unimpaired. Increasing the tablet compression pressure also 
appears to have no effect on disintegration time.(10–14) 
Sodium starch glycolate has also been investigated for use as 
a suspending vehicle.(21,22) 
8 Description 
Sodium starch glycolate is a white to off-white, odorless, 
tasteless, free-flowing powder. The PhEur 2005 states that it 
consists of oval or spherical granules, 30–100 mm in diameter, 
with some less-spherical granules ranging from 10–35 mm in 
diameter. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for sodium starch glycolate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Appearance of solution . — 
pH . 3.0–5.0 or 
5.5–7.5 
Type A 5.5–7.5 — 
Type B 3.0–5.9 — 
Type C 5.5–7.5 — 
Heavy metals 420 ppm 40.002% 
Iron 420 ppm 40.002% 
Loss on drying . . 
Type A 410.0% — 
Type B 410.0% — 
Type C 47.0% — 
Microbial limits . . 
Sodium chloride . . 
Type A 47.0% 47.0% 
Type B 47.0% 47.0% 
Type C 41.0% — 
Sodium glycolate 42.0% — 
Assay (of Na) . 2.8–4.2% 
Type A 2.8–4.2% — 
Type B 2.0–3.4% — 
Type C 2.8–5.0% — 
10 Typical Properties 
Acidity/alkalinity: pH = 3.0–5.0 or pH = 5.5–7.5 for a 3.3% 
w/v aqueous dispersion. See Section 18.

Ash: 415% for Explotab 
Density (bulk): 0.756 g/cm3; 
0.75 g/cm3 for Explotab; 
0.81 g/cm3 for Primojel; 
0.67 g/cm3 for Tablo. 
Density (tapped): 0.945 g/cm3; 
0.88 g/cm3 for Explotab; 
0.98 g/cm3 for Primojel; 
0.83 g/cm3 for Tablo. 
Density (true): 1.443 g/cm3; 
1.51 g/cm3 for Explotab; 
1.56 g/cm3 for Primojel; 
1.49 g/cm3 for Tablo. 
Melting point: does not melt, but chars at approximately 
2008C. 
Particle size distribution: 100% of particles less than 106 mm in 
size. Average particle size is 35–55 mm for Explotab. 
Solubility: sparingly soluble in ethanol (95%); practically 
insoluble in water. At a concentration of 2% w/v sodium 
starch glycolate disperses in cold water and settles in the 
form of a highly hydrated layer. 
Specific surface area: 0.24m2/g; 
0.202m2/g for Explotab; 
0.185m2/g for Primojel; 
0.335m2/g for Tablo; 
Swelling capacity: in water, sodium starch glycolate swells to up 
to 300 times its volume. 
Viscosity (dynamic): 4200 mPa s (200 cP) for a 4% w/v 
aqueous dispersion. Viscosity is 4.26 mPa s for a 2% w/v 
aqueous dispersion. 
SEM 1 
Excipient: Sodium starch glycolate (Explotab) 
Manufacturer: JRS Pharma 
Magnification: 300 Voltage: 5kV 
SEM 2 
Excipient: Sodium starch glycolate (Glycolys) 
Manufacturer: Roquettes Fre`res 
SEM 3 
Excipient: Sodium starch glycolate (Primojel) 
Manufacturer: DMV-International 
Magnification: 200 Voltage: 1.5 kV 
11 Stability and Storage Conditions 
Tablets prepared with sodium starch glycolate have good 
storage properties.(23–25) Sodium starch glycolate is stable and 
should be stored in a well-closed container in order to protect it 
from wide variations of humidity and temperature, which may 
cause caking. 
The physical properties of sodium starch glycolate remain 
unchanged for up to 3–5 years if it is stored at moderate 
temperatures and humidity. 
702 Sodium Starch Glycolate

SEM 4 
Excipient: Sodium starch glycolate (Vivastar P) 
Manufacturer: JRS Pharma 
Magnification: 300 Voltage: 5kV 
12 Incompatibilities 
Sodium starch glycolate is incompatible with ascorbic acid.(26) 
13 Method of Manufacture 
Sodium starch glycolate is a substituted derivative of potato 
starch. Typically, commercial products are also cross-linked. 
Starch is carboxymethylated by reacting it with sodium 
chloroacetate in an alkaline medium followed by neutralization 
with citric acid or some other acid. Crosslinking may be 
achieved either by physical methods or chemically by using 
reagents such as phosphorus oxytrichloride or sodium trimetaphosphate.(
27) 
14 Safety 
Sodium starch glycolate is widely used in oral pharmaceutical 
formulations and is generally regarded as a nontoxic and 
nonirritant material. However, oral ingestion of large quantities 
may be harmful. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Sodium starch glycolate may 
be irritant to the eyes; eye protection and gloves are 
recommended. A dust mask or respirator is recommended for 
processes that generate a large quantity of dust. 
16 Regulatory Acceptance 
Included in the FDA Inactive Ingredients Guide (oral capsules 
and tablets). Included in nonparenteral medicines licensed in 
the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Pregelatinized starch; starch. 
18 Comments 
The physical properties of sodium starch glycolate, and 
hence its effectiveness as a disintegrant, are affected by the 
degree of crosslinkage, extent of carboxymethylation, and 
purity.(28,29) 
Sodium starch glycolate has been reported to interact with 
glycopeptide antibiotics,(30,31) basic drugs, and increase the 
photostability of norfloxacin.(32) The solubility of the formulation 
matrix and mode of incorporation in wet granulation can 
affect the disintegration time; disintegration times can be slower 
in tablets containing high levels of soluble excipients.(33) 
Commercially, sodium starch glycolate is available in a 
number of speciality grades, e.g. low pH (Explotab Low pH, 
Glycolys Low pH); low viscosity (Explotab CLV, Glycolys LV); 
enhanced swelling (Explotab V17); low solvent (Vivastar PSF); 
and viscous (Vivastar P3500, P5000). 
19 Specific References 
1 Newton JM, Razzo FN. The interaction of formulation factors and 
dissolution fluid and the in vitro release of drug from hard gelatin 
capsules. J Pharm Pharmacol 1975; 27: 78P. 
2 Stewart AG, Grant DJW, Newton JM. The release of a model lowdose 
drug (riboflavine) from hard gelatin capsule formulations. J 
Pharm Pharmacol 1979; 31: 1–6. 
3 Chowhan ZT, Chi L-H. Drug–excipient interactions resulting from 
powder mixing III: solid state properties and their effect on drug 
dissolution. J Pharm Sci 1986; 75: 534–541. 
4 Botzolakis JE, Augsburger LL. Disintegrating agents in hard 
gelatin capsules part 1: mechanism of action. Drug Dev Ind Pharm 
1988; 14(1): 29–41. 
5 Hannula A-M, Marvola M, Jo. ns M. Release of ibuprofen from 
hard gelatin capsule formulations: effect of modern disintegrants. 
Acta Pharm Fenn 1989; 98: 189–196. 
6 MarvolaM, Hannula A-M, Ojantakanen S, et al. Effect of sodium 
bicarbonate and sodium starch glycolate on the in vivo disintegration 
of hard gelatin capsules – a radiological study in the dog. Acta 
Pharm Nord 1989; 1: 355–362. 
7 Khan KA, Rooke DJ. Effect of disintegrant type upon the 
relationship between compressional pressure and dissolution 
efficiency. J Pharm Pharmacol 1976; 28: 633–636. 
8 Rubinstein MH, Price EJ. In vivo evaluation of the effect of five 
disintegrants on the bioavailability of frusemide from 40 mg 
tablets. J Pharm Pharmacol 1977; 29: 5P. 
9 Caramella C, Colombo P, Coute U, La Manna A. The influence of 
disintegrants on the characteristics of coated acetylsalicylic acid 
tablets. Farmaco (Prat) 1978; 33: 498–507. 
10 Gebre Mariam T, Winnemoller M, Schmidt PC. Evaluation of the 
disintegration efficiency of a sodium starch glycolate prepared 
from enset starch in compressed tablets. Eur J Pharm Biopharm 
1996; 42(2): 124–132. 
11 Cid E, Jaminet F. Influence of adjuvants on the dissolution rate and 
stability of acetylsalicylic acid in compressed tablets [in French]. J 
Pharm Belg 1971; 26: 38–48. 
12 Gordon MS, Chowhan ZT. Effect of tablet solubility and 
hygroscopicity on disintegrant efficiency in direct compression 
tablets in terms of dissolution. J Pharm Sci 1987; 76: 907–909. 
13 Kaiho F, Luessen HL, Lehr CM, et al. Disintegration and gel 
forming behavior of carbomer and its sodium salt used as 
excipients for direct compression. STP Pharma Sci 1996; 6(6): 
385–389. 
Sodium Starch Glycolate 703

14 Sekulovic. D, Tufegdz.ic. N, Birmanc.evic. M. The investigation of the 
influence of Explotab on the disintegration of tablets. Pharmazie 
1986; 41: 153–154. 
15 Bolhius GK, Zuurman K, Te-Wierik GH. Improvement of 
dissolution of poorly soluble drugs by solid deposition on a super 
disintegrant. Part 2. Choice of super disintegrants and effect of 
granulation. Eur J Pharm Sci 1997; 5(2): 63–69. 
16 Joachim J, Kalantzis G, Joachim G, et al. Pregelatinized starches in 
wet granulation: experimental design and data analysis. Part 2. 
Case of tablets. STP Pharma Sci 1994; 4(6): 482–486. 
17 Khan KA, Rhodes CT. Disintegration properties of calcium 
phosphate dibasic dihydrate tablets. J Pharm Sci 1975; 64: 166– 
168. 
18 Khan KA, Rhodes CT. Water-sorption properties of tablet 
disintegrants. J Pharm Sci 1975; 64: 447–451. 
19 Wan LSC, Prasad KPP. Uptake of water by excipients in tablets. Int 
J Pharm 1989; 50: 147–153. 
20 Thibert R, Hancock BC. Direct visualization of superdisintegrant 
hydration using environmental scanning electron microscopy. J 
Pharm Sci 1996; 85: 1255–1258. 
21 Farley CA, Lund W. Suspending agents for extemporaneous 
dispensing: evaluation of alternatives to tragacanth. Pharm J 
1976; 216: 562–566. 
22 Smith G, McIntosh IEE. Suspending agents for extemporaneous 
dispensing [letter]. Pharm J 1976; 217: 42. 
23 Horhota ST, Burgio J, Lonski L, Rhodes CT. Effect of storage at 
specified temperature and humidity on properties of three directly 
compressible tablet formulations. J Pharm Sci 1976; 65: 1746– 
1749. 
24 Sheen P-C, Kim S-I. Comparative study of disintegrating agents in 
tiaramide hydrochloride tablets. Drug Dev Ind Pharm 1989; 
15(3): 401–414. 
25 Gordon MS, Chowhan ZT. The effect of aging on disintegrant 
efficiency in direct compression tablets with varied solubility and 
hygroscopicity, in terms of dissolution. Drug Dev Ind Pharm 1990; 
16(3): 437–447. 
26 Botha SA, Lo. tter AP, Du Preez JL. DSC screening for drug– 
excipient and excipient–excipient interactions in polypharmaceuticals 
intended for the alleviation of the symptoms of colds and flu. 
III. Drug Dev Ind Pharm 1987; 13(7): 1197–1215. 
27 Bolhuis GK, van Kamp HV, Lerk CF. On the similarity of sodium 
starch glycolate from different sources. Drug Dev Ind Pharm 
1986; 12(4): 621–630. 
28 Rudnic EM, Kanig JL, Rhodes CT. Effect of molecular structure 
variation on the disintegrant action of sodium starch glycolate. J 
Pharm Sci 1985; 74: 647–650. 
29 Bolhuis GK, van Kamp HV, Lerk CF. Effect of variation of degree 
of substitution, crosslinking and purity on the disintegrant 
efficiency of sodium starch glycolate. Acta Pharm Technol 1984; 
30: 24–32. 
30 Claudius JS, Neau SH. Kinetic and equilibrium characterization of 
interactions between glycopeptide antibiotics and sodium carboxymethyl 
starch. Int J Pharm 1996; 144: 71–79. 
31 Claudius JS, Neau SH. Solution stability of vancomycin in the 
presence and absence of sodium carboxymethyl starch. Int J 
Pharm 1998; 168: 41–48. 
32 Cordobo-Borrego M, Cordobo-Diaz M, Cordobo-Diaz D. Validation 
of a high performance liquid chromatographic method for the 
determination of norfloxacin and its application to stability studies 
(photostability study of norfloxacin). J Pharm Biomed Anal 1998; 
18: 919–926. 
33 Gordon MS, Rudraraju VS, Dani K, Chowhan ZT. Effect of the 
mode of super disintegrant incorporation on dissolution in wet 
granulated tablets. J Pharm Sci 1993; 82: 220–226. 
20 General References 
Augsberger LL, Hahm HA, Brzecko AW, Shah U. Superdisintegrants: 
characterisation and function. In: Swarbrick J, Boylan JC, eds. 
Encyclopedia of Pharmaceutical Technology, 2nd edn. New York: 
Marcel Dekker, 2002: 2623–2638. 
DMV-International. Technical literature: Primojel, 2003. 
Edge S, Belu AM, Potter UJ, et al. Chemical characterisation of sodium 
starch glycolate particles. Int J Pharm 2002; 240: 67–78. 
Edge S, Steele DF, Staniforth JN, et al. Powder compaction properties of 
sodium starch glycolate disintegrants. Drug Dev Ind Pharm 2002; 
28(8): 989–999. 
Ferrari F, Rossi S, Bonferoni MC, et al. The influence of product brand 
and batch to batch variability on superdisintegrant performance. 
STP Pharm Sci 2000; 10(6): 459–465. 
JRS Pharma. Technical literature: Explotab, Vivastar P, 2004. 
Khan KA, Rhodes CT. Further studies of the effect of compaction 
pressure on the dissolution efficiency of direct compression systems. 
Pharm Acta Helv 1974; 49: 258–261. 
Mantovani F, Grassi M, Colombo I, Lapasin R. A combination of vapor 
sorption and dynamic laser light scattering methods for the 
determination of the Flory parameter chi and the crosslink density 
of a powdered polymeric gel. Fluid Phase Equilib 2000; 167(1): 63– 
81. 
Mendell E. An evaluation of carboxymethyl starch as a tablet 
disintegrant. Pharm Acta Helv 1974; 49: 248–250. 
Roquette Fre`res. Technical literature: Glycolys, 2004. 
Shah U, Augsberger L. Multiple sources of sodium starch glycolate NF: 
evaluation of functional equivalence and development of standard 
performance tests. Drug Dev Ind Pharm 2002; 7(3): 345–359. 
21 Authors 
S Edge, RW Miller. 
22 Date of Revision 
17 August 2005. 
704 Sodium Starch Glycolate

Sodium Stearyl Fumarate 
1 Nonproprietary Names 
BP: Sodium stearyl fumarate 
PhEur: Natrii stearylis fumaras 
USPNF: Sodium stearyl fumarate 
2 Synonyms 
Fumaric acid, octadecyl ester, sodium salt; Pruv; sodium 
monostearyl fumarate. 
3 Chemical Name and CAS Registry Number 
2-Butenedioic acid, monooctadecyl ester, sodium salt [4070- 
80-8] 
4 Empirical Formula and Molecular Weight 
C22H39NaO4 390.5 
5 Structural Formula 
6 Functional Category 
Tablet and capsule lubricant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sodium stearyl fumarate is used as a lubricant in capsule and 
tablet formulations at 0.5–2.0% w/w concentration.(1–9) It is 
also used in certain food applications; see Section 16. 
8 Description 
Sodium stearyl fumarate is a fine, white powder with 
agglomerates of flat, circular-shaped particles. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for sodium stearyl fumarate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Water 45.0% 45.0% 
Lead — 40.001% 
Heavy metals — 40.002% 
Related substances . — 
Sodium stearyl maleate — 40.25% 
Stearyl alcohol — 40.5% 
Saponification value (anhydrous 
basis) 
— 142.2–146.0 
Organic volatile impurities — . 
Assay (anhydrous basis) 99.0–101.5% 99.0–101.5% 
10 Typical Properties 
Acidity/alkalinity: pH = 8.3 for a 5% w/v aqueous solution at 
908C. 
Density: 1.107 g/cm3 
Density (bulk): 0.2–0.35 g/cm3 
Density (tapped): 0.3–0.5 g/cm3 
Melting point: 224–2458C (with decomposition) 
Solubility: see Table II. 
Table II: Solubility of sodium stearyl fumarate. 
Solvent Solubility at 208C 
unless otherwise stated 
Acetone Practically insoluble 
Chloroform Practically insoluble 
Ethanol Practically insoluble 
Methanol Slightly soluble 
Water 1 in 20 000 at 258C 
1 in 10 at 808C 
1 in 5 at 908C 
Specific surface area: 1.2–2.0m2/g 
11 Stability and Storage Conditions 
At ambient temperature, sodium stearyl fumarate is stable for 
up to 3 years when stored in amber glass bottles with 
polyethylene screw caps. 
The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Sodium stearyl fumarate is reported to be incompatible with 
chlorhexidine acetate.(10) 
13 Method of Manufacture 
Stearyl alcohol is reacted with maleic anhydride. The product 
of this reaction then undergoes an isomerization step followed 
by salt formation to produce sodium stearyl fumarate.

SEM: 1 
Excipient: Sodium stearyl fumarate 
Manufacturer: JRS Pharma LP 
Lot No.: 255-01 
Magnification: 300 
SEM: 2 
Excipient: Sodium stearyl fumarate 
Manufacturer: JRS Pharma LP 
Lot No.: 255-01 
Magnification: 500 
SEM: 3 
Excipient: Sodium stearyl fumarate 
Manufacturer: JRS Pharma LP 
Lot No.: 255-01 
Magnification: 1000 
14 Safety 
Sodium stearyl fumarate is used in oral pharmaceutical 
formulations and is generally regarded as a nontoxic and 
nonirritant material. 
Metabolic studies of sodium stearyl fumarate in the rat and 
dog indicated that approximately 80% was absorbed and 35% 
was rapidly metabolized. The fraction absorbed was hydrolyzed 
to stearyl alcohol and fumaric acid, with the stearyl 
alcohol further oxidized to stearic acid. In the dog, sodium 
stearyl fumarate that was not absorbed was excreted 
unchanged in the feces within 24 hours.(11) 
Stearyl alcohol and stearic acid are naturally occurring 
constituents in various food products, while fumaric acid is a 
normal constituent of body tissue. Stearates and stearyl citrate 
have been reviewed by theWHOand an acceptable daily intake 
for stearyl citrate has been set at up to 50 mg/kg bodyweight.(
12) The establishment of an acceptable daily intake for 
stearates(12) and fumaric acid(13) was thought unnecessary. 
Disodium fumarate has been reported to have a toxicity not 
greatly exceeding that of sodium chloride.(14,15) 
See Fumaric Acid, Stearic Acid, and Stearyl Alcohol for 
further information. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Sodium stearyl fumarate 
should be handled in a well-ventilated environment; eye 
protection is recommended. 
706 Sodium Stearyl Fumarate

16 Regulatory Status 
GRAS listed. Permitted by the FDA for direct addition to food 
for human consumption as a conditioning or stabilizing agent 
in various bakery products, flour-thickened foods, dehydrated 
potatoes, and processed cereals up to 0.2–1.0% by weight of 
the food. Included in nonparenteral medicines licensed in the 
UK. Included in the FDA Inactive Ingredients Guide (oral 
capsules and tablets). Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
—
18 Comments 
Sodium stearyl fumarate is supplied in a pure form and is often 
of value when the less pure stearate-type lubricants are 
unsuitable owing to chemical incompatibility. Sodium stearyl 
fumarate is less hydrophobic than magnesium stearate or 
stearic acid and has a less retardant effect on tablet dissolution 
than magnesium stearate. A specification for sodium stearyl 
fumarate is contained in the Food Chemicals Codex (FCC). 
The EINECS number for sodium stearyl fumarate is 203- 
743-0. 
19 Specific References 
1 Sure.n G. Evaluation of lubricants in the development of tablet 
formula. Dansk Tidsskr Farm 1971; 45: 331–338. 
2 Ho. lzer AW, Sjo. gren J. Evaluation of sodium stearyl fumarate as a 
tablet lubricant. Int J Pharm 1979; 2: 145–153. 
3 Ho. lzer AW, Sjo. gren J. Evaluation of some lubricants by the 
comparison of friction coefficients and tablet properties. Acta 
Pharm Suec 1981; 18: 139–148. 
4 Saleh SI, Aboutaleb A, Kassem AA, Stamm A. Evaluation of some 
water soluble lubricants for direct compression. Lab Pharm Prob 
Tech 1984; 32: 588–591. 
5 Chowhan ZT, Chi L-H. Drug–excipient interactions resulting from 
powder mixing IV: role of lubricants and their effect on in vitro 
dissolution. J Pharm Sci 1986; 75: 542–545. 
6 Shah NH, Stiel D, Weiss M, et al. Evaluation of two new tablet 
lubricants sodium stearyl fumarate and glyceryl behenate. 
Measurement of physical parameters (compaction, ejection and 
residual forces) in the tableting process and the effect on the 
dissolution rate. Drug Dev Ind Pharm 1986; 12: 1329–1346. 
7 Davies PN, Storey DE, Worthington HEC. Some pitfalls in 
accelerated stability testing with tablet and capsule lubricants. J 
Pharm Pharmacol 1987; 39: 86P. 
8 Mu X, Tobyn MJ, Stanforth JN. Investigations into the food effect 
on a polysaccharide dosage form. Eur J Pharm Sci 1996; 4 (Suppl. 
1): S184. 
9 Michoel A, Rombaut P, Verhoye A. Comparative evaluation of coprocessed 
lactose and microcrystalline cellulose with their physical 
mixtures in the formulation of folic acid tablets. Pharm Dev 
Technol 2002; 7(1): 79–87. 
10 Pesonen T, Kanerva H, Hirvonen J, et al. Incompatibilities between 
chlorhexidine diacetate and some tablet excipients. Drug Dev Ind 
Pharm 1995; 21: 747–752. 
11 Figdor SK, Pinson R. The absorption and metabolism of orally 
administered tritium labelled sodium stearyl fumarate in the rat 
and dog. J Agric Food Chem 1970; 18(5): 872–877. 
12 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications. 
Seventeenth report of the joint FAO/WHO expert committee on 
food additives.World Health Organ Tech Rep Ser 1974; No. 539. 
13 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirty-fifth report of the FAO/WHO expert committee on 
food additives.World Health Organ Tech Rep Ser 1990; No. 789. 
14 Bodansky O, Gold H, ZahmW. The toxicity and laxative action of 
sodium fumarate. J Am Pharm Assoc (Sci) 1942; 31: 1–8. 
15 Locke A, Locke RB, Schlesinger H, Carr H. The comparative 
toxicity and cathartic efficiency of disodium tartrate and fumarate, 
and magnesium fumarate, for the mouse and rabbit. J Am Pharm 
Assoc (Sci) 1942; 31: 12–14. 
20 General References 
JRS Pharma LP 2003. Pruv sodium stearyl fumarate. 
http://www.jrspharma.com/lubricants_pdfs/pruv_rev_02.pdf 
(accessed 19 April 2005). 
Nicklasson M, Brodin A. The coating of disk surfaces by tablet 
lubricants, determined by an intrinsic rate of dissolution method. 
Acta Pharm Suec 1982; 19: 99–108. 
Zanowiak P. Lubrication in solid dosage form design and manufacture. 
In: Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical 
Technology, vol. 9. New York: Marcel Dekker, 1994: 87–111. 
21 Authors 
PJ Weller. 
22 Date of Revision 
19 April 2005. 
Sodium Stearyl Fumarate 707

Sodium Sulfite 
1 Nonproprietary Names 
BP: Sodium sulphite anhydrous 
JP: Dried sodium sulfite 
PhEur: Natrii sulfis anhydricus 
USPNF: Sodium sulfite anhydrous 
2 Synonyms 
Anhydrous sodium sulfite; disodium sulfite; exsiccated sodium 
sulfite; E221; sulfurous acid disodium salt. 
3 Chemical Name and CAS Registry Number 
Sodium sulfite [7757-83-7] 
4 Empirical Formula and Molecular Weight 
Na2SO3 126.04 
5 Structural Formula 
Na2SO3 
6 Functional Category 
Antimicrobial preservative; antioxidant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sodium sulfite is used as an antioxidant in applications similar 
to those for sodium metabisulfite(1) It is also an effective 
antimicrobial preservative, particularly against fungi at low pH 
(0.1% w/v of sodium sulfite is used). Sodium sulfite is used in 
cosmetics, food products, and pharmaceutical applications 
such as parenteral formulations, inhalations, oral formulations, 
and topical preparations. 
See also Sodium Metabisulfite. 
8 Description 
Sodium sulfite occurs as an odorless white powder or 
hexagonal prisms. Note that the commercially available 
sodium sulfite is often presented as a white to tan- or pinkcolored 
powder that would not conform to the pharmacopeial 
specification. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for sodium sulfite. 
Test JP 2001 PhEur 2005 USPNF 23 
Characters . . — 
Identification . . . 
Appearance of solution — . . 
Heavy metals 420 ppm 410 ppm 410 ppm 
Iron — 410 ppm 410 ppm 
Selenium — 410 ppm 410 ppm 
Thiosulfates . 40.1% . 
Zinc — 425 ppm 425 ppm 
Assay 597% 95.0–100.5% 95.0–100.5% 
10 Typical Properties 
Acidity/alkalinity: pH = 9 for an aqueous solution. 
Density: 2.633 g/cm3 
Hygroscopicity: hygroscopic. 
Solubility: soluble 1 in 3.2 parts of water; soluble in glycerin; 
practically insoluble in ethanol (95%). 
11 Stability and Storage Conditions 
Sodium sulfite should be stored in a well-closed container in a 
cool, dry, place. In solution, sodium sulfite is slowly oxidized to 
sulfate by dissolved oxygen; strong acids lead to formation of 
sulfurous acid/sulfur dioxide. On heating, sodium sulfite 
decomposes liberating sulfur oxides. 
12 Incompatibilities 
Sodium sulfite is incompatible with acids, oxidizing agents, 
many proteins, and vitamin B1. See also Sodium Metabisulfite. 
13 Method of Manufacture 
Sodium bisulfite is prepared by reacting sulfur dioxide gas with 
sodium hydroxide solution. The solid material is obtained by 
evaporation of water. Further neutralization with sodium 
hydroxide while keeping the temperature above 33.68C leads 
to crystallization of the anhydrous sodium sulfite (below this 
temperature the heptahydrate form is obtained). 
14 Safety 
Sodium sulfite is widely used in food and pharmaceutical 
applications as an antioxidant. It is generally regarded as 
relatively nontoxic and nonirritant when used as an excipient.(
2,3) However, contact dermatitis and hypersensitivity 
reactions have been reported.(4,5) The acceptable daily intake 
for sodium sulfite has been set at up to 350 mg/kg bodyweight 
daily.(6) 
LD50 (mouse, IP): 0.950 g/kg(7) 
LD50 (mouse, IV): 0.130 g/kg 
LD50 (mouse, oral): 0.820 g/kg 
LD50 (rabbit, IV): 0.065 g/kg 
LD50 (rabbit, oral): 1.181 g/kg 
LD50 (rat, IV): 0.115 g/kg

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in FDA Inactive Ingredients Guide (epidural, IM, IV, 
and SC injections; inhalation solution; ophthalmic solutions; 
oral syrups and suspensions; otic solutions; topical creams and 
emulsions). Included in nonparenteral medicines licensed in the 
UK. 
17 Related Substances 
Sodium sulfite heptahydrate; sodium metabisulfite. 
Sodium sulfite heptahydrate 
Synonyms: natrii sulfis heptahydricus. 
CAS number: [7785-83-7] 
Molecular weight: 252.15 
Description: colorless crystals. 
Density: 1.56 g/cm3 
Solubility: 1 in 1.6 of water; 1 in 30 of glycerin; sparingly 
soluble in ethanol (95%). 
Comments: sodium sulfite heptahydrate is included in the 
PhEur 2005. The heptahydrate is unstable, oxidizing in the 
air to the sulfate. 
18 Comments 
The EINECS number for sodium sulfite is 231-821-4. 
19 Specific References 
1 Islam MS, Asker AF. Photoprotection of daunorubicin hydrochloride 
with sodium sulfite. PDA J Pharm Sci Technol 1995; 49: 
122–126. 
2 Nair B, Elmore AR. Final report on the safety assessment of 
sodium sulfite, potassium sulfite, ammonium sulfite, sodium 
bisulfite, ammonium bisulfite, sodium metabisulfite and potassium 
metabisulfite. Int J Toxicol 2003; 22(2): 63–88. 
3 Gunnisson AF. Sulphite toxicity: a critical review of in vitro and in 
vivo data. Food Cosmet Toxicol 1981; 19: 667–682. 
4 Vissers-Croughs KJ, van der Kley AM, Vulto AG, Hulsman RF. 
Allergic contact dermatitis from sodium sulfite. Contact Dermatitis 
1988; 18(4): 252–253. 
5 Gunnisson AF, Jacobsen DW. Sulphite hypersensitivity: a critical 
review. CRC Crit Review Toxicol 1987; 17(3): 185–214. 
6 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirtieth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1987: No. 
751. 
7 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3281–3282. 
20 General References 
—
21 Authors 
HJ de Jong. 
22 Date of Revision 
17 August 2005. 
Sodium Sulfite 709

Sorbic Acid 
1 Nonproprietary Names 
BP: Sorbic acid 
PhEur: Acidum sorbicum 
USPNF: Sorbic acid 
2 Synonyms 
E200; (2-butenylidene) acetic acid; crotylidene acetic acid; 
hexadienic acid; hexadienoic acid; 2,4-hexadienoic acid; 1,3- 
pentadiene-1-carboxylic acid; 2-propenylacrylic acid; (E,E)- 
sorbic acid; Sorbistat K. 
3 Chemical Name and CAS Registry Number 
(E,E)-Hexa-2,4-dienoic acid [22500-92-1] 
4 Empirical Formula and Molecular Weight 
C6H8O2 112.13 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sorbic acid is an antimicrobial preservative(1) with antibacterial 
and antifungal properties used in pharmaceuticals, foods, 
enteral preparations, and cosmetics. Generally, it is used at 
concentrations of 0.05–0.2% in oral and topical pharmaceutical 
formulations, especially those containing nonionic surfactants. 
Sorbic acid is also used with proteins, enzymes, gelatin, 
and vegetable gums.(2) It has been shown to be an effective 
preservative for promethazine hydrochloride solutions in a 
concentration of 1 g/L.(3) 
Sorbic acid has limited stability and activity against bacteria 
and is thus frequently used in combination with other 
antimicrobial preservatives or glycols, when synergistic effects 
appear to occur; see Section 10. 
8 Description 
Sorbic acid is a tasteless, white to yellow-white crystalline 
powder with a faint characteristic odor. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for sorbic acid. 
Test PhEur 2005 USPNF 23 
Identification . . 
Appearance of solution . — 
Melting range 132–1368C 132–1358C 
Water 41.0% 40.5% 
Residue on ignition — 40.2% 
Sulfated ash 40.2% — 
Heavy metals 410 ppm 40.001% 
Aldehyde (as C2H4O) 40.15% — 
Organic volatile impurities — . 
Assay (anhydrous basis) 99.0–101.0% 99.0–101.0% 
10 Typical Properties 
Antimicrobial activity: sorbic acid is primarily used as an 
antifungal agent, although it also possesses antibacterial 
properties. The optimum antibacterial activity is obtained at 
pH 4.5; and practically no activity is observed above pH 
6.(4,5) The efficacy of sorbic acid is enhanced when it is used 
in combination with other antimicrobial preservatives or 
glycols since synergistic effects occur.(6) Reported minimum 
inhibitory concentrations (MICs) at pH 6 are shown in 
Table II.(7) 
Table II: Minimum inhibitory concentrations (MICs) of sorbic acid at 
pH 6. 
Microorganism MIC (mg/mL) 
Aspergillus niger 200–500 
Candida albicans 25–50 
Clostridium sporogenes 100–500 
Escherichia coli 50–100 
Klebsiella pneumoniae 50–100 
Penicillium notatum 200–300 
Pseudomonas aeruginosa 100–300 
Pseudomonas cepacia 50–100 
Pseudomonas fluorescens 100–300 
Saccharomyces cerevisiae 200–500 
Staphylococcus aureus 50–100 
Boiling point: 2288C with decomposition. 
Density: 1.20 g/cm3 
Dissociation constant: pKa = 4.76 
Flash point: 1278C 
Melting point: 134.58C 
Solubility: see Table III. In syrup, the solubility of sorbic acid 
decreases with increasing sugar content. 
Vapor pressure: <1.3 Pa (<0.01 mmHg) at 208C

Table III: Solubility of sorbic acid. 
Solvent Solubility at 208C 
unless otherwise stated 
Acetone 1 in 11 
Chloroform 1 in 15 
Ethanol 1 in 8 
Ethanol (95%) 1 in 10 
Ether 1 in 30 
Glycerin 1 in 320 
Methanol 1 in 8 
Propylene glycol 1 in 19 
Water 1 in 400 at 308C 
1 in 26 at 1008C 
SEM: 1 
Excipient: Sorbic acid 
Manufacturer: Pfizer Ltd. 
Magnification: 60 
11 Stability and Storage Conditions 
Sorbic acid is sensitive to oxidation, particularly in the presence 
of light; oxidation occurs more readily in aqueous solution than 
in the solid form. Sorbic acid may be stabilized by phenolic 
antioxidants such as 0.02% propyl gallate.(6) 
Sorbic acid is combustible when exposed to heat or flame. 
When heated to decomposition, it emits acrid smoke and 
irritating fumes. The bulk material should be stored in a wellclosed 
container, protected from light, at a temperature not 
exceeding 408C. 
12 Incompatibilities 
Sorbic acid is incompatible with bases, oxidizing agents, and 
reducing agents. Some loss of antimicrobial activity occurs in 
the presence of nonionic surfactants and plastics. Oxidation is 
catalyzed by heavy-metal salts. Sorbic acid will also react with 
sulfur-containing amino acids, although this can be prevented 
by the addition of ascorbic acid, propyl gallate, or butylhydroxytoluene. 
When stored in glass containers, the solution becomes very 
pH sensitive; therefore, preparations using sorbic acid as a 
preservative should be tested for their microbial purity after 
prolonged periods of storage. 
Aqueous solutions of sorbic acid without the addition of 
antioxidants are rapidly decomposed when stored in polypropylene, 
polyvinylchloride, and polyethylene containers. 
13 Method of Manufacture 
Naturally occurring sorbic acid may be extracted as the lactone 
(parasorbic acid) from the berries of the mountain ash Sorbus 
aucuparia L. (Fam. Rosaceae). Synthetically, sorbic acid may be 
prepared by the condensation of crotonaldehyde and ketene in 
the presence of boron trifluoride; by the condensation of 
crotonaldehyde and malonic acid in pyridine solution; or from 
1,1,3,5-tetraalkoxyhexane. Fermentation of sorbaldehyde or 
sorbitol with bacteria in a culture medium has also been used. 
14 Safety 
Sorbic acid is used as an antimicrobial preservative in oral and 
topical pharmaceutical formulations and is generally regarded 
as a nontoxic material. However, adverse reactions to sorbic 
acid and potassium sorbate, including irritant skin reactions(
8–11) and allergic hypersensitivity skin reactions (which 
are less frequent), have been reported.(12–14) 
Other adverse reactions that have been reported include 
exfoliative dermatitis due to ointments that contain sorbic 
acid,(15) and allergic conjunctivitis caused by contact lens 
solutions preserved with sorbic acid.(16) 
No adverse reactions have been described after systemic 
administration of sorbic acid, and it has been reported that it 
can be ingested safely by patients who are allergic to sorbic 
acid.(17) However, perioral contact urticaria has been 
reported.(11) 
The WHO has set an estimated total acceptable daily intake 
for sorbic acid, calcium sorbate, potassium sorbate, and sodium 
sorbate, expressed as sorbic acid, at up to 25 mg/kg bodyweight.(
18,19) 
Animal toxicological studies have shown no mammalian 
carcinogenicity or teratogenicity for sorbic acid consumed at up 
to 10% of the diet.(20) 
LD50 (mouse, IP): 2.82 g/kg(21) 
LD50 (mouse, oral): 3.20 g/kg 
LD50 (mouse, SC): 2.82 g/kg 
LD50 (rat, oral): 7.36 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Sorbic acid can be irritant to 
the skin, eyes, and respiratory system. Eye protection, gloves, 
and a dust mask or respirator are recommended. 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (ophthalmic solutions; oral 
capsules, solutions, syrups, tablets, topical and vaginal 
preparations). Included in nonparenteral medicines licensed in 
the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
Sorbic Acid 711

17 Related Substances 
Calcium sorbate; potassium sorbate; sodium sorbate. 
Calcium sorbate 
Empirical formula: C12H14O4Ca 
Synonyms: E203 
Molecular weight: 262.33 
CAS number: [7492-55-9] 
Appearance: white, odorless, tasteless, crystalline powder. 
Solubility: soluble 1 in 83 parts of water; practically insoluble in 
fats. 
Comments: the EINECS number for calcium sorbate is 231- 
321-6. 
Sodium sorbate 
Empirical formula: C6H7O2Na 
Synonyms: E201; sodium (E,E)-hexa-2,4-dienoate. 
Molecular weight: 134.12 
CAS number: [42788-83-0] 
Appearance: light, white, crystalline powder. 
Solubility: soluble 1 in 3 parts of water. 
Comments: the EINECS number for sodium sorbate is 231- 
819-3. 
18 Comments 
The trans,trans-isomer of sorbic acid is the commercial 
product. A specification for sorbic acid is contained in the 
Food Chemicals Codex (FCC). 
The EINECS number for sorbic acid is 203-768-7. 
19 Specific References 
1 Charvalos E, Tzatzarakis M, Tsatsakis A, Petrikkos G. Controlled 
release of water-soluble polymeric complexes of sorbic acid with 
antifungal activities. Appl Microbiol Biotechnol 2001; 57(5–6): 
770–775. 
2 Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation 
Agents: A Handbook of Excipients. New York: Marcel Dekker, 
1989: 179. 
3 Van-Doorne H, Leijen JB. Preservation of some oral liquid 
preparations: replacement of chloroform by other preservatives. 
Pharm World Sci 1994; 16(Feb 18): 18–21. 
4 Golightly LK, Smolinske SS, Bennett ML, et al. Adverse effects 
associated with inactive ingredients in drug products (part I). Med 
Toxicol 1988; 3: 128–165. 
5 Eklund T. The antimicrobial effect of dissociated and undissociated 
sorbic acid at different pH levels. J Appl Bacteriol 1983; 54: 383– 
389. 
6 Woodford R, Adams E. Sorbic acid. Am Perfum Cosmet 1970; 
85(3): 25–30. 
7 Wallha. usser KH. Sorbic acid. In: Kabara JJ, ed. Cosmetic and 
Drug Preservation Principles and Practice. New York: Marcel 
Dekker, 1984: 668–670. 
8 Soschin D, Leyden JJ. Sorbic acid-induced erythema and edema. J 
Am Acad Dermatol 1986; 14: 234–241. 
9 Fisher AA. Erythema limited to the face due to sorbic acid. Cutis 
1987; 40: 395–397. 
10 Clemmensen OJ, Schiodt M. Patch test reaction of the buccal 
mucosa to sorbic acid. Contact Dermatitis 1982; 8(5): 341–342. 
11 Clemmensen O, Hjorth N. Perioral contact urticaria from sorbic 
acid and benzoic acid in a salad dressing. Contact Dermatitis 1982; 
3: 1–6. 
12 Saihan EM, Harman RRM. Contact sensitivity to sorbic acid in 
‘Unguentum Merck’. Br J Dermatol 1978; 99: 583–584. 
13 Fisher AA. Cutaneous reactions to sorbic acid and potassium 
sorbate. Cutis 1980; 25: 350, 352, 423. 
14 Fisher AA. Allergic reactions to the preservatives in over-thecounter 
hydrocortisone topical creams and lotions. Cutis 1983; 32: 
222, 224, 230. 
15 Coyle HE, Miller E, Chapman RS. Sorbic acid sensitivity from 
Unguentum Merck. Contact Dermatitis 1981; 7: 56–57. 
16 Fisher AA. Allergic reactions to contact lens solutions. Cutis 1985; 
36: 209–211. 
17 Klaschka F, Beiersdorff HU. Allergic eczematous reaction from 
sorbic acid used as a preservative in external medicaments. Munch 
Med Wschr 1965; 107: 185–187. 
18 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications. 
Seventeenth report of the joint FAO/WHO expert committee on 
food additives.World Health Organ Tech Rep Ser 1974; No. 539. 
19 FAO/WHO. Evaluation of certain food additives and contaminants. 
Twenty-ninth report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1986; No. 733. 
20 Walker R. Toxicology of sorbic acid and sorbates. Food Addit 
Contam 1990; 7(5): 671–676. 
21 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3291. 
20 General References 
Radus TP, Gyr G. Determination of antimicrobial preservatives in 
pharmaceutical formulations using reverse-phase liquid chromatography. 
J Pharm Sci 1983; 72: 221–224. 
Sofos JN, Busta FF. Sorbates. In: Branen AL, Davidson PM, eds. 
Antimicrobials in Foods. New York: Marcel Dekker, 1983: 141– 
175. 
Warth A. Mechanism of resistance of Saccharomyces bailii to benzoic, 
sorbic and other weak acids used as food preservatives. J Appl 
Bacteriol 1977; 43: 215–230. 
21 Authors 
W Cook. 
22 Date of Revision 
4 August 2005. 
712 Sorbic Acid

Sorbitan Esters (Sorbitan Fatty Acid Esters) 
1 Nonproprietary Names 
BP: Sorbitan laurate 
Sorbitan oleate 
Sorbitan palmitate 
Sorbitan stearate 
Sorbitan trioleate 
JP: Sorbitan sesquioleate 
PhEur: Sorbitani lauras 
Sorbitani oleas 
Sorbitani palmitas 
Sorbitani sesquioleas 
Sorbitani stearas 
Sorbitani trioleas 
USPNF: Sorbitan monolaurate (sorbitan, esters monodecanoate) 
Sorbitan monooleate 
Sorbitan monopalmitate 
Sorbitan monostearate 
Sorbitan sesquioleate 
Sorbitan trioleate 
2 Synonyms 
See Table I. 
3 Chemical Names and CAS Registry Numbers 
See Table II. 
Table II: Chemical name and CAS Registry Number of selected 
sorbitan esters. 
Name Chemical name CAS number 
Sorbitan diisostearate Sorbitan diisooctadecanoate [68238-87-9] 
Sorbitan dioleate (Z,Z)-Sorbitan di-9- 
octadecanoate 
[29116-98-1] 
Sorbitan monolaurate Sorbitan monododecanoate [1338-39-2] 
Sorbitan monoisostearate Sorbitan 
monoisooctadecanoate 
[71902-01-7] 
Sorbitan monooleate (Z)-Sorbitan mono-9- 
octadecenoate 
[1338-43-8] 
Sorbitan monopalmitate Sorbitan monohexadecanoate[26266-57-9] 
Sorbitan monostearate Sorbitan mono-octadecanoate [1338-41-6] 
Sorbitan sesquiisostearateSorbitan 
sesquiisooctadecanoate 
[71812-38-9] 
Sorbitan sesquioleate (Z)-Sorbitan sesqui-9- 
octadecenoate 
[8007-43-0] 
Sorbitan sesquistearate Sorbitan sesqui-octadecanoate[51938-44-4] 
Sorbitan triisostearate Sorbitan triisooctadecanoate [54392-27-7] 
Sorbitan trioleate (Z,Z,Z)-Sorbitan tri-9- 
octadecenoate 
[26266-58-0] 
Sorbitan tristearate Sorbitan tri-octadecanoate [26658-19-5] 
4 Empirical Formula and Molecular Weight 
See Table III. 
Table I: Synonyms of selected sorbitan esters. 
Name Synonym 
Sorbitan monoisostearate 1,4-Anhydro-D-glucitol, 6-isooctadecanoate; anhydrosorbitol monoisostearate; Arlacel 987; Crill 6; sorbitan isostearate. 
Sorbitan monolaurate Arlacel 20; Armotan ML; Crill 1; Dehymuls SML; E493; Glycomul L; Hodag SML; Liposorb L; Montane 20; Protachem 
SML; Sorbester P12; Sorbirol L; sorbitan laurate; Span 20; Tego SML. 
Sorbitan monooleate Ablunol S-80; Arlacel 80; ArmotanMO; Capmul O; Crill 4; Crill 50; Dehymuls SMO; Drewmulse SMO; Drewsorb 80K; 
E494; Glycomul O; Hodag SMO; Lamesorb SMO; Liposorb O; Montane 80; Nikkol SO-10; Nissan Nonion OP- 
80R; Norfox Sorbo S-80; Polycon S80 K; Proto-sorb SMO; Protachem SMO; S-Maz 80K; Sorbester P17; SorbirolO; 
sorbitan oleate; Sorgen 40; Sorgon S-40-H; Span 80; Tego SMO. 
Sorbitan monopalmitate 1,4-Anhydro-D-glucitol, 6-hexadecanoate; Ablunol S-40; Arlacel 40; Armotan MP; Crill 2; Dehymuls SMP; E495; 
Glycomul P; Hodag SMP; Lamesorb SMP; Liposorb P; Montane 40; Nikkol SP-10; Nissan Nonion PP-40R; Protachem 
SMP; Proto-sorb SMP; Sorbester P16; Sorbirol P; sorbitan palmitate; Span 40. 
Sorbitan monostearate Ablunol S-60; Alkamuls SMS; 1,4-Anhydro-D-glucitol, 6-octadecanoate; anhydrosorbitol monostearate; Arlacel 60; 
Armotan MS; Atlas 110K; Capmul S; Crill 3; Dehymuls SMS; Drewmulse SMS; Drewsorb 60K; Durtan 6O; Durtan 
60K; E491; Famodan MS Kosher; Glycomul S FG; Glycomul S KFG; Hodag SMS; Lamesorb SMS; Liposorb S; 
Liposorb SC; Liposorb S-K; Montane 60; Nissan Nonion SP-60R; Norfox Sorbo S-60FG; Polycon S60K; Protachem 
SMS; Prote-sorb SMS; S-Maz 60K; S-Maz 60KHS; Sorbester P18; Sorbirol S; sorbitan stearate; Sorgen 50; Span 60; 
Span 60K; Span 60 VS; Tego SMS. 
Sorbitan sesquiisostearate Protachem SQI. 
Sorbitan sesquioleate Arlacel C; Arlacel 83; Crill 43; Glycomul SOC; Hodag SSO; Liposorb SQO; Montane 83; Nikkol SO-15; Nissan 
Nonion OP-83RAT; Protachem SOC; Sorgen 30; Sorgen S-30-H. 
Sorbitan trilaurate Span 25. 
Sorbitan trioleate Ablunol S-85; Arlacel 85; Crill 45; Glycomul TO; Hodag STO; Liposorb TO; Montane 85; Nissan Nonion OP-85R; 
Protachem STO; Prote- sorb STO; S-Maz 85K; Sorbester P37; Span 85; Tego STO. 
Sorbitan tristearate Alkamuls STS; Crill 35; Crill 41; Drewsorb 65K; E492; Famodan TS Kosher; Glycomul TS KFG; Hodag STS; Lamesorb 
STS; Liposorb TS; Liposorb TS-K; Montane 65; Protachem STS; Proteo-sorb STS; Sorbester P38; Span 65; Span 65K.

Table III: Empirical formula and molecular weight of selected sorbitan 
esters. 
Name Formula Molecular weight 
Sorbitan diisostearate C42H80O7 697 
Sorbitan dioleate C42H76O7 693 
Sorbitan monoisostearate C24H46O6 431 
Sorbitan monolaurate C18H34O6 346 
Sorbitan monooleate C24H44O6 429 
Sorbitan monopalmitate C22H42O6 403 
Sorbitan monostearate C24H46O6 431 
Sorbitan sesquiisostearate C33H63O6.5 564 
Sorbitan sesquioleate C33H60O6.5 561 
Sorbitan sesquistearate C33H63O6.5 564 
Sorbitan triisostearate C60H114O8 964 
Sorbitan trioleate C60H108O8 958 
Sorbitan tristearate C60H114O8 964 
5 Structural Formula 
R1 = R2 = OH, R3 = R (see below) for sorbitan monoesters 
R1 = OH, R2 = R3 = R for sorbitan diesters 
R1 = R2 = R3 = R for sorbitan triesters 
where R = 
(C17H35)COO for isostearate 
(C11H23)COO for laurate 
(C17H33)COO for oleate 
(C15H31)COO for palmitate 
(C17H35)COO for stearate 
The sesquiesters are equimolar mixtures of monoesters and 
diesters. 
6 Functional Category 
Emulsifying agent; nonionic surfactant; solubilizing agent; 
wetting and dispersing/suspending agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sorbitan monoesters are a series of mixtures of partial esters of 
sorbitol and its mono- and dianhydrides with fatty acids. 
Sorbitan diesters are a series of mixtures of partial esters of 
sorbitol and its monoanhydride with fatty acids. 
Sorbitan esters are widely used in cosmetics, food products, 
and pharmaceutical formulations as lipophilic nonionic surfactants. 
They are mainly used in pharmaceutical formulations as 
emulsifying agents in the preparation of creams, emulsions, and 
ointments for topical application. When used alone, sorbitan 
esters produce stable water-in-oil emulsions and microemulsions 
but are frequently used in combination with varying 
proportions of a polysorbate to produce water-in-oil or oil-inwater 
emulsions or creams of varying consistencies. 
Sorbitan monolaurate, sorbitan monopalmitate and sorbitan 
trioleate have also been used at concentrations of 
0.01–0.05% w/v in the preparation of an emulsion for 
intramuscular administration. See Table IV. 
Table IV: Uses of sorbitan esters. 
Use Concentration (%) 
Emulsifying agent 
Used alone in water-in-oil emulsions 1–15 
Used in combination with hydrophilic 
emulsifiers in oil-in-water emulsions 
1–10 
Used to increase the water-holding properties of 
ointments 
1–10 
Solubilizing agent 
For poorly soluble, active constituents in 
lipophilic bases 
1–10 
Wetting agent 
For insoluble, active constituents in 
lipophilic bases 
0.1–3 
8 Description 
Sorbitan esters occur as cream- to amber-colored liquids or 
solids with a distinctive odor and taste; see Table V. 
Table V: Appearance of selected sorbitan esters. 
Name Appearance 
Sorbitan monoisostearate Yellow viscous liquid 
Sorbitan monolaurate Yellow viscous liquid 
Sorbitan monooleate Yellow viscous liquid 
Sorbitan monopalmitate Cream solid 
Sorbitan monostearate Cream solid 
Sorbitan sesquioleate Amber viscous liquid 
Sorbitan trioleate Amber viscous liquid 
Sorbitan tristearate Cream/yellow solid 
9 Pharmacopeial Specifications 
See Table VI. 
10 Typical Properties 
Acid value: see Table VII. 
Density: see Table VII. 
Flash point: >1498C 
HLB value: see Table VII. 
Hydroxyl value: see Table VII. 
Iodine number: see Table VII. 
Melting point: see Table VII. 
Moisture content: see Table VIII. 
Pour point: see Table VII. 
Saponification value: see Table VIII. 
Solubility: sorbitan esters are generally soluble or dispersible in 
oils; they are also soluble in most organic solvents. In water, 
although insoluble, they are generally dispersible. 
Surface tension: see Table VIII. 
Viscosity (dynamic): see Table VIII. 
714 Sorbitan Esters (Sorbitan Fatty Acid Esters)

Table VI: Pharmacopeial specifications for sorbitan esters. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters — . — 
Acid value 
Sorbitan monolaurate — 47.0 48 
Sorbitan monooleate — 48.0 48 
Sorbitan monopalmitate — 48.0 48 
Sorbitan monostearate — 410.0 410 
Sorbitan sesquioleate — 416.0 414 
Sorbitan trioleate — 416.0 417 
Hydroxyl value 
Sorbitan monolaurate — 330–358 330–358 
Sorbitan monooleate — 190–210 190–215 
Sorbitan monopalmitate — 270–305 275–305 
Sorbitan monostearate — 235–260 235–260 
Sorbitan sesquioleate — 180–215 182–220 
Sorbitan trioleate — 55–75 50–75 
Iodine value 
Sobitan monolaurate — 410.0 — 
Sorbitan monooleate — 62–76 62–76 
Sorbitan sesquioleate — 70–95 65–75 
Sorbitan trioleate — 76–90 77–85 
Peroxide value 
Sorbitan monolaurate — 45.0 — 
Sorbitan monooleate — 410.0 — 
Sorbitan monopalmitate — 45.0 — 
Sorbitan monostearate — 45.0 — 
Sorbitan sesquioleate — 410.0 — 
Sorbitan trioleate — 410.0 — 
Saponification value 
Sorbitan monolaurate — 158–170 158–170 
Sorbitan monooleate — 145–160 145–160 
Sorbitan monopalmitate — 140–155 140–150 
Sorbitan monostearate — 147–157 147–157 
Sorbitan sesquioleate 150–168 145–166 143–165 
Sorbitan trioleate — 170–190 169–183 
Water 
Sorbitan monolaurate — 41.5% 41.5% 
Sorbitan monooleate — 41.5% 41.0% 
Sorbitan monopalmitate — 41.5% 41.5% 
Sorbitan monostearate — 41.5% 41.5% 
Sorbitan sesquioleate 43.0% 41.5% 41.0% 
Sorbitan trioleate — 41.5% 40.7% 
Residue on ignition 
Sorbitan monolaurate — — 40.5% 
Sorbitan monooleate — — 40.5% 
Sorbitan monopalmitate — — 40.5% 
Sorbitan monostearate — — 40.5% 
Sorbitan sesquioleate 41.0% — 41.4% 
Sorbitan trioleate — — 40.25% 
Total ash — 40.5% — 
Heavy metals 420 ppm 410 ppm 40.001% 
Arsenic 42 ppm — — 
Specific gravity 
Sorbitan laurate — 0.98 — 
Sorbitan oleate — 0.99 — 
Sorbitan sesquioleate 0.960–1.020 0.99 — 
Melting point 
Sorbitan palmitate — 44–518C — 
Sorbitan monostearate — 50–608C — 
Organic volatile impurities — — . 
Assay for fatty acids 
Sorbitan monolaurate — . 55.0–63.0% 
Continued 
Sorbitan Esters (Sorbitan Fatty Acid Esters) 715

11 Stability and Storage Conditions 
Gradual soap formation occurs with strong acids or bases; 
sorbitan esters are stable in weak acids or bases. 
Sorbitan esters should be stored in a well-closed container in 
a cool, dry place. 
12 Incompatibilities 
—
13 Method of Manufacture 
Sorbitol is dehydrated to form a hexitan (1,4-sorbitan), which 
is then esterified with the desired fatty acid. 
14 Safety 
Sorbitan esters are widely used in cosmetics, food products, and 
oral and topical pharmaceutical formulations and are generally 
regarded as nontoxic and nonirritant materials. However, there 
have been occasional reports of hypersensitive skin reactions 
following the topical application of products containing 
sorbitan esters.(1–4) When heated to decomposition, the 
sorbitan esters emit acrid smoke and irritating fumes. 
The WHO has set an estimated acceptable daily intake of 
sorbitan monopalmitate, monostearate, and tristearate,(5) and 
of sorbitan monolaurate and monooleate(6) at up to 25 mg/kg 
body-weight calculated as total sorbitan esters. 
Sorbitan monolaurate: LD50 (rat, oral): 33.6 g/kg.(7) 
Experimental neoplastigen. 
Sorbitan monostearate: LD50 (rat, oral): 31 g/kg.(7) 
Very mildly toxic by ingestion. Experimental reproductive 
effects. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. 
Test JP 2001 PhEur 2005 USPNF 23 
Sorbitan monooleate — . 72.0–78.0% 
Sorbitan monopalmitate — . 63.0–71.0% 
Sorbitan monostearate — . 68.0–76.0% 
Sorbitan sesquioleate — . 74.0–80.0% 
Sorbitan trioleate — . 85.5–90.0% 
Assay for polyols 
Sorbitan monolaurate — — 39.0–45.0% 
Sorbitan monooleate — — 25.0–31.0% 
Sorbitan monopalmitate — — 32.0–38.0% 
Sorbitan monostearate — — 27.0–34.0% 
Sorbitan sesquioleate — — 22.0–28.0% 
Sorbitan trioleate — — 13.0–19.0% 
Table VII: Typical properties of selected sorbitan esters. 
Name Acid value Density (g/cm3) HLB value Hydroxyl value Iodine number Melting point (8C) Pour point (8C) 
Sorbitan monoisostearate 48 — 4.7 220–250 — — — 
Sorbitan monolaurate 47 1.01 8.6 159–169 47 — 16–20 
Sorbitan monooleate 48 1.01 4.3 193–209 — — 12 
Sorbitan monopalmitate 3–7 1.0 6.7 270–303 41 43–48 — 
Sorbitan monostearate 5–10 — 4.7 235–260 41 53–57 — 
Sorbitan sesquioleate 8.5–13 1.0 3.7 188–210 — — — 
Sorbitan trioleate 10–14 0.95 1.8 55–70 — — — 
Sorbitan tristearate 47 — 2.1 60–80 — — — 
Table VIII: Typical properties of selected sorbitan esters. 
Name Saponification value Surface tension of 1% aqueous 
solution (mN/m) 
Viscosity at 258C (mPa s) Water content (%) 
Sorbitan monoisostearate 143–153 — — 41.0 
Sorbitan monolaurate 159–169 28 3900–4900 40.5 
Sorbitan monooleate 149–160 30 970–1080 40.5 
Sorbitan monopalmitate 142–152 36 Solid 41.0 
Sorbitan monostearate 147–157 46 Solid 41.0 
Sorbitan sesquioleate 149–160 — 1500 41.0 
Sorbitan trioleate 170–190 32 200–250 41.0 
Sorbitan tristearate 172–185 48 Solid 41.0 
Table VI: Continued 
716 Sorbitan Esters (Sorbitan Fatty Acid Esters)

16 Regulatory Status 
Certain sorbitan esters are accepted as food additives in the UK. 
Sorbitan esters are included in the FDA Inactive Ingredients 
Guide (inhalations; IM injections; ophthalmic, oral, topical, 
and vaginal preparations). Sorbitan esters are used in nonparenteral 
medicines licensed in the UK. Sorbitan esters are 
included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Polyoxyethylene sorbitan fatty acid esters. 
18 Comments 
EINECS numbers 
Sorbitan diisostearate [269-410-7] 
Sorbitan dioleate [249-448-0] 
Sorbitan laurate [215-663-3] 
Sorbitan oleate [215-665-4] 
Sorbitan palmitate [247-568-8] 
Sorbitan sesquiolate [232-360-1] 
Sorbitan sesquistearate [257-529-7] 
Sorbitan stearate [215-664-9] 
Sorbitan triisostearate [259-141-3] 
Sorbitan trioleate [247-569-3] 
Sorbitan tristearate 247-891-4 
19 Specific References 
1 Finn OA, Forsyth A. Contact dermatitis due to sorbitan monolaurate. 
Contact Dermatitis 1975; 1: 318. 
2 Hannuksela M, Kousa M, Pirila V. Allergy to ingredients of 
vehicles. Contact Dermatitis 1976; 2: 105–110. 
3 Austad J. Allergic contact dermatitis to sorbitan monooleate (Span 
80). Contact Dermatitis 1982; 8: 426–427. 
4 Boyle J, Kennedy CTC. Contact urticaria and dermatitis to 
Alphaderm. Contact Dermatitis 1984; 10: 178. 
5 FAO/WHO. Toxicological evaluations of certain food additives 
with a review of general principles and of specifications. 
Seventeenth report of the joint FAO/WHO expert committee on 
food additives.World Health Organ Tech Rep Ser 1974; No. 539. 
6 FAO/WHO. Evaluation of certain food additives and contaminants. 
Twenty-sixth report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1982; No. 683. 
7 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3291. 
20 General References 
Konno K, Jinno T, Kitahara A. Solubility, critical aggregating or 
micellar concentration and aggregate formation of non-ionic 
surfactants in non-aqueous solutions. J Colloid Interface Sci 1974; 
49: 383. 
Mittal KL, ed. Micellization, Solubilization and Microemulsions, vol. 1. 
New York: Plenum Press, 1977. 
Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 369–370. 
Suzuki E, Shirotani KI, Tsuda Y, Sekiguchi K. Studies on methods of 
particle size reduction of medicinal compounds VIII: size reduction 
by freeze-drying and the influence of pharmaceutical adjuvants on 
the micromeritic properties of freeze-dried powders. Chem Pharm 
Bull 1979; 27: 1214–1222. 
Whitworth CW, Pongpaibul Y. The influence of some additives on the 
stability of aspirin in an oleaginous suppository base. Can J Pharm 
Sci 1979; 14: 36–38. 
21 Authors 
MJ Lawrence. 
22 Date of Revision 
22 August 2005. 
Sorbitan Esters (Sorbitan Fatty Acid Esters) 717

Sorbitol 
1 Nonproprietary Names 
BP: Sorbitol 
JP: D-Sorbitol 
PhEur: Sorbitolum 
USPNF: Sorbitol 
2 Synonyms 
C*PharmSorbidex; E420; 1,2,3,4,5,6-hexanehexol; Liponic 
70-NC; Liponic 76-NC; Meritol; Neosorb; sorbite; D-sorbitol; 
Sorbitol Instant; Sorbogem. 
3 Chemical Name and CAS Registry Number 
D-Glucitol [50-70-4] 
4 Empirical Formula and Molecular Weight 
C6H14O6 182.17 
5 Structural Formula 
6 Functional Category 
Humectant; plasticizer; sweetening agent; tablet and capsule 
diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sorbitol is widely used as an excipient in pharmaceutical 
formulations. It is also used extensively in cosmetics and food 
products; see Table I. 
Sorbitol is used as a diluent in tablet formulations prepared 
by either wet granulation or direct compression.(1–5) It is 
particularly useful in chewable tablets owing to its pleasant, 
sweet taste and cooling sensation. In capsule formulations it is 
used as a plasticizer for gelatin. Sorbitol has been used as a 
plasticizer in film formulations.(6,7) 
In liquid preparations(8) sorbitol is used as a vehicle in sugarfree 
formulations and as a stabilizer for drug,(9) vitamin,(10,11) 
and antacid suspensions. It has also been shown to be a suitable 
carrier to enhance the in vitro dissolution rate of indometacin.(
12) In syrups it is effective in preventing crystallization 
around the cap of bottles. Sorbitol is additionally used in 
injectable(13) and topical preparations and therapeutically as an 
osmotic laxative. 
Sorbitol may also be used analytically as a marker for 
assessing liver blood flow.(14) 
Table I: Uses of sorbitol. 
Use Concentration (%) 
Humectant 3–15 
IM injections 10–25 
Moisture control agent in tablets 3–10 
Oral solutions 20–35 
Oral suspensions 70 
Plasticizer for gelatin and cellulose 5–20 
Prevention of ‘cap locking’ in syrups and elixirs 15–30 
Substitute for glycerin and propylene glycol 25–90 
Tablet binder and filler 25–90 
Toothpastes 20–60 
Topical emulsions 2–18 
8 Description 
Sorbitol is D-glucitol. It is a hexahydric alcohol related to 
mannose and is isomeric with mannitol. 
Sorbitol occurs as an odorless, white or almost colorless, 
crystalline, hygroscopic powder. Four crystalline polymorphs 
and one amorphous form of sorbitol have been identified that 
have slightly different physical properties, e.g., melting point.(3) 
Sorbitol is available in a wide range of grades and polymorphic 
forms such as granules, flakes, or pellets that tend to cake less 
than the powdered form and have more desirable compression 
characteristics. Sorbitol has a pleasant, cooling, sweet taste and 
has approximately 50–60% of the sweetness of sucrose. 
SEM: 1 
Excipient: Sorbitol 
Manufacturer: SPI Pharma 
Lot No.: 5224F8 
Magnification: 100 
9 Pharmacopeial Specifications 
See Table II.

10 Typical Properties 
Acidity/alkalinity: pH = 4.5–7.0 for a 10% w/v aqueous 
solution. 
Compressibility: compression characteristics and the degree of 
lubrication required vary, depending upon the particle size 
and grade of sorbitol used. 
Density: 1.49 g/cm3 
Density (bulk): 0.448 g/cm3 
Density (tapped): 0.400 g/cm3 
Density (true): 1.507 g/cm3 
Flowability: flow characteristics vary depending upon the 
particle size and grade of sorbitol used. Fine powder grades 
tend to be poorly flowing, while granular grades have good 
flow properties. 
Heat of solution: 110.9 J/g (–26.5 cal/g) 
Melting point: 
Anhydrous form: 110–1128C; 
Gamma polymorph: 97.78C; 
Metastable form: 938C. 
Moisture content: sorbitol is a very hygroscopic powder and 
relative humidities greater than 60% at 258C should be 
avoided when sorbitol is added to direct-compression tablet 
formulas. See also Figure 1. 
Table II: Pharmacopeial specifications for sorbitol. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters . . — 
Acidity or alkalinity . — — 
pH — — 3.5–7.0 
Appearance of solution . . . 
Arsenic 41.3 ppm — — 
Chloride 40.005% — 40.005% 
Sulfate 40.006% — 40.01% 
Conductivity — 420 mScm1 — 
Glucose . — — 
Heavy metals 45 ppm — — 
Lead — 40.5 ppm — 
Microbial contamination — . — 
Bacterial — 4102/g 4103/g 
Fungi — 4102/g 4102/g 
Bacterial endotoxins — . . 
Nickel . 41 ppm 41 mg/g 
Organic volatile 
impurities 
— — . 
Reducing sugars — 40.2% 40.3% 
Related products — 40.1% — 
Residue on ignition 40.02% — 40.1% 
Total sugars . — — 
Water 42.0% 41.5% 41.5% 
Assay (anhydrous basis) 597.0% 97.0–102.0% 91.0–100.5% 
Osmolarity: a 5.48% w/v aqueous solution of sorbitol 
hemihydrate is isoosmotic with serum. 
Particle size distribution: particle size distribution varies 
depending upon the grade of sorbitol. For fine powder 
grades, typically 87% <125 mm in size; for granular grades, 
22% <125 mm, 45% between 125 and 250 mm, and 33% 
between 250 and 590 mm. Individual suppliers’ literature 
should be consulted for further information. 
Solubility: see Table III. 
See also Section 17. 
Table III: Solubility of sorbitol. 
Solvent Solubility at 208C 
Chloroform Practically insoluble 
Ethanol (95%) 1 in 25 
Ethanol (82%) 1 in 8.3 
Ethanol (62%) 1 in 2.1 
Ethanol (41%) 1 in 1.4 
Ethanol (20%) 1 in 1.2 
Ethanol (11%) 1 in 1.14 
Ether Practically insoluble 
Methanol Slightly soluble 
Water 1 in 0.5 
Figure 1: Equilibrium moisture content of sorbitol USPNF. 
11 Stability and Storage Conditions 
Sorbitol is chemically relatively inert and is compatible with 
most excipients. It is stable in air in the absence of catalysts and 
in cold, dilute acids and alkalis. Sorbitol does not darken or 
decompose at elevated temperatures or in the presence of 
amines. It is nonflammable, noncorrosive, and nonvolatile. 
Although sorbitol is resistant to fermentation by many 
microorganisms, a preservative should be added to sorbitol 
solutions. Solutions may be stored in glass, plastic, aluminum, 
and stainless steel containers. Solutions for injection may be 
sterilized by autoclaving. 
The bulk material is hygroscopic and should be stored in an 
airtight container in a cool, dry place. 
12 Incompatibilities 
Sorbitol will form water-soluble chelates with many divalent 
and trivalent metal ions in strongly acidic and alkaline 
conditions. Addition of liquid polyethylene glycols to sorbitol 
solution, with vigorous agitation, produces a waxy, watersoluble 
gel with a melting point of 35–408C. Sorbitol solutions 
also react with iron oxide to become discolored. 
Sorbitol 719

Sorbitol increases the degradation rate of penicillins in 
neutral and aqueous solutions.(15) 
13 Method of Manufacture 
Sorbitol occurs naturally in the ripe berries of many trees and 
plants. It was first isolated in 1872 from the berries of the 
Mountain Ash (Sorbus americana). 
Industrially, sorbitol is prepared by high-pressure hydrogenation 
with a copper–chromium or nickel catalyst, or by 
electrolytic reduction of glucose and corn syrup. If cane or beet 
sugars are used as a source, the disaccharide is hydrolyzed to 
dextrose and fructose prior to hydrogenation. 
14 Safety 
Sorbitol is widely used in a number of pharmaceutical products 
and occurs naturally in many edible fruits and berries. It is 
absorbed more slowly from the gastrointestinal tract than 
sucrose and is metabolized in the liver to fructose and glucose. 
Its caloric value is approximately 16.7 J/g (4 cal/g). Sorbitol is 
better tolerated by diabetics than sucrose and is widely used in 
many sugar-free liquid vehicles. However, it is not considered to 
be unconditionally safe for diabetics. 
Reports of adverse reactions to sorbitol are largely due to its 
action as an osmotic laxative when ingested orally,(16–18) which 
may be exploited therapeutically. Ingestion of large quantities 
of sorbitol (>20 g/day in adults) should therefore be avoided. 
Sorbitol is not readily fermented by oral microorganisms 
and has little effect on dental plaque pH; hence, it is generally 
considered to be noncariogenic.(19) 
Sorbitol is generally considered to be more irritating than 
mannitol. 
LD50 (mouse, IV): 9.48 g/kg(20) 
LD50 (mouse, oral): 17.8 g/kg 
LD50 (rat, IV): 7.1 g/kg 
LD50 (rat, SC): 29.6 g/kg 
15 Handling Precautions 
Sorbitol may be harmful if ingested in great quantities. It may 
be irritant to the eyes. Observe normal precautions appropriate 
to the circumstances and quantity of material handled. Eye 
protection, gloves, and a dust mask or respirator are 
recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (intra-articular 
and IM injections; nasal; oral capsules, solutions, suspensions, 
syrups and tablets; rectal, topical, and vaginal preparations). 
Included in parenteral and nonparenteral medicines licensed in 
the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Maltitol solution; mannitol; sorbitol solution 70%; xylitol. 
Sorbitol solution 70% 
Synonyms: sorbitol liquid; Sorbo. 
Appearance: a clear, colorless and odorless, viscous liquid. 
Comments: sorbitol solution is an aqueous solution of 
hydrogenated, partly hydrolyzed starch. For physical 
properties, see Table IV. 
Table IV: Physical properties of sorbitol in water solutions. 
Concentration 
(% w/w) at 
258C 
Density 
(g/cm3) at 
258C 
Viscosity 
(mPa s) at 
258C 
Refractive 
index 
Freezing 
point (8C) 
10 1.034 1.2 1.348 1.1 
20 1.073 1.7 1.365 3.8 
30 1.114 2.5 1.383 8.0 
40 1.155 4.4 1.400 13.0 
50 1.197 9.1 1.418 26.0 
60 1.240 26.0 1.437 — 
70 1.293 110.0 1.458 — 
80 1.330 900.0 1.478 — 
18 Comments 
Sorbitol may be substituted for sucrose to prepare 70–90% w/v 
syrups. 
Several different grades of sorbitol, with different polymorphic 
form, particle size, and other physical characteristics 
are commercially available, e.g., Neosorb (Roquette Fre`res). 
Pyrogen-free grades are also available from some suppliers. 
A specification for sorbitol is contained in the Food 
Chemicals Codex (FCC). The EINECS number for sorbitol is 
200-061-5. 
19 Specific References 
1 Molokhia AM, Moustafa MA, Gouda MW. Effect of storage 
conditions on the hardness, disintegration and drug release from 
some tablet bases. Drug Dev Ind Pharm 1982; 8: 283–292. 
2 Bolton S, Atluri R. Crystalline sorbitol tablets: effect of mixing 
time and lubricants on manufacturing. Drug Cosmet Ind 1984; 
135(5): 44, 46, 47, 48, 50. 
3 DuRoss JW. Modification of the crystalline structure of sorbitol 
and its effects on tableting characteristics. Pharm Technol 1984; 
8(9): 42–53. 
4 Basedow AM, Mo. schl GA. Sorbitol instant – an excipient with 
unique tableting properties. Drug Dev Ind Pharm 1986; 12: 2061– 
2089. 
5 Schmidt PC, Vortisch W. Influence of manufacturing method of 
fillers and binders on their tableting properties: comparison of 8 
commercially available sorbitols [in German]. Pharm Ind 1987; 
49: 495–503. 
6 Krogars K, Heinaemaeki J, Karjalainen M, et al. Development and 
characterization of aqueous amylose-rich maize starch dispersion 
for film formation. Eur J Pharm Biopharm 2003; 56(2): 215–221. 
7 Cervera MF, Heina.ma. ki J, Krogars K, et al. Solid state and 
mechanical properties of aqueous chitosan-amylose starch films 
plasticized with polyols. AAPS Pharm Sci Tech 2004; 5(1): E15. 
8 Daoust RG, Lynch MJ. Sorbitol in pharmaceutical liquids. Drug 
Cosmet Ind 1962; 90(6): 689–691, 773, 776, 777, 779, 781–785. 
9 Sabatini GR, Gulesich JJ. Formulation of a stable and palatable 
oral suspension of procaine penicillin G. J Am Pharm Assoc (Pract 
Pharm) 1956; 17: 806–808. 
10 Bandelin FJ, Tuschhoff JV. The stability of ascorbic acid in various 
liquid media. J Am Pharm Assoc (Sci) 1955; 44: 241–244. 
11 Parikh BD, Lofgren FV. A further stability study of an oral 
multivitamin liquid preparation. Drug Standards 1958; 26: 56–61. 
12 Valizdeh H, Nokhodchi A, Qarakhari N, et al. Physicochemical 
characterization of solid dispersions of indometacin with PEG 
6000, Myri 52, lactose, sorbitol, dextrin, and Eudragit (R) E100. 
Drug Dev Ind Pharm 2004; 30(3): 303–317. 
720 Sorbitol

13 Lindvall S, Andersson NSE. Studies on a new intramuscular 
haematinic, iron–sorbitol. Br J Pharmacol 1961; 17: 358–371. 
14 Burggraaf J, Schoemaker RC, Lentjes EGWM, Cohen AF. Sorbitol 
as a marker for drug-induced decreases of variable duration in liver 
blood flow in healthy volunteers. Eur J Pharm Sci 2000; 12: 133– 
139. 
15 Bundgaard H. Drug allergy: chemical and pharmaceutical aspects. 
In: Florence AT, Salole EG, eds. Formulation Factors in Adverse 
Reactions. London: Wright, 1990: 23–55. 
16 Jain NK, Rosenberg DB, Ulahannan MJ, et al. Sorbitol intolerance 
in adults. Am J Gastroenterol 1985; 80: 678–681. 
17 Brown AM, Masson E. ‘Hidden’ sorbitol in proprietary medicines 
– a cause for concern? Pharm J 1990; 245: 211. 
18 Greaves RRSH, Brown RL, Farthing MJG. An air stewardess with 
puzzling diarrhoea. Lancet 1996; 348: 1488. 
19 Ayers CS, Abrams RA. Noncariogenic sweeteners: sugar substitutes 
for caries control. Dental Hygiene 1987; 61: 162–167. 
20 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3292. 
20 General References 
Barr M, Kohn SR, Tice LF. The solubility of sorbitol in hydroalcoholic 
solutions. Am J Pharm 1957; 129: 102–106. 
Blanchard J, Fink WT, Duffy JP. Effect of sorbitol on interaction of 
phenolic preservatives with polysorbate 80. J Pharm Sci 1977; 66: 
1470–1473. 
Burgess S. Sorbitol instant: a unique excipient. Manuf Chem 1987; 
58(6): 55, 57, 59. 
Collins J. Metabolic disease: time for fructose solutions to go. Lancet 
1993; 341: 600. 
Rabinowitz MP, Reisberg P, Bodin JI. GLC assay of sorbitol as cyclic nbutylboronate. 
J Pharm Sci 1974; 63: 1601–1604. 
Roquette Fre`res. Technical literature: Neosorb, 2000. 
Shah DN, White JL, Hem SL. Mechanism of interaction between 
polyols and aluminum hydroxide gel. J Pharm Sci 1981; 70: 1101– 
1104. 
Zatz JL, Lue R-Y. Flocculation of suspensions containing nonionic 
surfactants by sorbitol. J Pharm Sci 1987; 76: 157–160. 
21 Authors 
SC Owen. 
22 Date of Revision 
17 August 2005. 
Sorbitol 721

Soybean Oil 
1 Nonproprietary Names 
BP: Refined soya oil 
JP: Soybean oil 
PhEur: Soiae oleum raffinatum 
USP: Soybean oil 
2 Synonyms 
Calchem IVO-114; Lipex 107; Lipex 200; Shogun CT; soja 
bean oil; soyabean oil; soya bean oil. 
3 Chemical Name and CAS Registry Number 
Soybean oil [8001-22-7] 
4 Empirical Formula and Molecular Weight 
A typical analysis of refined soybean oil indicates the 
composition of the acids, present as glycerides, to be: linoleic 
acid 50–57%; linolenic acid 5–10%; oleic acid 17–26%; 
palmitic acid 9–13%; and stearic acid 3–6%. Other acids are 
present in trace quantities.(1) 
5 Structural Formula 
See Sections 4 and 8. 
6 Functional Category 
Oleaginous vehicle; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
In pharmaceutical preparations, soybean oil emulsions are 
primarily used as a fat source in total parenteral nutrition 
(TPN) regimens.(2) Although other oils, such as peanut oil, have 
been used for this purpose, soybean oil is now preferred 
because it is associated with fewer adverse reactions. Emulsions 
containing soybean oil have also been used as vehicles for the 
oral and intravenous administration of drugs;(3,4) drug 
substances that have been incorporated into such emulsions 
include amphotericin,(5–7) diazepam, retinoids,(8) vitamins,(9) 
poorly water-soluble steroids,(10,11) fluorocarbons,(12,13) and 
insulin.(14) In addition, soybean oil has been used in the 
formulation of many drug delivery systems such as liposomes,(
15) microspheres,(16) dry emulsions,(17) self-emulsifying 
systems,(18) and nanoemulsions and nanocapsules.(19) 
Soybean oil may also be used in cosmetics and is consumed 
as an edible oil. As soybean oil has emollient properties, it is 
used as a bath additive in the treatment of dry skin conditions. 
8 Description 
The USP 28 describes soybean oil as the refined fixed oil 
obtained from the seeds of the soya plant Glycine max Merr. 
(Fabaceae). The PhEur 2005 defines refined soya-bean oil as the 
fatty oil obtained from the seeds of Glycine soja Sieb. and Zucc. 
and Glycine max (L.) Merr. (G. hispida (Moench) Maxim.) by 
extraction and subsequent refining; it may contain a suitable 
antioxidant. The PhEur 2005 also includes a monograph for 
Hydrogenated Soybean Oil. See Vegetable Oil, hydrogenated, 
type 1. 
Soybean oil is a clear, pale-yellow colored, odorless or 
almost odorless liquid, with a bland taste that solidifies between 
10 and 168C. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for soybean oil. 
Test JP 2001 PhEur 2005 USP 28 
Identification — . — 
Characters — . — 
Specific gravity 0.916–0.922 0.922 0.916–0.922 
Refractive index — 1.475 1.465–1.475 
Heavy metals — — 40.001% 
Free fatty acids — — . 
Fatty acid 
composition 
— . . 
Acid value 40.2 40.5 — 
Iodine value 126–140 — 120–141 
Saponification 
value 
188–195 — 180–200 
Unsaponifiable 
matter 
41.0% 41.5% 41.0% 
Cottonseed oil — — . 
Peroxide — 410.0 or 45.0(a) . 
Alkaline 
impurities 
— . — 
Brassicasterol — 40.3% — 
Water — 40.1%(a) — 
(a) In soybean oil intended for parenteral use. 
10 Typical Properties 
Autoignition temperature: 4458C 
Density: 0.916–0.922 g/cm3 at 258C 
Flash point: 2828C 
Freezing point: 10 to 168C 
Hydroxyl value: 4–8 
Interfacial tension: 50mN/m (50 dynes/cm) at 208C. 
Refractive index: nD
25 = 1.471–1.475 
Solubility: practically insoluble in ethanol (95%) and water; 
miscible with carbon disulfide, chloroform, ether, and light 
petroleum. 
Surface tension: 25mN/m (25 dynes/cm) at 208C. 
Viscosity (dynamic): 
172.9 mPa s (172.9 cP) at 08C; 
99.7 mPa s (99.7 cP) at 108C; 
50.09 mPa s (50.09 cP) at 258C; 
28.86 mPa s (28.86 cP) at 408C.

11 Stability and Storage Conditions 
Soybean oil is a stable material if protected from atmospheric 
oxygen. 
The formation of undesirable flavors in soybean oil is 
accelerated by the presence of 0.01 ppm copper and 0.1 ppm 
iron, which act as catalysts for oxidation; this can be minimized 
by the addition of chelating agents. 
Prolonged storage of soybean oil emulsions, particularly at 
elevated temperatures, can result in the formation of free fatty 
acids, with a consequent reduction in the pH of the emulsion; 
degradation is minimized at pH 6–7. However, soybean oil 
emulsions are stable at room temperature if stored under 
nitrogen in a light-resistant glass container. Plastic containers 
are permeable to oxygen and should not be used for long-term 
storage since oxidative degradation can occur. 
The stability of soybean oil emulsions is considerably 
influenced by other additives in a formulation.(20–26) 
Soybean oil should be stored in a well-filled, airtight, lightresistant 
container at a temperature not exceeding 258C. 
12 Incompatibilities 
Soybean oil emulsions have been reported to be incompatible at 
258C with a number of materials including calcium chloride, 
calcium gluconate, magnesium chloride, phenytoin sodium, 
and tetracycline hydrochloride.(27) Lower concentrations of 
these materials, or lower storage temperatures, may result in 
improved compatibility. The source of the material may also 
affect compatibility; for example, while one injection from a 
particular manufacturer might be incompatible with a fat 
emulsion, an injection with the same amount of active drug 
substance from another manufacturer might be compatible. 
Amphotericin B has been reported to be incompatible with 
soybean oil containing fat emulsions under certain conditions.(
28) 
Soybean oil emulsions are also incompatible with many 
other drug substances, IV infusion solutions, and ions (above 
certain concentrations). 
When plastic syringes are used to store soybean oil 
emulsion, silicone oil may be extracted into the emulsion; 
swelling of the syringe pump also occurs, resulting in the 
necessity for increased forces to maintain the motion of the 
plunger.(29) 
13 Method of Manufacture 
Obtained by solvent extraction using petroleum hydrocarbons, 
or to a lesser extent by expression using continuous screw-press 
operations, of the seeds of either Glycine max (Leguminosae) or 
Glycine soja (Leguminosae). The oil is refined, deodorized, and 
clarified by filtration at about 08C. Any phospholipids or 
sterols present are removed by refining with alkali. 
14 Safety 
Soybean oil is widely used intramuscularly as a drug vehicle or 
as a component of emulsions used in parenteral nutrition 
regimens; it is also consumed as an edible oil. Generally, 
soybean oil is regarded as an essentially nontoxic and 
nonirritant material. However, serious adverse reactions to 
soybean oil emulsions administered parenterally have been 
reported. These include cases of hypersensitivity,(30) CNS 
reactions,(31) and fat embolism.(32) Interference with the anticoagulant 
effect of warfarin has also been reported.(33) 
Anaphylactic reactions have also been reported following 
the consumption of foods derived from, or containing, soy 
beans. Recently there has been concern at the concentration of 
phytoestrogens in some soy-derived products. Administration 
of soy protein to humans has resulted in significantly decreased 
serum lipid concentrations.(34) 
In 1999, the UK Medical Devices Agency announced the 
voluntary withdrawal of a breast implant that contained 
soybean oil. The decision was taken because not enough was 
known at that time about the long-term safety and the rate of 
breakdown of the soybean oil in the filling and its possible 
effects on the body.(35) 
LD50 (mouse, IV): 22.1 g/kg(36) 
LD50 (rat, IV): 16.5 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Spillages of soybean oil are 
slippery and should be covered with an inert absorbent material 
prior to disposal. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IV injections, 
oral capsules, and topical preparations). Included in nonparenteral 
(chewable tablets; oral capsules; topical bath additives) 
and parenteral (emulsions for IV injection or infusion) 
medicines licensed in the UK. Included in the Canadian List 
of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Canola oil; corn oil; cottonseed oil; peanut oil; sesame oil; 
sunflower oil. 
18 Comments 
The stability of soybean oil emulsions may be readily disturbed 
by the addition of other materials, and formulations containing 
soybean oil should therefore be evaluated carefully for their 
compatibility and stability. 
A specification for soybean oil is contained in the Food 
Chemicals Codex (FCC). 
19 Specific References 
1 British Standards Institute. Specification for Crude Vegetable Fats, 
BS 7207. London: HMSO, 1990. 
2 McNiff BL. Clinical use of 10% soybean oil emulsion. Am J Hosp 
Pharm 1977; 34: 1080–1086. 
3 Jeppsson R. Effects of barbituric acids using an emulsion form 
intravenously. Acta Pharm Suec 1972; 9: 81–90. 
4 Medina J, Salvado. A, del Pozo A. Use of ultrasound to prepare 
lipid emulsions of lorazepam for intravenous injection. Int J Pharm 
2001; 216(1–2): 1–8. 
5 Wasan KM. Amphotericin B-intralipid. Drugs of the Future 1994; 
19(3): 225–227. 
6 Vita E. Intralipid in prophylaxis of amphotericin B nephrotoxicity. 
Ann Pharmacother 1994; 28: 1182–1183. 
7 Pascual B, Ayestaran A, Montoro JB, et al. Administration of lipidemulsion 
versus conventional amphotericin B in patients with 
neutropenia. Ann Pharmacother 1995; 29: 1197–1201. 
8 Nankevis R, Davis SS, Day NH, et al. Studies on the intravenous 
pharmacokinetics of three retinoids in the rat. Int J Pharm 1994; 
101: 249–256. 
Soybean Oil 723

9 Dahl GB, Svensson L, Kinnander NJG, et al. Stability of vitamins 
in soybean oil fat emulsion under conditions simulating intravenous 
feeding of neonates and children. J Parenter Enteral Nutr 
1994; 18(3): 2234–2239. 
10 Malcolmson C, Lawrence MJ. A comparison of the incorporation 
of model steroids into non-ionic micellar and microemulsion 
systems. J Pharm Pharmacol 1993; 45: 141–143. 
11 Steroid anaesthetic agents [editorial]. Lancet 1992; 340: 83–84. 
12 Johnson OL, Washington C, Davis SS. Thermal stability of 
fluorocarbon emulsions that transport oxygen. Int J Pharm 
1990; 59: 131–135. 
13 Johnson OL, Washington C, Davis SS. Long-term stability studies 
of fluorocarbon oxygen transport emulsions. Int J Pharm 1990; 
63: 65–72. 
14 Morishita M, Matsuzawa A, Takayama K, et al. Improving insulin 
enteral absorption using water-in-oil emulsion. Int J Pharm 1998; 
172(1–2); 189–198. 
15 Stricker H, Mu. ller H. The storage stability of dispersions of 
soybean-lecithin liposomes [in German]. Pharm Ind 1984; 46: 
1175–1183. 
16 Salmero.n MD, Herna.ndez PJ, Cerezo A. Encapsulation study of 6- 
methylprednisolone in liquid microspheres. Drug Dev Ind Pharm 
1997; 23(2): 133–136. 
17 Pedersen GP, Fa. ldt P, Bergensta. hl B, et al. Solid state characterisation 
of a dry emulsion: a potential drug delivery system. Int J 
Pharm 1998; 171(2): 257–270. 
18 Krishna G, Sheth BB. A novel self emulsifying parenteral drug 
delivery system. PDA J Pharm Sci Technol 1999; 53(4): 168–176. 
19 Santos-Magalha. es NS, Pontes A, Pereira VMW, Caetano MNP. 
Colloidal carriers for benzathine penicillin G: nanoemulsions and 
nanocapsules. Int J Pharm 2000; 208(1–2): 71–80. 
20 Takamura A, Ishii F, Noro S, et al. Study of intravenous 
hyperalimentation: effect of selected amino acids on the stability 
of intravenous fat emulsions. J Pharm Sci 1984; 73: 91–94. 
21 Driscoll DF, Baptista RJ, Bistrian BR, Blackburn GL. Practical 
considerations regarding the use of total nutrient admixtures. Am J 
Hosp Pharm 1986; 43: 416–419. 
22 Washington C. The stability of intravenous fat emulsions in total 
parenteral nutrition mixtures. Int J Pharm 1990; 66: 1–21. 
23 Manning RJ, Washington C. Chemical stability of total parenteral 
nutrition mixtures. Int J Pharm 1992; 81: 1–20. 
24 Jumaa M, Mu. ller BW. The effect of oil components and 
homogenisation conditions on the physicochemical properties 
and stability of parenteral fat emulsions. Int J Pharm 1998; 
163(1–2): 81–89. 
25 Jumaa M, Mu. ller BW. The stabilisation of parenteral fat emulsion 
using non-ionic ABA copolymer surfactant. Int J Pharm 1998; 
174(1–2): 29–37. 
26 Warisnoicharoen W, Lansley AB, Lawrence MJ. Non-ionic oil-inwater 
microemulsions: the effects of oil type on phase behaviour. 
Int J Pharm 2000; 198(1): 7–27. 
27 Trissel LA. Handbook on Injectable Drugs, 9th edn. Bethesda, 
MD: American Society of Hospital Pharmacists, 1996: 435–447. 
28 Trissel LA. Amphotericin B does not mix with fat emulsion [letter]. 
Am J Health Syst Pharm 1995; 52: 1463–1464. 
29 Capes DF, Herring D, Sunderland VD, et al. The effect on syringe 
performance of fluid storage and repeated use: implications for 
syringe pumps. PDA J Pharm Sci Technol 1996; 50 (Jan–Feb): 40– 
50. 
30 Hiyama DT, Griggs B, Mittman RJ, et al. Hypersensitivity 
following lipid emulsion infusion in an adult patient. J Parenter 
Enteral Nutr 1989; 13: 318–320. 
31 Jellinek EH. Dangers of intravenous fat infusions [letter]. Lancet 
1976; ii: 967. 
32 Estebe JP, Malledant Y. Fat embolism after lipid emulsion infusion 
[letter]. Lancet 1991; 337: 673. 
33 Lutomski DM, Palascak JE, Bower RH. Warfarin resistance 
associated with intravenous lipid administration. J Parent Enteral 
Nutr 1987; 11(3): 316–318. 
34 Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis of 
the effects of soy protein intake on serum lipids. N Engl J Med 
1995; 333(5): 276–282. 
35 Bradbury J. Breast implants containing soy-bean oil withdrawn in 
UK [news]. Lancet 1999; 353: 903. 
36 Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. 
Cincinnati: US Department of Health, 1987: 4454. 
20 General References 
Benita S, Levy MY. Submicron emulsions as colloidal drug carriers for 
intravenous administration: comprehensive physicochemical characterization. 
J Pharm Sci 1993; 82: 1069–1079. 
Delaveau P, Hotellier F. Oils of pharmaceutical, dietetic, and cosmetic 
interest, part I: maize, soybean, sunflower [in French]. Ann Pharm 
Fr 1971; 29: 399–412. 
Mirtallo JM, Oh T. A key to the literature of total parenteral nutrition: 
update 1987. Drug Intell Clin Pharm 1987; 21: 594–606. 
Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. 
Boca Raton: FL: CRC Press, 1992: 383–385. 
Wolf WJ. In: Kirk-Othmer Encyclopedia of Chemical Technology, vol. 
21; 3rd edn. New York: Wiley-Interscience, 1981: 417–442. 
21 Authors 
CG Cable. 
22 Date of Revision 
23 August 2005. 
724 Soybean Oil

Starch 
1 Nonproprietary Names 
BP: Maize starch 
Potato starch 
Rice starch 
Tapioca starch 
Wheat starch 
JP: Corn starch 
Potato starch 
Rice starch 
Wheat starch 
PhEur: Maydis amylum (maize starch) 
Solani amylum (potato starch) 
Oryzae amylum (rice starch) 
Tritici amylum (wheat starch) 
USPNF: Corn starch 
Potato starch 
Tapioca 
Wheat starch 
Note that the USPNF 23 has individual monographs for corn 
(Zea mays), potato (Solanum tuberosum), tapioca (Manihot 
utilissima Pohl) and wheat starch (Triticum aestivum). The 
PhEur 2005 has monographs for each of these starches, except 
tapioca starch, along with an additional monograph for rice 
starch, Oryza sativa. Also note that the PhEur 2005 Suppl 5.0 
contains an updated monograph for maize (corn) starch. The 
BP 2004 similarly describes maize, potato, rice, tapioca 
(cassava), and wheat starch in individual monographs, tapioca 
starch being obtained from the rhizomes of Manihot utilissima 
Pohl. The JP 2001 similarly describes corn (maize), rice, potato 
and wheat starch in separate monographs. See also Section 18. 
2 Synonyms 
Amido; amidon; amilo; amylum; Aytex P; C*PharmGel; 
Fluftex W; Instant Pure-Cote; Melojel; Meritena; Paygel 55; 
Perfectamyl D6PH; Pure-Bind; Pure-Cote; Pure-Dent; Pure- 
Gel; Pure-Set; Purity 21; Purity 826; Tablet White. 
See also Sections 1 and 18. 
3 Chemical Name and CAS Registry Number 
Starch [9005-25-8] 
4 Empirical Formula and Molecular Weight 
(C6H10O5)n 50 000–160 000 
where n = 300–1000. 
Starch consists of amylose and amylopectin, two polysaccharides 
based on a-glucose. See also Sections 5 and 17. 
5 Structural Formula 
6 Functional Category 
Glidant; tablet and capsule diluent; tablet and capsule 
disintegrant; tablet binder. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Starch is used as an excipient primarily in oral solid-dosage 
formulations where it is utilized as a binder, diluent, and 
disintegrant. 
As a diluent, starch is used for the preparation of 
standardized triturates of colorants or potent drugs to facilitate 
subsequent mixing or blending processes in manufacturing 
operations. Starch is also used in dry-filled capsule formulations 
for volume adjustment of the fill matrix.(1) 
In tablet formulations, freshly prepared starch paste is used 
at a concentration of 5–25% w/w in tablet granulations as a 
binder. Selection of the quantity required in a given system is 
determined by optimization studies, using parameters such as 
granule friability, tablet friability, hardness, disintegration rate, 
and drug dissolution rate. 
Starch is one of the most commonly used tablet disintegrants 
at concentrations of 3–15% w/w.(2–9) However, unmodified 
starch does not compress well and tends to increase tablet 
friability and capping if used in high concentrations. In 
granulated formulations, about half the total starch content is 
included in the granulation mixture and the balance as part of 
the final blend with the dried granulation. Also, when used as a

disintegrant, starch exhibits type II isotherms and has a high 
specific surface for water sorption.(10) 
Starch has been investigated as an excipient in novel drug 
delivery systems for nasal,(11,12) oral,(13–16) periodontal,(17) and 
other site-specific delivery systems.(18,19) 
Starch is also used in topical preparations; for example, it is 
widely used in dusting powders for its absorbency, and is used 
as a protective covering in ointment formulations applied to the 
skin. Starch mucilage has also been applied to the skin as an 
emollient, has formed the base of some enemas, and has been 
used in the treatment of iodine poisoning. 
Therapeutically, rice starch-based solutions have been used 
in the prevention and treatment of dehydration due to acute 
diarrheal diseases. 
8 Description 
Starch occurs as an odorless and tasteless, fine, white-colored 
powder comprising very small spherical or ovoid granules 
whose size and shape are characteristic for each botanical 
variety. 
9 Pharmacopeial Specifications 
See Table I. 
10 Typical Properties 
Acidity/alkalinity: pH = 5.5–6.5 for a 2% w/v aqueous 
dispersion of corn starch, at 258C. 
Compressibility: see Figure 1. 
Density (bulk): 0.462 g/cm3 for corn starch. 
Density (tapped): 0.658 g/cm3 for corn starch. 
Density (true): 1.478 g/cm3 for corn starch. 
Flowability: 10.8–11.7 g/s for corn starch;(9) 30% for corn 
starch (Carr compressibility index).(20) Corn starch is 
cohesive and has poor flow characteristics. 
Gelatinization temperature: 738C for corn starch; 728C for 
potato starch; 638C for wheat starch. 
Moisture content: all starches are hygroscopic and rapidly 
absorb atmospheric moisture.(21,22) Approximate equilibrium 
moisture content values at 50% relative humidity are 
11% for corn starch; 18% for potato starch; 14% for rice 
starch; and 13% for wheat starch. Between 30% and 80% 
relative humidity, corn starch is the least hygroscopic starch 
and potato starch is the most hygroscopic. Commercially 
available grades of corn starch usually contain 10–14% 
water. See also Figures 2 and 3. 
Particle size distribution: 
Corn starch: 2–32 mm; 
Potato starch: 10–100 mm; 
Rice starch: 2–20 mm; 
Tapioca starch: 5–35 mm; 
Wheat starch: 2–45 mm. 
Median diameter for corn starch is 17 mm and for wheat 
starch is 23 mm. 
Solubility: practically insoluble in cold ethanol (95%) and in 
cold water. Starch swells instantaneously in water by about 
5–10% at 378C.(2,22) Polyvalent cations produce more 
swelling than monovalent ions, but pH has little effect. 
Specific surface area: 
0.41–0.43m2/g for corn starch; 
0.12m2/g for potato starch; 
0.27–0.31m2/g for wheat starch. 
Swelling temperature: 
658C for corn starch; 
648C for potato starch; 
558C for wheat starch. 
Viscosity (dynamic): 13.0 mPa s (13.0 cP) for a 2%w/v aqueous 
dispersion of corn starch at 258C. 
Table I: Pharmacopeial specifications for starch. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . .(a) 
Microbial limits — . . 
pH 
Corn starch — 4.0–7.0(b) 4.0–7.0 
Potato starch — 5.0–8.0 5.0–8.0 
Tapioca — — 4.5–7.0 
Wheat starch — 4.5–7.0 4.5–7.0 
Acidity (rice starch) — . — 
Loss on drying 
Corn starch 415.0% 415.0% 415.0% 
Rice starch 415.0% 415.0% — 
Potato starch 418.0% 420.0% 420.0% 
Tapioca — — 416.0% 
Wheat starch 415.0% 415.0% 415.0% 
Residue on ignition — — 40.6%(a) 
Sulfated ash 
Corn starch 40.5% 40.6% — 
Rice starch 41.0% 41.0% — 
Potato starch 40.5% 40.6% — 
Wheat starch 41.0% 40.6% — 
Iron
Corn starch — 410 ppm 410 ppm 
Potato starch — 410 ppm 410 ppm 
Tapioca starch — — 40.002% 
Wheat starch — 410 ppm 410 ppm 
Oxidizing substances 
Corn starch — 420 ppm 420 ppm 
Potato starch — 420 ppm 420 ppm 
Tapioca starch — — 40.002% 
Wheat starch — 420 ppm 420 ppm 
Sulfur dioxide 
Corn starch — 450 ppm 450 ppm 
Potato starch — 450 ppm 450 ppm 
Tapioca — — 40.005% 
Wheat starch — 450 ppm 450 ppm 
Total protein 
Corn starch — — — 
Rice starch — — — 
Potato starch — — — 
Wheat starch — 40.3% — 
Foreign matter — . — 
(a) See USPNF 23 Suppl 1.0. 
(b) See PhEur 2005 Suppl 5.0. 
726 Starch

SEM: 1 
Excipient: Corn starch 
Manufacturer: Anheuser Busch 
Lot No.: 96A-3 (67) 
Magnification: 2400 Voltage: 20 kV 
SEM: 2 
Excipient: Corn starch 
Manufacturer: AE Staley Mfg. Co. 
Lot No.: 96A-4 (G77912) 
Magnification: 2400 Voltage: 20 kV 
SEM: 3 
Excipient: Potato starch 
Manufacturer: Starchem 
Lot No.: 96A-5 (1179) 
Magnification: 2400 Voltage: 20 kV 
SEM: 4 
Excipient: Rice starch 
Supplier: Matheson, Coleman & Bell 
Magnification: 600 
Starch 727

SEM: 5 
Excipient: Rice starch 
Supplier: Matheson, Coleman & Bell 
Magnification: 3000 
SEM: 6 
Excipient: Wheat starch (Paygel 55) 
Manufacturer: Henkel Corp. 
Lot No.: 96A-1 (2917D) 
Magnification: 2400 Voltage: 20 kV 
SEM: 7 
Excipient: Wheat starch (Aytex P) 
Manufacturer: Henkel Corp. 
Lot No.: 96A-2 (2919D) 
Magnification: 2400 Voltage: 20 kV 
11 Stability and Storage Conditions 
Dry, unheated starch is stable if protected from high humidity. 
When used as a diluent or disintegrant in solid-dosage forms, 
starch is considered to be inert under normal storage 
conditions. However, heated starch solutions or pastes are 
physically unstable and are readily attacked by microorganisms 
to form a wide variety of starch derivatives and modified 
starches that have unique physical properties. 
Starch should be stored in an airtight container in a cool, dry 
place. 
12 Incompatibilities 
—
13 Method of Manufacture 
Starch is extracted from plant sources through a sequence of 
processing steps involving coarse milling, repeated water 
washing, wet sieving, and centrifugal separation. The wet 
starch obtained from these processes is dried and milled before 
use in pharmaceutical formulations. 
14 Safety 
Starch is widely used as an excipient in pharmaceutical 
formulations, particularly oral tablets. 
Starch is an edible food substance and is generally regarded 
as an essentially nontoxic and nonirritant material.(23) However, 
oral consumption of massive doses can be harmful owing 
the formation of starch calculi, which cause bowel obstruction.(
24) Starch may also cause granulomatous reactions when 
applied to the peritoneum or the meninges. Contamination of 
surgical wounds with the starch glove powder used by surgeons 
has also resulted in the development of granulomatous 
lesions.(25) 
728 Starch

Allergic reactions to starch are extremely rare and individuals 
apparently allergic to one particular starch may not 
experience adverse effects with a starch from a different 
botanical source. 
LD50 (mouse, IP): 6.6 g/kg(26) 
Figure 1: Compression characteristics of corn, potato and wheat 
starches. 
&: Corn starch 
*: Potato starch 
~: Wheat starch 
Tablet machine: Manesty F; speed: 50 per min; weight: 
490–510 mg. Strength test: Diametral compression 
between flat-faced rams. Upper ram stationary, lower 
moving at 66 mm/s. 
Figure 2: Sorption–desorption isotherm of corn starch. Anheuser 
Busch; Lot #67. 
Figure 3: Sorption–desorption isotherm of wheat starch. 
*: Paygel 55 (Henkel Corp.; Lot #2917D) 
~: Aytex P (Henkel Corp.; Lot #2919D) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and a dust 
mask are recommended. Excessive dust generation should be 
avoided to minimize the risks of explosion. 
In the UK, the long-term (8-hour TWA) occupational 
exposure limits for starch are 10 mg/m3 for total inhalable 
dust and 4 mg/m3 for respirable dust.(27) 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(buccal tablets, oral capsules, powders, suspensions and tablets; 
topical preparations; and vaginal tablets). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian 
List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Amylopectin; a-amylose; maltodextrin; starch, pregelatinized; 
starch, sterilizable maize. 
Amylopectin 
CAS number: [9037-22-3] 
Comments: amylopectin is a branched D-glucan with mostly 
a-D-(1!4) and approximately 4% a-D-(1!6) linkages. 
The EINECS number for amylopectin is 232-911-6. 
a-Amylose 
CAS number: [9005-82-7] 
Comments: amylose is a linear (1!4)-a-D-glucan. 
18 Comments 
Note that corn starch is also known as maize starch and that 
tapioca starch is also known as cassava starch. 
Starch 729

Whereas the USPNF 23 specifies that starch should be 
produced from corn, potato, tapioca, or wheat, the BP 2004 
also permits starch to be produced from rice. In tropical and 
subtropical countries where these starches may not be readily 
available, the BP 2004 additionally permits the use of tapioca 
starch, subject to additional requirements. 
Starches from different plant sources differ in their amylose/ 
amylopectin ratio. For example, corn starch contains about 
27% amylose, potato starch about 22%, and tapioca starch 
about 17%. In contrast, waxy corn starch contains almost 
entirely amylopectin, with no amylose. These differences 
modify the physical properties of the starches such that the 
various types may not be interchangeable in a given pharmaceutical 
application. For example, amylose-rich maize starch 
has been studied as a potential tablet film-coating ingredient.(
28) 
19 Specific References 
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release from hard gelatin capsules. Drug Dev Ind Pharm 1980; 6: 
605–627. 
2 Ingram JT, LowenthalW. Mechanism of action of starch as a tablet 
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378. J Pharm Sci 1966; 55: 614–617. 
3 Patel NR, Hopponen RE. Mechanism of action of starch as a 
disintegrating agent in aspirin tablets. J Pharm Sci 1966; 55: 1065– 
1068. 
4 LowenthalW. Mechanism of action of tablet disintegrants. Pharm 
Acta Helv 1973; 48: 589–609. 
5 Sakr AM, Kassem AA, Farrag NA. The effect of certain 
disintegrants on water soluble tablets. Manuf Chem Aerosol 
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6 Shangraw RF, Wallace JW, Bowers FM. Morphology and 
functionality in tablet excipients for direct compression: part II. 
Pharm Technol 1981; 5(10): 44–60. 
7 Kitamori N, Makino T. Improvement in pressure-dependent 
dissolution of trepibutone tablets by using intragranular disintegrants. 
Drug Dev Ind Pharm 1982; 8: 125–139. 
8 Rudnic EM, Rhodes CT, Welch S, Bernardo P. Evaluation of the 
mechanism of disintegrant action. Drug Dev Ind Pharm 1982; 8: 
87–109. 
9 Kottke MK, Chueh H-R, Rhodes CT. Comparison of disintegrant 
and binder activity of three corn starch products. Drug Dev Ind 
Pharm 1992; 18: 2207–2223. 
10 Faroongsarng D, Peck GE. Swelling and water reuptake of tablets. 
Part 3. Moisture sorption behavior of tablet disintegrants. Drug 
Dev Ind Pharm 1994; 20: 779–798. 
11 Illum L, Fisher AN, Jabbal-Gill I, Davis SS. Bioadhesive starch 
microspheres and absorption enhancing agents act synergistically 
to enhance the nasal absorption of polypeptides. Int J Pharm 2001; 
222: 109–119. 
12 Callens C, Ceulemans J, Ludwig A, et al. Rheological study on 
mucoadhesivity of some nasal powder formulations. Eur J Pharm 
Biopharm 2003; 55: 323–328. 
13 Henrist D, Van Bortel L, Lefebvre RA, Remon JP. In vitro and in 
vivo evaluation of starch-based hot stage extruded double matrix 
systems. J Control Release 2001; 75: 391–400. 
14 Palviainen P, Heinamaki J, Myllarinen P, et al. Corn starches as 
film formers in aqueous-based film coating. Pharm Dev Technol 
2001; 6: 353–361. 
15 Hauschild K, Picker-Freyer KM. Evaluation of a new coprocessed 
compound based on lactose and maize starch for tablet formulation. 
AAPS PharmSci 2004; 6:16 
16 Korhonen O, Kanerva H, Vidgren M, et al. Evaluation of novel 
starch acetate-diltiazem controlled release tablets in healthy human 
volunteers. J Control Release 2004; 95: 515–520. 
17 Bromberg LE, Buxton DK, Friden PM. Novel periodontal drug 
delivery systems for treatment of periodontitis. J Control Release 
2001; 71: 251–259. 
18 Clausen AE, Bernkop-Schnurch A. Direct compressible polymethacrylic 
acid-starch compositions for site-specific drug delivery. 
J Control Release 2001; 75: 93–102. 
19 Momin M, Pundarikakshundu K. In vitro studies on guar gum 
based formulation for the colon targeted delivery of Sennosides. J 
Pharm Pharm Sci 2004; 7: 325–331. 
20 Carr RL. Particle behaviour storage and flow. Br Chem Eng 1970; 
15: 1541–1549. 
21 Callahan JC, Cleary GW, Elefant M, et al. Equilibrium moisture 
content of pharmaceutical excipients. Drug Dev Ind Pharm 1982; 
8: 355–369. 
22 Wurster DE, Peck GE, Kildsig DO. A comparison of the moisture 
adsorption–desorption properties of corn starch, USP, and directly 
compressible starch. Drug Dev Ind Pharm 1982; 8: 343–354. 
23 Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation 
Agents: A Handbook of Excipients. New York: Marcel Dekker, 
1989: 91–92. 
24 Warshaw AL. Diagnosis of starch peritonitis by paracentesis. 
Lancet 1972; ii: 1054–1056. 
25 Michaels L, Shah NS. Dangers of corn starch powder [letter]. Br 
Med J 1973; 2: 714. 
26 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3299. 
27 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
28 Krogars K, Antikainen O, Heinamaki J, et al. Tablet film-coating 
with amylose-rich maize starch. Eur J Pharm Sci 2002; 17: 23–30. 
20 General References 
—
21 Authors 
LY Galichet. 
22 Date of Revision 
25 August 2005. 
730 Starch

Starch, Pregelatinized 
1 Nonproprietary Names 
BP: Pregelatinised starch 
PhEur: Amylum pregelificatum 
USPNF: Pregelatinized starch 
2 Synonyms 
Compressible starch; Instastarch; Lycatab C; Lycatab PGS; 
Merigel; National 78-1551; Pharma-Gel; Prejel; Sepistab ST 
200; Spress B820; Starch 1500 G; Tablitz; Unipure LD; 
Unipure WG220. 
3 Chemical Name and CAS Registry Number 
Pregelatinized starch [9005-25-8] 
4 Empirical Formula and Molecular Weight 
(C6H10O5)n where n = 300–1000. 
Pregelatinized starch is a starch that has been chemically 
and/or mechanically processed to rupture all or part of the 
starch granules and so render the starch flowable and directly 
compressible. Partially pregelatinized grades are also commercially 
available. Typically, pregelatinized starch contains 5% of 
free amylose, 15% of free amylopectin, and 80% unmodified 
starch. The USPNF 23 does not specify the botanical origin of 
the original starch, but the PhEur 2005 specifies that 
pregelatinized starch is obtained from maize (corn), potato, 
or rice starch. See also Starch and Section 13. 
5 Structural Formula 
See Starch. 
6 Functional Category 
Tablet and capsule diluent; tablet and capsule disintegrant; 
tablet binder. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Pregelatinized starch is a modified starch used in oral capsule 
and tablet formulations as a binder, diluent,(1,2) and disintegrant.(
3) 
In comparison to starch, grades of pregelatinized starch may 
be produced with enhanced flow and compression characteristics 
such that the pregelatinized material may be used as a 
tablet binder in dry-compression or direct compression 
processes.(4–14) In such processes, pregelatinized starch is selflubricating. 
However, when it is used with other excipients it 
may be necessary to add a lubricant to a formulation. Although 
magnesium stearate 0.25% w/w is commonly used for this 
purpose, concentrations greater than this may have adverse 
effects on tablet strength and dissolution. Therefore, stearic 
acid is generally the preferred lubricant with pregelatinized 
starch.(15) 
Pregelatinized starch may also be used in wet granulation 
processes.(16) See Table I. 
Table I: Uses of pregelatinized starch. 
Use Concentration (%) 
Diluent (hard gelatin capsules) 5–75 
Tablet binder (direct compression) 5–20 
Tablet binder (wet granulation) 5–10 
Tablet disintegrant 5–10 
8 Description 
Pregelatinized starch occurs as a moderately coarse to fine, 
white to off-white colored powder. It is odorless and has a slight 
characteristic taste. 
Examination of fully pregelatinized starch as a slurry in cold 
water, under a polarizing microscope, reveals no significant 
ungelatinized granules, i.e., no ‘maltese crosses’ characteristic 
of the starch birefringence pattern. Examination of samples 
suspended in glycerin shows characteristic forms depending 
upon the method of drying used during manufacture: either 
irregular chunks from drum drying or thin plates. Partially 
pregelatinized starch (e.g., Starch 1500G and Sepistab ST200) 
show retention of birefringence patterns typical of unmodified 
starch granules. 
SEM: 1 
Excipient: Lycatab PGS 
Manufacturer: Roquette Fre`res 
9 Pharmacopeial Specifications 
See Table II.

Table II: Pharmacopeial specifications for pregelatinized starch. 
Test PhEur 2005 USPNF 23 
Identification . . 
pH (10% w/v slurry) 4.5–7.0 4.5–7.0 
Iron 420 ppm 40.002% 
Oxidizing substances . . 
Sulfur dioxide 450 ppm 40.008% 
Microbial limits . . 
Loss on drying 415.0% 414.0% 
Residue on ignition — 40.5% 
Foreign matter . — 
Sulfated ash 40.6% — 
Organic volatile impurities — . 
10 Typical Properties 
Acidity/alkalinity: pH = 4.5–7.0 for a 10% w/v aqueous 
dispersion. 
Angle of repose: 40.78 (6) 
Compressibility: see Starch. 
Density (bulk): 0.586 g/cm3 
Density (tapped): 0.879 g/cm3 
Density (true): 1.516 g/cm3 
Flowability: 18–23% (Carr compressibility index)(17) 
Moisture content: pregelatinized maize starch is hygroscopic.(
14,18,19) See also Figure 1. 
Particle size distribution: 30–150 mm, median diameter 52 mm. 
For partially pregelatinized starch, greater than 90% 
through a US #100 mesh (149 mm); and less than 0.5% 
retained on a US #40 mesh (420 mm). 
Solubility: practically insoluble in organic solvents. Slightly 
soluble to soluble in cold water, depending upon the degree 
of pregelatinization. Pastes can be prepared by sifting the 
pregelatinized starch into stirred, cold water. Cold-watersoluble 
matter for partially pregelatinized starch is 10–20%. 
Specific surface area: 
0.26m2/g (Colorcon); 
0.18–0.28m2/g (Roquette Ltd). 
Viscosity (dynamic): 8–10 mPa s (8–10 cP) for a 2% w/v 
aqueous dispersion at 258C. 
Figure 1: Pregelatinized starch sorption–desorption isotherm. 
*: Sorption 
&: Desorption. 
11 Stability and Storage Conditions 
Pregelatinized starch is a stable but hygroscopic material, which 
should be stored in a well-closed container in a cool, dry place. 
12 Incompatibilities 
—
13 Method of Manufacture 
Food-grade pregelatinized starches are prepared by heating an 
aqueous slurry containing up to 42% w/w of starch at 
62–728C. Chemical additives that may be included in the 
slurry are gelatinization aids (salts or bases) and surfactants, 
added to control rehydration or minimize stickiness during 
drying. After heating, the slurry may be spray-dried, roll-dried, 
extruded, or drum-dried. In the last case, the dried material may 
be processed to produce a desired particle size range. 
Pharmaceutical grades of fully pregelatinized starch use no 
additives and are prepared by spreading an aqueous suspension 
of ungelatinized starch on hot drums where gelatinization and 
subsequent drying takes place. Partially pregelatinized starch is 
produced by subjecting moistened starch to mechanical 
pressure. The resultant material is ground and the moisture 
content is adjusted to specifications. 
14 Safety 
Pregelatinized starch and starch are widely used in oral soliddosage 
formulations. Pregelatinized starch is generally regarded 
as a nontoxic and nonirritant excipient. However, oral 
consumption of large amounts of pregelatinized starch may 
be harmful. 
See Starch for further information. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and a dust 
mask are recommended. Excessive dust generation should be 
avoided to minimize the risks of explosions. 
In the UK, the long-term (8-hour TWA) occupational 
exposure limits for starch are 10 mg/m3 for total inhalable 
dust and 4 mg/m3 for respirable dust.(20) 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral capsules, 
suspensions, and tablets; vaginal preparations). Included in 
nonparenteral medicines licensed in the UK. 
17 Related Substances 
Starch; starch, sterilizable maize. 
18 Comments 
A low-moisture grade of pregelatinized starch, Starch 1500 LM 
(Colorcon), containing less than 7% of water, specifically 
intended for use as a diluent in capsule formulations is 
commercially available.(15) 
Sepistab ST200 is described as an agglomerate of starch 
granules consisting of native and pregelatinized corn starch.(21) 
Compression characteristics of pregelatinized starches from 
732 Starch, Pregelatinized

sorghum and plantain have been evaluated against traditional 
corn-based products.(22) 
19 Specific References 
1 Small LE, Augsburger LL. Aspects of the lubrication requirements 
for an automatic capsule filling machine. Drug Dev Ind Pharm 
1978; 4: 345–372. 
2 Mattson S, Nystro.m C. Evaluation of critical binder properties 
affecting the compactability of binary mixtures. Drug Dev Ind 
Pharm 2001; 27: 181–194. 
3 Rudnic EM, Rhodes CT, Welch S, Bernardo P. Evaluations of the 
mechanism of disintegrant action. Drug Dev Ind Pharm 1982; 8: 
87–109. 
4 Manudhane KS, Contractor AM, Kim HY, Shangraw RF. 
Tableting properties of a directly compressible starch. J Pharm 
Sci 1969; 58: 616–620. 
5 UnderwoodTW, Cadwallader DE. Influence of various starches on 
dissolution rate of salicylic acid from tablets. J Pharm Sci 1972; 61: 
239–243. 
6 Bolhuis GK, Lerk CF. Comparative evaluation of excipients for 
direct compression. Pharm Weekbl 1973; 108: 469–481. 
7 Sakr AM, Elsabbagh HM, Emara KM. Sta-Rx 1500 starch: a new 
vehicle for the direct compression of tablets. Arch Pharm Chem 
(Sci) 1974; 2: 14–24. 
8 Schwartz JB, Martin ET, Dehner EJ. Intragranular starch: 
comparison of starch USP and modified cornstarch. J Pharm Sci 
1975; 64: 328–332. 
9 Rees JE, Rue PJ. Work required to cause failure of tablets in 
diametral compression. Drug Dev Ind Pharm 1978; 4: 131–156. 
10 Shangraw RF, Wallace JW, Bowers FM. Morphology and 
functionality in tablet excipients for direct compression: part II. 
Pharm Technol 1981; 5(10): 44–60. 
11 Chilamkurti RW, Rhodes CT, Schwartz JB. Some studies on 
compression properties of tablet matrices using a computerized 
instrumental press. Drug Dev Ind Pharm 1982; 8: 63–86. 
12 Malamataris S, Goidas P, Dimitriou A. Moisture sorption and 
tensile strength of some tableted direct compression excipients. Int 
J Pharm 1991; 68: 51–60. 
13 Iskandarani B, Shiromani PK, Clair JH. Scale-up feasability in 
high-shear mixers: determination through statistical procedures. 
Drug Dev Ind Pharm 2001; 27: 651–657. 
14 Shiromani PK, Clair J. Statistical comparison of high-shear versus 
low-shear granulation using a common formulation. Drug Dev 
Ind Pharm 2000; 26: 357–364. 
15 Colorcon Technical literature: Starch 1500. 1997. 
16 Jaiyeoba KT, Spring MS. The granulation of ternary mixtures: the 
effect of the stability of the excipients. J Pharm Pharmacol 1980; 
32: 1–5. 
17 Carr RL. Particle behaviour storage and flow. Br Chem Eng 1970; 
15: 1541–1549. 
18 Callahan JC, Cleary GW, Elefant M, et al. Equilibrium moisture 
content of pharmaceutical excipients. Drug Dev Ind Pharm 1982; 
8: 355–369. 
19 Wurster DE, Peck GE, Kildsig DO. A comparison of the moisture 
adsorption–desorption properties of corn starch USP, and directly 
compressible starch. Drug Dev Ind Pharm 1982; 8: 343–354. 
20 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
21 Seppic. Technical Literature: Sepistab ST200. 1997. 
22 Alebiowu G, Itiola OA. Compression characteristics of native and 
pregelatinized forms of sorghum, plantain, and corn starches, and 
the mechanical properties of their tablets. Drug Dev Ind Pharm 
2002; 28(6): 663–672. 
20 General References 
Alebiowu G, Itiola OA. The influence of pregelatinized starch 
disintegrants on interacting variables that act on disintegrant 
properties. Pharm Tech 2003; 24(8): 28–33. 
Monedeero Perales MC, Munoz-Ruiz A, Velasco-Antequera MV, et al. 
Comparative tableting and microstructural properties of a new 
starch for direct compression. Drug Dev Ind Pharm 1996; 22: 689– 
695. 
Rees, JH, Tsardaka KD. Some effects of moisture on the viscoelastic 
behavior of modified starch during powder compaction. Eur J 
Pharm Biopharm 1994; 40: 193–197. 
Roquette Fre`res. Technical literature: Lycatab PGS. 2001. 
Sanghvi PP, Collins CC, Shukla AJ. Evaluation of Preflo modified 
starches as new direct compression excipients I: tabletting characteristics. 
Pharm Res 1993; 10: 1597–1603. 
21 Authors 
AH Kibbe. 
22 Date of Revision 
17 August 2005. 
Starch, Pregelatinized 733

Starch, Sterilizable Maize 
1 Nonproprietary Names 
USP: Absorbable dusting powder 
2 Synonyms 
Bio-sorb; double-dressed, white maize starch; Fluidamid 
R444P; Keoflo ADP; Meritena; modified starch dusting 
powder; Pure-Dent B851; starch-derivative dusting powder; 
sterilizable corn starch. 
3 Chemical Name and CAS Registry Number 
Sterilizable maize starch 
4 Empirical Formula and Molecular Weight 
(C6H10O5)n where n = 300–1000. 
Sterilizable maize starch is a modified corn (maize) starch 
that may also contain up to 2.0% of magnesium oxide. 
See also Starch. 
5 Structural Formula 
See Starch. 
6 Functional Category 
Lubricant for surgeons’ and examination gloves; vehicle for 
medicated dusting powders. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sterilizable maize starch is a chemically or physically modified 
corn (maize) starch that does not gelatinize on exposure to 
moisture or steam sterilization. Sterilizable maize starch is 
primarily used as a lubricant for examination and surgeons’ 
gloves although because of safety concerns unlubricated gloves 
are now generally recommended. It is also used as a vehicle for 
medicated dusting powders. 
8 Description 
Sterilizable maize starch occurs as an odorless, white, freeflowing 
powder. Particles may be rounded or polyhedral in 
shape. 
9 Pharmacopeial Specifications 
See Table I. 
10 Typical Properties 
Acidity/alkalinity: pH = 9.5–10.8 for a 10% w/v suspension at 
258C. 
Density: 1.48 g/cm3 
Density (bulk): 0.47–0.59 g/cm3 
Table I: Pharmacopeial specifications for sterilizable maize starch. 
Test USP 28 
Identification . 
Stability to autoclaving . 
Sedimentation . 
pH (1 in 10 suspension) 10.0–10.8 
Loss on drying 412% 
Residue on ignition 43.0% 
Magnesium oxide 42.0% 
Heavy metals 40.001% 
Density (tapped): 0.64–0.83 g/cm3 
Flowability: 24–30% (Carr compressibility index)(1) 
Moisture content: 10–15% 
Particle size distribution: 6–25 mm; median diameter is 16 mm. 
Solubility: very slightly soluble in chloroform and ethanol 
(95%); practically insoluble in water. 
Specific surface area: 0.50–1.15m2/g 
11 Stability and Storage Conditions 
Sterilizable maize starch may be sterilized by autoclaving at 
1218C for 20 minutes, by ethylene oxide, or by irradiation.(2) 
Sterilizable maize starch should be stored in a well-closed 
container in a cool, dry place. 
SEM: 1 
Excipient: Sterilizable maize starch 
Manufacturer: Corn Products 
Magnification: 2000

SEM: 2 
Excipient: Sterilizable maize starch 
Manufacturer: Biosorb 
Magnification: 2000 
SEM: 3 
Excipient: Sterilizable maize starch 
Manufacturer: J & W Starches Ltd 
Magnification: 2000 
12 Incompatibilities 
—
13 Method of Manufacture 
Corn starch (maize starch) is physically or chemically modified 
by treatment with either phosphorus oxychloride or epichlorhydrin 
so that the branched-chain and straight-chain starch 
polymers crosslink. Up to 2.0% of magnesium oxide may also 
be added to the starch. 
See also Starch. 
14 Safety 
Sterilizable maize starch is primarily used as a lubricant for 
surgeons’ gloves and as a vehicle for topically applied dusting 
powders. 
Granulomatous reactions and peritonitis at operation sites 
have been attributed to contamination with surgical glove 
powders containing sterilizable maize starch.(3–8) The use of 
excessive quantities of sterilizable maize starch on surgeons’ 
gloves should therefore be avoided. 
See also Starch. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and a dust 
mask are recommended. Excessive dust generation should be 
avoided to minimize the risks of explosions. 
In the UK, the long-term (8-hour TWA) occupational exposure 
limits for starch are 10 mg/m3 for total inhalable dust and 
4 mg/m3 for respirable dust.(9) 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral tablets 
and topical preparations). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Starch; starch, pregelatinized. 
18 Comments 
—
19 Specific References 
1 Carr RL. Particle behaviour storage and flow. Br Chem Eng 1970; 
15: 1541–1549. 
2 Kelsey JC. Sterilization of glove powder by autoclaving. Mon Bull 
Minist Health 1962; 21: 17–21. 
3 Neely J, Davis JD. Starch granulomatosis of the peritoneum. Br 
Med J 1971; 3: 625–629. 
4 Michaels L, Shah NS. Dangers of corn starch powder [letter]. Br 
Med J 1973; 2: 714. 
5 Karcioglu ZA, Aran AJ, Holmes DL, et al. Inflammation due to 
surgical glove powders in the rabbit eye. Arch Ophthalmol 1988; 
106(6): 808–811. 
6 Ruhl CM, Urbancic JH, Foresman PA, et al. A new hazard of 
cornstarch, an absorbale dusting powder. J Emerg Med 1994; 
12(1): 11–14. 
7 Cote SJ, Fisher MD, Kheir JN, et al. Ease of donning commercially 
available latex examination gloves. J Biomed Mater Res 1998; 
43(3): 331–337. 
8 Truscott W. Post-surgical complications associated with the use of 
USP Absorbable Dusting Powder. Surg Technol Int 2000; VIII: 65– 
73. 
9 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002, Sudbury: Health and Safety Executive, 2002. 
Starch, Sterilizable Maize 735

20 General References 
El Saadany RMA, El Saadany FM, Foda YH. Degradation of corn 
starch under the influence of gamma irradiation. Staerke 1976; 28: 
208–211. 
Greenwood CT. The thermal degradation of starch. Adv Carbohydr 
Chem Biochem 1967; 22: 483–515. 
Greenwood CT. Starch. Adv Cereal Sci Technol 1976; 1: 119–157. 
21 Authors 
PJ Weller. 
22 Date of Revision 
13 April 2005. 
736 Starch, Sterilizable Maize

Stearic Acid 
1 Nonproprietary Names 
BP: Stearic acid 
JP: Stearic acid 
PhEur: Acidum stearicum 
USPNF: Stearic acid 
2 Synonyms 
Cetylacetic acid; Crodacid; E570; Edenor; Emersol; Hystrene; 
Industrene; Kortacid 1895; Pearl Steric; Pristerene; stereophanic 
acid; Tegostearic. 
3 Chemical Name and CAS Registry Number 
Octadecanoic acid [57-11-4] 
4 Empirical Formula and Molecular Weight 
C18H36O2 284.47 (for pure material) 
The USPNF 23 describe stearic acid as a mixture of stearic 
acid (C18H36O2) and palmitic acid (C16H32O2). In the USPNF 
23, the content of stearic acid is not less than 40.0% and the 
sum of the two acids is not less than 90.0%. The USPNF 23 also 
contains a monograph for purified stearic acid; see Section 17. 
The PhEur 2005 contains a single monograph for stearic acid 
but defines stearic acid 50, stearic acid 70, and stearic acid 95 as 
containing specific amounts of stearic acid (C18H36O2); see 
Section 9. 
5 Structural Formula 
6 Functional Category 
Emulsifying agent; solubilizing agent; tablet and capsule 
lubricant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Stearic acid is widely used in oral and topical pharmaceutical 
formulations. It is mainly used in oral formulations as a tablet 
and capsule lubricant;(1–3) see Table I, although it may also be 
used as a binder(4) or in combination with shellac as a tablet 
coating. It has also been suggested that stearic acid may be used 
as a sustained-release drug carrier.(5) 
In topical formulations, stearic acid is used as an emulsifying 
and solubilizing agent. When partially neutralized with alkalis 
or triethanolamine, stearic acid is used in the preparation of 
creams.(6,7) The partially neutralized stearic acid forms a 
creamy base when mixed with 5–15 times its own weight of 
aqueous liquid; the appearance and plasticity of the cream 
being determined by the proportion of alkali used. 
Stearic acid is used as the hardening agent in glycerin 
suppositories. 
Stearic acid is also widely used in cosmetics and food 
products. 
SEM: 1 
Excipient: Stearic acid, 95% (Emersol 153) 
Manufacturer: Emery Industries 
Lot No.: 18895 
Magnification: 120 Voltage: 10 kV 
SEM: 2 
Excipient: Stearic acid, food grade (Emersol 6332) 
Manufacturer: Emery Industries 
Lot No.: 18895 
Magnification: 120 Voltage: 10 kV

Table I: Uses of stearic acid. 
Use Concentration (%) 
Ointments and creams 1–20 
Tablet lubricant 1–3 
8 Description 
Stearic acid is a hard, white or faintly yellow-colored, somewhat 
glossy, crystalline solid or a white or yellowish white 
powder. It has a slight odor and taste suggesting tallow. 
See also Section 13. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for stearic acid. 
Test JP 2001 PhEur 2005 USPNF 23 
Acidity — . — 
Acid value 194–210 194–212 — 
Appearance — . — 
Characters — . — 
Content of stearic acid — — 540.0% 
Stearic acid 50 — 40–60% — 
Stearic acid 70 — 60–80% — 
Stearic acid 95 — 590.0% — 
Content of stearic and 
palmitic acids 
— — 590.0% 
Stearic acid 50 — 590.0% — 
Stearic acid 70 — 590.0% — 
Stearic acid 95 — 596.0% — 
Congealing temperature 56.0–72.08C — 5548C 
Freezing point . 
Stearic acid 50 — 53–598C — 
Stearic acid 70 — 57–648C — 
Stearic acid 95 — 64–698C — 
Iodine value 44.0 . 44.0 
Stearic acid 50 — 44.0% — 
Stearic acid 70 — 44.0% — 
Stearic acid 95 — 41.5% — 
Nickel — 41 ppm — 
Residue on ignition 40.1% — 40.1% 
Heavy metals 420 ppm — 40.001% 
Neutral fat or paraffin . — . 
Mineral acid . — . 
Organic volatile impurities — — . 
10 Typical Properties 
Acid value: 200–212 
Density (bulk): 0.537 g/cm3 
Density (tapped): 0.571 g/cm3 
Density (true): 0.980 g/cm3 
Melting point: 5548C 
Moisture content: contains practically no water. 
Saponification value: 200–220 
Solubility: freely soluble in benzene, carbon tetrachloride, 
chloroform, and ether; soluble in ethanol (95%), hexane, 
and propylene glycol; practically insoluble in water.(8) 
Specific surface area: 0.51–0.53m2/g 
See also Section 17 and Table III. 
11 Stability and Storage Conditions 
Stearic acid is a stable material; an antioxidant may also be 
added to it; see Section 13. The bulk material should be stored 
in a well-closed container in a cool, dry place. 
12 Incompatibilities 
Stearic acid is incompatible with most metal hydroxides and 
may be incompatible with oxidizing agents. 
Insoluble stearates are formed with many metals; ointment 
bases made with stearic acid may show evidence of drying out 
or lumpiness due to such a reaction when compounded with 
zinc or calcium salts. 
A number of differential scanning calorimetry studies have 
investigated the compatibility of stearic acid with drugs. 
Although such laboratory studies have suggested incompatibilities, 
e.g. with naproxen,(9) they may not necessarily be 
applicable to formulated products. 
Stearic acid has been reported to cause pitting in the film 
coating of tablets coated using an aqueous film-coating 
technique; the pitting was found to be a function of the melting 
point of the stearic acid.(10) 
13 Method of Manufacture 
Stearic acid is manufactured by hydrolysis of fat by continuous 
exposure to a countercurrent stream of high-temperature water 
and fat in a high-pressure chamber. The resultant mixture is 
purified by vacuum steam distillation and the distillates are then 
separated using selective solvents. 
Stearic acid may also be manufactured by the hydrogenation 
of cottonseed and other vegetable oils; by the hydrogenation 
and subsequent saponification of olein followed by recrystallization 
from alcohol; and from edible fats and oils by boiling 
with sodium hydroxide, separating any glycerin, and decomposing 
the resulting soap with sulfuric or hydrochloric acid. 
The stearic acid is then subsequently separated from any oleic 
acid by cold expression. 
Stearic acid is derived from edible fat sources unless it is 
intended for external use, in which case nonedible fat sources 
may be used. The USPNF 23 states that stearic acid labeled 
solely for external use is exempt from the requirement that it be 
prepared from edible sources. Stearic acid may contain a 
suitable antioxidant such as 0.005% w/w butylated hydroxytoluene. 
14 Safety 
Stearic acid is widely used in oral and topical pharmaceutical 
formulations; it is also used in cosmetics and food products. 
Stearic acid is generally regarded as a nontoxic and nonirritant 
material. However, consumption of excessive amounts may be 
harmful. 
LD50 (mouse, IV): 23 mg/kg(11) 
LD50 (rat, IV): 21.5 mg/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Stearic acid dust may be 
irritant to the skin, eyes, and mucous membranes. Eye 
protection, gloves, and a dust respirator are recommended. 
Stearic acid is combustible. 
738 Stearic Acid

16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe (fatty 
acids). Included in the FDA Inactive Ingredients Guide 
(sublingual tablets; oral capsules, solutions, suspensions, and 
tablets; topical and vaginal preparations). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian 
List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Calcium stearate; magnesium stearate; polyoxyethylene stearates; 
purified stearic acid; zinc stearate. 
Purified stearic acid 
Empirical formula: C18H36O2 
Molecular weight: 284.47 
CAS number: [57-11-4] 
Synonyms: octadecanoic acid. 
Acid value: 195–200 
Boiling point: 3618C 
Density: 0.847 g/cm3 at 708C 
Flash point: 1968C 
Iodine number: 41.5 
Melting point: 66–698C 
Refractive index: nD
80 = 1.4299 
Solubility: soluble 1 in 5 parts benzene, 1 in 6 parts carbon 
tetrachloride, 1 in 2 parts chloroform, 1 in 15 parts ethanol, 
1 in 3 parts ether; practically insoluble in water. 
Vapor density (relative): 9.80 (air = 1) 
Comments: The USPNF 23 describes purified stearic acid as a 
mixture of stearic acid (C18H36O2) and palmitic acid 
(C16H32O2), which together constitute not less than 
96.0% of the total content. The content of C18H36O2 is 
no less than 90.0% of the total. 
18 Comments 
A wide range of different grades of stearic acid are commercially 
available that have varying chemical compositions and 
hence different physical and chemical properties; see Table 
III.(12) A specification for stearic acid is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for stearic acid is 200-313-4. 
19 Specific References 
1 Iranloye TA, Parrott EL. Effects of compression force, particle size, 
and lubricants on dissolution rate. J Pharm Sci 1978; 67: 535–539. 
2 Jarosz PJ, Parrott EL. Effect of tablet lubricants on axial and radial 
work of failure. Drug Dev Ind Pharm 1982; 8: 445–453. 
3 Mitrevej KT, Augsburger LL. Adhesion of tablets in a rotary tablet 
press II: effects of blending time, running time, and lubricant 
concentration. Drug Dev Ind Pharm 1982; 8: 237–282. 
4 Musikabhumma P, Rubinstein MH, Khan KA. Evaluation of 
stearic acid and polyethylene glycol as binders for tabletting 
potassium phenethicillin. Drug Dev Ind Pharm 1982; 8: 169–188. 
5 Zhang Q, Yie G, Li Y, et al. Studies on the cyclosporin A loaded 
stearic acid nanoparticles. Int J Pharm 2000; 200: 153–159. 
6 Suzuki K. Rheological study of vanishing cream. Cosmet Toilet 
1976; 91(6): 23–31. 
7 Mores LR. Application of stearates in cosmetic creams and lotions. 
Cosmet Toilet 1980; 95(3): 79, 81–84. 
8 Yalkowsky SH, He Y, eds. Handbook of Solubility Data. Boca 
Raton, FL: CRC Press; 2003: 1119–1120. 
9 Botha SA, Lo. tter AP. Compatibility study between naproxen and 
tablet excipients using differential scanning calorimetry. Drug Dev 
Ind Pharm 1990; 16: 673–683. 
10 Rowe RC, Forse SF. Pitting: a defect on film-coated tablets. Int J 
Pharm 1983; 17: 347–349. 
11 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3229–3300. 
12 Phadke DS, Keeney MP, Norris DA. Evaluation of batch-to-batch 
and manufacturer-to-manufacturer variability in the physical 
properties of talc and stearic acid. Drug Dev Ind Pharm 1994; 
20: 859–871. 
20 General References 
Allen LV. Featured excipient: capsule and tablet lubricants. Int J Pharm 
Compound 2000; 4(5): 390–392, 404–405. 
Pilpel N. Metal stearates in pharmaceuticals and cosmetics. Manuf 
Chem Aerosol News 1971; 42(10): 37–40. 
21 Authors 
LV Allen. 
22 Date of Revision 
9 August 2005. 
Table III: Specifications of different stearic acid grades. 
Product Stearic acid content (%) Melting range (8C) Acid value Iodine value Saponification value Unsaponifiable matter (%) 
Hystrene 5016 44 54.5–56.5 206–210 40.5 206–211 40.2 
Hystrene 7018 68.5 61.0–62.5 200–205 40.5 200–206 40.2 
Hystrene 9718 90 66.5–68.0 196–201 40.8 196–202 40.3 
Industrene 7018 65 58.0–62.0 200–207 41.5 200–208 40.5 
Industrene 8718 87 64.5–67.5 196–201 42.0 196–202 41.5 
Stearic Acid 739

Stearyl Alcohol 
1 Nonproprietary Names 
BP: Stearyl alcohol 
JP: Stearyl alcohol 
PhEur: Alcohol stearylicus 
USPNF: Stearyl alcohol 
2 Synonyms 
Cachalot; Crodacol S95; Hyfatol 18-95; Hyfatol 18-98; 
Lanette 18; Lipocol S; Lipocol S-DEO; n-octadecanol; 
octadecyl alcohol; Rita SA; Stearol; Stenol; Tego Alkanol 18. 
3 Chemical Name and CAS Registry Number 
1-Octadecanol [112-92-5] 
4 Empirical Formula and Molecular Weight 
C18H38O 270.48 (for pure material) 
The PhEur 2005 describes stearyl alcohol as a mixture of 
solid alcohols containing not less than 95% of 1-octadecanol, 
C18H38O. The USPNF 23 states that stearyl alcohol contains 
not less than 90% of 1-octadecanol, the remainder consisting 
chiefly of related alcohols. 
5 Structural Formula 
6 Functional Category 
Stiffening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Stearyl alcohol is used in cosmetics(1,2) and topical pharmaceutical 
creams and ointments as a stiffening agent. By 
increasing the viscosity of an emulsion, stearyl alcohol increases 
its stability. Stearyl alcohol also has some emollient and weak 
emulsifying properties and is used to increase the water-holding 
capacity of ointments, e.g. petrolatum. In addition, stearyl 
alcohol has been used in controlled-release tablets,(3,4) suppositories,(
5,6) and microspheres.(7,8) It has also been investigated 
for use as a transdermal penetration enhancer.(9) 
8 Description 
Stearyl alcohol occurs as hard, white, waxy pieces, flakes, or 
granules with a slight characteristic odor and bland taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for stearyl alcohol. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification — . . 
Characters — . — 
Appearance of solution . . — 
Melting range 56–628C 57–608C 55–608C 
Acid value 41.0 41.0 42.0 
Iodine value 42.0 42.0 42.0 
Hydroxyl value 200–220 197–217 195–220 
Saponification value — 42.0 — 
Ester value 43.0 — — 
Residue on ignition 40.05% — — 
Assay (of C18H38O) — 595% 590.0% 
10 Typical Properties 
Autoignition temperature: 4508C 
Boiling point: 210.58C at 2 kPa (15 mmHg) 
Density (true): 0.884–0.906 g/cm3(10) 
Flash point: 1918C (open cup) 
Freezing point: 55–578C 
Melting point: 59.4–59.88C for the pure material. 
Refractive index: nD
60 = 1.4388 at 608C 
Solubility: soluble in chloroform, ethanol (95%), ether, hexane, 
propylene glycol, and vegetable oils; practically insoluble in 
water. 
Vapor pressure: 133.3 Pa (1mmHg) at 150.38C 
Viscosity (dynamic): 9.82 mPa s at 648C(10) 
11 Stability and Storage Conditions 
Stearyl alcohol is stable to acids and alkalis and does not 
usually become rancid. It should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Incompatible with strong oxidizing agents and strong acids. 
13 Method of Manufacture 
Historically, stearyl alcohol was prepared from sperm whale oil 
but is now largely prepared synthetically by reduction of ethyl 
stearate with lithium aluminum hydride. 
14 Safety 
Stearyl alcohol is generally considered to be an innocuous, 
nontoxic material. However, adverse reactions to stearyl 
alcohol present in topical preparations have been reported. 
These include contact urticaria and hypersensitivity reactions, 
which are possibly due to impurities contained in stearyl 
alcohol rather than stearyl alcohol itself.(11–15) 
The probable lethal oral human dose is greater than 15 g/kg. 
LD50 (rat, oral): 20 g/kg(16)

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. Stearyl alcohol is not a fire hazard, although it 
will burn and may give off noxious fumes containing carbon 
monoxide. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral tablets, 
rectal topical, and vaginal preparations). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian 
List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Cetostearyl alcohol; cetyl alcohol. 
18 Comments 
The EINECS number for stearyl alcohol is 204-017-6. 
19 Specific References 
1 Egan RR, Portwood O. Higher alcohols in skin lotions. Cosmet 
Perfum 1974; 89(3): 39–42. 
2 Alexander P. Organic rheological additives. Manuf Chem 1986; 
57(9): 49, 52. 
3 Prasad CM, Srivastava GP. Study of some sustained release 
granulations of aspirin. Indian J Hosp Pharm 1971; 8: 21–28. 
4 Kumar K, Chakrabarti T, Srivastava GP. Studies on the sustained 
release tablet formulation of diethylcarbamazine citrate (Hetrazan). 
Indian J Pharm 1975; 37: 57–59. 
5 Kaiho F, Aoki T, Nakagane F, Nagano K, Kato Y. Application of 
fatty alcohols to pharmaceutical dosage forms. Yakuzaigaku 1984; 
44: 99–102. 
6 Tanabe K, Yoshida S, Yamamoto K, et al. Effect of additives on 
release of ibuprofen from suppositories. Yakuzaigaku 1988; 48: 
262–269. 
7 Giannola LI, De Caro V. Entrapment of phenytoin into microspheres 
of oleaginous materials: process development and in vitro 
evaluation of drug release. Drug Dev Ind Pharm 1997; 23(12): 
1145–1152. 
8 Liggins RT, Burt HM. Paclitaxel loaded poly(L-lactic acid) microspheres: 
properties of microspheres made with low molecular 
weight polymers. Int J Pharm 2001; 222(1): 19–33. 
9 Chiang CH, Lai JS, Yang KH. The effects of pH and chemical 
enhancers on the percutaneous absorption of indomethacin. Drug 
Dev Ind Pharm 1991; 17: 91–111. 
10 Weller PJ. Stearyl alcohol. In: Kibbe AH, ed. Handbook of 
Pharmaceutical Excipients, 3rd edn. London and Washington, 
DC: Pharmaceutical Press and American Pharmaceutical Association, 
2000: 537–538. 
11 Gaul LE. Dermatitis from cetyl and stearyl alcohols. Arch 
Dermatol 1969; 99: 593. 
12 Fisher AA. Contact dermatitis from stearyl alcohol and propylene 
glycol. Arch Dermatol 1974; 110: 636. 
13 Black H. Contact dermatitis from stearyl alcohol in Metosyn 
(flucinonide) cream. Contact Dermatitis 1975; 1: 125. 
14 Cronin E. Contact Dermatitis. Edinburgh: Churchill Livingstone, 
1980: 808. 
15 Yesudian PD, King CM. Allergic contact dermatitis from stearyl 
alcohol in Efudix cream. Contact Dermatitis 2001; 45: 313–314. 
16 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2758. 
20 General References 
Barry BW. Continuous shear, viscoelastic and spreading properties of a 
new topical vehicle, FAPG base. J Pharm Pharmacol 1973; 25: 131– 
137. 
Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients Directory 1996. Tokyo: Yakuji Nippo, 1996: 527. 
Madan PL, Luzzi LA, Price JC. Microencapsulation of a waxy solid: 
wall thickness and surface appearance studies. J Pharm Sci 1974; 
63: 280–284. 
Rowe RC. A quantitative assessment of the reactivity of the fatty 
alcohols with cetrimide using immersion calorimetry. J Pharm 
Pharmacol 1987; 39: 50–52. 
Schott H, Han SK. Effect of inorganic additives on solutions of nonionic 
surfactants II. J Pharm Sci 1975; 64: 658–664. 
Wan LSC, Poon PKC. The interfacial activity of sodium lauryl sulfate in 
the presence of alcohols. Can J Pharm Sci 1970; 5: 104–107. 
21 Authors 
RT Guest. 
22 Date of Revision 
23 August 2005. 
Stearyl Alcohol 741

Sucralose 
1 Nonproprietary Names 
USPNF: Sucralose 
2 Synonyms 
Splenda; TGS; 10,40,60-trichlorogalactosucrose; 4,10,60-trichloro-
4,10,60-trideoxy-galacto-sucrose. 
3 Chemical Name and CAS Registry Number 
1,6-Dichloro-1,6-dideoxy-b-D-fructofuranosyl-4-chloro-4- 
deoxy-a-D-galactopyranoside [56038-13-2] 
4 Empirical Formula and Molecular Weight 
C12H19Cl3O8 397.64 
5 Structural Formula 
6 Functional Category 
Sweetening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sucralose is used as a sweetening agent in beverages, foods, and 
pharmaceutical applications. It has a sweetening power 
approximately 300–1000 times that of sucrose and has no 
aftertaste. It has no nutritional value, is noncariogenic, and 
produces no glycemic response. See also Table I. 
Table I: Uses of sucralose. 
Use Concentration (%) 
Food products 0.03–0.24 
8 Description 
Sucralose is a white to off-white colored, free-flowing, crystalline 
powder. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for sucralose. 
Test USPNF 23 
Identification . 
Specific rotation .84.08 to .87.58 
Water 42.0% 
Residue on ignition 40.7% 
Heavy metals 40.001% 
Limit of hydrolysis products 40.1% 
Limit of methanol 40.1% 
Related compounds 40.5% 
Assay (dried basis) 98.0–102.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 5–6 (10% w/v aqueous solution at 
208C) 
Density (bulk): 0.35 g/cm3 
Density (tapped): 0.62 g/cm3 
Density (true): 1.63 g/cm3 
Melting point: 1308C (for anhydrous crystalline form); 36.58C 
(for pentahydrate). 
Particle size distribution: 90% < 12 mm in size. 
Partition coefficient: log10 P = —0.51 (octanol:water) 
Refractive index: 1.33 to 1.37 
Solubility: freely soluble in ethanol (95%), methanol, and 
water; slightly soluble in ethyl acetate. 
Specific rotation [a]D
20: .84.08 to .87.58 (1% w/v aqueous 
solution); .68.28 (1.1% w/v solution in ethanol). 
Viscosity: 0.6–3.8 mPa s 
11 Stability and Storage Conditions 
Sucralose is a relatively stable material. In aqueous solution, at 
highly acidic conditions (pH < 3), and at high temperatures 
(4358C), it is hydrolyzed to a limited extent, producing 4- 
chloro-4-deoxygalactose and 1,6-dichloro-1,6-dideoxyfructose. 
In food products, sucralose remains stable throughout 
extended storage periods, even at low pH. However, it is most 
stable at pH 5–6. 
Sucralose should be stored in a well-closed container in a 
cool, dry place, at a temperature not exceeding 218C. Sucralose, 
when heated at elevated temperatures, may break down with 
the release of carbon dioxide, carbon monoxide, and minor 
amounts of hydrogen chloride. 
12 Incompatibilities 
—
13 Method of Manufacture 
Sucralose may be prepared by a variety of methods that involve 
the selective substitution of three sucrose hydroxyl groups by 
chlorine. Sucralose can also be synthesized by the reaction of 
sucrose (or an acetate) with thionyl chloride.

14 Safety 
Sucralose is generally regarded as a nontoxic and nonirritant 
material and is approved, in a number of countries, for use in 
food products. Following oral consumption, sucralose is 
mainly unabsorbed and is excreted in the feces.(1–3) 
TheWHO has set an acceptable daily intake for sucralose of 
up to 15 mg/kg body-weight.(4) 
LD50 (mouse, oral): > 16 g/kg 
LD50 (rat, oral): > 10 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
The FDA, in April 1998, approved sucralose for use as a 
tabletop sweetener and as an additive in a variety of food 
products. In the UK, sucralose was authorized for use in food 
products on a 2-year temporary basis in March 2002.(5) It is 
also accepted for use in many other countries worldwide. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Sucrose. 
18 Comments 
The sweetening effect of sucralose is not reduced by heating and 
food products containing sucralose may be subjected to hightemperature 
processes such as pasteurization, sterilization, 
UHT processing and baking. Sucralose is often blended with 
maltodextrin or dextrose as bulking agents in its granular form. 
A specification for sucralose is contained in the Food 
Chemicals Codex (FCC). 
19 Specific References 
1 Grice HC, Goldsmith LA. Sucralose – an overview of the toxicity 
data. Food Chem Toxicol 2000; 38 (Suppl. 2): S1–S6. 
2 Roberts A, Renwick AG, Sims J, Snodin DJ. Sucralose metabolism 
and pharmacokinetics in man. Food Chem Toxicol 2000; 38 
(Suppl. 2): S31–S41. 
3 Mclean Baird I, Shephard NW, Merritt RJ, Hildick-Smith G. 
Repeated dose study of sucralose tolerance in human subjects. 
Food Chem Toxicol 2000; 38(Suppl 2): S123–S129. 
4 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirty-seventh report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1991; No. 806: 21–23. 
5 Statutory Instrument (SI) 2002: No. 379. The Sweeteners in Food 
(Amendment) (England) Regulations 2002. London: Stationery 
Office, 2002. 
20 General References 
American Dietic Association. Position of the American Dietic Association: 
use of nutritive and nonnutritive sweetners. J Am Diet Assoc 
2004; 104: 255–275. 
Anonymous. Artificial sweeteners. Can Pharm J 1996; 129(Apr): 22. 
Anonymous. Sucralose – a new artificial sweetener. Med Lett Drugs 
Ther 1998; 40: 67–68. 
Jenner MR, Smithson A. Physicochemical properties of the sweetner 
sucralose. J Food Sci 1989; 54(6): 1646–1649. 
Kloesel L. Sugar substitutes. Int J Pharm Compound 2000; 4(2): 86–87. 
Knight I. The development and applications of sucralose, a new highintensity 
sweetener. Can J Physiol Pharmacol 1994; 72(4): 435– 
439. 
Kroschwiz JI, Howe-Grant M, eds. In: Kirk-Othmer Encyclopedia of 
Chemical Technology, 4th edn. New York: John Wiley & Sons, 
1994; 11: 295. 
McNeil Nutritionals. Splenda: the online guide to cooking, eating and 
living well. http://www.splenda.com (accessed 31 February 2004). 
Tate and Lyle. Technical literature: Sucralose. 2001. 
21 Authors 
BA Langdon, MP Mullarney. 
22 Date of Revision 
26 August 2005. 
Sucralose 743

Sucrose 
1 Nonproprietary Names 
BP: Sucrose 
JP: Sucrose 
PhEur: Saccharum 
USPNF: Sucrose 
2 Synonyms 
Beet sugar; cane sugar; a-D-glucopyranosyl-b-D-fructofuranoside; 
refined sugar; saccharose; sugar. 
3 Chemical Name and CAS Registry Number 
b-D-fructofuranosyl-a-D-glucopyranoside [57-50-1] 
4 Empirical Formula and Molecular Weight 
C12H22O11 342.30 
5 Structural Formula 
6 Functional Category 
Base for medicated confectionery; coating agent; granulating 
agent; sugar coating adjunct; suspending agent; sweetening 
agent; tablet binder; tablet and capsule diluent; tablet filler; 
viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sucrose is widely used in oral pharmaceutical formulations. 
Sucrose syrup, containing 50–67% w/w sucrose, is used in 
tableting as a binding agent for wet granulation. In the 
powdered form, sucrose serves as a dry binder (2–20% w/w) 
or as a bulking agent and sweetener in chewable tablets and 
lozenges.(1,2) Tablets that contain large amounts of sucrose may 
harden to give poor disintegration. 
Sucrose syrups are used as tablet-coating agents at 
concentrations between 50% and 67% w/w. With higher 
concentrations, partial inversion of sucrose occurs, which 
makes sugar coating difficult. 
Sucrose syrups are also widely used as vehicles in oral liquiddosage 
forms to enhance palatability or to increase viscosity.(
3,4) 
Sucrose has been used as a diluent in freeze-dried protein 
products.(5,6) 
Sucrose is also widely used in foods and confectionery, and 
therapeutically in sugar pastes that are used to promote wound 
healing.(7,8) See Table I. 
Table I: Uses of sucrose. 
Use Concentration (% w/w) 
Syrup for oral liquid formulations 67 
Sweetening agent 67 
Tablet binder (dry granulation) 2–20 
Tablet binder (wet granulation) 50–67 
Tablet coating (syrup) 50–67 
8 Description 
Sucrose is a sugar obtained from sugar cane (Saccharum 
officinarum Linne. (Fam. Gramineae)), sugar beet (Beta vulgaris 
Linne. (Fam. Chenopodiaceae)), and other sources. It contains 
no added substances. Sucrose occurs as colorless crystals, as 
crystalline masses or blocks, or as a white crystalline powder; it 
is odorless and has a sweet taste. 
9 Pharmacopeial Specifications 
See Table II. 
10 Typical Properties 
Density (bulk): 
0.93 g/cm3 (crystalline sucrose); 
0.60 g/cm3 (powdered sucrose). 
Density (tapped): 
1.03 g/cm3 (crystalline sucrose); 
0.82 g/cm3 (powdered sucrose). 
Density (true): 1.6 g/cm3 
Dissociation constant: pKa = 12.62 
Flowability: crystalline sucrose is free flowing, whereas 
powdered sucrose is a cohesive solid. 
Melting point: 160–1868C (with decomposition) 
Moisture content: finely divided sucrose is hygroscopic and 
absorbs up to 1% water.(9) See Figure 1. 
Osmolarity: a 9.25% w/v aqueous solution is isoosmotic with 
serum. 
Particle size distribution: powdered sucrose is a white, 
irregular-sized granular powder. The crystalline material 
consists of colorless crystalline, roughly cubic granules. See 
Figures 2 and 3.

Table II: Pharmacopeial specifications for sucrose. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters — . — 
Appearance of 
solution 
. . — 
Acidity or alkalinity . . — 
Specific optical 
rotation 
.66.38 to 
.67.08 
.66.38 to 
.67.08 
5.65.98 
Color value — 445 — 
Conductivity . . — 
Loss on drying 40.1% 40.1% — 
Bacterial endotoxins(a) 40.25 IU/mg 40.25 IU/mg — 
Dextrins(a) . . — 
Reducing sugars — . — 
Invert sugar . — . 
Chloride — — 40.0035% 
Sulfate — — 40.006% 
Sulfites 415 ppm 410 ppm — 
Calcium — — 45 ppm 
Heavy metals — — 45 ppm 
Lead 40.5 ppm 40.5 ppm — 
Residue on ignition — — 40.05% 
Organic volatile 
impurities 
— — . 
(a) If sucrose is to be used in large volume infusions. 
Refractive index: nD
25 = 1.34783 (10% w/v aqueous solution) 
Solubility: see Table III. 
Specific gravity: see Table IV. 
Table III: Solubility of sucrose. 
Solvent Solubility at 208C unless otherwise stated 
Chloroform Practically insoluble 
Ethanol 1 in 400 
Ethanol (95%) 1 in 170 
Propan-2-ol 1 in 400 
Water 1 in 0.5 
1 in 0.2 at 1008C 
Table IV: Specific gravity of aqueous sucrose solutions. 
Concentration of aqueous 
sucrose solution (% w/w) 
Specific gravity at 208C 
2 1.0060 
6 1.0219 
10 1.0381 
20 1.0810 
30 1.1270 
40 1.1764 
50 1.2296 
60 1.2865 
70 1.3471 
76 1.3854 
SEM: 1 
Excipient: Sucrose 
Manufacturer: Great Western Sugar Co. 
Lot No.: 1-2-80 
Magnification: 60 Voltage: 10 kV 
SEM: 2 
Excipient: Sucrose 
Manufacturer: Great Western Sugar Co. 
Lot No.: 1-2-80 
Magnification: 600 Voltage: 10 kV 
11 Stability and Storage Conditions 
Sucrose has good stability at room temperature and at 
moderate relative humidity. It absorbs up to 1% moisture, 
which is released upon heating at 908C. Sucrose caramelizes 
when heated to temperatures above 1608C. Dilute sucrose 
solutions are liable to fermentation by microorganisms but 
resist decomposition at higher concentrations, e.g., above 60% 
Sucrose 745

w/w concentration. Aqueous solutions may be sterilized by 
autoclaving or filtration. 
When sucrose is used as a base for medicated confectionery, 
the cooking process, at temperatures rising from 110 to 1458C, 
causes some inversion to form dextrose and fructose (invert 
sugar). The fructose imparts stickiness to confectionery but 
prevents cloudiness due to graining. Inversion is accelerated 
particularly at temperatures above 1308C and by the presence 
of acids. 
The bulk material should be stored in a well-closed 
container in a cool, dry place. 
Figure 1: Moisture sorption–desorption isotherm of powdered 
sucrose. 
Samples dried initially at 608C over silica gel for 24 
hours. Note: at 90% relative humidity, sufficient water 
was absorbed to cause dissolution of the solid. 
12 Incompatibilities 
Powdered sucrose may be contaminated with traces of heavy 
metals, which can lead to incompatibility with active ingredients, 
e.g. ascorbic acid. Sucrose may also be contaminated 
with sulfite from the refining process. With high sulfite content, 
color changes can occur in sugar-coated tablets; for certain 
colors used in sugar-coating the maximum limit for sulfite 
content, calculated as sulfur, is 1 ppm. In the presence of dilute 
or concentrated acids, sucrose is hydrolyzed or inverted to 
dextrose and fructose (invert sugar). Sucrose may attack 
aluminum closures.(10) 
13 Method of Manufacture 
Sucrose is obtained from the sugar cane plant, which contains 
15–20% sucrose, and sugar beet, which contains 10–17% 
sucrose. Juice from these sources is heated to coagulate watersoluble 
proteins, which are removed by skimming. The 
resultant solution is then decolorized with an ion-exchange 
resin or charcoal and concentrated. Upon cooling, sucrose 
crystallizes out. The remaining solution is concentrated again 
and yields more sucrose, brown sugar, and molasses. 
Figure 2: Particle size distribution of crystalline sucrose. 
Figure 3: Particle size distribution of powdered sucrose. 
14 Safety 
Sucrose is hydrolyzed in the small intestine by the enzyme 
sucrase to yield dextrose and fructose, which are then absorbed. 
When administered intravenously, sucrose is excreted 
unchanged in the urine. 
Although sucrose is very widely used in foods and 
pharmaceutical formulations, sucrose consumption is a cause 
of concern and should be monitored in patients with diabetes 
mellitus or other metabolic sugar intolerance.(11) 
Sucrose is also considered to be more cariogenic than other 
carbohydrates since it is more easily converted to dental plaque. 
746 Sucrose

For this reason, its use in oral pharmaceutical formulations is 
declining. 
Although sucrose has been associated with obesity, renal 
damage, and a number of other diseases, conclusive evidence 
linking sucrose intake with some diseases could not be 
established.(12,13) It was, however, recommended that sucrose 
intake in the diet should be reduced.(13) 
LD50 (mouse, IP): 14 g/kg(14) 
LD50 (rat, oral): 29.7 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. In the UK, the occupational exposure limit for 
sucrose is 10 mg/m3 long-term (8-hour TWA) and 20 mg/m3 
short-term.(15) 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(injections; oral capsules, solutions, syrups, and tablets; topical 
preparations). Included in nonparenteral and parenteral 
medicines licensed in the UK. Included in the Canadian List 
of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Compressible sugar; confectioner’s sugar; invert sugar; sugar 
spheres. 
Invert sugar 
Empirical formula: C6H12O6 
Molecular weight: 180.16 
CAS number: [8013-17-0] 
Comments: an equimolecular mixture of dextrose and fructose 
prepared by the hydrolysis of sucrose with a suitable mineral 
acid such as hydrochloric acid. Invert sugar may be used as a 
stabilizing agent to help prevent crystallization of sucrose 
syrups and graining in confectionery. A 10% aqueous 
solution is also used in parenteral nutrition. 
18 Comments 
For typical boiling points of sucrose syrups, without inversion 
of the sugar, see Table V. A specification for sucrose is contained 
in the Food Chemicals Codex (FCC). 
The EINECS number for sucrose is 200-334-9. 
Table V: Boiling points of sucrose syrups. 
Sucrose concentration (% w/v) Boiling point (8C) 
50 101.5 
60 103 
64 104 
72 105.5 
75 107 
77.5 108.5 
80 110.5 
19 Specific References 
1 Allen LV. Featured excipient: capsule and tablet diluents. Int J 
Pharm Compound 2000; 4(4): 306–310, 324–325. 
2 Mullarney MP, Hancock BC, Carlson GT, et al. The powder flow 
and compact mechanical properties of sucrose and three high 
intensity sweeteners used in chewable tablets. Int J Pharm 2003; 
257(1–2): 227–236. 
3 Salazar DSM, Saavedra C. Application of a sensorial response 
model to the design of an oral liquid pharmaceutical dosage form. 
Drug Dev Ind Pharm 2000; 26(1): 55–60. 
4 Cooper J. A question of taste: uses of sucrose. Manuf Chem 2003; 
74(10): 71–72, 74. 
5 Izutsu K, Kojima S. Excipient crystallinity and its protein structure 
stabilizing effect during freeze-drying. J Pharm Pharmacol 2002; 
54(8): 1033–1039. 
6 Johnson RE, Kirchoff CF, Gand HE. Mannitol-sucrose mixtures: 
versatile formulations for protein lyophilisation. J Pharm Sci 2002; 
91(4): 914–922. 
7 Middleton KR, Seal D. Sugar as an aid to wound healing. Pharm J 
1985; 235: 757–758. 
8 Thomas S. Wound Management and Dressings. London: Pharmaceutical 
Press, 1990: 62–63. 
9 Hancock BC, Dalton CR. Effect of temperature on water vapour 
sorption by some amorphous pharmaceutical sugars. Pharm Dev 
Technol 1999; 4(1): 125–131. 
10 Tressler LJ. Medicine bottle caps [letter]. Pharm J 1985; 235: 99. 
11 Golightly LK, Smolinske SS, Bennett ML, et al. Pharmaceutical 
excipients: adverse effects associated with ‘inactive’ ingredients in 
drug products (part II). Med Toxicol 1988; 3: 209–240. 
12 Yudkin J. Sugar and disease. Nature 1972; 239: 197–199. 
13 Anonymous. Report on Health and Social Subjects 37. London: 
HMSO, 1989. 
14 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3318. 
15 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
Armstrong NA. In: Swarbrick J, Boylan JC, eds. Encyclopedia of 
Pharmaceutical Technology, 2nd edn, vol. 3. New York: Marcel 
Dekker, 2002: 2713–2732. 
Barry RH, Weiss M, Johnson JB, DeRitter E. Stability of phenylpropanolamine 
hydrochloride in liquid formulations containing sugars. 
J Pharm Sci 1982; 71: 116–118. 
Jackson EB, ed. Sugar Confectionery Manufacture. Glasgow: Blackie, 
1990. 
Lipari JM, Reiland TL. Flavors and flavor modifiers. In: Swarbrick J, 
Boylan JC, eds. Encyclopedia of Pharmaceutical Technology, 2nd 
edn, vol. 2. New York: Marcel Dekker, 2002: 1255–1263. 
Wolraich ML, Lindgreen SD, Stumbo PJ, et al. Effects of diets high in 
sucrose or aspartame on the behavior and cognitive performance of 
children. N Engl J Med 1994; 330: 301–307. 
21 Authors 
NA Armstrong. 
22 Date of Revision 
17 August 2005. 
Sucrose 747

Sugar, Compressible 
1 Nonproprietary Names 
USPNF: Compressible sugar 
2 Synonyms 
Di-Pac; direct compacting sucrose. 
3 Chemical name and CAS Registry Number 
See Sections 4 and 18. 
4 Empirical Formula and Molecular Weight 
The USPNF 23 states that compressible sugar contains not less 
than 95.0% and not more than 98.0% of sucrose (C12H22O11). 
It may contain starch, maltodextrin, or invert sugar, and may 
contain a suitable lubricant. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Sweetening agent; tablet and capsule diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Compressible sugar is used primarily in the preparation of 
direct-compression chewable tablets. Its tableting properties 
can be influenced by small changes in moisture level;(1,2) see 
Table I. 
Table I: Uses of compressible sugar. 
Use Concentration (%) 
Dry binder in tablet formulations 5–20 
Filler in chewable tablets 20–60 
Filler in tablets 20–60 
Sweetener in chewable tablets 10–50 
8 Description 
Compressible sugar is a sweet-tasting, white, crystalline 
powder. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for compressible sugar. 
Test USPNF 23 
Identification . 
Calcium . 
Chloride 40.014% 
Heavy metals 45 ppm 
Loss on drying 0.25–1.0% 
Residue on ignition 40.1% 
Microbial limits . 
Organic volatile impurities . 
Sulfate 40.010% 
Assay 95.0–98.0% 
10 Typical Properties 
Density (bulk): 0.492 g/cm3 
Density (tapped): 0.6 g/cm3 
Moisture content: 0.57% 
Particle size distribution: for Di-Pac, 3%maximum retained on 
a #40 (425 mm) mesh; 75% minimum through a #100 
(150 mm) mesh; 5% maximum through #200 (75 mm) mesh. 
Solubility: the sucrose portion is water-soluble. 
Specific surface area: 0.13–0.14m2/g 
11 Stability and Storage Conditions 
Compressible sugar is stable in air under normal storage 
conditions of room temperature and low relative humidity. The 
bulk material should be stored in a well-closed container in a 
cool, dry place. 
12 Incompatibilities 
Incompatible with dilute acids, which cause hydrolysis of 
sucrose to invert sugar, and with alkaline earth hydroxides, 
which react with sucrose to form sucrates. 
13 Method of Manufacture 
Compressible sugar is prepared by cocrystallization of sucrose 
with other excipients such as maltodextrin.(1) Compressible 
sugar may also be prepared using a dry granulation process. 
14 Safety 
Compressible sugar is generally regarded as a relatively 
nontoxic and nonirritant material. See also Sucrose. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. See also Sucrose.

16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral capsules 
and tablets). Included in nonparenteral medicines licensed in 
the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Confectioner’s sugar; sucrose; sugar spheres; Sugartab. 
Sugartab 
Appearance: Sugartab (JRS Pharma LC) is a compressible sugar 
that does not conform to the USPNF 23 specification. It is an 
agglomerated sugar product containing approximately 
90–93% sucrose, the balance being invert sugar. 
Density (bulk): 0.60 g/cm3 
Density (tapped): 0.69 g/cm3 
EINECS number: [64333-34-2] 
Flowability: 42.7 g/s 
Moisture content: 0.20–0.57%. 
Particle size distribution: 30% through a #20 (850 mm) mesh; 
3% through a #30 (600 mm) mesh. 
18 Comments 
— 
19 Specific References 
1 Rizzuto AB, Chen AC, Veiga MF. Modification of the sucrose 
crystal structure to enhance pharmaceutical properties of excipient 
and drug substances. Pharm Technol 1984; 8(9): 32, 34, 36, 38– 
39. 
2 Tabibi SE, Hollenbeck RG. Interaction of water vapor and 
compressible sugar. Int J Pharm 1984; 18: 169–183. 
20 General References 
JRS Pharma LC. Technical literature: Sugartab, 2003. 
Mendes RW, Gupta MR, Katz IA, O’Neil JA. Nu-tab as a chewable 
direct compression carrier. Drug Cosmet Ind 1974; 115(6): 42–46, 
130–133. 
Ondari CO, Kean CE, Rhodes CT. Comparative evaluation of several 
direct compression sugars. Drug Dev Ind Pharm 1983; 9: 1555– 
1572. 
Ondari CO, Kean CE, Rhodes CT. Comparative evaluation of several 
direct compression sugars. Drug Dev Ind Pharm 1988; 14: 1517– 
1527. 
Shangraw RF, Wallace JW, Bowers FM. Morphology and functionality 
in tablet excipients for direct compression. Pharm Technol 1981; 5: 
69–78. 
21 Authors 
AW Wood. 
22 Date of Revision 
17 August 2005. 
Sugar, Compressible 749

Sugar, Confectioner’s 
1 Nonproprietary Names 
USPNF: Confectioner’s sugar 
2 Synonyms 
Icing sugar; powdered sugar. 
3 Chemical Name and CAS Registry Number 
See Section 4. 
4 Empirical Formula and Molecular Weight 
The USPNF 23 describes confectioner’s sugar as a mixture of 
sucrose (C12H22O11) and corn starch that has been ground to a 
fine powder; it contains not less than 95.0% sucrose. 
5 Structural Formula 
See Section 4 and Sucrose. 
6 Functional Category 
Sugar coating adjunct; sweetening agent; tablet and capsule 
diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Confectioner’s sugar is used in pharmaceutical formulations 
when a rapidly dissolving form of sugar is required for 
flavoring or sweetening. It is used as a diluent in solid-dosage 
formulations when a small particle size is necessary to achieve 
content uniformity in blends with finely divided active 
ingredients. In solutions, at high concentrations (70% w/v), 
confectioner’s sugar provides increased viscosity along with 
some preservative effects. Confectioner’s sugar is also used in 
the preparation of sugar-coating solutions and in wet granulations 
as a binder/diluent. See Table I. 
Table I: Uses of confectioner’s sugar. 
Use Concentration (%) 
Sweetening agent in tablets 10–20 
Tablet diluent 10–50 
See also Section 18. 
8 Description 
Confectioner’s sugar occurs as a sweet-tasting, fine, white, 
odorless powder. 
SEM: 1 
Excipient: Confectioner’s sugar 
Manufacturer: Frost 
Lot No.: 101A-1 
Magnification: 60 Voltage: 20 kV 
SEM: 2 
Excipient: Confectioner’s sugar 
Manufacturer: Frost 
Lot No.: 101A-1 
Magnification: 600 Voltage: 20 kV

9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for confectioner’s sugar. 
Test USPNF 23 
Identification . 
Chloride 40.014% 
Calcium . 
Heavy metals 45 ppm 
Loss on drying 41.0% 
Microbial limits . 
Organic volatile impurities . 
Residue on ignition 40.08% 
Specific rotation 5.62.68 
Sulfate 40.006% 
Assay 495.0% 
10 Typical Properties 
Density (bulk): 0.465 g/cm3 
Density (tapped): 0.824 g/cm3 
Moisture content: 0.1–0.31% 
Particle size distribution: various grades with different particle 
sizes are commercially available, e.g., 6X, 10X, and 12X 
grades of confectioner’s sugar from the Domino Sugar Corp. 
Mean particle size is 14.3 mm. 
For 6X, 94% through a #200 (75 mm) mesh. 
For 10X, 99.9% through a #100 (150 mm) mesh and 
97.5% through a #200 (75 mm) mesh. 
For 12X, 99% through a #200 (75 mm) mesh and 96% 
through a #325 (45 mm) mesh. 
Solubility: the sucrose portion is water-soluble while the starch 
portion is insoluble in water, although it forms a cloudy 
solution. 
11 Stability and Storage Conditions 
Confectioner’s sugar is stable in air at moderate temperatures 
but may caramelize and decompose above 1608C. It is more 
hygroscopic than granular sucrose. Microbial growth may 
occur on dry storage if adsorbed moisture is present or in dilute 
aqueous solutions. 
Confectioner’s sugar should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Confectioner’s sugar is incompatible with dilute acids, which 
cause the hydrolysis of sucrose to invert sugar. It is also 
incompatible with alkaline earth hydroxides, which react with 
sucrose to form sucrates. 
13 Method of Manufacture 
Confectioner’s sugar is usually manufactured by grinding 
refined granulated sucrose with corn starch to produce a fine 
powder. Other anticaking agents, such as tricalcium phosphate 
and various silicates, have also been used but are less common. 
14 Safety 
Confectioner’s sugar is used in confectionery and oral 
pharmaceutical formulations. It is generally regarded as a 
relatively nontoxic and nonirritant material. See also Sucrose. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. See also Sucrose. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (capsules and 
tablets). Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Compressible sugar; sucrose; sugar spheres. 
18 Comments 
Confectioner’s sugar is not widely used in pharmaceutical 
formulations because the poor-flow characteristics prevent its 
use in direct-compression blends. However, confectioner’s 
sugar is used when a smooth mouth feel or a rapidly dissolving 
sweetener is required, and when a milled/micronized active 
ingredient must be blended with a diluent of similar particle size 
for powders or wet granulations. 
Low-starch grades of confectioner’s sugar containing 
0.01% w/w starch are also commercially available. 
19 Specific References 
20 General References 
Barry RH, Weiss M, Johnson JB, DeRitter E. Stability of phenylpropanolamine 
hydrochloride in liquid formulations containing 
sugars. J Pharm Sci 1982; 71: 116–118. 
Czeisler JL, Perlman KP. Diluents. In: Swarbrick J, Boylan JC, eds. 
Encyclopedia of Pharmaceutical Technology, vol. 4. New York: 
Marcel Dekker, 1988: 37–84. 
Edwards WP. The Science of Sugar Confectionery. Cambridge: Royal 
Society of Chemistry, 2000. 
Jackson EB, ed. Sugar Confectionery Manufacture. Glasgow: Blackie, 
1990. 
Onyekweli AO, Pilpel N. Effect of temperature changes on the 
densification and compression of griseofulvin and sucrose powders. 
J Pharm Pharmacol 1981; 33: 377–381. 
Wolraich ML, Lindgren SD, Stumbo PJ, et al. Effects of diets high in 
sucrose or aspartame on the behavior and cognitive performance of 
children. N Engl J Med 1994; 330: 301–307. 
21 Authors 
AH Kibbe. 
22 Date of Revision 
12 August 2005. 
Sugar, Confectioner’s 751

Sugar Spheres 
1 Nonproprietary Names 
BP: Sugar spheres 
PhEur: Sacchari spheri 
USPNF: Sugar spheres 
2 Synonyms 
Non-pareil; non-pareil seeds; NPTAB; Nu-Core; Nu-Pareil PG; 
sugar seeds; Suglets. 
3 Chemical Name and CAS Registry Number 
—
4 Empirical Formula and Molecular Weight 
See Section 8. 
5 Structural Formula 
See Section 8. 
6 Functional Category 
Tablet and capsule diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sugar spheres are mainly used as inert cores in capsule and 
tablet formulations, particularly multiparticulate sustainedrelease 
formulations.(1–4) They form the base upon which a 
drug is coated, usually followed by a release-modifying 
polymer coating. 
Alternatively, a drug and matrix polymer may be coated 
onto the cores simultaneously. The active drug is released over 
an extended period either via diffusion through the polymer or 
through to the controlled erosion of the polymer coating. 
Complex drug mixtures contained within a single-dosage 
form may be prepared by coating the drugs onto different 
batches of sugar spheres with different protective polymer 
coatings. 
Sugar spheres are also used in confectionery products. 
8 Description 
The USPNF 23 describes sugar spheres as approximately 
spherical granules of a labeled nominal-size range with a 
uniform diameter and containing not less than 62.5% and not 
more than 91.5% of sucrose, calculated on the dried basis. The 
remainder is chiefly starch. 
The PhEur 2005 states that sugar spheres contain not more 
than 92% of sucrose calculated on the dried basis. The 
remainder consists of corn (maize) starch and may also contain 
starch hydrolysates and color additives. The diameter of sugar 
spheres varies from 200 to 2000 mm and the upper and lower 
limits of the size of the sugar spheres are stated on the label. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for sugar spheres. 
Test PhEur 2005 USPNF 23 
Identification . . 
Heavy metals 45 ppm 45 ppm 
Loss on drying 45.0% 44.0% 
Microbial limits . . 
Organic volatile impurities — . 
Particle size distribution . . 
Residue on ignition 40.2% 40.25% 
Specific rotation — .418 to .618 
Sucrose (dried basis) 492% 62.5–91.5% 
10 Typical properties 
Density: 
1.57–1.59 g/cm3 for Suglets less than 500 mm in size; 
1.55–1.58 g/cm3 for Suglets more than 500 mm in size. 
Flowability: <10 seconds, free flowing. 
Particle size distribution: sugar spheres are of a uniform 
diameter. The following sizes are commercially available 
from various suppliers (US standard sieves): 
45–60 mesh (250–355 mm) 
40–50 mesh (300–425 mm) 
35–45 mesh (355–500 mm) 
35–40 mesh (420–500 mm) 
30–35 mesh (500–600 mm) 
25–30 mesh (610–710 mm) 
20–25 mesh (710–850 mm) 
18–20 mesh (850–1000 mm) 
16–20 mesh (850–1180 mm) 
14–18 mesh (1000–1400 mm) 
Solubility: solubility in water varies according to the sucrose-tostarch 
ratio. The sucrose component is freely soluble in 
water, whereas the starch component is practically insoluble 
in cold water. 
Specific surface area: 
0.1–0.2m2/g for Suglets less than 500 mm in size; 
>0.2m2/g for Suglets more than 500 mm in size. 
11 Stability and Storage Conditions 
Sugar spheres are stable when stored in a well-closed container 
in a cool, dry place. 
12 Incompatibilities 
See Starch and Sucrose for information concerning the 
incompatibilities of the component materials of sugar spheres. 
13 Method of Manufacture 
Sugar spheres are prepared from crystalline sucrose, which is 
coated using sugar syrup and a starch dusting powder.

14 Safety 
Sugar spheres are used in oral pharmaceutical formulations. 
The sucrose and starch components of sugar spheres are widely 
used in edible food products and oral pharmaceutical formulations. 
The adverse reactions and precautions necessary with the 
starch and sucrose components should be considered in any 
product containing sugar spheres. For example, sucrose is 
generally regarded as more cariogenic than other carbohydrates, 
and in higher doses is also contraindicated in diabetic 
patients. 
See Starch and Sucrose for further information. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral capsules 
and tablets). Included in nonparenteral medicines licensed in 
the UK and Europe. The sucrose and starch components of 
sugar spheres are individually approved for use as food 
additives in Europe and the USA. Included in the Canadian 
List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Compressible sugar; confectioner’s sugar; starch; sucrose. 
18 Comments 
—
19 Specific References 
1 Narsimhan R, Labhasetwar VD, Lakhotia CL, Dorle A. Timedrelease 
noscapine microcapsules. Indian J Pharm Sci 1988; 50: 
120–122. 
2 Bansal AK, Kakkar AP. Solvent deposition of diazepam over 
sucrose pellets. Indian J Pharm Sci 1990; 52: 186–187. 
3 Ho H-O, Su H-L, Tsai T, Sheu M-T. The preparation and 
characterization of solid dispersions on pellets using a fluidizedbed 
system. Int J Pharm 1996; 139: 223–229. 
4 Miller RA, Leung EM, Oates RJ. The compression of spheres 
coated with an aqueous ethylcellulose dispersion. Drug Devel Ind 
Pharm 1999; 25(4): 503–511. 
20 General References 
Birch GG, Parker KJ, eds. Sugar: Science and Technology. London: 
Applied Science Publications, 1979. 
21 Authors 
RC Moreton. 
22 Date of Revision 
26 August 2005. 
Sugar Spheres 753

Sulfobutylether b-Cyclodextrin 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
b-Cyclodextrin sulfobutylether, sodium salt; Captisol; (SBE)7mbeta-
CD; SBE7-b-CD; SBECD; sulfobutylether-b-cyclodextrin, 
sodium salt. 
3 Chemical Name and CAS Registry Number 
b-Cyclodextrin sulfobutylether, sodium salt [1824100-00-0] 
4 Empirical Formula and Molecular Weight 
C42H70–nO35(C4H8SO3Na)n 2163 (where n = approximately 
6.5) 
5 Structural Formula 
R = H21–n or (CH2CH2CH2CH2SO2ONa)n where n = 
6.0–7.1 
Note: the substitution pattern is random, yielding a 
heterogeneous mixture both in terms of the site of substitution 
as well as degree of substitution. The n value is an average 
number derived from the average degree of substitution. 
6 Functional Category 
Dissolution-enhancing agent; drug delivery system; osmotic 
agent; solubilizing agent; stabilizing agent; tablet and capsule 
diluent; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Cyclodextrins are crystalline, nonhygroscopic, cyclic oligosaccharides 
derived from starch (see Cyclodextrins). Sulfobutylether 
b-cyclodextrin is an amorphous, anionic substituted 
b-cyclodextrin derivative (see Section 8); other substituted 
cyclodextrin derivatives are also available (see Section 17). 
Sulfobutylether b-cyclodextrin can form noncovalent complexes 
with many types of compounds including small organic 
molecules, peptides,(1) and proteins.(2) It can also enhance their 
solubility(3,4) and stability(4–6) in water. The first application of 
sulfobutylether b-cyclodextrin was in injectable preparations;(7) 
it can also be used in oral solid(8,9) and liquid(10) dosage forms, 
and ophthalmic,(11,12) inhalation, and intranasal formulations.(
13) Sulfobutylether b-cyclodextrin can function as an 
osmotic agent and/or a solubilizer for controlled-release 
delivery,(9) and has antimicrobial preservative properties 
when present at sufficient concentrations. 
The amount of sulfobutylether b-cyclodextrin that may be 
used is dependent on the purpose for inclusion in the 
formulation, the route of administration, and the ability of 
the cyclodextrin to complex with the drug being delivered. The 
minimum amount required for solubilization is, in general, a 
cyclodextrin/drug molar ratio of approximately 1–5 (the exact 
ratio being experimentally determined from complexation 
data). The maximum use in a formulation may be limited by 
physicochemical constraints such as viscosity (e.g. syringeable 
concentrations may be considered up to 50% w/v), tonicity, or 
the total weight and size of solid dosage forms (e.g. less than a 
gram in an individual tablet). It may also be limited by 
pharmacokinetic/pharmacodynamic (PK/PD) considerations. 
As dilution of a cyclodextrin formulation leads to an increase 
in the amount of uncomplexed drug, formulations that are not 
diluted upon administration, such as ophthalmic formulations, 
are sensitive to cyclodextrin concentration. In formulations 
such as these, cyclodextrin concentrations greater than the 
minimum required for solubilization can reduce the availability 
of uncomplexed drug and thereby affect PK/PD expectations by 
producing effects such as slower onset, lower Cmax, and 
bioavailability. 
8 Description 
b-Cyclodextrin is a cyclic oligosaccharide containing seven D- 
(.)-glucopyranose units attached by a(1!4) glucoside bonds 
(see Cyclodextrins). Sulfobutylether b-cyclodextrin is an 
anionic b-cyclodextrin derivative with a sodium sulfonate salt 
separated from the hydrophobic cavity by a butyl spacer group. 
The substituent is introduced at positions 2, 3, and 6 in at least 
one of the glucopyranose units in the cyclodextrin structure. 
Introducing the SBE into b-cyclodextrin can produce materials 
with different degrees of substitution, theoretically from 1 to 
21; the hepta-substituted preparation (SBE7-b-CD) being the 
cyclodextrin with the most desirable drug carrier properties.(14) 
Sulfobutylether b-cyclodextrin occurs as a white amorphous 
powder. 
9 Pharmacopeial Specifications 
—

10 Typical Properties 
Acidity/alkalinity: pH = 6 (30% w/w aqueous solution)(15) 
Angle of repose: 
20.58 for freeze-dried Captisol; 
31.68 for spray-dried Captisol. 
Appearance of solution: a 30% w/v solution in water is clear, 
colorless, and essentially free from particles of foreign 
matter. 
Average degree of substitution: 6.0–7.1(15) 
Compressibility: see Figure 1. 
Density (bulk): 
0.446–0.482 g/cm3 for freeze-dried Captisol; 
0.524 g/cm3 for spray-dried Captisol; 
0.482 g/cm3 for spray-agglomerated reprocessed Captisol. 
Density (tapped): 
0.565–0.597 g/cm3 for freeze-dried Captisol; 
0.624 g/cm3 for spray-dried Captisol; 
0.595 g/cm3 for spray-agglomerated reprocessed Captisol. 
Flowability: 50 g/s for freeze-dried Captisol. 
Hygroscopicity: reversibly picks up water at relative humidities 
(RH) up to 60%. Equilibration at RH equal to or above 
60% will result in deliquescence and a water content of 
approximately 16%w/w. See Figure 2. 
Melting point: decomposition at 2758C. 
Moisture content: 2–5% typically; maximum 10%. 
Osmolarity: a 12.7% w/v solution of Captisol is iso-osmotic 
with serum. 
Particle size distribution: typical mean particle size for spraydried 
sulfobutylether b-cyclodextrin sodium is 70–120 mm. 
Various processing and handling methods may result in 
different nominal mean particle sizes. 
Specific rotation [a]D
20: .948 
Solubility: soluble 1 in less than 2 of water; 1 in 30–40 of 
methanol; practically insoluble in ethanol, n-hexane, 
1-butanol, acetonitrile, 2-propanol, and ethyl acetate. 
Viscosity (dynamic): 1.75 mPa s for a 8.5% w/w aqueous 
solution at 258C, 1.09 mPa s at 608C; 
528 mPa s for a 60% w/w aqueous solution at 258C, 
87 mPa s at 608C.(15) 
SEM: 1 
Excipient: Freeze-dried sulfobutylether b-cyclodextrin sodium 
(Captisol) 
Manufacturer: CyDex 
Magnification: 150 
SEM: 2 
Excipient: Spray-dried sulfobutylether b-cyclodextrin sodium 
(Captisol) 
Manufacturer: CyDex 
Magnification: 150 
SEM: 3 
Excipient: Spray-agglomerated sulfobutylether b-cyclodextrin sodium 
(reprocessed Captisol) 
Manufacturer: CyDex 
Magnification: 150 
11 Stability and Storage Conditions 
Sulfobutylether b-cyclodextrin is stable in the solid state and 
should be protected from high humidity. It should be stored in a 
tightly sealed container in a cool, dry place. 
It will reversibly take up moisture without any effect on the 
appearance of the material at humidities up to 60% RH. 
Equilibration at RH values above 60% will result in 
deliquescence. Once in this state, the material can be dried, 
but will give a glasslike product. This water absorption 
behavior is typical of amorphous hygroscopic materials. 
Sulfobutylether b-Cyclodextrin 755

Figure 1: Compression characteristics of sulfobutylether b-cyclodextrin 
sodium. 
*: Spray-dried (CyDex, Captisol, Lot No.: CY-03A- 
02046) 
}: Spray-agglomerated (Reprocessed CyDex Lot No.: CY- 
03A-099020) 
&: Freeze-dried (CyDex, Captisol, Lot No.: RPP-96- 
CDSBE-BA#1) 
Mean tablet weight: 220mg 
Tablet dimensions: 5/16 inch std concave 
Lubricated with 0.5% magnesium stearate 
Tablet machine: Instrumented Stokes Model F, Single Punch 
Press 
Figure 2: Moisture sorption–desorption isotherm of sulfobutylether bcyclodextrin 
sodium, at 308C. 
&: Freeze-dried (native moisture content: 3.7%) 
~: Spray-dried (native moisture content: 5.2%) 
Sulfobutylether b-cyclodextrin is stable in aqueous solutions 
at values above about pH1. It can degrade in highly acidic (pH 
< 1) solutions, particularly at elevated temperatures; producing 
the ring-opened form, followed by hydrolysis of the a(1!4) 
glucoside bonds. 
Sulfobutylether b-cyclodextrin solutions may be autoclaved.(
15) 
12 Incompatibilities 
The preservative activity of benzalkonium chloride is reduced 
in the presence of sulfobutylether b-cyclodextrin. 
13 Method of Manufacture 
Sulfobutylether b-cyclodextrin is prepared by alkylation of bcyclodextrin 
using 1,4-butane sultone under basic conditions. 
The degree of substitution in b-cyclodextrin is controlled by the 
stoichiometric ratio of b-cyclodextrin to sultone used in the 
process. 
14 Safety 
Sulfobutylether b-cyclodextrin is derived from b-cyclodextrin, 
which is toxic when administered parenterally (see Cyclodextrins). 
However, studies have shown that sulfobutylether bcyclodextrin 
is well tolerated at high doses, when administered 
via intravenous bolus injections, orally, and by inhalation.(
1,8,16) Up to 9 g/day may be administered by IV infusion 
in a licensed voriconazole formulation.(15) 
Sulfobutylether b-cyclodextrin has been subjected to an 
extensive battery of in vitro and in vivo genotoxicity and 
pharmacological evaluations. No genotoxic or mutagenic 
changes were observed with sulfobutylether b-cyclodextrin 
administration. Sulfobutylether b-cyclodextrin is biocompatible 
and exhibits no pharmacological activity. It is rapidly 
eliminated unmetabolized when administered intravenously. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
Sulfobutylether b-cyclodextrin is included in IV and IM 
injectable products currently approved and marketed in the 
USA and Europe. It is included in the FDA inactive ingredient 
guide for IM and IV use. Its use by other routes, including oral, 
inhalation, and ophthalmic, is being evaluated in clinical 
studies. 
17 Related Substances 
a-Cyclodextrin; b-cyclodextrin; g-cyclodextrin; dimethyl-bcyclodextrin; 
2-hydroxyethyl-b-cyclodextrin; 2-hydroxypropyl-
b-cyclodextrin; 3-hydroxypropyl-b-cyclodextrin; trimethyl-
b-cyclodextrin. 
18 Comments 
In addition to its use in pharmaceutical formulations, 
sulfobutylether b-cyclodextrin is also used in chromatographic 
separations, particularly in chiral separations by HPLC(17) and 
capillary electrophoresis(18–21) and in tissue imaging.(22) 
19 Specific References 
1 Johnson MD, Hoesterey BL, Anderson BD. Solubilization of a 
tripeptide HIV protease inhibitor using a combination of ioniza- 
756 Sulfobutylether b-Cyclodextrin

tion and complexation with chemically modified cyclodextrins. J 
Pharm Sci 1994; 83(8): 1142–1146. 
2 Tokihiro K, Irie T, Uekama K. Varying effects of cyclodextrin 
derivatives on aggregation and thermal behavior of insulin in 
aqueous solution. Chem Pharm Bull 1997; 45(3): 525–531. 
3 Zia V, Rajewski RA, Stella VJ. Effect of cyclodextrin charge on 
complexation of neutral and charged substrates: comparison of 
(SBE)7m-Beta-CD to HP-Beta-CD. Pharm Res 2001; 18(5): 667– 
673. 
4 Ueda H, Ou D, Endo T, et al. Evaluation of a sulfobutyl ether betacyclodextrin 
as a solubilizing/stabilizing agent for several drugs. 
Drug Dev Ind Pharm 1998; 24(9): 863–867. 
5 Uekama K, Hieda Y, Hirayama F, et al. Stabilizing and solubilizing 
effects of sulfobutyl ether b-cyclodextrin on prostaglandin E1 
analogue. Pharm Res 2001; 18(11): 1578–1585. 
6 Narisawa S, Stella VJ. Increased shelf-life of fosphenytoin: 
solubilization of a degradant, phenytoin, through complexation 
with (SBE)(7m)-beta-CD. J Pharm Sci 1998; 87(8): 926–930. 
7 Tokihiro K, Arima H, Tajiri S, et al. Improvement of subcutaneous 
bioavailability of insulin by sulphobutyl ether beta-cyclodextrin in 
rats. J Pharm Pharmacol 2000; 52(8): 911–917. 
8 Lefeuvre C, Le Corre P, Dollo G, et al. Biopharmaceutics and 
pharmacokinetics of 5-phenyl-1,2-dithiole-3-thione complexed 
with sulfobutyl ether-7-beta-cyclodextrin in rabbits. J Pharm Sci 
1999; 88(10): 1016–1020. 
9 Okimoto K, Miyake M, Ohnishi N, et al. Design and evaluation of 
an osmotic pump tablet (opt) for prednisolone, a poorly water 
soluble drug, using (SBE)(7m)-beta-CD. Pharm Res 1998; 15(10): 
1562–1568. 
10 Kaukonen AM, Lennernas H, Mannermaa JP. Water-soluble betacyclodextrins 
in paediatric oral solutions of spironolactone: 
preclinical evaluation of spironolactone bioavailability from 
solutions of beta-cyclodextrin derivatives in rats. J Pharm 
Pharmacol 1998; 50(6): 611–619. 
11 Jarho P, Jarvinen K, Urtti A, Stella V, Jarvinen T. The use of 
cyclodextrins in ophthalmic formulations of dipivefrin. Int J 
Pharm 1997; 153: 225–233. 
12 Jarho P, Ja. rvinen K, Urtti A, Stella VJ, Ja. rvinen T. Modified betacyclodextrin 
(SBE7-b-CyD) with viscous vehicle improves the 
ocular delivery and tolerability of pilocarpine prodrug in rabbits. J 
Pharm Pharmacol 1996; 48: 263–269. 
13 Gudmundsdottir H, Sigurjnsdottir JF, Masson M, et al. Intranasal 
administration of midazolam in a cyclodextrin based formulation: 
bioavailability and clinical evaluation in humans. Pharmazie 2001; 
56(12): 963–966. 
14 CyDex Inc. Technical literature: Captisol, Sulfobutyl Ether b- 
Cyclodextrin, 2002. 
15 CyDex Inc. Captisol sulfobutylether b-cyclodextrin frequently 
asked questions. http://www.cydexinc.com/ 
CyDexCaptisolFAQJun2005.pdf (accessed 1 September 2005). 
16 Rajewski RA, Traiger G, Bresnahan J, et al. Preliminary safety 
evaluation of parenterally administered sulfoalkyl ether betacyclodextrin 
derivatives. J Pharm Sci 1995; 84(8): 927–932. 
17 Owens PK, Fell AF, Coleman M, Berridge JC. Method development 
in liquid chromatography with a charged cyclodextrin 
additive for chiral resolution of rac-amlodipine utilizing a central 
composite design. Chirality 1996; 8(7): 466–476. 
18 Dolezalova M, Fanali S. Enantiomeric separation of dihydroxyphenylalanine 
(dopa), methyldihydroxyphenylalanine (Mdopa) 
and hydrazinomethyldihydroxyphenylalanine (Cdopa) by using 
capillary electrophoresis with sulfobutyl ether-beta-cyclodextrin as 
a chiral selector. Electrophoresis 2000; 21(15): 3264–3269. 
19 Fanali S, Cannazza G, Mandrioli R, et al. Separation of reboxetine 
enantiomers by means of capillary electrophoresis. Electrophoresis 
2002; 23(12): 1870–1877. 
20 Aumatell A,Wells RJ. Enantiomeric differentiation of a wide range 
of pharmacologically active substances by cyclodextrin-modified 
micellar electrokinetic capillary chromatography using a bile salt. J 
Chromatogr A 1994; 688(1–2): 329–337. 
21 Chankvetadze B, Endresz G, Blaschke G. About some aspects of 
the use of charged cyclodextrins for capillary electrophoresis 
enantio-separation. Electrophoresis 1994; 15(6): 804–807. 
22 Kay AR, Alfonso A, Alford S, et al. Imaging synaptic activity in 
intact brain and slices with FM1-43 in C. elegans, lamprey, and rat. 
Neuron 1999; 24(4): 809–817. 
20 General References 
Irie T, Uekama K. Pharmaceutical applications of cyclodextrins. III. 
Toxicological issues and safety evaluation. J Pharm Sci 1997; 86(2): 
147–162. 
Loftsson T, Brewster ME. Pharmaceutical applications of cyclodextrins. 
I. Drug solubilization and stabilization. J Pharm Sci 1996; 85(10): 
1017–1027. 
Rajewski RA, Stella VJ. Pharmaceutical applications of cyclodextrins. 
II. In vivo drug delivery. J Pharm Sci 1996; 85(11): 1142–1169. 
Schneiderman E, Stalcup AM. Cyclodextrins: a versatile tool in 
separation science. J Chromatogr B 2000; 745(1): 83–102. 
Stella V. SBE7-b-CD, a new, novel and safe polyanionic b-cyclodextrin 
derivative: characterization and biomedical applications. In: Szejtli 
J, Szente L, eds. Proceedings 8th International Symposium, 
Cyclodextrins. Dordrecht: Kluwer Academic Publishers, 1996: 
471–476. 
Stella VJ, Rao VM, Zannou EA, Zia V. Mechanisms of drug release 
from cyclodextrin complexes. Adv Drug Delivery Rev 1999; 36(1): 
3–16. 
Stella VJ, Rajewski RA. Cyclodextrins: their future in drug formulation 
and delivery. Pharm Res 1997; 14(5): 556–567. 
Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical 
Technology. New York: Marcel Dekker, 2000; 19(2): 49–88. 
Thompson DO. Cyclodextrins-enabling excipients: their present and 
future use in pharmaceuticals. Critl Rev Ther Drug Carrier Syst 
1997; 14(1): 1–104. 
21 Authors 
GL Mosher, JD Pipkin. 
22 Date of Revision 
1 September 2005. 
Sulfobutylether b-Cyclodextrin 757

Sulfuric Acid 
1 Nonproprietary Names 
BP: Sulphuric acid 
PhEur: Acidum sulfuricum 
USPNF: Sulfuric acid 
2 Synonyms 
E513; hydrogen sulfate; oil of vitriol. 
3 Chemical Name and CAS Registry Number 
Sulfuric acid [7664-93-9]. 
4 Empirical Formula and Molecular Weight 
H2SO4 98.08 
5 Structural Formula 
H2SO4 
6 Functional Category 
Acidifying agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sulfuric acid is used as an acidifying agent in a variety of 
pharmaceutical and food preparations. It may also be used to 
prepare dilute sulfuric acid, which, in addition to its use as an 
excipient, has some therapeutic use for the treatment of gastric 
hypoacidity, as an astringent in diarrhea, or to stimulate 
appetite. Sulfuric acid has been used in parenteral, oral, topical, 
and ophthalmic pharmaceutical formulations. 
8 Description 
Sulfuric acid occurs as a clear, colorless, odorless, oily liquid. It 
is very corrosive and has a great affinity for water. 
The USPNF 23 specifies that sulfuric acid contains not less 
than 95% and not more than 98%, by weight, of H2SO4; the 
remainder is water. See also Section 9. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for sulfuric acid. 
Test PhEur 2005 USPNF 23 
Identification . . 
Appearance of solution . — 
Residue on ignition — 40.005% 
Chloride 450 ppm 40.005% 
Arsenic 41 ppm 41 ppm 
Heavy metals 45 ppm 45 ppm 
Weight per mL 1.84 — 
Iron 425 ppm — 
Nitrate . — 
Reducing substances — . 
Assay (of H2SO4) 95.0–100.5% 95.0–98.0% 
10 Typical Properties 
Boiling point: 
2908C for H2SO4 (95%–98% w/w); 
3308C for H2SO4 (100% w/w). 
Density: 1.84 g/cm3 at 208C 
Dissociation constant: 
pKa1 = 3.00; 
pKa2 = 1.99. 
Freezing point: 
108C for H2SO4 (100% w/w); 
38C for H2SO4 (98% w/w); 
328C for H2SO4 (93% w/w). 
Solubility: miscible with ethanol and water. 
Vapor density: 3.4 (air = 1.0) 
Vapor pressure: <0.3mmHg at 208C 
11 Stability and Storage Conditions 
Sulfuric acid is stable but very corrosive and hygroscopic. It will 
draw moisture from the atmosphere. Sulfuric acid should be 
stored in a tightly closed container in an explosion-proof area. 
Containers should be stored out of direct sunlight and away 
from heat. Avoid heat and moisture. Isolate from incompatible 
materials. See also Section 12. 
12 Incompatibilities 
Avoid storage in close proximity to water, most common 
metals, organic materials, strong reducing agents, combustible 
materials, strong bases, carbonates, sulfides, cyanides, strong 
oxidizing agents, and carbides. 
Sulfuric acid is a powerful oxidizer and may ignite or 
explode on contact with many materials. 
It can react violently with the evolution of a large amount of 
heat. Oxides of sulfur and hydrogen can be generated during 
reactions. 
Great care must be exercised when mixing with other 
liquids.

13 Method of Manufacture 
Sulfuric acid may be prepared industrially by either the contact 
process or the chamber process.(1,2) 
Contact Process 
2SO2 .O2 !2SO3 
SO3 .H2O ! H2SO4 
Chamber Process 
2NO . O2 ! 2NO2 
NO2 . SO2 . H2O ! H2SO4 . NO 
14 Safety 
Sulfuric acid is widely used in a variety of pharmaceutical 
formulations. Although concentrated sulfuric acid is very 
corrosive, it is normally used well diluted in formulations. 
Concentrated sulfuric acid will react violently with water and 
much heat is generated. When diluting sulfuric acid, the acid 
should always be added to the other liquid with great caution. 
The concentrated solution is extremely corrosive and can 
cause severe damage or necrosis on contact with the eyes and 
skin. Ingestion may cause severe injury or death. Inhalation of 
concentrated vapors can cause serious lung damage. 
LD50 (rat, oral): 2.14 g/kg(3) 
15 Handling Precautions 
Caution should be exercised when handling sulfuric acid and 
suitable protection against inhalation and spillage should be 
made. Respiratory protection may not be required where 
adequate ventilation exists. Eye protection (safety goggles and 
face shield), rubber gloves, and apron are recommended, 
depending on the circumstances and quantity of sulfuric acid 
handled. Do not dilute spills of concentrated acid with water 
since an exothermic reaction will occur. Spills should be 
neutralized with soda ash or lime. Splashes on the skin and 
eyes should be treated by immediate and prolonged washing 
with large amounts of water followed by the application of 
sodium bicarbonate and medical attention should be sought. 
Fumes can cause irritation or permanent damage to the eyes, 
nose, and respiratory system; prolonged exposure to fumes may 
damage the lungs. 
In the UK, the long-term exposure limit (8-hour TWA) for 
sulfuric acid is 1 mg/m3.(4,5) 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (IM, IV, and IP 
injections, inhalation solutions, irrigation solutions, nasal, 
ophthalmic solutions and suspensions, oral solutions, and 
topical emulsions and creams). Included in nonparenteral and 
parenteral medicines licensed in Europe. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Dilute sulfuric acid; fuming sulfuric acid. 
Dilute sulfuric acid 
Density: 1.062–1.072 g/cm3 
Comments: prepared by adding 104 g of sulfuric acid to 896 g 
of purified water with constant stirring and cooling. Dilute 
sulfuric acid contains between 9.5% and 10.5% w/w of 
H2SO4. 
Fuming sulfuric acid 
Synonyms: oleum. 

Comments: fuming sulfuric acid consists of H2SO4 with free 
sulfur trioxide (SO3). It is prepared by adding sulfur trioxide 
to sulfuric acid. Available in grades containing up to about 
80% free SO3. 
Fuming sulfuric acid is a colorless or slightly colored, 
viscous liquid that emits choking fumes of sulfur trioxide. It 
is extremely corrosive and should be handled with great care 
and stored in tightly closed glass-stoppered bottles. 
18 Comments 
A specification for sulfuric acid is contained in the Food 
Chemicals Codex (FCC). The EINECS number for sulfuric acid 
is 231-639-5. 
19 Specific References 
1 Druecker WW, West JR. The Manufacture of Sulfuric Acid. New 
York: Reinhold, 1959: 515. 
2 Nickless G, ed. Inorganic Sulphur Chemistry. New York: Elsevier, 
1968: 535–561. 
3 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3331–3332. 
4 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
5 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002 Supplement 2003. Sudbury: Health and Safety 
Executive, 2003. 
20 General References 
—
21 Authors 
GE Amidon. 
22 Date of Revision 
17 August 2005. 
Sulfuric Acid 759

Sunflower Oil 
1 Nonproprietary Names 
BP: Sunflower oil, refined 
PhEur: Helianthi annui oleum raffinatum 
2 Synonyms 
Huile de tournesol; oleum helianthi; sunflowerseed oil. 
3 Chemical Name and CAS Registry Number 
Sunflower oil [8001-21-6] 
4 Empirical Formula and Molecular Weight 
See Section 5. 
5 Structural Formula 
Sunflower oil is classified as an oleic–linoleic acid oil. Its 
composition includes linoleic acid (66%), oleic acid (21.3%), 
palmitic acid (6.4%), arachidic acid (4.0%), stearic acid 
(1.3%), and behenic acid (0.8%). 
The PhEur 2005 describes sunflower oil as the refined fatty 
oil obtained from the seeds of Helianthus annus C. by 
mechanical expression or by extraction. A suitable antioxidant 
may be added. 
6 Functional Category 
Diluent; emollient; emulsifying agent; solvent; tablet binder. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Sunflower oil is widely used as an edible oil, primarily in 
oleomargarine. It is also used extensively in cosmetics and 
pharmaceutical formulations. 
Therapeutically, sunflower oil is used to provide energy and 
essential fatty acids for parenteral nutrition. Studies have 
shown that sunflower oil may be used in intramuscular 
injections without inducing tissue damage.(1) 
8 Description 
Sunflower oil occurs as a clear, light yellow-colored liquid with 
a bland, agreeable taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for sunflower oil. 
Test PhEur 2005 
Identification . 
Characters . 
Acid value 40.5 
Peroxide value 410.0 
Unsaponifiable matter 41.5% 
Alkaline impurities . 
Composition of fatty acids . 
Palmitic acid 4.0–9.0% 
Stearic acid 1.0–7.0% 
Oleic acid 14.0–40.0% 
Linoleic acid 48.0–74.0% 
10 Typical Properties 
Boiling point: 40–608C 
Density: 0.915–0.919 
Hydroxyl value: 14–16 
Iodine number: 125–140 
Melting point: 188C 
Refractive index: 
nD
25 = 1.472–1.474; 
nD
40 = 1.466–1.468. 
Saponification number: 188–194 
Solubility: miscible with benzene, chloroform, carbon tetrachloride, 
diethyl ether, and light petroleum; practically 
insoluble in ethanol (95%) and water. 
11 Stability and Storage Conditions 
Sunflower oil should be stored in an airtight, well-filled 
container, protected from light. Stability may be improved by 
the addition of an antioxidant such as butylated hydroxytoluene. 
12 Incompatibilities 
The oxidative stability of sunflower oil is reduced in the 
presence of iron oxides and zinc oxide.(2) 
Sunflower oil forms a ‘skin’ after being exposed to air for 
2–3 weeks. 
13 Method of Manufacture 
Sunflower oil is obtained from the fruits and seeds (achenes) of 
the sunflower, Helianthus annus (Compositae), by mechanical 
means or by extraction. 
14 Safety 
Sunflower oil is widely used in food products and on its own as 
an edible oil. It is also used extensively in cosmetics and topical 
pharmaceutical formulations and is generally regarded as a 
relatively nontoxic and nonirritant material.

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. When heated to decomposition, 
sunflower oil emits acrid smoke and irritating fumes. 
16 Regulatory Status 
GRAS listed. Included in nonparenteral medicines licensed in 
the UK. 
17 Related Substances 
Corn oil; cottonseed oil; peanut oil; sesame oil; soybean oil. 
18 Comments 
High oleic acid content sunflower oil with good oxidative 
stability and emollient properties is commercially available for 
use in cosmetic formulations.(3) Sunflower oil with marked 
oxidative stability is particularly suitable for the manufacture 
of sunscreen agents.(4) 
Sunflower oil should be labeled to indicate the name and 
concentration of any antioxidant added, and also whether the 
oil was obtained by mechanical expression or extraction. A 
specification for sunflower oil is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for sunflower oil is 232-273-9. 
19 Specific References 
1 Vinardell MP, Vives MA. Plasma creatine kinase activity after 
intramuscular injection of oily vehicles in rabbits. Pharm 
Pharmacol Lett 1996; 6(2): 54–55. 
2 Brown JH, Arquette DJ, Kleiman R, et al. Oxidative stability of 
botanical emollients. Cosmet Toilet 1997; 112(7): 87–90, 92, 94, 
96–98. 
3 Arquette DJ, Cummings M, Dwyer K, et al. A natural oil made to 
last. Cosmet Toilet 1997; 112(1): 67–72. 
4 Arquette DJ, Brown J, Dwyer K, Reinhardt J. Oils and fats: place in 
the sun. Soap Perfum Cosmet 1994; 67(Nov): 49, 51. 
20 General References 
—
21 Authors 
SC Owen, PJ Sheskey. 
22 Date of Revision 
12 August 2005. 
Sunflower Oil 761

Suppository Bases, Hard Fat 
1 Nonproprietary Names 
BP: Hard fat 
PhEur: Adeps solidus 
USPNF: Hard fat 
2 Synonyms 
Adeps neutralis; Akosoft; Akosol; Cremao CS-34; Cremao CS- 
36; hydrogenated vegetable glycerides; Massa estarinum; 
Massupol; Novata; semisynthetic glycerides; Suppocire; Wecobee; 
Witepsol. 
3 Chemical Name and CAS Registry Number 
Hard fat triglyceride esters 
4 Empirical Formula and Molecular Weight 
Hard fat suppository bases consist mainly of mixtures of the 
triglyceride esters of the higher saturated fatty acids 
(C8H17COOH to C18H37COOH) along with varying proportions 
of mono- and diglycerides. Special grades may contain 
additives such as beeswax, lecithin, polysorbates, ethoxylated 
fatty alcohols, and ethoxylated partial fatty glycerides. 
5 Structural Formula 
where R = H or OC(CH2)nCH3; n = 7–17 
Not all Rs can be H at the same time. 
6 Functional Category 
Suppository base. 
7 Applications in Pharmaceutical Formulation 
or Technology 
The primary application of hard fat suppository bases, or 
semisynthetic glycerides, is as a vehicle for the rectal or vaginal 
administration of a variety of drugs, either to exert local effects 
or to achieve systemic absorption. 
Selection of a suppository base cannot usually be made in 
the absence of knowledge of the physicochemical properties 
and intrinsic thermodynamic activity of the drug substance. 
Other drug-related factors that can affect release and absorption 
and which must therefore be considered are the particle 
size distribution of insoluble solids, the oil : water partition 
coefficient, and the dissociation constant. The displacement 
value should also be known, as well as the ratio of drug to base. 
Properties of the suppository base that may or may not be 
modified by the drug, or that can influence drug release, are the 
melting characteristics, chemical reactivity, and rheology. The 
presence of additives in the base can also affect performance. 
Melting characteristics Fatty-based suppositories intended for 
systemic use should liquefy at just below body temperature. 
Softening or dispersion may be adequate for suppositories 
intended for local action or modified release. High-meltingpoint 
bases may be indicated for fat-soluble drugs that tend 
to depress the melting point of bases or for suppositories used 
in warm climates. Drugs that dissolve in bases when hot may 
create problems if they deposit as crystals of different form or 
increased size on cooling or on storage. Low-melting-point 
bases, particularly those that melt to liquids of low viscosity, 
can be of value when large volumes of insoluble substances 
are to be incorporated; there is a risk of sedimentation in 
such instances. An important factor during processing is the 
time required for setting. This is affected by the temperature 
difference between the melting point and the solidification 
point.(1,2) 
Chemical reactivity Although the use of bases with low hydroxyl 
values (low partial ester content) is indicated to minimize 
the risk of interaction with chemically reactive compounds, 
formulators should be aware that hydroxyl values are also 
related to hydrophilic properties, which, in turn, can modify 
both release and absorption rates. Bases with low hydroxyl 
values tend to be less plastic than those with higher values 
and, if cooled rapidly, may become excessively brittle. Peroxide 
values give a measure of the resistance of the base to 
oxidation and are a guide to the onset of rancidity. 
Rheology The viscosity of the melted base can affect the uniformity 
of distribution of suspended solids during manufacture. 
It can also influence the release and absorption of the 
drug in the rectum. Further reduction in the particle size of 
insoluble solids is the method of choice to minimize the risk 
of sedimentation. However, the presence of a high content of 
fine, suspended particles is likely to increase viscosity. It may 
also make pouring difficult, delay melting, and induce brittleness 
on solidification. Additives are sometimes included to 
modify rheological properties and to maintain homogeneity, 
e.g. microcrystalline wax, but the extent of their effect on 
drug release should first be assessed. Release from a base in 
which viscosity has been enhanced by an added thickener 
may vary and be related to the aqueous solubility of the drug 
itself. 
Additives Some grades of commercial bases already contain 
additives, and these are usually identified by the manufacturers 
by means of suitable letters and numbers. Additives 
may also be incorporated by formulators. Properties of suppositories 
that have been modified and additives or types of 
additives that have been used are shown in Table I. Water is 
undesirable as an additive because it enhances hydrolysis and

the potential for a chemical reaction between constituents of 
the suppository. In low concentration, water plays little part 
in drug release and can serve as a medium for microbial 
growth. 
Table I: Selected suppository additives. 
Property Additive 
Dispersants (release and/or absorption 
enhancers) 
Surfactants 
Hygroscopicity (reduced) Colloidal silicon dioxide 
Hardeners (or increasing melting point) Beeswax 
Cetyl alcohol 
Stearic acid 
Stearyl alcohol 
Aluminum monostearate (or 
di- and tristearate) 
Bentonite 
Magnesium stearate 
Colloidal silicon dioxide 
Plasticizers (or decreasing melting point) Glyceryl monostearate 
Myristyl alcohol 
Polysorbate 80 
Propylene glycol 
8 Description 
A white or almost white, practically odorless, waxy, brittle 
mass. When heated to 508C it melts to give a colorless or 
slightly yellowish liquid. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for suppository bases. 
Test PhEur 2005 USPNF 23 
Identification . — 
Characters . — 
Melting range 30–458C 27–448C 
Residue on ignition — 40.05% 
Total ash 40.05% — 
Acid value 40.5 41.0 
Iodine value 43.0 47.0 
Saponification value 210–260 215–255 
Hydroxyl value 450 470 
Peroxide value 43.0 — 
Unsaponifiable matter 40.6% 43.0% 
Alkaline impurities . . 
Heavy metals 410 ppm — 
10 Typical Properties 
Acid value: see Table III. 
Color number: 
43 for Massa estarinum (iodine color index); 
43 for Suppocire excluding L grades (Gardener scale); 
45 for Suppocire L grades (Gardener scale); 
43 for Witepsol (iodine color index). 
Density: 
0.955–0.975 g/cm3 for Massa estarinum at 208C; 
0.950–0.960 g/cm3 for Suppocire at 208C; 
0.950–0.980 g/cm3 for Witepsol at 208C. 
Heat of melting (22–408C): 
145 J/g/8C for Massa estarinum; 
100–130 J/g/8C for Suppocire; 
145 J/g/8C for Witepsol. 
Hydroxyl value: see Table III. 
Iodine value: see Table III. 
Melting point: see Table III. 
Moisture content: 
40.2% w/w for Massa estarinum; 
<0.5% w/w for Suppocire; 
40.2% w/w for Witepsol. 
Peroxide value: 
43 for Massa estarinum; 
41.2 for Suppocire; 
43 for Witepsol. 
Saponification value: see Table III. 
Solidification point: see Table III. 
Solubility: freely soluble in carbon tetrachloride, chloroform, 
ether, toluene, and xylene; slightly soluble in warm ethanol; 
practically insoluble in water. 
Specific heat: 
2.6 J/g/8C for Massa estarinum; 
1.7–2.5 J/g/8C for Suppocire; 
2.6 J/g/8C for Witepsol. 
Unsaponifiable matter: see Table III. 
11 Stability and Storage Conditions 
Hard fat suppository bases are fairly stable toward oxidation 
and hydrolysis, with the iodine value being a measure of their 
resistance to oxidation and rancidity. Water content is usually 
low and deterioration due to hygroscopicity rarely occurs. 
Melting characteristics, hardness, and drug-release profiles 
alter with time, and the melting point may rise by more than 
1.08C after storage for several months. Owing to the complexity 
of bases, elucidation of the mechanisms that induce these 
changes on aging is difficult. Evidence has been presented(3) 
that supports a finite transition from amorphous to crystalline 
forms in which polymorphism may or may not contribute, 
whereas other workers have found melting point changes to be 
closely associated with the conversion of triglycerides to more 
stable polymorphic forms.(4) Before melting point determinations 
are made, bases are ‘conditioned’ to a stable crystalline 
form. 
Suppository bases should be stored protected from light in 
an airtight container at a temperature at least 58C less than their 
stated melting point. Refrigeration is usually recommended for 
molded suppositories. 
Suppositories that are not effectively packaged may develop 
a ‘bloom’ of powdery crystals at the surface. This is usually due 
to the presence of high-melting-point components in the base 
and can often be overcome by using a different base. 
Alternatively, the base can be precrystallized prior to pouring, 
since the crystals will cause a quick and complete crystallization 
into its end crystal form. This process is called ‘tempering.’ 
12 Incompatibilities 
Incompatibilities with suppository bases are not now extensively 
reported in the literature. The occurrence of a chemical 
reaction between a hard fat suppository base and a drug is 
relatively rare, but any potential for such a reaction may be 
indicated by the magnitude of the hydroxyl value of the base. 
The risk of hydrolysis of aspirin, for example, may be reduced 
by the use of a base with a low hydroxyl value (<5) and, 
Suppository Bases, Hard Fat 763

Table III: Typical properties of suppository bases. 
Product Acid 
value 
Hydroxyl 
value 
Iodine 
value 
Melting 
point (8C) 
Saponification 
value 
Solidification 
point (8C) 
Unsaponifiable 
matter (%) 
Cremao CS-34 <0.3 — <2 33–35 250 — — 
CS-36 <0.3 — <1 34–37 250 — — 
Massa Estarinum B 40.3 20–30 43 33–35.5 225–240 31–33 40.3 
BC 40.3 30–40 43 33.5–35.5 225–240 30.5–32.5 40.3 
C 40.3 20–30 43 36–38 225–235 33–35 40.3 
299 40.3 42 43 33.5–35.5 240–255 32–34.5 40.3 
Massupol — — 42 34–36 240–250 31–32.5 — — 
Massupol 15 — — 43 35–37 220–230 31–33 — — 
Suppocire A <0.5 20–30 <2 35–36.5 225–245 — 40.5 
AM <0.2 46 <2 35–36.5 225–245 — 40.5 
AML <0.5 46 <2 35–36.5 225–245 — 40.6 
AIML <0.5 46 <3 33–35 225–245 — 40.6 
AS2 <0.5 15–25 <2 35–36.5 225–245 — 40.5 
AS2X <0.5 15–25 <2 35–36.5 225–245 — 40.6 
AT <0.5 25–35 <2 35–36.5 225–245 — 40.5 
AP <1.0 30–50 <1 33–35 200–220 — 40.5 
AI <0.5 20–30 <2 33–35 225–245 — 40.5 
AIX <0.5 20–30 <2 33–35 220–240 — <0.6 
AIM <0.3 <6 <2 33–35 225–245 — 40.5 
AIP <1.0 30–50 <1 30–33 205–225 — <0.5 
B <0.5 20–30 <2 36–37.5 225–245 — 40.5 
BM <0.2 <6 <2 36–37.5 225–245 — 40.5 
BML <0.5 <6 <3 36–37.5 225–245 — 40.6 
BS2 <0.5 15–25 <2 36–37.5 225–245 — 40.5 
BS2X <0.5 15–25 43 36–37.5 220–240 — 40.6 
BT <0.5 25–35 <2 36–37.5 225–245 — 40.5 
BP <1.0 30–50 <1 36–37 200–220 — <0.5 
C <0.5 20–30 <2 38–40 220–240 — 40.5 
CM <0.2 <6 <2 38–40 225–245 — 40.5 
CS2 <0.5 15–25 <2 38–40 220–240 — 40.5 
CS2X <0.5 15–25 <2 38–40 220–240 — <0.6 
CT <0.5 25–35 <2 38–40 220–240 — 40.5 
CP <1.0 450 <1 37–39 200–220 — <0.5 
D <0.5 20–30 <2 42–45 215–235 — 40.5 
DM <0.2 <6 <2 42–45 215–235 — 40.5 
NA <0.5 <40 <2 35.5–37.5 225–245 — <0.5 
NB <0.5 <40 <2 36.5–38.5 215–235 — <0.5 
NC <0.5 <40 <2 38.5–40.5 220–240 — <0.5 
NAI 0 <0.5 43 <2 33.5–35.5 220–245 — <0.5 
NAI 5 <0.5 45 <2 33.5–35.5 220–245 — <0.5 
NAI 10 <0.5 <15 <2 33.5–35.5 220–245 — <0.5 
NAI <0.5 <40 <2 33.5–35.5 225–245 — <0.5 
NAIL <1.0 <40 <3 33.5–35.5 225–245 — <0.6 
NAIX <0.5 <40 <2 33.5–35.5 220–240 — <0.6 
NA 0 <0.5 43 <2 35.5–37.5 225–245 — <0.5 
NA 5 <0.5 45 <2 35.5–37.5 225–245 — <0.5 
NA 10 <0.5 415 <2 35.5–37.5 225–245 — <0.5 
NAL <0.5 <40 <2 33.5–35.5 225–245 — <0.6 
NAX <0.5 <40 <2 35.5–37.5 220–240 — <0.6 
NBL <0.5 <40 <3 36.5–38.5 220–240 — <0.6 
NBX <0.5 <40 <2 36.5–38.5 215–235 — <0.6 
ND <0.5 <40 <2 42–45 210–230 — <0.5 
Witepsol H5 40.2 45 42 34–36 235–245 33–35 40.3 
H12 40.2 5–15 43 32–33.5 240–255 29–33 40.3 
H15 40.2 5–15 43 33.5–35.5 230–245 32.5–34.5 40.3 
H19(a) 40.2 20–30 47 33.5–35.5 230–240 — 40.3 
H32 40.2 43 43 31–33 240–250 30–32.5 40.3 
H35 40.2 43 43 33.5–35.5 240–250 32–35 40.3 
H37 40.2 43 43 36–38 225–245 35–37 40.3 
H175(a) 40.7 5–15 43 34.5–36.5 225–245 32–34.5 41.0 
H185 40.2 5–15 43 38–39 220–235 34–37 40.3 
Continued 
764 Suppository Bases, Hard Fat

additionally, by minimization of the water content of both the 
base and the aspirin. 
There is evidence that aminophylline reacts with the 
glycerides in some hard fat bases to form diamides. On aging 
or exposure to elevated temperatures, degradation is accompanied 
by hardening and suppositories tend to exhibit a 
marked increase in melting point. The ethylenediamine content 
is also reduced.(5,6) 
Certain fat-soluble medications, such as chloral hydrate, 
may depress the melting point when incorporated into a base. 
Similarly, when large amounts of an active substance, either 
solid or liquid, have to be dispersed into a base, the rheological 
characteristics of the resultant suppository may be changed, 
with concomitant effects on release and absorption. Careful 
selection of bases or the inclusion of additives may therefore be 
necessary. 
13 Method of Manufacture 
The most common method of manufacture involves the 
hydrolysis of natural vegetable oils such as coconut or palm 
kernel oil, followed by fractional distillation of the free fatty 
acids produced. The C8 to C18 fractions are then hydrogenated 
and reesterified under controlled conditions with glycerin to 
form a mixture of tri-, di-, and monoglycerides of the required 
characteristics and hydroxyl value. This process is used for 
Witepsol. 
In an alternative procedure, coconut or palm kernel oil is 
directly hydrogenated and then subjected to an interesterification 
either with itself or with glycerin to form a mixture of tri-, 
di-, and monoglycerides of the required characteristics and 
hydroxyl value, e.g. Suppocire. 
14 Safety 
Suppository bases are generally regarded as nontoxic and 
nonirritant materials when used in rectal formulations. However, 
animal studies have suggested that some bases, particularly 
those types with a high hydroxyl value, may be irritant to 
the rectal mucosa.(7) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. There is a slight fire hazard 
on exposure to heat or flame. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (rectal and 
vaginal preparations). Included in nonparenteral medicines 
licensed in the UK. 
17 Related Substances 
Glycerin; medium-chain triglycerides; polyethylene glycol; 
theobroma oil. 
Theobroma oil 
CAS number: [8002-31-1] 
Synonyms: cocoa butter; oleum cacao; oleum theobromatis. 
Appearance: a yellowish or white, brittle solid with a slight 
odor of cocoa. 
Melting point: 31–348C 
Solubility: freely soluble in chloroform, ether, and petroleum 
spirit; soluble in boiling ethanol; slightly soluble in ethanol 
(95%). 
Stability and storage conditions: heating theobroma oil to more 
than 368C during the preparation of suppositories can result 
in an appreciable lowering of the solidification point owing 
to the formation of metastable states; this may lead to 
difficulties in the setting of the suppository. Theobroma oil 
should be stored at a temperature not exceeding 258C. 
Comments: theobroma oil is a fat of natural origin used as a 
suppository base. It comprises a mixture of the triglycerides 
of saturated and unsaturated fatty acids, in which the 
unsaturated acid is preferentially situated on the 2-position 
of the glyceride. Theobroma oil is also a major ingredient of 
chocolate. 
18 Comments 
— 
Product Acid 
value 
Hydroxyl 
value 
Iodine 
value 
Melting 
point (8C) 
Saponification 
value 
Solidification 
point (8C) 
Unsaponifiable 
matter (%) 
Witepsol (cont.) W25 40.3 20–30 43 33.5–35.5 225–240 29–33 40.3 
W31 40.3 25–35 43 35–37 225–240 30–33 40.5 
W32 40.3 40–50 43 32–33.5 225–245 25–30 40.3 
W35 40.3 40–50 43 33.5–35.5 225–235 27–32 40.3 
W45 40.3 40–50 43 33.5–35.5 225–235 29–34 40.3 
S51(a) 41.0 55–70 48 30–32 215–230 25–27 42.0 
S52(a) 41.0 50–65 43 32–33.5 220–230 27–30 42.0 
S55(a) 41.0 50–65 43 33.5–35.5 215–230 28–33 42.0 
S58(a) 41.0 60–70 47 31.5–33 215–225 27–29 42.0 
E75(a) 41.3 5–15 43 37–39 220–230 32–36 43.0 
E76 40.3 30–40 43 37–39 220–230 31–35 40.5 
E85 40.3 5–15 43 42–44 220–230 37–42 40.5 
(a) Note that these types are mixtures containing hard fat and therefore do not comply with the specifications of the PhEur 2005 and USPNF 23. 
Table III: Continued 
Suppository Bases, Hard Fat 765

19 Specific References 
1 Setnikar I, Fantelli S. Softening and liquefaction temperature of 
suppositories. J Pharm Sci 1963; 52: 38–43. 
2 Kro. wczynski L. A simple device for testing suppositories [in 
Polish]. Diss Pharm 1959; 11: 269–273. 
3 Coben LJ, Lordi NG. Physical stability of semisynthetic suppository 
bases. J Pharm Sci 1980; 69: 955–960. 
4 Liversidge GG, Grant DJW, Padfield JM. Influence of physicochemical 
interactions on the properties of suppositories I: 
interactions between the constituents of fatty suppository bases. 
Int J Pharm 1981; 7: 211–223. 
5 Brower JF, Juenge EC, Page DP, Dow ML. Decomposition of 
aminophylline in suppository formulations. J Pharm Sci 1980; 69: 
942–945. 
6 Taylor JB, Simpkins DE. Aminophylline suppositories: in vitro 
dissolution and bioavailability in man. Pharm J 1981; 227: 601– 
603. 
7 De Muynck C, Cuvelier C, Van Steenkiste D, et al. Rectal mucosa 
damage in rabbits after subchronical application of suppository 
bases. Pharm Res 1991; 8: 945–950. 
20 General References 
Allen LV. Compounding suppositories Part I: Theoretical considerations. 
Int J Pharm Compound 2000; 4(4): 289–293: 324–325. 
Allen LV. Compounding suppositories Part II: Extemporaneous 
preparation. Int J Pharm Compound 2000; 4(5): 372–373, 404– 
405. 
Anschel J, Lieberman HA. Suppositories. In: Lachman L, Lieberman 
HA, Kanig JL, eds. The Theory and Practice of Industrial Pharmacy, 
2nd edn. Philadelphia: Lea and Febiger, 1976: 245–269. 
Realdon N, Ragazzi E, Dal-Zotto M. Effects of silicon dioxide on drug 
release from suppositories. Drug Dev Ind Pharm 1997; 23(11): 
1025–1041. 
Realdon N, Ragazzi E, Dal-Zotto M. Layered excipient suppositories: 
the possibility of modulating drug availability. Int J Pharm 1997; 
148: 155–163. 
Schoonen AJM, Moolenarr F, Huizinga T. Release of drugs from fatty 
suppository bases I: the release mechanism. Int J Pharm 1979; 4: 
141–152. 
Senior N. Review of rectal suppositories 1: formulation and manufacture. 
Pharm J 1969; 203: 703–706. 
Senior N. Review of rectal suppositories 2: resorption studies and 
medical applications. Pharm J 1969; 203: 732–736. 
Senior N. Rectal administration of drugs. In: Bean HS, Beckett AH, 
Carless JE, eds. Advances in Pharmaceutical Sciences, vol. 4. 
London: Academic Press, 1974: 363–435. 
Sutananta W, Craig DQM, Newton JM. An evaluation of the 
mechanism of drug release from glyceride bases. J Pharm Pharmacol 
1995; 47: 182–187. 
21 Authors 
RC Moreton. 
22 Date of Revision 
1 September 2005. 
766 Suppository Bases, Hard Fat

Talc 
1 Nonproprietary Names 
BP: Purified talc 
JP: Talc 
PhEur: Talcum 
USP: Talc 
2 Synonyms 
Altalc; E553b; hydrous magnesium calcium silicate; hydrous 
magnesium silicate; Luzenac Pharma; magnesium hydrogen 
metasilicate; Magsil Osmanthus; Magsil Star; powdered talc; 
purified French chalk; Purtalc; soapstone; steatite; Superiore. 
3 Chemical Name and CAS Registry Number 
Talc [14807-96-6] 
4 Empirical Formula and Molecular Weight 
Talc is a purified, hydrated, magnesium silicate, approximating 
to the formula Mg6(Si2O5)4(OH)4. It may contain small, 
variable amounts of aluminum silicate and iron. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Anticaking agent; glidant; tablet and capsule diluent; tablet and 
capsule lubricant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Talc was once widely used in oral solid dosage formulations as 
a lubricant and diluent, see Table I,(1–3) although today it is less 
commonly used. However, it is widely used as a dissolution 
retardant in the development of controlled-release products.(
4–6) Talc is also used as a lubricant in tablet formulations;(
7) in a novel powder coating for extended-release 
pellets;(8) and as an adsorbant.(9) 
In topical preparations, talc is used as a dusting powder, 
although it should not be used to dust surgical gloves; see 
Section 14. Talc is a natural material; it may therefore 
frequently contain microorganisms and should be sterilized 
when used as a dusting powder; see Section 11. 
Talc is additionally used to clarify liquids and is also used in 
cosmetics and food products, mainly for its lubricant properties. 
Table I: Uses of talc. 
Use Concentration (%) 
Dusting powder 90.0–99.0 
Glidant and tablet lubricant 1.0–10.0 
Tablet and capsule diluent 5.0–30.0 
8 Description 
Talc is a very fine, white to grayish-white, odorless, impalpable, 
unctuous, crystalline powder. It adheres readily to the skin and 
is soft to the touch and free from grittiness. 
SEM: 1 
Excipient: Talc (Purtalc) 
Manufacturer: Charles B Chrystal Co., Inc. 
Lot No.: 1102A-2 
Magnification: 1200 Voltage: 10 kV 
9 Pharmacopeial Specifications 
See Table II. 
10 Typical Properties 
Acidity/alkalinity: pH = 7–10 for a 20% w/v aqueous 
dispersion. 
Hardness (Mohs): 1.0–1.5 
Moisture content: talc absorbs insignificant amounts of water 
at 258C and relative humidities up to about 90%. 
Particle size distribution: varies with the source and grade of 
material. Two typical grades are 599% through a 74 mm 
(#200 mesh) or 599% through a 44 mm (#325 mesh). 
Refractive index: nD
20 = 1.54–1.59 
Solubility: practically insoluble in dilute acids and alkalis, 
organic solvents, and water. 
Specific gravity: 2.7–2.8 
Specific surface area: 2.41–2.42m2/g

Table II: Pharmacopeial specifications for talc. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters . . — 
Acid-soluble substances 42.0% — 42.0% 
Acidity or alkalinity — . — 
Production — . — 
pH — 7.0–9.0 — 
Water-soluble substances — 40.2% 40.1% 
Aluminum — 42.0% — 
Calcium — 40.9% — 
Iron — 40.25% — 
Lead — 410 ppm — 
Magnesium — 17.0–19.5 — 
Loss on ignition 45.0% 47.0% 46.5% 
Microbial contamination — . 4500/g 
Aerobic bacteria — 4102/g — 
Fungi — 4102/g — 
Acid and alkali-soluble 
substances 
44.0mg — 42.0% 
Water-soluble iron . — . 
Arsenic 44 ppm — 43 ppm 
Heavy metals — — 40.004% 
Lead — — 40.001% 
11 Stability and Storage Conditions 
Talc is a stable material and may be sterilized by heating at 
1608C for not less than 1 hour. It may also be sterilized by 
exposure to ethylene oxide or gamma irradiation.(10) 
Talc should be stored in a well-closed container in a cool, 
dry place. 
12 Incompatibilities 
Incompatible with quaternary ammonium compounds. 
13 Method of Manufacture 
Talc is a naturally occurring hydropolysilicate mineral found in 
many parts of the world including Australia, China, Italy, India, 
France, and the USA.(11) 
The purity of talc varies depending on the country of origin. 
For example, Italian types are reported to contain calcium 
silicate as the contaminant; Indian types contain aluminum and 
iron oxides; French types contain aluminum oxide; and 
American types contain calcium carbonate (California), iron 
oxide (Montana), aluminum and iron oxides (North Carolina), 
or aluminum oxide (Alabama).(12) 
Naturally occurring talc is mined and pulverized before 
being subjected to flotation processes to remove various 
impurities such as asbestos (tremolite); carbon; dolomite; iron 
oxide; and various other magnesium and carbonate minerals. 
Following this process, the talc is finely powdered, treated with 
dilute hydrochloric acid, washed with water, and then dried. 
The processing variables of agglomerated talc strongly influence 
its physical characteristics.(13–15) 
14 Safety 
Talc is used mainly in tablet and capsule formulations. Talc is 
not absorbed systemically following oral ingestion and is 
therefore regarded as an essentially nontoxic material. However, 
intranasal or intravenous abuse of products containing 
talc can cause granulomas in body tissues, particularly the 
lungs.(16–18) Contamination of wounds or body cavities with 
talc may also cause granulomas; therefore, it should not be used 
to dust surgical gloves. Inhalation of talc causes irritation and 
may cause severe respiratory distress in infants;(19) see also 
Section 15. 
Although talc has been extensively investigated for its 
carcinogenic potential, and it has been suggested that there is an 
increased risk of ovarian cancer in women using talc, the 
evidence is inconclusive.(20,21) However, talc contaminated 
with asbestos has been proved to be carcinogenic in humans, 
and asbestos-free grades should therefore be used in pharmaceutical 
products.(22) 
Also, long-term toxic effects of talc contaminated with large 
quantities of hexachlorophene caused serious irreversible 
neurotoxicity in infants accidentally exposed to the substance.(
23) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Talc is irritant if inhaled and 
prolonged excessive exposure may cause pneumoconiosis. 
In the UK, the occupational exposure limit for talc is 
1 mg/m3 of respirable dust long-term (8-hour TWA).(24) Eye 
protection, gloves, and a respirator are recommended. 
16 Regulatory Status 
Accepted for use as a food additive in Europe. Included in the 
FDA Inactive Ingredients Guide (buccal tablets; oral capsules 
and tablets; rectal and topical preparations). Included in 
nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Bentonite; magnesium aluminum silicate; magnesium silicate; 
magnesium trisilicate. 
18 Comments 
Various different grades of talc are commercially available that 
vary in their chemical composition depending upon their source 
and method of preparation.(11,25,26) 
Talc derived from deposits that are known to contain 
associated asbestos is not suitable for pharmaceutical use. Tests 
for amphiboles and serpentines should be carried out to ensure 
that the product is free of asbestos. A specification for talc is 
contained in the Food Chemicals Codex (FCC). 
The EINECS number for talc is 238-877-9. 
19 Specific References 
1 Dawoodbhai S, Rhodes CT. Pharmaceutical and cosmetic uses of 
talc. Drug Dev Ind Pharm 1990; 16: 2409–2429. 
2 Dawoodbhai S, Suryanarayan ER,Woodruff CW. Optimization of 
tablet formulations containing talc. Drug Dev Ind Pharm 1991; 
17: 1343–1371. 
3 Wang DP, Yang MC, Wong CY. Formulation development of oral 
controlled release pellets of diclofenac sodium. Drug Dev Ind 
Pharm 1997; 23: 1013–1017. 
4 Fassihi RA, McPhillips AM, Uraizee SA, Sakr AM. Potential use of 
magnesium stearate and talc as dissolution retardants in the 
development of controlled release drug delivery systems. Pharm 
Ind 1994; 56: 579–583. 
768 Talc

5 Fassihi R, Fabian J, Sakr AM. Application of response surface 
methodology to design optimization in formulation of a typical 
controlled release system. Drugs Made Ger 1996; 39(Oct–Dec): 
122–126. 
6 Schultz P, Tho I, Kleinebudde P. New multiparticulate delayed 
release system. Part 2. Coating formulation and properties of free 
films. J Control Release 1997; 47: 191–199. 
7 Oetari RA, Yuwano T, Fudhdi A. Formulation of PGV-O a new 
antiinflammatory agent as a tablet dosage form. Indonesian J 
Pharm 2003; 14(4): 160–168. 
8 Pearnchob N, Bodmeier R. Dry powder coating of pellets with 
micronized Eudragil (R) RS for extended drug release. Pharm Res 
2003; 20(12); 1970–1976. 
9 Mani N, Suh HR, Jun HW. Microencapsulation of a hydrophilic 
drug into a hydrophobic matrix using a salting-out procedure: II. 
Effects of adsorbents on microsphere properties. Drug Dev Ind 
Pharm 2004; 30(1): 83–93. 
10 Bubik JS. Preparation of sterile talc for treatment of pleural 
effusion [letter]. Am J Hosp Pharm 1992; 49: 562–563. 
11 Grexa RW, Parmentier CJ. Cosmetic talc properties and specifications. 
Cosmet Toilet 1979; 94(2): 29–33. 
12 Hoepfner EM, Reng A, Schmidt PC, eds. Fiedler Encyclopedia of 
Excipients for Pharmaceuticals, Cosmetics and Related Areas, 5th 
edn, vol. II. Aulendorf: Editio Cantor Verlag, 2002: 1556–1559. 
13 Lin K, Peck GE. Development of agglomerated talc. Part 1. 
Evaluation of fluidized bed granulation parameters on the physical 
properties of agglomerated talc. Drug Dev Ind Pharm 1995; 21: 
447–460. 
14 Lin K, Peck GE. Development of agglomerated talc. Part 2. 
Optimization of the processing parameters for the preparation of 
granulated talc. Drug Dev Ind Pharm 1995; 21: 159–173. 
15 Lin K, Peck GE. Development of agglomerated talc. Part 3. 
Comparisons of the physical properties of the agglomerated talc 
prepared by three different processing methods. Drug Dev Ind 
Pharm 1996; 22: 383–392. 
16 Schwartz IS, Bosken C. Pulmonary vascular talc granulomatosis. 
J Am Med Assoc 1986; 256: 2584. 
17 Johnson DC, Petru A, Azimi PH. Foreign body pulmonary 
granulomas in an abuser of nasally inhaled drugs. Pediatrics 
1991; 88: 159–161. 
18 Sparrow SA, Hallam LA. Talc granulomas [letter]. Br Med J 1991; 
303: 58. 
19 Pairaudeau PW, Wilson RG, Hall MA, Milne M. Inhalation of 
baby powder: an unappreciated hazard. Br Med J 1991; 302: 
1200–1201. 
20 Longo DL, Young RC. Cosmetic talc and ovarian cancer. Lancet 
1979; ii: 349–351. 
21 Phillipson IM. Talc quality [letter]. Lancet 1980; i: 48. 
22 International Agency for Research on Cancer/World Health 
Organization. Silica and Some Silicates: IARC Monographs on 
the Evaluation of the Carcinogenic Risk of Chemicals to Humans. 
Geneva: WHO, 1987: 42. 
23 Anonymous. Long-term sequelae of hexachlorophene poisoning. 
Prescrire Int 1992; 1: 168. 
24 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
25 Phadke DS, Keeney MP, Norris DA. Evaluation of batch-to-batch 
and manufacturer-to-manufacturer variability in the physical 
properties of talc and stearic acid. Drug Dev Ind Pharm 1994; 
20: 859–871. 
26 Lin K, Peck GE. Characterization of talc samples from different 
sources. Drug Dev Ind Pharm 1994; 20: 2993–3003. 
20 General References 
Gold G, Campbell JA. Effects of selected USP talcs on acetylsalicylic 
acid stability in tablets. J Pharm Sci 1964; 53: 52–54. 
21 Authors 
AH Kibbe. 
22 Date of Revision 
17 August 2005. 
Talc 769

Tartaric Acid 
1 Nonproprietary Names 
BP: Tartaric acid 
JP: Tartaric acid 
PhEur: Acidum tartaricum 
USPNF: Tartaric acid 
2 Synonyms 
L-(.)-2,3-Dihydroxybutanedioic acid; (2R,3R)-2,3-dihydroxybutane-
1,4-dioic acid; 2,3-dihydroxysuccinic acid; E334; dtartaric 
acid; L-(.)-tartaric acid. 
3 Chemical Name and CAS Registry Number 
[R-(R*,R*)]-2,3-Dihydroxybutanedioic acid [87-69-4] 
4 Empirical Formula and Molecular Weight 
C4H6O6 150.09 
5 Structural Formula 
6 Functional Category 
Acidifying agent; flavor enhancer; sequestering agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Tartaric acid is used in beverages, confectionery, food products, 
and pharmaceutical formulations as an acidulant. It may also 
be used as a sequestering agent and as an antioxidant synergist. 
In pharmaceutical formulations, it is widely used in combination 
with bicarbonates, as the acid component of effervescent 
granules, powders, and tablets. 
8 Description 
Tartaric acid occurs as colorless monoclinic crystals, or a white 
or almost white crystalline powder. It is odorless, with an 
extremely tart taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for tartaric acid. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters — . — 
Appearance of solution — . — 
Specific rotation — .12.08 to 
.12.88 
.12.08 to 
.13.08 
Loss on drying 40.5% 40.2% 40.5% 
Sulfated ash — 40.1% — 
Residue on ignition 40.05% — 40.1% 
Organic volatile 
impurities 
— — . 
Chloride — 4100 ppm — 
Oxalic acid — 4350 ppm — 
Oxalate . — . 
Sulfate 40.048% 4150 ppm . 
Calcium . 4200 ppm — 
Heavy metals 410 ppm 410 ppm 40.001% 
Arsenic 41 ppm — — 
Assay (dried basis) 599.7% 99.5–101.0% 99.7–100.5% 
10 Typical Properties 
Acidity/alkalinity: pH = 2.2 (1.5% w/v aqueous solution) 
Density: 1.76 g/cm3 
Dissociation constant: 
pKa1 = 2.93 at 258C; 
pKa2 = 4.23 at 258C. 
Heat of combustion: 1151 kJ/mol (275.1 kcal/mol) 
Melting point: 168–1708C 
Osmolarity: a 3.9% w/v aqueous solution is isoosmotic with 
serum. 
Solubility: see Table II. 
Specific heat: 1.20 J/g (0.288 cal/g) at 208C 
Specific rotation [a]D
20: .12.08 (20% w/v aqueous solution) 
Table II: Solubility of tartaric acid. 
Solvent Solubility at 208C 
unless otherwise stated 
Chloroform Practically insoluble 
Ethanol (95%) 1 in 2.5 
Ether 1 in 250 
Glycerin Soluble 
Methanol 1 in 1.7 
Propan-1-ol 1 in 10.5 
Water 1 in 0.75 
1 in 0.5 at 1008C 
11 Stability and Storage Conditions 
The bulk material is stable and should be stored in a well-closed 
container in a cool, dry place.

12 Incompatibilities 
Tartaric acid is incompatible with silver and reacts with metal 
carbonates and bicarbonates (a property exploited in effervescent 
preparations). 
13 Method of Manufacture 
Tartaric acid occurs naturally in many fruits as the free acid or 
in combination with calcium, magnesium, and potassium. 
Commercially, L-(.)-tartaric acid is manufactured from 
potassium tartrate (cream of tartar), a by-product of wine 
making. Potassium tartrate is treated with hydrochloric acid, 
followed by the addition of a calcium salt to produce insoluble 
calcium tartrate. This precipitate is then removed by filtration 
and reacted with 70% sulfuric acid to yield tartaric acid and 
calcium sulfate. 
14 Safety 
Tartaric acid is widely used in food products and oral, topical, 
and parenteral pharmaceutical formulations. It is generally 
regarded as a nontoxic and nonirritant material, however, 
strong tartaric acid solutions are mildly irritant and if ingested 
undiluted may cause gastroenteritis. 
An acceptable daily intake for L-(.)-tartaric acid has not 
been set by the WHO, although an acceptable daily intake of up 
to 30 mg/kg body-weight for monosodium L-(.)-tartrate has 
been established.(1) 
LD50 (mouse, IV): 0.49 g/kg(2) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Tartaric acid may be irritant 
to the eyes; eye protection and rubber or plastic gloves are 
recommended. When heated to decomposition, tartaric acid 
emits acrid smoke and fumes. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (IM and IV 
injections; oral solutions, syrups and tablets; sublingual tablets; 
topical films; rectal and vaginal preparations). Included in 
nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Citric acid monohydrate; fumaric acid; malic acid. 
18 Comments 
L-(.)-tartaric acid, the optical isomer usually encountered, is 
the naturally occurring form and is specified as tartaric acid in 
the PhEur 2005 and USPNF 23. 
A specification for tartaric acid is contained in the Food 
Chemicals Codex (FCC). The EINECS number for tartaric acid 
is 205-105-7. 
19 Specific References 
1 FAO/WHO. Evaluation of certain food additives. Twenty-first 
report of the joint FAO/WHO expert committee on food additives. 
World Health Organ Tech Rep Ser 1978; No. 617. 
2 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3349. 
20 General References 
Sendall FEJ, Staniforth JN. A study of powder adhesion to metal 
surfaces during compression of effervescent pharmaceutical tablets. 
J Pharm Pharmacol 1986; 38: 489–493. 
Usui F, Carstensen JT. Interactions in the solid state I: interactions of 
sodium bicarbonate and tartaric acid under compressed conditions. 
J Pharm Sci 1985; 74: 1293–1297. 
21 Authors 
KD Vaughan. 
22 Date of Revision 
13 August 2005. 
Tartaric Acid 771

Tetrafluoroethane (HFC) 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Dymel 134a/P; fluorocarbon 134a; Frigen 134a; Genetron 
134a; HFA 134a; HFC 134a; Isceon 134a; Klea 134a; 
propellant 134a; refrigerant 134a; Solkane 134a; Suva 134a; 
Zephex 134a. 
3 Chemical Name and CAS Registry Number 
1,1,1,2-Tetrafluoroethane [811-97-2] 
4 Empirical Formula and Molecular Weight 
C2H2F4 102.0 
5 Structural Formula 
6 Functional Category 
Aerosol propellant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Tetrafluoroethane is a hydrofluorocarbon (HFC) or hydrofluoroalkane 
(HFA) aerosol propellant (contains hydrogen, 
fluorine, and carbon) as contrasted to a CFC (chlorine, 
fluorine, and carbon). The lack of chlorine in the molecule 
and the presence of hydrogen reduces the ozone depletion 
activity to practically zero. Hence tetrafluoroethane can be 
considered as an alternative to CFCs in the formulation of 
metered-dose inhalers (MDIs).(1–9) It has replaced CFC-12 as a 
refrigerant since it has essentially the same vapor pressure. Its 
very low Kauri-butanol value and solubility parameter indicate 
that it is not a good solvent for the commonly used surfactants 
for MDIs. Sorbitan trioleate, sorbitan sesquioleate, oleic acid, 
and soya lecithin show limited solubility in tetrafluoroethane 
and the amount of surfactant that actually dissolves may not be 
sufficient to keep a drug readily dispersed. 
When tetrafluoroethane (P-134a) is used for pharmaceutical 
aerosols and MDIs, the pharmaceutical grade must be specified. 
Industrial grades may not be satisfactory due to their impurity 
profiles. 
8 Description 
Tetrafluoroethane is a liquefied gas and exists as a liquid at 
room temperature when contained under its own vapor 
pressure, or as a gas when exposed to room temperature and 
atmospheric pressure. The liquid is practically odorless and 
colorless. The gas in high concentrations has a slight etherlike 
odor. Tetrafluoroethane is noncorrosive, nonirritating, and 
nonflammable. 
9 Pharmacopeial Specifications 
—
10 Typical Properties 
Boiling point: 26.28C 
Critical pressure: 4.11MPa (40.55 atm) 
Critical temperature: 101.08C 
Density: 
1.226 g/cm3 for liquid at 208C; 
1.207 g/cm3 for liquid at 258C. 
Flammability: nonflammable. 
Freezing point: 1088C 
Kauri-butanol value: 8 
Solubility: soluble in ethanol (95%), ether, and 1 in 1294 parts 
of water at 208C. 
Surface tension: 8.6 kN/m 
Vapor density (absolute): 4.466 g/cm3 at standard temperature 
and pressure. 
Vapor density (relative): 3.53 (air = 1) 
Vapor pressure: 
569 kPa at 208C; 
662 kPa at 258C. 
Viscosity (dynamic): 
0.222 mPa s (0.222 cP) for liquid at 208C; 
0.210 mPa s (0.210 cP) for liquid at 258C. 
11 Stability and Storage Conditions 
Tetrafluoroethane is a nonreactive and stable material. The 
liquified gas is stable when used as a propellant and should be 
stored in a metal cylinder in a cool dry place. 
12 Incompatibilities 
The major incompatibility of tetrafluoroethane is its lack of 
miscibility with water. Since it has a very low Kauri-butanol 
value, tetrafluoroethane is considered to be a very poor solvent 
for most drugs used in MDI formulations. It also shows a low 
solubility for some of the commonly used MDI surfactants. 
13 Method of Manufacture 
Tetrafluoroethane can be prepared by several different routes; 
however, the following routes of preparation illustrate the 
methods used: 
Isomerization/hydrofluorination of 1,1,2-trichloro-1,2,2- 
trifluoroethane (CFC-113) to 1,1-dichloro-1,2,2,2-tetrafluoroethane 
(CFC-114a), followed by hydrodechlorination of the 
latter. 
Hydrofluorination of trichloroethylene, via 1-chloro-1,1,1- 
trifluoroethane (HCFC-133a).

14 Safety 
Tetrafluoroethane is used as a refrigerant and as a non-CFC 
propellant in various aerosols including pharmaceuticals 
(MDIs). Tetrafluoroethane is regarded as nontoxic and nonirritating 
when used as directed. No acute or chronic hazard is 
present when exposures to the vapor are below the acceptable 
exposure limit (AEL) of 1000 ppm, 8-hour and 12-hour time 
weighed average (TWA).(10) In this regard it has the same value 
as the threshold limit value (TLV) for CFC-12. Inhaling a high 
concentration of tetrafluoroethane vapors can be harmful and 
is similar to inhaling vapors of CFC-12. Intentional inhalation 
of vapors of tetrafluoroethane can be dangerous and may cause 
death. The same labeling required on CFC aerosols would be 
required for those containing tetrafluoroethane as a propellant 
(except for the EPA requirement). See Chlorofluorocarbons, 
Section 14. 
15 Handling Precautions 
Tetrafluoroethane is usually encountered as a liquefied gas and 
appropriate precautions for handling should be taken. Eye 
protection, gloves, and protective clothing are recommended. 
Tetrafluoroethane should be handled in a well-ventilated 
environment. The vapors are heavier than air and do not 
support life; therefore, when cleaning large tanks that have 
contained the propellant, adequate provisions for oxygen 
supply in the tanks must be made in order to protect workers 
cleaning the tanks. 
Although nonflammable, when heated to decomposition 
tetrafluoroethane emits toxic fumes. 
In the UK, the long-term exposure limit (8-hour TWA) for 
tetrafluoroethane is 4240 mg/m3 (1000 ppm).(11) 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (aerosol 
formulations for inhalation and nasal applications). Included 
in nonparenteral medicines licensed in the UK. 
17 Related Substances 
Difluoroethane; heptafluoropropane. 
18 Comments 
The use of tetrafluoroethane as a propellant for MDIs has been 
the subject of numerous patents throughout the world. These 
patents cover the formulation of MDIs and use of specific 
surfactants, cosolvents, etc. A US patent claims a self-propelling 
aerosol formulation that may be free of CFCs and which 
comprises a medicament, 1,1,1,2-tetrafluoroethane, a surfaceactive 
agent, and at least one compound having a higher 
polarity than 1,1,1,2-tetrafluoroethane.(12) Another patent has 
been issued by the European Patent Office and has 14 claims, 
among them a claim that includes tetrafluoroethane, an alcohol 
(such as ethanol), surfactant, and medicament.(13) The formulator 
is referred to the patent literature prior to formulating 
a MDI with tetrafluoroethane as the propellant. The formulation 
of MDI with this non-CFC propellant is complicated since 
tetrafluoroethane serves as a replacement for dichlorodifluoromethane 
or dichlorotetrafluoroethane. The use of an HFC as 
the propellant also requires a change in manufacturing 
procedure, which necessitates a redesign of the filling and 
packaging machinery for a MDI.(14) 
Currently, there are no pharmacopeial specifications for 
tetrafluoroethane. However, typical specifications are shown in 
Table I. 
Table I: Typical product specifications for tetrafluoroethane. 
Test Value 
Appearance Clear and colorless 
High boiling impurities 40.01% 
Acidity as HCl 40.1 ppm 
Non-volatile residue 45 ppm 
Non-absorbable gases 41.5% 
Water 410 ppm 
Total unidentified impurities 410 ppm 
Assay 599.99% 
19 Specific References 
1 Strobach DR. Alternative to CFCs. Aerosol Age 1988; 33(7): 32– 
33, 42–43. 
2 Daly J. Properties and toxicology of CFC alternatives. Aerosol Age 
1990; 35(2): 26–27, 40. 
3 Dalby RN, Byron PR, Shepherd HR, Papadopoulos E. CFC 
propellant substitution: P-134a as a potential replacement for P-12 
in MDIs. Pharm Technol 1990; 14(3): 26–33. 
4 Kontny MJ, Destefano G, Jagen PD, et al. Issues surrounding MDI 
formulation development with non-CFC propellants. J Aerosol 
Med 1991; 4(3): 181–187. 
5 Anonymous. 3M first with a CFC-free asthma inhaler. Pharm J 
1995; 254: 388. 
6 Taggart SCO, Custovic A, Richards DH, Woodcock A. 
GR106642X: a new, non-ozone depleting propellant for inhalers. 
Br Med J 1995; 310: 1639–1640. 
7 Elvecrog J. Metered dose inhalers in a CFC-free future. Pharm 
Technol Eur 1997; 9(1): 52–55. 
8 Tansey IP. Changing to CFC-free inhalers: the technical and clinical 
challenges. Pharm J 1997; 259: 896–898. 
9 McDonald KJ, Martin GP. Transition to CFC-free metered dose 
inhalers: into the new millenium. Int J Pharm 2000; 201: 89–107. 
10 DuPont. Technical literature: Dymel 134a/P pharmaceutical grade 
HFC-134a propellant, 1996. 
11 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
12 Purewal TS, Greenleaf DJ. Medicinal aerosol formulations. United 
States Patent No. 5,605,674; 1997. 
13 Purewal TS, Greenleaf DJ. Medicinal aerosol formulations. 
European Patent 372777B1; 1993. 
14 Tzou T, Pachuta RR, Coy RB, Schultz RK. Drug form selection in 
albuterol-containing metered-dose inhaler formulations and its 
impact on chemical and physical stability. J Pharm Sci 1997; 86: 
1352–1357. 
20 General References 
Harrison LI, Donnell D, Simmons JL, et al. Twenty-eight day doubleblind 
safety study of an HFA 134a inhalation aerosol system in 
healthy subjects. J Pharm Pharmacol 1996; 48: 596–600. 
Hoet P, Graf MLM, Bourdi M, et al. Epidemic of liver disease caused by 
hydrochlorofluorocarbons used as ozone-sparing substitutes of 
chlorofluorocarbons. Lancet 1997; 350: 556–559. 
Sawyer E, Green B, Colton HM. Microorganism survival in non-CFC 
propellant P134a and a combination of CFC propellants P11 and 
P12. Pharm Technol 2001; 25(3): 90–96. 
Tetrafluoroethane (HFC) 773

Steed KP, Hooper G, Brickwell J, Newman SP. The oropharyngeal and 
lung deposition patterns of a fusafungine MDI spray delivered by 
HFA 134a propellant or by CFC 12 propellant. Int J Pharm 1995; 
123: 291–293. 
Tiwari D, Goldman D, Dixit S, et al. Compatibility evaluation of 
metered-dose inhaler valve elastomers with tetrafluoroethane 
(P134a), a non-CFC propellant. Drug Dev Ind Pharm 1998; 24: 
345–352. 
21 Authors 
CJ Sciarra, JJ Sciarra. 
22 Date of Revision 
21 August 2005. 
774 Tetrafluoroethane (HFC)

Thaumatin 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
E957; Talin; taumatin; thalin; thaumatine; thaumatins; thaumatins 
protein. 
3 Chemical Name and CAS Registry Number 
Thaumatin [53850-34-3] 
4 Empirical Formula and Molecular Weight 
See Section 5. 
5 Structural Formula 
Thaumatin is a mixture of five thaumatin proteins; thaumatins 
I, II, III, and a and b; where thaumatins I and II predominate. 
Thaumatins I and II consist of almost identical sequences of 
amino acids. There are no unusual side-chains or peptide 
linkages, and there are no end-group substitutions. 
6 Functional Category 
Flavor enhancer; sweetening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Thaumatin is a naturally occurring intense sweetening agent 
approximately 2000–3000 times as sweet as sucrose. It has a 
delayed-onset taste profile and long (up to one hour) licoricelike 
aftertaste. It is used extensively in food applications as a 
sweetening agent and flavor enhancer and has potential for use 
in pharmaceutical applications such as oral suspensions.(1) The 
typical level used in foods is 0.5–3 ppm, although higher levels 
are used in certain applications such as chewing gum. 
Synergistic effects with other intense sweeteners such as 
acesulfame K and saccharin occur. The extensive disulfide 
crosslinking within thaumatin maintains the tertiary structure 
of the polypeptide: cleavage of just one disulfide bridge has 
been shown to result in the loss of the sweet taste of 
thaumatin.(2) 
8 Description 
Thaumatin occurs as a pale-brown colored, odorless, hygroscopic 
powder with an intensely sweet taste. 
9 Pharmacopeial Specifications 
—
10 Typical Properties 
Solubility: see Table I. 
Table I: Solubility of thaumatin 
Solvent Solubility at 258C unless otherwise stated 
Acetone Practically insoluble 
Ethanol (95%) Soluble 
Glycerin Soluble 
Propylene glycol Soluble 
Water 1 in 5 at pH 3 
11 Stability and Storage Conditions 
Thaumatin is stable in aqueous solutions at pH 2–8. It is also 
heat-stable at less than pH 5.5 (e.g., during baking, canning, 
pasteurizing, or UHT processes). 
12 Incompatibilities 
—
13 Method of Manufacture 
Thaumatin is a naturally occurring intense sweetener isolated 
from the fruit of the African plant Thaumatococcus daniellii 
(Benth).(3) Commercially, thaumatin is produced by aqueous 
extraction under reduced pH conditions followed by other 
physical processes such as reverse osmosis. 
14 Safety 
Thaumatin is accepted for use in food products either as a 
sweetener or as a flavor modifier in a number of areas including 
Europe and Australia. It is also used in oral hygiene products 
such as mouthwashes and toothpastes and has been proposed 
for use in oral pharmaceutical formulations. Thaumatin is 
generally regarded as a relatively nontoxic and nonirritant 
material when used as an excipient. In Europe, because of its 
lack of toxicity, an ADI has been set of ‘not specified’.(4,5) 
LD50 (mouse, oral): >20 g/kg(5) 
LD50 (rat, oral): >20 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in nonparenteral medicines licensed in the UK. 
17 Related Substances 
—

18 Comments 
As thaumatin is a protein it has some calorific value; however, 
in food products and pharmaceutical formulations the quantities 
used are so small that the calorific value is insignificant. 
The EINECS number for thaumatin is 258-822-2. 
19 Specific References 
1 Odusote MO, Nasipuri RN. Effect of pH and storage conditions 
on the stability of a novel chloroquine phosphate syrup formulation. 
Pharm Ind 1988; 50(3): 367–369. 
2 Iyengar RB, Smits P, van der Oureraa F, et al. The complete aminoacid 

sequence of the sweet protein thaumatin. Eur J Biochem 1979; 
96: 193–204. 
3 Daniell WF. Katemfe, or the miraculous fruit of the Soudan. Pharm 
J 1855; 14: 158–160. 
4 Higginbotham JD, Snodin DJ, Eaton KK, Daniel JW. Safety 
evaluation of thaumatin (Talin Protein). Food Chem Toxicol 1983; 
21(6): 815–823. 
5 FAO/WHO. Toxicological evaluation of certain food additives and 
contaminants. Twenty-ninth report of the joint FAO/WHO expert 
committee on food additives. WHO Food Add Ser 1985; No. 20. 
20 General References 
Dodson AG, Wright SJC. New sweeteners: confectioner’s viewpoint. 
Food Flavour Ingred Packag Process 1982; 4(Sep): 29, 31, 32, 59. 
Green C. Thaumatin: a natural flavour ingredient. World Rev Nutr 
Diet 1999; 85: 129–132. 
Hart H. Thaumatin. In: Birch G, ed. Ingredients Handbook: Sweeteners, 
2nd edn. Leatherhead: Leatherhead Publishing, 2000: 255– 
263. 
Higginbotham JD. Talin protein (thaumatin). In: O’Brien Nabors L, 
Gelardi RC, eds. Alternative Sweeteners. New York: Marcel Dekker, 
1986: 103–134. 
Kinghorn AD, Compadre CM. Naturally occurring intense sweeteners. 
Pharm Int 1985; 6(Aug): 201–204. 
Kinghorn AD, Compadre CM. Less common high-potency sweeteners. 
In: O’Brien Nabors L, ed. Alternative Sweeteners, 3rd edn. New 
York: Marcel Dekker, 2001: 214–215. 
Sanyude S. Alternative sweeteners. Can Pharm J 1990; 123(Oct): 455– 
456, 459–460. 
Witty M, Higginbotham JD, eds. Thaumatin. Boca Raton, FL: CRC 
Press, 1994. 
21 Authors 
PJ Weller. 
22 Date of Revision 
23 May 2005. 
776 Thaumatin

Thimerosal 
1 Nonproprietary Names 
BP: Thiomersal 
PhEur: Thiomersalum 
USP: Thimerosal 
2 Synonyms 
[(o-Carboxyphenyl)thio]ethylmercury sodium salt; ethyl 
(2-mercaptobenzoato-S)-mercury, sodium salt; ethyl (sodium 
o-mercaptobenzoato)mercury; mercurothiolate; sodium ethylmercurithiosalicylate; 
Thimerosal Sigmaultra; thiomersalate. 
3 Chemical Name and CAS Registry Number 
Ethyl[2-mercaptobenzoato(2–)-O,S]-mercurate(1–) sodium 
[54-64-8] 
4 Empirical Formula and Molecular Weight 
C9H9HgNaO2S 404.81 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; antiseptic. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Thimerosal has been used as an antimicrobial preservative in 
biological and pharmaceutical preparations since the 1930s;(1) 
see Table I. 
It is used as an alternative to benzalkonium chloride and 
other phenylmercuric preservatives and has both bacteriostatic 
and fungistatic activity. Increasing concerns over its safety have, 
however, led to questions regarding its continued use in 
formulations; see Section 14. 
Thimerosal is also used in cosmetics (see Section 16) and to 
preserve soft contact lens solutions. 
Therapeutically, thimerosal is occasionally used as a 
bacteriostatic and fungistatic mercurial antiseptic, which is 
usually applied topically at a concentration of 0.1% w/w.(2) 
However, its use is declining owing to its toxicity and effects on 
the environment. 
8 Description 
Thimerosal is a light cream-colored crystalline powder with a 
slight, characteristic odor. 
Table I: Uses of thimerosal. 
Use Concentration (%) 
IM, IV, SC injections 0.01 
Ophthalmic solutions 0.001–0.15 
Ophthalmic suspensions 0.001–0.004 
Otic preparations 0.001–0.01 
Topical preparations 0.01 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for thimerosal. 
Test PhEur 2005 
(Suppl. 5.1) 
USP 28 
Identification . . 
Characters . — 
Appearance of solution . — 
Melting point 103–1058C — 
pH 6.0–8.0 — 
Inorganic mercury compounds 40.70% — 
Loss of drying 40.5% 40.5% 
Ether-soluble substances — 40.8% 
Mercury ions — 40.70% 
Readily carbonizable substances — . 
Assay 97.0–101.0% 97.0–101.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 6.7 for a 1% w/v aqueous solution at 
208C. 
Antimicrobial activity: thimerosal is bactericidal at acidic pH, 
bacteriostatic and fungistatic at alkaline or neutral pH. 
Thimerosal is not effective against spore-forming organisms. 
See also Section 12. For reported minimum inhibitory 
concentrations (MICs), see Table III.(3) 
Table III: Reported minimum inhibitory concentrations (MICs) for 
thimerosal.(3) 
Microorganism MIC (mg/mL) 
Aspergillus niger 128.0 
Candida albicans 32.0 
Escherichia coli 4.0 
Klebsiella pneumoniae 4.0 
Penicillium notatum 128.0 
Pseudomonas aeruginosa 8.0 
Pseudomonas cepacia 8.0 
Pseudomonas fluorescens 4.0 
Staphylococcus aureus 0.2

Density (bulk): <0.33 g/cm3 
Dissociation constant: pKa = 3.05 at 258C. 
Melting point: 232–2338C with decomposition. 
Solubility: soluble 1 in 8 of ethanol (95%), 1 in 1 of water; 
practically insoluble in benzene and ether. 
11 Stability and Storage Conditions 
Thimerosal is stable at normal temperatures and pressures; 
exposure to light may cause discoloration. 
Aqueous solutions may be sterilized by autoclaving but are 
sensitive to light. The rate of oxidation in solutions is increased 
by the presence of trace amounts of copper and other metals. 
Edetic acid or edetates may be used to stabilize solutions but 
have been reported to reduce the antimicrobial efficacy of 
thimerosal solutions; see Section 12. 
The solid material should be stored in a well-closed 
container, protected from light, in a cool, dry place. 
12 Incompatibilities 
Incompatible with aluminum and other metals, strong oxidizing 
agents, strong acids and bases, sodium chloride solutions,(4) 
lecithin, phenylmercuric compounds, quaternary ammonium 
compounds, thioglycolate, and proteins. The presence of 
sodium metabisulfite, edetic acid, and edetates in solutions 
can reduce the preservative efficacy of thimerosal.(5) 
In solution, thimerosal may be adsorbed by plastic packaging 
materials, particularly polyethylene. It is strongly adsorbed 
by treated or untreated rubber caps that are in contact with 
solutions.(6,7) 
When it was used with cyclodextrin, the effectiveness of 
thimerosal was reduced; however, this was related to the lipid 
nature of the other ingredients in the preparation.(8) 
13 Method of Manufacture 
Thimerosal is prepared by the interaction of ethylmercuric 
chloride, or hydroxide, with thiosalicylic acid and sodium 
hydroxide, in ethanol (95%). 
14 Safety 
Thimerosal is widely used as an antimicrobial preservative in 
parenteral and topical pharmaceutical formulations. However, 
concern over the use of thimerosal in pharmaceuticals has 
increased as a result of a greater awareness of the toxicity of 
mercury and other associated mercury compounds.(9,10) The 
increasing number of reports of adverse reactions, particularly 
hypersensitivity,(11,12) to thimerosal and doubts as to its 
effectiveness as a preservative have led to suggestions that it 
should not be used as a preservative in eye drops(13) or 
vaccines.(14–16) In both Europe and the USA, regulatory bodies 
have recommended that thimerosal in vaccines be phased 
out.(17–19) 
More recent studies assessing the safety of thimerosal in 
vaccines have however suggested that while the risk of 
hypersensitivity reactions is present, the relative risk of 
neurological harm in infants is negligible given the quantities 
of thimerosal present in vaccines.(20–22) Regulatory bodies in 
Europe and the USA have therefore updated their advice on the 
use of thimerosal in vaccines by stating that while it would be 
desirable for thimerosal to not be included in vaccines and other 
formulations the benefits of vaccines far outweigh any risks of 
adverse effects associated with their use.(23,24) 
The most frequently reported adverse reaction to thimerosal, 
particularly in vaccines,(14–27) is hypersensitivity, usually 
with erythema and papular or vesicular eruptions. Although 
not all thimerosal-sensitive patients develop adverse reactions 
to vaccines containing thimerosal, there is potential risk. Patch 
testing in humans and animal experiments have suggested that 
0.1% w/v thimerosal can sensitize children.(28) The incidence of 
sensitivity to thimerosal appears to be increasing; a study of 
256 healthy subjects showed approximately 6% with positive 
sensitivity.(29) 
Adverse reactions to thimerosal used to preserve contact lens 
solutions have also been reported. Reactions include ocular 
redness, irritation, reduced lens tolerance, and conjunctivitis.(
30–32) One estimate suggests that approximately 10% of 
contact lens wearers may be sensitive to thimerosal.(33) 
Thimerosal has also been associated with false positive 
reactions to old tuberculin,(34) ototoxicity,(35) and an unusual 
reaction to aluminum(36) in which a patient suffered a burn 
5 cm in diameter at the site of an aluminum foil diathermy 
electrode after preoperative preparation of the skin with a 
0.1% w/v thimerosal solution in ethanol (50%). Investigation 
showed that considerable heat was generated when such a 
solution came into contact with aluminum. 
An interaction between orally administered tetracyclines 
and thimerosal, which resulted in varying extents of ocular 
irritation, has been reported in patients using a contact lens 
solution preserved with thimerosal.(37) 
Controversially, some have claimed a connection between 
the use of thimerosal in vaccines and the apparent rise in the 
incidence of autism. However, recent studies have shown no 
association between thimerosal exposure and autism.(38,39) 
LD50 (mouse, oral): 91 mg/kg(40) 
LD50 (rat, oral): 75 mg/kg 
LD50 (rat, SC): 98 mg/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Thimerosal is irritant to the 
skin and mucous membranes and may be systemically absorbed 
through the skin and upper respiratory tract. Thimerosal 
should be handled in a well-ventilated environment. Eye 
protection, gloves, and a respirator are recommended. 
Chemical decomposition may cause the release of toxic 
fumes containing oxides of carbon, sulfur, and mercury in 
addition to mercury vapor. In the UK, the occupational 
exposure limit for mercury-containing compounds, calculated 
as mercury, is 0.01 mg/m3 long-term (8-hour TWA) and 
0.03 mg/m3 short-term.(41) 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IM, IV, and SC 
injections; ophthalmic, otic, and topical preparations). Included 
in nonparenteral and parenteral medicines licensed in the UK. 
In the UK, the use of thimerosal in cosmetics is limited to 
0.003% w/w (calculated as mercury) as a preservative in 
shampoos and hair-creams, which contain nonionic emulsifiers 
that would render other preservatives ineffective. The total 
permitted concentration (calculated as mercury) when mixed 
with other mercury compounds is 0.007% w/w.(42) Included in 
the Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Phenylmercuric acetate; phenylmercuric borate; phenylmercuric 
nitrate. 
778 Thimerosal

18 Comments 
Some variation between the results obtained when comparing 
different thimerosal assay methods has been reported.(43) 
The EINECS number for thimerosal is 200-210-4. 
19 Specific References 
1 Amieson WA, Powell HM. Merthiolate as a preservative for 
biological products. Am J Hyg 1931; 14: 218–224. 
2 Sweetman SC, ed. Martindale: the Complete Drug Reference, 34th 
edn. London. Pharmaceutical Press. 2005: 1194. 
3 Wallha. usser KH. Thimerosal. In: Kabara JJ, ed. Cosmetic and 
Drug Preservation Principles and Practice. New York: Marcel 
Dekker, 1984: 735–737. 
4 Reader MJ. Influence of isotonic agents on the stability of 
thimerosal in ophthalmic formulations. J Pharm Sci 1984; 73(6): 
840–841. 
5 Richards RME, Reary JME. Changes in antibacterial activity of 
thiomersal and PMN on autoclaving with certain adjuvants. J 
Pharm Pharmacol 1972; 24 (Suppl.): 84P–89P. 
6 Wiener S. The interference of rubber with the bacteriostatic action 
of thiomersalate. J Pharm Pharmacol 1955; 7: 118–125. 
7 Birner J, Garnet JR. Thimerosal as a preservative in biological 
preparations III: factors affecting the concentration of thimerosal 
in aqueous solutions and in vaccines stored in rubber-capped 
bottles. J Pharm Sci 1964; 53: 1424–1426. 
8 Lehner SJ, Muller BW, Seydel JK. Effect of hydroxypropyl-betacyclodextrin 
on the antimicrobial action of preservatives. J Pharm 
Pharmacol 1994; 46(3): 186–191. 
9 Van’t Veen AJ. Vaccines without thiomersal: why so necessary, why 
so long in coming? Drugs 2001; 61(5): 565–572. 
10 Clements CJ, Ball LK, Ball R, Pratt RD. Thimerosal in vaccines: is 
removal warranted? Drug Saf 2001; 24(8): 567–574. 
11 Suneja T, Belsito DV. Thimerosal in the detection of clinically 
relevant allergic, contact reactions. J Am Acad Dermatol 2001; 
45(1): 23–27. 
12 Audicana MT, Munoz D, del Pozo MD, et al. Allergic contact 
dermatitis from mercury antiseptics and derivatives: study protocol 
of tolerance to intramuscular injections of thimerosal. Am J 
Contact Dermat 2002; 13(1): 3–9. 
13 Ford JL, Brown MW, Hunt PB. A note on the contamination of 
eye-drops following use by hospital out-patients. J Clin Hosp 
Pharm 1985; 10(2): 203–209. 
14 Cox NH, Forsyth A. Thiomersal allergy and vaccination reactions. 
Contact Dermatitis 1988; 18: 229–233. 
15 Seal D, Ficker L,Wright P, Andrews V. The case against thiomersal 
[letter]. Lancet 1991; 338(8762): 315–316. 
16 Noel I, Galloway A, Ive FA. Hypersensitivity to thiomersal in 
hepatitis B vaccine [letter]. Lancet 1991; 338: 705. 
17 Anonymous. Thiomersal to be removed from vaccines in the US. 
Pharm J 1999; 263: 112. 
18 European Agency for the Evaluation of Medicinal Products 
(EMEA). EMEA public statement on thiomersal containing 
medicinal products, 8 July 1999. EMEA publication no. (20962/ 
99). Full version: http://www.emea.eu.int/pdfs/human/press/pus/ 
2096299EN.pdf (accessed 13 April 2005). 
19 American Academy of Pediatrics, United States Public Health 
Service. Thimerosal in vaccines: a joint statement of the American 
Academy of Pediatrics and the Public Health Service. MMWR 
1999; 48: 563–565. 
20 Clements CJ. The evidence for the safety of thimerosal in newborn 
and infant vaccines. Vaccine 2004; 22(15–16): 1854–1861. 
21 Counter SA, Buchanan LH. Mercury exposure in children: a 
review. Toxicol Appl Pharmacol 2004; 198(2): 209–230. 
22 Bigham M, Copes R. Thimerosal in vaccines: balancing the risks of 
adverse effects with the risk of vaccine-preventable disease. Drug 
Safety 2005; 28(2): 89–101. 
23 European Medicines Evaluation Agency 2004. EMEA public 
statement on thiomersal in vaccines for human use—recent 
evidence supports safety of thiomersal-containing vaccines. 
http://www.emea.eu.int/pdfs/human/press/pus/119404eu.pdf 
(accessed 13 April 2005). 
24 Committee on Safety of Medicines. Safety of thiomersal-containing 
vaccines. Current Problems 2003; 29: 9. 
25 Rietschel RL, Adams RM. Reactions to thimerosal in hepatitis B 
vaccines. Dermatol Clin 1990; 8(1): 161–164. 
26 Golightly LK, Smolinske SS, Bennett ML, et al. Pharmaceutical 
excipients: adverse effects associated with inactive ingredients in 
drug products (part I). Med Toxicol 1988; 3: 128–165. 
27 Lee-Wong M, Resnick D, Chong K. A generalized reaction to 
thimerosal from an influenza vaccine. Ann Allergy Asthma 
Immunol 2005; 94(1): 90–94. 
28 Osawa J, Kitamura K, Ikezawa Z, Nakajima H. A probable role 
for vaccines containing thimerosal in thimerosal hypersensitivity. 
Contact Dermatitis 1991; 24(3): 178–182. 
29 Seidenari S, Manzini BM, Modenese M, Danese P. Sensitization 
after contact with thimerosal in a healthy population [in Italian]. G 
Ital Dermatol Venereol 1989; 124(7–8): 335–339. 
30 Mondino BJ, Groden LR. Conjunctival hyperemia and corneal 
infiltrates with chemically disinfected soft contact lenses. Arch 
Ophthalmol 1980; 98(10): 1767–1770. 
31 Sendele DD, Kenyon KR, Mobilia EF, et al. Superior limbic 
keratoconjunctivitis in contact lens wearers. Ophthalmology 
1983; 90: 616–622. 
32 Fisher AA. Allergic reactions to contact lens solutions. Cutis 1985; 
36(3): 209–211. 
33 Miller JR. Sensitivity to contact lens solutions. West J Med 1984; 
140: 791. 
34 Hansson H, Mo. ller H. Intracutaneous test reactions to tuberculin 
containing merthiolate as a preservative. Scand J Infect Dis 1971; 
3: 169–172. 
35 Honigman JL. Disinfectant ototoxicity. Pharm J 1975; 215: 523. 
36 Jones HT. Danger of skin burns from thiomersal. Br Med J 1972; 
2: 504–505. 
37 Crook TG, Freeman JJ. Reactions induced by the concurrent use of 
thimerosal and tetracyclines. Am J Optom Physiol Opt 1983; 60: 
759–761. 
38 Department of Health. Public letter from the Chief Medical 
Officer: current vaccine and immunisation issues, 15 October 
2001, (PL/CMO/2001/5). Full version: http://www.doh.gov.uk/ 
cmo/plcmo2001-5.pdf (accessed 1 October 2002). 
39 Parker SK, Schwartz B, Todd J, Pickering LK. Thimerosalcontaining 
vaccines and autistic spectrum disorder: a critical 
review of published original data. Pediatrics 2004; 114(3): 793– 
804. 
40 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2321. 
41 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
42 Statutory Instrument 2233. Consumer protection: the consumer 
products (safety) regulations 1989. London: HMSO, 1989. 
43 Fleitman JS, Partridge IW, Neu DA. Thimerosal analysis in 
ketorolac tromethamine ophthalmic solution. Drug Dev Ind 
Pharm 1991; 17: 519–530. 
20 General References 
Axton JHM. Six cases of poisoning after a parenteral organic mercurial 
compound (Merthiolate). Postgrad Med J 1972; 48: 417–421. 
Caraballo I, Rabasco AM, Ferna.ndez-Are.valo M. Study of thimerosal 
degradation mechanism. Int J Pharm 1993; 89: 213–221. 
Rabasco AM, Caraballo I, Ferna.ndez-Are.valo M. Formulation factors 
affecting thimerosal stability. Drug Dev Ind Pharm 1993; 19: 1673– 
1691. 
Tan M, Parkin JE. Route of decomposition of thiomersal (thimerosal). 
Int J Pharm 2000; 208: 23–34. 
21 Authors 
PJ Weller. 
22 Date of Revision 
13 April 2005. 
Thimerosal 779

Thymol 
1 Nonproprietary Names 
BP: Thymol 
PhEur: Thymolum 
USPNF: Thymol 
2 Synonyms 
Acido trimico; 3-p-cymenol; p-cymen-3-ol; Flavinol; 3- 
hydroxy-p-cymene; 3-hydroxy-1-methyl-4-isopropylbenzene; 
Intrasol; isopropyl cresol; isopropyl-m-cresol; 6-isopropyl-mcresol; 
isopropyl metacresol; 2-isopropyl-5-methylphenol; 1- 
methyl-3-hydroxy-4-isopropylbenzene; 5-methyl-2-isopropylphenol; 
5-methyl-2-(1-methylethyl) phenol; Medophyll; thyme 
camphor; thymic acid; m-thymol; timol. 
3 Chemical Name and CAS Registry Number 
Thymol [89-83-8] 
4 Empirical Formula and Molecular Weight 
C10H14O 150.24 
5 Structural Formula 
6 Functional Category 
Antioxidant; antiseptic; cooling agent; disinfectant; flavoring 
agent; skin penetrant; therapeutic agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Thymol is a phenolic antiseptic, which has antibacterial and 
antifungal activity. However, it is not suitable for use as a 
preservative in pharmaceutical formulations because of its low 
aqueous solubility. The antimicrobial activity of thymol against 
eight oral bacteria has been studied in vitro. Inhibitory activity 
was noted against almost all organisms, and a synergistic effect 
was observed for combinations of thymol and eugenol and of 
thymol and carvacrol.(1) The activity of thymol against bacteria 
commonly involved in upper respiratory tract infections has 
also been shown.(2) 
Thymol is a more powerful disinfectant than phenol, but its 
low water solubility, its irritancy to tissues, and its inactivation 
by organic material, such as proteins, limit its use as a 
disinfectant. Thymol is chiefly used as a deodorant in antiseptic 
mouthwashes, gargles, and toothpastes, such as in Compound 
Thymol Glycerin BP, in which it has no antiseptic action. 
Thymol is also a true antioxidant and has been used at 
concentrations of 0.01% as an antioxidant for halothane, 
trichloroethylene, and tetrachloroethylene. 
More recently, thymol has been shown to enhance the in 

vitro percutaneous absorption of a number of drugs, including 
5-fluorouracil,(3) piroxicam,(4) propranolol,(5) naproxen,(6) and 
tamoxifen.(7) Studies have also demonstrated that the melting 
point of lidocaine is significantly lowered when it is mixed with 
thymol.(8,9) 
The inhalation of thymol, in combination with other volatile 
substances, is used to alleviate the symptoms of colds, coughs, 
and associated respiratory disorders. Externally, thymol has 
been used in dusting powders for the treatment of fungal skin 
infections. Thymol was formerly used in the treatment of 
hookworm infections but has now been superseded by less 
toxic substances. 
In dentistry, thymol has been mixed with phenol and 
camphor to prepare cavities before filling, and mixed with zinc 
oxide to form a protective cap for dentine. 
Thymol has been included in food, perfume, and cosmetic 
products, and has also been used as a pesticide and fungicide. 
8 Description 
Thymol occurs as colorless or often large translucent crystals, 
or as a white crystalline powder with a herbal odor (aromatic 
and thyme-like) and a pungent caustic taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for thymol. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Melting range 48–528C 48–518C 
Appearance of solution . — 
Acidity . — 
Related substances . — 
Residue on evaporation 40.05% 40.05% 
Organic volatile impurities — . 
Assay — 99.0–101.0% 
10 Typical Properties 
Acidity/alkalinity: a 4%solution in ethanol (50%) is neutral to 
litmus. 
Boiling point: about 2338C 
Density: 0.97 g/cm3 at 258C; has a greater density than water, 
but when liquefied by fusion is less dense than water. 
Dissociation constant: pKa = 10.6 at 208C 
Melting point: 48–518C, but, once melted, remains liquid at a 
considerably lower temperature.

Partition coefficient: log (octanol–water) = 3.3 
Phenol coefficient: about 50 
Refractive index: 
nD
25 = 0.15204; 
nD
20 = 0.15227. 
Solubility: soluble 1 in 0.7–1.0 of chloroform, 1 in 1 of ethanol 
(95%), 1 in 1.5 of ether, glacial acetic acid, 1 in 1.7–2.0 of 
olive oil, 1 in 1000 of water. Freely soluble in essential oils, 
fixed oils, and fats. Sparingly soluble in glycerin. Dissolves 
in dilute solutions of alkali hydroxides, forming salts that 
have increased solubility but whose solutions darken on 
standing. 
Vapor pressure: 0.04mmHg at 208C 
Volatility appreciable volatility at 1008C; volatile in water 
vapor at 258C. 
11 Stability and Storage Conditions 
Thymol should be stored in well-closed, light-resistant containers, 
in a cool, dry, place. Thymol is affected by light. 
12 Incompatibilities 
Thymol is incompatible with iodine, alkalis, and oxidizing 
agents. It liquefies, or forms soft masses, on trituration with 
acetanilide, antipyrine, camphor, monobromated camphor, 
chloral hydrate, menthol, phenol, or quinine sulfate. 
13 Method of Manufacture 
Thymol is obtained from the volatile oil of thyme (Thymus 
vulgaris Linne (Fam Labiatae)) by fractional distillation 
followed by extraction and recrystallization. Thyme oil yields 
about 20–30% thymol. Thymol may also be produced 
synthetically from p-cymene, menthone, or piperitone, or by 
the interaction of m-cresol with isopropyl chloride. 
14 Safety 
Thymol is used in cosmetics, foods, and pharmaceutical 
applications as an excipient. However, thymol may be irritating 
when inhaled or following contact with the skin or eyes. It may 
also cause abdominal pain and vomiting, and sometimes 
stimulation followed by depression of the central nervous 
system following oral consumption. 
Respiratory arrest, attributed to acute nasal congestion and 
edema, has been reported in a 3-week-old patient due to the 
erroneous intranasal application of Karvol, a combination 
product that includes thymol. The patient recovered, but it was 
recommended that inhalation decongestants should not be used 
in children under the age of 5 years.(10) 
LD50 (guinea pig, oral): 0.88 g/kg(11) 
LD50 (mouse, IP): 0.11 g/kg 
LD50 (mouse, IV): 0.1 g/kg 
LD50 (mouse, oral): 0.64 g/kg 
LD50 (mouse, SC): 0.243 g/kg 
LD50 (rat, oral): 0.98 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Special precautions should be 
taken to avoid inhalation, or contact with the skin or eyes. Eye 
protection and gloves are recommended. When thymol is 
heated to decomposition, carbon dioxide and carbon monoxide 
are formed. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(inhalation, liquid; oral, powder for solution). Included in 
nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Menthol. 
18 Comments 
The EINECS number for thymol is 201-944-8. 
19 Specific References 
1 Didry N, Dubreuil L, Pinkas M. Activity of thymol, carvacrol, 
cinnamaldehyde and eugenol on oral bacteria. Pharm Acta Helv 
1994; 69(1): 25–28. 
2 Didry N, Dubreuil L, Pinkas M. Antimicrobial activity of thymol, 
carvacrol and cinnamaldehyde alone or in combination. Pharmazie 
1993; 48: 301–304. 
3 Gao S, Singh J. Mechanism of transdermal transport of 5- 
fluorouracil by terpenes: carvone, 1,8-cineole and thymol. Int J 
Pharm 1997; 154(1): 67–77. 
4 Doliwa A, Santoyo S, Ygartua P. Effect of passive and iontophoretic 
skin pretreatments with terpenes on the in vitro skin transport 
of piroxicam. Int J Pharm 2001; 229(1-2): 37–44. 
5 Songkro S, Rades T, Becket G. The effects of p-menthane 
monoterpenes and related compounds on the percutaneous 
absorption of propranolol hydrochloride across newborn pig 
skin I. In vitro skin permeation and retention studies. STP Pharma 
Sci 2003; 13(5): 349–357. 
6 Ray S, Ghosal SK. Release and skin permeation studies of 
naproxen from hydrophilic gels and effect of terpenes as enhancers 
on its skin permeation. Boll Chim Farm 2003; 142(3): 125–129. 
7 Gao S, Singh J. In vitro percutaneous absorption enhancement of 
the lipophilic drug tamoxifen by terpenes. J Control Release 1998; 
51: 193–199. 
8 Kang L, Jun HW, Mani N. Preparation and characterisation of 
two-phase melt systems of lignocaine. Int J Pharm 2001; 222(1): 
35–44. 
9 Kang L, Jun HW. Formulation and efficacy studies of new topical 
anaesthetic creams. Drug Dev Ind Pharm 2003; 29(5): 505–512. 
10 Blake KD. Dangers of common cold treatments in children. Lancet 
1993; 341: 640. 
11 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3462–3463. 
20 General References 
—
21 Authors 
CG Cable. 
22 Date of Revision 
19 August 2005. 
Thymol 781

Titanium Dioxide 
1 Nonproprietary Names 
BP: Titanium dioxide 
JP: Titanium oxide 
PhEur: Titanii dioxidum 
USP: Titanium dioxide 
2 Synonyms 
Anatase titanium dioxide; brookite titanium dioxide; color 
index number 77891; E171; Kronos 1171; pigment white 6; 
rutile titanium dioxide; Tioxide; TiPure; titanic anhydride; 
Tronox. 
3 Chemical Name and CAS Registry Number 
Titanium oxide [13463-67-7] 
4 Empirical Formula and Molecular Weight 
TiO2 79.88 
5 Structural Formula 
TiO2 
6 Functional Category 
Coating agent; opacifier; pigment. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Titanium dioxide is widely used in confectionery, cosmetics, 
and foods, in the plastics industry, and in topical and oral 
pharmaceutical formulations as a white pigment. 
Owing to its high refractive index, titanium dioxide has 
light-scattering properties that may be exploited in its use as a 
white pigment and opacifier. The range of light that is scattered 
can be altered by varying the particle size of the titanium 
dioxide powder. For example, titanium dioxide with an average 
particle size of 230nm scatters visible light, while titanium 
dioxide with an average particle size of 60nm scatters 
ultraviolet light and reflects visible light.(1) 
In pharmaceutical formulations, titanium dioxide is used as 
a white pigment in film-coating suspensions,(2,3) sugar-coated 
tablets, and gelatin capsules. Titanium dioxide may also be 
admixed with other pigments. 
Titanium dioxide is also used in dermatological preparations 
and cosmetics, such as sunscreens.(1,4) 
SEM: 1 
Excipient: Titanium dioxide 
Magnification: 1200 Voltage: 10 kV 
8 Description 
White, amorphous, odorless, and tasteless nonhygroscopic 
powder. Although the average particle size of titanium dioxide 
powder is less than 1 mm, commercial titanium dioxide 
generally occurs as aggregated particles of approximately 
100 mm diameter. 
Titanium dioxide may occur in several different crystalline 
forms: rutile; anatase; and brookite. Of these, rutile and anatase 
are the only forms of commercial importance. Rutile is the more 
thermodynamically stable and is used more frequently than the 
other crystalline forms. 
9 Pharmacopeial Specifications 
See Table I. 
10 Typical Properties 
Density (bulk): 0.4–0.62 g/cm3(5) 
Density (tapped): 0.625–0.830 g/cm3(6) 
Density (true): 
3.8–4.1 g/cm3 for Anatase; 
3.9–4.2 g/cm3 for Rutile. 
Dielectric constant: 
48 for Anatase; 
114 for Rutile. 
Hardness (Mohs): 
5–6 for Anatase; 
6–7 for Rutile. 
See also Section 18. 
Melting point: 18558C

Table I: Pharmacopeial specifications for titanium dioxide. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters — . — 
Appearance of solution — . — 
Acidity or alkalinity — . — 
Water-soluble 
substances 
45.0mg 425mg 40.25% 
Antimony — . — 
Arsenic 410 ppm 45 ppm 
41 ppm 
Barium — . — 
Heavy metals — 420 ppm — 
Iron — . — 
Loss on drying 40.5% — 40.5% 
Loss on ignition — — 413% 
Acid-soluble substances — — 40.5% 
Organic volatile 
impurities 
— — . 
Lead 460 ppm — 
—
Assay 598.5% 98.0–100.5% 99.0–100.5% 
Moisture content: 0.44% 
Particle size distribution: average particle size = 1.05 mm.(5) See 
also Figures 1 and 2. 
Refractive index: 
2.55 for Anatase; 
2.76 for Rutile. 
Specific heat: 
0.71 J/g (0.17 cal/g) for Anatase; 
0.71 J/g (0.17 cal/g) for Rutile. 
Specific surface area: 9.90–10.77m2/g 
Solubility: practically insoluble in dilute sulfuric acid, hydrochloric 
acid, nitric acid, organic solvents, and water. Soluble 
in hydrofluoric acid and hot concentrated sulfuric acid. 
Solubility depends on previous heat treatment; prolonged 
heating produces a less-soluble material. 
Figure 1: Particle-size distribution of titanium dioxide (fine powder). 
Figure 2: Particle-size distribution of titanium dioxide (agglomerated 
particles). 
Tinting strength (Reynolds): 
1200–1300 for Anatase; 
1650–1900 for Rutile. 
11 Stability and Storage Conditions 
Titanium dioxide is extremely stable at high temperatures. This 
is due to the strong bond between the tetravalent titanium ion 
and the bivalent oxygen ions. However, titanium dioxide can 
lose small, unweighable amounts of oxygen by interaction with 
radiant energy. This oxygen can easily recombine again as a 
part of a reversible photochemical reaction, particularly if there 
is no oxidizable material available. These small oxygen losses 
are important because they can cause significant changes in the 
optical and electrical properties of the pigment. 
Titanium dioxide should be stored in a well-closed 
container, protected from light, in a cool, dry place. 
12 Incompatibilities 
Owing to a photocatalytic effect, titanium dioxide may interact 
with certain active substances, e.g. famotidine.(7) Studies have 
shown that titanium dioxide monatonically degrades film 
mechanical properties and increases water vapor permeability 
of polyvinyl alcohol coatings when used as an inert filler and 
whitener.(6) 
Titanium dioxide has also been shown to induce photooxidation 
of unsaturated lipids.(8) 
13 Method of Manufacture 
Titanium dioxide occurs naturally as the minerals rutile 
(tetragonal structure), anatase (tetragonal structure), and 
brookite (orthorhombic structure). 
Titanium dioxide may be prepared commercially by direct 
combination of titanium and oxygen; by treatment of titanium 
salts in aqueous solution; by the reaction of volatile inorganic 
Titanium Dioxide 783

titanium compounds with oxygen; and by the oxidation or 
hydrolysis of organic compounds of titanium. 
14 Safety 
Titanium dioxide is widely used in foods and oral and topical 
pharmaceutical formulations. It is generally regarded as an 
essentially nonirritant and nontoxic excipient. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection, gloves, and a 
dust mask are recommended. Titanium dioxide is regarded as a 
relatively innocuous nuisance dust,(9) that may be irritant to the 
respiratory tract. In the UK, the long-term (8-hour TWA) 
exposure limit is 10 mg/m3 for total inhalable dust and 4 mg/m3 
for respirable dust.(10) 
Titanium dioxide particles in the 500nm range have been 
reported to translocate to all major body organs after oral 
administration in the rat.(11) 
16 Regulatory Status 
Accepted as a food additive in Europe. Included in the FDA 
Inactive Ingredients Guide (dental paste; intrauterine suppositories; 
ophthalmic preparations; oral capsules, suspensions, 
tablets; topical and transdermal preparations). Included in 
nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Coloring agents. 
18 Comments 
Titanium dioxide is a hard, abrasive material. Coating 
suspensions containing titanium dioxide have been reported 
to cause abrasion and wear of a steel-coated pan surface, which 
led to white tablets being contaminated with black specks.(12) 
If titanium dioxide is used as a pigment it should conform to 
the appropriate food standards specifications, which are more 
demanding than the pharmacopeial specifications. 
When mixed with methylcellulose, titanium dioxide can 
reduce the elongation and tensile strength of the film but 
slightly increase the adhesion between pigmented film and the 
tablet surface.(13) A specification for titanium dioxide is 
contained in the Food Chemicals Codex (FCC). 
The EINECS number for titanium dioxide is 236-675-5. 
19 Specific References 
1 Hewitt JP. Titanium dioxide: a different kind of sunshield. Drug 
Cosmet Ind 1992; 151(3): 26, 28, 30, 32. 
2 Rowe RC. Quantitative opacity measurements on tablet film 
coatings containing titanium dioxide. Int J Pharm 1984; 22: 17– 
23. 
3 Be.chard SR, Quraishi O, Kwong E. Film coating: effect of titanium 
dioxide concentration and film thickness on the photostability of 
nifedipine. Int J Pharm 1992; 87: 133–139. 
4 Alexander P. Ultrafine titanium dioxide makes the grade. Manuf 
Chem 1991; 62(7): 21, 23. 
5 Brittain HG, Barbera G, DeVincentis J, Newman AW. Titanium 
dioxide. In: Brittain HG, ed. Analytical Profiles of Drug 
Substances and Excipients, volume 21. San Diego: Academic 
Press, 1992: 659–691. 
6 Hsu ER, Gebert MS, Becker NT, Gaertner AL. Effects of 
plasticizers and titanium dioxide on the properties of poly(vinyl 
alcohol) coatings. Pharm Dev Technol 2001; 6(2): 277–284. 
7 Kakinoki K, Yamane K, Teraoka R, et al. Effect of relative 
humidity on the photocatalytic activity of titanium dioxide and 
photostability of famotidine. J Pharm Sci 2004; 93(3): 582–589. 
8 Sayre RM, Dowdy JC. Titanium dioxide and zinc oxide induce 
photooxidation of unsaturated lipids. Cosmet Toilet 2000; 115; 
75–80, 82. 
9 Driscoll KE, Maurer JK, Lindenschmidt RC, et al. Respiratory 
tract responses to dust: relationships between dust burden, lung 
injury, alveolar macrophage fibronectin release, and the development 
of pulmonary fibrosis. Toxicol Appl Pharmacol 1990; 106: 
88–101. 
10 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
11 Jani PU, McCarthy DE, Florence AT. Titanium dioxide (rutile) 
particle uptake from the rat GI tract and translocation to systemic 
organs after oral administration. Int J Pharm 1994; 105(May 2); 
157–168. 
12 Rosoff M, Sheen P-C. Pan abrasion and polymorphism of titanium 
dioxide in coating suspensions. J Pharm Sci 1983; 72: 1485. 
13 Lehtola VM, Heinamaki JT, Nikupaavo P, Yliruusi JK. Effect of 
titanium dioxide on mechanical, permeability and adhesion 
properties of aqueous-based hydroxypropyl methylcellulose films. 
Boll Chim Farm 1994; 133(Dec): 709–714. 
20 General References 
Judin VPS. The lighter side of TiO2. Chem Br 1993; 29(6): 503–505. 
Loden M, Akerstrom U, Lindahl K, Berne B. Novel method for studying 
photolability of topical formulations: a case study of titanium 
dioxide stabilization of ketoprofen. J Pharm Sci 2005; 94(4): 781– 
787. 
Ortyl TT, Peck GE. Surface charge of titanium dioxide and its effect on 
dye adsorption and aqueous suspension stability. Drug Dev Ind 
Pharm 1991; 17: 2245–2268. 
Rowe RC. Materials used in the film coating of oral dosage forms. In: 
Florence AT, ed. Critical Reports on Applied Chemistry, volume 6. 
Oxford: Blackwell Scientific, 1984: 1–36. 
21 Authors 
PJ Weller. 
22 Date of Revision 
13 April 2005. 
784 Titanium Dioxide

Tragacanth 
1 Nonproprietary Names 
BP: Tragacanth 
JP: Tragacanth 
PhEur: Tragacantha 
USPNF: Tragacanth 
See also Section 18. 
2 Synonyms 
E413; goat’s thorn; gum benjamin; gum dragon; gum 
tragacanth; persian tragacanth; trag; tragant. 
3 Chemical Name and CAS Registry Number 
Tragacanth gum [9000-65-1] 
4 Empirical Formula and Molecular Weight 
Tragacanth is a naturally occurring dried gum obtained from 
Astragalus gummifer Labillardie`re and other species of 
Astragalus grown in Western Asia; see Section 13. 
The gum consists of a mixture of water-insoluble and watersoluble 
polysaccharides. Bassorin, which constitutes 60–70% 
of the gum, is the main water-insoluble portion, while the 
remainder of the gum consists of the water-soluble material 
tragacanthin. On hydrolysis, tragacanthin yields L-arabinose, 
L-fucose, D-xylose, D-galactose, and D-galacturonic acid. 
Tragacanth gum also contains small amounts of cellulose, 
starch, protein, and ash. 
Tragacanth gum has an approximate molecular weight of 
840 000. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Suspending agent; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Tragacanth gum is used as an emulsifying and suspending agent 
in a variety of pharmaceutical formulations. It is used in 
creams, gels, and emulsions at various concentrations according 
to the application of the formulation and the grade of gum 
used. 
Tragacanth gum is also used similarly in cosmetics and food 
products, and has been used as a diluent in tablet formulations. 
8 Description 
Tragacanth gum occurs as flattened, lamellated, frequently 
curved fragments, or as straight or spirally twisted linear pieces 
from 0.5–2.5mm in thickness; it may also be obtained in a 
powdered form. White to yellowish in color, tragacanth is a 
translucent, odorless substance, with an insipid mucilaginous 
taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for tragacanth. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters — . — 
Botanical characteristics — — . 
Microbial limits — . . 
Flow time — . — 
Lead — — 40.001% 
Heavy metals — — 420 ppm 
Methylcellulose — . — 
Acacia — . — 
Foreign matter — 41.0% — 
Karaya gum . — . 
Sterculia gum — . — 
Organic volatile impurities — — . 
Ash 44.0% 44.0% — 
10 Typical Properties 
Acidity/alkalinity: pH = 5–6 for a 1% w/v aqueous dispersion. 
Acid value: 2–5 
Moisture content: 415% w/w 
Particle size distribution: for powdered grades 50% w/w passes 
through a 73.7 mm mesh. 
Solubility: practically insoluble in water, ethanol (95%), and 
other organic solvents. Although insoluble in water, 
tragacanth gum swells rapidly in 10 times its own weight 
of either hot or cold water to produce viscous colloidal sols 
or semigels. See also Section 18. 
Specific gravity: 1.250–1.385 
Viscosity (dynamic): the viscosity of tragacanth dispersions 
varies according to the grade and source of the material. 
Typically, 1% w/v aqueous dispersions may range in 
viscosity from 100–4000 mPa s (100–4000 cP) at 208C. 
Viscosity increases with increasing temperature and concentration, 
and decreases with increasing pH. Maximum 
initial viscosity occurs at pH 8, although the greatest 
stability of tragacanth dispersions occurs at about pH 5. 
See also Sections 11 and 12. 
11 Stability and Storage Conditions 
Both the flaked and powdered forms of tragacanth are stable. 
Tragacanth gels are liable to exhibit microbial contamination 
with enterobacterial species, and stock solutions should therefore 
contain suitable antimicrobial preservatives. In emulsions, 
glycerin or propylene glycol are used as preservatives; in gel 
formulations, tragacanth is usually preserved with either 0.1% 
w/v benzoic acid or sodium benzoate. A combination of 0.17%

w/v methylparaben and 0.03% w/v propylparaben is also an 
effective preservative for tragacanth gels;(1) see also Section 12. 
Gels may be sterilized by autoclaving. Sterilization by gamma 
irradiation causes a marked reduction in the viscosity of 
tragacanth dispersions.(2) 
Tragacanth dispersions are most stable at pH 4–8, although 
stability is satisfactory at higher pH or as low as pH 2. 
The bulk material should be stored in an airtight container 
in a cool, dry place. 
12 Incompatibilities 
At pH 7, tragacanth has been reported to considerably reduce 
the efficacy of the antimicrobial preservatives benzalkonium 
chloride, chlorobutanol, and methylparaben, and to a lesser 
extent that of phenol and phenylmercuric acetate.(3) However, 
at pH < 5 tragacanth was reported to have no adverse effects 
on the preservative efficacy of benzoic acid, chlorobutanol, or 
methylparaben.(1) 
The addition of strong mineral and organic acids can reduce 
the viscosity of tragacanth dispersions. Viscosity may also be 
reduced by the addition of alkali or sodium chloride, 
particularly if the dispersion is heated. Tragacanth is compatible 
with relatively high salt concentrations and most other 
natural and synthetic suspending agents such as acacia, 
carboxymethylcellulose, starch, and sucrose. A yellow colored, 
stringy, precipitate is formed with 10% w/v ferric chloride 
solution. 
13 Method of Manufacture 
Tragacanth gum is the air-dried gum obtained from Astragalus 
gummifer Labillardie`re and other species of Astragalus grown 
principally in Iran, Syria, and Turkey. A low-quality gum is 
obtained by collecting the natural air-dried exudate from 
Astragalus bushes. A higher-grade material is obtained by 
making incisions in the trunk and branches of the bush, which 
are held open with variously sized wooden pegs. The exudate is 
left to drain from the incision and dry naturally in the air before 
being collected. The size and position of the wooden wedges 
determine the physical form of the exudate, while the drying 
conditions determine the color of the gum. After collection, the 
tragacanth gum is sorted by hand into various grades, such as 
ribbons or flakes. 
14 Safety 
Tragacanth has been used for many years in oral pharmaceutical 
formulations and food products, and is generally regarded 
as an essentially nontoxic material. Tragacanth has been shown 
to be noncarcinogenic.(4) However, hypersensitivity reactions, 
which are occasionaly severe, have been reported following 
ingestion of products containing tragacanth.(5,6) Contact 
dermatitis has also been reported following the topical use of 
tragacanth formulations.(7) 
The WHO has not specified an acceptable daily intake for 
tragacanth gum, as the daily intake necessary to achieve a 
desired effect, and its background levels in food, were not 
considered to be a hazard to health.(8) 
LD50 (hamster, oral): 8.8 g/kg(9) 
LD50 (mouse, oral): 10 g/kg 
LD50 (rabbit, oral): 7.2 g/kg 
LD50 (rat, oral): 16.4 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Tragacanth gum may be 
irritant to the skin and eyes. Eye protection, gloves, and a dust 
mask are recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (buccal/ 
sublingual tablets, oral powders, suspensions, syrups, and 
tablets). Included in nonparenteral medicines licensed in the 
UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
See Section 18. 
18 Comments 
Tragacanth gum is a naturally occurring material whose 
physical properties vary greatly according to the grade and 
source of the material. Samples can contain relatively high 
levels of bacterial contamination.(10,11) 
Hog gum (caramania gum), obtained from species of 
Prunus, and sterculia gum have been used in industrial 
applications as substitutes for tragacanth. 
Powdered tragacanth gum tends to form lumps when added 
to water and aqueous dispersions should therefore be agitated 
vigorously with a high-speed mixer. However, aqueous dispersions 
are more readily prepared by first prewetting the 
tragacanth with a small quantity of a wetting agent such as 
ethanol (95%), glycerin, or propylene glycol. If lumps form, 
they usually disperse on standing. Dispersion is generally 
complete after 1 hour. If other powders, such as sucrose, are to 
be incorporated into a tragacanth formulation the powders are 
best mixed together in the dry state. 
Some pharmacopeias, such as JP 2001, contain a specification 
for powdered tragacanth. 
A specification for tragacanth is contained in the Food 
Chemicals Codex (FCC). 
19 Specific References 
1 Taub A, MeerWA, Clausen LW. Conditions for the preservation of 
gum tragacanth jellies. J Am Pharm Assoc (Sci) 1958; 47: 235– 
239. 
2 Jacobs GP, Simes R. The gamma irradiation of tragacanth: effect 
on microbial contamination and rheology. J Pharm Pharmacol 
1979; 31: 333–334. 
3 Eisman PC, Cooper J, Jaconia D. Influence of gum tragacanth on 
the bactericidal activity of preservatives. J Am Pharm Assoc (Sci) 
1957; 46: 144–147. 
4 Hagiwara A, Boonyaphiphat P, Kawabe M, et al. Lack of 
carcinogenicity of tragacanth gum in B6C3F1 mice. Food Chem 
Toxicol 1992; 30(8): 673–679. 
5 Danoff D, Lincoln L, Thomson DMP, Gold P. Big Mac attack 
[letter]. N Engl J Med 1978; 298: 1095–1096. 
6 Rubinger D, Friedlander M, Superstine E. Hypersensitivity to 
tablet additives in transplant recipients on prednisone [letter]. 
Lancet 1978; ii: 689. 
7 Coskey RJ. Contact dermatitis caused by ECG electrode jelly. Arch 
Dermatol 1977; 113: 839–840. 
8 FAO/WHO. Evaluation of certain food additives and contaminants. 
Twenty-ninth report of the joint FAO/WHO expert 
786 Tragacanth

committee on food additives. World Health Organ Tech Rep Ser 
1986; No. 733. 
9 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3500. 
10 Westwood N. Microbial contamination of some pharmaceutical 
raw materials. Pharm J 1971; 207: 99–102. 
11 De La Rosa MC, Del Rosario Medina M, Vivar C. Microbiological 
quality of pharmaceutical raw materials. Pharm Acta Helv 1995; 
70: 227–232. 
20 General References 
Fairbairn JW. The presence of peroxidases in tragacanth [letter]. J 
Pharm Pharmacol 1967; 19: 191. 
Verbeken D, Dierckx S, Dewettinck K. Exudate gums: occurence, 
production, and applications. Appl Microbiol Biotechnol 2003; 
63(1): 10–21. 
21 Authors 
PJ Weller. 
22 Date of Revision 
13 April 2005. 
Tragacanth 787

Trehalose 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
C*Ascend; (a-D-glucosido)-a-D-glucoside; mycose; natural trehalose; 
a,a-trehalose; trehalose dihydrate. 
3 Chemical Name and CAS Registry Number 
a-D-Glucopyranosyl-a-D-glucopyranoside anhydrous [99- 
20-7] 
a-D-Glucopyranosyl-a-D-glucopyranoside dihydrate [6138- 
23-4] 
See also Section 17. 
4 Empirical Formula and Molecular Weight 
C12H22O11 342.31 (anhydrous) 
C12H22O112H2O 378.33 (dihydrate) 
5 Structural Formula 
a,a-Trehalose dihydrate 
6 Functional Category 
Coloring adjuvant; flavor enhancer; freeze-drying excipient; 
humectant; stabilizing agent; sweetening agent; tablet diluent; 
thickening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Trehalose is used for the lyoprotection of therapeutic proteins, 
particularly for parenteral administration. Other pharmaceutically 
relevant applications include use as an excipient for 
diagnostic assay tablets;(1) for stabilization during the freeze– 
thaw and lyophilization of liposomes;(2) and for stabilization of 
blood cells,(3) cosmetics,(4) and monoclonal antibodies.(5) 
Trehalose may also be used in formulations for topical 
application.(6) 
8 Description 
Trehalose occurs as virtually odorless, white or almost white 
crystals with a sweet taste (approximately 45% of the 
sweetness of sucrose). 
9 Pharmacopeial Specifications 
—
10 Typical Properties 
Acidity/alkalinity: pH = 4.5–6.5 (30% w/v aqueous solution) 
Melting point: 978C (for the dihydrate) 
Moisture content: 9.5% (for the dihydrate) 
Solubility: soluble in water; very slightly soluble in ethanol 
(95%); practically insoluble in ether. 
Specific rotation[a]D
20: .179.78 (5% w/v aqueous solution) 
See also Section 18. 
11 Stability and Storage Conditions 
Trehalose is a relatively stable material. At 608C for 5 hours it 
loses not more than 1.5% w/w of water (the dihydrate water of 
crystallization is retained). Open stored powder may liquefy at 
high relative humidity (590%). 
Trehalose should be stored in a cool, dry place in a wellsealed 
container. 
12 Incompatibilities 
Trehalose is incompatible with strong oxidizing agents, 
especially in the presence of heat. 
13 Method of Manufacture 
Trehalose is prepared from liquefied starch by a multistep 
enzymatic process.(7) The commercial product is the dihydrate. 
14 Safety 
Trehalose is used in cosmetics, foods, and parenteral and 
nonparenteral pharmaceutical formulations. It is generally 
regarded as a relatively nontoxic and nonirritant material 
when used as an excipient. 
In the gut, trehalose is rapidly metabolized to glucose by the 
specific enzyme trehalase. A small minority of the population 
exhibits a primary (hereditary) or secondary (acquired) 
trehalase deficiency and thus may experience intestinal 
discomfort after ingestion of excessive amounts of trehalose 
owing to the osmotic activity of undigested trehalose in the gut. 
However, smaller amounts of trehalose are tolerated by such 
individuals without any symptoms.(7) 
Trehalose is reported to have substantially less cariogenic 
potential than sucrose. 
LD50 (dog, IV): >1 g/kg 
LD50 (dog, oral): >5 g/kg 
LD50 (mouse, IV): >1 g/kg 
LD50 (mouse, oral): >5 g/kg 
LD50 (rat, IV): >1 g/kg 
LD50 (rat, oral): >5 g/kg

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. 
16 Regulatory Status 
GRAS listed. In the UK trehalose may be used in certain food 
applications. Included in parenteral and nonparenteral investigational 
formulations. 
17 Related Substances 
Isotrehalose; neotrehalose. 
Isotrehalose 
CAS number: [499-23-0] 
Synonyms: b,b-trehalose. 
Neotrehalose 
CAS number: [585-91-1] 
Synonyms: a,b-trehalose. 
18 Comments 
a,a-Trehalose is the only naturally occurring isomer of 
trehalose and occurs as the dihydrate. However, a,b-trehalose 
(neotrehalose) and b,b-trehalose (isotrehalose) have been 
synthesized and are also available commercially. See also 
Section 17. 
Trehalose is a nonreducing sugar and therefore does not 
react with amino acids or proteins as a part of Maillard 
browning. It is relatively stable under low-pH conditions 
compared to other disaccharides. 
It should be noted that although trehalose dihydrate is 
quoted to have a melting point of 978C, the true nature of this 
melting process has been the subject of debate in the 
literature,(810) including the transformation of the dihydrate 
into the anhydrous form. Anhydrous crystalline trehalose has 
been reported to melt at 2038C,(11) although higher values 
(2158C) have also been quoted in the literature.(12) 
The glass transition temperature of trehalose is reported to 
be approximately 1208C (anhydrous amorphous phase).(13) 
The EINECS number for trehalose is 202-739-6. 
19 Specific References 
1 Bollin E, Fletcher G. Trehalose as excipient and stabilizer for 
diagnostic assay tablets. United States Patent No. 4,678,812; 
1987. 
2 Vemuri S, Yu CD, DeGroot JS, et al. Effect of sugars on freeze– 
thaw and lyophilisation of liposomes. Drug Dev Ind Pharm 1991; 
17(3): 327–348. 
3 Ligler FS, Stratton LP, Rudolph AS. Liposome encapsulated 
hemoglobin; stabilization, encapsulation and storage. Prog Clin 
Biol Res 1989; 319: 435–455. 
4 Pauly M. Pharmaceuticals and cosmetics containing glucidic 
compounds as active agents for skin regeneration. French Patent 
2 609 397; 1988. 
5 Matsuo E, Yamazaki S. Freeze-dried composition containing 
enzyme-labeled antihuman b-interferon antibody. International 
Patent 09 402 05; 1989. 
6 Giandala G, DeCaro V, Cordone L. Trehalose-hydroxyethylcellulose 
microspheres containing vancomycin for topical drug delivery. 
Eur J Pharm Biopharm 2001; 52(1): 83–89. 
7 Ba. r A. Trehalose produced by a novel enzymatic process. 
http://www.foodstandards.gov.uk/multimedia/pdfs/0_1.pdf 
(accessed 7 April 2005). 
8 Sussich F, Szopec C, Brady J, Cesaro A. Reversible dehydration of 
trehalose and anhydrobiosis: from solution state to an exotic 
crystal? Carbohydr Res 2001; 334: 165–176. 
9 Taylor LS, York P. Characterisation of the phase transitions of 
trehalose dihydrate on heating and subsequent dehydration. J 
Pharm Sci 1998; 87: 347–355. 
10 McGarvey OS, Kett VL, Craig DQM. An investigation into the 
crystallization of alpha, alpha-trehalose from the amorphous state. 
J Phys Chem B 2003; 107: 6614–6620. 
11 O’Neil MJ, ed. Trehalose. The Merck Index: an Encyclopedia of 
Chemicals, Drugs, and Biologicals, 13th edn. Whitehouse Station, 
NJ: Merck, 2001: 1709. 
12 Sussich F, Cesaro A. Transitions and phenomenology of a,atrehalose 
polymorphs inter-conversion. J Therm Anal Calorim 
2000; 62: 757–767. 
13 Hatley RHM, Blair JA. Stabilisation and delivery of labile 
materials by amorphous carbohydrates and their derivatives. J 
Mol Cat B 1999; 7: 11–19. 
20 General References 
Pikal MJ. Freeze drying. In: Swarbrick J, Boylan JC, eds. Encyclopedia 
of Pharmaceutical Technology, 2nd edn, vol. 2. New York: Marcel 
Dekker, 2002: 1299–1326. 
21 Authors 
OS McGarvey, DQM Craig, VL Kett. 
22 Date of Revision 
7 August 2005. 
Trehalose 789

Triacetin 
1 Nonproprietary Names 
BP: Triacetin 
PhEur: Glycerolum triacetas 
USP: Triacetin 
2 Synonyms 
Captex 500; E1518; glycerol triacetate; glyceryl triacetate; 
triacetyl glycerine. 
3 Chemical Name and CAS Registry Number 
1,2,3-Propanetriol triacetate [102-76-1] 
4 Empirical Formula and Molecular Weight 
C9H14O6 218.21 
5 Structural Formula 
6 Functional Category 
Humectant; plasticizer; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Triacetin is mainly used as a hydrophilic plasticizer in both 
aqueous and solvent-based polymeric coating of capsules, 
tablets, beads, and granules; typical concentrations used are 
10–35% w/w.(1,2) 
Triacetin is used in cosmetics, perfumery, and foods as a 
solvent and as a fixative in the formulation of perfumes and 
flavors. 
8 Description 
Triacetin is a colorless, viscous liquid with a slightly fatty odor. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for triacetin. 
Test PhEur 2005 USP 28 
Appearance . — 
Characters . — 
Identification . . 
Specific gravity 1.159–1.164 1.152–1.158 
Refractive index 1.429–1.432 1.429–1.430 
Acidity . . 
Water 40.2% 40.2% 
Assay (anhydrous basis) 97.0–100.5% 97.0–100.5% 
10 Typical Properties 
Autoignition temperature: 4328C 
Boiling point: 2588C 
Density: 1.16 g/cm3 at 258C 
Explosive limits: 
1.05% at 1898C lower limit; 
7.73% at 2158C upper limit. 
Flash point: 1538C (open cup) 
Freezing point: 3.28C (supercools to about –708C) 
Melting point: 788C 
Refractive index: nD
25 = 1.4296 
Solubility: see Table II. 
Table II: Solubility of triacetin. 
Solvent Solubility at 208C 
Carbon disulfide Miscible 
Chloroform Miscible 
Ethanol Miscible 
Ethanol (95%) Miscible 
Ether Miscible 
Toluene Miscible 
Water 1 in 14 
Vapor density (relative): 7.52 (air = 1) 
Vapor pressure: 133 Pa (1 mmHg) at 1008C 
Viscosity (dynamic): 
1111 mPa s (1111 cP) at –17.88C; 
107 mPa s (107 cP) at 08C; 
17.4 mPa s (17.4 cP) at 258C; 
1.8 mPa s (1.8 cP) at 1008C. 
11 Stability and Storage Conditions 
Triacetin is stable and should be stored in a well-closed, 
nonmetallic container, in a cool, dry place. 
12 Incompatibilities 
Triacetin is incompatible with metals and may react with 
oxidizing agents. Triacetin may destroy rayon fabric.

13 Method of Manufacture 
Triacetin is prepared by the esterification of glycerin with acetic 
anhydride. 
14 Safety 
Triacetin is used in oral pharmaceutical formulations and is 
generally regarded as a relatively nontoxic and nonirritant 
material at the levels employed as an excipient.(3) 
LD50 (dog, IV): 1.5 g/kg(4) 
LD50 (mouse, IP): 1.4 g/kg 
LD50 (mouse, IV): 1.6 g/kg 
LD50 (mouse, oral): 1.1 g/kg 
LD50 (mouse, SC): 2.3 g/kg 
LD50 (rabbit, IV): 0.75 g/kg 
LD50 (rat, IP): 2.1 g/kg 
LD50 (rat, oral): 3 g/kg 
LD50 (rat, SC): 2.8 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Triacetin may be irritant to 
the eyes; eye protection and gloves are recommended. 
16 Regulatory Status 
GRAS listed. Accepted in Europe as a food additive in certain 
applications. Included in the FDA Inactive Ingredients Guide 
(oral capsules and tablets and gels). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
—
18 Comments 
A specification for triacetin is contained in the Food Chemicals 
Codex (FCC). The EINECS number for triacetin is 203-051-9. 
19 Specific References 
1 Shah PS, Zatz JL. Plasticization of cellulose esters used in the 
coating of sustained release solid dosage forms. Drug Dev Ind 
Pharm 1992; 18: 1759–1772. 
2 Williams RO, Wheatley TA, Liu J. Influence of plasticization and 
curing conditions on the mechanical properties of aqueous based 
cellulose acetate films. STP Pharma Sci 1999; 9(6): 545–553. 
3 Fiume MZ. Final report on the safety assessment of triacetin. Int J 
Toxicol 2003; 22(Suppl 2): 1–10. 
4 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3503. 
20 General References 
Gutierrez-Rocca JC, McGinity JW. Influence of aging on the physicalmechanical 
properties of acrylic resin films cast from aqueous 
dispersions and organic solutions. Drug Dev Ind Pharm 1993; 19: 
315–332. 
Johnson K, Hathaway R, Leung P, Franz R. Effect of triacetin and 
polyethylene glycol 400 on some physical properties of hydroxypropyl 
methylcellulose free films. Int J Pharm 1991; 73: 197– 
208. 
Lehmann KOR. Chemistry and application properties of polymethacrylate 
coating systems. In: McGinity JW, ed. Aqueous Polymeric 
Coatings for Pharmaceutical Dosage Forms. New York: Marcel 
Dekker, 1989: 224. 
Lin S-Y, Lee C-J, Lin Y-Y. The effect of plasticizers on compatibility, 
mechanical properties, and adhesion strength of drug-free Eudragit 
E films. Pharm Res 1991; 8: 1137–1143. 
Rowe RC. Materials used in the film coating of oral dosage forms. In: 
Florence AT, ed. Critical Reports on Applied Chemistry, vol. 6. 
Oxford: Blackwell Scientific, 1984: 1–36. 
21 Authors 
A Palmieri. 
22 Date of Revision 
13 April 2005. 
Triacetin 791

Tributyl Citrate 
1 Nonproprietary Names 
USPNF: Tributyl citrate 
2 Synonyms 
Citric acid, tributyl ester; Citroflex 4; TBC; tri-n-butyl citrate; 
tributyl 2-hydroxy-1,2,3-propanetricarboxylate. 
3 Chemical Name and CAS Registry Number 
1,2,3-Propanetricarboxylic acid, 2-hydroxy, tributyl ester [77- 
94-1] 
4 Empirical Formula and Molecular Weight 
C18H32O7 360.5 
5 Structural Formula 
6 Functional Category 
Plasticizer. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Tributyl citrate is used to plasticize polymers in formulated 
pharmaceutical coatings. The coating applications include 
capsules, tablets, beads, and granules for taste masking, 
immediate release, sustained-release, and enteric formulations.(
1–6) 
8 Description 
Tributyl citrate is a clear, odorless, practically colorless, oily 
liquid. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for tributyl citrate. 
Test USPNF 23 
Identification . 
Specific gravity 1.037–1.045 
Refractive index 1.443–1.445 
Acidity . 
Water 40.2% 
Heavy metals 40.001% 
Assay (anhydrous basis) 599.0% 
10 Typical Properties 
Acid value: 0.02 
Boiling point: 3228C (decomposes) 
Flash point: 1858C 
Pour point: 628C 
Solubility: miscible with acetone, ethanol, and vegetable oil; 
practically insoluble in water. 
Viscosity: 32 mPa s (32 cP) at 258C 
11 Stability and Storage Conditions 
Tributyl citrate should be stored in well-closed containers in a 
cool, dry location at temperatures not exceeding 388C. When 
stored in accordance with these conditions, tributyl citrate is a 
stable material. 
12 Incompatibilities 
Tributyl citrate is incompatible with strong alkalis and 
oxidizing materials. 
13 Method of Manufacture 
Tributyl citrate is prepared by the esterification of citric acid 
with butanol. 
14 Safety 
Tributyl citrate is used in oral pharmaceutical formulations. It is 
generally regarded as an essentially nontoxic and nonirritating 
material. However, ingestion of large quantities may be 
harmful. 
LD50 (cat, oral): >50 mL/kg(7) 
LD50 (mouse, IP): 2.9 g/kg 
LD50 (rat, oral): >30 mL/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Tributyl citrate may be 
irritating to the eyes. It may also be irritating to the respiratory 
system at elevated temperatures. 
Gloves and eye protection are recommended for normal 
handling, and a respirator is recommended for elevated 
temperatures.

16 Regulatory Status 
Approved in the US for indirect food contact in food films. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Acetyltributyl citrate; acetyltriethyl citrate; triethyl citrate. 
18 Comments 
The EINECS number for tributyl citrate is 201-071-2. 
19 Specific References 
1 Gutierrez-Rocca JC, McGinity JW. Influence of water soluble and 
insoluble plasticizer on the physical and mechanical properties of 
acrylic resin copolymers. Int J Pharm 1994; 103: 293–301. 
2 Lehmann K. Chemistry and application properties of polymethacrylate 
coating systems. In: McGinity JW, ed. Aqueous Polymeric 
Coatings for Pharmaceutical Dosage Forms. New York: Marcel 
Dekker, 1989: 153–245. 
3 Steurnagel CR. Latex emulsions for controlled drug delivery. In: 
McGinity JW, ed. Aqueous Polymeric Coatings for Pharmaceutical 
Dosage Forms. New York: Marcel Dekker, 1989: 1–61. 
4 Gutierrez-Rocca JC, McGinity JW. Influence of aging on the 
physical-mechanical properties of acrylic resin films cast from 
aqueous dispersions and organic solutions. Drug Dev Ind Pharm 
1993; 19(3): 315–332. 
5 Felton LA, McGinity JW. Influence of plasticisers on the adhesive 
properties of an acrylic resin copolymer to hydrophilic and 
hydrophobic tablet compacts. Int J Pharm 1997; 154(2): 167–178. 
6 Okarter TU, Singla K. The effects of plasticisers on the release of 
metoprolol tartrate from granules coated with a polymethacrylate 
film. Drug Dev Ind Pharm 2000; 26(3): 323–329. 
7 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3513. 
20 General References 
Morflex Inc. Technical literature: Citrate esters, 2000. 
21 Authors 
SW Kennedy. 
22 Date of Revision 
13 August 2005. 
Tributyl Citrate 793

Triethanolamine 
1 Nonproprietary Names 
BP: Triethanolamine 
PhEur: Trolaminum 
USPNF: Trolamine 
2 Synonyms 
TEA; Tealan; triethylolamine; trihydroxytriethylamine; tris 
(hydroxyethyl)amine. 
3 Chemical Names and CAS Registry Number 
2,20,200-Nitrilotriethanol [102-71-6] 
4 Empirical Formula and Molecular Weight 
C6H15NO3 149.19 
5 Structural Formula 
6 Functional Category 
Alkalizing agent; emulsifying agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Triethanolamine is widely used in topical pharmaceutical 
formulations primarily in the formation of emulsions. 
When mixed in equimolar proportions with a fatty acid, 
such as stearic acid or oleic acid, triethanolamine forms an 
anionic soap with a pH of about 8, which may be used as an 
emulsifying agent to produce fine-grained, stable oil-in-water 
emulsions. Concentrations that are typically used for emulsification 
are 2–4% v/v of triethanolamine and 2–5 times that of 
fatty acids. In the case of mineral oils, 5% v/v of triethanolamine 
will be needed, with an appropriate increase in the 
amount of fatty acid used. Preparations that contain triethanolamine 
soaps tend to darken on storage. However, discoloration 
may be reduced by avoiding exposure to light and contact 
with metals and metal ions. 
Triethanolamine is also used in salt formation for injectable 
solutions and in topical analgesic preparations. It is also used in 
sun-screen preparations.(1) 
Triethanolamine is used as an intermediate in the manufacturing 
of surfactants, textile specialties, waxes, polishes, 
herbicides, petroleum demulsifiers, toilet goods, cement additives, 
and cutting oils. Triethanolamine is also claimed to be 
used for the production of lubricants for the rubber gloves and 
textile industries. Other general uses are as buffers, solvents, 
and polymer plasticizers, and as a humectant. 
See also Section 18. 
8 Description 
Triethanolamine is a clear, colorless to pale yellow-colored 
viscous liquid having a slight ammoniacal odor. It is a mixture 
of bases, mainly 2,20,200-nitrilotriethanol although it also 
contains 2,20-iminobisethanol (diethanolamine) and smaller 
amounts of 2-aminoethanol (monoethanolamine). 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for triethanolamine. 
Test PhEur 2005 USPNF 23 
Characters . — 
Identification . . 
Appearance of solution . — 
Related substances . — 
Heavy metals 410 ppm — 
Water 41.0% 40.5% 
Sulfated ash 40.1% 40.05% 
Impurities . — 
Organic volatile impurities — . 
Specific gravity — 1.120–1.128 
Refractive index — 1.481–1.486 
Assay 99.0–103.0% 99.0–107.4% 
10 Typical Properties 
Acidity/alkalinity: pH = 10.5 (0.1N solution) 
Boiling point: 3358C 
Flash point: 2088C 
Freezing point: 21.68C 
Hygroscopicity: very hygroscopic. 
Melting point: 20–218C 
Moisture content: 0.09% 
Solubility: see Table II. 
Table II: Solubility of triethanolamine. 
Solvent Solubility at 208C 
Acetone Miscible 
Benzene 1 in 24 
Carbon tetrachloride Miscible 
Ethyl ether 1 in 63 
Methanol Miscible 
Water Miscible 
Surface tension: 48.9mN/m (48.9 dynes/cm) at 258C 
Viscosity (dynamic): 590 mPa s (590 cP) at 308C

11 Stability and Storage Conditions 
Triethanolamine may turn brown on exposure to air and light. 
The 85% grade of triethanolamine tends to stratify below 
158C; homegeneity can be restored by warming and mixing 
before use. 
Triethanolamine should be stored in an airtight container 
protected from light, in a cool, dry place. 
See Monoethanolamine for further information. 
12 Incompatibilities 
Triethanolamine is a tertiary amine that contains hydroxy 
groups; it is capable of undergoing reactions typical of tertiary 
amines and alcohols. Triethanolamine will react with mineral 
acids to form crystalline salts and esters. With the higher fatty 
acids, triethanolamine forms salts that are soluble in water and 
have characteristics of soaps. Triethanolamine will also react 
with copper to form complex salts. Discoloration and 
precipitation can take place in the presence of heavy metal salts. 
Triethanolamine can react with reagents such as thionyl 
chloride to replace the hydroxy groups with halogens. The 
products of these reactions are very toxic, resembling other 
nitrogen mustards. 
13 Method of Manufacture 
Triethanolamine is prepared commercially by the ammonolysis 
of ethylene oxide. The reaction yields a mixture of monoethanolamine, 
diethanolamine, and triethanolamine, which are 
separated to obtain the pure products. 
14 Safety 
Triethanolamine is used primarily as an emulsifying agent in a 
variety of topical pharmaceutical preparations. Although 
generally regarded as a nontoxic material,(2) triethanolamine 
may cause hypersensitivity or be irritant to the skin when 
present in formulated products. The lethal human oral dose of 
triethanolamine is estimated to be 5–15 g/kg body-weight. 
Following concern about the possible production of 
nitrosamines in the stomach, the Swiss authorities have 
restricted the use of triethanolamine to preparations intended 
for external use.(3) 
LD50 (guinea pig, oral): 5.3 g/kg(4) 
LD50 (mouse, IP): 1.45 g/kg 
LD50 (mouse, oral): 7.4 g/kg 
LD50 (rat, oral): 8 g/kg 
15 Handling Precautions 
Triethanolamine may be irritant to the skin, eyes, and mucous 
membranes. Inhalation of vapor may be harmful. Protective 
clothing, gloves, eye protection, and a respirator are recommended. 
Ideally, triethanolamine should be handled in a fume 
cupboard. On heating, triethanolamine forms highly toxic 
nitrous fumes. Triethanolamine is combustible. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (rectal, topical, 
and vaginal preparations). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Diethanolamine; monoethanolamine. 
18 Comments 
Various grades of triethanolamine are available. The standard 
commercial grade contains 85% triethanolamine. The superior 
grade contains 98–99% triethanolamine. 
One volume part of triethanolamine with 5–7 parts of a 
mixture of CaO2 and ZnO2 is used as a filling material that 
enhances the restorative process in periodontal tissues. 
Triethanolamine is recommended as the preferred stabilizer to 
be used in latex polymerization because of its weak mutagenic 
effect in the Ames tests. 
The EINECS number for triethanolamine is 203-049-8. 
19 Specific References 
1 Turkoglu M, Yener S. Design and in vivo evaluation of ultrafine 
inorganic-oxide-containing-sunscreen formulations. Int J Cosmet 
Sci 1997; 19(4): 193–201. 
2 Maekawa A, Onodera H, Tanigawa H, et al. Lack of carcinogenicity 
of triethanolamine in F344 rats. J Toxicol Environ Health 
1986; 19(3): 345–357. 
3 Anonymous. Trolamine: concerns regarding potential carcinogenicity. 
WHO Drug Inf 1991; 5: 9. 
4 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3568. 
20 General References 
Friberg SE, Wohn CS, Lockwood FE. The influence of solvent on 
nonaqueous lyotropic liquid crystalline phase formed by triethanolamine 
oleate. J Pharm Sci 1985; 74(7): 771–773. 
Ramsay B, Lawrence CM, Bruce JM, Shuster S. The effect of 
triethanolamine application on anthralin-induced inflammation 
and therapeutic effect in psoriasis. J Am Acad Dermatol 1990; 23: 
73–76. 
Yano H, Noda A, Hukuhara T, Miyazawa K. Generation of maillardtype 
compounds from triethanolamine alone. J Am Oil Chem Soc 
1997; 74(7): 891–893. 
21 Authors 
SR Goskonda, JC Lee. 
22 Date of Revision 
13 April 2005. 
Triethanolamine 795

Triethyl Citrate 
1 Nonproprietary Names 
BP: Triethyl citrate 
PhEur: Triethylis citras 
USPNF: Triethyl citrate 
2 Synonyms 
Citric acid, ethyl ester; Citroflex 2; Citrofol AI; E1505; 
Hydagen CAT; TEC. 
3 Chemical Name and CAS Registry Number 
2-Hydroxy-1,2,3-propanetricarboxylic acid, triethyl ester [77- 
93-0] 
4 Empirical Formula and Molecular Weight 
C12H20O7 276.29 
5 Structural Formula 
6 Functional Category 
Plasticizer. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Triethyl citrate and the related esters acetyltriethyl citrate, 
tributyl citrate, and acetyltributyl are used to plasticize 
polymers in formulated pharmaceutical coatings.(1–5) The 
coating applications include capsules, tablets, beads, and 
granules for taste masking, immediate release, sustainedrelease, 
and enteric formulations. 
Triethyl citrate is also used as a direct food additive for 
flavoring, for solvency, and as a surface active agent. 
8 Description 
Triethyl citrate is a clear, odorless, practically colorless, oily 
liquid. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for triethyl citrate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Appearance . — 
Specific gravity — 1.135–1.139 
Refractive index 1.440–1.446 1.439–1.441 
Acidity . . 
Related substances . — 
Sulfated ash 40.1% — 
Heavy metals 45 ppm 40.001% 
Water 40.25% 40.25% 
Assay (anhydrous basis) 98.5–101.0% 99.0–100.5% 
10 Typical Properties 
Acid value: 0.02 
Boiling point: 2888C (decomposes) 
Flash point: 1558C 
Pour point: 458C 
Solubility: soluble 1 in 125 of peanut oil, 1 in 15 of water. 
Miscible with ethanol (95%), acetone, and propan-2-ol. 
Viscosity (dynamic): 35.2 mPa s (35.2 cP) at 258C 
11 Stability and Storage Conditions 
Triethyl citrate should be stored in a closed container in a cool, 
dry location. When stored in accordance with these conditions, 
triethyl citrate is a stable product. 
12 Incompatibilities 
Triethyl citrate is incompatible with strong alkalis and 
oxidizing materials. 
13 Method of Manufacture 
Triethyl citrate is prepared by the esterification of citric acid and 
ethanol in the presence of a catalyst. 
14 Safety 
Triethyl citrate is used in oral pharmaceutical formulations and 
as a direct food additive. It is generally regarded as a nontoxic 
and nonirritant material. However, ingestion of large quantities 
may be harmful. 
LD50 (mouse, IP): 1.75 g/kg(6) 
LD50 (rat, IP): 4 g/kg 
LD50 (rat, oral): 5.9 g/kg 
LD50 (rat, SC): 6.6 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Triethyl citrate is irritating to 
the eyes and may irritate the skin. Irritating to the respiratory

system as a mist or at elevated temperatures. Gloves, eye 
protection, and a respirator are recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral capsules 
and tablets). Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Acetyltributyl citrate; acetyltriethyl citrate; tributyl citrate. 
18 Comments 
A specification for triethyl citrate is contained in the Food 
Chemicals Codex (FCC). The EINECS number for triethyl 
citrate is 201-070-7. 
19 Specific References 
1 Gutierrez-Rocca JC, McGinity JW. Influence of water soluble and 
insoluble plasticizers on the physical and mechanical properties of 
acrylic resin copolymers. Int J Pharm 1994; 103: 293–301. 
2 Lehmann K. Chemistry and application properties of polymethacrylate 
coating systems. In: McGinity JW, ed. Aqueous Polymeric 
Coatings for Pharmaceutical Dosage Forms. New York: Marcel 
Dekker, 1989: 153–245. 
3 Steurnagel CR. Latex emulsions for controlled drug delivery. In: 
McGinity JW, ed. Aqueous Polymeric Coatings for Pharmaceutical 
Dosage Forms. New York: Marcel Dekker, 1989: 1–61. 
4 Gutierrez-Rocca JC, McGinity JW. Influence of aging on the 
physical–mechanical properties of acrylic resin films cast from 
aqueous dispersions and organic solutions. Drug Dev Ind Pharm 
1993; 19(3): 315–332. 
5 Liu J, Williams R. Properties of heat-humidity cured cellulose 
acetate phthalate free films. Eur J Pharm Sci 2002; 17(1–2): 31–41. 
6 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3546. 
20 General References 
—
21 Authors 
SW Kennedy. 
22 Date of Revision 
13 August 2005. 
Triethyl Citrate 797

Vanillin 
1 Nonproprietary Names 
BP: Vanillin 
PhEur: Vanillinum 
USPNF: Vanillin 
2 Synonyms 
4-Hydroxy-m-anisaldehyde; p-hydroxy-m-methoxybenzaldehyde; 
3-methoxy-4-hydroxybenzaldehyde; methylprotocatechuic 
aldehyde; Rhovanil; vanillic aldehyde. 
3 Chemical Name and CAS Registry Number 
4-Hydroxy-3-methoxybenzaldehyde [121-33-5] 
4 Empirical Formula and Molecular Weight 
C8H8O3 152.15 
5 Structural Formula 
6 Functional Category 
Flavoring agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Vanillin is widely used as a flavor in pharmaceuticals, foods, 
beverages, and confectionery products, to which it imparts a 
characteristic taste and odor of natural vanilla. It is also used in 
perfumes, as an analytical reagent and as an intermediate in the 
synthesis of a number of pharmaceuticals, particularly methyldopa. 
Additionally, it has been investigated as a potential 
therapeutic agent in sickle cell anemia(1) and is claimed to have 
some antifungal properties.(2) 
In food applications, vanillin has been investigated as a 
preservative.(3,4) 
As a pharmaceutical excipient, vanillin is used in tablets, 
solutions (0.01–0.02% w/v), syrups, and powders to mask the 
unpleasant taste and odor characteristics of certain formulations, 
such as caffeine tablets and polythiazide tablets. It is 
similarly used in film coatings to mask the taste and odor of 
vitamin tablets. 
Vanillin has also been investigated as a photostabilizer in 
furosemide 1% w/v injection, haloperidol 0.5% w/v injection, 
and thiothixene 0.2% w/v injection.(5) 
8 Description 
White or cream, crystalline needles or powder with characteristic 
vanilla odor and sweet taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for vanillin. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
Appearance of solution . — 
Melting range 81–848C 81–838C 
Loss on drying 41.0% 41.0% 
Sulfated ash 40.05% — 
Residue on ignition — 40.05% 
Related substances . — 
Reaction with sulfuric acid . — 
Organic volatile impurities — . 
Assay (dried basis) 99.0–101.0% 97.0–103.0% 
10 Typical Properties 
Acidity/alkalinity: aqueous solutions are acid to litmus. 
Boiling point: 284–2858C (with decomposition) 
Density (bulk): 0.6 g/cm3 
Flash point: 1538C (closed cup) 
Melting point: 81–838C 
Solubility: see Table II. 
Specific gravity: 1.056 (liquid) 
Table II: Solubility of vanillin. 
Solvent Solubility at 208C 
unless otherwise stated 
Acetone Soluble 
Alkali hydroxide solutions Soluble 
Chloroform Soluble 
Ethanol (95%) 1 in 2 
Ethanol (70%) 1 in 3 
Ether Soluble 
Glycerin 1 in 20 
Methanol Soluble 
Oils Soluble 
Water 1 in 100 
1 in 16 at 808C

11 Stability and Storage Conditions 
Vanillin oxidizes slowly in moist air and is affected by light. 
Solutions of vanillin in ethanol decompose rapidly in light to 
give a yellow-colored, slightly bitter tasting solution of 6,60- 
dihydroxy-5,50-dimethoxy-1,10-biphenyl-3,30-dicarbaldehyde. 
Alkaline solutions also decompose rapidly to give a browncolored 
solution. However, solutions stable for several months 
may be produced by adding sodium metabisulfite 0.2% w/v as 
an antioxidant.(6) 
The bulk material should be stored in a well-closed 
container, protected from light, in a cool, dry place. 
12 Incompatibilities 
Incompatible with acetone, forming a brightly colored compound.(
7) A compound practically insoluble in ethanol is 
formed with glycerin. 
13 Method of Manufacture 
Vanillin occurs naturally in many essential oils and particularly 
in the pods of Vanilla planifolia and Vanilla tahitensis. 
Industrially, vanillin is prepared from lignin, which is obtained 
from the sulfite wastes produced during paper manufacture. 
Lignin is treated with alkali at elevated temperature and 
pressure, in the presence of a catalyst, to form a complex 
mixture of products from which vanillin is isolated. Vanillin is 
then purified by successive recrystallizations. 
Vanillin may also be prepared synthetically by condensation, 
in weak alkali, of a slight excess of guaiacol with glyoxylic 
acid at room temperature. The resultant alkaline solution, 
containing 4-hydroxy-3-methoxymandelic acid is oxidized in 
air, in the presence of a catalyst, and vanillin is obtained by 
acidification and simultaneous decarboxylation. Vanillin is 
then purified by successive recrystallizations. 
14 Safety 
There have been few reports of adverse reactions to vanillin, 
although it has been speculated that cross-sensitization with 
other structurally similar molecules, such as benzoic acid, may 
occur.(8) Adverse reactions that have been reported include 
contact dermatitis(9) and bronchospasm caused by hypersensitivity.(
10) 
The WHO has allocated an estimated acceptable daily 
intake for vanillin of up to 10 mg/kg body-weight.(11) 
LD50 (guinea pig, IP): 1.19 g/kg(12) 
LD50 (guinea pig, oral): 1.4 g/kg 
LD50 (mouse, IP): 0.48 g/kg 
LD50 (rat, IP): 1.16 g/kg 
LD50 (rat, oral): 1.58 g/kg 
LD50 (rat, SC): 1.5 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the quantity of 
material handled. Eye protection is recommended. Heavy 
airborne concentrations of dust may present an explosion 
hazard. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(oral solutions, suspensions, syrups, and tablets). Included in 
nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Ethyl vanillin. 
18 Comments 
One part of synthetic vanillin is equivalent to 400 parts of 
vanilla pods. The EINECS number for vanillin is 204-465-2. 
19 Specific References 
1 Abraham DJ, Mehanna AS, Wireko FC, et al. Vanillin, a potential 
agent for the treatment of sickle cell anemia. Blood 1991; 77: 
1334–1341. 
2 Lisa. M, Leifertova. I, Baloun J. A contribution to the antifungal 
effect of propolis [in German]. Folia Pharm 1989; 13(1): 29–44. 
3 Fitzgerald DJ, Stratford M, Narbad A. Analysis of the inhibition of 
food spoilage yeasts by vanillin. Int J Food Microbiol 2003; 
86(1–2): 113–122. 
4 Fitzgerald DJ, Stratford M, Gasson MJ, Narbad A. The potential 
application of vanillin in preventing yeast spoilage of soft drinks 
and fruit juices. J Food Prot 2004; 67(2): 391–395. 
5 Thoma K, Klimek R. Photostabilization of drugs in dosage forms 
without protection from packaging materials. Int J Pharm 1991; 
67: 169–175. 
6 Jethwa SA, Stanford JB, Sugden JK. Light stability of vanillin 
solutions in ethanol. Drug Dev Ind Pharm 1979; 5: 79–85. 
7 Thakur AB, Dayal S. Schiff base formation with nitrogen of a 
sulfonamido group. J Pharm Sci 1982; 71: 1422. 
8 Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation 
Agents: A Handbook of Excipients. New York: Marcel Dekker, 
1989: 238–239. 
9 Wang X-S, Xue Y-S, Jiang Y, et al. Occupational contact dermatitis 
in manufacture of vanillin. Chin Med J 1987; 100: 250–254. 
10 Van Assendelft AHW. Bronchospasm induced by vanillin and 
lactose. Eur J Respir Dis 1984; 65: 468–472. 
11 FAO/WHO. Specifications for the identity and purity of food 
additives and their toxicological evaluation: some flavouring 
substances and non-nutritive sweetening agents. Eleventh report 
of the joint FAO/WHO expert committee on food additives.World 
Health Organ Tech Rep Ser 1968; No. 383. 
12 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3661–3662. 
20 General References 
Clark GS. Vanillin. Perfum Flavor 1990; 15(Mar/Apr): 45–54. 
Rhodia Inc. Technical literature: Rhovanil. 2001. 
Rees DI. Determination of vanillin and ehtyl vanillin in food products. 
Chem Ind 1965; 1: 16–17. 
21 Authors 
PJ Weller. 
22 Date of Revision 
18 August 2005. 
Vanillin 799

Vegetable Oil, Hydrogenated 
1 Nonproprietary Names 
BP: Hydrogenated vegetable oil 
JP: Hydrogenated oil 
USPNF: Hydrogenated vegetable oil 
See also Sections 8,9, and 17. 
2 Synonyms 
Some trade names for materials derived from stated vegetable 
oils are shown below: 
Hydrogenated cottonseed oil: Akofine; Lubritab; Sterotex. 
Hydrogenated palm oil: Softisan 154. 
Hydrogenated soybean oil: Lipovol HS-K; Sterotex HM. 
3 Chemical Name and CAS Registry Number 
Hydrogenated vegetable oil [68334-00-9] 
Hydrogenated soybean oil [8016-70-4] 
4 Empirical Formula and Molecular Weight 
The USPNF 23 defines two types of hydrogenated vegetable oil, 
type I and type II, which differ in their physical properties and 
applications; see Sections 9 and 17. 
5 Structural Formula 
R1COOCH2—CH(OOCR2)—CH2OOCR3 
where R1, R2, and R3 are mainly C15 and C17. 
6 Functional Category 
Tablet and capsule lubricant; tablet binder. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Hydrogenated vegetable oil type I is used as a lubricant in tablet 
and capsule formulations.(1,2) It is used at concentrations of 
1–6% w/w, usually in combination with talc. It may also be 
used as an auxiliary binder in tablet formulations. 
Hydrogenated vegetable oil type I is additionally used as the 
matrix-forming material in lipophilic-based controlled-release 
formulations;(3–6) it may also be used as a coating aid in 
controlled-release formulations. 
Other uses of hydrogenated vegetable oil type I include use 
as a viscosity modifier in the preparation of oil-based liquid and 
semisolid formulations; in the preparation of suppositories, to 
reduce the sedimentation of suspended components and to 
improve the solidification process; and in the formulation of 
liquid and semisolid fills for hard gelatin capsules.(7) 
Fully hydrogenated vegetable oil products may also be used 
as alternatives to hard waxes in cosmetics and topical 
pharmaceutical formulations. 
See also Section 17. 
8 Description 
Hydrogenated vegetable oil is a mixture of triglycerides of fatty 
acids. The two types that are defined in the USPNF 23 are 
characterized by their physical properties; see Section 9. 
Hydrogenated vegetable oil type I occurs in various forms, 
e.g. fine powder, flakes, or pellets. The color of the material 
depends on the manufacturing process and the form. In general, 
the material is white to yellowish-white with the powder grades 
appearing more white-colored than the coarser grades. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for hydrogenated vegetable 
oil. 
Test BP 2004 JP 2001 USPNF 23 
Type I Type II 
Identification . — — — 
Characters . . — — 
Melting range 57–708C — 57–858C 20–508C 
Heavy metals 410 ppm . 40.001% 40.001% 
Moisture and 
coloration 
— . — — 
Alkali — . — — 
Chloride — . — — 
Nickel — . — — 
Iodine value 45 — 0–5 55–80 
Saponification value 175–205 — 175–200 175–200 
Loss on drying 40.1% — 40.1% 40.1% 
Acid value 44.0 42.0 44.0 44.0 
Unsaponifiable 
matter 
40.8% — 40.8% 40.8% 
Residue on ignition — 40.1% — — 
Organic volatile 
impurities 
— — . . 
10 Typical Properties 
Density (tapped): 0.57 g/cm3 for Lubritab 
Melting point: 61–668C for Lubritab 
Particle size distribution: 85% < 177 mm, 25% < 74 mm in size 
for Lubritab. Average particle size is 104 mm. 
Solubility: soluble in chloroform, petroleum spirit, and hot 
propan-2-ol; practically insoluble in water. 
11 Stability and Storage Conditions 
Hydrogenated vegetable oil type I is a stable material; typically 
it is assigned a 2-year shelf-life. 
The bulk material should be stored in a well-closed 
container in a cool, dry place.

12 Incompatibilities 
Incompatible with strong oxidizing agents. 
13 Method of Manufacture 
Hydrogenated vegetable oil type I is prepared from refined 
vegetable oils, which are hydrogenated using a catalyst. 
14 Safety 
Hydrogenated vegetable oil type I is used in food products and 
oral pharmaceutical formulations and is generally regarded as a 
nontoxic and nonirritant excipient. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Gloves, eye protection, and a 
dust mask are recommended when handling fine powder 
grades. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(oral capsules and tablets; rectal and vaginal suppositories and 
topical preparations). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Castor oil, hydrogenated; hydrogenated vegetable oil, type II; 
medium-chain triglycerides; suppository bases. 
Hydrogenated vegetable oil, type II 
Comments: hydrogenated vegetable oil type II includes partially 
hydrogenated vegetable oils from different sources that have 
a wide range of applications. In general, type II materials 
have lower melting ranges and higher iodine values than 
type I materials. Many type II materials are prepared to meet 
specific customer requirements for use in cosmetics. Type II 
materials may also be used in the manufacture of 
suppositories. See also Section 9. 
18 Comments 
Products from different manufacturers may vary owing to 
differences in the source of the vegetable oil used for 
hydrogenation. Certain materials are made from mixed 
hydrogenated oils, e.g. hydrogenated soybean oil and hydrogenated 
castor oil (Sterotex K). 
19 Specific References 
1 Ho. lzer AW, Sjo. gren J. Evaluation of some lubricants by the 
comparison of friction coefficients and tablet properties. Acta 
Pharm Suec 1981; 18: 139–148. 
2 Staniforth JN. Use of hydrogenated vegetable oil as a tablet 
lubricant. Drug Dev Ind Pharm 1987; 13: 1141–1158. 
3 Lockwood PJ, Baichwal AR, Staniforth JN. Influence of drug type 
and formulation variables on mechanisms of release from wax 
matrices. Proc Int Symp Control Release Bioact Mater 1987; 14: 
198–199. 
4 Wang PY. Lipids as excipients in sustained release insulin implants. 
Int J Pharm 1989; 54: 223–230. 
5 C. iftc.i K, C. apan Y, O.
ztu. rk O, Hincal AA. Formulation and in 
vitro–in vivo evaluation of sustained release lithium carbonate 
tablets. Pharm Res 1990; 7: 359–363. 
6 Watanbe Y, Kogoshi T, Amagai Y, Matsumoto M. Preparation and 
evaluation of enteric granules of aspirin prepared by acylglycerols. 
Int J Pharm 1990; 64: 147–154. 
7 Du. rr M, Fribolin HU, Gneuss KD. Dosing of liquids into liquid 
gelatin capsules at the production scale: development of compositions 
and procedures [in German]. Acta Pharm Technol 1983; 
29(3): 245–251. 
20 General References 
Banker GS, Peck GE, Baley G. Tablet formulation and design. In: 
Lieberman HA, Lachman L, eds. Pharmaceutical Dosage Forms: 
Tablets I. New York: Marcel Dekker, 1989. 
Bardon J, Se.bert P, Chaumat C, et al. Temperature elevation undergone 
by mixtures of powders or granules during their transformation into 
tablets II: influence of nature and rate of lubricant [in French]. STP 
Pharma 1985; 1: 948–955. 
Miller TA, York P. Pharmaceutical tablet lubrication. Int J Pharm 1988; 
41: 1–19. 
Staniforth JN, Cryer S, Ahmed HA, Davies SP. Aspects of pharmaceutical 
tribology. Drug Dev Ind Pharm 1989; 15: 2265–2294. 
21 Authors 
RC Moreton. 
22 Date of Revision 
26 August 2005.
Vegetable Oil, Hydrogenated 801

Water 
1 Nonproprietary Names 
BP: Purified water 
JP: Purified water 
PhEur: Aqua purificata 
USP: Purified water 
See also Sections 8 and 17. 
2 Synonyms 
Aqua; hydrogen oxide. 
3 Chemical Name and CAS Registry Number 
Water [7732-18-5] 
4 Empirical Formula and Molecular Weight 
H2O 18.02 
5 Structural Formula 
H2O 
6 Functional Category 
Solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Water is the most widely used excipient in pharmaceutical 
production operations. Specific grades of water are used for 
particular applications in concentrations up to 100%; see Table 
I. Purified water and water for injection are also used for 
cleaning operations during production of pharmaceutical 
products. 
8 Description 
The term ‘water’ is used to describe potable water that is freshly 
drawn direct from the public supply and is suitable for 
drinking. The chemical composition of potable water is 
variable and the nature and concentrations of the impurities 
in it depend upon the source from which it is drawn. Although 
potable water must be both palatable and safe to drink, for 
most pharmaceutical applications potable water is purified by 
distillation, ion exchange treatment, reverse osmosis, or some 
other suitable process to produce ‘purified water’. For certain 
applications, water with pharmacopeial specifications differing 
from those of purified water should be used, e.g. water for 
injection; see Sections 9 and 18. 
Water is a clear, colorless, odorless, and tasteless liquid. 
Table I: Typical applications of specific grades of water. 
Type Use 
Bacteriostatic water for 
injection 
Diluent for ophthalmic and multiple-dose 
injections. 
Potable water Public supply suitable for drinking, the purity 
of which is unlikely to be suitable for use in 
the manufacture of pharmaceuticals. 
Purified water Vehicle and solvent for the manufacture of 
drug products and pharmaceutical 
preparations; not suitable for use in the 
manufacture of parenteral products. 
Sterile water for 
inhalation 
Diluent for inhalation therapy products. 
Sterile water for 
injection 
Diluent for injections. 
Sterile water for 
irrigation 
Diluent for internal irrigation therapy products. 
Water for injections in 
bulk 
Water for the bulk preparation of medicines 
for parenteral administration. 
9 Pharmacopeial Specifications 
See Table II. 
10 Typical Properties 
Boiling point: 1008C 
Critical pressure: 22.1MPa (218.3 atm) 
Critical temperature: 374.28C 
Dielectric constant: D25 = 78.54 
Dipole moment: 
1.76 in benzene at 258C; 
1.86 in dioxane at 258C. 
Ionization constant: 1.008  1014 at 258C. 
Latent heat of fusion: 6 kJ/mol (1.436 kcal/mol) 
Latent heat of vaporization: 40.7 kJ/mol (9.717 kcal/mol) 
Melting point: 08C 
Refractive index: nD
20 = 1.3330 
Solubility: miscible with most polar solvents. 
Specific gravity: 0.9971 at 258C. 
Specific heat (liquid): 4.184 J/g/8C (1.00 cal/g/8C) at 148C. 
Surface tension: 71.97 mN/m (71.97 dynes/cm) at 258C. 
Vapor pressure: 3.17 kPa (23.76 mmHg) at 258C. 
Viscosity (dynamic): 0.89 mPa s (0.89 cP) at 258C. 
11 Stability and Storage Conditions 
Water is chemically stable in all physical states (ice, liquid, and 
vapor). Water for specific purposes should be stored in 
appropriate containers; see Table III.

Table II: Pharmacopeial specifications of water for different pharmaceutical applications. 
Test Water 
JP 2001 
Purified 
water 
JP 2001 
Purified 
water in 
bulk 
PhEur 2005 
Purified 
water in 
containers 
PhEur 2005 
Purified 
water 
USP 28 
Water, 
highly 
purified 
PhEur 2005 
Sterile 
water for 
injection 
USP 28 
Bacteriostatic 
water for 
injection 
USP 28 
Suppl. 1 
Sterile 
water for 
inhalation 
USP 28 
Suppl. 1 
Sterile 
water for 
irrigation 
USP 28 
Sterile 
purified 
water 
USP 28 
Suppl. 1 
Water for 
injection(a) 
JP 2001 
Water 
for 
injection 
USP 28 
Water for 
injection 
(in bulk) 
PhEur 
2005 
Sterile 
water for 
injection 
PhEur 2005 
Sterile 
purified 
water 
JP 2001 
Identification — — — — — — — — — — — — — — . — 
Production — — . — — . — — — — — — — . — — 
Characters . . . . — . — — — — — — — . — . Appearance of 
solution . . — — — — — — — — — — — — — . 
Odor and taste . . — — — — — — — — — — — — — . pH 5.8–8.6 — — — — — 5.0–7.0 4.5–7.0 4.5–7.5 5.0–7.0 5.0–7.0 — 5.0–7.0 — — — 
Acid or alkali — . — . — — — — — — — . — — . . Cadmium 40.01 mg/L — — — — — — — — — — — — — — — 
Chloride 4200 mg/L . — . — — . — . . . . . — . . Cyanide 40.01 mg/L — — — — — — — — — — — — — — — 
Copper 41 mg/L — — — — — — — — — — — — — — — 
Sulfate — . — . — — . . . . . . . — . . Ammonium 40.05 mg/L 40.05 mg/L — 40.2 ppm — — . — . . . . . — 40.2 ppm 40.05 mg/L 
Iron 40.3 ppm — — — — — — — — — — — — — — — 
Calcium — — — . — — . . . . . — . — . — 
Lead 40.1 mg/L — — — — — — — — — — — — — — — 
Magnesium — — — . — — — — — — — — — — . — 
Aluminum — — 410 ppb — — 410 ppb — — — — — — — 410 ppb — — 
Nitrate — — 40.2 ppm — — 40.2 ppm — — — — — . — 40.2 ppm 40.2 ppm . Nitrogen from 
nitrate 
410 mg/L . — — — — — — — — — — — — — — 
Nitrogen from 
nitrite . . — — — — — — — — — — — — — — 
Carbon dioxide — — — — — — . . . . . — . — — — 
Heavy metals 41 mg/L . 40.1 ppm . — 40.1 ppm — — — — — . — 40.1 ppm . . Oxidizable 
substances 
— — — . — — . — . . . — . — . — 
Potassium 
permanganatereducing 
substances 
410 mg/L . — — — — — — — — — — — — — — 
Residue on 
evaporation 
4500 mg/L 41.0mg — 40.001% — — — — — — — . — — . 41.0mg 
Total organic 
carbon 
— — — — . 40.5 mg/L — — — — — .(b) . 40.5 mg/L . — 
Total hardness 4300 mg/L — — — — — — — — — — — — — — — 
Conductivity — — . — . . — — — — — — . . 425 mS/cm 
for containers 
410 ml, 
45 mS/cm 
for containers 
510 ml 
— 
Anionic surfactants 40.5 mg/L — — — — — — — — — — — — — — — 
Antimicrobial 
agents 
— — — — — — — . — — — — — — — — 
Sterility — — — — — — . . . . . . . — . . Particulate matter — — — — — — . . — — — — — — . — 
Microbial 
contamination . — — 4102/mL — — — — — — — — — — — — 
Bacterial 
endotoxins 
— — 40.25 IU/mL 40.25 IU/mL — 40.25 IU/mL 40.25 EU/mL <0.5 EU/mL <0.5 EU/mL 40.25 EU/mL — 40.25 EU/mL 40.25 EU/mL 40.25 IU/mL <0.25 IU/mL — 
(a) For water for injection preserved in containers and sterilized, the JP 2001 provides separate tests for acid or alkali, chloride, ammonium, and residue on evaporation within the monograph. 
(b) For water for injection prepared by reverse osmosis–ultrafiltration. 
Water 803

Table III: Storage requirements for different grades of water. 
Type Storage requirements(a) 
Bacteriostatic water 
for injection 
Preserve in single-dose and multiple-dose 
containers, preferably of Type I or Type II 
glass, not larger than 30 mL in size. 
Potable water Preserve in tightly sealed containers. 
Purified water Preserve in tightly sealed containers. If it is 
stored in bulk, the conditions of storage 
should be designed to limit the growth of 
microorganisms and avoid any other 
contamination. 
Sterile water for 
inhalation 
Preserve in single-dose containers, preferably 
of Type I or Type II glass. 
Sterile water for 
injection 
Preserve in single-dose containers, preferably 
of Type I or Type II glass, not more than 
1000 mL in size. 
Water for injection Preserve in tightly sealed containers. 
Water for injections 
in bulk 
Collect and store in conditions designed to 
prevent growth of microorganisms and 
avoid any other contamination. 
(a) To prevent evaporation and to maintain quality. 
12 Incompatibilities 
In pharmaceutical formulations, water can react with drugs and 
other excipients that are susceptible to hydrolysis (decomposition 
in the presence of water or moisture) at ambient and 
elevated temperatures. 
Water can react violently with alkali metals and rapidly with 
alkaline metals and their oxides, such as calcium oxide and 
magnesium oxide. Water also reacts with anhydrous salts to 
form hydrates of various compositions, and with certain 
organic materials and calcium carbide. 
13 Method of Manufacture 
Unlike other excipients, water is not purchased from outside 
suppliers but is manufactured in-house by pharmaceutical 
companies. The selection of the most appropriate system and 
the overall design of the system are crucial factors to ensure that 
water of the correct quality is produced.(1,2) 
To produce potable or drinking water, insoluble matter is 
first removed from a water supply by coagulation, settling, and 
filtering processes. Pathogenic microorganisms present are then 
destroyed by aeration, chlorination, or some other means. 
Water may also be rendered free of viable pathogenic 
microorganisms by active boiling for 15–20 minutes. Finally, 
the palatability of the water is improved by aeration and 
charcoal filtration. 
The quality attributes of water for injection (WFI) are 
stricter than for purified water. Consequently, the preparation 
methods typically vary in the last stage to ensure good control 
of quality of WFI. Methods for the production of WFI are the 
subject of current debate. The PhEur 2005 indicates that only 
distillation would give assurance of consistent supply of the 
appropriate quality. However, the PhEur 2005 permits distillation, 
ion exchange, reverse osmosis, or any other suitable 
method that complies with regulations on water intended for 
human consumption laid down by the competent authority. 
The USP 28 and the JP 2001 permit the use of reverse 
osmosis (RO) in addition to distillation and ultrafiltration. 
Purified water suitable for use in pharmaceutical formulations 
is usually prepared by purifying potable water by one of several 
processes, such as distillation; deionization; or reverse osmosis.(
1,3–8) 
Distillation A wide variety of stills are available to produce 
purified or distilled water. A typical design consists of an evaporator, 
vapor separator, and compressor. The distilland (raw 
feed water) is heated in the evaporator to boiling and the 
vapor produced is separated from entrained distilland in the 
separator. The vapor then enters a compressor where the temperature 
of the vapors is raised to 1078C. Superheated vapors 
are then condensed on the outer surface of the tubes of the 
evaporator containing cool distilland circulating within. 
Vapor compression stills of various sizes are commercially 
available and can be used to produce water of high purity when 
properly constructed. A high-quality distillate, such as water 
for injection, can be obtained if the water is first deionized. The 
best stills are constructed of types 304 or 316 stainless steel and 
coated with pure tin, or are made from chemical-resistant glass. 
De-ionization Cationic and anionic ion exchange resins are 
used to purify potable water by removing any dissolved ions. 
Dissolved gases are also removed, while chlorine, in the concentrations 
generally found in potable water, is destroyed by 
the resin itself. Some organics and colloidal particles are 
removed by adsorption and filtration. Resin beds may, however, 
foster microbial life and produce pyrogenic effluent 
unless adequate precautions are taken to prevent contamination. 
Mixed-bed units produce purer water (lower conductivity) 
than do stills. However, the organic matter content is 
usually higher. Ion exchange units are normally used today to 
treat raw feed water prior to distillation or reverse osmosis 
processing. 
Reverse osmosis Water is forced through a semipermeable 
membrane in the opposite direction to normal osmotic diffusion. 
A very small proportion of inorganic salts passes 
through, but undissolved materials (bacteria and large molecules 
such as viruses, pyrogens, and high-molecular-weight 
organics) are removed. 
Ultrafiltration A permeable membrane is used for mechanical 
separation. Impurities including endotoxins are removed by 
the membrane. 
14 Safety 
Water is the base for many biological life forms, and its safety in 
pharmaceutical formulations is unquestioned provided it meets 
standards of quality for potability(9) and microbial content; see 
Sections 9 and 18. Plain water is considered slightly more toxic 
upon injection into laboratory animals than physiological salt 
solutions such as normal saline or Ringer’s solution. 
Ingestion of excessive quantities of water can lead to water 
intoxication, with disturbances of the electrolyte balance. 
Water for injection should be free from pyrogens. 
LD50 (mouse, IP): 25 g/kg(10) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
804 Water

16 Regulatory Status 
Included in nonparenteral and parenteral medicines licensed in 
the UK and USA. 
17 Related Substances 
Bacteriostatic water for injection; carbon dioxide-free water; 
de-aerated water; hard water; soft water; sterile water for 
inhalation; sterile water for injection; sterile water for irrigation; 
water for injection. 
Bacteriostatic water for injection 
Comments: the USP 28 (Suppl. 1.0) describes bacteriostatic 
water for injection as sterile water for injection that contains 
one or more suitable antimicrobial agents. 
Carbon dioxide-free water 
Comments: purified water that has been boiled vigorously for 5 
minutes and allowed to cool while protecting it from 
absorption of atmospheric carbon dioxide. 
De-aerated water 
Comments: purified water that has been boiled vigorously for 5 
minutes and cooled to reduce the air (oxygen) content. 
Hard water 
Comments: water containing the equivalent of not less than 
120 mg/L and not more than 180 mg/L of calcium carbonate. 
Soft water 
Comments: water containing the equivalent of not more than 
60 mg/L of calcium carbonate. 
Sterile water for inhalation 
Comments: the USP 28 (Suppl. 1.0) describes sterile water for 
inhalation as water purified by distillation or by reverse 
osmosis and rendered sterile. It contains no antimicrobial 
agents or other added substances, except where used in 
humidifiers or other similar devices, and where liable to 
contamination over a period of time. 
Sterile water for injection 
Comments: the USP 28 describes sterile water for injection as 
water for injection sterilized and suitably packaged. It 
contains no antimicrobial agents or other substances. 
Sterile water for irrigation 
Comments: the USP 28 describes sterile water for irrigation as 
water for injection sterilized and suitably packaged. It 
contains no antimicrobial agents or other substances. 
Water for injection 
Comments: the USP 28 describes water for injection as water 
purified by distillation or reverse osmosis. It contains no 
added substances. The PhEur 2005 title is ‘water for 
injections’ and comprises two parts: ‘water for injections 
in bulk’ and ‘sterilized water for injection.’ The PhEur 2005 
states that water for injections is produced by distillation. 
18 Comments 
In most pharmacopeias, the term ‘water’ now refers to purified 
or distilled water. 
Without further purification, ‘water’ may be unsuitable for 
certain pharmaceutical applications; for example, the presence 
of calcium in water affects the viscosity and gel strength of 
algins and pectin dispersions, while the use of potable water 
affects the clarity and quality of cough mixtures, and the 
stability of antibiotic liquid preparations. 
Water commonly contains salts of aluminum, calcium, iron, 
magnesium, potassium, sodium, and zinc. Toxic substances 
such as arsenic, barium, cadmium, chromium, cyanide, lead, 
mercury, and selenium may constitute a danger to health if 
present in excessive amounts. Ingestion of water containing 
high amounts of calcium and nitrate is also contraindicated. 
National standards generally specify the maximum limits for 
these inorganic substances in potable water. Limits have also 
been placed on microorganisms, detergents, phenolics, chlorinated 
phenolics, and other organic substances. The WHO(11) 
and national bodies have issued guidelines for water quality, 
although many countries have their own standards for water 
quality embodied in specific legislation.(12) See Table IV. 
Control of microbiological contamination is critical for 
waters used in preparation of pharmaceuticals as proliferation 
of microorganisms can potentially occur during all stages of 
manufacture, storage, or distribution. Suitable control is 
achieved by ensuring that the water system is well designed 
and well maintained. Purified water that is produced, stored, 
and circulated at ambient temperatures is susceptible to the 
establishment of biofilms; therefore, frequent monitoring, high 
usage, correct flow rate, and appropriate sanitization are all 
factors that require consideration to ensure that water is 
satisfactory.(13) 
Table IV: Limits for inorganic substances in potable water (mg/L). 
Contaminant UK (mg/L) WHO (mg/L) 
Aluminum 0.2 0.2 
Ammonium 0.5 — 
Antimony 0.01 — 
Arsenic 0.05 0.05 
Barium 1.0 No limit 
Beryllium — No limit 
Boron 2.0 — 
Cadmium 0.005 0.005 
Calcium 250 — 
Chloride 400 250 
Chromium 0.05 0.05 
Copper 3.0 1.0 
Cyanide 0.05 0.1 
Fluoride 1.5 1.5 
Iron 0.2 0.3 
Lead 0.05 0.05 
Magnesium 50 — 
Manganese 0.05 0.1 
Mercury 0.001 0.001 
Nickel 0.05 No limit 
Nitrate (as N) — 10 
Nitrate (as NO3) 50 — 
Nitrite (as NO2) 0.1 — 
Phosphorus 2.2 — 
Potassium 12 — 
Selenium 0.01 0.01 
Silver 0.01 No limit 
Sodium 150 200 
Sulfate 250 400 
Zinc 5.0 5.0 
Water 805

Monitoring of the whole system is essential in order to 
demonstrate that correct microbiological quality is achieved. 
For WFI the recommended methodology is membrane filtration 
(0.45 mm) as a large sample size (100–300 mL) is required. For 
purified water, membrane filtration or plate count methods are 
typically used depending on the quality requirements of the 
system. It is important to set appropriate target, alert, and 
action limits to serve as an indication of action required to bring 
the quality of water back under control. It is recognized that 
limits are not intended as pass/fail criteria for water or product 
batches; however, an investigation regarding the implications 
should be conducted.(14) 
Validation is conducted to provide a high level of assurance 
that the water production and distribution system will 
consistently produce water conforming to a defined quality 
specification. The validation process serves to qualify the design 
(DQ), installation (IQ), operation (OQ), and performance (PQ) 
of the system. The extent of monitoring data required should be 
defined, with consideration given to whether validation to FDA 
guidelines is required.(14) It is also important to have an 
ongoing control program with respect to maintenance and 
periodic reviews of the performance of the water system. 
19 Specific References 
1 Thomas WH, Harvey H. Achieving purity in pharmaceutical 
water. Manuf Chem Aerosol News 1976; 47(10): 32, 36, 39, 40. 
2 McWilliam AJ. High purity water distribution systems. Pharm Eng 
1995; Sept/Oct: 54–71. 
3 Honeyman T. Purified water for pharmaceuticals. Manuf Chem 
1987; 58(3): 53, 54, 57, 59. 
4 Cross J. Treating waters for the pharmaceutical industry. Manuf 
Chem 1988; 59(3): 34–35. 
5 Cross J. Steam sterilisable ultrafiltration membranes. Manuf Chem 
1989; 60(3): 25–27. 
6 Horry JM, Cross JR. Purifying water for ophthalmic and injectable 
preparations. Pharm J 1989; 242: 169–171. 
7 Smith VC. Pure water. Manuf Chem 1990; 61(3): 22–24. 
8 Burrows WD, Nelson JH. IV fluidmakers: preparation of sterile 
water for injection in a field setting. J Parenter Sci Technol 1993; 
47(3): 124–129. 
9 Walker A. Drinking water – doubts about quality. Br Med J 1992; 
304: 175–178. 
10 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3692. 
11 World Health Organization. Guidelines for Drinking-water 
Quality, vol. 1: Recommendations. Geneva: WHO, 1984. 
12 Statutory Instrument 1147. The water supply (water quality) 
regulations 1989. London: HMSO, 1989. 
13 Riedewald F. Biofilms in pharmaceutical waters. Pharm Eng 1997; 
Nov/Dec: 8–18. 
14 Food and Drug Administration. Guide to Inspections of High 
Purity Water Systems. Washington, DC: FDA, 1993. 
20 General References 
Santoro M, Maini C. Which water for pharmaceutical use? Eur J 
Parenter Pharm Sci 2003; 8: 15–20. 
Ro. ssler R. Water and air, two important media in the manufacture of 
sterile pharmaceuticals, with regard to the GMP. Drugs Made Ger 
1976; 19: 130–136. 
21 Authors 
LY Galichet. 
22 Date of Revision 
20 August 2005. 
806 Water

Wax, Anionic Emulsifying 
1 Nonproprietary Names 
BP: Emulsifying wax 
2 Synonyms 
Collone HV; Crodex A; Cyclonette Wax; Lanette wax SX BP. 
3 Chemical Name and CAS Registry Number 
Anionic emulsifying wax [8014-38-8] 
4 Empirical Formula and Molecular Weight 
The BP 2004 describes anionic emulsifying wax as containing 
cetostearyl alcohol, purified water, and either sodium lauryl 
sulfate or a sodium salt of a similar sulfated higher primary 
aliphatic alcohol. See also Sections 13 and 18. 
5 Structural Formula 
See Section 4. 
6 Functional Categories 
Emulsifying agent; stiffening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Anionic emulsifying wax is used in cosmetics and topical 
pharmaceutical formulations primarily as an emulsifying agent. 
The wax is added to fatty or paraffin bases to facilitate the 
production of oil-in-water emulsions that are nongreasy. In 
concentrations of about 2%, emulsions are pourable; stiffer 
emulsions, e.g., aqueous cream BP, may contain up to 10% of 
anionic emulsifying wax. 
Creams should be adequately preserved and can usually be 
sterilized by autoclaving. A better-quality emulsion is produced 
by incorporating some alkali into the aqueous phase, although 
care should be taken not to use an excess. 
Anionic emulsifying wax (3–30%) may also be mixed with 
soft and liquid paraffins to prepare anhydrous ointment bases 
such as emulsifying ointment BP. A preparation of 80% anionic 
emulsifying wax in white soft paraffin has been used as a soap 
substitute in the treatment of eczema. 
In addition, anionic emulsifying wax (10%) has been added 
to theobroma oil to produce a suppository base with a melting 
point of 348C. 
8 Description 
An almost white or pale yellow colored, waxy solid or flakes 
which when warmed become plastic before melting. Anionic 
emulsifying wax has a faint characteristic odor and a bland 
taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for anionic emulsifying wax. 
Test BP 2004 
Identification . 
Characters . 
Acidity . 
Alkalinity . 
Alcohols . 
Iodine value 43.0 
Saponification value 42.0 
Sodium alkyl sulfates 58.7% 
Sulfated ash 2.5–4.0% 
Unsaponifiable matter 586.0% 
Water 44.0% 
10 Typical Properties 
Density: 0.97 g/cm3 
Flash point: >1008C 
Melting point: 528C 
Solubility: soluble in chloroform, ethanol (95%), ether, and, on 
warming, in fixed oils and mineral oil; practically insoluble 
in water, forming an emulsion. 
11 Stability and Storage Conditions 
Solid anionic emulsifying wax is chemically stable and should 
be stored in a well-closed container in a cool, dry place. 
12 Incompatibilities 
Incompatibilities of anionic emulsifying wax are essentially 
those of sodium alkyl sulfates and include cationic compounds 
(quaternary ammonium compounds, acriflavine, ephedrine 
hydrochloride, antihistamines, and other nitrogenous compounds), 
salts of polyvalent metals (aluminum, zinc, tin, and 
lead), and thioglycollates. Anionic emulsifying wax is compatible 
with most acids above pH 2.5. It is also compatible with 
alkalis and hard water. 
Iron vessels should not be used when heating anionic 
emulsifying wax; stainless steel containers are satisfactory. 
13 Method of Manufacture 
Anionic emulsifying wax is prepared by melting cetostearyl 
alcohol and heating to about 958C. Sodium lauryl sulfate, or 
some other suitable anionic surfactant, and purified water are 
then added. The mixture is heated to 1158C and, while this 
temperature is maintained, the mixture is stirred vigorously 
until any frothing ceases. The wax is then rapidly cooled. 
The BP 2004 specifies that the formula of anionic 
emulsifying wax is: 
Cetostearyl alcohol 90 g 
Sodium lauryl sulfate 10 g 
Purified water 4mL

14 Safety 
Anionic emulsifying wax is used primarily in topical pharmaceutical 

formulations and is generally regarded as a nontoxic 
and nonirritant material. However, sodium lauryl sulfate, a 
constituent of anionic emulsifying wax, is known to be irritant 
to the skin at high concentrations; sodium cetyl sulfate is 
claimed to be less irritating. 
Emulsifying ointment BP, which contains anionic emulsifying 
wax, has been found to have major sunscreen activity in 
clinically normal skin and should therefore not be used before 
phototherapy procedures.(1) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection is recommended. 
16 Regulatory Status 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Cetostearyl alcohol; sodium lauryl sulfate; wax, nonionic 
emulsifying. 
A number of emulsifying waxes are commercially available 
that contain different sodium alkyl sulfates and may not meet 
official compendial specifications. See also Section 18. 
18 Comments 
The nomenclature for emulsifying wax is confused since there 
are three groups of emulsifying waxes, with different titles in 
the UK and USA; see Table II. 
Table II: Nomenclature for emulsifying wax. 
UK USA 
Nonionic Cetomacrogol emulsifying wax Emulsifying wax 
Anionic Emulsifying wax — 
Cationic Cetrimide emulsifying wax — 
The waxes have similar physical properties but vary in the 
type of surfactant used, which, in turn, affects the range of 
compatibilities. Emulsifying wax BP and emulsifying wax USP 
contain anionic and nonionic surfactants, respectively, and are 
therefore not interchangeable in formulations. 
19 Specific References 
1 Cox NH, Sharpe G. Emollients, salicylic acid, and ultraviolet 
erythema [letter]. Lancet 1990; 335: 53–54. 
20 General References 
Eccleston GM. Properties of fatty alcohol mixed emulsifiers and 
emulsifying waxes. In: Florence AT, ed. Materials Used in 
Pharmaceutical Formulation: Critical Reports on Applied Chemistry, 
vol. 6. Oxford: Blackwell Scientific, 1984: 124–156. 
21 Authors 
AJ Winfield. 
22 Date of Revision 
15 August 2005. 
808 Wax, Anionic Emulsifying

Wax, Carnauba 
1 Nonproprietary Names 
BP: Carnauba wax 
JP: Carnauba wax 
PhEur: Cera carnauba 
USPNF: Carnauba wax 
2 Synonyms 
Brazil wax; caranda wax; E903. 
3 Chemical Name and CAS Registry Number 
Carnauba wax [8015-86-9] 
4 Empirical Formula and Molecular Weight 
Carnauba wax consists primarily of a complex mixture of 
esters of acids and hydroxy acids, mainly aliphatic esters, ohydroxy 
esters, p-methoxycinnamic aliphatic esters, and phydroxycinnamic 
aliphatic diesters composed of several chain 
lengths, in which C26 and C32 alcohols are the most 
prevalent.(1) 
Also present are acids, oxypolyhydric alcohols, hydrocarbons, 
resinous matter, and water. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Coating agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Carnauba wax is widely used in cosmetics, certain foods, and 
pharmaceutical formulations. Cosmetically, carnauba wax is 
commonly used in lip balms.(2) 
Carnauba wax is the hardest and highest-melting of the 
waxes commonly used in pharmaceutical formulations and is 
used primarily as a 10% w/v aqueous emulsion to polish sugarcoated 
tablets. Aqueous emulsions may be prepared by mixing 
carnauba wax with an ethanolamine compound and oleic acid. 
The carnauba wax coating produces tablets of good luster 
without rubbing. Carnauba wax may also be used in powder 
form to polish sugar-coated tablets. 
Carnauba wax (10–50% w/w) is also used alone or with 
other excipients such as hypromellose, hydroxypropyl cellulose, 
alginate/pectin-gelatin, Eudragit, and stearyl alcohol to 
produce sustained-release solid-dosage formulations.(3–10) 
Additionally, carnauba wax has been experimentally 
investigated for use in producing microparticles in a novel hot 
air coating (HAC) process developed as an alternative to 
conventional spray-congealing techniques.(11) 
8 Description 
Carnauba wax occurs as a light brown- to pale yellow-colored 
powder, flakes, or irregular lumps of a hard, brittle wax. It has a 
characteristic bland odor and practically no taste. It is free from 
rancidity. Various types and grades are available commercially. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for carnauba wax. 
Test JP 2001 PhEur 2005 USPNF 23 
Characters . . — 
Identification — . — 
Appearance of solution — . — 
Melting range 80–868C 80–888C 80–868C 
Acid value 410.0 2–7 2–7 
Saponification value 78–95 78–95 78–95 
Total ash — 40.25% 40.25% 
Heavy metals — — 420 mg/g 
Organic volatile impurities — — . 
Iodine value 5–14 — — 
Specific gravity 0.990–1.002 — — 
10 Typical Properties 
Flash point: 270–3308C 
Refractive index: nD
90 = 1.450 
Solubility: soluble in warm chloroform and in warm toluene; 
slightly soluble in boiling ethanol (95%); practically 
insoluble in water. 
Specific gravity: 0.990–0.999 at 258C 
Unsaponified matter: 50–55% 
11 Stability and Storage Conditions 
Carnauba wax is stable and should be stored in a well-closed 
container, in a cool, dry place. 
12 Incompatibilities 
—
13 Method of Manufacture 
Carnauba wax is obtained from the leaf buds and leaves of the 
Brazilian carnauba palm, Copernicia cerifera. The leaves are 
dried and shredded and the wax is then removed by the 
addition of hot water. 
14 Safety 
Carnauba wax is widely used in oral pharmaceutical formulations, 
cosmetics, and certain food products. It is generally 
regarded as an essentially nontoxic and nonirritant material.(
12–14)

There have been reports of allergic contact dermatitis from 
carnauba wax in mascara.(15) 
The WHO has established an acceptable daily intake of up 
to 7 mg/kg body-weight for carnauba wax.(16) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral capsules 
and tablets). Included in nonparenteral medicines licensed in 
the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
—
18 Comments 
In cosmetics, carnauba wax is mainly used to increase the 
stiffness of formulations, e.g. lipsticks and mascaras. 
The EINECS number for carnauba wax is 232-399-4. 
19 Specific References 
1 Ema. s M, Nyqvist H. Methods of studying aging and stabilization 
of spray-congealed solid dispersions with carnauba wax. 1: 
microcalorimetric investigation. Int J Pharm 2000; 197: 117–127. 
2 Marti-Mestres G, Nielland F, Rigal S, et al. Texture and sensory 
analysis in stick formulations. STP Pharma Sci 1999; 9(4): 371– 
375. 
3 Reza MS, Quadir MA, Haider SS. Comparative evaluation of 
plastic, hydrophobic and hydrophilic polymers as matrices for 
controlled-release drug delivery. J Pharm Pharm Sci 2003; 6(2): 
282–291. 
4 Gioannola LI, De Caro V, Severino A. Carnauba wax microspheres 
loaded with valproic acid: preparation and evaluation of drug 
release. Drug Dev Ind Pharm 1995; 21: 1563–1572. 
5 Miyagawa Y, Okabe T, Yamaguchi Y, et al. Controlled-release of 
diclofenac sodium from wax matrix granule. Int J Pharm 1996; 
138(2): 215–224. 
6 Aritomi H, Yamasaki Y, Yamada K, et al. Development of 
sustained-release formulation of chlorpheniramie maleate using 
powder-coated microsponge prepared by dry impact blending 
method. J Pharm Sci Tech Yakukzaigaku 1996; 56(1): 49–56. 
7 Huang HP, Mehta SC, Radebaugh GW, Fawzi MB. Mechanism of 
drug release from an acrylic polymer-wax matrix tablet. J Pharm 
Sci 1994; 83(6): 795–797. 
8 Joseph I, Venkataram S. Indomethacin sustained release from 
alginate-gelatin or pectin-gelatin coacervates. Int J Pharm 1995; 
126: 161–168. 
9 Kumar K, Chakrabarti T, Srivastava GP. Sustained release tablet 
formulation of diethylcarbamazine citrate (Hetrazan). Indian J 
Pharm 1975; 37: 57–59. 
10 Dave SC, Chakrabarti T, Srivastava GP. Sustained release tablet 
formulation of diphenhydramine hydrochloride (Benadryl) - part 
II. Indian J Pharm 1974; 36: 94–96. 
11 Rodriguez L, Albertini B, Passerin N, et al. Hot air coating 
technique as a novel method to produce microparticles. Drug Dev 
Ind Pharm 2004; 30(9): 913–923. 
12 Parent RA, Cox GE, Babish JG, et al. Subchronic feeding study of 
carnauba wax in beagle dogs. Food Chem Toxicol 1983; 21(1): 
85–87. 
13 Parent RA, Re TA, Babish JG, et al. Reproductive and subchronic 
feeding study of carnauba wax in rats. Food Chem Toxicol 1983; 
21(1): 89–93. 
14 Rowland IR, Butterworth KR, Gaunt IF, et al. Short-term toxicity 
study of carnauba wax in rats. Food Chem Toxicol 1982; 20(4): 
467–471. 
15 Chowdhury MM. Allergic contact dermatitis from prime yellow 
carnauba wax and coathylene in mascara. Contact Dermatitis 
2002; 46(6): 244. 
16 FAO/WHO. Evaluation of certain food additives and naturally 
occurring toxicants. Thirty-ninth report of the joint FAO/WHO 
expert committee on food additives. World Health Organ Tech 
Rep Ser 1992; No. 828. 
20 General References 
—
21 Authors 
PJ Weller. 
22 Date of Revision 
5 April 2005. 
810 Wax, Carnauba

Wax, Cetyl Esters 
1 Nonproprietary Names 
USPNF: Cetyl esters wax 
2 Synonyms 
Cera cetyla; Crodamol SS; Cutina CP; Liponate SPS; Protachem 
MST; Ritaceti; Ritachol SS; spermaceti wax replacement; 
Starfol Wax CG; Synaceti 116; synthetic spermaceti. 
3 Chemical Name and CAS Registry Number 
Cetyl esters wax [977067-67-6] 
4 Empirical Formula and Molecular Weight 
CnH2nO2 where n = 26–38.470–490 
The USPNF 23 describes cetyl esters wax as a mixture 
consisting primarily of esters of saturated fatty alcohols (C14– 
C18) and saturated fatty acids (C14–C18). 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Emollient; stiffening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Cetyl esters wax is a stiffening agent and emollient used in 
creams and ointments as a replacement for naturally occurring 
spermaceti. 
Cetyl esters wax is hydrophobic and has been proposed as a 
suitable component of an ophthalmic gelatin-based, controlledrelease 
delivery matrix.(1) 
The physical properties of cetyl esters wax vary greatly from 
manufacturer to manufacturer owing to differences between 
the mixtures of fatty acids and fatty alcohol esters that are used. 
Differences between products appear most obviously in the 
melting point, which can range from 43–478C (USPNF 23 
range) to 51–558C, depending on the mixture. Materials with a 
high melting point tend to contain predominantly cetyl and 
stearyl palmitates. See Table I. 
Table I: Uses of cetyl esters wax. 
Use Concentration (%) 
Cold cream 12.5 
Rose water ointment 12.5 
Spermaceti ointment 20.0 
Topical creams and ointments 1–15 
8 Description 
Cetyl esters wax occurs as white to off-white, somewhat 
translucent flakes (typically in the range of 5 mm to several 
millimeters in the largest dimension), having a crystalline 
structure and a pearly luster when caked. It has a faint, 
aromatic odor and a bland, mild taste. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for cetyl esters wax. 
Test USPNF 23 
Melting range 43–478C 
Acid value 45 
Iodine value 41 
Saponification value 109–120 
Paraffin and free acids . 
10 Typical Properties 
Dielectric constant: 6–18 
Flash point: >2408C 
Peroxide value: 40.5 
Refractive index: nD
60 = 1.440 
Solubility: high melting materials tend to be less soluble. See 
Table III. 
Table III: Solubility of cetyl esters wax. 
Solvent Solubility at 208C 
unless otherwise stated 
Acetone 1 in 500 
Chloroform 1 in 2.5 
Dichloromethane 1 in 3 
Ethanol 1 in 170 
Ethanol (95%) Practically insoluble 
1 in 2.5 at 788C 
Ether Soluble 
Ethyl acetate 1 in 80 
Fixed and volatile oils Soluble 
Hexane 1 in 8 
Mineral oil 1 in 70 
Water Practically insoluble 
Specific gravity: 0.820–0.840 at 508C 
Viscosity (dynamic): 6.7–7.4 mPa s (6.7–7.4 cP) at 1008C 
11 Stability and Storage Conditions 
Store in a well-closed container in a cool, dry place. Avoid 
exposure to excessive heat (above 408C).

12 Incompatibilities 
Incompatible with strong acids or bases. 
13 Method of Manufacture 
Cetyl esters wax is prepared by the direct esterification of the 
appropriate mixtures of fatty alcohols and fatty acids. 
14 Safety 
Cetyl esters wax is an innocuous material generally regarded as 
essentially nontoxic and nonirritant. 
LD50 (rat, oral): >16 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (topical 
preparations). Included in nonparenteral medicines licensed in 
the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Spermaceti wax. 
Spermaceti wax 
CAS number: [8002-23-1] 
Appearance: spermaceti is a waxy substance obtained from the 
head of the sperm whale. It consists of a mixture of the cetyl 
esters of fatty acids (C12–C18) with cetyl laurate, cetyl 
myristate, cetyl palmitate, and cetyl stearate comprising at 
least 85% of the total esters. It occurs as white, translucent, 
slightly unctuous masses with a faint odor and mild, bland 
taste. 
Iodine value: 3.0–4.4 
Melting point: 44–528C 
Refractive index: nD
80 = 1.4330 
Saponification value: 120–136 
Solubility: soluble in chloroform, boiling ethanol (95%), ether, 
and fixed or volatile oils; practically insoluble in ethanol 
(95%) and water. 
Specific gravity: 0.938–0.944 
Uses: spermaceti has been used in creams, ointments, and 
suppositories,(2) although it has largely been superseded in 
pharmaceutical and cosmetics formulation by the synthetic 
material, cetyl esters wax. 
Comments: the EINECS number for spermaceti wax is 232- 
302-5. 
18 Comments 
—
19 Specific References 
1 Nadkarni SR, Yalkowsky SH. Controlled delivery of pilocarpine 1: 
in vitro characterization of Gelfoam matrices. Pharm Res 1993; 
10: 109–112. 
2 Baichwal MR, Lohit TV. Medicament release from fatty suppository 
bases. J Pharm Pharmacol 1970; 22: 427–432. 
20 General References 
Egan RR, Portwood O. Higher alcohols in skin lotions. Cosmet Perfum 
1974; 89(3): 39–42. 
Holloway PJ. The chromatographic analysis of spermaceti. J Pharm 
Pharmacol 1968; 20: 775–779. 
Spencer GF, Kleiman R. Detection of spermaceti in a hand cream. J Am 
Oil Chem Soc 1978; 55: 837–838. 
21 Authors 
PJ Weller. 
22 Date of Revision 
18 February 2005. 
812 Wax, Cetyl Esters

Wax, Microcrystalline 
1 Nonproprietary Names 
USPNF: Microcrystalline wax 
2 Synonyms 
Amorphous wax; E907; petroleum ceresin; petroleum wax 
(microcrystalline). 
3 Chemical Name and CAS Registry Number 
Microcrystalline wax [63231-60-7] 
4 Empirical Formula and Molecular Weight 
Microcrystalline wax is composed of a mixture of straightchain 
and randomly branched saturated alkanes obtained from 
petroleum. The carbon chain lengths range from C41 to C57; 
cyclic hydrocarbons are also present. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Coating agent; controlled-release vehicle; stiffening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Microcrystalline wax is used mainly as a stiffening agent in 
topical creams and ointments. 
The wax is used to modify the crystal structure of other 
waxes (particularly paraffin wax) present in a mixture so that 
changes in crystal structure, usually exhibited over a period of 
time, do not occur. Microcrystalline wax also minimizes the 
sweating or bleeding of oils from blends of oils and waxes. 
Microcrystalline wax generally has a higher melting point than 
paraffin wax, and higher viscosity when molten, thereby 
increasing the consistency of creams and ointments when 
incorporated into such formulations. 
Microcrystalline wax is also used in oral controlled-release 
matrix pellet formulations for various active compounds(1–3) 
and as a tablet- and capsule-coating agent. In controlled-release 
systems, microcrystalline wax coatings can also be used to 
affect the release of drug from ion-exchange resin beads.(4) 
Microcrystalline wax is also used in confectionery, cosmetics, 
and food products. 
8 Description 
Microcrystalline wax occurs as odorless and tasteless waxy 
lumps or flakes containing small irregularly shaped crystals. It 
may vary in color from white to yellow, amber, brown, or black 
depending on the grade of material; pharmaceutical grades are 
usually white or yellow. 
The USPNF 23 describes microcrystalline wax as a mixture 
of straight-chain, branched-chain, and cyclic hydrocarbons, 
obtained by solvent fractionation of the still-bottom fraction of 
petroleum by suitable means of dewaxing or de-oiling. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for microcrystalline wax. 
Test USPNF 23 
Color . 
Melting range 54–1028C 
Consistency 3–100 
Acidity . 
Alkalinity . 
Residue on ignition 40.1% 
Organic acids . 
Fixed oils, fats, and rosin . 
Organic volatile impurities . 
10 Typical Properties 
Acid value: 1.0 
Density: 0.928–0.941 g/cm3 
Freezing point: 60.0–75.08C 
Refractive index: nD
100 = 1.435–1.445 
Saponification value: 0.05–0.10 
Solubility: soluble in benzene, chloroform, and ether; slightly 
soluble in ethanol; practically insoluble in water. When 
melted, microcrystalline wax is miscible with volatile oils 
and most warm fixed oils. 
Viscosity (dynamic): 10.0–30.0 mPa s (10.0–30.0 cP) at 1008C. 
11 Stability and Storage Conditions 
Microcrystalline wax is stable in the presence of acids, alkalis, 
light, and air. The bulk material should be stored in a wellclosed 
container in a cool, dry place. 
12 Incompatibilities 
—
13 Method of Manufacture 
Microcrystalline wax is obtained by solvent fractionation of the 
still-bottom fraction of petroleum by suitable dewaxing or deoiling. 
14 Safety 
Microcrystalline wax is mainly used in topical pharmaceutical 
formulations but is also used in some oral products. It is 
generally regarded as a nontoxic and nonirritating material.

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection is recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral capsules; 
topical and vaginal preparations). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Paraffin. 
18 Comments 
Rheological studies of a model ointment containing microcrystalline 
wax, white petroleum, and mineral oil showed that 
while the latter two substances control the rheology of the 
ointment, microcrystalline wax incorporates itself into the 
existing white petroleum structure and builds up the structure 
of the ointment.(5) 
19 Specific References 
1 De Brabander C, Vervaet C, Gortz JP, et al. Bioavailability of 
ibuprofen from matrix minitablets based on a mixture of starch 
and microcrystalline wax. Int J Pharm 2000; 208: 81–86. 
2 De Brabander C, Vervaet C, Fiermans L, Reman JP. Matrix 
minitablets based on starch/microcrystalline wax mixtures. Int J 
Pharm 2000; 199: 195–203. 
3 Vergote GJ, Vervaet C, Van Driessche I, et al. Oral controlled 
release matrix pellet formulation containing nanocrystalline 
ketoprofen. Int J Pharm 2001; 219: 81–87. 
4 Motycka S, Nairn J. Influence of wax coatings on release rate of 
anions from ion-exchange resin beads. J Pharm Sci 1978; 67: 500– 
503. 
5 Pena LE, Lee BL, Stearns JF. Structural rheology of a model 
ointment. Pharm Res 1994; 11: 875–881. 
20 General References 
Tennant DR. The usage, occurrences and dietary intakes of white 
mineral oils and waxes in Europe. Food Chem Toxicol 2004; 42: 
481–492. 
21 Authors 
AH Kibbe. 
22 Date of Revision 
5 April 2005. 
814 Wax, Microcrystalline

Wax, Nonionic Emulsifying 
1 Nonproprietary Names 
BP: Cetomacrogol emulsifying wax 
USPNF: Emulsifying wax 
2 Synonyms 
Collone NI; Crodex N; Emulgade 1000NI; Permulgin D; 
Polawax; Ritachol 2000; T-Wax. 
3 Chemical Name and CAS Registry Number 
Nonionic emulsifying wax [977069-99-0] 
4 Empirical Formula and Molecular Weight 
The USPNF 23 designates nonionic emulsifying wax as 
emulsifying wax that is prepared from cetostearyl alcohol and 
contains a polyoxyethylene derivative of a fatty acid ester of 
sorbitan. However, the BP 2004 describes nonionic emulsifying 
wax as cetomacrogol emulsifying wax prepared from cetostearyl 
alcohol and macrogol cetostearyl ether (22) (cetomacrogol 
1000). The UK and US materials are therefore 
constitutionally different. See also Section 18. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Emulsifying agent; stiffening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Nonionic emulsifying wax is used as an emulsifying agent in the 
production of oil-in-water emulsions that are unaffected by 
moderate concentrations of electrolytes and are stable over a 
wide pH range. The concentration of wax used alters the 
consistency of a product owing to its ‘self-bodying action’; at 
concentrations up to about 5% a product is pourable. 
Concentrations of about 15% of nonionic emulsifying wax 
are commonly used in creams, but concentrations as high as 
25% may be employed, e.g., in chlorhexidine cream BP. 
Nonionic emulsifying wax is particularly recommended for 
use with salts of polyvalent metals and medicaments based on 
nitrogenous compounds. Creams are susceptible to microbial 
spoilage and should be adequately preserved. 
Nonionic emulsifying wax is also used in nonaqueous 
ointment bases, such as cetomacrogol emulsifying ointment BP, 
and in barrier creams. 
8 Description 
Nonionic emulsifying wax is a white or off-white waxy solid or 
flakes which melt when heated to give a clear, almost colorless 
liquid. Nonionic emulsifying wax has a faint odor characteristic 
of cetostearyl alcohol. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for nonionic emulsifying wax. 
Test BP 2004 USPNF 23 
Identification . — 
Characters . — 
Melting range — 50–548C 
Solidifying point 45–538C — 
pH (3% dispersion) — 5.5–7.0 
Alkalinity . — 
Acid value 40.5 — 
Hydroxyl value 175–192 178–192 
Iodine value — 43.5 
Refractive index (at 608C) 1.435–1.439 — 
Saponification value 42.0 414 
Sulfated ash 40.1% — 
10 Typical Properties 
Density: 0.94 g/cm3 
Flash point: >558C 
Solubility: freely soluble in aerosol propellants, chloroform, 
and hydrocarbons; moderately soluble in ethanol (96%); 
partly soluble in ether and insoluble in water (forms 
emulsions). 
11 Stability and Storage Conditions 
Nonionic emulsifying wax is stable and should be stored in a 
well-closed container in a cool, dry place. 
12 Incompatibilities 
Nonionic emulsifying wax is incompatible with tannin, phenol 
and phenolic materials, resorcinol, and benzocaine. It may 
reduce the antibacterial efficacy of quaternary ammonium 
compounds. 
13 Method of Manufacture 
The BP 2004 specifies that cetomacrogol emulsifying wax 
(nonionic emulsifying wax) may be prepared by melting and 
mixing together 800 g of cetostearyl alcohol and 200 g of 
macrogol cetostearyl ether (22) (cetomacrogol 1000). The 
mixture is then stirred until cold. 
The USPNF 23 formula for nonionic emulsifying wax is a 
mixture of unstated proportions of cetostearyl alcohol and a 
polyoxyethylene derivative of a fatty acid ester of sorbitan. 
14 Safety 
Nonionic emulsifying wax is used in cosmetics and topical 
pharmaceutical formulations and is generally regarded as a 
nontoxic and nonirritant material.

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection is recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (topical 
aerosols, emulsions, lotions, and ointments). Included in 
nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Cationic emulsifying wax; cetostearyl alcohol; polyoxyethylene 
alkyl ethers; wax, anionic emulsifying. 
It should be noted that there are many similar nonionic 
emulsifying waxes composed of different nonionic surfactants 
and fatty alcohols. 
Cationic emulsifying wax 
Synonyms: cetrimide emulsifying wax; Crodex C. 
Method of manufacture: cetrimide emulsifying wax is prepared 
similarly to nonionic emulsifying wax and contains 90 g of 
cetostearyl alcohol and 10 g of cetrimide. 
Comments: cationic emulsifying wax is claimed to be of 
particular value in cosmetic and pharmaceutical formulations 
when cationic characteristics are important. Thus it 
can be used in medicated creams, germicidal creams, 
ointments and lotions, hair conditioners, baby creams, and 
skin care products in which cationic compounds are 
included. Cationic emulsifying wax is compatible with 
cationic and nonionic materials, but is incompatible with 
anionic surfactants and drugs. Additional antimicrobial 
preservatives should be included in creams. Cetrimide may 
cause irritation to the eye; see Cetrimide. 
18 Comments 
The nomenclature for emulsifying wax is confused since there 
are three groups of emulsifying waxes with different titles in the 
UK and USA; see Table II. 
Table II: Nomenclature for emulsifying wax. 
UK USA 
Nonionic Cetomacrogol emulsifying wax Emulsifying wax 
Anionic Emulsifying wax — 
Cationic Cetrimide emulsifying wax — 
The waxes have similar physical properties but vary in the 
type of surfactant used, which, in turn, affects the range of 
compatibilities. Emulsifying wax BP and emulsifying wax USP 
contain anionic and nonionic surfactants, respectively, and are 
therefore not interchangeable in formulations. 
19 Specific References 
—
20 General References 
Eccleston GM. Properties of fatty alcohol mixed emulsifiers and 
emulsifying waxes. In: Florence AT, ed. Materials Used in 
Pharmaceutical Formulation: Critical Reports on Applied Chemistry, 
vol. 6. Oxford: Blackwell Scientific, 1984: 124–156. 
Hadgraft JW. The emulsifying properties of polyethyleneglycol ethers of 
cetostearyl alcohol. J Pharm Pharmacol 1954; 6: 816–829. 
21 Authors 
AJ Winfield. 
22 Date of Revision 
15 August 2005. 
816 Wax, Nonionic Emulsifying

Wax, White 
1 Nonproprietary Names 
BP: White beeswax 
JP: White beeswax 
PhEur: Cera alba 
USPNF: White wax 
2 Synonyms 
Bleached wax; E901. 
3 Chemical Name and CAS Registry Number 
White beeswax [8012-89-3] 
4 Empirical Formula and Molecular Weight 
White wax is the chemically bleached form of natural beeswax; 
see Section 13. 
Beeswax consists of 70–75% of a mixture of various esters 
of straight-chain monohydric alcohols with even-numbered 
carbon chains from C24 to C36 esterified with straight-chain 
acids. These straight-chain acids also have even numbers of 
carbon atoms up to C36 together with some C18 hydroxy acids. 
The chief ester is myricyl palmitate. Also present are free acids 
(about 14%) and carbohydrates (about 12%) as well as 
approximately 1% free wax alcohols and stearic esters of fatty 
acids. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Controlled-release vehicle; stabilizing agent; stiffening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
White wax is a chemically bleached form of yellow wax and is 
used in similar applications: for example, to increase the 
consistency of creams and ointments, and to stabilize water-inoil 
emulsions. White wax is used to polish sugar-coated tablets 
and to adjust the melting point of suppositories. 
White wax is also used as a film coating in sustained-release 
tablets.(1)White beeswax microspheres may be used in oral 
dosage forms to retard the absorption of an active ingredient 
from the stomach, allowing the majority of absorption to occur 
in the intestinal tract. Wax coatings can also be used to affect 
the release of drug from ion-exchange resin beads.(2–4) 
See also Yellow Wax. 
8 Description 
White wax consists of tasteless, white or slightly yellow-colored 
sheets or fine granules with some translucence. Its odor is 
similar to that of yellow wax but is less intense. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for white wax. 
Test JP 2001 PhEur 2005 USPNF 23 
Characters . . — 
Drop point 60–678C 61–668C 62–658C 
Acid value 5–9 or 17–22 17–24 17–24 
Ester value — 70–80 72–79 
Ester value : acid value 
ratio 
— 3.3 : 4.3 — 
Saponification value 80–100 87–104 . 
Ceresin, paraffins, and 
certain other waxes 
— . . 
Glycerols and other polyols — . . 
Saponification cloud test — — . 
Purity . — — 
Relative density — 0.960 — 
10 Typical Properties 
Arsenic: 43 ppm 
Density: 0.95–0.96 g/cm3 
Flash point: 245–2588C 
Heavy metals: 40.004% 
Iodine number: 8–11 
Lead: 410 ppm 
Melting point: 61–658C 
Peroxide value: 48 
Solubility: soluble in chloroform, ether, fixed oils, volatile oils, 
and warm carbon disulfide; sparingly soluble in ethanol 
(95%); practically insoluble in water. 
Unsaponified matter: 52–55% 
11 Stability and Storage Conditions 
When the wax is heated above 1508C, esterification occurs with 
a consequent lowering of acid value and elevation of melting 
point. White wax is stable when stored in a well-closed 
container, protected from light. 
12 Incompatibilities 
Incompatible with oxidizing agents. 
13 Method of Manufacture 
Yellow wax (beeswax) is obtained from the honeycomb of the 
bee (Apis mellifera Linne. (Fam. Apidae)); see Yellow Wax. 
Subsequent treatment with oxidizing agents bleaches the wax 
to yield white wax. 
14 Safety 
White wax is used in both topical and oral formulations, and is 
generally regarded as an essentially nontoxic and nonirritant

material. However, although rare, hypersensitivity reactions to 
beeswax (attributed to contaminants in the wax) have been 
reported.(5,6) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral capsules 
and tablets, rectal, topical, and vaginal preparations). Included 
in nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Yellow wax. 
18 Comments 
—
19 Specific References 
1 Nughroho AK, Fudholi A. Comparison of mefenamic acid 
dissolution in sustained release tablets using hydroxypropyl 
methylcellulose and cera alba as film coating. Indonesian J Pharm 
1999; 10(2): 78–84. 
2 Giannola L, Stefano V, Caro V. White beeswax microspheres: a 
comparative in vitro evaluation of cumulative release of the 
anticancer agents fluorouracil and ftorafur. Pharmazie 1993; 48: 
123–126. 
3 Giannola LI, De Caro V, Rizzo MC. Preparation of white beeswax 
microspheres loaded with valproic acid and kinetic study of drug 
release. Drug Dev Ind Pharm 1995; 21: 793–807. 
4 Motycka S, Nairn J. Influence of wax coatings on release rate of 
anions from ion-exchange resin beads. J Pharm Sci 1978; 67: 500– 
503. 
5 Cronin E. Contact dermatitis from cosmetics. J Soc Cosmet Chem 
1967; 18: 681–691. 
6 Rothenborg HW. Occupational dermatitis in beekeeper due to 
poplar resins in beeswax. Arch Dermatol 1967; 95: 381–384. 
20 General References 
Puleo SL. Beeswax. Cosmet Toilet 1987; 102(6): 57–58. 
Tennant DR. The usage, occurrences and dietary intakes of white 
mineral oils and waxes in Europe. Food Chem Toxicol 2004; 42: 
481–492. 
21 Authors 
AH Kibbe. 
22 Date of Revision 
5 April 2005. 
818 Wax, White

Wax, Yellow 
1 Nonproprietary Names 
BP: Yellow beeswax 
JP: Yellow beeswax 
PhEur: Cera flava 
USPNF: Yellow wax 
2 Synonyms 
Apifil; E901; refined wax. 
3 Chemical Name and CAS Registry Number 
Yellow beeswax [8012-89-3] 
4 Empirical Formula and Molecular Weight 
Yellow wax is naturally obtained beeswax; see Section 13. 
Beeswax consists of 70–75% of a mixture of various esters 
of straight-chain monohydric alcohols with even-numbered 
carbon chains from C24 to C36 esterified with straight-chain 
acids. These straight-chain acids also have even numbers of 
carbon atoms up to C36 together with some C18 hydroxy acids. 
The chief ester is myricyl palmitate. Also present are free acids 
(about 14%) and carbohydrates (about 12%) as well as 
approximately 1% free wax alcohols and stearic esters of fatty 
acids. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Controlled-release vehicle; polishing agent; stabilizing agent; 
stiffening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Yellow wax is used in food, cosmetics, and confectionery 
products. Its main use is in topical pharmaceutical formulations, 
where it is used at a concentration of 5–20%, as a 
stiffening agent in ointments and creams. Yellow wax is also 
employed in emulsions because it enables water to be 
incorporated into water-in-oil emulsions. 
In some oral formulations yellow wax is used as a polishing 
agent for sugar-coated tablets. It is also used in sustainedrelease 
formulations. Yellow wax coatings can be used to affect 
the release rate of drug from ion-exchange resin beads,(1) and 
has also been used in multiparticulate controlled-release dosage 
forms of chlorphenamine maleate.(2) 
Yellow wax forms a soap with borax. 
8 Description 
Yellow or light brown pieces or plates with a fine-grained matt, 
noncrystalline fracture and a faint characteristic odor. The wax 
becomes soft and pliable when warmed. 
The PhEur 2005 describes yellow wax as the wax obtained 
by melting the walls of the honeycomb made by the honeybee, 
Apis mellifera, with hot water and removing foreign matter. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for yellow wax. 
Test JP 2001 PhEur 2005 USPNF 23 
Characters . . — 
Drop point 60–678C 61–668C 62–658C 
Relative density — 0.960 — 
Acid value 5–9 or 17–22 17–22 17–24 
Ester value — 70–80 72–79 
Ester value : acid value 
ratio 
— 3.3 : 4.3 — 
Saponification value 80–100 87–102 — 
Ceresin, paraffins, and 
certain other waxes 
— . . 
Purity . — — 
Glycerol and other polyols 
(as glycerol) 
— 40.5% . 
Saponification cloud test — — . 
10 Typical Properties 
Acid value: 20 
Arsenic: 43 ppm 
Density: 0.95–0.96 g/cm3 
Flash point: 245–2588C 
Heavy metals: 40.004% 
Iodine number: 8–11 
Lead: 410 ppm 
Melting point: 61–658C 
Peroxide value: 48 
Solubility: soluble in chloroform, ether, fixed oils, volatile oils, 
and warm carbon disulfide; sparingly soluble in ethanol 
(95%); practically insoluble in water. 
Unsaponified matter: 52–55% 
Viscosity (kinematic): 1470mm2/s (1470 cSt) at 998C 
11 Stability and Storage Conditions 
When the wax is heated above 1508C esterification occurs with 
a consequent lowering of acid value and elevation of melting 
point. Yellow wax is stable when stored in a well-closed 
container, protected from light. 
12 Incompatibilities 
Incompatible with oxidizing agents.

13 Method of Manufacture 
Yellow wax is a natural secretion of bees (Apis mellifera Linne. 
(Fam. Apidae)) and is obtained commercially from honeycombs. 
Honey is abstracted from combs either by draining or 
centrifugation and water is added to the remaining wax to 
remove soluble impurities. Hot water is then added to form a 
floating melt, which is strained to remove foreign matter. The 
wax is then poured into flat dishes or molds to cool and harden. 
14 Safety 
Yellow wax is generally regarded as an essentially nontoxic and 
nonirritant material, and is used in both topical and oral 
formulations. However, hypersensitivity reactions attributed to 
contaminants in the wax, although rare, have been 
reported.(3,4) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral capsules 
and tablets, and topical preparations). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian 
List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
White wax. 
18 Comments 
Studies have shown that yellow wax, when added to 
suppository formulations, increased the melting point of the 
preparation significantly and decreased the rate of release of the 
active substance.(5) 
19 Specific References 
1 Motycka S, Nairn J. Influence of wax coatings on release rate of 
anions from ion-exchange resin beads. J Pharm Sci 1978; 67: 500– 
503. 
2 Griffin EN, Niebergall PJ. Release kinetics of a controlled-release 
multiparticulate dosage form prepared using a hot-melt fluid bed 
coating method. Pharm Dev Technol 1999; 4(1): 117–124. 
3 Cronin E. Contact dermatitis from cosmetics. J Soc Cosmet Chem 
1967; 18: 681–691. 
4 Rothenborg HW. Occupational dermatitis in beekeeper due to 
poplar resins in beeswax. Arch Dermatol 1967; 95: 381–384. 
5 Murrukmihadi M. Effect of cera flava on the release of sodium 
salicylate from suppository dosage form. Indonesian J Pharm 
1999; 10(3): 135–139. 
20 General References 
Puleo SL. Beeswax. Cosmet Toilet 1987; 102(6): 57–58. 
21 Authors 
AH Kibbe. 
22 Date of Revision 
5 April 2005. 
820 Wax, Yellow

Xanthan Gum 
1 Nonproprietary Names 
BP: Xanthan gum 
PhEur: Xanthani gummi 
USPNF: Xanthan gum 
2 Synonyms 
Corn sugar gum; E415; Keltrol; polysaccharide B-1459; 
Rhodigel; Vanzan NF; Xantural. 
3 Chemical Name and CAS Registry Number 
Xanthan gum [11138-66-2] 
4 Empirical Formula and Molecular Weight 
(C35H49O29)n Approximately 2  106 
The USPNF 23 describes xanthan gum as a high molecular 
weight polysaccharide gum. It contains D-glucose and Dmannose 
as the dominant hexose units, along with Dglucuronic 
acid, and is prepared as the sodium, potassium, or 
calcium salt. 
5 Structural Formula 
Each xanthan gum repeat unit contains five sugar residues: two 
glucose, two mannose, and one glucuronic acid. The polymer 
backbone consists of four b-D-glucose units linked at the 1 and 
4 positions, and is therefore identical in structure to cellulose. 
Trisaccharide side chains on alternating anhydroglucose units 
distinguish xanthan from cellulose. Each side chain comprises a 
glucuronic acid residue between two mannose units. At most of 
the terminal mannose units is a pyruvate moiety; the mannose 
nearest the main chain carries a single group at C-6. The 
resulting stiff polymer chain may exist in solution as a single, 
double, or triple helix that interacts with other xanthan gum 
molecules to form complex, loosely bound networks.(1,2) 
6 Functional Category 
Stabilizing agent; suspending agent; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Xanthan gum is widely used in oral and topical pharmaceutical 
formulations, cosmetics, and foods as a suspending and 
stabilizing agent.(3–5) It is also used as a thickening and 
emulsifying agent. It is nontoxic, compatible with most other 
pharmaceutical ingredients, and has good stability and 
viscosity properties over a wide pH and temperature range; 
see Section 11. Xanthan gum gels show pseudoplastic behavior, 
the shear thinning being directly proportional to the shear rate. 
The viscosity returns to normal immediately on release of shear 
stress. 
When xanthan gum is mixed with certain inorganic 
suspending agents, such as magnesium aluminum silicate, or 
organic gums, synergistic rheological effects occur.(6) In general, 
mixtures of xanthan gum and magnesium aluminum silicate in 
ratios between 1 : 2 and 1 : 9 produce the optimum properties. 
Similarly, optimum synergistic effects are obtained with 
xanthan gum : guar gum ratios between 3 : 7 and 1 : 9. 
Although primarily used as a suspending agent, xanthan 
gum has also been used to prepare sustained-release matrix 
tablets.(7–10) Controlled-release tablets of diltiazem hydrochloride 
prepared using xanthan gum have been reported to sustain 
the drug release in a predictable manner and the drug release 
profiles of these tablets were not affected by pH and agitation 
rate.(11) 
Xanthan gum has been incorporated in an ophthalmic 
liquid dosage form, which interacts with mucin, thereby 
helping in the prolonged retention of the dosage form in the 
precorneal area.(12) 
Recent studies have revealed that xanthan gum can also be 
used as an excipient for spray-drying and freeze-drying 
processes for better results.(13,14) 
Xanthan gum can be used to increase the bioadhesive 
strength in vaginal formulations and as a binder in colon 
specific drug delivery systems.(15,16) 
Xanthan gum is also used as a hydrocolloid in the food 
industry, and in cosmetics it has been used as a thickening agent 
in shampoo.(17) 
8 Description 
Xanthan gum occurs as a cream- or white-colored, odorless, 
free-flowing, fine powder. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for xanthan gum. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters . — 
pH 6.0–8.0 — 
Viscosity 5600 mPas 5600 mPas 
Propan-2-ol 4750 ppm 40.075% 
Other polysaccharides . — 
Loss on drying 415.0% 415.0% 
Total ash 6.5–16.0% 6.5–16.0% 
Microbial contamination . . 
Bacteria 4103/g — 
Fungi 4102/g — 
Pyruvic acid — 41.5% 
Arsenic — 43 mg/g 
Lead — 45 mg/g 
Heavy metals — 40.003% 
Organic volatile impurities — . 
Assay — 91.0–108.0%

10 Typical Properties 
Acidity/alkalinity: pH = 6.0–8.0 for a 1% w/v aqueous 
solution. 
Freezing point: 08C for a 1% w/v aqueous solution. 
Heat of combustion: 14.6 J/g (3.5 cal/g) 
Melting point: chars at 2708C. 
Particle size distribution: various grades with different particle 
sizes are available; for example, 100% less than 180 mm in 
size for Keltrol CG; 100% less than 75 mm in size for Keltrol 
CGF; 100% less than 250 mm, 95% less than 177 mm in size 
for Rhodigel; 100% less than 177 mm, 92% less than 74 mm 
in size for Rhodigel 200. 
Refractive index: nD
20 = 1.333 for a 1% w/v aqueous solution. 
Solubility: practically insoluble in ethanol and ether; soluble in 
cold or warm water. 
Specific gravity: 1.600 at 258C 
Viscosity (dynamic): 1200–1600 mPa s (1200–1600 cP) for a 
1% w/v aqueous solution at 258C. 
11 Stability and Storage Conditions 
Xanthan gum is a stable material. Aqueous solutions are stable 
over a wide pH range (pH 3–12), although they demonstrate 
maximum stability at pH 4–10 and temperatures of 10–608C. 
Xanthan gum solutions of less than 1% w/v concentration may 
be adversely affected by higher than ambient temperatures: for 
example, viscosity is reduced. Solutions are also stable in the 
presence of enzymes, salts, acids, and bases. 
The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Xanthan gum is an anionic material and is not usually 
compatible with cationic surfactants, polymers, or preservatives 
as precipitation occurs. Anionic and amphoteric surfactants 
at concentrations above 15% w/v cause precipitation of 
xanthan gum from a solution. 
Under highly alkaline conditions, polyvalent metal ions such 
as calcium cause gelation or precipitation; this may be inhibited 
by the addition of a glucoheptonate sequestrant. The presence 
of low levels of borates (<300 ppm) can also cause gelation. 
This may be avoided by increasing the boron ion concentration 
or by lowering the pH of a formulation to less than pH 5. The 
addition of ethylene glycol, sorbitol, or mannitol may also 
prevent this gelation. 
Xanthan gum is compatible with most synthetic and natural 
viscosity-increasing agents. If it is to be combined with cellulose 
derivatives, then xanthan gum free of cellulase should be used 
to prevent depolymerization of the cellulose derivative. 
The viscosity of xanthan gum solutions is considerably 
increased, or gelation occurs, in the presence of some materials 
such as ceratonia, guar gum, and magnesium aluminum 
silicate.(6) This effect is most pronounced in deionized water 
and is reduced by the presence of salt. This interaction may be 
desirable in some instances and can be exploited to reduce the 
amount of xanthan gum used in a formulation; see Section 7. 
Xanthan gum solutions are stable in the presence of up to 
60% water-miscible organic solvents such as acetone, methanol, 
ethanol, or propan-2-ol. However, above this concentration 
precipitation or gelation occurs. 
Xanthan gum is incompatible with oxidizing agents, some 
tablet film-coatings,(4) carboxymethylcellulose sodium,(18) 
dried aluminum hydroxide gel,(19) and some active ingredients 
such as amitriptyline, tamoxifen, and verapamil.(3) 
13 Method of Manufacture 
Xanthan gum is a polysaccharide produced by a pure-culture 
aerobic fermentation of a carbohydrate with Xanthomonas 
campestris. The polysaccharide is then purified by recovery 
with propan-2-ol, dried, and milled.(20,21) 
14 Safety 
Xanthan gum is widely used in oral and topical pharmaceutical 
formulations, cosmetics, and food products and is generally 
regarded as nontoxic and nonirritant at the levels employed as a 
pharmaceutical excipient. 
The estimated acceptable daily intake for xanthan gum has 
been set by the WHO at up to 10 mg/kg body-weight.(22) 
LD50 (dog, oral): >20 g/kg(22) 
LD50 (rat, oral): >45 g/kg 
LD50 (mouse, oral): >1 g/kg(23) 
LD50 (mouse, IP): >50 mg/kg(23) 
LD50 (mouse, IV): 100–250 mg/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral solutions, 
suspensions, and tablets; rectal and topical preparations). 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Ceratonia; guar gum. 
18 Comments 
Xanthan gum is available in several different grades that have 
varying particle sizes. Fine-mesh grades of xanthan gum are 
used in applications where high solubility is desirable since they 
dissolve rapidly in water. However, fine-mesh grades disperse 
more slowly than coarse grades and are best used dry blended 
with the other ingredients of a formulation. In general, it is 
preferable to dissolve xanthan gum in water first and then add 
the other ingredients of a formulation. 
When added to liquid ophthalmics, xanthan gum delays the 
release of active substances, increasing the therapeutic activity 
of the pharmaceutical formulations.(24) 
Xanthan gum has also been used to produce directly 
compressed matrices that display a high degree of swelling 
due to water uptake, and a small amount of erosion due to 
polymer relaxation.(25) 
The USPNF 23 also includes a monograph for xanthan gum 
solution. A specification for xanthan gum is contained in the 
Food Chemicals Codex (FCC). 
The EINECS number for xanthan gum is 234-394-2. 
822 Xanthan Gum

19 Specific References 
1 Jansson PE, Kenne L, Lindberg B. Structure of extracellular 
polysaccharide from Xanthamonas campestris. Carbohydr Res 
1975; 45: 275–282. 
2 Melton LD, Mindt L, Rees DA, Sanderson GR. Covalent structure 
of the polysaccharide from Xanthamonas campestris: evidence 
from partial hydrolysis studies. Carbohydr Res 1976; 46: 245– 
257. 
3 Bumphrey G. ‘Extremely useful’ new suspending agent. Pharm J 
1986; 237: 665. 
4 Evans BK, Fenton-May V. Keltrol [letter]. Pharm J 1986; 237: 
736–737. 
5 Chollet JK, Jozwiakowski MJ, Phares KR, et al. Development of a 
topically active imiquimod formulation. Pharm Dev Technol 
1999; 4(1): 35–43. 
6 Kovacs P. Useful incompatibility of xanthan gum with galactomannans. 
Food Technol 1973; 27(3): 26–30. 
7 Talukdar M, Van der Mooter G, Augustijus P. In vivo evaluation of 
xanthan gum as a potential excipient for oral controlled-release 
matrix tablet formulation. Int J Pharm 1998; 169: 105–113. 
8 Lu MF, Woodward L, Borodkin S. Xanthan gum and alginate 
based controlled release theophylline formulations. Drug Dev Ind 
Pharm 1991; 17: 1987–2004. 
9 Dhopeshwarkar V, Zatz JL. Evaluation of xanthan gum in the 
preparation of sustained release matrix tablets. Drug Dev Ind 
Pharm 1993; 19: 999–1017. 
10 Billa N, Yuen KH, Khader MA, Omar A. Gamma scintigraphic 
study of the gastrointestinal transit and in vivo dissolution of a 
controlled release diclofenac sodium formulation in xanthan gum 
matrices. Int J Pharm 2000; 201: 109–120. 
11 Peh KK, Wong CF. Application of similarity factor in the 
development of controlled release diltiazem tablet. Drug Dev Ind 
Pharm 2000; 26: 723–730. 
12 Ceulemans J, Vinckier I, Ludwig A. The use of xanthan gum in an 
ophthalmic liquid dosage form: rheological characterization of the 
interaction with mucin. J Pharm Sci 2002; 91(4): 1117–1127. 
13 Patel N, Craddock BL, Staniforth JN, et al. Spray-dried insulin 
particles retain biological activity in rapid in-vitro assay. J Pharm 
Pharmacol 2001; 53(10): 1415–1418. 
14 Corveleyn S, Remon JP. Stability of freeze-dried tablets at different 
relative humidities. Drug Dev Ind Pharm 1999; 25(9): 1005–1013. 
15 Vermani K, Garg S, Zaneveld LJ. Assemblies for in vitro 
measurement of bioadhesive strength and retention characteristics 
in simulated vaginal environment. Drug Dev Ind Pharm 2002; 
28(9): 1133–1146. 
16 Sinha VR, Kumria R. Binders for colon specific drug delivery: an in 
vitro evaluation. Int J Pharm 2002; 249(1–2): 23–31. 
17 Howe AM, Flowers AE. Introduction to shampoo thickening. 
Cosmet Toilet 2000; 115: 63–66, 68–69. 
18 Walker CV, Wells JI. Rheological synergism between ionic and 
non-ionic cellulose gums. Int J Pharm 1982; 11: 309–322. 
19 Zatz JL, Figler D, Livero K. Fluidization of aluminum hydroxide 
gels containing xanthan gum. Drug Dev Ind Pharm 1986; 12: 
561–568. 
20 Jeanes AR, Pittsley JE, Senti FR. Polysaccharide B-1459: a new 
hydrocolloid polyelectrolyte produced from glucose by bacterial 
fermentation. J Appl Polym Sci 1961; 5(17): 519–526. 
21 Godet P. Fermentation of polysaccharide gums. Process Biochem 
1973; 8(1): 33. 
22 FAO/WHO. Evaluation of certain food additives and contaminants. 
Twenty-ninth report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1986; No. 733. 
23 Booth AN, Hendrickson AP, De Eds F. Physiologic effects of three 
microbial polysaccharides on rats. Toxicol Appl Pharmacol 1963; 
5: 478–484. 
24 Hoepfner E, Reng A, Schmidt PC, eds. Fielder Encyclopedia of 
Excipients for Pharmaceuticals, Cosmetics and Related Areas, 5th 
edn. Aulendorf: Edito Cantor Verlag, 2002: 1690. 
25 Munday DL, Cox PJ. Compressed xantham and karaya gum 
matrices: hydration, erosion and drug release mechanisms. Int J 
Pharm 2000; 203: 179–192. 
20 General References 
Gamini A, De Bleijer J, Leute JC. Physicochemical properties of 
aqueous solutions of xanthan: an NMR study. Carbohydr Res 
1991; 220: 33–47. 
Kelco Division of Merck & Co Inc. Technical literature: Xanthan 
gum—natural biogum for scientific water control, 3rd edn, 1991. 
Rhodia. Technical literature: Rhodigel—food grade xanthan gum, 
1998. 
Shatwell KP, Sutherland IW, Ross-Murphy SB. Influence of acetyl and 
pyruvate substituents on the solution properties of xanthan 
polysaccharide. Int J Biol Macromol 1990; 12(2): 71–78. 
Vendruscolo CW, Andreazza IF, Ganter JLMS, et al. Xanthan and 
galactomannan (from M. scabrella) matrix tablets for oral 
controlled delivery of theophylline. Int J Pharm 2005; 296: 1–11. 
Whitcomb PJ. Rheology of xanthan gum. J Rheol 1978; 22(5): 493– 
505. 
Zatz JL. Applications of gums in pharmaceutical and cosmetic 
suspensions. Ind Eng Chem Prod Res Dev 1984; 23: 12–16. 
21 Authors 
KK Singh. 
22 Date of Revision 
7 August 2005. 
Xanthan Gum 823

Xylitol 
1 Nonproprietary Names 
BP: Xylitol 
JP: Xylitol 
PhEur: Xylitolum 
USPNF: Xylitol 
2 Synonyms 
E967; Klinit; meso-xylitol; xilitol; Xylifin; Xylisorb; xylit; 
Xylitab; xylite; Xylitolo. 
3 Chemical Name and CAS Registry Number 
xylo-Pentane-1,2,3,4,5-pentol [87-99-0] 
4 Empirical Formula and Molecular Weight 
C5H12O5 152.15 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; base for medicated confectionery; 
coating agent; emollient; humectant; sweetening agent; tablet 
and capsule diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Xylitol is used as a noncariogenic sweetening agent in a variety 
of pharmaceutical dosage forms, including tablets, syrups, and 
coatings. It is also widely used as an alternative to sucrose in 
foods and confectionery. Xylitol is finding increasing application 
in chewing gum,(1,2) mouthrinses,(3) and toothpastes(4) as 
an agent that decreases dental plaque and tooth decay (dental 
caries). Unlike sucrose, xylitol is not fermented into cariogenic 
acid end products(5) and it has been shown to reduce dental 
caries by inhibiting the growth of cariogenic Streptococcus 
mutans bacteria.(6,7) As xylitol has an equal sweetness intensity 
to sucrose, combined with a distinct cooling effect upon 
dissolution of the crystal, it is highly effective in enhancing the 
flavor of tablets and syrups and masking the unpleasant or 
bitter flavors associated with some pharmaceutical actives and 
excipients. 
In topical cosmetic and toiletry applications, xylitol is used 
primarily for its humectant and emollient properties, although 
it has also been reported to enhance product stability through a 
combination of potentiation of preservatives and its own 
bacteriostatic and bactericidal properties. 
Granulates of xylitol are used as diluents in tablet 
formulations, where they can provide chewable tablets with a 
desirable sweet taste and cooling sensation, without the 
‘chalky’ texture experienced with some other tablet diluents. 
Xylitol solutions are employed in tablet-coating applications at 
concentrations in excess of 65% w/w. Xylitol coatings are 
stable and provide a sweet-tasting and durable hard coating. 
In liquid preparations, xylitol is used as a sweetening agent 
and vehicle for sugar-free formulations. In syrups, it has a 
reduced tendency to ‘cap-lock’ by effectively preventing 
crystallization around the closures of bottles. Xylitol also has 
a lower water activity and a higher osmotic pressure than 
sucrose, therefore enhancing product stability and freshness. In 
addition, xylitol has also been demonstrated to exert certain 
specific bacteriostatic and bactericidal effects, particularly 
against common spoilage organisms.(8,9) 
Therapeutically, xylitol is additionally utilized as an energy 
source for intravenous infusion following trauma.(10) 
8 Description 
Xylitol occurs as a white, granular solid comprising crystalline, 
equidimensional particles having a mean diameter of about 
0.4–0.6 mm. It is odorless, with a sweet taste that imparts a 
cooling sensation. Xylitol is also commercially available in 
powdered form and several granular, directly compressible 
forms.(11) See also Section 17. 
SEM: 1 
Excipient: Xylitol (unsieved) 
Magnification: 60

9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for xylitol. 
Test JP 2001 PhEur2005 USPNF 23 
Identification . . . 
Characters . . — 
Clarity and color of 
solution 
. . — 
Water 41.0% 41.0% 40.5% 
pH (50% w/w 
solution) 
5.0–7.0 — — 
Melting point 93.0–95.08C 92–968C — 
Residue on ignition 40.1% — 40.5% 
Chloride 40.005% — — 
Sulfate 40.006% — — 
Nickel . 41 ppm — 
Arsenic 41.3 ppm — — 
Heavy metals 45 ppm — 40.001% 
Reducing sugars (as 
dextrose) 
. 40.2% 40.2% 
Other polyols — — 42.0% 
Related substances — 42.0% — 
Lead — 40.5 ppm — 
Bacterial 
endotoxins(a) 
— 42.5 IU/g — 
Conductivity — 420 mScm1 — 
Organic volatile 
impurities 
— — . 
Assay (anhydrous 
basis) 
598.0% 98.0–102.0% 98.5–101.0% 
(a) If intended for use in parenteral products. 
10 Typical Properties 
Acidity/alkalinity: pH = 5.0–7.0 (10% w/v aqueous solution). 
Boiling point: 215–2178C 
Compressibility: see Figure 1. Crystalline xylitol, under the 
same test conditions as illustrated in Figure 1, produces 
12.5mm tablets of 40N hardness at 20kN compression 
force. 
Density (true): 1.52 g/cm3 
Density (bulk): 
0.8–0.85 g/cm3 for crystalline xylitol; 
0.5–0.7 g/cm3 for directly compressible granulated grades. 
Flowability: flow characteristics vary depending upon the 
particle size of xylitol used. Fine-milled grades tend to be 
relatively poorly flowing, while granulated grades have 
good flow properties. 
Heat of solution: 157.1 kJ/kg (–36.7 cal/g) 
Melting point: 92.0–96.08C 
Moisture content: xylitol is a moderately hygroscopic powder 
under normal conditions; see also Figure 2. At 208C and 
52% relative humidity, the equilibrium moisture content of 
xylitol is 0.1% w/w. After drying in a vacuum, over P2O5 at 
808C for 4 hours, xylitol loses less than 0.5% w/w water. 
Osmolarity: a 4.56% w/v aqueous solution is iso-osmotic with 
serum. 
Particle size distribution: the particle size distribution of xylitol 
depends upon the grade selected. Normal crystalline 
material typically has a mean particle size of 0.4–0.6 mm. 
Milled grades are commercially available that offer mean 
particle sizes as low as 50 mm. Individual suppliers’ literature 
should be consulted for further information. For particle size 
distributions of granulated xylitol, see Figure 3. 
Solubility: see Table II. 
Table II: Solubility of xylitol. 
Solvent Solubility at 208C 
Ethanol 1 in 80 
Glycerin Very slightly soluble 
Methanol 1 in 16.7 
Peanut oil Very slightly soluble 
Propan-2-ol 1 in 500 
Propylene glycol 1 in 15 
Pyridine Soluble 
Water 1 in 1.6 
Specific rotation: not optically active. 
Viscosity (dynamic): see Figure 4. 
Figure 1: Compression characteristics of Xylitab 100 and Xylitab 
200 (Danisco Sweeteners Ltd.). 
*: Xylitol with 3.5% polydextrose (Xylitab 100) 
&: Xylitol with 2.0% carboxymethylcellulose (Xylitab 200) 
11 Stability and Storage Conditions 
Xylitol is stable to heat but is marginally hygroscopic. 
Caramelization can occur only if it is heated for several minutes 
near its boiling point. Crystalline material is stable for at least 3 
years if stored at less than 65% relative humidity and 258C. 
Milled and specialized granulated grades of xylitol have a 
tendency to cake and should therefore be used within 6 months. 
Aqueous xylitol solutions have been reported to be stable, even 
on prolonged heating and storage. Since xylitol is not utilized 
by most microorganisms, products made with xylitol are 
usually safe from fermentation and microbial spoilage.(8,9) 
Xylitol should be stored in a well-closed container in a cool, 
dry place. 
Xylitol 825

Figure 2: Moisture sorption isotherm of xylitol at 208C. 
Figure 3: Particle size distribution of granulated xylitol (Xylitab, 
Danisco Sweeteners Ltd.). 
*: Xylitab 100 granulated with 3.5% polydextrose 
&: Xylitab 200 granulated with 2.0% carboxymethylcellulose 
~: Xylitab 300 wet granulated. 
12 Incompatibilities 
Xylitol is incompatible with oxidizing agents. 
13 Method of Manufacture 
Xylitol occurs naturally in many fruits and berries, although 
extraction from such sources is not considered to be 
commercially viable. Industrially, xylitol is most commonly 
derived from various types of hemicellulose obtained from such 
sources as wood, cane pulp, seed hulls, and shells. These 
materials usually contain 20–35% xylan, which is readily 
converted to xylose (wood sugar) by hydrolysis. This xylose is 
subsequently converted to xylitol via hydrogenation (reduction). 
Following the hydrogenation step, there are a number of 
separation and purification steps that ultimately yield highpurity 
xylitol crystals. The nature of this process, and the 
stringent purification procedures employed, result in a finished 
product with a very low impurity content. Potential impurities 
that may appear in small quantities are mannitol, sorbitol, 
galactitol, or arabitol. 
Less commonly employed methods of xylitol manufacture 
include the conversion of glucose (dextrose) to xylose followed 
by hydrogenation to xylitol, and the microbiological conversion 
of xylose to xylitol. 
Figure 4: Viscosity of aqueous xylitol solutions at 208C. 
14 Safety 
Xylitol is used in oral pharmaceutical formulations, confectionery, 
and food products and is generally regarded as an 
essentially nontoxic, nonallergenic, and nonirritant material. 
Xylitol has an extremely low glycemic index and is 
metabolized independently of insulin. Following ingestion of 
xylitol, the blood glucose and serum insulin responses are 
significantly lower than following ingestion of glucose or 
sucrose. These factors make xylitol a suitable sweetener for use 
in diabetic or carbohydrate-controlled diets.(12) 
Up to 100 g of xylitol in divided oral doses may be tolerated 
daily, although, as with other polyols, large doses may have a 
laxative effect. The laxative threshold depends on a number of 
factors, including individual sensitivity, mode of ingestion, 
daily diet, and previous adaptation to xylitol. Single doses of 
20–30 g and daily doses of 0.5–1.0 g/kg bodyweight are usually 
well tolerated by most individuals. Approximately 25–50% of 
the ingested xylitol is absorbed, with the remaining 50–75% 
passing to the lower gut, where it undergoes indirect 
metabolism via fermentative degradation by the intestinal flora. 
826 Xylitol

An acceptable daily intake for xylitol of ‘not specified’ has 
been set by the WHO since the levels used in foods do not 
represent a hazard to health.(13) 
LD50 (mouse, IP): 22.1 g/kg(14,15) 
LD50 (mouse, IV): 12 g/kg 
LD50 (mouse, oral): 12.5 g/kg 
LD50 (rat, oral): 17.3 g/kg 
LD50 (rat, IV): 10.8 g/kg 
LD50 (rabbit, oral): 16.5 g/kg 
LD50 (rabbit, IV): 4 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Xylitol may be harmful if 
ingested in large quantities; and may also be irritant to the eyes. 
Eye protection and gloves are recommended. Xylitol is 
flammable, but does not ignite readily. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral solution, 
chewing gum). Included in nonparenteral medicines licensed in 
the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Various directly compressible forms of xylitol that contain 
other excipients are commercially available, e.g., Xylitab 100, 
which contains 3.5% polydextrose, and Xylitab 200, which 
contains 2.0% carboxymethylcellulose (both Danisco Sweeteners 
Ltd.). A directly compressible form of pure xylitol is also 
available, Xylitab 300 (Danisco Sweeteners Ltd.), which is 
produced via wet granulation. 
Pyrogen-free grades of xylitol suitable for parenteral use are 
also commercially available. 
18 Comments 
The sweetening power of xylitol is approximately equal to that 
of sucrose, although it has been shown to be pH-, concentration-, 
and temperature-dependent; xylitol is approximately 2.5 
times as sweet as mannitol. 
Xylitol is highly chemically stable, meaning that it will not 
interact with pharmaceutical actives or excipients, and can be 
utilized over a wide pH range (pH 1–11). 
The EINECS number for xylitol is 201-788-0. 
Xylitol has a negative heat of solution that is far larger than 
that of other alternative sweetening agents; see Table III. 
Because of this, xylitol produces an intense cooling effect as the 
crystalline material dissolves. Xylitol’s combination of sweetness 
and cooling can create product appeal while helping to 
mask the undesirable taste of many pharmaceutical actives or 
excipients. 
A specification for xylitol is contained in the Food 
Chemicals Codex (FCC). 
19 Specific References 
1 Tanzer JM. Xylitol chewing gum and dental caries. Int Dent J 
1995; 45(1): 65–76. 
2 Soderling E, Trahan L, Tammiala T, Hakkinen L. Effects of xylitol, 
xylitol-sorbitol, and placebo chewing gums on the plaque of 
habitual xylitol consumers. Eur J Oral Sci 1997; 105(2): 170–177. 
Table III: Comparison of the heat of solution of selected sweetening 
agents. 
Sweetening agent Heat of solution (kJ/kg) 
Lactitol (anhydrous) 35.0 
Maltitol 69.2 
Mannitol 120.9 
Sorbitol 106.3 
Sucrose 23.0 
Xylitol 157.1 
3 Cobanera A, Morasso A, White E, et al. Xylitol-sodium fluoride: 
effect on plaque. J Dent Res 1987; 66: 814. 
4 Sintes JL, Escalante C, Stewart B, et al. Enhanced anticaries 
efficacy of a 0.243% sodium fluoride/10% xylitol/silica dentifrice: 
3-year clinical results. Am J Dent 1995; 8(5): 231–235. 
5 Trahan L. Xylitol: a review of its action on mutans streptococci 
and dental plaque – its clinical significance. Int Dent J 1995; 45(1): 
77–92. 
6 Hayes C. The effect of non-cariogenic sweeteners on the 
prevention of dental caries: a review of the evidence. J Dent 
Educ 2001; 65(10): 1106–1109. 
7 Makinen KK, Chen CCY, Makinen PL, et al. Properties of whole 
saliva and dental plaque in relation to 40-month consumption of 
chewing gums containing xylitol, sorbitol and sucrose. Caries Res 
1996; 30(3): 180–188. 
8 Emodi A. Xylitol: its properties and food applications. Food 
Technol 1978; Jan: 28–32. 
9 Makinen KK, Soderling E. Effect of xylitol on some food spoilage 
microorganisms. J Food Sci 1981; 46(3): 950–951. 
10 Georgieff M, Moldawer LL, Bistrian BR, Blackburn GL. Xylitol, 
an energy source for intravenous nutrition after trauma. J Parenter 
Enteral Nutr 1985; 9: 199–209. 
11 Garr JSM, Rubinstein MH. Direct compression characteristics of 
xylitol. Int J Pharm 1990; 64: 223–226. 
12 Natah SS, Hussien KR, Touminen JA, Koivisto VA. Metabolic 
response to lactitol and xylitol in healthy men. Am J Clin Nutr 
1997; 65(4): 947–950. 
13 FAO/WHO. Evaluation of certain food additives and contaminants. 
Twenty-seventh report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1983; No. 696. 
14 Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. 
Cincinnati: US Department of Health, 1987: 5127–5128. 
15 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3707. 
20 General References 
Counsell JN. Xylitol. London: Applied Science Publishers, 1978. 
O’Brien Nabors L, Gelardi RC, eds. Alternative Sweeteners, 2nd edn. 
New York: Marcel Dekker, 1991. 
Thomas SE, Ali MA, Craig DQM, et al. The use of xylitol as a carrier 
for liquid-filled hard-gelatin capsules. Pharm Technol Int 1991; 
3(9): 36–40. 
Ylikahri R. Metabolic and nutritional aspects of xylitol. Adv Food Res 
1979; 25: 159–180. 
21 Authors 
M Bond. 
22 Date of Revision 
23 August 2005. 
Xylitol 827

Zein 
1 Nonproprietary Names 
USPNF: Zein 
2 Synonyms 
—
3 Chemical Name and CAS Registry Number 
Zein [9010-66-6] 
4 Empirical Formula and Molecular Weight 
Zein is a prolamin with a molecular weight of approximately 
38 000. 
5 Structural Formula 
See Section 8. 
6 Functional Category 
Coating agent; extended-release agent; tablet binder. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Zein is used as a tablet binder in wet-granulation processes or 
as a tablet-coating agent mainly as a replacement for shellac. It 
is used primarily as an enteric-coating agent or in extendedrelease 
oral tablet formulations.(1) Zein is also used in food 
applications as a coating agent. See Table I. 
Table I: Uses of zein. 
Use Concentration (%) 
Tablet coating agent 15 
Tablet sealer 20 
Wet granulation binder 30 
8 Description 
Zein is a prolamin obtained from corn (Zea mays Linne. (Fam. 
Gramineae)). It occurs as a granular, straw- to pale yellowcolored 
amorphous powder or fine flakes and has a characteristic 
odor and bland taste. 
For amino acid composition, see Section 18. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for zein. 
Test USPNF 23 
Identification . 
Microbial limits 41000/g 
Loss on drying 48.0% 
Residue on ignition 42.0% 
Heavy metals 40.002% 
Organic volatile impurities . 
Nitrogen content (dried basis) 13.1–17.0% 
10 Typical Properties 
Density: 1.23 g/cm3 
Melting point: when completely dry, zein may be heated to 
2008C without visible signs of decomposition. 
Particle size distribution: 100% less than 840 mm in size. 
Solubility: practically insoluble in acetone, ethanol, and water; 
soluble in aqueous alcohol solutions, aqueous acetone 
solutions (60–80% v/v), and glycols. Also soluble in 
aqueous alkaline solutions of pH 11.5 and above. 
11 Stability and Storage Conditions 
Zein should be stored in an airtight container, in a cool, dry 
place. It has not been reported to polymerize.(2,3) 
12 Incompatibilities 
Incompatible with oxidizing agents. 
13 Method of Manufacture 
Zein is extracted from corn gluten meal with dilute propan-2- 
ol. 
14 Safety 
Zein is used in oral pharmaceutical formulations and food 
products and is generally regarded as an essentially nontoxic 
and nonirritant material at the levels employed as an excipient. 
However, it may be harmful if ingested in large quantities. See 
also Section 18. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Zein may be irritant to the 
eyes and may evolve toxic fumes on combustion. Eyeprotection 
and gloves are recommended. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(oral tablets). Included in nonparenteral medicines licensed in 
the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients.

17 Related Substances 
—
18 Comments 
The EINECS number for zein is 232-722-9. 
Zein is a protein derivative that does not contain lysine or 
tryptophan. For the approximate amino acid content of zein, 
see Table III. 
Zein may be safely consumed by persons sensitive to gluten. 
A specification for zein is contained in the Food Chemicals 
Codex (FCC). 
Table III: Approximate amino acid content of zein. 
Alanine 8.3% /Leucine 19.3% 
Arginine 1.8% Methionine 2.0% 
Asparagine 4.5% Phenylalanine 6.8% 
Cystine 0.8% Proline 9.0% 
Glutamic acid 1.5% Serine 5.7% 
Glutamine 21.4% Threonine 2.7% 
Glycine 0.7% Tyrosine 5.1% 
Histidine 1.1% Valine 3.1% 
Isoleucine 6.2% 
19 Specific References 
1 Katayama H, Kanke M. Drug release from directly compressed 
tablets containing zein. Drug Dev Ind Pharm 1992; 18: 2173– 
2184. 
2 Porter SC. Tablet coating. Drug Cosmet Ind 1996; May: 46–93. 
3 Seitz JA, Mehta SP, Yeager JL. Tablet coating. In: Lachman L, 
Liebermann HA, Kanig JL, eds. The Theory and Practice of 
Industrial Pharmacy. Philadelphia: Lea and Febiger, 1986: 346– 
373. 
20 General References 
Beck MI, Tomka I,Waysek E. Physico-chemical characterization of zein 
as a film coating polymer: a direct comparison with ethyl cellulose. 
Int J Pharm 1996; 141: 137–150. 
21 Authors 
O AbuBaker. 
22 Date of Revision 
5 August 2005. 
Zein 829

Zinc Acetate 
1 Nonproprietary Names 
PhEur: Zinc acetas dihydricus 
USP: Zinc acetate 
2 Synonyms 
Acetic acid, zinc salt; dicarbomethoxy zinc; zinc (II) acetate; 
zinc diacetate; zinc ethanoate. 
3 Chemical Name and CAS Registry Number 
Zinc acetate dihydrate [5970-45-6] 
Zinc acetate anhydrous [557-34-6] 
4 Empirical Formula and Molecular Weight 
C4H6O4Zn2H2O 219.50 (for dihydrate) 
C4H6O4Zn 183.47 (for anhydrous) 
5 Structural Formula 
6 Functional Category 
Emollient; emulsion stabilizer; gelling agent; opacifier; stabilizing 
agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Zinc acetate has been used as an excipient in a variety of 
pharmaceutical formulations including topical gels, lotions, 
and solutions, and subcutaneous injections. It has also been 
investigated for use in an oral controlled-release formulation 
for water-soluble drugs in combination with sodium alginate 
and xanthan gum.(1) 
Therapeutically, zinc acetate has been used in oral capsules 
for the treatment of Wilson’s disease.(2,3) Zinc acetate has also 
been demonstrated to be effective as a spermicide in vaginal 
contraceptives.(4) 
8 Description 
Zinc acetate occurs as white crystalline, lustrous plates with a 
faint acetic odor and an astringent taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for zinc acetate. 
Test PhEur 2005 USP 28 
Identification . . 
Appearance of solution . — 
pH (5% w/v) 5.8–7.0 6.0–8.0 
Reducing substances . — 
Insoluble matter — . 
Arsenic 42 ppm 43 ppm 
Lead 410 ppm 40.002% 
Chlorides 450 ppm 40.005% 
Sulfates 4100 ppm 40.010% 
Aluminum 45 ppm — 
Cadmium 42 ppm — 
Copper 450 ppm — 
Iron 450 ppm — 
Alkalis and alkaline earths — 40.2% 
Organic volatile impurities — . 
Assay 99.0–101.0% 98.0–102.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 6.0–8.0 (5% w/v aqueous solution of 
the dihydrate) 
Boiling point: decomposes. 
Melting point: 2378C 
Solubility: for the dihydrate, see Table II. 
Specific gravity: 1.735 
Table II: Solubility of zinc acetate dihydrate. 
Solvent Solubility at 208C unless otherwise stated 
Ethanol (95%) 1 in 30 
1 in 1 of boiling ethanol (95%) 
Water 1 in 2.3 
1 in 1.6 at 1008C 
11 Stability and Storage Conditions 
Zinc acetate loses water of hydration above 1008C. Zinc 
acetate should be stored in a well-closed container in a cool, 
dry, place. 
12 Incompatibilities 
Zinc acetate is incompatible with oxidizing agents, zinc salts, 
alkalis and their carbonates, oxalates, phosphates, and 
sulfides.(5) 
13 Method of Manufacture 
Zinc acetate is synthesized by reacting zinc oxide with glacial 
acetic acid, with subsequent crystallization, separation by 
centrifugation, and drying and milling of the crystals. No 
organic solvents are used during the synthesis.

14 Safety 
Zinc acetate is used in topical pharmaceutical formulations and 
subcutaneous injections, where it is generally regarded as 
relatively nontoxic and nonirritant when used as an excipient. 
However, zinc acetate is poisonous by intravenous and 
intraperitoneal routes; it is also moderately toxic following 
oral consumption.(5) 
Zinc acetate: 
LD50 (rat, oral): 2.510 g/kg(5) 
LD50 (IP, mouse): 0.057 g/kg 
Zinc acetate dihydrate: 
LD50 (mouse, IP): 0.108 g/kg 
LD50 (mouse, oral): 0.287 g/kg 
LD50 (rat, IP): 0.162 g/kg 
LD50 (rat, oral): 0.794 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. When heated to decomposition, zinc acetate 
emits toxic fumes of zinc oxide. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (SC injections; 
topical lotions and solutions). Included in medicines licensed in 
the UK. 
17 Related Substances 
— 
18 Comments 
A specification for zinc acetate is included in the Japanese 
Pharmaceutical Excipients (JPE) 2004.(6) The EINECS number 
for zinc acetate is 209-170-2. 
19 Specific References 
1 Zeng WM. Oral controlled-release formulation for highly watersoluble 
drugs: drug–sodium alginate–xanthan gum–zinc acetate 
matrix. Drug Dev Ind Pharm 2004; 30: 491–495. 
2 Brewer GJ. Zinc acetate for the treatment of Wilson’s disease. 
Expert Opin Pharmacother 2001; 2: 1473–1477. 
3 Fahim MS, Wang M. Zinc acetate and lyophilized Aloe 
barbadensis as vaginal contraceptive. Contraception 1996; 53: 
231–236. 
4 European Medicines Evaluation Agency. Summary scientific 
opinion for the approval of Wilzin (zinc acetate dehydrate). 
http://www.emea.eu.int/humandocs/PDFs/EPAR/Wilzin/ 
099104en6.pdf (accessed 12 April 2005). 
5 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3717–3718. 
6 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004: 945–946. 
20 General References 
—
21 Authors 
LY Galichet 
22 Date of Revision 
24 August 2005 
Zinc Acetate 831

Zinc Stearate 
1 Nonproprietary Names 
BP: Zinc stearate 
PhEur: Zinci stearas 
USP: Zinc stearate 
2 Synonyms 
Cecavon; dibasic zinc stearate; HyQual; stearic acid zinc salt; 
zinc distearate; zinc soap. 
3 Chemical Name and CAS Registry Number 
Octadecanoic acid zinc salt [557-05-1] 
4 Empirical Formula and Molecular Weight 
C36H70O4Zn 632.33 (for pure material) 
The USP 28 describes zinc stearate as a compound of zinc 
with a mixture of solid organic acids obtained from fats, and 
consists chiefly of variable proportions of zinc stearate and zinc 
palmitate. It contains the equivalent of 12.5–14.0% of zinc 
oxide (ZnO). 
The PhEur 2005 states that zinc stearate 
[(C17H35COO)2Zn] may contain varying proportions of zinc 
palmitate [(C15H31COO)2Zn] and zinc oleate 
[(C17H33COO)2Zn]. It contains not less than 10.0% and not 
more than 12.0% of zinc. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Tablet and capsule lubricant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Zinc stearate is primarily used in pharmaceutical formulations 
as a lubricant in tablet and capsule manufacture at concentrations 
up to 1.5% w/w. It has also been used as a thickening and 
opacifying agent in cosmetic and pharmaceutical creams and as 
a dusting powder. See Table I. 
Table I: Uses of zinc stearate. 
Use Concentration (%) 
Tablet lubricant 0.5–1.5 
Water-repellent ointments 2.5 
8 Description 
Zinc stearate occurs as a fine, white, bulky, hydrophobic 
powder, free from grittiness and with a faint characteristic odor. 
9 Pharmacopeial Specifications 
See Table II. 
SEM: 1 
Excipient: Zinc stearate 
Magnification: 600 
SEM: 2 
Excipient: Zinc stearate 
Magnification: 2400

Table II: Pharmacopeial specifications for zinc stearate. 
Test PhEur 2005 USP 28 
Identification . . 
Characters . — 
Acidity or alkalinity . — 
Alkalis and alkaline earths — 41.0% 
Appearance of solution . — 
Acid value of the fatty acids 195–210 — 
Appearance of solution of fatty acids . — 
Arsenic — 41.5 ppm 
Cadmium 45 ppm — 
Lead 425 ppm 40.001% 
Chlorides 4250 ppm — 
Sulfates 40.6% — 
Organic volatile impurities — . 
Assay (as Zn) 10.0–12.0% — 
Assay (as ZnO) — 12.5–14.0% 
10 Typical Properties 
Autoignition temperature: 4218C 
Density: 1.09 g/cm3 
Density (tapped): 0.26 g/cm3 for standard grade (Durham 
Chemicals). 
Flash point: 2778C 
Melting point: 120–1228C 
Particle size distribution: 100% through a 44.5-mm sieve (#325 
mesh). 
Solubility: practically insoluble in ethanol (95%), ether, water, 
and oxygenated solvents; soluble in acids, benzene, and 
other aromatic solvents. 
11 Stability and Storage Conditions 
Zinc stearate is stable and should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Zinc stearate is decomposed by dilute acids. 
13 Method of Manufacture 
An aqueous solution of zinc sulfate is added to sodium stearate 
solution to precipitate zinc stearate. The zinc stearate is then 
washed with water and dried. Zinc stearate may also be 
prepared from stearic acid and zinc chloride. 
14 Safety 
Zinc stearate is used in oral and topical pharmaceutical 
formulations and is generally regarded as a nontoxic and 
nonirritant excipient. However, following inhalation, it has 
been associated with fatal pneumonitis, particularly in 
infants.(1) As a result, zinc stearate has now been removed 
from baby dusting powders. 
LD50 (rat, IP): 0.25 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. Zinc stearate may be harmful on inhalation and 
should be used in a well-ventilated environment; a respirator is 
recommended. In the UK, the long-term (8-hour TWA) 
occupational exposure limit for zinc stearate is 10 mg/m3 for 
total inhalable dust and 4 mg/m3 for respirable dust. The shortterm 
(15-minutes) exposure limit for total inhalable dust is 
20 mg/m3.(2) In the US, the OSHA limit is 15 mg/m3 for total 
dust, 5 mg/m3 respirable fraction for zinc stearate.(3) 
When heated to decomposition, zinc stearate emits acrid 
smoke and fumes of zinc oxide. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(oral capsules and tablets). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Calcium stearate; magnesium stearate; stearic acid. 
18 Comments 
The EINECS number for zinc stearate is 209-151-9. 
See Magnesium Stearate for further information and 
references. 
19 Specific References 
1 Ueda A, Harada K, Ueda T, Nomura S. Experimental study on the 
pathological changes in lung tissue caused by zinc stearate dust. 
Ind Health 1984; 22: 243–253. 
2 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
3 JT Baker (2005). Zinc stearate safety data sheet. 
http://www.jtbaker.com/msds/englishhtml/z4275.htm (accessed 5 
April 2005). 
20 General References 
—
21 Authors 
LV Allen. 
22 Date of Revision 
5 April 2005. 
Zinc Stearate 833


Appendix I: Suppliers Directory 
Excipients List 
Acacia 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
AF Suter and Co Ltd 
Colloides Naturels UK Ltd 
Courtin & Warner Ltd 
JT Baker UK 
Paroxite (London) Ltd 
Thew, Arnott and Co Ltd 
Other European 
Alland & Robert 
Colloides Naturels International 
USA 
Colloides Naturels Inc 
Delta Distributors Inc 
Chart Corp Inc 
JT Baker Inc 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
TIC Gums 
Voigt Global Distribution LLC 
Acesulfame Potassium 
UK 
Nutrinova UK Ltd 
Other European 
Nutrinova Nutrition Specialities & Food 
Ingredients GmbH 
USA 
Aceto Corp 
Nutrinova Inc 
Acetic Acid, Glacial 
UK 
Acetex Chemicals Ltd 
Blagden Specialty Chemicals Ltd 
BP plc 
Eastman Company UK Ltd 
Fisher Scientific UK Ltd 
JT Baker UK 
Peter Whiting (Chemicals) Ltd 
Tennants (Distribution) Ltd 
Wacker Chemicals Ltd 
Other European 
Acetex Chimie SA 
August Hedinger GmbH & Co 
Brenntag AG 
Wacker-Chemie GmbH 
USA 
Ashland 
BP Inc 
Brenntag Inc 
Delta Distributors Inc 
Eastman Chemical Co 
EM Industries Inc 
Fisher Scientific 
JT Baker Inc 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Vopak USA Inc 
Wacker Chemical Corp 
Acetone 
UK 
BP plc 
Leading Solvent Supplies Ltd 
Other European 
Dow Benelux NV 
Rohm and Haas Belgium NV 
USA 
Amresco Inc 
Ashland 
Dow Chemical Co 
Eastman Chemical Co 
EMD Chemicals Inc 
Penta Manufacturing Co 
Sigma-Aldrich Corp 
Vopak USA Inc 
Acetyltributyl Citrate 
UK 
Ubichem plc 
Other European 
Jungbunzlauer 
USA 
Morflex Inc 
Penta Manufacturing Co 
Acetyltriethyl Citrate 
UK 
Ubichem plc 
Other European 
Jungbunzlauer 
USA 
Morflex Inc 
Penta Manufacturing Co 
Agar 
UK 
Mast Group Ltd 
Sigma-Aldrich Company Ltd 
USA 
Alfa Chem 
Amresco Inc 
Ashland 
EMD Chemicals Inc 
Penta Manufacturing Co 
TIC Gums 
Vopak USA Inc 
Albumin 
UK 
Aarhus United UK Ltd 
Paroxite (London) Ltd 
Other European 
Aarhus United Denmark A/S 
Kraeber GmbH & Co 
USA 
Aarhus United USA Inc 
AerChem Inc 
Amresco Inc 
ZLB Behring 
Penta Manufacturing Co 
Voigt Global Distribution LLC 
Alcohol 
UK 
Tennants (Distribution) Ltd 
Other European 
Amylum Ibe.rica, SA 
Brenntag AG 
USA 
Ashland 
Brenntag Inc 
Delta Distributors Inc 
Dow Chemical Co 
Grain Processing Corp 
Alginic Acid 
UK 
Blagden Specialty Chemicals Ltd 
Forum Biosciences Ltd 
Honeywill & Stein 
JRS Pharma Ltd 
Other European 
FMC Biopolymer 
J Rettenmaier & So. hne GmbH and Co

USA 
Aceto Corp 
FMC Biopolymer 
International Specialty Products 
JRS Pharma LP 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Aliphatic Polyesters 
UK 
Alfa Chemicals Ltd/Gattefosse. UK 
Purac Biochem (UK) 
Other European 
Boehringer Ingelheim GmbH 
USA 
Boehringer Ingelheim Chemicals Inc 
Purac America Inc 
Alitame 
UK 
Danisco Sweeteners Ltd 
USA 
Danisco USA Inc 
Almond Oil 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Aarhus United UK Ltd 
Alembic Products Ltd 
Paroxite (London) Ltd 
Peter Whiting (Chemicals) Ltd 
White Sea and Baltic Company Ltd 
William Ransom & Son plc 
Other European 
Aarhus United Denmark A/S 
USA 
Aarhus United USA Inc 
Arista Industries Inc 
Charkit Chemical Corp 
Chart Corp Inc 
Mutchler Inc 
Penta Manufacturing Co 
Pokonobe Industries Inc 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Welch, Holme & Clark Co Inc 
Alpha Tocopherol 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Alembic Products Ltd 
Cognis UK Ltd 
Cornelius Group plc 
Eastman Company UK Ltd 
Ubichem plc 
Other European 
BASF Aktiengesellschaft 
Brenntag AG 
Cognis Deutschland GmbH 
Helm AG 
USA 
Aceto Corp 
Alfa Chem 
BASF Corp 
Brenntag Inc 
Cognis Corp 
Eastman Chemical Co 
Helm New York Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Takeda Pharmaceuticals North 
America Inc 
Triple Crown America 
Others 
Takeda Chemical Industries Ltd 
Aluminum Hydroxide Adjuvant 
UK 
Reheis 
Other European 
Reheis 
USA 
Reheis Inc 
Aluminum Oxide 
UK 
Pumex (UK) Limited 
Fisher Scientific UK Ltd 
Other European 
Degussa AG 
USA 
Alfa Chem 
EMD Chemicals Inc 
Penta Manufacturing Co 
Ruger Chemical Co Inc 
SPI Pharma Group 
Vopak USA Inc 
Others 
Sumitomo Chemical 
Aluminum Phosphate Adjuvant 
UK 
Reheis 
Other European 
Reheis 
USA 
Reheis Inc 
Aluminum Stearate 
Other European 
Magnesia GmbH 
USA 
Acme-Hardesty 
AerChem Inc 
Alfa Chem 
Ashland 
Eastech Chemical Inc 
Penta Manufacturing Co 
Ruger Chemical Co Inc 
Spectrum Quality Products Inc 
Ammonia Solution 
UK 
Tennants (Distribution) Ltd 
William Ransom & Son plc 
USA 
Triple Crown America 
Vopak USA Inc 
Ammonium Alginate 
USA 
CP Kelco US Inc 
Ascorbic Acid 
UK 
Fisher Scientific UK Ltd 
JT Baker UK 
Peter Whiting (Chemicals) Ltd 
Raught Ltd 
Roche Products Ltd 
Tennants (Distribution) Ltd 
Thew, Arnott and Co Ltd 
Other European 
BASF Aktiengesellschaft 
Brenntag AG 
Helm AG 
USA 
Aceto Corp 
AerChem Inc 
Alfa Chem 
Amresco Inc 
Barrington Chemical Corp 
BASF Corp 
Brenntag Inc 
Charkit Chemical Corp 
Charles Bowman & Co 
Delta Distributors Inc 
EM Industries Inc 
Fisher Scientific 
George Uhe Co Inc 
Hawkins Chemical Inc 
Helm New York Inc 
JT Baker Inc 
Kraft Chemical Co 
Mutchler Inc 
Particle Dynamics Inc 
Penta Manufacturing Co 
Seltzer Chemicals Inc 
Spectrum Quality Products Inc 
Takeda Pharmaceuticals North 
America Inc 
Triple Crown America 
Voigt Global Distribution LLC 
Vopak USA Inc 
Others 
Shijiazhuang Pharmaceutical Group 
Co Ltd 
Takeda Pharmaceutical Company Ltd 
836 Appendix I: Suppliers Directory

Ascorbyl Palmitate 
UK 
Roche Products Ltd 
Other European 
BASF Aktiengesellschaft 
USA 
Aceto Corp 
BASF Corp 
Delta Distributors Inc 
EM Industries Inc 
George Uhe Co Inc 
Hawkins Chemical Inc 
Helm New York Inc 
Penta Manufacturing Co 
RIA International 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Others 
Xinchem Co 
Aspartame 
UK 
Blagden Specialty Chemicals Ltd 
DSM UK Ltd 
Tennants (Distribution) Ltd 
Other European 
Ajinomoto Switzerland AG 
Brenntag AG 
DSM Fine Chemicals 
Helm AG 
USA 
Aceto Corp 
AerChem Inc 
Ashland 
Brenntag Inc 
Delta Distributors Inc 
DSM Fine Chemicals Inc 
Hawkins Chemical Inc 
Helm New York Inc 
Merisant 
Spectrum Quality Products Inc 
Triple Crown America 
Voigt Global Distribution LLC 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
Xinchem Co 
Bentonite 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Paroxite (London) Ltd 
Raught Ltd 
Tennants (Distribution) Ltd 
Thew, Arnott and Co Ltd 
Wilfrid Smith Ltd 
USA 
American Colloid Co 
Charles B Chrystal Co Inc 
Farma International Inc 
Kraft Chemical Co 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Whittaker Clark, and Daniels Inc 
Benzalkonium Chloride 
UK 
Raught Ltd 
Tennants (Distribution) Ltd 
Ubichem plc 
Other European 
Brenntag AG 
FeF Chemicals A/S 
USA 
AerChem Inc 
Alfa Chem 
Brenntag Inc 
EM Industries Inc 
Penta Manufacturing Co 
RIA International 
Sanofi-Synthelabo Inc 
Spectrum Quality Products Inc 
Triple Crown America 
Others 
Yee Young Cerachem Ltd 
Benzethonium Chloride 
UK 
Lonza UK Ltd 
Other European 
Lonza Ltd 
USA 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Benzoic Acid 
UK 
Ashland 
Clariant UK Ltd 
Cornelius Group plc 
Courtin & Warner Ltd 
Dow Chemical Company (UK) 
DSM UK Ltd 
Fisher Scientific UK Ltd 
JT Baker UK 
Raught Ltd 
Sparkford Chemicals Ltd 
Tennants (Distribution) Ltd 
Ubichem plc 
Other European 
Brenntag AG 
DSM Fine Chemicals 
Haltermann GmbH 
USA 
Aceto Corp 
AerChem Inc 
Amresco Inc 
Brenntag Inc 
Charkit Chemical Corp 
DSM Fine Chemicals Inc 
EM Industries Inc 
Fisher Scientific 
JT Baker Inc 
Mutchler Inc 
Napp Technologies Inc 
Nipa Laboratories Inc 
Penta Manufacturing Co 
RIA International 
Spectrum Quality Products Inc 
Triple Crown America 
Voigt Global Distribution LLC 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
San Fu Chemical Company Ltd 
Benzyl Alcohol 
UK 
DSM UK Ltd 
Fisher Scientific UK Ltd 
Haarmann & Reimer Ltd 
JT Baker UK 
Raught Ltd 
Tennants (Distribution) Ltd 
Ubichem plc 
Other European 
Brenntag AG 
Chemco France 
DSM Fine Chemicals 
Haarmann & Reimer GmbH 
Tessenderlo Chemie 
USA 
AerChem Inc 
Brenntag Inc 
Charkit Chemical Corp 
DSM Fine Chemicals Inc 
EM Industries Inc 
Fisher Scientific 
Hawkins Chemical Inc 
JT Baker Inc 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
Benzyl Benzoate 
UK 
Dow Chemical Company (UK) 
Haarmann & Reimer Ltd 
Raught Ltd 
William Ransom & Son plc 
Other European 
Haarmann & Reimer GmbH 
Haltermann GmbH 
Helm AG 
USA 
Helm New York Inc 
Morflex Inc 
Mutchler Inc 
Penta Manufacturing Co 
Reilly Industries Inc 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Appendix I: Suppliers Directory 837

Others 
LS Raw Materials Ltd 
Bronopol 
UK 
Honeywill & Stein 
Raught Ltd 
Tennants (Distribution) Ltd 
Other European 
BASF Aktiengesellschaft 
USA 
BASF Corp 
Inolex Chemical Co 
Spectrum Quality Products Inc 
Others 
Cosmos Chemical Co Ltd 
LS Raw Materials Ltd 
Butylated Hydroxyanisole 
UK 
Eastman Company UK Ltd 
Honeywill & Stein 
Sparkford Chemicals Ltd 
Other European 
Brenntag AG 
USA 
Aceto Corp 
Ashland 
Brenntag Inc 
Delta Distributors Inc 
Eastman Chemical Co 
Kraft Chemical Co 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Others 
LS Raw Materials Ltd 
Butylated Hydroxytoluene 
UK 
Eastman Company UK Ltd 
Honeywill & Stein 
Raught Ltd 
Sparkford Chemicals Ltd 
Other European 
Brenntag AG 
Helm AG 
USA 
Aceto Corp 
Alfa Chem 
Ashland 
Brenntag Inc 
Delta Distributors Inc 
Eastman Chemical Co 
Helm New York Inc 
Kraft Chemical Co 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Others 
LS Raw Materials Ltd 
Butylparaben 
UK 
Clariant UK Ltd 
JT Baker UK 
Other European 
Chemag Aktiengesellschaft 
Induchem AG 
USA 
JT Baker Inc 
Lipo Chemicals Inc 
Napp Technologies Inc 
Nipa Laboratories Inc 
Penta Manufacturing Co 
Protameen Chemicals 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Vopak USA Inc 
Calcium Carbonate 
UK 
Blagden Specialty Chemicals Ltd 
DMV UK 
Fisher Scientific UK Ltd 
Forum Biosciences Ltd 
JT Baker UK 
Paroxite (London) Ltd 
Peter Whiting (Chemicals) Ltd 
Tennants (Distribution) Ltd 
Thew, Arnott and Co Ltd 
Other European 
August Hedinger GmbH & Co 
Brenntag AG 
DMV Pharma 
Dr Paul Lohmann GmbH KG 
J Rettenmaier & So. hne GmbH and Co 
Lehmann & Voss & Co 
Magnesia GmbH 
Schaefer Kalk KG 
USA 
Aceto Corp 
AerChem Inc 
Barrington Chemical Corp 
Brenntag Inc 
Charles B Chrystal Co Inc 
Delta Distributors Inc 
EM Industries Inc 
EM Sergeant Pulp & Chemical Co Inc 
Fisher Scientific 
Generichem Corp 
Hawkins Chemical Inc 
JT Baker Inc 
Mutchler Inc 
Particle Dynamics Inc 
Penta Manufacturing Co 
RIA International 
Spectrum Quality Products Inc 
SPI Pharma Group 
Triple Crown America 
Voigt Global Distribution LLC 
Vopak USA Inc 
Whittaker Clark, and Daniels Inc 
Calcium Phosphate, Dibasic Anhydrous 
UK 
Forum Biosciences Ltd 
JRS Pharma Ltd 
Peter Whiting (Chemicals) Ltd 
Raught Ltd 
Rhodia Organic Fine Ltd 
Other European 
Brenntag AG 
USA 
Brenntag Inc 
Charkit Chemical Corp 
Fuji Chemical Industries Health Science 
(USA) Inc 
Gallard-Schlesinger Industries 
JRS Pharma LP 
Mutchler Inc 
Penta Manufacturing Co 
Rhodia Pharma Solutions Inc 
Spectrum Quality Products Inc 
Triple Crown America 
Others 
Fuji Chemical Industry Co Ltd 
Calcium Phosphate, Dibasic Dihydrate 
UK 
Fisher Scientific UK Ltd 
Forum Biosciences Ltd 
JRS Pharma Ltd 
Peter Whiting (Chemicals) Ltd 
Raught Ltd 
Rhodia Organic Fine Ltd 
Other European 
Brenntag AG 
USA 
Aceto Corp 
Brenntag Inc 
Fisher Scientific 
Gallard-Schlesinger Industries 
JRS Pharma LP 
Mutchler Inc 
Penta Manufacturing Co 
Rhodia Pharma Solutions Inc 
Spectrum Quality Products Inc 
Triple Crown America 
Calcium Phosphate, Tribasic 
UK 
Fisher Scientific UK Ltd 
Peter Whiting (Chemicals) Ltd 
Raught Ltd 
Rhodia Organic Fine Ltd 
Other European 
Brenntag AG 
Brenntag NV 
USA 
Brenntag Inc 
Fisher Scientific 
Gallard-Schlesinger Industries 
Penta Manufacturing Co 
Rhodia Pharma Solutions Inc 
Spectrum Quality Products Inc 
Triple Crown America 
838 Appendix I: Suppliers Directory

Calcium Stearate 
UK 
Allchem Pharma 
James M Brown Ltd 
Paroxite (London) Ltd 
Raught Ltd 
Tennants (Distribution) Ltd 
Other European 
Brenntag AG 
Dr Paul Lohmann GmbH KG 
Magnesia GmbH 
USA 
Aceto Corp 
AerChem Inc 
Alfa Chem 
Ashland 
Brenntag Inc 
Charkit Chemical Corp 
Kraft Chemical Co 
JT Baker Inc 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Voigt Global Distribution LLC 
Vopak USA Inc 
Whittaker Clark, and Daniels Inc 
Calcium Sulfate 
UK 
Forum Biosciences Ltd 
JRS Pharma Ltd 
Paroxite (London) Ltd 
Peter Whiting (Chemicals) Ltd 
Other European 
Dr Paul Lohmann GmbH KG 
USA 
AerChem Inc 
Charles B Chrystal Co Inc 
JRS Pharma LP 
Particle Dynamics Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Voigt Global Distribution LLC 
Vopak USA Inc 
Whittaker Clark, and Daniels Inc 
Canola Oil 
UK 
Aarhus United UK Ltd 
Adina Chemicals Ltd 
Karlshamns Ltd 
Other European 
Aarhus United Denmark A/S 
Karlshamns AB 
USA 
Aarhus United USA Inc 
Arista Industries Inc 
Charkit Chemical Corp 
Lipo Chemicals Inc 
Penta Manufacturing Co 
Pokonobe Industries Inc 
Welch, Holme & Clark Co Inc 
Carbomer 
UK 
Goldschmidt UK Ltd 
USA 
Noveon Inc 
Rita Corp 
Spectrum Quality Products Inc 
Carbon Dioxide 
UK 
Air Liquide UK Ltd 
Air Products (Gases) plc 
BOC Gases 
USA 
Air Liquide America Corp 
BOC Gases 
Carboxymethylcellulose Calcium 
USA 
Aceto Corp 
Ashland 
Kraft Chemical Co 
Carboxymethylcellulose Sodium 
UK 
Hercules Ltd 
Honeywill & Stein 
Other European 
Akzo Nobel Functional Chemicals bv 
Brenntag AG 
Lehmann & Voss & Co 
Noviant 
USA 
Aqualon 
Ashland 
Brenntag Inc 
Delta Distributors Inc 
FMC Biopolymer 
Kraft Chemical Co 
Spectrum Quality Products Inc 
Whittaker Clark, and Daniels Inc 
Carrageenan 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Paroxite (London) Ltd 
Thew, Arnott and Co Ltd 
Other European 
Brenntag AG 
FMC Biopolymer 
Lehmann & Voss & Co 
USA 
Aqualon 
Ashland 
Brenntag Inc 
Charkit Chemical Corp 
Delta Distributors Inc 
FMC Biopolymer 
Spectrum Quality Products Inc 
TIC Gums 
Voigt Global Distribution LLC 
Castor Oil 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Adina Chemicals Ltd 
Alembic Products Ltd 
Blagden Speciality Chemicals Ltd 
Corcoran Chemicals Ltd 
Croda Chemicals Ltd 
Fisher Scientific UK Ltd 
JT Baker UK 
Kimpton Brothers Ltd 
Paroxite (London) Ltd 
White Sea and Baltic Company Ltd 
William Ransom & Son plc 
WS Lloyd Ltd 
USA 
Acme-Hardesty 
Arista Industries Inc 
Avatar Corp 
Charkit Chemical Corp 
Croda Inc 
Fisher Scientific 
JT Baker Inc 
Lipo Chemicals Inc 
Mutchler Inc 
Paddock Laboratories Inc 
Penta Manufacturing Co 
Pokonobe Industries Inc 
Spectrum Quality Products Inc 
Triple Crown America 
Voigt Global Distribution LLC 
Vopak USA Inc 
Welch, Holme & Clark Co Inc 
Castor Oil, Hydrogenated 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Cognis UK Ltd 
Cornelius Group plc 
Croda Chemicals Ltd 
Goldschmidt UK Ltd 
Paroxite (London) Ltd 
White Sea and Baltic Company Ltd 
Other European 
Arion & Delahaye 
Cognis Deutschland GmbH 
USA 
ABITEC Corp 
Cognis Corp 
Croda Inc 
GR O’Shea Company 
Cellulose, Microcrystalline 
UK 
Allchem Pharma 
Cornelius Group plc 
DMV UK 
Forum Biosciences Ltd 
Honeywill & Stein 
ISP Europe 
JRS Pharma Ltd 
Appendix I: Suppliers Directory 839

Other European 
DMV Pharma 
FMC Biopolymer 
Helm AG 
J Rettenmaier & So. hne GmbH and Co 
Lehmann & Voss & Co 
NP Pharm 
USA 
Alfa Chem 
Ashland 
Barrington Chemical Corp 
Delta Distributors Inc 
FMC Biopolymer 
Helm New York Inc 
International Specialty Products 
JRS Pharma LP 
Mutchler Inc 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Others 
Aastrid International 
Asahi Kasei Corporation 
Glide Chem Pvt Ltd 
LS Raw Materials Ltd 
Cellulose, Powdered 
UK 
Allchem Pharma 
Other European 
CFF GmbH and Co KG 
J Rettenmaier & So. hne GmbH and Co 
USA 
Alfa Chem 
International Fiber Corporation 
Mutchler Inc 
Triple Crown America 
Voigt Global Distribution LLC 
Cellulose, Silicified Microcrystalline 
UK 
JRS Pharma Ltd 
Other European 
J Rettenmaier & So. hne GmbH and Co 
USA 
JRS Pharma LP 
Cellulose Acetate 
UK 
Eastman Company UK Ltd 
Honeywill & Stein 
Eastman Chemical Co 
Cellulose Acetate Phthalate 
UK 
Eastman Company UK Ltd 
Honeywill & Stein 
Raught Ltd 
Other European 
FMC Biopolymer 
Lehmann & Voss & Co 
USA 
Eastman Chemical Co 
FMC Biopolymer 
Ceratonia 
UK 
Rhodia Organic Fine Ltd 
Other European 
Brenntag AG 
USA 
Ashland 
Brenntag Inc 
Rhodia Pharma Solutions Inc 
TIC Gums 
Cetostearyl Alcohol 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Cognis UK Ltd 
Croda Chemicals Ltd 
Efkay Chemicals Ltd 
Goldschmidt UK Ltd 
H Foster & Co (Stearines) Ltd 
Raught Ltd 
White Sea and Baltic Company Ltd 
Other European 
BASF Aktiengesellschaft 
Cognis Deutschland GmbH 
USA 
Avatar Corp 
BASF Corp 
Cognis Corp 
Croda Inc 
Penta Manufacturing Co 
Rita Corp 
Spectrum Quality Products Inc 
Others 
LS Raw Materials Ltd 
Cetrimide 
UK 
Cornelius Group plc 
Raught Ltd 
Other European 
FeF Chemicals A/S 
USA 
Aceto Corp 
Alfa Chem 
Triple Crown America 
Others 
LS Raw Materials Ltd 
Cetyl Alcohol 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Aarhus United UK Ltd 
Adina Chemicals Ltd 
Cognis UK Ltd 
Croda Chemicals Ltd 
Efkay Chemicals Ltd 
Goldschmidt UK Ltd 
Kimpton Brothers Ltd 
Raught Ltd 
White Sea and Baltic Company Ltd 
Other European 
Aarhus United Denmark A/S 
Brenntag AG 
Cognis Deutschland GmbH 
USA 
Aarhus United USA Inc 
Avatar Corp 
Brenntag Inc 
Cognis Corp 
Croda Inc 
Hawkins Chemical Inc 
Kraft Chemical Co 
Lipo Chemicals Inc 
M Michel and Company Inc 
Mutchler Inc 
Penta Manufacturing Co 
Protameen Chemicals 
Rita Corp 
Spectrum Quality Products Inc 
Stepan Co 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
Cetylpyridinium Chloride 
USA 
Aceto Corp 
Chitosan 
UK 
FMC Biopolymer 
USA 
FMC Biopolymer 
Seltzer Chemicals Inc 
Chlorhexidine 
UK 
Raught Ltd 
USA 
George Uhe Co Inc 
Napp Technologies Inc 
Others 
LS Raw Materials Ltd 
Chlorobutanol 
UK 
Blagden Specialty Chemicals Ltd 
Courtin & Warner Ltd 
Raught Ltd 
USA 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Others 
LS Raw Materials Ltd 
840 Appendix I: Suppliers Directory

Chlorocresol 
UK 
Raught Ltd 
Others 
LS Raw Materials Ltd 
Chlorodifluoroethane (HCFC) 
UK 
Allchem Pharma 
Other European 
DuPont de Nemours Int’l SA 
Solvay Fluor GmbH 
USA 
DuPont 
Chloroxylenol 
UK 
Coventry Chemicals Ltd 
Raught Ltd 
USA 
Nipa Laboratories Inc 
Spectrum Quality Products Inc 
Cholesterol 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Croda Chemicals Ltd 
JT Baker UK 
Paroxite (London) Ltd 
Ubichem plc 
USA 
Aceto Corp 
Amresco Inc 
Avanti Polar Lipids Inc 
Charles Bowman & Co 
Croda Inc 
EM Industries Inc 
JT Baker Inc 
Penta Manufacturing Co 
Rita Corp 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Citric Acid Monohydrate 
UK 
Blagden Specialty Chemicals Ltd 
Cerestar UK Ltd 
Courtin & Warner Ltd 
Fisher Scientific UK Ltd 
JT Baker UK 
Peter Whiting (Chemicals) Ltd 
Raught Ltd 
Roche Products Ltd 
Tate and Lyle plc 
Tennants (Distribution) Ltd 
Thew, Arnott and Co Ltd 
Ubichem plc 
Other European 
Arion & Delahaye 
Brenntag AG 
Cerestar International 
Dr Paul Lohmann GmbH KG 
Jungbunzlauer 
USA 
Aceto Corp 
Amresco Inc 
Ashland 
Avatar Corp 
Brenntag Inc 
Charkit Chemical Corp 
Delta Distributors Inc 
EM Industries Inc 
EM Sergeant Pulp & Chemical Co Inc 
Fisher Scientific 
George Uhe Co Inc 
Hawkins Chemical Inc 
JT Baker Inc 
Kraft Chemical Co 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Voigt Global Distribution LLC 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
Colloidal Silicon Dioxide 
UK 
Degussa Ltd 
Grace Davison 
Wacker Chemicals Ltd 
Other European 
Biesterfeld Spezialchemie GmbH 
Brenntag AG 
Cabot GmbH 
Degussa AG 
Wacker-Chemie GmbH 
USA 
Brenntag Inc 
Cabot Corp 
Degussa Corp 
Mutchler Inc 
Vopak USA Inc 
Wacker Chemical Corp 
Coloring Agents 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Colorcon Ltd 
DMV UK 
Thew, Arnott and Co Ltd 
Other European 
DMV Pharma 
USA 
Ashland 
Colorcon 
Triple Crown America 
Warner Jenkinson Pharmaceutical 
Whittaker Clark, and Daniels Inc 
Copovidone 
UK 
BASF Plc 
Other European 
ISP Europe 
BASF Aktiengesellschaft 
USA 
BASF Corp 
International Specialty Products 
Corn Oil 
UK 
Aarhus United UK Ltd 
Alembic Products Ltd 
Cerestar UK Ltd 
Cognis UK Ltd 
Efkay Chemicals Ltd 
Karlshamns Ltd 
Other European 
Aarhus United Denmark A/S 
Cerestar International 
Cognis Deutschland GmbH 
Karlshamns AB 
USA 
Aarhus United USA Inc 
Arista Industries Inc 
Avatar Corp 
Cargill Corp 
Charkit Chemical Corp 
Cognis Corp 
Grain Processing Corp 
Penta Manufacturing Co 
Pokonobe Industries Inc 
Spectrum Quality Products Inc 
Welch, Holme & Clark Co Inc 
Cottonseed Oil 
UK 
Blagden Specialty Chemicals Ltd 
Fisher Scientific UK Ltd 
Karlshamns Ltd 
Other European 
Karlshamns AB 
USA 
Arista Industries Inc 
Charkit Chemical Corp 
Fisher Scientific 
Hawkins Chemical Inc 
Mutchler Inc 
Penta Manufacturing Co 
Pokonobe Industries Inc 
Spectrum Quality Products Inc 
Welch, Holme & Clark Co Inc 
Cresol 
USA 
Amresco Inc 
Penta Manufacturing Co 
PMC Specialities Group Inc 
Spectrum Quality Products Inc 
Appendix I: Suppliers Directory 841

Croscarmellose Sodium 
UK 
Allchem Pharma 
Avebe UK Ltd 
DMV UK 
Honeywill & Stein 
Other European 
Akzo Nobel Functional Chemicals bv 
Avebe Group 
DMV Pharma 
FMC Biopolymer 
J Rettenmaier & So. hne GmbH and Co 
Lehmann & Voss & Co 
USA 
Avebe America Inc 
FMC Biopolymer 
Generichem Corp 
Mutchler Inc 
RIA International 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Crospovidone 
UK 
BASF Plc 
Blagden Specialty Chemicals Ltd 
ISP Europe 
Other European 
August Hedinger GmbH & Co 
BASF Aktiengesellschaft 
USA 
BASF Corp 
International Specialty Products 
Cyclodextrins 
UK 
Cerestar UK Ltd 
Pfanstiehl (Europe) Ltd 
Roquette (UK) Ltd 
Wacker Chemicals Ltd 
Other European 
Cerestar International 
Roquette Fre`res 
Wacker-Chemie GmbH 
USA 
Cargill Corp 
CTD Inc 
Ferro Pfanstiehl Laboratories Inc 
Research Diagnostics Inc 
Roquette America Inc 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Wacker Chemical Corp 
Cyclomethicone 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Dow Corning 
USA 
Dow Corning 
Denatonium Benzoate 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
USA 
Barrington Chemical Corp 
Burlington Bio-medical and Scientific Corp 
Chart Corp Inc 
Others 
Fine Chemicals Corporation (Pty) Ltd 
Dextrates 
UK 
Forum Biosciences Ltd 
JRS Pharma Ltd 
Other European 
J Rettenmaier & So. hne GmbH and Co 
JRS Pharma LP 
USA 
Spectrum Quality Products Inc 
Dextrin 
UK 
Avebe UK Ltd 
Roquette (UK) Ltd 
Tennants (Distribution) Ltd 
Other European 
Avebe Group 
USA 
Avebe America Inc 
Generichem Corp 
Mutchler Inc 
Roquette Fre`res 
Vopak USA Inc 
Dextrose 
UK 
Cerestar UK Ltd 
Corcoran Chemicals Ltd 
Fisher Scientific UK Ltd 
Forum Biosciences Ltd 
JT Baker UK 
Pfanstiehl (Europe) Ltd 
Raught Ltd 
Roquette (UK) Ltd 
Other European 
Biesterfeld Spezialchemie GmbH 
Brenntag AG 
Cerestar International 
Helm AG 
Roquette Fre`res 
USA 
Ashland 
Brenntag Inc 
Cargill Corp 
Delta Distributors Inc 
EM Sergeant Pulp & Chemical Co Inc 
Fisher Scientific 
Helm New York Inc 
JT Baker Inc 
Mutchler Inc 
Penta Manufacturing Co 
Ferro Pfanstiehl Laboratories Inc 
Roquette America Inc 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
Dibutyl Sebacate 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
USA 
Aceto Corp 
Morflex Inc 
Penta Manufacturing Co 
Reilly Industries Inc 
Sigma-Aldrich Corp 
Diethanolamine 
UK 
Sasol UK Ltd 
Tennants (Distribution) Ltd 
Ubichem plc 
Other European 
Brenntag AG 
USA 
Amresco Inc 
Brenntag Inc 
Sasol North America Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Vopak USA Inc 
Diethyl Phthalate 
UK 
BASF Plc 
Eastman Company UK Ltd 
Other European 
BASF Aktiengesellschaft 
Brenntag AG 
USA 
BASF Corp 
Brenntag Inc 
Eastman Chemical Co 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Vopak USA Inc 
Difluoroethane (HFC) 
Other European 
DuPont de Nemours Int’l SA 
Solvay Fluor GmbH 
USA 
Aeropres Corp 
842 Appendix I: Suppliers Directory

Dimethicone 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Dow Corning 
Goldschmidt UK Ltd 
Honeywill & Stein 
Raught Ltd 
Other European 
Biesterfeld Spezialchemie GmbH 
USA 
Crompton Corp 
Dow Corning 
Dimethyl Ether 
UK 
Air Liquide UK Ltd 
Other European 
DuPont de Nemours Int’l SA 
USA 
Aeropres Corp 
Dimethyl Sulfoxide 
USA 
Spectrum Quality Products Inc 
Dimethylacetamide 
UK 
BASF Plc 
JT Baker UK 
Sigma-Aldrich Company Ltd 
Other European 
BASF Aktiengesellschaft 
DuPont de Nemours Int’l SA 
USA 
DuPont 
Spectrum Quality Products Inc 
Docusate Sodium 
USA 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Edetic Acid 
Other European 
Akzo Nobel Functional Chemicals bv 
USA 
Brenntag Inc 
Dow Chemical Co 
Spectrum Quality Products Inc 
Erythorbic Acid 
USA 
Biddle Sawyer Corp 
Brainerd Chemical Company Inc 
Premium Ingredients Ltd 
Seidler Chemical Company 
Zhong Ya Chemical (USA) Ltd 
Others 
Univar Canada Ltd 
Wintersun Chemical 
Erythritol 
UK 
Cerestar UK Ltd 
Other European 
Cerestar International 
USA 
Cargill Corp 
Others 
Mitsubishi-Kagaku Foods Corporation 
Ethyl Acetate 
UK 
BP plc 
Corcoran Chemicals Ltd 
Eastman Company UK Ltd 
Fisher Scientific UK Ltd 
Raught Ltd 
Tennants (Distribution) Ltd 
Other European 
August Hedinger GmbH & Co 
USA 
BP Inc 
AerChem Inc 
Dow Chemical Co 
Eastman Chemical Co 
Fisher Scientific 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Others 
Aastrid International 
Ethyl Maltol 
Other European 
Helm AG 
USA 
Helm New York Inc 
Penta Manufacturing Co 
Ethyl Oleate 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Croda Chemicals Ltd 
USA 
Croda Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Ethyl Vanillin 
UK 
Blagden Specialty Chemicals Ltd 
Courtin & Warner Ltd 
Other European 
Brenntag AG 
Helm AG 
USA 
AerChem Inc 
Ashland 
Brenntag Inc 
Chart Corp Inc 
Delta Distributors Inc 
Helm New York Inc 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Vopak USA Inc 
Ethylcellulose 
UK 
Hercules Ltd 
Honeywill & Stein 
Other European 
FMC Biopolymer 
USA 
Aqualon 
Dow Chemical Co 
FMC Biopolymer 
Mutchler Inc 
Spectrum Quality Products Inc 
Vopak USA Inc 
Others 
Glide Chem Pvt Ltd 
Ethylene Vinyl Acetate 
UK 
3M United Kingdom Plc 
USA 
3M Drug Delivery Systems 
Ethylparaben 
UK 
Clariant UK Ltd 
Other European 
Brenntag AG 
Chemag Aktiengesellschaft 
Induchem AG 
USA 
Brenntag Inc 
Lipo Chemicals Inc 
Napp Technologies Inc 
Nipa Laboratories Inc 
Penta Manufacturing Co 
Protameen Chemicals 
Spectrum Quality Products Inc 
Vopak USA Inc 
Fructose 
UK 
Cerestar UK Ltd 
Corcoran Chemicals Ltd 
Danisco Sweeteners Ltd 
Fisher Scientific UK Ltd 
Forum Biosciences Ltd 
Pfanstiehl (Europe) Ltd 
Appendix I: Suppliers Directory 843

Other European 
Amylum Ibe.rica, SA 
Brenntag AG 
Cerestar International 
USA 
Aceto Corp 
Tate & Lyle 
Alfa Chem 
Amresco Inc 
Ashland 
Barrington Chemical Corp 
Brenntag Inc 
Cargill Corp 
Danisco USA Inc 
EM Industries Inc 
Fisher Scientific 
Penta Manufacturing Co 
Ferro Pfanstiehl Laboratories Inc 
Spectrum Quality Products Inc 
SPI Pharma Group 
Voigt Global Distribution LLC 
Others 
LS Raw Materials Ltd 
Fumaric Acid 
UK 
DSM UK Ltd 
Lonza UK Ltd 
Peter Whiting (Chemicals) Ltd 
Raught Ltd 
Sparkford Chemicals Ltd 
Other European 
Brenntag AG 
DSM Fine Chemicals 
Helm AG 
Lonza Ltd 
USA 
Aceto Corp 
Tate & Lyle 
Alfa Chem 
Ashland 
Brenntag Inc 
DSM Fine Chemicals Inc 
Gallard-Schlesinger Industries 
Helm New York Inc 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Takeda Pharmaceuticals North 
America Inc 
Triple Crown America 
Vopak USA Inc 
Others 
Aastrid International 
Takeda Pharmaceutical Company Ltd 
Gelatin 
UK 
Corcoran Chemicals Ltd 
Croda Chemicals Ltd 
Global Ceramic Materials Ltd 
JT Baker UK 
Paroxite (London) Ltd 
PB Gelatins UK Ltd 
Thew, Arnott and Co Ltd 
Other European 
Gelatine Smits Beheer BV 
PB Gelatins Belgium 
USA 
Ashland 
Gallard-Schlesinger Industries 
JT Baker Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Glucose, Liquid 
UK 
Cerestar UK Ltd 
Courtin & Warner Ltd 
Roquette (UK) Ltd 
Other European 
Amylum Ibe.rica, SA 
Cerestar International 
Roquette Fre`res 
USA 
Cargill Corp 
Delta Distributors Inc 
Penta Manufacturing Co 
Roquette America Inc 
Glycerin 
UK 
Cognis UK Ltd 
Corcoran Chemicals Ltd 
Courtin & Warner Ltd 
Croda Chemicals Ltd 
Efkay Chemicals Ltd 
Fisher Scientific UK Ltd 
H Foster & Co (Stearines) Ltd 
JT Baker UK 
Karlshamns Ltd 
Kimpton Brothers Ltd 
Lonza UK Ltd 
Raught Ltd 
Stan Chem International Ltd 
Tennants (Distribution) Ltd 
Uniqema 
White Sea and Baltic Company Ltd 
William Ransom & Son plc 
Other European 
August Hedinger GmbH & Co 
Brenntag AG 
Cognis Deutschland GmbH 
Karlshamns AB 
Lonza Ltd 
USA 
Alfa Chem 
Ashland 
Avatar Corp 
Brenntag Inc 
Cognis Corp 
Delta Distributors Inc 
Dow Chemical Co 
Fisher Scientific 
JT Baker Inc 
Kraft Chemical Co 
Penta Manufacturing Co 
Protameen Chemicals 
Rita Corp 
Spectrum Quality Products Inc 
Triple Crown America 
Voigt Global Distribution LLC 
Vopak USA Inc 
Welch, Holme & Clark Co Inc 
Others 
Gadot Petrochemical Industries Ltd 
Glyceryl Behenate 
UK 
Alfa Chemicals Ltd/Gattefosse. UK 
Other European 
Gattefosse. s.a. 
USA 
Gattefosse. Corp 
Glyceryl Monooleate 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Alfa Chemicals Ltd/Gattefosse. UK 
Cognis UK Ltd 
Croda Chemicals Ltd 
Goldschmidt UK Ltd 
Honeywill & Stein 
Lonza UK Ltd 
Other European 
Cognis Deutschland GmbH 
Gattefosse. s.a. 
Lonza Ltd 
USA 
ABITEC Corp 
Cognis Corp 
Croda Inc 
Penta Manufacturing Co 
Gattefosse. Corp 
Stepan Co 
Vopak USA Inc 
Glyceryl Monostearate 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Alfa Chemicals Ltd 
Cognis UK Ltd 
Corcoran Chemicals Ltd 
Croda Chemicals Ltd 
Goldschmidt UK Ltd 
H Foster & Co (Stearines) Ltd 
Honeywill & Stein 
Lonza UK Ltd 
Sasol UK Ltd 
Other European 
Cognis Deutschland GmbH 
Gattefosse. s.a. 
Lonza Ltd 
USA 
ABITEC Corp 
Sasol North America Inc 
Cognis Corp 
Croda Inc 
844 Appendix I: Suppliers Directory

Delta Distributors Inc 
Gattefosse. Corp 
Lipo Chemicals Inc 
Mutchler Inc 
Penta Manufacturing Co 
Protameen Chemicals 
Rita Corp 
Stepan Co 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
Glyceryl Palmitostearate 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Alfa Chemicals Ltd/Gattefosse. UK 
Other European 
Gattefosse. s.a. 
USA 
Gattefosse. Corp 
Guar Gum 
UK 
AF Suter and Co Ltd 
Corcoran Chemicals Ltd 
Rhodia Organic Fine Ltd 
Stan Chem International Ltd 
Thew, Arnott and Co Ltd 
Other European 
Brenntag AG 
Helm AG 
USA 
Aqualon 
Ashland 
Barrington Chemical Corp 
Brenntag Inc 
Charkit Chemical Corp 
Chart Corp Inc 
Delta Distributors Inc 
Helm New York Inc 
Penta Manufacturing Co 
Rhodia Pharma Solutions Inc 
Spectrum Quality Products Inc 
TIC Gums 
Triple Crown America 
Voigt Global Distribution LLC 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
Hectorite 
USA 
Rennecker Ltd 
Heptafluoropropane (HFC) 
Other European 
DuPont de Nemours Int’l SA 
Hydrocarbons (HC) 
UK 
Air Products (Gases) plc 
Tennants (Distribution) Ltd 
Other European 
Chevron Texaco Global Lubricants 
Benelux 
Hydrochloric Acid 
UK 
JT Baker UK 
Tennants (Distribution) Ltd 
Other European 
Brenntag AG 
USA 
AerChem Inc 
Ashland 
Brenntag Inc 
Delta Distributors Inc 
EM Industries Inc 
JT Baker Inc 
Spectrum Quality Products Inc 
Triple Crown America 
Vopak USA Inc 
Hydroxyethyl Cellulose 
UK 
Clariant UK Ltd 
Hercules Ltd 
Honeywill & Stein 
Paroxite (London) Ltd 
USA 
Aqualon 
Clariant Corp 
Delta Distributors Inc 
Dow Chemical Co 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Hydroxyethylmethyl Cellulose 
UK 
Clariant UK Ltd 
Hercules Ltd 
USA 
Aqualon 
Clariant Corp 
Hydroxypropyl Cellulose 
UK 
Hercules Ltd 
Honeywill & Stein 
Other European 
Nippon Soda Co Ltd 
USA 
Aqualon 
Nippon Soda Co Ltd 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Others 
Nippon Soda Co Ltd 
Hydroxypropyl Cellulose, Lowsubstituted 
UK 
RW Unwin & Co Ltd 
USA 
Biddle Sawyer Corp 
Voigt Global Distribution LLC 
Others 
Shin-Etsu Chemical Co Ltd 
Hydroxypropyl Starch 
UK 
Tate & Lyle plc 
Cerestar UK Ltd 
USA 
Lipscomb Chemical Company Inc 
Hypromellose 
UK 
Clariant UK Ltd 
Colorcon Ltd 
RW Unwin & Co Ltd 
Ubichem plc 
USA 
Ashland 
Biddle Sawyer Corp 
Clariant Corp 
Colorcon 
Cornelius Group plc 
Dow Chemical Co 
Hawkins Chemical Inc 
Spectrum Quality Products Inc 
Warner Jenkinson Pharmaceutical 
Vopak USA Inc 
Others 
Glide Chem Pvt Ltd 
Shin-Etsu Chemical Co Ltd 
Hypromellose Acetate Succinate 
UK 
RW Unwin & Co Ltd 
Others 
Shin-Etsu Chemical Co Ltd 
Hypromellose Phthalate 
UK 
RW Unwin & Co Ltd 
Ubichem plc 
USA 
Biddle Sawyer Corp 
Others 
Shin-Etsu Chemical Co Ltd 
Imidurea 
UK 
ISP Europe 
USA 
International Specialty Products 
Protameen Chemicals 
Spectrum Quality Products Inc 
Appendix I: Suppliers Directory 845

Inulin 
Other European 
Orafti 
Palatinit GmbH 
Sensus 
USA 
Sensus America LLC 
TIC Gums 
Iron Oxides 
UK 
Lanxess Ltd 
PMC Chemicals Ltd 
USA 
Reade Advanced Materials Inc 
Lanxess Corp 
Isomalt 
Other European 
Cargill Cerestar BVBA 
Palatinit GmbH 
USA 
Cargill Corp 
Others 
Cerestar Jiliang Maize Industry Co Ltd 
Isopropyl Alcohol 
UK 
Honeywill & Stein 
JT Baker UK 
Sasol UK Ltd 
Tennants (Distribution) Ltd 
William Ransom & Son plc 
Other European 
August Hedinger GmbH & Co 
Brenntag AG 
Sasol Germany GmbH 
USA 
Amresco Inc 
Brenntag Inc 
Delta Distributors Inc 
Dow Chemical Co 
JT Baker Inc 
Penta Manufacturing Co 
Sasol North America Inc 
Spectrum Quality Products Inc 
Triple Crown America 
Vopak USA Inc 
Isopropyl Myristate 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Adina Chemicals Ltd 
Cognis UK Ltd 
Corcoran Chemicals Ltd 
Croda Chemicals Ltd 
Dow Chemical Company (UK) 
Goldschmidt UK Ltd 
Paroxite (London) Ltd 
Uniqema 
Other European 
Brenntag AG 
Cognis Deutschland GmbH 
Haltermann GmbH 
USA 
Akzo Nobel Inc 
Brenntag Inc 
Cognis Corp 
Croda Inc 
Delta Distributors Inc 
Inolex Chemical Co 
Kraft Chemical Co 
Lipo Chemicals Inc 
Penta Manufacturing Co 
Rita Corp 
Spectrum Quality Products Inc 
Stepan Co 
Others 
LS Raw Materials Ltd 
Isopropyl Palmitate 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Adina Chemicals Ltd 
Cognis UK Ltd 
Croda Chemicals Ltd 
Dow Chemical Company (UK) 
Goldschmidt UK Ltd 
Paroxite (London) Ltd 
Other European 
Brenntag AG 
Cognis Deutschland GmbH 
Haltermann GmbH 
USA 
Alzo International Inc 
Brenntag Inc 
Cognis Corp 
Croda Inc 
Eastech Chemical Inc 
Inolex Chemical Co 
Kraft Chemical Co 
Lipo Chemicals Inc 
Penta Manufacturing Co 
Noveon Inc 
Protameen Chemicals 
Rita Corp 
Spectrum Quality Products Inc 
Stepan Co 
Others 
Choice Korea Co 
Pachem Distributions Inc 
Kaolin 
UK 
Fisher Scientific UK Ltd 
JT Baker UK 
Paroxite (London) Ltd 
Raught Ltd 
Sigma-Aldrich Company Ltd 
Tennants (Distribution) Ltd 
Thew, Arnott and Co Ltd 
USA 
Sigma-Aldrich Corp 
Charles B Chrystal Co Inc 
Fisher Scientific 
JT Baker Inc 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Whittaker Clark, and Daniels Inc 
William Ransom & Son plc 
Lactic Acid 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Corcoran Chemicals Ltd 
Fisher Scientific UK Ltd 
JT Baker UK 
Peter Whiting (Chemicals) Ltd 
Pfanstiehl (Europe) Ltd 
Purac Biochem (UK) 
Raught Ltd 
Tennants (Distribution) Ltd 
Other European 
Arion & Delahaye 
Brenntag AG 
Dr Paul Lohmann GmbH KG 
USA 
AerChem Inc 
Amresco Inc 
Brenntag Inc 
EM Sergeant Pulp & Chemical Co Inc 
Fisher Scientific 
Inolex Chemical Co 
JT Baker Inc 
Kraft Chemical Co 
Mutchler Inc 
Penta Manufacturing Co 
Ferro Pfanstiehl Laboratories Inc 
Purac America Inc 
Rita Corp 
Spectrum Quality Products Inc 
Triple Crown America 
Voigt Global Distribution LLC 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
Lactitol 
UK 
Danisco Sweeteners Ltd 
Purac Biochem (UK) 
USA 
Danisco USA Inc 
Penta Manufacturing Co 
Purac America Inc 
Lactose, Anhydrous 
UK 
Borculo Domo Ingredients Ltd 
DMV UK 
Other European 
Borculo Domo Ingredients 
DMV Pharma 
Molkerei Meggle Wasserburg GmbH 
846 Appendix I: Suppliers Directory

USA 
Foremost Farms USA 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Others 
Lactose New Zealand 
Lactose, Monohydrate 
UK 
Borculo Domo Ingredients Ltd 
DMV UK 
Forum Biosciences Ltd 
Honeywill & Stein 
JT Baker UK 
Other European 
Borculo Domo Ingredients 
Brenntag AG 
DMV Pharma 
Molkerei Meggle Wasserburg GmbH 
USA 
Brenntag Inc 
EMD Chemicals Inc 
Foremost Farms USA 
JT Baker Inc 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Others 
Lactose New Zealand 
LS Raw Materials Ltd 
Lactose, Spray-Dried 
UK 
Borculo Domo Ingredients Ltd 
DMV UK 
Forum Biosciences Ltd 
Other European 
Borculo Domo Ingredients 
DMV Pharma 
Molkerei Meggle Wasserburg GmbH 
USA 
Foremost Farms USA 
Mutchler Inc 
Spectrum Quality Products Inc 
Others 
Lactose New Zealand 
Lanolin 
UK 
Blagden Specialty Chemicals Ltd 
Croda Chemicals Ltd 
Fisher Scientific UK Ltd 
JT Baker UK 
Paroxite (London) Ltd 
Raught Ltd 
Other European 
Brenntag AG 
USA 
Brenntag Inc 
Croda Inc 
Fisher Scientific 
JT Baker Inc 
Kraft Chemical Co 
Mutchler Inc 
Penta Manufacturing Co 
Protameen Chemicals 
Rita Corp 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Lanolin, Hydrous 
UK 
Adina Chemicals Ltd 
USA 
Lipo Chemicals Inc 
Penta Manufacturing Co 
Rita Corp 
Spectrum Quality Products Inc 
Lanolin Alcohols 
UK 
Croda Chemicals Ltd 
Paroxite (London) Ltd 
USA 
Charkit Chemical Corp 
Croda Inc 
Kraft Chemical Co 
Penta Manufacturing Co 
Rita Corp 
Lauric Acid 
USA 
Astro Chemicals Inc 
Lecithin 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Aarhus United UK Ltd 
Alembic Products Ltd 
Allchem Pharma 
Forum Biosciences Ltd 
Other European 
Aarhus United Denmark A/S 
Brenntag AG 
Lucas Meyer 
Stern Lecithin and Soja GmbH 
USA 
Aarhus United USA Inc 
Aceto Corp 
Alfa Chem 
American Lecithin Co 
Ashland 
Avatar Corp 
Brenntag Inc 
Charkit Chemical Corp 
Kraft Chemical Co 
Lucas Meyer Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Voigt Global Distribution LLC 
Welch, Holme & Clark Co Inc 
Leucine 
UK 
Sigma-Aldrich Company Ltd 
USA 
Alfa Chem 
Penta Manufacturing Co 
Scandinavian Formulas Inc 
Seltzer Chemicals Inc 
Linoleic Acid 
USA 
Loos & Dilworth Inc 
Macrogol 15 Hydroxystearate 
UK 
BASF Plc 
USA 
BASF Corp 
Magnesium Aluminum Silicate 
UK 
Paroxite (London) Ltd 
USA 
American Colloid Co 
Fuji Chemical Industries Health Science 
(USA) Inc 
Kraft Chemical Co 
Mutchler Inc 
Penta Manufacturing Co 
RT Vanderbilt Company Inc 
Spectrum Quality Products Inc 
Whittaker Clark, and Daniels Inc 
Others 
Fuji Chemical Industry Co Ltd 
Magnesium Carbonate 
UK 
Chance & Hunt 
Courtin & Warner Ltd 
Fisher Scientific UK Ltd 
Intermag Co Ltd 
JT Baker UK 
Paroxite (London) Ltd 
Tennants (Distribution) Ltd 
William Ransom & Son plc 
Other European 
Brenntag AG 
Dr Paul Lohmann GmbH KG 
Lehmann & Voss & Co 
Magnesia GmbH 
USA 
AerChem Inc 
Alfa Chem 
Barrington Chemical Corp 
Brenntag Inc 
Charkit Chemical Corp 
EM Sergeant Pulp & Chemical Co Inc 
Appendix I: Suppliers Directory 847

Fisher Scientific 
Gallard-Schlesinger Industries 
Generichem Corp 
JT Baker Inc 
Kraft Chemical Co 
Mutchler Inc 
Particle Dynamics Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Vopak USA Inc 
Whittaker Clark, and Daniels Inc 
Magnesium Oxide 
UK 
Fisher Scientific UK Ltd 
Intermag Co Ltd 
JT Baker UK 
Paroxite (London) Ltd 
Tennants (Distribution) Ltd 
Other European 
Brenntag AG 
Dr Paul Lohmann GmbH KG 
Magnesia GmbH 
USA 
AerChem Inc 
Alfa Chem 
Ashland 
Barrington Chemical Corp 
Brenntag Inc 
Fisher Scientific 
Gallard-Schlesinger Industries 
Generichem Corp 
JT Baker Inc 
Mutchler Inc 
Particle Dynamics Inc 
Penta Manufacturing Co 
RIA International 
Spectrum Quality Products Inc 
Vopak USA Inc 
Whittaker Clark, and Daniels Inc 
Others 
LS Raw Materials Ltd 
Magnesium Silicate 
UK 
Intermag Co Ltd 
Magnesium Stearate 
UK 
Allchem Pharma 
Corcoran Chemicals Ltd 
Fisher Scientific UK Ltd 
Intermag Co Ltd 
James M Brown Ltd 
JRS Pharma Ltd 
Paroxite (London) Ltd 
Raught Ltd 
Other European 
Biesterfeld Spezialchemie GmbH 
Brenntag AG 
Dr Paul Lohmann GmbH KG 
J Rettenmaier & So. hne GmbH and Co 
Lehmann & Voss & Co 
Magnesia GmbH 
USA 
Aceto Corp 
AerChem Inc 
Alfa Chem 
Ashland 
Avatar Corp 
Barrington Chemical Corp 
Brenntag Inc 
Charkit Chemical Corp 
EM Industries Inc 
EM Sergeant Pulp & Chemical Co Inc 
Fisher Scientific 
Generichem Corp 
JRS Pharma LP 
Kraft Chemical Co 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Vopak USA Inc 
Whittaker Clark, and Daniels Inc 
Others 
LS Raw Materials Ltd 
Magnesium Trisilicate 
UK 
Courtin & Warner Ltd 
Intermag Co Ltd 
Raught Ltd 
William Ransom & Son plc 
Other European 
Dr Paul Lohmann GmbH KG 
Magnesia GmbH 
USA 
Gallard-Schlesinger Industries 
Generichem Corp 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Others 
LS Raw Materials Ltd 
Malic Acid 
UK 
Corcoran Chemicals Ltd 
DSM UK Ltd 
Lonza UK Ltd 
Peter Whiting (Chemicals) Ltd 
Tennants (Distribution) Ltd 
Ubichem plc 
Other European 
Brenntag AG 
DSM Fine Chemicals 
Lonza Ltd 
USA 
AerChem Inc 
Ashland 
Brenntag Inc 
DSM Fine Chemicals Inc 
Kraft Chemical Co 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Voigt Global Distribution LLC 
Vopak USA Inc 
Maltitol 
UK 
Cerestar UK Ltd 
Roquette (UK) Ltd 
Other European 
Cerestar International 
Roquette Fre`res 
USA 
Ashland 
Cargill Corp 
Penta Manufacturing Co 
Roquette America Inc 
Maltitol Solution 
UK 
Cerestar UK Ltd 
Lonza UK Ltd 
Roquette (UK) Ltd 
Other European 
Cerestar International 
Lonza Ltd 
Roquette Fre`res 
USA 
Roquette America Inc 
Maltodextrin 
UK 
Avebe UK Ltd 
Cerestar UK Ltd 
Corcoran Chemicals Ltd 
Roquette (UK) Ltd 
Other European 
Amylum Ibe.rica, SA 
Avebe Group 
Brenntag AG 
Cerestar International 
Roquette Fre`res 
USA 
Ashland 
Avebe America Inc 
Brenntag Inc 
Cargill Corp 
Generichem Corp 
Grain Processing Corp 
Roquette America Inc 
Tate & Lyle 
Voigt Global Distribution LLC 
Maltol 
Other European 
Helm AG 
USA 
Ashland 
Helm New York Inc 
Penta Manufacturing Co 
Maltose 
UK 
Cerestar UK Ltd 
Forum Biosciences Ltd 
Pfanstiehl (Europe) Ltd 
848 Appendix I: Suppliers Directory

Other European 
Cerestar International 
USA 
Cargill Corp 
Penta Manufacturing Co 
Ferro Pfanstiehl Laboratories Inc 
SPI Pharma Group 
Others 
Hayashibara Co Ltd 
Mannitol 
UK 
Cerestar UK Ltd 
Corcoran Chemicals Ltd 
Fisher Scientific UK Ltd 
Forum Biosciences Ltd 
JT Baker UK 
Pfanstiehl (Europe) Ltd 
Roquette (UK) Ltd 
Ubichem plc 
Other European 
Brenntag AG 
Cerestar International 
Helm AG 
Roquette Fre`res 
USA 
Aceto Corp 
AerChem Inc 
Alfa Chem 
Amresco Inc 
Ashland 
Brenntag Inc 
Cargill Corp 
EM Industries Inc 
Fisher Scientific 
George Uhe Co Inc 
JT Baker Inc 
Mutchler Inc 
Penta Manufacturing Co 
Ferro Pfanstiehl Laboratories Inc 
RIA International 
Roquette America Inc 
Spectrum Quality Products Inc 
SPI Pharma Group 
Voigt Global Distribution LLC 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
Medium-chain Triglycerides 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Alfa Chemicals Ltd/Gattefosse. UK 
Allchem Pharma 
Blagden Specialty Chemicals Ltd 
Cognis UK Ltd 
Croda Chemicals Ltd 
Karlshamns Ltd 
Lonza UK Ltd 
Other European 
Cognis Deutschland GmbH 
Gattefosse. s.a. 
Karlshamns AB 
Lonza Ltd 
USA 
ABITEC Corp 
Arista Industries Inc 
Cognis Corp 
Croda Inc 
Gattefosse. Corp 
Meglumine 
UK 
EM Industries Inc 
Spectrum Quality Products Inc 
Menthol 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Courtin & Warner Ltd 
Haarmann & Reimer Ltd 
Raught Ltd 
Stan Chem International Ltd 
Thew, Arnott and Co Ltd 
Other European 
Haarmann & Reimer GmbH 
Helm AG 
USA 
Charkit Chemical Corp 
Chart Corp Inc 
George Uhe Co Inc 
Helm New York Inc 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Others 
LS Raw Materials Ltd 
Methylcellulose 
UK 
Colorcon Ltd 
RW Unwin & Co Ltd 
Other European 
Brenntag AG 
USA 
Alfa Chem 
Aqualon 
Biddle Sawyer Corp 
Brenntag Inc 
Colorcon 
Dow Chemical Co 
Mutchler Inc 
Spectrum Quality Products Inc 
Others 
Shin-Etsu Chemical Co Ltd 
Methylparaben 
UK 
Clariant UK Ltd 
Cornelius Group plc 
Other European 
Brenntag AG 
Chemag Aktiengesellschaft 
Induchem AG 
USA 
Ashland 
Avatar Corp 
Brenntag Inc 
Charkit Chemical Corp 
Kraft Chemical Co 
Lipo Chemicals Inc 
Napp Technologies Inc 
Nipa Laboratories Inc 
Penta Manufacturing Co 
Protameen Chemicals 
Rita Corp 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
San Fu Chemical Company Ltd 
Mineral Oil 
UK 
British Wax Refining Co 
Fisher Scientific UK Ltd 
Fuchs Lubricants (UK) plc 
JT Baker UK 
Other European 
Brenntag AG 
Parafluid Mineraloelges MBH 
Chevron Texaco Global Lubricants 
Benelux 
USOCO BV 
USA 
Astro Chemicals Inc 
Avatar Corp 
Brenntag Inc 
Fisher Scientific 
JT Baker Inc 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Vopak USA Inc 
Mineral Oil, Light 
UK 
British Wax Refining Co 
Fisher Scientific UK Ltd 
Fuchs Lubricants (UK) plc 
Other European 
Chevron Texaco Global Lubricants 
Benelux 
Parafluid Mineraloelges MBH 
USOCO BV 
USA 
Amresco Inc 
Fisher Scientific 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Appendix I: Suppliers Directory 849

Mineral Oil and Lanolin Alcohols 
UK 
Paroxite (London) Ltd 
USA 
Protameen Chemicals 
Rita Corp 
Monoethanolamine 
UK 
Tennants (Distribution) Ltd 
Other European 
Brenntag AG 
USA 
Brenntag Inc 
Dow Chemical Co 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Monosodium Glutamate 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Other European 
Amylum Ibe.rica, SA 
Brenntag AG 
Helm AG 
USA 
Ashland 
Brenntag Inc 
Delta Distributors Inc 
Helm New York Inc 
Mutchler Inc 
Penta Manufacturing Co 
Triple Crown America 
Vopak USA Inc 
Xinchem Co 
Myristic Acid 
UK 
Brenntag (UK) Ltd 
Other European 
Cognis Deutschland GmbH 
USA 
Ashland 
Crompton Corp 
Penta Manufacturing Co 
Ruger Chemical Co Inc 
Others 
EPS Impex Co. 
Neohesperidin Dihydrochalcone 
Other European 
Exquim S.A. 
Natura Internacional S.L. 
Nitrogen 
UK 
Air Liquide UK Ltd 
Air Products (Gases) plc 
BOC Gases 
USA 
BOC Gases 
Nitrous Oxide 
UK 
Air Liquide UK Ltd 
BOC Gases 
USA 
BOC Gases 
Octyldodecanol 
Other European 
Cognis Deutschland GmbH 
USA 
Jarchem Industries Inc 
Others 
Charles Tennant & Co (Canada) Ltd 
Oleic Acid 
UK 
Croda Chemicals Ltd 
Fisher Scientific UK Ltd 
H Foster & Co (Stearines) Ltd 
JT Baker UK 
Kimpton Brothers Ltd 
Tennants (Distribution) Ltd 
White Sea and Baltic Company Ltd 
Other European 
Brenntag AG 
USA 
AerChem Inc 
Brenntag Inc 
Croda Inc 
Delta Distributors Inc 
Fisher Scientific 
JT Baker Inc 
Kraft Chemical Co 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Voigt Global Distribution LLC 
Vopak USA Inc 
Welch, Holme & Clark Co Inc 
Others 
LS Raw Materials Ltd 
Oleyl Alcohol 
UK 
ISP Europe 
Other European 
Cognis Deutschland GmbH 
USA 
Alfa Chem 
Croda Inc 
Penta Manufacturing Co 
Olive Oil 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Aarhus United UK Ltd 
Alembic Products Ltd 
Paroxite (London) Ltd 
Peter Whiting (Chemicals) Ltd 
White Sea and Baltic Company Ltd 
Other European 
Aarhus United Denmark A/S 
USA 
Aarhus United USA Inc 
Arista Industries Inc 
Avatar Corp 
Charkit Chemical Corp 
Hawkins Chemical Inc 
Mutchler Inc 
Penta Manufacturing Co 
Pokonobe Industries Inc 
Spectrum Quality Products Inc 
Triple Crown America 
Voigt Global Distribution LLC 
Palmitic Acid 
UK 
Sigma-Aldrich Company Ltd 
Other European 
Cognis Deutschland GmbH 
USA 
Alfa Chem 
Ashland 
Crompton Corp 
Mutchler Inc 
Penta Manufacturing Co 
Ruger Chemical Co Inc 
Others 
Charles Tennant & Co (Canada) Ltd 
Paraffin 
UK 
AF Suter and Co Ltd 
British Wax Refining Co 
Cornelius Group plc 
Poth Hille 
William Ransom & Son plc 
Other European 
Brenntag AG 
Chevron Texaco Global Lubricants 
Benelux 
USA 
Brenntag Inc 
Delta Distributors Inc 
Koster Keunen Inc 
Mutchler Inc 
Penta Manufacturing Co 
Rita Corp 
Spectrum Quality Products Inc 
Strahl & Pitsch Inc 
USOCO BV 
Voigt Global Distribution LLC 
Vopak USA Inc 
850 Appendix I: Suppliers Directory

Others 
LS Raw Materials Ltd 
Peanut Oil 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Aarhus United UK Ltd 
Alembic Products Ltd 
Alfa Chemicals Ltd 
Allchem Pharma 
Croda Chemicals Ltd 
Efkay Chemicals Ltd 
Karlshamns Ltd 
White Sea and Baltic Company Ltd 
Other European 
Aarhus United Denmark A/S 
Gattefosse. s.a. 
Karlshamns AB 
USA 
Aarhus United USA Inc 
Arista Industries Inc 
Charkit Chemical Corp 
Croda Inc 
Gattefosse. Corp 
Penta Manufacturing Co 
Pokonobe Industries Inc 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Welch, Holme & Clark Co Inc 
Pectin 
UK 
ISP Europe 
Ingredients Consultancy Ltd, The 
USA 
Alfa Chem 
CP Kelco US Inc 
KIC Chemicals Inc 
Penta Manufacturing Co 
Ruger Chemical Co Inc 
TIC Gums 
Petrolatum 
UK 
Efkay Chemicals Ltd 
Fuchs Lubricants (UK) plc 
Poth Hille 
Other European 
Brenntag AG 
Parafluid Mineraloelges MBH 
Chevron Texaco Global Lubricants 
Benelux 
USOCO BV 
USA 
Avatar Corp 
Brenntag Inc 
Delta Distributors Inc 
Mutchler Inc 
Penta Manufacturing Co 
Rita Corp 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Vopak USA Inc 
Petrolatum and Lanolin Alcohols 
UK 
Rita Corp 
Phenol 
UK 
Chance & Hunt 
Fisher Scientific UK Ltd 
JT Baker UK 
Tennants (Distribution) Ltd 
Other European 
Brenntag AG 
Chemco France 
USA 
Amresco Inc 
Brenntag Inc 
Dow Chemical Co 
Fisher Scientific 
JT Baker Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Vopak USA Inc 
Phenoxyethanol 
UK 
Clariant UK Ltd 
Haarmann & Reimer Ltd 
Paroxite (London) Ltd 
Ubichem plc 
Other European 
Haarmann & Reimer GmbH 
Induchem AG 
USA 
Kraft Chemical Co 
Lipo Chemicals Inc 
Nipa Laboratories Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Phenylethyl Alcohol 
UK 
Haarmann & Reimer Ltd 
Other European 
Haarmann & Reimer GmbH 
USA 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Phenylmercuric Acetate 
UK 
Dow Agrosciences 
USA 
Dow Agrosciences LLC 
George Uhe Co Inc 
Spectrum Quality Products Inc 
Phenylmercuric Borate 
UK 
Fluorochem Ltd 
USA 
Spectrum Quality Products Inc 
Phenylmercuric Nitrate 
USA 
George Uhe Co Inc 
Spectrum Quality Products Inc 
Phosphoric Acid 
UK 
JT Baker UK 
Peter Whiting (Chemicals) Ltd 
Other European 
Brenntag AG 
USA 
Ashland 
Brenntag Inc 
Delta Distributors Inc 
EM Industries Inc 
EM Sergeant Pulp & Chemical Co Inc 
JT Baker Inc 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
Polacrilin Potassium 
UK 
Rohm and Haas UK Ltd 
USA 
Rohm and Haas Co 
Poloxamer 
UK 
BASF Plc 
Other European 
BASF Aktiengesellschaft 
USA 
BASF Corp 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Polycarbophil 
USA 
Noveon Inc 
Polydextrose 
UK 
Danisco Sweeteners Ltd 
USA 
Ashland 
Danisco USA Inc 
Tate & Lyle 
Polyethylene Glycol 
UK 
Adina Chemicals Ltd 
Appendix I: Suppliers Directory 851

Alfa Chemicals Ltd 
BASF Plc 
Blagden Speciality Chemicals Ltd 
Corcoran Chemicals Ltd 
Cornelius Group plc 
Fisher Scientific UK Ltd 
Honeywill & Stein 
Sasol UK Ltd 
Tennants (Distribution) Ltd 
Other European 
BASF Aktiengesellschaft 
Brenntag AG 
Gattefosse. s.a. 
USA 
Ashland 
BASF Corp 
Brenntag Inc 
Dow Chemical Co 
Fisher Scientific 
Gattefosse. Corp 
Hawkins Chemical Inc 
Lipo Chemicals Inc 
Mutchler Inc 
Penta Manufacturing Co 
Polysciences Inc 
Protameen Chemicals 
Sasol North America Inc 
Spectrum Quality Products Inc 
Vopak USA Inc 
Others 
Aastrid International 
LS Raw Materials Ltd 
Polyethylene Oxide 
UK 
Dow Chemical Co 
Polymethacrylates 
UK 
BASF Plc 
Eastman Company UK Ltd 
Honeywill & Stein 
Ubichem plc 
Other European 
BASF Aktiengesellschaft 
Ro.hm GmbH 
USA 
BASF Corp 
Eastman Chemical Co 
Rohm America Inc 
Vopak USA Inc 
Poly(methyl vinyl ether/maleic 
anhydride) 
UK 
Sigma-Aldrich Company Ltd 
Other European 
Matrix Marketing GmbH 
USA 
Fisher Scientific 
Polyoxyethylene Alkyl Ethers 
UK 
Adina Chemicals Ltd 
BASF Plc 
Cognis UK Ltd 
Croda Chemicals Ltd 
Goldschmidt UK Ltd 
Other European 
BASF Aktiengesellschaft 
Cognis Deutschland GmbH 
USA 
BASF Corp 
Cognis Corp 
Croda Inc 
ICI Surfactants 
Lipo Chemicals Inc 
Protameen Chemicals 
Rita Corp 
Polyoxyethylene Castor Oil Derivatives 
UK 
Adina Chemicals Ltd 
BASF Plc 
Cognis UK Ltd 
Farma International Inc 
Paroxite (London) Ltd 
Uniqema 
White Sea and Baltic Company Ltd 
Other European 
BASF Aktiengesellschaft 
Cognis Deutschland GmbH 
USA 
ABITEC Corp 
BASF Corp 
Cognis Corp 
Jeen International Corp 
Lipo Chemicals Inc 
Protameen Chemicals 
Others 
Nikko Chemicals Co Ltd 
Polyoxyethylene Sorbitan Fatty Acid 
Esters 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Adina Chemicals Ltd 
BASF Plc 
Cognis UK Ltd 
Croda Chemicals Ltd 
Goldschmidt UK Ltd 
JT Baker UK 
Lonza UK Ltd 
Other European 
BASF Aktiengesellschaft 
Brenntag AG 
Cognis Deutschland GmbH 
Lonza Ltd 
USA 
BASF Corp 
Brenntag Inc 
Cognis Corp 
Croda Inc 
Hawkins Chemical Inc 
JT Baker Inc 
Lipo Chemicals Inc 
Protameen Chemicals 
Rita Corp 
Polyoxyethylene Stearates 
UK 
Adina Chemicals Ltd 
BASF Plc 
Other European 
BASF Aktiengesellschaft 
USA 
BASF Corp 
Lipo Chemicals Inc 
Rita Corp 
Polyvinyl Acetate Phthalate 
UK 
Colorcon Ltd 
USA 
Colorcon 
Polyvinyl Alcohol 
UK 
Acetex Chemicals Ltd 
BASF Plc 
Blagden Speciality Chemicals Ltd 
Nippon Gohsei (UK) Ltd 
Honeywill & Stein 
Other European 
Acetex Chimie SA 
BASF Aktiengesellschaft 
DuPont de Nemours Int’l SA 
USA 
Astro Chemicals Inc 
BASF Corp 
DuPont 
Penta Manufacturing Co 
Polysciences Inc 
Spectrum Quality Products Inc 
Vopak USA Inc 
Potassium Alginate 
UK 
ISP Europe 
USA 
International Specialty Products 
Potassium Benzoate 
UK 
Dow Chemical Company (UK) 
DSM UK Ltd 
Other European 
Brenntag AG 
DSM Fine Chemicals 
Haltermann GmbH 
USA 
AerChem Inc 
Ashland 
852 Appendix I: Suppliers Directory

Brenntag Inc 
Delta Distributors Inc 
DSM Fine Chemicals Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Voigt Global Distribution LLC 
Vopak USA Inc 
Potassium Chloride 
UK 
Fisher Scientific UK Ltd 
ISP Europe 
JT Baker UK 
Peter Whiting (Chemicals) Ltd 
Reheis Inc 
Stan Chem International Ltd 
Tennants (Distribution) Ltd 
Other European 
Brenntag AG 
Dr Paul Lohmann GmbH KG 
USA 
AerChem Inc 
Amresco Inc 
Brenntag Inc 
Delta Distributors Inc 
EM Industries Inc 
Fisher Scientific 
International Specialty Products 
JT Baker Inc 
Mutchler Inc 
Particle Dynamics Inc 
Penta Manufacturing Co 
Reheis Inc 
Spectrum Quality Products Inc 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
Potassium Citrate 
UK 
Courtin & Warner Ltd 
Fisher Scientific UK Ltd 
Peter Whiting (Chemicals) Ltd 
Ubichem plc 
Other European 
Brenntag AG 
Dr Paul Lohmann GmbH KG 
Jungbunzlauer 
USA 
AerChem Inc 
Ashland 
Brenntag Inc 
Delta Distributors Inc 
Fisher Scientific 
Gallard-Schlesinger Industries 
Kraft Chemical Co 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Tate & Lyle 
Vopak USA Inc 
Others 
San Fu Chemical Company Ltd 
Potassium Hydroxide 
UK 
Corcoran Chemicals Ltd 
Fisher Scientific UK Ltd 
JT Baker UK 
Peter Whiting (Chemicals) Ltd 
Tennants (Distribution) Ltd 
Ubichem plc 
Other European 
Brenntag AG 
USA 
AerChem Inc 
Brenntag Inc 
Charkit Chemical Corp 
Delta Distributors Inc 
EM Industries Inc 
Fisher Scientific 
JT Baker Inc 
Mutchler Inc 
Penta Manufacturing Co 
Voigt Global Distribution LLC 
Vopak USA Inc 
Potassium Metabisulfite 
UK 
Allchem Pharma 
Fisher Scientific UK Ltd 
Ubichem plc 
Other European 
Brenntag AG 
USA 
Brenntag Inc 
Fisher Scientific 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Vopak USA Inc 
Potassium Sorbate 
UK 
Blagden Speciality Chemicals Ltd 
JT Baker UK 
Peter Whiting (Chemicals) Ltd 
Tennants (Distribution) Ltd 
Thew, Arnott and Co Ltd 
White Sea and Baltic Company Ltd 
Other European 
Brenntag AG 
Helm AG 
USA 
AerChem Inc 
Ashland 
Avatar Corp 
Brenntag Inc 
Charkit Chemical Corp 
Delta Distributors Inc 
Helm New York Inc 
JT Baker Inc 
Mutchler Inc 
Penta Manufacturing Co 
Pfizer Corp 
Protameen Chemicals 
Spectrum Quality Products Inc 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
Povidone 
UK 
BASF Plc 
Blagden Speciality Chemicals Ltd 
ISP Europe 
Raught Ltd 
Other European 
August Hedinger GmbH & Co 
BASF Aktiengesellschaft 
Helm AG 
USA 
BASF Corp 
Hawkins Chemical Inc 
Helm New York Inc 
International Specialty Products 
Napp Technologies Inc 
Penta Manufacturing Co 
Others 
Glide Chem Pvt Ltd 
Propionic Acid 
UK 
Tennants (Distribution) Ltd 
White Sea and Baltic Company Ltd 
Other European 
Brenntag AG 
USA 
Brenntag Inc 
Delta Distributors Inc 
Dow Chemical Co 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Vopak USA Inc 
Propyl Gallate 
UK 
Eastman Company UK Ltd 
USA 
Aceto Corp 
Alfa Chem 
Delta Distributors Inc 
Eastman Chemical Co 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Propylene Carbonate 
Other European 
Brenntag AG 
USA 
Brenntag Inc 
Penta Manufacturing Co 
Vopak USA Inc 
Propylene Glycol 
UK 
Alfa Chemicals Ltd 
Appendix I: Suppliers Directory 853

BASF Plc 
Corcoran Chemicals Ltd 
Delta Distributors Inc 
Eastman Company UK Ltd 
Fisher Scientific UK Ltd 
JT Baker UK 
Lyondell Chemical Europe 
Raught Ltd 
Sasol UK Ltd 
Tennants (Distribution) Ltd 
Other European 
August Hedinger GmbH & Co 
BASF Aktiengesellschaft 
Brenntag AG 
Gattefosse. s.a. 
USA 
Amresco Inc 
Ashland 
Avatar Corp 
BASF Corp 
Brenntag Inc 
Dow Chemical Co 
Eastman Chemical Co 
Fisher Scientific 
Gattefosse. Corp 
JT Baker Inc 
Kraft Chemical Co 
Lyondell Chemical Co 
Mutchler Inc 
Penta Manufacturing Co 
Rita Corp 
Sasol North America Inc 
Spectrum Quality Products Inc 
Stepan Co 
Voigt Global Distribution LLC 
Vopak USA Inc 
Others 
Gadot Petrochemical Industries Ltd 
Propylene Glycol Alginate 
USA 
Delta Distributors Inc 
Spectrum Quality Products Inc 
Propylparaben 
UK 
Bayer plc 
Clariant UK Ltd 
Other European 
Chemag Aktiengesellschaft 
Induchem AG 
USA 
Ashland 
Avatar Corp 
Bayer Corp 
Charkit Chemical Corp 
Delta Distributors Inc 
Kraft Chemical Co 
Lipo Chemicals Inc 
Napp Technologies Inc 
Nipa Laboratories Inc 
Penta Manufacturing Co 
Protameen Chemicals 
Rita Corp 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
San Fu Chemical Company Ltd 
2-Pyrrolidone 
UK 
BASF Plc 
ISP Europe 
Other European 
BASF Aktiengesellschaft 
USA 
BASF Corp 
EMD Chemicals Inc 
International Specialty Products 
Kraft Chemical Co 
Saccharin 
UK 
Corcoran Chemicals Ltd 
Tennants (Distribution) Ltd 
Other European 
Brenntag AG 
Helm AG 
Hermes Sweetners Ltd 
USA 
Aceto Corp 
AerChem Inc 
Ashland 
Brenntag Inc 
Delta Distributors Inc 
Helm New York Inc 
Mutchler Inc 
Penta Manufacturing Co 
Pfaltz & Bauer 
PMC Specialities Group Inc 
Spectrum Quality Products Inc 
Triple Crown America 
Voigt Global Distribution LLC 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
Saccharin Sodium 
UK 
Fisher Scientific UK Ltd 
JT Baker UK 
Other European 
Helm AG 
USA 
Delta Distributors Inc 
Fisher Scientific 
George Uhe Co Inc 
Helm New York Inc 
JT Baker Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Sesame Oil 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Aarhus United UK Ltd 
Adina Chemicals Ltd 
Alembic Products Ltd 
Croda Chemicals Ltd 
Efkay Chemicals Ltd 
Other European 
Aarhus United Denmark A/S 
USA 
Aarhus United USA Inc 
Arista Industries Inc 
Charkit Chemical Corp 
Croda Inc 
Hawkins Chemical Inc 
Lipo Chemicals Inc 
Penta Manufacturing Co 
Pokonobe Industries Inc 
Protameen Chemicals 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Welch, Holme & Clark Co Inc 
Shellac 
UK 
AF Suter and Co Ltd 
Cornelius Group plc 
Kimpton Brothers Ltd 
Mantrose (UK) Ltd 
Paroxite (London) Ltd 
Thew, Arnott and Co Ltd 
Other European 
Alland & Robert 
USA 
Mantrose-Haeuser Co Inc 
Penta Manufacturing Co 
Simethicone 
UK 
Dow Corning 
USA 
Dow Corning 
Sodium Alginate 
UK 
Blagden Speciality Chemicals Ltd 
Other European 
FMC Biopolymer 
Sobel NV 
USA 
AerChem Inc 
FMC Biopolymer 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Sodium Ascorbate 
UK 
BASF Plc 
854 Appendix I: Suppliers Directory

Peter Whiting (Chemicals) Ltd 
Roche Products Ltd 
Other European 
BASF Aktiengesellschaft 
Brenntag AG 
Helm AG 
USA 
AerChem Inc 
BASF Corp 
Brenntag Inc 
Delta Distributors Inc 
Helm New York Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Takeda Pharmaceuticals America Inc 
Triple Crown America 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
Shijiazhuang Pharmaceutical Group 
Co Ltd 
Takeda Chemical Industries Ltd 
Sodium Benzoate 
UK 
Corcoran Chemicals Ltd 
Courtin & Warner Ltd 
Dow Chemical Company (UK) 
DSM UK Ltd 
Fisher Scientific UK Ltd 
JT Baker UK 
Peter Whiting (Chemicals) Ltd 
Tennants (Distribution) Ltd 
Ubichem plc 
Other European 
Brenntag AG 
Dr Paul Lohmann GmbH KG 
DSM Fine Chemicals 
Haltermann GmbH 
Helm AG 
USA 
Aceto Corp 
AerChem Inc 
Ashland 
Brenntag Inc 
Delta Distributors Inc 
DSM Fine Chemicals Inc 
EM Industries Inc 
Fisher Scientific 
Helm New York Inc 
JT Baker Inc 
Kraft Chemical Co 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
San Fu Chemical Company Ltd 
Sodium Bicarbonate 
UK 
Blagden Speciality Chemicals Ltd 
Brunner Mond (UK) Ltd 
Courtin & Warner Ltd 
Fisher Scientific UK Ltd 
Forum Biosciences Ltd 
JT Baker UK 
Peter Whiting (Chemicals) Ltd 
Raught Ltd 
Tennants (Distribution) Ltd 
Other European 
Brenntag AG 
USA 
Brenntag Inc 
Charkit Chemical Corp 
Church and Dwight Co Inc 
Delta Distributors Inc 
EM Industries Inc 
EM Sergeant Pulp & Chemical Co Inc 
Fisher Scientific 
JT Baker Inc 
Mutchler Inc 
Penta Manufacturing Co 
SPI Pharma Group 
Spectrum Quality Products Inc 
Triple Crown America 
Vopak USA Inc 
Sodium Borate 
UK 
Borax Europe Ltd 
JT Baker UK 
Sigma-Aldrich Company Ltd 
USA 
Alfa Chem 
Brenntag Inc 
EMD Chemicals Inc 
Ferro Pfanstiehl Laboratories Inc 
Mutchler Inc 
Penta Manufacturing Co 
Ruger Chemical Co Inc 
Others 
Highland International 
Wuxi Dazhong Chemical Industry Co Ltd 
Sodium Chloride 
UK 
JT Baker UK 
Tennants (Distribution) Ltd 
Ubichem plc 
USA 
AerChem Inc 
Cargill Corp 
Charkit Chemical Corp 
Delta Distributors Inc 
EM Industries Inc 
Fisher Scientific 
Hawkins Chemical Inc 
JT Baker Inc 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Vopak USA Inc 
Sodium Citrate Dihydrate 
UK 
Cerestar UK Ltd 
Courtin & Warner Ltd 
Fisher Scientific UK Ltd 
JT Baker UK 
Peter Whiting (Chemicals) Ltd 
Roche Products Ltd 
Other European 
Cerestar International 
Dr Paul Lohmann GmbH KG 
Jungbunzlauer 
USA 
AerChem Inc 
Cargill Corp 
Delta Distributors Inc 
EM Industries Inc 
Fisher Scientific 
JT Baker Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Tate & Lyle 
Vopak USA Inc 
Others 
San Fu Chemical Company Ltd 
Sodium Cyclamate 
UK 
Blagden Speciality Chemicals Ltd 
Others 
LS Raw Materials Ltd 
Sodium Hyaluronate 
Other European 
Chemos GmbH 
Contipro C a.s. 
Matrix Marketing GmbH 
NovaMatrix 
USA 
AnMar International 
Others 
Kibun Food Chemifa Co Ltd 
Shangyuchem 
Sodium Hydroxide 
UK 
Fisher Scientific UK Ltd 
JT Baker UK 
Tennants (Distribution) Ltd 
Ubichem plc 
Other European 
Brenntag AG 
USA 
AerChem Inc 
Brenntag Inc 
Charkit Chemical Corp 
Delta Distributors Inc 
EM Industries Inc 
Fisher Scientific 
JT Baker Inc 
Mutchler Inc 
Appendix I: Suppliers Directory 855

Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
Sodium Lactate 
UK 
Roquette (UK) Ltd 
Other European 
Dr Paul Lohmann GmbH KG 
Interchim Austria GES.M.B.H 
Roquette Fre`res 
USA 
Alfa Chem 
Amresco Inc 
Ashland 
EMD Chemicals Inc 
Ferro Pfanstiehl Laboratories Inc 
Penta Manufacturing Co 
Purac America Inc 
Ruger Chemical Co Inc 
Others 
Jiangxi Mosashino Co Ltd 
Sodium Lauryl Sulfate 
UK 
Cognis UK Ltd 
Fisher Scientific UK Ltd 
Sigma-Aldrich Company Ltd 
Other European 
Brenntag AG 
Cognis Deutschland GmbH 
USA 
Brenntag Inc 
Cognis Corp 
Delta Distributors Inc 
Fisher Scientific 
Kraft Chemical Co 
Mutchler Inc 
Penta Manufacturing Co 
Sigma-Aldrich Corp 
Spectrum Quality Products Inc 
Stepan Co 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
Sodium Metabisulfite 
UK 
Corcoran Chemicals Ltd 
Fisher Scientific UK Ltd 
Peter Whiting (Chemicals) Ltd 
Tennants (Distribution) Ltd 
Ubichem plc 
William Blythe Ltd 
Other European 
Brenntag AG 
USA 
AerChem Inc 
Brenntag Inc 
Delta Distributors Inc 
Fisher Scientific 
Hawkins Chemical Inc 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Others 
LS Raw Materials Ltd 
Sodium Phosphate, Dibasic 
UK 
Fisher Scientific UK Ltd 
JT Baker UK 
Peter Whiting (Chemicals) Ltd 
Tennants (Distribution) Ltd 
Ubichem plc 
Other European 
Brenntag AG 
USA 
AerChem Inc 
Brenntag Inc 
Delta Distributors Inc 
EM Industries Inc 
EM Sergeant Pulp & Chemical Co Inc 
Fisher Scientific 
Gallard-Schlesinger Industries 
JT Baker Inc 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Sodium Phosphate, Monobasic 
UK 
Fisher Scientific UK Ltd 
JT Baker UK 
Peter Whiting (Chemicals) Ltd 
Tennants (Distribution) Ltd 
Ubichem plc 
Other European 
Brenntag AG 
USA 
AerChem Inc 
Brenntag Inc 
Delta Distributors Inc 
EM Industries Inc 
EM Sergeant Pulp & Chemical Co Inc 
Fisher Scientific 
JT Baker Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Sodium Propionate 
UK 
Ubichem plc 
Other European 
Brenntag AG 
Dr Paul Lohmann GmbH KG 
USA 
Brenntag Inc 
Delta Distributors Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Vopak USA Inc 
Sodium Starch Glycolate 
UK 
Allchem Pharma 
Avebe UK Ltd 
Forum Biosciences Ltd 
JRS Pharma Ltd 
Other European 
Avebe Group 
J Rettenmaier & So. hne GmbH and Co 
USA 
Alfa Chem 
Avebe America Inc 
Barrington Chemical Corp 
Generichem Corp 
JRS Pharma LP 
Mutchler Inc 
Penta Manufacturing Co 
RIA International 
Spectrum Quality Products Inc 
Sodium Stearyl Fumarate 
UK 
Blagden Speciality Chemicals Ltd 
Forum Biosciences Ltd 
JRS Pharma Ltd 
Other European 
J Rettenmaier & So. hne GmbH and Co 
USA 
Aceto Corp 
JRS Pharma LP 
Spectrum Quality Products Inc 
Sodium Sulfite 
UK 
BASF Plc 
JT Baker UK 
Sigma-Aldrich Company Ltd 
Other European 
Chemos GmbH 
Degussa AG 
USA 
Amresco Inc 
Ashland 
Biddle Sawyer Corp 
EMD Chemicals Inc 
Penta Manufacturing Co 
Ruger Chemical Co Inc 
Vopak USA Inc 
Others 
Xiamen Topusing Chemical Co Ltd 
856 Appendix I: Suppliers Directory

Sorbic Acid 
UK 
Blagden Speciality Chemicals Ltd 
Peter Whiting (Chemicals) Ltd 
Tennants (Distribution) Ltd 
Other European 
Brenntag AG 
USA 
AerChem Inc 
Ashland 
Brenntag Inc 
Charkit Chemical Corp 
Delta Distributors Inc 
Penta Manufacturing Co 
Protameen Chemicals 
Spectrum Quality Products Inc 
Triple Crown America 
Voigt Global Distribution LLC 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
Sorbitan Esters (Sorbitan Fatty Acid 
Esters) 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Adina Chemicals Ltd 
Cognis UK Ltd 
Croda Chemicals Ltd 
Goldschmidt UK Ltd 
Lonza UK Ltd 
Other European 
Brenntag AG 
Cognis Deutschland GmbH 
Lonza Ltd 
USA 
Ashland 
Brenntag Inc 
Cognis Corp 
Croda Inc 
Delta Distributors Inc 
Lipo Chemicals Inc 
Penta Manufacturing Co 
Protameen Chemicals 
Spectrum Quality Products Inc 
Vopak USA Inc 
Sorbitol 
UK 
Adina Chemicals Ltd 
Cerestar UK Ltd 
Corcoran Chemicals Ltd 
Cornelius Group plc 
Forum Biosciences Ltd 
Lonza UK Ltd 
Pfanstiehl (Europe) Ltd 
Roquette (UK) Ltd 
Other European 
Amylum Ibe.rica, SA 
Biesterfeld Spezialchemie GmbH 
Brenntag AG 
Cerestar International 
Lonza Ltd 
Roquette Fre`res 
USA 
Alfa Chem 
Ashland 
Avatar Corp 
Barrington Chemical Corp 
Brenntag Inc 
Cargill Corp 
Delta Distributors Inc 
EM Industries Inc 
EM Sergeant Pulp & Chemical Co Inc 
Kraft Chemical Co 
Lipo Chemicals Inc 
Mutchler Inc 
Penta Manufacturing Co 
Ferro Pfanstiehl Laboratories Inc 
Roquette America Inc 
Spectrum Quality Products Inc 
SPI Pharma Group 
Thornley Company 
Triple Crown America 
Voigt Global Distribution LLC 
Vopak USA Inc 
Soybean Oil 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Aarhus United UK Ltd 
Corcoran Chemicals Ltd 
Croda Chemicals Ltd 
Karlshamns Ltd 
Other European 
Aarhus United Denmark A/S 
Karlshamns AB 
USA 
Aarhus United USA Inc 
Arista Industries Inc 
Avatar Corp 
Charkit Chemical Corp 
Croda Inc 
Mutchler Inc 
Penta Manufacturing Co 
Pokonobe Industries Inc 
Spectrum Quality Products Inc 
Starch 
UK 
Avebe UK Ltd 
Cerestar UK Ltd 
National Starch & Chemical Ltd 
Paroxite (London) Ltd 
Roquette (UK) Ltd 
Tennants (Distribution) Ltd 
Other European 
Amylum Ibe.rica, SA 
Avebe Group 
Brenntag AG 
Cerestar International 
Roquette Fre`res 
USA 
Ashland 
Avebe America Inc 
Brenntag Inc 
Cargill Corp 
Delta Distributors Inc 
Generichem Corp 
Grain Processing Corp 
Mutchler Inc 
National Starch & Chemical Co 
Penta Manufacturing Co 
Roquette America Inc 
Spectrum Quality Products Inc 
Voigt Global Distribution LLC 
Starch, Pregelatinized 
UK 
Avebe UK Ltd 
Cerestar UK Ltd 
Colorcon Ltd 
National Starch & Chemical Ltd 
Paroxite (London) Ltd 
Roquette (UK) Ltd 
Other European 
Amylum Ibe.rica, SA 
Avebe Group 
Cerestar International 
Roquette Fre`res 
USA 
Avebe America Inc 
Cargill Corp 
Colorcon 
Generichem Corp 
Grain Processing Corp 
Mutchler Inc 
National Starch & Chemical Co 
Particle Dynamics Inc 
Penta Manufacturing Co 
Roquette America Inc 
Starch, Sterilizable Maize 
UK 
Corcoran Chemicals Ltd 
Roquette (UK) Ltd 
Other European 
Amylum Ibe.rica, SA 
Roquette Fre`res 
USA 
Roquette America Inc 
Stearic Acid 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Cognis UK Ltd 
Corcoran Chemicals Ltd 
Croda Chemicals Ltd 
H Foster & Co (Stearines) Ltd 
James M Brown Ltd 
JT Baker UK 
Kimpton Brothers Ltd 
Paroxite (London) Ltd 
Poth Hille 
Tennants (Distribution) Ltd 
Thew, Arnott and Co Ltd 
Uniqema 
White Sea and Baltic Company Ltd 
Other European 
Brenntag AG 
Cognis Deutschland GmbH 
Appendix I: Suppliers Directory 857

USA 
Aceto Corp 
Alfa Chem 
Ashland 
Astro Chemicals Inc 
Akzo Nobel Inc 
Brenntag Inc 
Cognis Corp 
Delta Distributors Inc 
EM Sergeant Pulp & Chemical Co Inc 
Generichem Corp 
JT Baker Inc 
Koster Keunen Inc 
Kraft Chemical Co 
Mutchler Inc 
Penta Manufacturing Co 
Protameen Chemicals 
Rita Corp 
Spectrum Quality Products Inc 
Triple Crown America 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
Stearyl Alcohol 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Aarhus United UK Ltd 
Adina Chemicals Ltd 
Cognis UK Ltd 
Croda Chemicals Ltd 
Efkay Chemicals Ltd 
Goldschmidt UK Ltd 
Kimpton Brothers Ltd 
Other European 
Aarhus United Denmark A/S 
Brenntag AG 
Cognis Deutschland GmbH 
USA 
Aarhus United USA Inc 
Avatar Corp 
Brenntag Inc 
Cognis Corp 
Croda Inc 
Delta Distributors Inc 
Koster Keunen Inc 
Kraft Chemical Co 
Lipo Chemicals Inc 
M Michel and Company Inc 
Penta Manufacturing Co 
Protameen Chemicals 
Rita Corp 
Spectrum Quality Products Inc 
Stepan Co 
Vopak USA Inc 
Sucralose 
UK 
Tate & Lyle plc 
USA 
McNeil Nutritionals 
Sucrose 
UK 
Fisher Scientific UK Ltd 
JT Baker UK 
Pfanstiehl (Europe) Ltd 
Tate & Lyle plc 
Other European 
Brenntag AG 
NP Pharm 
USA 
Ashland 
Brenntag Inc 
Delta Distributors Inc 
EM Industries Inc 
Fisher Scientific 
JT Baker Inc 
Mutchler Inc 
Penta Manufacturing Co 
Ferro Pfanstiehl Laboratories Inc 
Spectrum Quality Products Inc 
Tate & Lyle 
Voigt Global Distribution LLC 
Sugar, Compressible 
UK 
Forum Biosciences Ltd 
Wilfrid Smith Ltd 
USA 
Mutchler Inc 
Tate & Lyle 
Sugar, Confectioner’s 
USA 
Mutchler Inc 
Sugar Spheres 
UK 
DMV UK 
Forum Biosciences Ltd 
Honeywill & Stein 
JRS Pharma Ltd 
Other European 
DMV Pharma 
J Rettenmaier & So. hne GmbH and Co 
NP Pharm 
USA 
JRS Pharma LP 
Sulfobutylether b-Cyclodextrin 
USA 
Cydex Inc 
Sulfuric Acid 
UK 
Fisher Scientific UK Ltd 
JT Baker UK 
Tennants (Distribution) Ltd 
Other European 
Brenntag AG 
USA 
Ashland 
Brenntag Inc 
Delta Distributors Inc 
Fisher Scientific 
JT Baker Inc 
Spectrum Quality Products Inc 
Triple Crown America 
Vopak USA Inc 
Suppository Bases, Hard Fat 
UK 
Aarhus United UK Ltd 
Alfa Chemicals Ltd 
Blagden Speciality Chemicals Ltd 
Cognis UK Ltd 
Karlshamns Ltd 
Other European 
Aarhus United Denmark A/S 
Cognis Deutschland GmbH 
Gattefosse. s.a. 
Karlshamns AB 
USA 
Aarhus United USA Inc 
Cognis Corp 
Gattefosse. Corp 
Voigt Global Distribution LLC 
Talc 
UK 
Colin Stewart Minchem Ltd 
Fisher Scientific UK Ltd 
JT Baker UK 
Paroxite (London) Ltd 
Pumex (UK) Limited 
Tennants (Distribution) Ltd 
Thew, Arnott and Co Ltd 
Other European 
Brenntag AG 
Luzenac Europe 
USA 
Brenntag Inc 
Charles B Chrystal Co Inc 
EM Sergeant Pulp & Chemical Co Inc 
Fisher Scientific 
JT Baker Inc 
Luzenac America 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Voigt Global Distribution LLC 
Vopak USA Inc 
Whittaker Clark, and Daniels Inc 
Tartaric Acid 
UK 
Fisher Scientific UK Ltd 
JT Baker UK 
Peter Whiting (Chemicals) Ltd 
Tennants (Distribution) Ltd 
Ubichem plc 
858 Appendix I: Suppliers Directory

Other European 
Arion & Delahaye 
Brenntag AG 
Dr Paul Lohmann GmbH KG 
Helm AG 
Pah.. SL 
USA 
Aceto Corp 
Ashland 
Brenntag Inc 
Charkit Chemical Corp 
Delta Distributors Inc 
EM Sergeant Pulp & Chemical Co Inc 
Fisher Scientific 
George Uhe Co Inc 
Helm New York Inc 
JT Baker Inc 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
Thaumatin 
Other European 
ABCR GmbH 
USA 
RFI Ingredients 
Thimerosal 
UK 
Sigma-Aldrich Company Ltd 
Ubichem plc 
USA 
Alfa Chem 
Charkit Chemical Corp 
George Uhe Co Inc 
Napp Technologies Inc 
Sigma-Aldrich Corp 
Spectrum Quality Products Inc 
Others 
LS Raw Materials Ltd 
Thymol 
UK 
Sigma-Aldrich Company Ltd 
Other European 
Alfa Aesar Johnson Matthey GmbH 
USA 
Alfa Chem 
EMD Chemicals Inc 
Mutchler Inc 
Penta Manufacturing Co 
Ruger Chemical Co Inc 
Thomas Scientific 
Vopak USA Inc 
Others 
Sarman Industries 
Titanium Dioxide 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
BASF Plc 
Cornelius Group plc 
Tioxide Europe Ltd 
Kronos Ltd 
Paroxite (London) Ltd 
Peter Whiting (Chemicals) Ltd 
Tennants (Distribution) Ltd 
Other European 
BASF Aktiengesellschaft 
Brenntag AG 
Chemco France 
DuPont de Nemours Int’l SA 
USA 
AerChem Inc 
Ashland 
BASF Corp 
Brenntag Inc 
Delta Distributors Inc 
DuPont 
Tioxide Americas Inc 
Kraft Chemical Co 
Mutchler Inc 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triple Crown America 
Voigt Global Distribution LLC 
Vopak USA Inc 
Whittaker Clark, and Daniels Inc 
Tragacanth 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
AF Suter and Co Ltd 
Fisher Scientific UK Ltd 
Thew, Arnott and Co Ltd 
Other European 
Alland & Robert 
USA 
Ashland 
Charkit Chemical Corp 
Chart Corp Inc 
Delta Distributors Inc 
Fisher Scientific 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Triacetin 
UK 
Eastman Company UK Ltd 
Honeywill & Stein 
Tennants (Distribution) Ltd 
USA 
ABITEC Corp 
Eastman Chemical Co 
Penta Manufacturing Co 
Spectrum Quality Products Inc 
Tributyl Citrate 
UK 
Ubichem plc 
Other European 
Jungbunzlauer 
USA 
Morflex Inc 
Penta Manufacturing Co 
Reilly Industries Inc 
Triethanolamine 
UK 
Corcoran Chemicals Ltd 
Fisher Scientific UK Ltd 
Sasol UK Ltd 
Sigma-Aldrich Company Ltd 
Tennants (Distribution) Ltd 
Ubichem plc 
Other European 
Brenntag AG 
USA 
Brenntag Inc 
Fisher Scientific 
Mutchler Inc 
Penta Manufacturing Co 
Rita Corp 
Sasol North America Inc 
Sigma-Aldrich Corp 
Spectrum Quality Products Inc 
Triple Crown America 
Vopak USA Inc 
Triethyl Citrate 
UK 
Alfa Chemicals Ltd/Gattefosse. UK 
Cognis UK Ltd 
Ubichem plc 
Other European 
Cognis Deutschland GmbH 
Gattefosse. s.a. 
Jungbunzlauer 
USA 
Charkit Chemical Corp 
Cognis Corp 
Gattefosse. Corp 
Jungbunzlauer Inc 
Morflex Inc 
Penta Manufacturing Co 
Reilly Industries Inc 
Vanillin 
UK 
Blagden Speciality Chemicals Ltd 
Cornelius Group plc 
Fisher Scientific UK Ltd 
Raught Ltd 
Rhodia Organic Fine Ltd 
Tennants (Distribution) Ltd 
Ubichem plc 
Other European 
Biesterfeld Spezialchemie GmbH 
Brenntag AG 
Helm AG 
Appendix I: Suppliers Directory 859

USA 
Ashland 
Brenntag Inc 
Charkit Chemical Corp 
Chart Corp Inc 
Delta Distributors Inc 
Fisher Scientific 
Helm New York Inc 
Mutchler Inc 
Penta Manufacturing Co 
Rhodia Pharma Solutions Inc 
Spectrum Quality Products Inc 
Triple Crown America 
Virginia Dare 
Voigt Global Distribution LLC 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
Vegetable Oil, Hydrogenated 
UK 
Adina Chemicals Ltd 
Forum Biosciences Ltd 
JRS Pharma Ltd 
Karlshamns Ltd 
White Sea and Baltic Company Ltd 
Other European 
Aarhus United Denmark A/S 
J Rettenmaier & So. hne GmbH and Co 
Karlshamns AB 
Chevron Texaco Global Lubricants 
Benelux 
USA 
Aarhus United USA Inc 
ABITEC Corp 
JRS Pharma LP 
Lipo Chemicals Inc 
Mutchler Inc 
Stepan Co 
Water 
UK 
Fisher Scientific UK Ltd 
Tennants (Distribution) Ltd 
USA 
Fisher Scientific 
Spectrum Quality Products Inc 
Wax, Anionic Emulsifying 
UK 
Adina Chemicals Ltd 
British Wax Refining Co 
Cognis UK Ltd 
Croda Chemicals Ltd 
Other European 
Cognis Deutschland GmbH 
USA 
Cognis Corp 
Croda Inc 
Lipo Chemicals Inc 
Spectrum Quality Products Inc 
Wax, Carnauba 
UK 
AF Suter and Co Ltd 
British Wax Refining Co 
Cornelius Group plc 
Kimpton Brothers Ltd 
Paroxite (London) Ltd 
Poth Hille 
Tennants (Distribution) Ltd 
Thew, Arnott and Co Ltd 
Ubichem plc 
USA 
Charkit Chemical Corp 
Koster Keunen Inc 
Mutchler Inc 
Penta Manufacturing Co 
Strahl & Pitsch Inc 
Whittaker Clark, and Daniels Inc 
Wax, Cetyl Esters 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Cognis UK Ltd 

Croda Chemicals Ltd 
Other European 
Cognis Deutschland GmbH 
USA 
Cognis Corp 
Croda Inc 
Koster Keunen Inc 
Rita Corp 
Spectrum Quality Products Inc 
Others 
LS Raw Materials Ltd 
Wax, Microcrystalline 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
AF Suter and Co Ltd 
British Wax Refining Co 
Cornelius Group plc 
Kimpton Brothers Ltd 
Paroxite (London) Ltd 
Poth Hille 
Thew, Arnott and Co Ltd 
Other European 
Chevron Texaco Global Lubricants 
Benelux 
USOCO BV 
USA 
Avatar Corp 
Koster Keunen Inc 
Strahl & Pitsch Inc 
Voigt Global Distribution LLC 
Whittaker Clark, and Daniels Inc 
Wax, Nonionic Emulsifying 
UK 
Adina Chemicals Ltd 
Cognis UK Ltd 
Croda Chemicals Ltd 
Efkay Chemicals Ltd 
Paroxite (London) Ltd 
Other European 
Cognis Deutschland GmbH 
USA 
Cognis Corp 
Croda Inc 
Koster Keunen Inc 
Lipo Chemicals Inc 
Rita Corp 
Wax, White 
UK 
British Wax Refining Co 
Cornelius Group plc 
Fisher Scientific UK Ltd 
Kimpton Brothers Ltd 
Paroxite (London) Ltd 
Poth Hille 
Thew, Arnott and Co Ltd 
Other European 
Chevron Texaco Global Lubricants 
Benelux 
USOCO BV 
USA 
Avatar Corp 
Charkit Chemical Corp 
Fisher Scientific 
Koster Keunen Inc 
Mutchler Inc 
Penta Manufacturing Co 
Rita Corp 
Spectrum Quality Products Inc 
Strahl & Pitsch Inc 
Triple Crown America 
Voigt Global Distribution LLC 
Whittaker Clark, and Daniels Inc 
Wax, Yellow 
UK 
British Wax Refining Co 
Cornelius Group plc 
Fisher Scientific UK Ltd 
Kimpton Brothers Ltd 
Paroxite (London) Ltd 
Poth Hille 
Thew, Arnott and Co Ltd 
Other European 
Gattefosse. s.a. 
USOCO BV 
USA 
Charkit Chemical Corp 
Fisher Scientific 
Koster Keunen Inc 
Mutchler Inc 
Penta Manufacturing Co 
Rita Corp 
Spectrum Quality Products Inc 
Strahl & Pitsch Inc 
Triple Crown America 
Voigt Global Distribution LLC 
Whittaker Clark, and Daniels Inc 
860 Appendix I: Suppliers Directory

Xanthan Gum 
UK 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
AF Suter and Co Ltd 
Corcoran Chemicals Ltd 
CP Kelco UK Ltd 
Rhodia Organic Fine Ltd 
Thew, Arnott and Co Ltd 
Other European 
Biesterfeld Spezialchemie GmbH 
Brenntag AG 
Jungbunzlauer 
USA 
Ashland 
Brenntag Inc 
Charkit Chemical Corp 
Chart Corp Inc 
CP Kelco US Inc 
Delta Distributors Inc 
Hawkins Chemical Inc 
Penta Manufacturing Co 
Rhodia Pharma Solutions Inc 
RT Vanderbilt Company Inc 
Spectrum Quality Products Inc 
TIC Gums 
Voigt Global Distribution LLC 
Vopak USA Inc 
Others 
LS Raw Materials Ltd 
Xylitol 
UK 
Cerestar UK Ltd 
Danisco Sweeteners Ltd 
Forum Biosciences Ltd 
Pfanstiehl (Europe) Ltd 
Roquette (UK) Ltd 
Thew, Arnott and Co Ltd 
Other European 
Arion & Delahaye 
Cerestar International 
Helm AG 
Roquette Fre`res 
USA 
Aceto Corp 
Alfa Chem 
Cargill Corp 
Danisco USA Inc 
Delta Distributors Inc 
George Uhe Co Inc 
Helm New York Inc 
Penta Manufacturing Co 
Ferro Pfanstiehl Laboratories Inc 
Roquette America Inc 
Spectrum Quality Products Inc 
Triple Crown America 
Voigt Global Distribution LLC 
Zein 
UK 
Paroxite (London) Ltd 
Ubichem plc 
Zinc Acetate 
UK 
JT Baker UK 
Other European 
Chemos GmbH 
Honeywell Specialty Chemicals Seelze 
USA 
Alfa Chem 
Amresco Inc 
EMD Chemicals Inc 
Gallard-Schlesinger Industries Inc 
Penta Manufacturing Co 
Ruger Chemical Co Inc 
Thomas Scientific 
Universal Preserv-A-Chem Inc 
Vopak USA Inc 
Zinc Stearate 
UK 
Allchem Pharma 
Fisher Scientific UK Ltd 
James M Brown Ltd 
JT Baker UK 
Paroxite (London) Ltd 
Tennants (Distribution) Ltd 
Other European 
Brenntag AG 
Dr Paul Lohmann GmbH KG 
USA 
Aceto Corp 
Alfa Chem 
Brenntag Inc 
Fisher Scientific 
George Uhe Co Inc 
Kraft Chemical Co 
Mutchler Inc 
Penta Manufacturing Co 
RIA International 
Spectrum Quality Products Inc 
Triple Crown America 
Voigt Global Distribution LLC 
Vopak USA Inc 
Whittaker Clark, and Daniels Inc 
Suppliers List: UK 
3M United Kingdom Plc 
3M Centre 
Cain Road 
Bracknell 
RG12 8HT 
Tel: .44 (0)8705 360036 
Web: www.3m.com 
Trade names: CoTran. 
A and E Connock (Perfumery and 
Cosmetics) Ltd 
Alderholt Mill House 
Fordingbridge 
SP6 1PU 
Tel: .44 (0)142 565 3367 
Fax: .44 (0)142 565 6041 
E-mail: sales@connock.co.uk 
Web: www.connock.co.uk 
Aarhus United UK Ltd 
King George Dock 
Kingston-upon-Hull 
HU9 5PX 
Tel: .44 (0)1482 701 271 
Fax: .44 (0)1482 709 447 
E-mail: uk.info@aarhusunited.com 
Web: www.aarhusunited.com/uk 
Trade names: Aextreff CT; Albutein; 
Colzao CT; Cremao CS-34; Cremao 
CS-36; Hyfatol 16-95; Hyfatol 16-98; 
Shogun CT. 
Acetex Chemicals Ltd 
Canterbury House 
41/53 Gosport Street 
Lymington 
SO41 9BB 
Tel: .44 (0)1590 688 222 
Fax: .44 (0)1590 688 333 
E-mail: sales@acetex.co.uk 
Web: www.acetex-eu.com 
Adina Chemicals Ltd 
12 Chapman Way 
Tunbridge Wells 
TN2 3EF 
Tel: .44 (0)1892 517585 
Fax: .44 (0)1892 517565 
E-mail: sales@adina.co.uk 
Web: www.adina.co.uk 
Trade names: Lipocol; Lipocol C; Lipolan; 
Liponate IPP; Lipovol SES. 
AF Suter and Co Ltd 
Thames House 
18 Park Street 
London 
SE1 9EQ 
Tel: .44 (0)207 403 6555 
Fax: .44 (0)207 378 8582 
E-mail: afsuter@afsuter.com 
Web: www.afsuter.com 
Trade names: Swanlac. 
Air Liquide UK Ltd 
Cedar House 
39 London House 
Reigate 
RH2 9QE 
Tel: .44 (0)737 241133 
Fax: .44 (0)737 241842 
Web: www.airliquide.com 
Air Products (Gases) plc 
2 Millennium Gate 
Westmere Drive 
Crewe 
CW1 6AP 
Tel: .44 (0)800 389 0202 
Fax: .44 (0)1932 258 502 
Air Products plc see Air Products (Gases) 
plc 
Appendix I: Suppliers Directory 861

Alembic Products Ltd 
Unit 2 Brymau Est. 
River Lane 
Saltney 
Chester 
CH4 8RB 
Tel: .44 (0)1244 680147 
Fax: .44 (0)1244 680155 
Web: www.alembicproducts.co.uk 
Alfa Chemicals Ltd see Alfa Chemicals 
Ltd/Gattefosse. UK 
Trade names: Resomer. 
Alfa Chemicals Ltd/Gattefosse. UK 
Arc House 
Terrace Road South 
Binfield 
Bracknell 
RG42 4PZ 
Tel: .44 (0)1344 861800 
Fax: .44 (0)1344 451400 
E-mail: info@alfa-chemicals.co.uk 
Web: www.alfa-chemicals.co.uk 
Trade names: Labrafac CC; Precirol ATO 
5; Resomer. 
Allchem Pharma 
Broadway House 
21 Broadway 
Maidenhead 
SL6 1NJ 
Tel: .44 (0)1753 443322 
Fax: .44 (0)1753 443323 
E-mail: info@allchem.co.uk 
Web: www.allchem.co.uk 
Trade names: Bergabest; Elcema; 
Genetron; Genetron 142b; Genetron 152a; 
Sternpur; Vivastar P; Vivapur; Vivasol. 
Alpha Therapeutic Europe Limited see 
Aarhus United UK Ltd 
Avebe UK Ltd 
Thornton Hall 
Thornton Curtis 
Ulceby 
DN39 6XD 
Tel: .44 (0)1469 532 222 
Fax: .44 (0)1469 531 488 
Web: www.avebe.com 
Trade names: Paselli MD10 PH; 
Perfectamyl D6PH; Prejel; Primellose; 
Primogran W; Primojel. 
Baker see JT Baker UK 
BASF Plc 
PO Box 4 
Earl Road 
Cheadle Hulme 
Cheadle 
SK8 6QG 
Tel: .44 (0)161 485 6222 
Fax: .44 (0)161 486 0891 
Web: www.basf.de/uk 
Trade names: Cremophor; Cremophor A; 
Kollicoat MAE 30 D; Kollicoat MAE 30 
DP; Kollidon; Kollidon CL; Kollidon 
CL-M; Kollidon VA 64; Lutrol E; 
Luviskol VA; Plurafac; Soluphor P; Solutol 
HS 15. 
Bayer plc 
Bayer House 
Strawberry Hill 
Newbury 
RG14 1JA 
Tel: .44 (0)1635 563000 
Fax: .44 (0)1635 563 393 
E-mail: 
corporate.communications@bayer.co.uk 
Web: www.bayer.co.uk 
Trade names: Solbrol A; Solbrol P. 
Blagden Specialty Chemicals Ltd 
Osprey House 
Black Eagle Square 
Westerham 
TN16 1PA 
Tel: .44 (0)1959 562000 
Fax: .44 (0)1959 565511 
E-mail: sales@blagdenspecchem.co.uk 
Web: www.blagdenspecchem.co.uk 
BOC Gases 
The Priestley Centre 
10 Priestly Road 
Surrey Research Park 
Guildford 
GU2 5XY 
Tel: .44 (0)800 111333 
Web: www.boc.com 
Borax Europe Ltd 
1A The Guildford Business Park 
Guildford 
GU2 8XG 
Tel: .44 (0)1483 242 000 
Fax: .44 (0)1483 242 001 
Borculo Domo Ingredients Ltd 
Riverside House 
Brymau Three Estate 
River Lane 
Saltney 
Chester 
CH4 8RQ 
Tel: .44 (0)1244 680127 
Fax: .44 (0)1244 671703 
E-mail: sales@bdiuk.co.uk 
Web: www.borculodomo.com 
Trade names: Lactochem; Lactopress 
Anhydrous; Lactopress Spray-Dried. 
BP plc 
1 St James’s Square 
London 
SW1Y 4PD 
Tel: .44 (0)20 7496 4000 
Fax: .44 (0)20 7496 4630 
Web: www.bp.com 
Brenntag (UK) Ltd 
Ham Lane 
Kingswinford 
DY6 7JU 
Tel: .44 (0)1384 400222 
Fax: .44 (0)1384 400020 
E-mail: sales@brenntag.co.uk 
Web: www.brenntag.co.uk 
British Traders & Shippers Ltd see Nippon 
Gohsei (UK) Ltd 
British Wax Refining Co 
62 Holmethorpe Avenue 
Holmethorpe Industrial Estate 
Surrey 
RH1 2NL 
Tel: .44 (0)1737 761242 
Fax: .44 (0)1737 761472 
Brunner Mond (UK) Ltd 
PO Box 4 
Mond House 
Northwich 
CW8 4DT 
Tel: .44 (0)1606 724000 
Fax: .44 (0)1606 781353 
Web: www.brunnermond.com 
Cerestar UK Ltd 
Trafford Park 
Manchester 
M17 1PA 
Tel: .44 (0)161 872 5959 
Fax: .44 (0)161 848 9034 
Web: www.cerestar.com 
Trade names: Cavitron; C*Ascend; 
C*Eridex; C*Pharm; C*PharmDex; 
C*PharmDry; C*PharmGel; 
C*PharmMaltidex; C*PharmMannidex; 
C*PharmSorbidex; C*PharmSweet. 
Chance & Hunt 
Alexander House 
Crown Gate 
Runcorn 
WA7 2UP 
Tel: .44 (0)1928 793000 
Fax: .44 (0)1928 714351 
E-mail: passport@chance-hunt.com 
Web: www.chance-hunt.com 
Clariant UK Ltd 
Calverleyy Lane 
Horsforth 
Leeds 
LS18 4RP 
Tel: .44 (0)113 258 4646 
Fax: .44 (0)113 239 8473 
Web: www.clariant.co.uk 
Trade names: Ethyl parasept; Nipacide 
PX; Nipanox BHA; Nipanox BHT; 
Nipantiox 1-F; Tylopur; Tylopur MH; 
Tylopur MHB; Tylose CB; Tylose MB; 
Tylose MH; Tylose MHB; Tylose PHA. 
Cognis UK Ltd 
Charleston Road 
Hardley 
Southampton 
SO45 3ZG 
Tel: .44 (0)2380 894666 
Fax: .44 (0)2380 243113 
Web: www.uk.cognis.com 
862 Appendix I: Suppliers Directory

Trade names: Copherol F1300; Cutina CP; 
Cutina GMS; Cutina HR; Dehymuls; 
Emulgade 1000NI; Eumulgin; Hydagen 
CAT; Lanette O; Majsao CT; Monomuls 
90-O18; Myritol; Novata; Texapon K12P. 
Colin Stewart Minchem Ltd 
Weaver Valley Road 
Winsford 
CW7 3BU 
Tel: .44 (0)1606 868 200 
Fax: .44 (0)1606 868 268 
Web: www.csminchem.co.uk 
Trade names: Magsil Star. 
Colloides Naturels UK Ltd 
The Triangle Business Centre 
Exchange Square 
Manchester 
M4 3TR 
Tel: .44 (0)161 838 5744 
Fax: .44 (0)161 838 5746 
Web: www.cniworld.com 
Colorcon Ltd 
Flagship House 
Victory Way 
Crossways 
Dartford 
DA2 6QD 
Tel: .44 (0)1322 293000 
Fax: .44 (0)1322 627200 
E-mail: infouk@colorcon.com 
Web: www.colorcon.com 
Trade names: Methocel; Opaseal; 
Phthalavin; Starch 1500 G; Surelease; 
Sureteric. 
Connock see A and E Connock (Perfumery 
and Cosmetics) Ltd 
Corcoran Chemicals Ltd 
Oak House 
Oak Close 
Wilmslow 
SK9 6DF 
Tel: .44 (0)1625 532 731 
Fax: .44 (0)1625 539 096 
E-mail: a.bryne@corcoran-chemicals.co.uk 
Web: www.corcoranchemicals.com 
Trade names: Maldex; Meritol. 
Cornelius Group plc 
Cornelius House 
Dunmow Road 
Woodside 
Bishop’s Stortford 
CM23 5RG 
Tel: .44 (0)1279 714 300 
Fax: .44 (0)1279 714 320 
E-mail: sales.dept@cornelius.co.uk 
Web: www.cornelius.co.uk 
Trade names: Tronox. 
Courtin & Warner Ltd 
19 Phoenix Place 
Lewes 
BN7 1JX 
Tel: .44 (0)1273 480611 
Fax: .44 (0)1273 472249 
Web: www.c-and-w.co.uk 
Coventry Chemicals Ltd 
Woodhams Road 
Siskin Drive 
Coventry 
CV3 4FX 
Tel: .44 (0)24 7663 9739 
Fax: .44 (0)24 7663 9717 
CP Kelco UK Ltd 
Cleeve Court 
Cleeve Road 
Leatherhead 
KT22 7UD 
Tel: .44 (0)1372 369 400 
Fax: .44 (0)1372 369 401 
Web: www.cpkelco.com 
Trade names: Keltrol; Xantural. 
Croda Chemicals Ltd 
Cowick Hall 
Snaith 
Goole 
DN14 9AA 
Tel: .44 (0)1405 860551 
Fax: .44 (0)1405 860205 
E-mail: healthcare-sales@crodaoleochemicals.
com 
Web: www.croda.co.uk 
Trade names: Byco; Cithrol; Crill; Crillet; 
Crodacid; Crodacol C70; Crodacol C90; 
Crodacol CS90; Crodacol S95; Crodamol 
IPM; Crodamol IPP; Crodamol SS; 
Croderol; Crodex A; Crodex N; Croduret; 
Crossential 094; Etocas; Hartolan; 
Polawax; Volpo. 
Danisco Sweeteners Ltd 
41–51 Brighton Road 
Redhill 
RH1 6YS 
Tel: .44 (0)1737 773732 
Fax: .44 (0)1737 773117 
E-mail: sweeteners@danisco.com 
Web: www.daniscosweeteners.com 
Trade names: Litesse. 
Degussa Hu. ls Ltd see Degussa Ltd 
Degussa Ltd 
Winterton House 
Winterton Way 
Macclesfield 
SK11 0LP 
Tel: .44 (0)1625 503050 
Fax: .44 (0)1625 502096 
Web: www.degussa.com 
Trade names: Aerosil. 
DMV UK 
PO Box 11 
Teddington 
TW11 8YG 
Tel: .44 (0)20 8943 5220 
Fax: .44 (0)20 8943 5231 
E-mail: robern@dmv-international.com 
Trade names: Nu-Core; Nu-Pareil PG; 
Pharmacel; Pharmatose DCL 11; 
Pharmatose DCL 14; Pharmatose DCL 
15; Pharmatose DCL 21; Pharmatose 
DCL 22; Pharmatose 50M; Pharmatose 
80M; Pharmatose 90M; Pharmatose 
100M; Pharmatose 110M; Pharmatose 
125M; Pharmatose 150M; Pharmatose 
200M; Pharmatose 350M; Pharmatose 
450M; Primellose. 
Dow Agrosciences 
Latchmore Court 
Brand Street 
Hitchin 
SG5 1HZ 
Tel: .44 (0)146 245 7272 
Fax: .44 (0)146 242 6605 
E-mail: fhihotl@dow.com 
Web: www.dowagro.com 
Trade names: Gallotox; Liquiphene. 
Dow Chemical Company (UK) 
2 Heathrow Boulevard 
284 Bath Road 
West Drayton 
UB7 0DQ 
Tel: .44 (0)208 917 5000 
Fax: .44 (0)208 917 5400 
Web: www.dow.com 
Dow Corning 
Center Northern Europe 
Meriden Business Park 
Copse Drive 
Allesley 
Coventry 
CV5 9RG 
Tel: .44 (0)1676 528000 
Fax: .44 (0)1676 528001 
Web: www.dowcorning.com 
Trade names: Dow Corning 245 Fluid; 
Dow Corning 246 Fluid; Dow Corning 
345 Fluid; Dow Corning Q7-2243 LVA; 
Dow Corning Q7-2587; Dow Corning 
Q7-9120. 
DSM UK Ltd 
DSM House 
Papermill Drive 
Redditch 
B98 8QJ 
Tel: .44 (0)1527 590590 
Fax: .44 (0)1527 590555 
Web: www.dsm.com 
Eastman Company UK Ltd 
European Technical Centre 
Acornfield Road 
Knowsley Industrial Park North 
Kirkby 
L33 7UF 
Appendix I: Suppliers Directory 863

Tel: .44 (0)151 547 2002 
Fax: .44 (0)151 548 5100 
Trade names: Eastacryl 30D; Eastman 
Vitamin E TPGS; Tenox BHA; Tenox 
BHT; Tenox PG. 
Edward Mendell see JRS Pharma Ltd 
Efkay Chemicals Ltd 
Allen House 
The Maltings 
Station Road 
Sawbridgeworth 
CM21 9JX 
Tel: .44 (0)1279 721 888 
Fax: .44 (0)1279 722 261 
E-mail: efkachem@aol.com 
Web: www.efkay.com 
Fisher Scientific UK Ltd 
Bishop Meadow Road 
Loughborough 
LE11 5RG 
Tel: .44 (0)1509 231166 
Fax: .44 (0)1509 231893 
E-mail: info@fisher.co.uk 
Web: www.fisher.co.uk 
Fluorochem Ltd 
Wesley Street 
Old Glossop 
SK13 7RY 
Tel: .44 (0)1457 868921 
Fax: .44 (0)1457 869360/860927 
E-mail: enquiries@fluorochem.co.uk 
Web: www.fluorochem.net 
Forum Biosciences Ltd 
41–51 Brighton Road 
Redhill 
RH1 6YS 
Tel: .44 (0)1737 773711 
Fax: .44 (0)1737 773116 
Web: www.forum.co.uk 
Trade names: Candex; Compactrol; 
Dextrofin; Effer-Soda; Emcocel; 
Emcompress; Emdex; Explotab; Lubritab; 
Mannogem; ProSolv; Pruv; Satialgine H8; 
Sorbogem; Xylitab. 
Foster & Co see H Foster & Co 
(Stearines) Ltd 
Fuchs Lubricants (UK) plc 
New Century Street 
Hanley 
Stoke-on-Trent 
ST1 5HU 
Tel: .44 (0)8701 200 400 
Fax: .44 (0)1782 202072/3 
E-mail: contact-uk@fuchs-oil.com 
Web: www.fuchslubricants.com 
Trade names: Silkolene; Sirius. 
Global Ceramic Materials Ltd 
Milton Works 
Leek New Road 
Milton 
Stoke-on-Trent 
ST2 7PX 
Tel: .44 (0)1782 537297 
Fax: .44 (0)1782 537867 
E-mail: info@Globalcm.co.uk 
Goldschmidt UK Ltd 
Tego House 
Chippenham Drive 
Kingston 
Milton Keynes 
MK10 OAF 
Tel: .44 (0)1908 582250 
Fax: .44 (0)1908 582254 
Web: www.goldschmidtsurfactants.com 
Trade names: ABIL; Tegin; Tegin 503; 
Tegin 515; Tegin 4100; Tegin M; Tegosept 
E; Tegosoft M. 
Grace Davison 
Oak Park Business Centre 
Alington Road 
Little Barford 
St Neots 
PE19 6WL 
Tel: .44 (0)1480 324430 
Fax: .44 (0)1480 324433 
Web: www.grace.com 
Haarmann & Reimer Ltd 
Fieldhouse Lane 
Marlow 
SL7 1TB 
Tel: .44 (0)1628 472 051 
Fax: .44 (0)1635 562 007 
E-mail: usuk@hr-gmbh.de 
Trade names: Arosol. 
Haltermann Ltd see Dow Chemical 
Company (UK) 
Hercules Ltd 
Aqualon Division 
Langley Road 
Salford 
M6 6JU 
Tel: .44 (0)161 736 4461 
Fax: .44 (0)161 745 7009 
Trade names: Aqualon; Aquasorb; 
Blanose; Culminal MHEC; Klucel; 
Natrosol. 
H Foster & Co (Stearines) Ltd 
103 Kirkstall Road 
Leeds 
LS3 1JL 
Tel: .44 (0)113 243 9016 
Fax: .44 (0)113 242 2418 
E-mail: info@hfoster.co.uk 
Web: www.hfoster.co.uk 
Honeywill & Stein 
Times House 
Throwley Way 
Sutton 
SM1 4AF 
Tel: .44 (0)208 770 7090 
Fax: .44 (0)208 770 7295 
E-mail: info@honeywill.co.uk 
Web: www.honeywill.co.uk 
Trade names: Ac-Di-Sol; Aquacoat cPD; 
Aquacoat ECD; Avicel PH; Blanose; 
Celphere; Gelcarin; Klucel; Myvatex; 
Myvaplex 600 P; Natrosol; NPTAB; 
Pluriol E; Protacid; Protanal; Wyndale. 
Huntsman Tioxide see Tioxide Europe Ltd 
Ingredients Consultancy Ltd, The 
PO Box 66 
Tewkesbury 
GL20 6YQ 
Tel: .44 (0)1684 59 4949 
Fax: .44 (0)1684 59 4748 
E-mail: info@theingredients.co.uk 
Web: theingredients.co.uk 
Intermag Co Ltd 
Felling Industrial Estate 
Bath Road 
Gateshead 
NE10 0LG 
Tel: .44 (0)191 495 2220 
Fax: .44 (0)191 438 4717 
ISP Europe 
Waterfield 
Tadworth 
KT20 5HQ 
Tel: .44 (0)20 7519 5054 
Fax: .44 (0)20 7519 5056 
Trade names: Celex; Germall 115; 
Kelcosol; Keltone; Pharmasolve; Plasdone; 
Plasdone S-630; Polyplasdone XL; 
Polyplasdone XL-10. 
James M Brown Ltd 
Napier Street 
Fenton 
Stoke-on-Trent 
ST4 4NX 
Tel: .44 (0)1782 744171 
Fax: .44 (0)1782 744473 
E-mail: sales@jamesmbrown.co.uk 
Web: www.jamesmbrown.co.uk 
JRS Pharma Ltd 
Church House 
48 Church Street 
Reigate 
RH2 0SN 
Tel: .44 (0)1737 222323 
Fax: .44 (0)1737 222545 
E-mail: techsales@jrspharma.co.uk 
Web: www.jrspharma.com 
Trade names: Emcompress Anhydrous; 
Candex; Compactrol; Emcompress; 
Emcocel; Emdex; Explotab; Lubritab; 
ProSolv; Pruv; Satialgine H8. 
JT Baker UK 
Mallinkrodt Baker UK 
107/112 Leadenhall Street 
London 
EC3A 4AH 
Tel: .44 (0)1908 506000 
Fax: .44 (0)1908 503290 
E-mail: 
jtbaker.uk@emea.tycohealthcare.com 
864 Appendix I: Suppliers Directory

Web: www.jtbaker.com 
Trade names: HyQual. 
Karlshamns Ltd 
220 Wincolmlee 
Hull 
HU2 0PX 
Tel: .44 (0)1482 586747 
Fax: .44 (0)1482 587004 
E-mail: info@karlshamns.co.uk 
Web: www.karlshamns.com 
Trade names: Akofine; Akosoft; Akosol; 
Lipex 107; Lipex 108; Lipex 200; Lipex 
204. 
Kelco see CP Kelco UK Ltd 
Kimpton Brothers Ltd 
10–14 Hewett Street 
London 
EC2A 3RL 
Tel: .44 (0)20 7456 9999 
Fax: .44 (0)20 7247 2784/7375 3584 
E-mail: info@kimpton.co.uk 
Web: www.kimpton.com 
Kronos Ltd 
Barons Court 
Manchester Road 
Wilmslow 
SK9 1BQ 
Tel: .44 (0)1625 547200 
Fax: .44 (0)1625 533123 
E-mail: sales@kronosww.com 
Trade names: Kronos 1171. 
Lanxess Ltd 
Lichfield Road 
Burton-Trent 
DE14 3WH 
Tel: .44 (0)1283 714200 
Fax: .44 (0)1283 714201 
E-mail: john.bridges@lanxess.com 
Web: www.bayferrox.de 
Trade names: Bayferrox 306; Bayferrox 
920Z. 
Leading Solvent Supplies Ltd 
Rudgate 
Tockwith 
York 
YO26 7QF 
Tel: .44 (0)1423 358000 
Fax: .44 (0)1423 358923 
E-mail: sales@Leading-Solvent.co.uk 
Web: www.Leading-Solvent.co.uk 
Lloyd Ltd see WS Lloyd Ltd 
Lonza UK Ltd 
228 Bath Road 
Slough 
SL1 4DX 
Tel: .44 (0)1753 777000 
Fax: .44 (0)1753 777001 
E-mail: contact.slough@lonza.com 
Web: www.lonzagroup.com 
Trade names: Aldo MO; Glycon; Glycon 
G-100; Hyamine 1622; Hyamine 3500. 
Lyondell Chemical Europe 
Bridge Avenue 
Maidenhead 
SL6 1YP 
Tel: .44 (0)1628 775000 
Fax: .44 (0)1628 775180 
E-mail: david.hancock@lyondell.com 
Web: www.lyondell.com 
Mantrose (UK) Ltd 
Unit 7B Northfield Farm 
Great Shefford 
RG17 7BY 
Tel: .44 (0)1488 648 988 
Fax: .44 (0)1488 648 890 
Web: www.mbzgroup.com 
Trade names: CertiSeal; Mantrolac R-49. 
Mast Group Ltd 
Mast House 
Derby Road 
Bootle 
L20 1EA 
Tel: .44 (0)151 9337277 
Fax: .44 (0)151 9441332 
Web: www.mastgrp.com 
Mendell see JRS Pharma Ltd 
Messer UK Ltd see Air Liquide UK Ltd 
National Starch & Chemical Ltd 
Prestbury Court 
Greencourts Business Park 
333 Styal Road 
Manchester 
M22 5LW 
Tel: .44 (0)161 435 3200 
Fax: .44 (0)161 435 3300 
Web: www.nationalstarch.com 
www.excipients.com 
Trade names: National 78-1551; Purity 
21; Purity 826; Unipure LD; Unipure 
WG220. 
Nipa Laboratories Ltd see Clariant UK Ltd 
Nippon Gohsei (UK) Ltd 
Soarnol House 
Kingston upon Hull 
HU12 8DS 
Tel: .44 (0)1482 333320 
Fax: .44 (0)1482 333325 
E-mail: info@nippon-gohsei.com 
Web: www.nippon-gohsei.com 
Trade names: Gohsenol. 
Nutrinova UK Ltd 
Atrium Court 
The Ring 
Bracknell 
RG12 1BW 
E-mail: 
caroline.boardman@nutrinova.co.uk 
Web: www.nutrinova.com 
Trade names: Sunett. 
Paroxite (London) Ltd 
Office Unit 2 
7 Dryden Court 
Renfrew Road 
Kennington 
London 
SE11 4NH 
Tel: .44 (0)20 7735 2425 
Fax: .44 (0)20 7735 4408 
E-mail: paroxite@clara.co.uk 
Trade names: Albagel; EmCon CO; 
Fancol; Hygum TP-1; Phenoxen; Pure- 
Dent; Pure-Dent B851; Spress B820; 
Waglinol 6014. 
PB Gelatins UK Ltd 
Treforest 
Pontypridd 
CF37 5SQ 
Tel: .44 (0)1443 849300 
Fax: .44 (0)1443 844209 
E-mail: nop@tessenderlo.com 
Web: www.tessenderlogroup.com 
Trade names: Cryogel; Instagel; Solugel. 
Penwest Ltd see JRS Pharma Ltd 
Peter Whiting (Chemicals) Ltd 
1 Oil Mill Lane 
Hammersmith 
London 
W6 9UA 
Tel: .44 (0)20 8741 4025 
Fax: .44 (0)20 8741 1737 
E-mail: sales@whiting-chemicals.co.uk 
Web: www.whiting-chemicals.co.uk 
Pfanstiehl (Europe) Ltd 
Unit 27 Meridian House 
Road One 
Winsford Industrial Estate 
Winsford 
CW7 3QG 
Tel: .44 (0)1606 559163 
Fax: .44 (0)1606 559641 
E-mail: custserv@pfaneur.u-net.com 
Web: www.pfanstiehl.com 
PMC Chemicals Ltd 
12 Downham Chase 
Timperley 
Altrincham 
WA15 7TJ 
Tel: .44 (0)161 904 0499 
Fax: .44 (0)161 904 7080 
E-mail: sales@pmcchemicals.com 
Web: pmcchemicals.com 
Poth Hille 
37 High Street 
Stratford 
London 
E15 2QD 
Tel: .44 (0)20 8534 7091 
Fax: .44 (0)20 8534 2291 
Web: www.poth-hille.co.uk 
Appendix I: Suppliers Directory 865

Pumex (UK) Limited 
Unit D4 
Grampian House 
Meridian Gate 
Marsh Wall 
London 
E14 9YT 
Tel: .44 (0)20 7363 5456 
Fax: .44 (0)20 7363 5780 
E-mail: info@pumex.co.uk 
Web: www.pumex.co.uk 
Trade names: Magsil Osmanthus. 
Purac Biochem (UK) 
50–54 St Paul’s Square 
Birmingham 
B3 1QS 
Tel: .44 (0)121 236 1828 
Fax: .44 (0)121 236 1401 
E-mail: puk@purac.com 
Web: www.purac.com 
Trade names: Lacty; Purasorb; Purasorb 
PD; Purasorb PDL; Pursasorb PDLG; 
Purasorb PG; Pursasorb PL. 
Raught Ltd 
38 Cambridge Road 
Barking 
IG11 8NW 
Tel: .44 (0)20 8591 6933 
Fax: .44 (0)20 8507 8066 
E-mail: info@raught.co.uk 
Web: www.raught.co.uk 
Reheis 
Willowbank House 
97 Oxford Road 
Highbridge Estate 
Uxbridge 
UB8 1LU 
Tel: .44 (0)1895 819316 
Fax: .44 (0)1895 819333 
Web: www.reheis.com 
Trade names: Rehydraphos. 
Rhodia Organic Fine Ltd 
PO Box 46 
St Andrews Road 
Avonmouth 
Bristol 
BS11 9YF 
Tel: .44 (0)117 948 4242 
Fax: .44 (0)117 948 4249 
Trade names: A-TAB; DI-TAB; 
Meyprodor; Meyprofin; Meyprofleur; 
Meyprogat; Rhodiarome; Rhodigel; 
Rhovanil; TRI-TAB; TRI-CAL WG. 
Roche Products Ltd 
40 Broadwater Road 
PO Box 8 
Welwyn Garden City 
AL7 3AY 
Tel: .44 (0)170 736 6000 
Fax: .44 (0)170 733 8297 
Web: www.roche.com 
Rohm and Haas UK Ltd 
Heckmondwike Road 
Dewsbury Moor 
Dewsbury 
WF13 3NG 
Tel: .44 (0)1924 403367 
Fax: .44 (0)1824 405166 
Web: www.rohmhaas.com/ionexchange 
Trade names: Amberlite IRP-88. 
Roquette (UK) Ltd 
Sallow Road 
Corby 
NN17 5JX 
Tel: .44 (0)1536 273000 
Fax: .44 (0)1536 263873 
E-mail: roquette.uo.phar@wanadoo.fr 
Web: www.roquette.com 
Trade names: Flolys; Fluidamid R444P; 
Glucidex; Keoflo ADP; Kleptose; Lycadex 
PF; Lycasin 80/55; Lycasin HBC; Lycatab 
C; Lycatab DSH; Lycatab PGS; Maltisorb; 
Maltisorb 75/75; Neosorb; Pearlitol; 
Roclys; Roferose; Xylisorb. 
RW Unwin & Co Ltd 
Prospect Place 
Welwyn 
AL6 9EW 
Tel: .44 (0)1438 716441 
Fax: .44 (0)1438 716067 
E-mail: sales@rwunwin.co.uk 
Web: www.rwunwin.co.uk 
Trade names: Aqoat; Aqoat AS-HF/HG; 
Aqoat AS-LF/LG; Aqoat AS-MF/MG; 
Metolose. 
Sasol UK Ltd 
No. 1 Hockley Court 
2401 Stratford Road 
Hockley Heath 
Solihull 
B94 6NW 
Tel: .44 (0)1564 783 060 
Fax: .44 (0)1564 784 088 
E-mail: hugh.odonnell@sasol.com 
Web: www.sasol.com 
Trade names: Imwitor 191; Imwitor 900; 
Lipoxol. 
Shin-Etsu Chemical Co Ltd see RW Unwin 
& Co Ltd 
Sigma-Aldrich Company Ltd 
Fancy Road 
Poole 
BH12 4QH 
Tel: .44 (0)1747 833000 
Fax: .44 (0)1202 712239 
E-mail: ukcustsv@europe.sial.com 
Web: www.sigma-aldrich.com 
Trade names: Thimerosal Sigmaultra. 
Sparkford Chemicals Ltd 
58 The Avenue 
Southampton 
SO17 2 1XS 
Tel: .44 (0)23 8022 8747 
Fax: .44 (0)23 8021 0240 
E-mail: info@sparkford.co.uk 
Web: www.sparkford.co.uk 
Stan Chem International Ltd 
4 Kings Road 
Reading 
RG1 3AA 
Tel: .44 (0)118 958 0247 
Fax: .44 (0)118 958 9580 
E-mail: info@stanchem.co.uk 
Web: www.stanchem.co.uk 
Tate & Lyle plc 
Head Office 
Sugar Quay 
Lower Thames Street 
London 
EC3R 6DQ 
Tel: .44 (0)20 7626 6525 
Fax: .44 (0)20 7623 5213 
Web: www.tate-lyle.co.uk 
Tennants (Distribution) Ltd 
Hazelbottom Road 
Cheatham 
Manchester 
M8 0GR 
Tel: .44 (0)161 2054454 
Fax: .44 (0)161 2035985 
Thew, Arnott and Co Ltd 
Newman Works 
270 London Road 
Wallington 
SM6 7DJ 
Tel: .44 (0)20 8669 3131 
Fax: .44 (0)20 8669 7747 
E-mail: sales@thewarnott.co.uk 
Web: www.thewarnott.co.uk 
Tioxide Europe Ltd 
(Huntsman Tioxide) 
Tees Road 
Hartlepool 
TS25 2DD 
Tel: .44 (0)1642 376376 
Fax: .44 (0)1642 376446 
Web: www.huntsman.com 
Trade names: Tioxide. 
Ubichem plc 
Mayflower Close 
Chandlers Ford Industrial Estate 
Eastleigh 
SO53 4AR 
Tel: .44 (0)23 8026 3030 
Fax: .44 (0)23 8026 3012 
E-mail: sales@ubichem.com 
Web: www.ubichem.com 
Uniqema 
PO Box 90 
Wilton Centre 
Middlesbrough 
TS90 8JE 
Tel: .44 (0)16 4245 4144 
Fax: .44 (0)16 4243 7374 
Web: www.uniqema.com 
Trade names: Estol IPM; Pricerine; 
Pristerene. 
866 Appendix I: Suppliers Directory

Unwin see RW Unwin & Co Ltd 
Wacker Chemicals Ltd 
120 Bridge Road 
Chertsey 
T16 8LA 
Tel: .44 (0)870 048202 
Fax: .44 (0)870 0480203 
Web: www.wacker.com 
Trade names: Cavamax W6 Pharma; 
Cavamax W7 Pharma; Cavamax W8 
Pharma; Wacker HDK. 
White Sea and Baltic Company Ltd 
Arndale House 
Otley Road 
Headingley 
Leeds 
LS6 2UU 
Tel: .44 (0)113 230 4774 
Fax: .44 (0)113 230 4770 
E-mail: sales@whitesea.co.uk 
Web: www.whitesea.co.uk 
Whiting (Chemicals) Ltd see Peter Whiting 
(Chemicals) Ltd 
Wilfrid Smith Ltd 
Elm House 
Medlicott Close 
Oakley Hay 
Corby 
NN18 9NF 
Tel: .44 (0)1536 460020 
Fax: .44 (0)1536 462400 
Web: www.wilfrid-smith.co.uk 
William Blythe Ltd 
Church 
Accrington 
BB5 4PD 
Tel: .44 (0)125 432 0000 
Fax: .44 (0)125 432 0001 
E-mail: info@wm-blythe.co.uk 
Web: www.wm-blythe.co.uk 
William Ransom & Son plc 
Alexander House 
40A Wilbury Way 
Hitchin 
SG4 0AP 
Tel: .44 (0)1462 437 615 
Fax: .44 (0)1462 420 528 
E-mail: info@williamransom.com 
Web: www.williamransom.com 
WS Lloyd Ltd 
7 Redgrove House 
Stonards Hill 
Epping 
CM16 4QQ 
Tel: .44 (0)1992 572670 
Fax: .44 (0)1992 578074 
E-mail: enquiries@wslloyd.com 
Web: www.wslloyd.com 
Xyrofin (UK) Ltd see Danisco Sweeteners 
Ltd 
Suppliers List: Other European 
Aarhus Oliefabrik A/S see Aarhus United 
Denmark A/S 
Aarhus United Denmark S/S 
MP Brunns Gade 27 
PO Box 50 
DK-8100 Aarhus C 
Denmark 
Tel: .45 8730 6000 
Fax: .45 8730 6012 
E-mail: aarhus@aarhusunited.com 
Web: www.aarhusunited.com/dk 
Trade names: Aextreff CT; Albutein; 
Colzao CT; Cremao CS-34; Cremao CS- 
36; Hyfatol 16-95; Hyfatol 16-98; Shogun 
CT. 
ABCR GmbH 
Postfach 21 01 35 
D-76151 Karlsruhe 
Germany 
Tel: .49 721 95061 0 
Fax: .49 721 95061 80 
E-mail: inquiry@abcr.de 
Web: www.abcr.de 
Acetex Chimie SA 
BP 194 
164 bis Avenue Charles de Gaulle 
F-92205 Neuilly Sur Seine Cedex 
France 
Tel: .33 1 47 38 97 00 
Fax: .33 1 47 38 97 32 
E-mail: info.siege@acetex-eu.com 
Web: www.acetex-eu.com 
Ajinomoto Switzerland AG 
Innere Gu. terstrasse 2-4 
PO Box 4559 
CH-6304 Zug 
Switzerland 
Tel: .41 41 728 66 66 
Fax: .41 41 728 65 65/66 
Web: www.ajinomoto.ch 
Akzo Nobel Functional Chemicals bv 
Barchman Wuytierslaan 10 
PO Box 247 
NL-3800 AE Amersfoort 
Netherlands 
Tel: .31 33 467 6767 
Fax: .31 33 467 6146 
Trade names: Akucell; Dissolvine. 
Alfa Aesar Johnson Matthey GmbH 
Postbox 11 07 65 
D-76057 Karlsruhe 
Germany 
Tel: .49 721 84007 280 
Fax: 49 721 84007 300 
E-mail: gcat@matthey.com 
Web: www.alfa-chemcat.com 
Alland & Robert 
9 rue de Saintonge 
F-75003 Paris 
France 
Tel: .33 1 44 59 21 31 
Fax: .33 1 42 72 54 38 
E-mail: info@allandetrobert.fr 
Web: www.allandetrobert.fr 
Amylum Ibe.rica, SA 
Division of Tate & Lyle 
Avda. Salvador Allende, 76-78 
50015 Zaragoza 
Spain 
Tel: .34 976 738 100 
Fax: .34 976 738 128 
E-mail: spain@amylum.com 
Web: www.amylumgroup.com 
Trade names: Fructamyl; Glucodry; 
Glucomalt; Glucosweet; Maldex; Merigel; 
Meritena; Meritol; Mylose. 
Arion & Delahaye 
Grote Markt.7 
B-2000 
Antwerpen 
Belgium 
Tel: .32 (0)3 22 22 044 
Fax: .32 (0)3 22 22 045 
E-mail: info@arion-delahaye.com 
Web: www.kreglinger-europe.com 
August Hedinger GmbH & Co 
Holy Meadows 26 
D-70327 Stuttgart 
Germany 
Tel: .49 0711 402050 
Fax: .49 0711 4020535 
Web: www.hedinger.de 
Avebe Group 
PO Box 15 
9640 AA Veendam 
Netherlands 
Tel: .31 598 66 91 11 
Fax: .31 598 66 43 68 
E-mail: info@avebe.com 
Web: www.avebe.com 
Trade names: Paselli MD10 PH; 
Perfectamyl D6PH; Prejel; Primellose; 
Primogran W; Primojel. 
BASF Aktiengesellschaft 
Carl-Bosch-Strasse 38 
D-67056 Ludwigshafen 
Germany 
Tel: .49 621 60 42525 
Fax: .49 621 60 97060 
E-mail: info.service@basf-ag.de 
Web: www.basf-ag.de 
Trade names: Cremophor; Cremophor A; 
Kollicoat MAE 30 D; Kollicoat MAE 30 
DP; Kollidon; Kollidon CL; Kollidon CLM; 
Kollidon VA 64; Lutrol E; Luviskol 
VA; Myacide; Plurafac; Soluphor P. 
Appendix I: Suppliers Directory 867

Biesterfeld Spezialchemie GmbH 
Ferdinandstrasse 41 
D-20095 Hamburg 
Germany 
Tel: .49 (0) 40 32 008 437 
Fax: .49 (0) 40 32 008 443 
E-mail: spezialchemie@biesterfeld.com 
Web: www.biesterfeld.com 
Boehringer Ingelheim GmbH 
Corporate Department 
Marketing & Sales Fine Chemicals 
Binger Strasse 173 
D-55216 Ingelheim 
Germany 
Tel: .49 6132 77 3978 
Fax: .49 6132 77 4227 
Web: www.boehringer-ingelheim.com/ 
finechem 
Trade names: Resomer. 
Borculo Domo Ingredients 
Hanzeplaein 25 
8017 JD Zwolle 
PO Box 449 
NL-8000 AK Zwolle 
Netherlands 
Tel: .31 38 46 77 444 
Fax: .31 38 46 77 579 
Web: www.borculodomo.com 
Trade names: Lactochem; Lactopress 
Anhydrous; Lactopress Spray-Dried. 
Brenntag AG 
Stinnes-Platz 1 
D-45472 Mu. lheim an der Ruhr 
Germany 
Tel: .49 208 7828 7425 
Fax: .49 208 7828 635 
E-mail: anne.hubertz@brenntag.de 
Web: www.brenntag.de 
Brenntag NV 
Nijverheidslaan 38 
B-8540 Deerlijk 
Belgium 
Tel: .32 56 77 69 44 
Fax: .32 56 77 57 11 
E-mail: infor@brenntag.be 
Web: www.brenntag.be 
Trade names: Tri-Cafos. 
Cabot GmbH 
Postfach 90 11 20 
Josef-Bautz-Strasse 15 
D-63420 Hanau 
Germany 
Tel: .49 6181 505150 
Fax: .49 6181 505201 
Web: www.cabot-corp.com/cabosil 
Trade names: Cab-O-Sil. 
Cargill Cerestar BVBA 
Office Park Mechelen 
Bedrijvenlaan 9 
2800 Mechelen 
Belgium 
Tel: .32 15 400 411 
Fax: .32 15 400 410 
Trade names: C*PharmSweet; Isomaltidex 
16500. 
Cerestar International 
7 rue du Mare.chal Joffre 
F-59482 Haubourdin Cedex BP109 
France 
Tel: .33 (0)3 20 44 3535 
Fax: .33 (0)3 20 44 3567 
Web: www.cerestar.com 
Trade names: Cavitron; C*Ascend; 
C*Eridex; C*Pharm; C*PharmDex; 
C*PharmDry; C*PharmGel; 
C*PharmMaltidex; C*PharmMannidex; 
C*PharmSorbidex; C*PharmSweet. 
CFF GmbH and Co KG 
Arnstaedter Str.2 
D-98708 Gehren 
Germany 
Tel: .49 (0) 36 78 38 82 0 
Fax: .49 (0) 36 78 38 82 25 2 
E-mail: customerservice@cff.de 
Web: www.cff.de 
Trade names: Sanacel. 
Chemag Aktiengesellschaft 
Lurgiallee 5 
D-60439 Frankfurt am Main 
Germany 
Tel: .49 (0)69 57 00 75 00 
Fax: .49 (0)69 57 00 75 17 
E-mail: info@solvadis.com 
Web: www.chemag.de 
Chemco France 
10 av Maurice Berteaux 
F-78300 Poissy 
France 
Tel: .33 1 30 65 75 00 
Fax: .33 1 30 65 74 94 
E-mail: chemco@wanadoo.fr 
Web: www.chemco-france.fr 
Chemos GmbH 
Werner-von-Siemensstr. 3 
93128 Regenstauf 
Germany 
Tel: .49 9402 9336 0 
Fax: .49 9402 9336 13 
E-mail: sales@chemos-group.com 
Web: www.chemos-group.com 
Chevron Texaco Global Lubricants 
Benelux 
Techologiepark Zwijnaarde 2 
B-9052 Gent 
Belgium 
Tel: .32 9 240 71 11 
Fax: .32 9 240 71 95 
E-mail: bnllubles@chevrontexaco.com 
Web: www.texaco.com 
Clariant GmbH 
Am Unisyspark 1 
D-65843 Sulzbach 
Germany 
Tel: .49 6196 75760 
Trade names: Tylopur; Tylopur MH; 
Tylopur MHB; Tylose CB; Tylose MB; 
Tylose MH; Tylose MHB; Tylose PHA. 
Cognis Deutschland GmbH 
KG Paul-Thomas Str. 56 
Postfach 130164 
D-40551 Du. sseldorf 
Germany 
Tel: .49 211 7940 0 
Fax: .49 211 798 2431 
E-mail: care.chemicals@cognis.de 
Web: www.cognis.com 
Trade names: Copherol F1300; Cutina CP; 
Cutina GMS; Cutina HR; Emulgade 
1000NI; Eumulgin; Eutanol G PH; HDEutanol 
V PH; Hydagen CAT; Lanette 16; 
Lanette O; Monomuls 90-O18; Myritol; 
Novata; Texapon K12P. 
Colloides Naturels International 
129 Chemin de Croisset 
PO Box 4151 
F-76723 Rouen Cedex 3 
France 
Tel: .33 2 32 83 18 18 
Fax: .33 2 32 83 19 19 
E-mail: client-order@cniworld.com 
Web: www.cniworld.com 
Contipro C a.s. 
Doln.. Dobrouc. 401 
561 02 Doln.. Dobrouc. 
Czech Republic 
Tel: .420 465 520 035 
Fax: .420 465 524 098 
E-mail: sales@contipro.cz 
Web: www.cpn-contipro.com 
Degussa AG 
Weissfrauenstrasse 9 
D-60311 Frankfurt am Main 
Germany 
Tel: .49 69 218 01 
Fax: .49 69 218 3218 
Web: www.degussa.com 
Trade names: Aerosil. 
Degussa Hu. ls AG see Degussa AG 
DMV Pharma 
PO Box 13 
NL-5460 BA Veghel 
Netherlands 
Tel: .31 413 372 222 
Fax: .31 413 372930 
E-mail: service@dmv-international.com 
Web: www.dmv-international.com 
Trade names: Nu-Core; Nu-Pareil PG; 
Pharma-Carb; Pharmacel; Pharmatose 
DCL 11; Pharmatose DCL 14; 
Pharmatose DCL 15; Pharmatose DCL 
21; Pharmatose DCL 22; Pharmatose 
50M; Pharmatose 80M; Pharmatose 90M; 
Pharmatose 100M; Pharmatose 110M; 
Pharmatose 125M; Pharmatose 150M; 
Pharmatose 200M; Pharmatose 350M; 
Pharmatose 450M; Primellose. 
868 Appendix I: Suppliers Directory

Dow Benelux NV 
Prins Boudewijnlaan 41 
2650 Edegem 
Belgium 
Tel: .32 (0)3 4502011 
Fax: .32 (0) 3 4502913 
Web: www.dow.com 
Dr Paul Lohmann GmbH KG 
PO Box 1220 
D-31857 Emmerthal 
Germany 
Tel: .49 5155 630 
Fax: .49 5155 63134 
E-mail: sales@lohmann-chemikalien.de 
Web: www.lohmann4minerals.com 
DSM Fine Chemicals 
PO Box 43 
NL-6130 AA Sittard 
Netherlands 
Tel: .31 46 477 3487 
Fax: .31 46 477 3172 
E-mail: dfcvenlo.sales@dsm-group.com 
Web: www.dsm.com 
DuPont de Nemours Int’l SA 
2, Chemin du Pavillion Box 50 
CH-1218 Le Grand Saconnex 
Geneva 
Switzerland 
Tel: . 41 22 717 5111 
Fax: . 41 22 717 5500 
Web: www.dupont.com 
Trade names: Dymel; Dymel 134a/P; 
Dymel 142b; Dymel 152a; Dymel 227 
EA/P; Dymel A; Elvanol; TiPure. 
Exquim S.A. 
PO Box 70-08190 
S. Cugat del Valles 
Barcelona 
Spain 
Tel: 93 5044400 
Fax: 93 5894502 
E-mail: exquim@ferrergrupo.com 
Web: www.exquim.com 
Trade names: Citrosa. 
FeF Chemicals A/S 
PO Box 230 
Kobenhavnsvej 216 
DK-4600 Koge 
Denmark 
Tel: .45 5667 1000 
Fax: .45 5667 1001 
E-mail: jsbi@novonordisk.com 
Web: www.fef-chem.com 
FMC Biopolymer 
Avenue Mounier 83, Box 2 
B-1200 Brussels 
Belgium 
Tel: .32 2 775 8311 
Fax: .32 2 775 8300 
E-mail: pharm_info@fmc.com 
Web: www.fmcbiopolymer.com 
Trade names: Ac-Di-Sol; Aquacoat cPD; 
Aquacoat ECD; Avicel PH; Celphere; 
Gelcarin; Marine Colloids; Protacid; 
Protanal; SeaSpen PF; Viscarin. 
Gattefosse. s.a. 
Parc des Barbanniers 
5 Promenade de la Bonnette 
F-92632 Gennevilliers 
France 
Tel: .33 1 4147 1900 
Fax: .33 1 4147 1929 
E-mail: infopharma@gattefosse.com 
Web: www.gattefosse.fr 
Trade names: Apifil; Compritol 888 ATO; 
Labrafac CC; Peceol; Precirol ATO 5. 
Haarmann & Reimer GmbH 
Division of Symrise GmbH & Co KG 
Muehlenfeldstrasse 1 
D-37603 Holzminden 
Germany 
Tel: .49 5531 900 
Fax: .49 5531 901649 
Web: www.symrise.de 
Trade names: Arosol. 
Haltermann GmbH 
Schlengendeich 17 
D-21107 Hamburg 
Germany 
Tel: .49 40 75 146 
Fax: .49 40 75 190 
E-mail: info@hg.haltermann.de 
Web: www.haltermann.com 
Hedinger GmbH see August Hedinger 
GmbH & Co 
Helm AG 
Nordkanalstrasse 28 
D-20097 Hamburg 
Germany 
Tel: .49 40 2375 0 
Fax: .49 40 2375 1845 
E-mail: info@helmag.com 
Web: www.helmag.com 
Hermes Sweeteners Ltd 
Ankerstrasse 53 
CH-8026 Zurich 
Switzerland 
Tel: .41 (0)44 245 43 00 
Fax: .41 (0)44 245 43 35 
E-mail: info@hermesetas.com 
Web: www.hermesetas.com 
Trade names: Hermesetas. 
Hollandse Melksuikerfabriek 
PO Box 13 
NL-5460 BA Veghel 
Netherlands 
Tel: .31 (0)413 372348 
Fax: .31 (0)413 340797 
E-mail: hms@hmssales.com 
Trade names: HMS. 
Honeywell Specialty Chemicals Seelze 
Po Box 10 02 62 
D-30918 Seelze 
Germany 
Tel: .49 5137 999 630 
Fax: .49 5137 999 103 
E-mail: Michaela.kapp@honeywell.com 
Web: www.honeywell-lifescience.com 
Induchem AG 
Industrestrasse 26 
CH-8604 Volketswil 
Switzerland 
Tel: .44 908 4333 
Fax: .44 908 4330 
E-mail: contact@induchem.com 
Web: www.induchem.com 
Interchim Austria GES.M.B.H 
Brixentaler Strasse 67 
A-6300 Wo. rgl 
Austria 
Tel: .43 5332 71947 
Fax: .43 5332 75361 
E-mail: office@interchim.at 
Web: www.interchim.at 
J Rettenmaier & So. hne GmbH and Co 
Holzmu. hle 1 
D-73494 Rosenberg 
Germany 
Tel: .49 7967 152330 
Fax: .49 7967 152345 
E-mail: info@jrs.de 
Web: www.jrs.de 
Trade names: Arbocel; Vivapress Ca; 
Vivapur; Vivasol; Vivastar P. 
Jungbunzlauer 
St Alban-Vorstadt 90 
CH-4002 Basel 
Switzerland 
Tel: .41 61 295 51 00 
Fax: .41 61 295 51 08 
E-mail: jblint@jungbunzlauer.com 
Web: www.jungbunzlauer.com 
Trade names: Citrofol AI. 
Karlshamns AB 
Vastra Kajen 
SE-374 82 Karlshamn 
Sweden 
Tel: .46 (0)454 82000 
Fax: .46 (0)454 82810 
E-mail: info@karlshamns.se 
Web: www.karlshamns.com 
Trade names: Akofine; Akosoft; Akosol; 
Lipex 107; Lipex 200. 
Kraeber GmbH & Co 
Pharmazeutische Rohstoffe 
Waldhofstrasse 14 
D-25474 Ellerbek 
Germany 
Tel: .49 4101 3053 0 
Fax: .49 4101 3053 90 
E-mail: info@kraeber.de 
Web: www.kraeber.de 
Lehmann & Voss & Co 
Alsterufer 19 
D-20354 Hamburg 
Germany 
Appendix I: Suppliers Directory 869

Tel: .49 40 44197 0 
Fax: .49 40 44197 219 
E-mail: info@lehvoss.de 
Web: www.lehvoss.de 
Lonza Ltd 
Muenchensteinerstrasse 38 
PO Box 
CH-4002 Basel 
Switzerland 
Tel: .41 61 316 81 11 
Fax: .41 61 316 91 11 
E-mail: info@lonzagroup.com 
Web: www.lonzagroup.com 
Trade names: Aldo MO; Glycon; Glycon 
G-100; Hyamine 1622. 
Lucas Meyer 
Ausschla. ger Elbdeich 62 
D-20539 Hamburg 
Germany 
Tel: .49 40 789 55 0 
Fax: .49 40 789 83 29 
E-mail: info@lucas-meyer.com 
Luzenac Europe 
BP 1162 
F-31036 Toulouse Cedex 1 
France 
Tel: .33 561 502 020 
Fax: .33 561 502 000 
Web: www.luzenac.com 
Trade names: Luzenac Pharma; Superiore. 
Magnesia GmbH 
PO Box 2168 
D-21311 Lu. neburg 
Germany 
Tel: .49 4131 8710 0 
Fax: .49 4131 8710 50 
E-mail: info@magnesia.de 
Web: www.magnesia.de 
Trade names: MagGran CC. 
Matrix Marketing GmbH 
Bahnweg Norg 35 
CH-9475 Sevelen 
Switzerland 
Tel: .41 (0)81 740 5830 
Fax: .41 (0)81 740 5831 
E-mail: info@matrix-marketing.ch 
Web: www.matrix-marketing.ch 
Meggle Gmbh see Molkerei Meggle 
Wasserburg GmbH 
Molkerei Meggle Wasserburg GmbH 
Megglestr. 6–12 
D-83512 Wasserburg 
Germany 
Tel: .49 80 71 73 487 
Fax: .49 80 71 73 320 
E-mail: service.pharma@meggle.de 
Web: www.meggle-pharma.de 
Trade names: CapsuLac; FlowLac 100; 
GranuLac; Inhalac; PrismaLac; SacheLac; 
SorboLac; SpheroLac; Tablettose. 
Natura Internacional S.L. 
Rio Guadalquivir 4 
30130 Beniel 
Spain 
Tel: 34 96 6708283 
Fax: 34 96 5606076 
E-mail: natinter@telefonica.net 
Web: www.ricote.biz 
Nippon Soda Co Ltd 
Nisso Chemical Europe GmbH 
Stein Str. 27 
D-40210 Du. sseldorf 
Germany 
Tel: .49 211 323 0135 
Fax: .49 211 328 231, 133003 
Web: www.nippon-soda.co.jp 
Trade names: Nisso HPC. 
NovaMatrix 
FMC Biopolymer 
Gaustadalle.en 21 
N-0349 Oslo 
Norway 
Tel: .47 2295 8638 
Fax: .47 3220 3510 
E-mail: novamatrix_info@fmc.com 
Web: www.novamatrix.com 
Noviant 
Noviant Headquarters 
Winselingseweg 12 
PO Box 31 
NL-6500 AA Nijmegen 
Netherlands 
Tel: .31 24 371 9900 
Fax: .31 24 371 9999 
E-mail: info@noviantgroup.com 
Web: www.noviantgroup.com 
Trade names: Finnfix; Nymcel; Nymcel 
ZSC; Nymcel ZSX. 
NP Pharm 
54 bis Route de Paris 
F-78550 Bazainville 
France 
Tel: .33 134 877 897 
Fax: .33 134 877 896 
E-mail: info@nppharm.fr 
Web: www.nppharm.fr 
Trade names: Cutina HR; Ethispheres; 
NPTAB; Suglets. 
Nutrinova Nutrition Specialities & Food 
Ingredients GmbH 
Industriepark Ho. chst 
D-65926 Frankfurt am Main 
Germany 
Tel: .49 69305 84771 
Fax: .49 69305 815412 
E-mail: harflett@nutrinova.com 
Web: www.nutrinova.com 
Trade names: Sunett. 
Orafti 
Aandorenstraat 1 
3300 Tienen 
Belgium 
Tel: .32 (0)16 801 301 
Fax: .32 (0)16 801 308 
E-mail: group@orafti.com 
Web: www.orafti.com 
Trade names: Raftiline. 
Pah.. SL 
66 Madrid Ave 
08208 Barcelona 
Spain 
Tel: .34 93 656 24 09; .34 93 656 23 51 
Fax: .34 93 656 53 09 
E-mail: pahi@tartaricchemicals.com 
Web: www.tartaricchemicals.com 
Palatinit GmbH 
Gottlieb-Daimler Str 12 
68165 Mannheimn 
Germany 
Tel: .49 621 421 150 
Fax: .49 621 421 160 
E-mail: galenIQ@palatinit.de 
Web: www.palatinit.de 
Trade names: Beneo; GalenIQ; Palatinit. 
Palatinit Su. .ungsmittel GmbH see 
Palatinit GmbH 
Parafluid Mineraloelges MBH 
Export Department 
PO Box 602060 
Uberseering 9 
D-22297 Hamburg 
Germany 
Tel: .49 406 3704 00 
Fax: .49 406 3704 100 
E-mail: info@parafluid.de 
PB Gelatins Belgium 
Division of Tessenderlo Chemie nv 
Marius Duchestraat 260 
B-1800 Vilvoorde 
Belgium 
Tel: .32 2 255 62 11 
Fax: .32 2 255 63 34 
E-mail: nop@tessenderlo.com 
Web: www.tessenderlo.com 
Trade names: Cryogel; Instagel; Solugel. 
Reheis 
Haansberg 100 
NL-4874 Etten-Leur 
Netherlands 
Tel: .31 76 526 4530 
Fax: .31 76 526 4531 
E-mail: cvandongen@reheis.com 
Trade names: Rehydraphos. 
Rettenmaier see J Rettenmaier & So. hne 
GmbH and Co 
Rohm and Haas Belgium NV 
Ankerrui 9 
2000 Antwerpen 
Belgium 
Tel: .32 (0) 3 4513600 
Fax: .32 (0) 3 4513630 
870 Appendix I: Suppliers Directory

Ro.hm GmbH 
Kirschenallee 
D-64293 Darmstadt 
Germany 
Tel: .49 61 51 18 01 
Fax: .49 61 51 18 02 
E-mail: s-com@degussa.com 
Web: www.roehm.com 
Trade names: Eudragit. 
Roquette Fre`res 
F-62080 Lestrem Cedex 
France 
Tel: .33 (0)3 21 63 36 00 
Fax: .33 (0)3 21 63 38 50 
E-mail: roquette.uo.phar@wanadoo.fr 
Web: www.roquette.fr 
Trade names: Flolys; Fluidamid R444P; 
Glucidex; Keoflo ADP; Kleptose; Lycadex 
PF; Lycasin 80/55; Lycasin HBC; Lycatab 
C; Lycatab DSH; Lycatab PGS; Maltisorb; 
Maltisorb 75/75; Neosorb; Pearlitol; 
Roclys; Roferose; Xylisorb. 
Sasol Germany GmbH 
Arthur-Imhausen-Str. 92 
D-58453 Witten 
Germany 
Tel: .49 23 02 92 53 13 
Fax: .49 23 02 92 55 00 
Schaefer Kalk KG 
Louise Seher Strasse 6 
D-65582 Diez 
Germany 
Tel: .49 6432 503 0 
Fax: .49 6432 503 269 
E-mail: info@schaeferkalk.de 
Web: www.schaeferkalk.de 
Sensus 
Sensus Operations CV 
Borchwerf 3 
4704 RG Roosendaal 
Netherlands 
Tel: .31 165 58 2500 
Fax: .31 165 56 7796 
E-mail: info.sensus@sensus.nl 
Web: www.sensus.nl 
Trade names: Frutafit. 
SKW Biosystems see Sobel NV 
Sobel NV 
NCB Weg 10 
NL-5681 RH BEST 
Netherlands 
Tel: .31 499 364 555 
Fax: .31 499 393 084 
E-mail: sobel@sobel.nl 
Web: www.sobel.nl 
Solvay Fluor GmbH 
Carl Ulrich Strasse 34 
D-74206 AN Bad Wimpfen 
Germany 
Tel: .49 7063 510 
Fax: .49 7063 512 55 
Web: www.solvay-fluor.com 
Trade names: Solkane 142b; Solkane 152a. 
Solvay Fluor und Derivative see Solvay 
Fluor GmbH 
Stern Lecithin and Soja GmbH 
An der Alster 81 
D-20099 Hamburg 
Germany 
Tel: .49 (0)172 451 6591 
Su. dzucker AG see Palatinit GmbH 
Tessenderlo Chemie 
Rue du Tro. ne 130 
B-1050 Bruxelles 
Belgium 
Tel: .32 2 639 1811 
Fax: .32 2 639 1702 
E-mail: tcgroup@tessenderlo.com 
Web: www.tessenderlo.com 
Texas Global Products Benelux see 
Chevron Texaco Global Lubricants 
Benelux 
USOCO BV 
Mandenmakerstraat 21 
NL-2984 AS Ridderkerk 
Netherlands 
Tel: .31 0180 41 61 55 
Fax: .31 0180 41 28 36 
E-mail: info@usoco.nl 
Web: www.usoco.nl 
Wacker-Chemie GmbH 
Business Line Biotechnology 
Johannes Hess Str. 24 
D-84489 Burghausen 
Germany 
Tel: .49 8677 830 
Fax: .49 8677 833 100 
Web: www.wacker-biochem.com 
Trade names: Cavamax W6 Pharma; 
Cavamax W7 Pharma; Cavamax W8 
Pharma; Wacker HDK. 
Suppliers List: USA 
3M Drug Delivery Systems 
3M Center 
St Paul 
MN 55144-1000 
Tel: .1 888 364 3577 
Web: www.3m.com 
Trade names: CoTran. 
Aarhus United USA Inc 
131 Marsh Street 
Port Newark 
NJ 07114 
Tel: .1 973 344 1300 
Fax: .1 973 344 9049 
E-mail: us.soles@aarhusunited.com 
Web: www.aarhusunited.com 
Trade names: Aextreff CT; Albutein; 
Colzao CT; Cremao CS-34; Cremao CS- 
36; Hyfatol 16-95; Hyfatol 16-98; Shogun 
CT. 
ABITEC Corp 
501 West First Avenue 
PO Box 569 
Columbus 
OH 43216-0569 
Tel: .1 614 429 6464 
Fax: .1 614 299 8279 
E-mail: sales@abiteccorp.com 
Web: www.abiteccorp.com 
Trade names: Acconon; Capmul GMO; 
Capmul GMS-50; Captex 300; Captex 
355; Captex 500; Sterotex; Sterotex HM. 
Aceto Corp 
One Hollow Lane 
Lake Success 
NY 11042-1215 
Tel: .1 516 627 6000 
Fax: .1 516 627 6093 
E-mail: aceto@aceto.com 
Web: www.aceto.com 
Acme-Hardesty 
1787 Sentry Parkway West 
Suite 18-460 
Blue Bell 
PA 19422 
Tel: .1 215 591 3610 
Fax: .1 215 591 3620 
E-mail: sales@acme-hardesty.com 
Web: www.acme-hardesty.com 
Advance Scientific & Chemical Inc 
2345 SW 34th Street 
Fort Lauderdale FL 33312 
Tel: .1 954 327 0900 
Fax: .1 954 327 0903 
Web: www.advance-scientific.com 
AerChem Inc 
3935 W Roll Avenue 
Bloomington 
IN 47403 
Tel: .1 812 334 9996 
Fax: .1 812 334 1960 
E-mail: aerchem@aerchem.com 
Web: www.aerchem.com 
Aeropres Corp 
Aeropres Headquarters 
1324 North Hearne 
Suite 200 
PO Box 78588 
Shreveport 
LA 71137-8588 
Tel: .1 318 221 6282 
Fax: .1 318 213 1270 
Web: www.aeropres.com 
Trade names: Aeropres 17; Aeropres 31; 
Aeropres 108. 
AE Staley Mfg Co see Tate & Lyle 
Air Liquide America Corp 
2700 Post Oak Boulevard 
Suite 1800 
Houston 
TX 77056 
Tel: .1 800 820 2522 
Appendix I: Suppliers Directory 871

Akzo Nobel 
525 West Van Burewn Street 
Chicago 
l 60607 
Tel: .1 312 5447000 
E-mail: CSRUS@Akzo-Nobel.com 
Web: www.akzonobelusa.com 
Trade names: Elfan 240; Dissolvine; 
Kessco IPM 95; Kortacid 1895. 
Aldrich see Sigma-Aldrich Corp 
Alfa Chem 
2 Harbor Way 
King’s Point 
NY 11024 
Tel: .1 516 504 0059 
Fax: .1 516 504 0039 
E-mail: alfachem1@aol.com 
Web: www.alfachem1.com 
Alzo International Inc 
650 Jernee Mill Road 
Sayreville 
NJ 08872 
Tel: .1 732 254 1901 
Fax: .1 732 254 4423 
E-mail: carolyn.zofchak@mail. 
alzointernational.com 
Web: www.alzointernational.com 
Trade names: Wickenol 111. 
American Colloid Co 
1500 West Shure Drive 
Arlington Heights 
IL 60004 
Tel: .1 847 392 4600 
Fax: .1 847 506 6199 
Web: www.colloid.com 
Trade names: Magnabrite; Polargel. 
American Lecithin Co 
115 Hurley Road 
Unit 2B 
Oxford 
CT 06478 
Tel: .1 203 262 7100 
Fax: .1 203 262 7101 
Web: www.americanlecithin.com 
Trade names: Phosal 53 MCT; 
Phospholipon 100 H. 
Amresco Inc 
30175 Solon Industrial Parkway 
Solon 
OH 44139 
Tel: .1 800 829 2805 
Fax: .1 440 349 1182 
E-mail: info@amresco-inc.com 
Web: www.amresco-inc.com 
AnMar International 
PO Box 2343 
Bridgeport 
CT 06608 
Tel: .1 203 336 8330 
Fax: .1 203 336 5508 
E-mail: BlancoAnMar@snet.net 
Web: www.anmarinternational.com 
Aqualon 
(Division of Hercules Inc) 
Hercules Plaza 
1313 North Market Street 
Wilmington 
DE 19894-0001 
Tel: .1 302 594 5000 
Fax: .1 302 594 5400 
E-mail: aqualon-us@herc.com 
Web: www.herc.com 
Trade names: Aqualon; Benecel; Benecel 
MHPC; Blanose; Culminal MC; Culminal 
MHEC; Galactosol; Genu; Klucel; 
Natrosol. 
Arista Industries Inc 
557 Danbury Road 
Wilton 
CT 06897 
Tel: .1 800 255 6457 
Fax: .1 203 761 4980 
E-mail: info@aristaindustries.com 
Web: www.aristaindustries.com 
Ashland 
PO Box 2219 
Columbus 
OH 43216 2219 
Tel: .1 614 790 3333 
Web: www.ashchem.com 
Astro Chemicals Inc 
64–94 Shaw’s Lane 
PO Box 2248 
Springfield 
MA 01102 
Tel: .1 413 781 7240 
Fax: .1 413 781 7246 
Web: www.astrochemicals.com 
Trade names: Airvol; Drakeol; Hystrene; 
Hystrene 9512; Industrene; Nipasol M. 
Avanti Polar Lipids Inc 
700 Industrial Park Drive 
Alabaster 
AL 35007-9105 
Tel: .1 800 227 0651 
Fax: .1 205 6630756 
E-mail: info@avantilipids.com 
Web: www.avantilipids.com 
Avatar Corp 
500 Central Avenue 
University Park 
IL 60466 
Tel: .1 708 534 5511 
Fax: .1 708 534 0123 
E-mail: sales@avatarcorp.com 
Web: www.avatarcorp.com 
Trade names: Avatech; Avol; Citation; LSC 
5050; LSC 6040; Snow white. 
Avebe America Inc 
South Rail Road 
North Charleston 
SC 29420 
Tel: .1 843 863 1055 
Web: www.avebe.com 
Trade names: Paselli MD10 PH; 
Perfectamyl D6PH; Prejel; Primellose; 
Primogran W; Primojel. 
Aventis Behring LLC see ZLB Behring 
Barrington Chemical Corp see Barrington 
Nutritionals Inc 
Barrington Nutritionals Inc 
500 Mamaroneck Ave 
Harrison 
NY 10528 
Tel: .1 914 381 3500 
Fax: .1 914 381 2232 
E-mail: info@barringtonchem.com 
Web: www.barringtonchem.com 
BASF Corp 
100 Campus Drive 
Florham Park 
NJ 07932 
Tel: .1 973 245 6000 
Fax: .1 973 245 6002 
Web: www.basf.com 
Trade names: Cremophor; Cremophor A; 
Kollicoat MAE 30 D; Kollicoat MAE 30 
DP; Kollidon; Kollidon CL; Kollidon CLM; 
Kollidon VA 64; Lutrol E; Luviskol 
VA; Myacide; Plurafac; Soluphor P. 
Bayer Corp 
100 Bayer Road 
Building 14 
Pittsburgh 
PA 15205-9741 
Tel: .1 412 777 3934 
Fax: .1 412 778 6526 
Web: www.bayer.com 
Trade names: Solbrol A; Solbrol P. 
BF Goodrich Speciality Chemicals see 
Noveon Inc 
Biddle Sawyer Corp 
21 Penn Plaza 
360 West 31st Street 
New York 
NY 10001-2727 
Tel: .1 212 736 1580 
Fax: .1 212 239 1089 
E-mail: BSC@biddlesawyer.com 
Web: www.biddlesawyer.com 
Trade names: Metolose. 
BOC Gases 
575 Mountain Avenue 
Murray Hill 
NJ 07974 2082 
Tel: .1 908 464 8100 
Web: www.boc.com 
Boehringer Ingelheim Chemicals Inc 
PO Box 1658 
3330 South Crater Road 
Petersburg 
VA 23805 
Tel: .1 804 863 0098 
Fax: .1 804 862 3246 
872 Appendix I: Suppliers Directory

E-mail: cvance@bichemicals.com 
Web: www.boehringer-ingelheim.com/ 
finechem 
Trade names: Resomer. 
BP Inc 
535 Madison Avenue 
New York 
NY 10022-4212 
Tel: .1 212 421 5010 
Fax: .1 212 421 5084 
Web: www.bp.com 
Brainerd Chemical Company Inc 
1200 North Peoria 
PO Box 470010 
Tulsa 
OK 74147-0010 
Tel: .1 918 622 1214 
Fax: .1 918 632 0851 
E-mail: sales@brainerdchemical.com 
Web: www.brainerdchemical.com 
Brenntag Inc 
PO Box 13786 
Reading 
PA 19612 3786 
Tel: .1 610 926 6100 
Fax: .1 610 926 0420 
E-mail: brenntag@brenntag.com 
Web: www.brenntagnorthamerica.com 
Trade names: Sequestrene AA. 
Burlington Bio-medical and Scientific Corp 
71 Carolyn Boulevard 
Farmingdale 
NY 11735 
Tel: .1 631 694 4700 
Fax: .1 631 694 9177 
Trade names: Bitterguard. 
Cabot Corp 
5401 Venice Ave 
Albuquerque 
NM 87113 
Tel: .1 505 342 1492 
Web: www.cabot-corp.com/cabosil 
Trade names: Cab-O-Sil; Cab-O-Sil M-5P. 
Cargill Corp 
Cargill Office Center 
PO Box 9300 
Minneapolis 
MN 55440 9300 
Tel: .1 952 742 7575 
Web: www.cargill.com 
Trade names: Cavitron. 
Cerestar USA Inc see Cargill Corp 
Charkit Chemical Corp 
9 Old Kings Highway South 
PO Box 1725 
Darien 
CT 06820 1725 
Tel: .1 203 655 3400 
Fax: .1 203 655 8643 
E-mail: sales@charkit.com 
Web: www.charkit.com 
Charles B Chrystal Co Inc 
30 Vesey Street 
New York 
NY 10007 
Tel: .1 212 227 2151 
Fax: .1 212 233 7916 
E-mail: info@cbchrystal.com 
Web: www.cbchrystal.com 
Trade names: Lion; Purtalc; Sim 90. 
Charles Bowman & Co 
PO Box 2427 
Holland 
MI 49424-2427 
Tel: .1 616 786 4000 
Fax: .1 616 786 2864 
E-mail: cbc@charlesbowman.com 
Web: www.charlesbowman.com 
Chart Corp Inc 
787 East 27th Street 
Paterson 
NJ 07504 
Tel: .1 201 345 5554 
Fax: .1 201 345 2139 
Church and Dwight Co Inc 
469 North Harrison Street 
Princeton 
NJ 08543 
Tel: .1 800 221 0453 
Fax: .1 609 497 7176 
Web: www.ahperformance.com 
Clariant Corp 
4000 Monroe Road 
Charlotte 
NC 28205 
Tel: .1 704 331 7000 
Fax: .1 704 331 7810 
Web: www.clariant.com 
Trade names: Tylopur; Tylopur MH; 
Tylopur MHB; Tylose CB; Tylose MB; 
Tylose MH; Tylose MHB; Tylose PHA. 
Cognis Corp 
North America Headquarters 
5051 Estecreek Drive 
Cincinnati 
OH 45232-1446 
Tel: .1 513 482 3000 
Fax: .1 513 482 5503 
Web: www.na.cognis.com 
Trade names: Copherol F1300; Cutina CP; 
Cutina GMS; Cutina HR; Emulgade 
1000NI; Eumulgin; Hydagen CAT; 
Lanette 16; Lanette O; Monomuls 90- 
O18; Myritol; Novata; Texapon K12P. 
Colloides Naturels Inc 
1170 US Highway 22 
Suite 204 
Bridgewater 
NJ 08807 
Tel: .1 908 707 9400 
Fax: .1 908 707 9405 
Colorcon 
415 Moyer Boulevard 
West Point 
PA 19486 
Tel: .1 215 699 7733 
Fax: .1 215 661 2605 
E-mail: infous@colorcon.com 
Web: www.colorcon.com 
Trade names: Methocel; Opaseal; 
Phthalavin; Starch 1500 G; Surelease; 
Sureteric. 
CP Kelco US Inc 
1000 Parkwood Circle 
Suite 1000 
Atlanta 
GA 30339 
Tel: .1 678 247 7300 
Fax: .1 302 594 6260 
Web: www.cpkelco.com 
Trade names: Keltose; Keltrol; Xantural. 
Croda Inc 
300-A Columbus Circle 
Edison 
NJ 08837 
Tel: .1 732 417 0800 
Fax: .1 732 417 0804 
E-mail: marketing@crodausa.com 
Web: www.crodausa.com 
Trade names: Byco; Crill; Crillet; Crodacol 
C90; Crodacol CS90; Crodacol S95; 
Crodamol GTC/C; Crodamol IPM; 
Crodamol IPP; Crodamol SS; Crodex A; 
Crodex N; Croduret; Crossential 094; 
Etocas; Hartolan; Polawax; Volpo. 
Crompton Corp 
Global Corporate Headquarters 
199 Benson Road 
Middlebury 
CT 06749 
Tel: .1 203 573 2000 
Trade names: Sentry. 
CTD Inc 
27317 NW 78th Avenue 
High Springs 
FL 32643 
Tel: .1 386 454 0887 
Fax: .1 386 454 8134 
Web: www.cyclodex.com 
Cultor Food Science see Danisco USA Inc 
Cydex Inc 
12980 Metcalf Avenue 
Suite 470 
Overland Park 
KS 66213 
Tel: .1 913 685 8850 
Fax: .1 913 685 8856 
E-mail: cdinfo@cydexinc.com 
Web: www.cydex.com 
Trade names: Captisol. 
Appendix I: Suppliers Directory 873

Danisco Cultor America Inc see Danisco 
USA Inc 
Danisco USA Inc 
440 Saw Mill River Road 
Ardsley 
NY 10502-2605 
Tel: .1 913 764 8100 
Fax: .1 914 674 6542 
E-mail: sweeteners@danisco.com 
Web: www.daniscosweeteners.com 
Trade names: Litesse. 
Degussa Corp 
379 Interpace Parkway 
PO Box 677 
Parsipanny 
NJ 07054-0677 
Tel: .1 973 541 8000 
Fax: .1 973 541 8501 
Web: www.degussa.com 
Trade names: Aerosil. 
Degussa Hu. ls Corp see Degussa Corp 
Delta Distributors Inc 
610 Fisher Road 
Longview 
TX 75604 
Tel: .1 903 759 7151 
Fax: .1 903 759 7548 
Dow Agrosciences LLC 
9330 Zionsville Road 
Indianapolis 
IN 46268 
Tel: .1 317 337 3000 
Fax: .1 800 905 7326 
Web: www.dowagro.com 
Dow Chemical Co 
2030 Dow Center 
Midland 
MI 48642 
Tel: .1 989 636 1000 
Fax: .1 989 636 3518 
Web: www.dow.com 
Trade names: Carbowax; Carbowax 
Sentry; Cellosize HEC; Ethocel; Methocel; 
Optim; Versene Acid. 
Dow Corning 
Corporate Center 
PO Box 994 
Midland 
MI 48686-0994 
Tel: .1 989 496 4400 
Fax: .1 989 496 6731 
Web: www.dowcorning.com 
Trade names: Dow Corning 245 Fluid; 
Dow Corning 246 Fluid; Dow Corning 
345 Fluid; Dow Corning Q7-2243 LVA; 
Dow Corning Q7-2587; Dow Corning 
Q7-9120. 
DSM Fine Chemicals Inc 
Park 80 West 
Plaza Two 
Saddle Brook 
NJ 07663 5817 
Tel: .1 (201) 226 7403 
Fax: .1 (201) 845 44 06 
Web: www.dsmfinechemicals.com 
DuPont 
Packaging and Industrial Polymers 
Barley Mill Plaza 26-2122 
Lancaster Pike, Route 141 
PO Box 80026 
Wilmington 
DE 19880-0026 
Tel: .1 302 922 5225 
Fax: .1 302 922 3495 
E-mail: info@dupont.com 
Web: www.dupont.com 
Trade names: Dymel 142b; Dymel 152a; 
Dymel 227 EA/P; Dymel A; Elvanol; 
TiPure. 
DuPont (Packaging and Industrial 
Polymers) see DuPont 
Eastech Chemical Inc 
5700 Tacony Street 
Philadelphia 
PA 19135 
Tel: .1 215 537 1000 
Fax: .1 215 537 8575 
E-mail: mail@eastechchemical.com 
Web: www.eastechchemical.com 
Trade names: Unimate GMS; Unimate IPP. 
Eastman Chemical Co 
100 North Eastman Road 
PO Box 511 
Kingsport 
TN 37662-5075 
Tel: .1 423 229 2000 
Fax: .1 423 229 2145 
Web: www.eastman.com 
Trade names: Eastacryl 30D; Eastman 
Vitamin E TPGS; Tenox BHA; Tenox 
BHT; Tenox PG. 
Edward Mendell Co see JRS Pharma LP 
EMD Chemicals Inc 
480 South Democrat Road 
Gibbstown 
NJ 08027 
Tel: .1 856 423 6300 
Fax: .1 856 423 4389 
E-mail: emdinfo@emdchemicals.com 
Web: www.emdchemicals.com 
Trade names: Sorbitol Instant. 
EM Industries Inc see EMD Chemicals Inc 
EM Sergeant Pulp & Chemical Co Inc 
6 Chelsea Road 
Clifton 
NJ 07012 
Tel: .1 973 4729111 
Fax: .1 973 472 5686 
E-mail: info@sergeantchem.com 
Web: www.sergeantchem.com 
Farma International Inc 
9501 Old Dixie Highway 
Miami 
FL 33156 
Tel: .1 305 670 4416 
Fax: .1 305 670 4417 
E-mail: farma2@aol.com 
Web: www.farmainternational.com 
Trade names: Eumulgin; Veegum HS. 
Ferro Pfanstiehl Laboratories Inc 
1219 Glen Rock Avenue 
Waukegan 
IL 60085 
Tel: .1 847 623 0370 
Fax: .1 847 623 9173 
E-mail: pfanstiehl-info@ferro.com 
Web: www.ferro.com 
Fisher Scientific 
2000 Park Lane 
Pittsburgh 
PA 15275 
Tel: .1 800 766 7000 
Fax: .1 800 926 1166 
Web: www.fishersci.com 
FMC Biopolymer 
1735 Market Street 
Philadelphia 
PA 19103 
Tel: .1 800 526 3649 
Fax: .1 215 299 6291 
E-mail: pharm_info@fmc.com 
Web: www.fmcbiopolymer.com 
Trade names: Ac-Di-Sol; Aquacoat cPD; 
Aquacoat ECD; Avicel PH; Celphere; 
Gelcarin; Marine Colloids; Protacid; 
Protanal; SeaSpen PF; Viscarin;. 
Foremost Farms USA 
E10889A Penny Lane 
PO Box 111 
Baraboo 
WI 53913 0111 
Tel: .1 800 362 9196 
Fax: .1 608 356 9005 
E-mail: commdept@foremostfarms.com 
Web: www.foremostfarms.com 
Fuji Chemical Industries Health Science 
(USA) Inc 
7B Marlen Drive 
Robbinsville 
NJ 08691 
Tel: .1 856 234 3636 
Fax: .1 856 778 2297 
E-mail: contact@fcihealthscience.com 
Web: www.fcihealthscience.com 
Trade names: Fujicalin; Neusilin. 
Fuji Chemical Industries (USA) Inc see Fuji 
Chemical Industries Health Science (USA) 
Inc 
874 Appendix I: Suppliers Directory

Gallard-Schlesinger Industries Inc 
245 Newtown Road 
Suite 305 
Palinview 
NY 11803 
Tel: .1 516 683 6900 
Fax: .1 516 683 6990 
E-mail: info@gallard.com 
Web: www.gallard-schlesinger.com 
Gattefosse. Corp 
650 From Road 
Paramus 
NJ 07652 
Tel: .1 201 265 4800 
Fax: .1 201 265 4853 
E-mail: info@gattefossecorp.com 
Web: www.gattefossecorp.com 
Trade names: Compritol 888 ATO; 
Labrafac CC; Precirol ATO 5. 
Generichem Corp 
PO Box 457 
Totowa 
NJ 07511-0457 
Tel: .1 973 256 9266 
Fax: .1 973 256 0069 
E-mail: info@generichem.com 
Web: www.generichem.com 
Trade names: Prejel; Primellose; 
Primogran W; Primojel. 
George Uhe Co Inc 
12 Route 17 North 
PO Box 970 
Paramus 
NJ 07653 0970 
Tel: .1 800 850 4075 
Fax: .1 201 843 7517 
E-mail: global@uhe.com 
Web: www.uhe.com 
Grain Processing Corp 
1600 Oregon Street 
Muscatine 
IA 52761 
Tel: .1 563 264 4265 
Fax: .1 563 264 4289 
E-mail: sales@grainprocessing.com 
Web: www.varied.com 
Trade names: Instant Pure-Cote; Maltrin; 
Maltrin QD; Pure-Bind; Pure-Cote; Pure- 
Dent; Pure-Dent B851; Pure-Gel; Pure-Set; 
Spress B820. 
GR O’Shea Company 
650 East Devon Avenue 
Suite 180 
Itasca 
IL 60143-3142 
Tel: .1 630 773 3223 
Fax: .1 630 773 3553 
E-mail: general@groshea.com 
Web: www.groshea.com 
Trade names: Castorwax; Castorwax MP 
70; Castorwax MP 80. 
Hawkins Chemical Inc 
Pharmaceutical Group 
3100 East Hennepin Avenue 
Minneapolis 
MN 55413 
Tel: .1 612 331 6910 
Fax: .1 612 331 5304 
Web: www.hawkinschemical.com 
Helm New York Inc 
1110 Centennial Avenue 
Piscataway 
NJ 08854-4169 
Tel: .1 732 981 1160 
Fax: .1 732 981 0965 
E-mail: info@helmnewyork.com 
Web: www.helmnewyork.com 
Hercules Inc see Aqualon 
Huntsman Tioxide see Tioxide Americas 
Inc 
ICI Surfactants 
PO Box 8340 
Wilmington 
DE 19803 8340 
Tel: .1 302 887 5739 
Fax: .1 302 887 3525 
Web: www.ici.com 
Trade names: Brij. 
Inolex Chemical Co 
Jackson & Swanson Streets 
Philadelphia 
PA 19148 3497 
Tel: .1 215 271 0800 
Fax: .1 215 271 2621 
E-mail: cheminfo@inolex.com 
Web: http://www.inolex.com 
Trade names: Lexalt L; Lexgard B; Lexol 
IPP-NF. 
International Fiber Corporation 
50 Bridge Street 
North Tonawanda 
NY 14120 
Tel: .1 716 693 4040 
Fax: .1 716 693 3528 
E-mail: ifc@ifcfiber.com 
Web: http://www.ifcfiber.com 
Trade names: Solka-Floc. 
International Specialty Products 
1361 Alps Road 
Wayne 
NJ 07470 
Tel: .1 973 628 4000 
Fax: .1 973 872 1583 
E-mail: info@ispcorp.com 
Web: www.ispcorp.com 
Trade names: Celex; Germall 115; Kelacid; 
Kelcosol; Keltone; Pharmasolve; Plasdone; 
Plasdone S-630; Polyplasdone XL; 
Polyplasdone XL-10. 
ISP see International Specialty Products 
Jarchem Industries Inc 
414 Wilson Avenue 
Newark 
NJ 07105 
Tel: .1 973 344 0600 
Fax: .1 973 344 5743 
E-mail: info@jarchem.com 
Web: www.jarchem.com 
Trade names: Jarcol 1-20. 
Jeen International Corp 
24 Madison Road 
Fairfield 
NJ 07004 
Tel: .1 800 771 5336 
Fax: .1 973 439 1402 
E-mail: info@jeen.com 
Web: www.jeen.com 
Trade names: Jeechem. 
J Rettenmaier USA see JRS Pharma LP 
JRS Pharma LP 
2981 Route 22, Suite 1 
Patterson 
NY 12563 
Tel: .1 845 878 3414 
Fax: .1 845 878 3484 
E-mail: sales@jrspharma.com 
Web: www.jrspharma.com 
Trade names: Arbocel; Candex; 
Compactrol; Emcocel; Emcompress; 
Emcompress Anhydrous; Emdex; 
Explotab; Lubritab; ProSolv; Pruv; 
Satialgine H8; Vivapress Ca; Vivapur; 
Vivasol; Vivastar P. 
JT Baker Inc 
Mallinkrodt Baker Inc 
222 Red School Lane 
Phillipsburg 
NJ 08865 
Tel: .1 908 859 2151 
Fax: .1 908 859 6905 
E-mail: infombi2@tycohealthcare.com 
Web: www.jtbaker.com 
Trade names: HyQual. 
Jungbunzlauer Inc 
7 Wells Avenue 
Newton Centre 
MA 02459 
Tel: .1 617 969 0900 
Fax: .1 617 964 3007 
Web: www.jungbunzlauer.com 
Trade names: Citrofol AI. 
KIC Chemicals Inc 
84 Business Park drive 
Armonk 
NY 10504 
Tel: .1 914 273 6555 
Fax: .1 914 273 6760 
E-mail: Sales@KICgroup.com 
Web: www.kicgroup.com 
Appendix I: Suppliers Directory 875

Koster Keunen LLC 
1021 Echo Lake Road 
PO Box 69 
Watertown 
CT 06795 
Tel: .1 860 945 3333 
Fax: .1 860 945 0330 
E-mail: info@kosterkeunen.com 
Web: www.kosterkeunen.com 
Trade names: Permulgin D. 
Kraft Chemical Co 
1975 N Hawthorne Avenue 
Melrose Park 
IL 60160 
Tel: .1 800 345 5200 
Fax: .1 708 345 4005 
E-mail: kraftchem@aol.com 
Web: www.kraftchemical.com 
Lanxess Corp 
111, RIDC Park West Drive 
Pittsburg 
PA 15275-1112 
Tel: .1 412 809 1000 
Web: www.lanxess.com; 
www.bayferrox.com 
Trade names: Bayferrox 306; Bayferrox 
920Z. 
Lipo Chemicals Inc 
207 19th Avenue 
Paterson 
NJ 07504 
Tel: .1 973 345 8600 
Fax: .1 973 345 8365 
E-mail: 
salesandmarketing@lipochemicals.com 
Web: www.lipochemicals.com 
Trade names: Lipo GMS 410; Lipo GMS 
450; Lipo GMS 600; Lipocol; Lipocol C; 
Lipolan; Liponate IPP; Lipovol CAN; 
Lipovol SES; Uniphen P-23. 
Lipscomb Chemical Company Inc 
4401 Atlantic Ave 
Suite 410 
Long Beach 
CA 90807 
Tel: .1 562 728 6321 
Fax: .1 562 728 9170 
E-mail: scrawford@lipscombchemical.com 
Web: www.lipscombchemical.com 
Loos & Dilworth Inc 
61 East Green Lane 
Bristol 
PA 19007 
Tel: .1 215 785 3591 
Fax: .1 215 785 3597 
E-mail: dtompkins@loosanddilworth.com 
Web: www.loosanddilworth.com 
Trade names: Pamolyn. 
Lucas Meyer Inc 
PO Box 3218 
Decatur 
IL 62524 3218 

Tel: .1 217 8753660 
Fax: .1 217 8775046 
E-mail: lecithin@midwest.net 
Web: www.lucas-meyer.com 
Luzenac America 
345 Inverness Drive South 
Suite 310 
Centennial 
CO 80112 
Tel: .1 303 643 0400 
Fax: .1 303 643 0444 
Web: www.luzenac.com 
Trade names: Altalc. 
Lyondell Chemical Co 
PO Box 3646 
Houston 
TX 77253 3646 
Tel: .1 713 652 7200 
Web: www.lyondell.com 
Mantrose Bradshaw Zinsser Group see 
Mantrose-Haeuser Co Inc 
Mantrose-Haeuser Co Inc 
1175 Post Road East 
Westport 
CT 06880 
Tel: .1 203 454 1800 
Fax: .1 203 227 0558 
E-mail: susan.coleman@mantrose.com 
Web: www.mbzgroup.com 
Trade names: CertiSeal; Mantrolac R-49. 
McNeil Nutritionals LLC 
McNeil Specialty Products Co 
501 George Street 
PO Box 2400 
New Brunswick 
NJ 0891 1161 
Tel: .1 732 524 6704 
Fax: .1 732 247 7482 
Web: www.splenda.com 
Trade names: Splenda. 
Mendell see Penwest Pharmaceuticals Co 
Merisant 
10 South Riverside Plaza 
Suite 850 
Chicago 
IL 60606 
Tel: .1 312 840 6000 
Fax: .1 312 840 5400 
Web: www.merisant.com 
Trade names: Canderel; Equal; 
NutraSweet. 
M Michel and Company Inc 
PO Box 788 
Planetarium Station 
New York 
NY 10024 0545 
Tel: .1 212 344 3878 
Fax: .1 212 344 3880 
Web: www.mmichel.com 
Trade names: Cachalot. 
Morflex Inc 
2110 High Point Road 
Greensboro 
NC 27403 2642 
Tel: .1 336 292 1781 
Fax: .1 336 854 4058 
E-mail: skennedy@morflex.com 
Web: www.morflex.com 
Trade names: Citroflex 4; Citroflex A-2; 
Citroflex A-4. 
Mutchler Inc 
20 Elm Street 
Harrington Park 
NJ 07640 
Tel: .1 201 768 1100 
Fax: .1 201 768 9960 
E-mail: info@mutchlerchem.com 
Web: www.mutchlerchem.com 
Napp Technologies Inc 
401 Hackensack Ave 
Hackensack 
NJ 0760 
Tel: .1 201 843 4664 
Fax: .1 201 843 4737 
Web: www.napptech.com 
National Starch & Chemical Co 
742 Grayson Street 
Berkeley 
CA 94710 2677 
Tel: .1 510 548 6722 
Fax: .1 510 841 3150 
E-mail: nscinquiry@adh.com 
Web: www.nationalstarch.com 
Trade names: National 78-1551; Purity 
21; Purity 826; Unipure WG220. 
Nipa Laboratories Inc 
(Clariant Corporation) 
625 East Catawba Avenue 
Mount Holly 
NC 28210 
Tel: .1 973 334 9227 
Fax: .1 704 822 2241 
Trade names: Nipacide PX; Propyl 
parasept. 
Nippon Soda Co Ltd 
Nisso America Inc 
220 East 42nd Street 
Suite 3002 
New York 
NY 10017 
Tel: .1 212 490 0350, 0351 
Fax: .1 212 972 9361 
Web: www.nippon-soda.co.jp 
Trade names: Nisso HPC. 
Noveon Inc 
9911 Brecksville Road 
Cleveland 
OH 44141-3247 
Tel: .1 216 447 5000 
Web: www.noveoninc.com 
Trade names: Carbopol; Noveon AA-1; 
Pemulen; Protachem; Protachem IPP. 
876 Appendix I: Suppliers Directory

NutraSweet Company, The see Merisant 
Nutrinova Inc 
285 Davidson Avenue 
Suite 102 
Somerset 
NJ 08873 
Tel: .1 800 786 3883 
Fax: .1 732 271 7235 
Trade names: Sunett. 
O’Shea Company see GR O’Shea 
Company 
Paddock Laboratories Inc 
3940 Quebec Avenue North 
Minneapolis 
MN 55429 
Tel: .1 763 546 4676 
Fax: .1 763 546 4676 
E-mail: info@paddocklabs.com 
Web: www.paddocklabs.com 
Particle Dynamics Inc 
KV Pharmaceutical Co 
2601 South Hanley Road 
Saint Louis 
MO 63144 
Tel: .1 314 968 2376 
Fax: .1 314 968 5208 
E-mail: info@particledynamics.com 
Web: www.particledynamics.com 
Trade names: Destab; Tablitz. 
Penta Manufacturing Co 
50 Okner Parkway 
Livingston 
NJ 07039-1604 
Tel: .1 973 740 2300 
Fax: .1 973 740 1839 
E-mail: sales@pentamfg.com 
Web: www.pentamfg.com 
Penwest Pharmaceuticals Co see JRS 
Pharma LP 
Pfaltz & Bauer 
172 E. Aurora St 
Waterbury 
CT 06708 
Tel: .1 203 574 0075 
Fax: .1 203 574 3181 
E-mail: sales@pfaltzandbauer.com 
Web: www.pfaltzandbauer.com 
Trade names: Garantose. 
Pfanstiehl Laboratories Inc see Ferro 
Pfanstiehl Laboratories Inc 
Pfizer Corp 
235 East 42nd Street 
New York 
NY 10017 5755 
Tel: .1 212 573 2323 
Fax: .1 212 573 7851 
E-mail: info@pfizer.com 
Web: www.pfizer.com 
PMC Specialities Group Inc 
501 Murray Road 
Cincinnati 
OH 45217 
Tel: .1 800 543 2466 
Fax: .1 513 482 7373 
Web: www.pmcsg.com 
Pokonobe Industries Inc 
PO Box 1756 
Santa Monica 
CA 90406 
Tel: .1 310 392 1259 
Fax: .1 310 392 3659 
E-mail: info@pokonobe.com 
Web: www.pokonobe.com 
Polysciences Inc 
400 Valley Road 
Warrington 
PA 18976 
Tel: .1 800 523 2575 
Fax: .1 800 343 3291 
E-mail: info@polysciences.com 
Web: www.polysciences.com 
Premium Ingredients Ltd 
285 East Fullerton Avenue 
Carol Stream 
IL 60188 
Tel: .1 630 868 0380 
Fax: .1 630 868 0390 
E-mail: sales@premiumingredients.com 
Web: www.premiumingredients.com 
Protameen Chemicals 
375 Minnisink Road 
Totowa 
NJ 07511 
Tel: .1 973 256 4374 
Fax: .1 973 256 6764 
E-mail: info@protameen.com 
Web: www.protameen.com 
Trade names: Procol; Protachem; 
Protachem GMS-450; Protachem IPP; 
Protalan anhydrous; Protalan M-16; 
Protalan M-26. 
Purac America Inc 
111 Barclay Boulevard 
Lincolnshire Corporate Center 
Lincolnshire 
IL 60069 
Tel: .1 847 634 6330 
Fax: .1 847 634 1992 
E-mail: pam@purac.com 
Web: www.purac.com 
Trade names: Lacty; Purac 88 PH; 
Pursasorb; Purasorb PD; Pursasorb PDL; 
Pursasorb PDLG; Purasorb PG; Purasorb 
PL. 
Reade Advanced Materials Inc 
Post Office Drawer 15039 
3708 Pawtucket Avenue 
Providence 
RI 02915-0039 
Tel: .1 401 433 7000 
Fax: . 401 433 7001 
E-mail: sales.east@reade.com 
Web: www.reade.com 
Reheis Inc 
235 Snyder Ave 
Berkeley Heights 
NJ 07922 
Tel: .1 908 464 1500 
Fax: .1 908 464 7726 
Web: www.reheis.com 
Trade names: Rehydraphos. 
Reilly Industries Inc 
300 N Meridian Street 
Indianapolis 
IN 46204-1763 
Tel: .1 317 247 8141 
Fax: .1 317 248 6472 
E-mail: webmaster@reillyind.com 
Web: www.reillyind.com 
Trade names: Citroflex 2. 
Rennecker Ltd 
Cleveland 
Ohio 
Tel: .1 330 225 2326 
Fax: .1 330 225 1542 
E-mail: sales@renneckerltd.com 
Web: www.renneckerltd.com 
Trade names: Hectabrite AW; Hectabrite 
DP. 
Research Diagnostics Inc 
Pleasant Hill Road 
Flanders 
NJ 07836 
Tel: .1 973 584 7093 
Fax: .1 973 584 0210 
E-mail: sales@researchd.com 
Web: www.researchd.com 
Trade names: Encapsin. 
Rettenmaier see JRS Pharma LP 
RFI Ingredients 
300 Corporate Drive, Suite 14 
Blauvelt 
NY 10913 
Tel: .1 845 358 8600 
Fax: .1 845 358 9003 
E-mail: rfi@rfiingredients.com 
Web: www.rfiingredients.com 
Trade names: Talin. 
Rhodia Inc see Rhodia Pharma Solutions 
Inc 
Rhodia Pharma Solutions Inc 
259 Prospect Plains Road 
CN 7500 
Cranbury 
NJ 08512 7500 
Tel: .1 888 776 7337 
Fax: .1 609 860 0344 
Web: www.rhodia-pharmasolutions.com 
Trade names: A-TAB; DI-TAB; 
Meyprodor; Meyprofin; Meyprofleur; 
Meyprogat; Rhodiarome; Rhodigel; 
Rhovanil; TRI-CAL WG; TRI-TAB. 
Appendix I: Suppliers Directory 877

RIA International 
9 Whippany Road 
#C3 
Whippany 
NJ 07981 
Tel: .1 973 581 1282 
Fax: .1 973 581 1283 
E-mail: ria@riausa.com 
Web: www.riausa.com 
Rita Corp 
PO Box 457 
850 South Rt. 31 
Crystal Lake 
IL 60014-0457 
Tel: .1 815 337 2500 
Fax: .1 815 337 2522 
E-mail: info@ritacorp.com 
Web: www.ritacorp.com 
Trade names: Acritamer; Forlan 500; 
Patlac LA; Rita CA; Rita GMS; RITA HA 
C-1-C; Rita IPM; Rita SA; Ritaceti; 
Ritachol 2000; Ritawax; Ritoleth; Ritox; 
Tealan. 
Rohm America Inc 
2 Turner Place 
PO Box 365 
Piscataway 
NJ 08855 
Tel: .1 877 764 6872 
Fax: .1 732 981 5484 
Web: www.rohmamerica.com 
Trade names: Eudragit. 
Rohm and Haas Co 
100 Independence Mall West 
Philadelphia 
PA 19106 2399 
Tel: .1 215 592 3000 
Fax: .1 219 592 3377 
Web: www.rohmhaas.com 
Trade names: Amberlite IRP-88. 
Roquette America Inc 
1417 Exchange Street 
PO Box 6647 
Keokuk 
IA 52632-6647 
Tel: .1 319 524 5757 
Fax: .1 319 526 2345 
E-mail: roquette.jur@wanadoo.fr 
Web: www.roquette.com 
Trade names: Flolys; Fluidamid R444P; 
Glucidex; Keoflo ADP; Kleptose; Lycadex 
PF; Lycasin 80/55; Lycasin HBC; Lycatab 
C; Lycatab DSH; Lycatab PGS; Maltisorb; 
Maltisorb 75/75; Neosorb; Pearlitol; 
Roclys; Roferose; Xylisorb. 
RT Vanderbilt Company Inc 
30 Winfield Street 
PO Box 5150 
Norwalk 
CT 06856-5150 
Tel: .1 800 243 6064 
Fax: .1 203 853 1452 
Web: www.rtvanderbilt.com 
Trade names: Vanzan NF; Veegum. 
Ruger Chemical Co Inc 
1515 West Blancke Street 
Linden 
NJ 07036 
Tel: .1 973 926 0331 
Fax: .1 973 926 4921 
Web: www.rugerchemical.com 
Sanofi-Synthelabo Inc 
90 Park Avenue 
New York 
NY 10016 
Tel: .1 212 551 400 
Web: www.sanofi-synthelabous.com 
Trade names: Zephiran. 
Sasol North America Inc 
900 Threadneedle 
Suite 100 
Houston 
TX 77079-2990 
Tel: .1 281 588 3000 
Fax: .1 281 588 3144 
E-mail: info@us.sasol.com 
Web: www.sasolCustomer1.com 
Trade names: Imwitor 191; Imwitor 900; 
Lipoxol. 
Scandinavian Formulas Inc 
140 East Church St 
Sellersville 
PA 18960 
Tel: .1 215 453 2507 
Fax: .1 215 257 9781 
E-mail: info@scandinavianformulas.com 
Web: www.scandinavianformulas.com 
Seidler Chemical Company 
537 Raymond Blvd 
Newark 
NJ 07105 
Tel: .1 973 465 1122 
Fax: .1 973 465 4469 
E-mail: sales@sedielerchem.com 
Web: www.seidlerchem.com 
Seltzer Chemicals Inc 
5927 Geiger Court 
Carlsbad 
CA 92008-7305 
Tel: .1 800 735 8137 
Fax: .1 760 438 0336 
Web: www.seltzerchemicals.com 
Sensus America LLC 
Princeton Coporate Plaza 
1 Deer Park Drive 
Suite J 
Manmouth Junction 
NJ 08852 
Tel: .1 646 452 6140 
Fax: .1 646 452 6150 
E-mail: contact@sensus.us 
Web: www.sensus.us 
Trade names: Frutafit. 
Sigma-Aldrich Corp 
PO Box 14508 
Saint Louis 
MO 63178 
Tel: .1 314 771 5765 
Fax: .1 314 771 5757 
E-mail: OC_DOM_HC@sial.com 
Web: www.sigmaaldrich.com 
Trade names: Kodaflex DBS; Thimerosal 
Sigmaultra. 
Spectrum Quality Products Inc 
14422 South San Pedro Street 
Gardena 
CA 90248 2027 
Tel: .1 800 813 1514 
Fax: .1 800 525 2299 
E-mail: sales@spectrumchemical.com 
Web: www.spectrumchemical.com 
SPI Pharma Group 
SPI Polyols, Inc 
321 Cherry Lane 
New Castle 
DE 19720 2780 
Tel: .1 302 576 8554 
Fax: .1 302 576 8569 
Web: www.spipharma.com 
Trade names: Advantose 100; Advantose 
FS 95; Effer-Soda; Maltisweet 3145; 
Mannogem; Sorbogem; Sunmalt; Sunmalt 
S. 
Staley Mfg Co see Tate & Lyle 
Stepan Co 
22 West Frontage Road 
Northfield 
IL 60093 
Tel: .1 847 446 7500 
Fax: .1 847 501 2100 
Trade names: Kessco CA; Kessco EO; 
Kessco GMO; Kessco GMS; Kessco IPP; 
Stepan GMO; Stepan GMS; Stepan IPM; 
Stepan IPP; Wecobee. 
Strahl & Pitsch Inc 
230 Great East Neck Road 
West Babylon 
NY 11704 
Tel: .1 631 587 9000 
Fax: .1 631 587 9120 
E-mail: info@strahlpitsch.com 
Web: www.spwax.com 
Takeda Pharmaceuticals North America 
Inc 
475 Half Day Road 
Suite 500 
Lincolnshire 
IL 60069 
Tel: .1 847 383 3000 
Web: www.takedapharm.com 
878 Appendix I: Suppliers Directory

Tate & Lyle 
Cerel Sweeteners 
2200 E Eldorado Street 
PO Box 151 
Decatur 
IL 62526 
Tel: .1 800 526 5728 
Fax: .1 217 421 3167 
Web: www.tateandlyle.com 
Trade names: Di-Pac; Krystar; Star-Dri. 
Thomas Scientific 
PO Box 99 
Swedesboro 
NJ 08085 
Tel: .1 856 467 2000 
Fax: .1 856 467 3087 
E-mail: value@thomassci.com 
Web: www.thomassci.com 
Thornley Company 
Suite 204 1500 
East Newport Pike 
Wilmington 
DE 19804 2346 
Tel: .1 302 933 8300 
Fax: .1 302 933 8308 
E-mail: Murphy@Thornleycompany.com 
Web: www.thornleycompany.com 
Trade names: Liponic 70-NC; Liponic 76- 
NC. 
TIC Gums 
4609 Richlynn Drive 
PO Box 369 
Belcamp 
MD 21017 
Tel: .1 410 273 7300 
Fax: .1 410 273 6469 
E-mail: svandenheuvel@ticgums.com 
Web: www.ticgums.com 
Tioxide Americas Inc 
(Huntsman Tioxide) 
4575 Weaver Parkway 
Warrenville 
IL 60555 
Tel: .1 630 836 2400 
Fax: .1 630 836 2480 
Web: www.huntsman.com 
Trade names: Tioxide. 
Triple Crown America 
13 North Seventh Street 
Perkasie 
PA 18944 
Tel: .1 215 453 2500 
Fax: .1 215 453 2508 
E-mail: info@triplecrownamerica.com 
Web: www.triplecrownamerica.com 
Universal Preserv-A-Chem Inc 
33, Truman Drive South 
Edison 
NJ 08817-2426 
Tel: .1 732 777 7338 
Fax: .1 732 777 7885 
Web: www.upichem.com 
Vanderbilt Company Inc see RT Vanderbilt 
Company Inc 
Van Waters and Rogers Inc see Vopak 
USA Inc 
Virginia Dare 
882 Third Avenue 
Brooklyn 
NY 11232 
Tel: .1 718 788 1776 
Fax: .1 718 768 3978 
E-mail: webinfo@virginiadare.com 
Web: www.virginiadare.com 
Voigt Global Distribution LLC 
PO Box 412762 
Kansas City 
MO 64141-2762 
Tel: .1 877 484 3552 
Fax: .1 816 471 9502 
Vopak USA Inc 
2000 West Loop South 
Suite 2200 
Houston 
TX 77027 
Tel: .1 713 561 7200 
Fax: .1 713 561 7322 
E-mail: Jackie.gault@vopak.com 
Wacker Biochem Corp see Wacker 
Chemical Corp 
Wacker Chemical Corp 
1 Wacker Drive 
Eddyville 
IA 52553 
Tel: .1 515 969 4817 
Fax: .1 515 969 4929 
E-mail: info.finechemicals@wacker.com 
Web: www.wacker-biochem.com 
Trade names: Cavamax W6 Pharma; 
Cavamax W7 Pharma; Cavamax W8 
Pharma; Wacker HDK. 
Warner Jenkinson Pharmaceutical 
107 Wade Avenue 
PO Box 705 
South Plainfield 
NJ 07080 1311 
Tel: .1 908 757 4500 
Fax: .1 908 757 3170 
E-mail: wje@aes.co.uk 
Welch, Holme & Clark Co Inc 
7 Avenue L 
Newark 
NJ 07105 
Tel: .1 973 465 1200 
Fax: .1 973 465 7332 
Web: www.welch-holme-clark.com 
Whittaker Clark, and Daniels Inc 
1000 Coolidge St 
S. Plainfield 
NJ 07080 
Tel: .1 908 561 6100 
Fax: .1 800 833 8139 
E-mail: customerservice@wcdinc.com 
Web: www.wcdinc.com 
Trade names: Albagel. 
Witco Corp see Crompton Corp 
Zhong Ya Chemical (USA) Ltd 
50 Colonial Drive 
Piscataway 
NJ 08854 
Tel: .1 732 981 9288 
Fax: .1 732 981 9488 
E-mail: sales@zhongyachemical.com 
Web: www.zhongyachemical.com 
ZLB Behring 
1020 First Avenue 
PO Box 61501 
King of Prussia 
PA 19406 0901 
Web: www.zlbbehring.com 
Suppliers List: Others 
Aastrid International 
247-248 Udyog Bhavan 
Sonawala Lane 
Goregaon East 
Mumbai 400 063 
India 
Tel: .91 22 5691 4333 
Fax: .91 22 5691 4334 
E-mail: aastrid@vsnl.com 
Web: www.aastrid.com 
Ajinomoto Co Inc 
15-1, Kyobashi 
1-chome, Chuo-ku 
Tokyo 104-8315 
Japan 
Tel: .81 (3)5250 8111 
E-mail: g-webmaster@ajinimoto.com 
Web: www.ajinomoto.com 
Trade names: Pal Sweet; Pal Sweet Diet. 
Asahi Kasei Corporation 
Hibiya-Mitsui Building 
Functional Additives Division 
1-2 Yuraku-cho 1-Chome 
Chiyoda-ku 
Tokyo 100-8440 
Japan 
Tel: .81 3 3507 2060 
Fax: .81 3 3507 2495 
Web: www.asahi-kasei.co.jp 
Trade names: Celphere; Ceolus KG. 
Cerestar Jiliang Maize Industry Co Ltd 
Songyuan 
Jianguan Industry Development Zone 
138006 Songyuan Jilin Province 
China 
Tel: .86 (0)438 2180 812 
Fax: .86 (0)438 2180 813 
E-mail: cjmicom@mail.jl.cn 
Web: www.cargillchina.com 
Appendix I: Suppliers Directory 879

Charles Tennant & Co (Canada) Ltd 
34 Clayson Road 
Toronto 
ON M9M 2G8 
Canada 
Tel: .1 416 741 9264 
Fax: .1 416 741 6642 
Web: www.ctc.ca 
Trade names: Jeecol ODD. 
Choice Korea Co 
207 Shin Song Plaza 1423-2 
Kwanyang-1 Dong 
Donan-Ku 
Anyang City 
Kyunggi-do 
Korea 
Tel: .82 314 240 212 
Fax: .82 314 240 213 
E-mail: choice4@kornet.net 
Web: www.choicekorea.com 
Trade names: Waglinol 6016. 
Cosmos Chemical Co Ltd 
506 Jianda Building 
223 North Zhongshan Road 
Nanjing 210009 
China 
Tel: .86 25 3346885 
Fax: .86 25 3346877 
E-mail: cosmos@cosmoschem.com 
Web: cosmoschem.com 
EPS Impex Co 
PO Box 21904 
Damai Plaza Luyang 
88777 Kota Kinabalu 
Malaysia 
Tel: .60 88 316470 
Fax: .60 88 316741 
E-mail: patwary@streamyx.com 
Web: www.epsimpex.com 
Fine Chemicals Corporation (Pty) Ltd 
PO Box 253 
Eppindust 7475 
South Africa 
Tel: .27 21 531 6421 
Fax: .27 21 531 1458 
E-mail: maske@iafrica.com 
Fuji Chemical Industry Co Ltd 
55 Yokohoonji 
Kamiichi-machi 
Nakanikawa-gun 
Toyama 930-0397 
Japan 
Tel: .81 764 72 2323 
Fax: .81 764 72 5539 
E-mail: info@fujichemical.co.jp 
Web: www.fujichemical.co.jp 
Trade names: Fujicalin; Neusilin. 
Gadot Petrochemical Industries Ltd 
16 Habonim Street 
Netanya South Industrial Zone 
42504 Israel 
Israel 
Tel: .972 9 892 9530 
Fax: .972 9 865 3385 
E-mail: gsales@gadot.com 
Web: www.gadot.com 
Glide Chem Pvt Ltd 
Corporate Office 
S-39 Rajouri Garden 
New Delhi 110027 
India 
Tel: .91 11 514 43531 
Fax: .91 11 511 1752/591 1962 
E-mail: glide@bol.net.in 
Web: www.glideindia.com 
Hayashibara Co Ltd 
1-2-3 Shimoishii 
Okayama 
700-0907 
Japan 
Tel: .81 86 224 4311 
Fax: .81 86 222 8942 
Web: www.hayashibara.co.jp 
Trade names: Maltose HH. 
Henley Chemicals 
199 Courtland Avenue 
Concord 
Ontario 
L4K 4T2 
Canada 
Tel: .1 416 661 1500 
Web: www.henleychem.com 
Trade names: Tego Alkanol 1618; Tego 
Alkanol 6855. 
Highland International 
25 Kembrose Estate 
Off Lbs Marg, Bhandup 
Mumbai 400 078 
India 
Tel: .91 22 256 50529 
Fax: .91 22 264 81356 
Web: www.indiamart.com/ 
highland-international 
Jiangxi Mosashino Co Ltd 
Xiaolan Industry Park of Nanchang 
Jiangxi 330200 
China 
Tel: .86 791 576 1066 
Fax: .86 791 576 1063 
E-mail: admini@china-musashino.com 
Web: www.china-musashino.com 
Kibun Food Chemifa Co Ltd 
2-12-11 Minato 
Chuo-ku 
Tokyo 104 
Japan 
Tel: .81 3 3206 0776 
Fax: .81 3 3206 0788 
E-mail: webmaster@kibunfc.co.jp 
Web: www.kibunfc.co.jp 
Lactose New Zealand 
PO Box 424 
Hawera 
New Zealand 
Tel: .64 6 274 8869 
Fax: .64 6 274 8927 
E-mail: marketing@lactose.co.nz 
Web: www.lactose.co.nz 
Trade names: Wyndale. 
LS Raw Materials Ltd 
Harav Kook 
30/3 Petach Tikvah 
49315 
Israel 
Tel: 972 3 922 3966 
Fax: 972 3 921 2647 
E-mail: info@ls-rawmaterials.com 
Web: www.ls-rawmaterials.com 
Mitsubishi-Kagaku Foods Corporation 
1-3-9 Ginza 
Chuo-ku 
Tokyo 104 
Japan 
Tel: .81 3 3563 1514 
Fax: .81 3 3563 1676 
Web: www.mfc.co.jp 
Nikko Chemicals Co Ltd 
Nikko Chemicals Co Ltd 
Chuo-ku 
Tokyo 103-0002 
Japan 
Tel: .81 3 3661 1677 
Fax: .81 3 3664 8620 
E-mail: info@nikkol.co.jp 
Web: www.nikkol.co.jp 
Trade names: Nikkol. 
Nippon Soda Co Ltd 
2-1 Otemachi 2-chome 
Chiyoda-ku Tokyo 
100-8165 
Japan 
Tel: .81 3324 56054 
Fax: .81 3324 56238 
Web: www.nippon-soda.co.jp 
Trade names: Nisso HPC. 
Pachem Distributions Inc 
1800 Boulevard 
Michelin 
Laval (Que.bec) 
H7L 4R3 
Canada 
Tel: .1 450 682 4044 
Fax: .1 450 682 2044 
E-mail: service@pachemdistribution.com 
Web: www.pachemdistribution.com 
Trade names: Emerest 2316. 
Raw Materials Ltd see LS Raw Materials 
Ltd 
880 Appendix I: Suppliers Directory

San Fu Chemical Company Ltd 
Rm 1704, 17/F 
Greenfield Tower 
Concordia Plaza 
1, Science Museum Road TST 
Kowloon, Hong Kong 
China 
Tel: .1 852 2609 1138 
Fax: .1 852 2609 0731 
E-mail: info@fangda.com.hk 
Web: www.cyclamate.com 
Sarman Industries 
A-37 Gandhi Nagar 
Moradabad 244001 
India 
Tel: .91 591 249 3544 
Fax: .91 591 249 3544 
E-mail: sahaj1@sancharnet.in 
Web: www.indiamart.com/ 
sarmanindustries 
Shangyuchem 
Biochem Division 
Sanpeng Bridge 
Baiguan 
Shangyu 312351 
China 
Tel: .86 575 2210376 
Fax: .86 575 2129555 
E-mail: sales@shangyuchem.com 
Web: www.biochemicals.cn 
Shijiazhuang Pharmaceutical Group Co 
Ltd 
276 Zhongshan West Road 
Shijiazhuang 
China 
Tel: .86 311 7037015 
Fax: .86 311 7039608 
E-mail: zhangiv@mail.ecspc.com 
Web: www.e-cspc.com 
Shin-Etsu Chemical Co Ltd 
Cellulose and Pharmaceutical Excipients 
Asahi-Tokai Building 
Department 6-1, Ohtemachi 2-chrome 
Chiyoda-ku 
Tokyo 
Japan 
Tel: .81 3 3246 5261 
Fax: .81 3 3246 5372 
Web: www.shinetsu.co.jp 
Trade names: Aqoat; Aqoat AS-HF/HG; 
Aqoat AS-LF/LG; Aqoat AS-MF/MG; 
Metolose. 
Sumitomo Chemical 
27-1 Shinkawa 2-chome 
Chuo-ku 
Tokyo 104-8260 
Japan 
Tel: . 81-3-5543-5500 
Fax: . 81-3-5543-5901 
Web: www.sumitomo-chem.co.jp 
Takeda Chemical Industries Ltd see 
Takeda Pharmaceutical Company ltd 
Takeda Pharmaceutical Company Ltd 
1-1 Doshomachi 4-chrome 
Chuo-ku 
Osaka 540 8645 
Japan 
Tel: .81 6 6204 2111 
Fax: .81 6 6204 2880 
Web: www.takeda.co.jp 
Univar Canada Ltd 
9800 Van Horne Way 
Richmond 
BC V6X 1W5 
Canada 
Tel: .1 604 273 1441 
Fax: .1 604 273 2046 
E-mail: webmaster@univarcanada.com 
Web: www.univarcanada.com 
Wintersun Chemical 
3100 East Cedar Street 
Suite #15 
Ontario 91761 
Canada 
Tel: .1 909 930 1688 
Fax: .1 909 947 1788 
E-mail: sales@wintersunchem.com 
Web: www.wintersunchem.com 
Wuxi Dazhong Chemical Industry Co Ltd 
81 Yehuayan 
Guangrui Road 
Wuxi City 214 011 
China 
Tel: .86 510 244 9082 
Fax: .86 510 244 9082z 
Xiamen Topusing Chemical Co Ltd 
7/H Chang An Building 
Lvling Road 
Jiangtou 
Xiamen 361 009 
China 
Tel: .86 592 553 8032 
Fax: .86 592 553 8092 
E-mail: tuchem@public.xm.fj.cn 
Web: www.topusing.com 
Xinchem Co 
401/17, 3455 Chunshen Road 
Shanghai 201100 
China 
Tel: .86 21 34123252 
Fax: .86 21 54153973 
E-mail: info@finechemnet.com 
Web: www.finechemnet.com 
Yee Young Cerachem Ltd 
Room 1506 
Chungho Building 
51–2 Pangi 2-Dong 
Songpa-Ku 
Seoul 
South Korea 
Tel: .82 24 200 331 
Fax: .82 24 241 877 
E-mail: khchang@yeeyoung.co.kr 
Web: www.yeeyoung.co.kr 
Trade names: Pentonium. 
Appendix I: Suppliers Directory 881

Appendix II: List of Excipient ‘E’ Numbers 
E Number Excipient 
E100 Curcumin 192 
E101 Riboflavin 192 
E102 Tartrazine 192, 198 
E104 Quinoline Yellow 192 
E110 Sunset Yellow FCF 192, 198 
E120 Carmine 192 
E122 Carmoisine 192 
E123 Amaranth 192 
E124 Ponceau 4R 192 
E127 Erythrosine 192 
E129 Allura Red AC 192 
E131 Patent Blue V 192 
E132 Indigo Carmine 192, 197 
E133 Brilliant Blue FCF 192 
E140 Chlorophylls 192 
E141 Copper Complexes of Chlorophylls and 
Chlorophyllins 
192 
E142 Green S 192 
E150 Caramel 192 
E151 Brilliant Black BN 192 
E153 Vegetable Carbon 192 
E160 Carotenoids, Alpha-, Beta-, Gamma-carotene 192 
E160 Carotenoids, Beta-apo-80 Carotenal 192 
E160 Carotenoids, Capsanthin 192 
E160 Carotenoids, Capsorubin 192 
E160 Carotenoids, Ethyl Ester of Beta-apo-80 
Carotenoic Acid 
192 
E160 Carotenoids, Lycopene 192 
E160a Beta-carotene 196 
E161 Xanthophylls, Canthaxanthin 192 
E161 Xanthophylls, Lutein 192 
E162 Beetroot Red 192 
E163 Anthocyanins, Cyanidin 192 
E163 Anthocyanins, Delphidin 192 
E163 Anthocyanins, Malvidin 192 
E163 Anthocyanins, Pelargonidin 192 
E163 Anthocyanins, Peonidin 192 
E163 Anthocyanins, Petunidin 192 
E170 Calcium Carbonate 89, 192 
E171 Titanium Dioxide 192, 782 
E172 Iron Oxides 364 
E172 Iron Oxides and Hydroxides 192 
E173 Aluminum 192 
E200 Sorbic Acid 710 
E201 Sodium Sorbate 712 
E202 Potassium Sorbate 609 
E203 Calcium Sorbate 712 
E210 Benzoic Acid 66 
E211 Sodium Benzoate 662 
E212 Potassium Benzoate 596 
E214 Ethylparaben 287 
E215 Ethylparaben Sodium 289 
E216 Propylparaben 629 
E217 Propylparaben Sodium 631 
E218 Methylparaben 466 
E219 Methylparaben Sodium 469 
E Number Excipient 
E221 Sodium Sulfite 708 
E222 Sodium Bisulfite 691 
E223 Sodium Metabisulfite 690 
E224 Potassium Metabisulfite 607 
E228 Potassium Bisulfite 608 
E260 Acetic Acid, Glacial 6 
E262 Sodium Acetate 654 
E270 Lactic Acid 381 
E280 Propionic Acid 617 
E281 Sodium Propionate 699 
E281 Anhydrous Sodium Propionate 700 
E281 Sodium Propionate 699 
E282 Calcium Propionate 700 
E283 Potassium Propionate 700 
E284 Boric Acid 74 
E285 Sodium Borate 669 
E290 Carbon Dioxide 116 
E296 Malic Acid 436 
E297 Fumaric Acid 293 
E300 Ascorbic Acid 48 
E301 Sodium Ascorbate 659 
E302 Calcium Ascorbate 660 
E304 Ascorbyl Palmitate 51 
E307 Alpha Tocopherol 32 
E308 Gamma Tocopherol 34 
E309 Delta Tocopherol 34 
E310 Propyl Gallate 619 
E311 Octyl Gallate 621 
E312 Dodecyl Gallate 620 
E315 Erythorbic Acid 264 
E316 Sodium Erythorbate 265 
E320 Butylated Hydroxyanisole 79 
E321 Butylated Hydroxytoluene 81 
E322 Lecithin 409 
E325 Sodium Lactate 685 
E330 Citric Acid Monohydrate 185 
E330 Anhydrous Citric Acid 187 
E331 Sodium Citrate Dihydrate 675 
E332 Potassium Citrate 603 
E334 Tartaric Acid 770 
E338 Phosphoric Acid 530 
E339 Sodium Phosphate, Dibasic 693 
E339 Sodium Phosphate, Monobasic 696 
E340 Dibasic Potassium Phosphate 694 
E340 Monobasic Potassium Phosphate 697 
E341 Calcium Phosphate, Dibasic Anhydrous 93 
E341 Calcium Phosphate, Dibasic Dihydrate 96 
E341 Calcium Phosphate, Tribasic 100 
E385 Edetate Calcium Disodium 262 
E400 Alginic Acid 21 
E401 Sodium Alginate 656 
E402 Potassium Alginate 594 
E404 Ammonium Alginate 46 
E404 Calcium Alginate 86 
E405 Propylene Glycol Alginate 627 
E406 Agar 14

E Number Excipient 
E407 Carrageenan 124 
E410 Ceratonia 148 
E412 Guar Gum 315 
E413 Tragacanth 785 
E414 Acacia 1 
E415 Xanthan Gum 821 
E420 Sorbitol 718 
E421 Mannitol 449 
E422 Glycerin 301 
E431 Polyoxyl 40 Stearate 585 
E432 Polysorbate 20 580 
E433 Polysorbate 80 580 
E434 Polysorbate 40 580 
E435 Polysorbate 60 580 
E436 Polysorbate 65 580 
E440 Pectin 507 
E460 Cellulose, Microcrystalline 132 
E460 Cellulose, Powdered 136 
E461 Methylcellulose 462 
E462 Ethylcellulose 278 
E463 Hydroxypropyl Cellulose 336 
E464 Hypromellose 346 
E466 Carboxymethylcellulose Sodium 120 
E471 Glyceryl Behenate 304 
E491 Sorbitan Monostearate 713 
E492 Sorbitan Tristearate 713 
E493 Sorbitan Monolaurate 713 
E494 Sorbitan Monooleate 713 
E495 Sorbitan Monopalmitate 713 
E500 Sodium Bicarbonate 665 
E501 Potassium Bicarbonate 598 
E504 Magnesium Carbonate 422 
E504 Magnesium Carbonate Anhydrous 424 
E504 Magnesium Carbonate Hydroxide 424 
E504 Normal Magnesium Carbonate 424 
E507 Hydrochloric Acid 328 
E508 Potassium Chloride 600 
E513 Sulfuric Acid 758 
E516 Calcium Sulfate Anhydrous 105 
E516 Calcium Sulfate Dihydrate 105 
E516 Calcium Sulfate Hemihydrate 106 
E524 Sodium Hydroxide 683 
E525 Potassium Hydroxide 605 
E Number Excipient 
E530 Magnesium Oxide 426 
E553a Magnesium Silicate 428 
E553a Magnesium Trisilicate 434 
E553a Calcium Trisilicate Anhydrous 435 
E553b Talc 767 
E558 Bentonite 58 
E559 Kaolin 378 
E570 Stearic Acid 737 
E621 Monosodium Glutamate 480 
E900 Dimethicone 244 
E901 Wax, White 817 
E901 Wax, Yellow 819 
E903 Wax, Carnauba 809 
E904 Shellac 649 
E907 Wax, Microcrystalline 813 
E913 Lanolin 399 
E941 Nitrogen 488 
E942 Nitrous Oxide 490 
E943a Butane 325 
E943b Isobutane 325 
E944 Propane 325 
E950 Acesulfame Potassium 4 
E951 Aspartame 53 
E952 Sodium Cyclamate 678 
E952 Calcium Cyclamate 679 
E952 Cyclamic Acid 679 
E953 Isomalt 366 
E954 Saccharin 638 
E954 Saccharin Sodium 641 
E957 Thaumatin 775 
E959 Neohesperidin Dihydrochalcone 486 
E965 Maltitol 438 
E965 Maltitol Solution 440 
E966 Lactitol 383 
E967 Xylitol 824 
E968 Erythritol 266 
E1200 Polydextrose 542 
E1201 Povidone 611 
E1202 Crospovidone 214 
E1440 Hydroxypropyl Starch 344 
E1505 Triethyl Citrate 796 
E1518 Triacetin 790 
E1520 Propylene Glycol 624 
Appendix II: List of Excipient ‘E’ Numbers 883

Appendix III: List of Excipient ‘EINECS’ Numbers 
EINECS Excipient 
200-018-0 Lactic Acid 382 
200-061-5 Sorbitol 720 
200-066-2 Ascorbic Acid 50 
200-075-1 Dextrose 233 
200-075-1 Glucose, Liquid 300 
200-143-0 Bronopol 77 
200-210-4 Thimerosal 779 
200-238-7 Chlorhexidine 166 
200-289-5 Glycerin 303 
200-302-4 Chlorhexidine Acetate 166 
200-312-9 Palmitic Acid 502 
200-313-4 Stearic Acid 739 
200-317-6 Chlorobutanol 169 
200-333-3 Fructose 292 
200-334-9 Sucrose 747 
200-338-0 Propylene Glycol 625 
200-353-2 Cholesterol 183 
200-431-6 Chlorocresol 173 
200-449-4 Edetic Acid 262 
200-456-2 Phenylethyl Alcohol 520 
200-470-9 Linoleic Acid 415 
200-522-0 Leucine 413 
200-529-9 Edetate Calcium Disodium 262 
200-532-5 Phenylmercuric Acetate 522 
200-559-2 Lactose, Anhydrous 387 
200-559-2 Lactose, Monohydrate 394 
200-578-6 Alcohol 20 
200-580-7 Acetic Acid, Glacial 7 
200-618-2 Benzoic Acid 68 
200-661-7 Isopropyl Alcohol 372 
200-662-2 Acetone 9 
200-675-3 Sodium Citrate Dihydrate 677 
200-711-8 Mannitol 452 
200-716-5 Maltose 448 
200-772-0 Sodium Lactate 686 
201-066-5 Acetyltriethyl Citrate 13 
201-067-0 Acetyltributyl Citrate 11 
201-069-1 Citric Acid Anhydrous 187 
201-070-7 Triethyl Citrate 797 
201-071-2 Tributyl Citrate 793 
201-176-3 Propionic Acid 618 
201-321-0 Saccharin 640 
201-550-6 Diethyl Phthalate 241 
201-557-4 Dibutyl Phthalate 235 
201-788-0 Xylitol 827 
201-793-8 Chloroxylenol 181 
201-928-0 Erythorbic Acid 265 
201-939-0 Menthol 461 
201-944-8 Thymol 781 
202-307-7 Propylparaben 631 
202-318-7 Butylparaben 85 
202-495-0 Monothioglycerol 483 
202-598-0 Ethyl Lactate 271 
202-601-5 Malic Acid 437 
202-739-6 Trehalose 789 
202-785-7 Methylparaben 469 
202-859-9 Benzyl Alcohol 71 
EINECS Excipient 
203-049-8 Triethanolamine 795 
203-051-9 Triacetin 791 
203-068-1 Phenylmercuric Borate 525 
203-572-1 Propylene Carbonate 623 
203-577-9 Cresol 209 
203-632-7 Phenol 515 
203-672-5 Dibutyl Sebacate 237 
203-743-0 Fumaric Acid 294 
203-743-0 Sodium Stearyl Fumarate 707 
203-751-4 Isopropyl Myristate 375 
203-768-7 Sorbic Acid 712 
203-889-5 Ethyl Oleate 275 
203-993-0 Methyl Linoleate 414 
204-007-1 Oleic Acid 495 
204-017-6 Stearyl Alcohol 741 
204-065-8 Dimethyl Ether 247 
204-214-7 Dibutyl Phthalate 235 
204-399-4 Ethylparaben 289 
204-402-9 Benzyl Benzoate 73 
204-464-7 Ethyl Vanillin 277 
204-465-2 Vanillin 799 
204-479-9 Benzethonium Chloride 65 
204-498-2 Propyl Gallate 621 
204-589-7 Phenoxyethanol 518 
204-593-9 Cetylpyridinium Chloride 158 
204-648-7 2-Pyrrolidone 634 
204-696-9 Carbon Dioxide 117 
204-823-8 Sodium Acetate 655 
204-826-4 Dimethylacetamide 254 
204-881-4 Butylated Hydroxytoluene 82 
205-011-6 Dimethyl Phthalate 249 
205-105-7 Tartaric Acid 771 
205-126-1 Sodium Ascorbate 660 
205-290-4 Sodium Propionate 700 
205-305-4 Ascorbyl Palmitate 52 
205-316-4 Ethyl Lactate 271 
205-358-3 Disodium Edetate 256 
205-483-3 Monoethanolamine 479 
205-500-4 Ethyl Acetate 269 
205-513-5 Hexetidine 324 
205-538-1 Monosodium Glutamate 481 
205-571-1 Isopropyl Palmitate 377 
205-582-1 Lauric Acid 407 
205-597-3 Oleyl Alcohol 497 
205-633-8 Sodium Bicarbonate 667 
205-737-3 Erythritol 267 
205-758-8 Trisodium Edetate 262 
205-788-1 Sodium Lauryl Sulfate 689 
206-059-0 Potassium Bicarbonate 599 
206-101-8 Aluminum Stearate 42 
206-376-4 Lauric Acid 407 
206-988-1 Palmitic Acid 502 
207-439-9 Calcium Carbonate 92 
208-534-8 Sodium Benzoate 663 
208-578-8 Aleuritic Acid 650 
208-868-4 Ethyl Linoleate 414 
208-875-2 Myristic Acid 485

EINECS Excipient 
208-915-9 Magnesium Carbonate 424 
209-150-3 Magnesium Stearate 432 
209-151-9 Zinc Stearate 833 
209-170-2 Zinc Acetate 831 
209-406-4 Docusate Sodium 259 
209-481-3 Potassium Benzoate 597 
209-566-5 Lactitol 384 
209-567-0 Maltitol 439 
211-082-4 Sodium Laurate 407 
211-279-5 Aluminum Stearate 43 
212-487-9 Sodium Myristate 485 
212-755-5 Potassium Citrate 604 
212-828-1 2-Pyrrolidone 634 
214-291-9 Cetrimide 154 
214-620-6 Dodecyl Gallate 620 
215-108-5 Bentonite 60 
215-168-2 Iron Oxides 365 
215-171-9 Magnesium Oxide 427 
215-181-3 Potassium Hydroxide 606 
215-185-5 Sodium Hydroxide 684 
215-277-5 Iron Oxides 365 
215-289-0 Saponite 645 
215-478-8 Magnesium Aluminum Silicate 421 
215-540-4 Sodium Borate Anhydrous 670 
215-663-3 Sorbitan Laurate 717 
215-664-9 Sorbitan Stearate 717 
215-665-4 Sorbitan Oleate 717 
215-681-1 Magnesium Silicate 429 
215-691-6 Aluminum Oxide 38 
215-710-8 Calcium Silicate 435 
215-798-8 Alpha Tocopherol 34 
216-472-8 Calcium Stearate 104 
217-895-0 Dipotassium Edetate 261 
220-491-7 Sunset Yellow FCF 198 
221-450-6 Magnesium Lauryl Sulfate 689 
223-026-6 Chlorhexidine Hydrochloride 166 
223-095-2 Denatonium Benzoate 225 
226-242-9 Octyldodecanol 493 
228-973-6 Erythorbic Acid 265 
230-325-5 Aluminum Stearate 43 
230-636-6 Beta-carotene 197 
231-211-8 Potassium Chloride 601 
231-321-6 Calcium Sorbate 712 
231-449-2 Sodium Phosphate, Monobasic 697 
231-493-2 Cyclodextrins 220 
231-545-4 Colloidal Silicon Dioxide 190 
231-595-7 Hydrochloric Acid 329 
231-598-3 Sodium Chloride 673 
231-633-2 Phosphoric Acid 531 
231-635-3 Ammonia Solution 45 
231-639-5 Sulfuric Acid 759 
231-673-0 Sodium Metabisulfite 691 
231-783-9 Nitrogen 489 
231-819-3 Sodium Sorbate 712 
231-821-4 Sodium Sulfite 709 
231-837-1 Calcium Phosphate, Dibasic Anhydrous 94 
231-837-1 Calcium Phosphate, Dibasic Dihydrate 98 
231-837-1 Calcium Phosphate, Tribasic 101 
231-900-3 Calcium Sulfate 106 
231-913-4 Monobasic Potassium Phosphate 697 
232-273-9 Sunflower Oil 761 
232-280-7 Cottonseed Oil 207 
232-281-2 Corn Oil 205 
232-292-2 Castor Oil, Hydrogenated 131 
232-293-8 Castor Oil 129 
232-302-5 Spermaceti Wax 812 
232-307-2 Lecithin 411 
232-313-5 Canola Oil 109 
EINECS Excipient 
232-315-6 Paraffin 504 
232-348-6 Lanolin 400 
232-360-1 Sorbitan Sesquiolate 717 
232-373-2 Petrolatum 510 
232-399-4 Wax, Carnauba 810 
232-430-1 Lanolin Alcohols 403 
232-519-5 Acacia 2 
232-524-2 Carrageenan 126 
232-536-8 Guar Gum 316 
232-541-5 Ceratonia 149 
232-549-9 Shellac 651 
232-553-0 Pectin 508 
232-554-6 Gelatin 297 
232-658-1 Agar 15 
232-674-9 Cellulose, Powdered 138 
232-675-4 Dextrin 230 
232-678-0 Sodium Hyaluronate 682 
232-679-6 Hydroxypropyl Starch 344 
232-680-1 Alginic Acid 23 
232-722-9 Zein 829 
232-911-6 Amylopectin 729 
232-940-4 Maltodextrin 444 
233-032-0 Nitrous Oxide 491 
233-139-2 Boric Acid 75 
234-394-2 Xanthan Gum 822 
234-406-6 Quaternium 18-Hectorite 319 
235-192-7 Magnesium Carbonate Hydroxide 424 
235-340-0 Hectorite 319 
236-550-5 Potassium Myristate 485 
236-675-5 Titanium Dioxide 784 
238-877-9 Talc 768 
239-076-7 Magnesium Trisilicate 435 
240-795-3 Potassium Metabisulfite 608 
242-354-0 Chlorhexidine Gluconate 166 
242-471-7 Glyceryl Tribehenate 305 
243-978-6 Neohesperidin Dihydrochalcone 487 
246-376-1 Potassium Sorbate 610 
246-563-8 Butylated Hydroxyanisole 80 
247-038-6 Glyceryl Monooleate 307 
247-568-8 Sorbitan Palmitate 717 
247-569-3 Sorbitan Triolate 717 
247-891-4 Sorbitan Tristearate 717 
249-448-0 Sorbitan Dioleate 717 
250-097-0 Glyceryl Behenate 305 
252-073-5 Octyl Gallate 621 
253-149-0 Cetyl Alcohol 156 
254-372-6 Imidurea 360 
257-569-7 Sorbitan Sesquisterate 717 
258-822-2 Thaumatin 776 
259-141-3 Sorbitan Triisostearate 717 
260-080-8 Benzalkonium Chloride 63 
264-151-6 Benzalkonium Chloride 63 
265-154-5 Paraffin 504 
269-410-7 Sorbitan Diisostearate 717 
269-919-4 Benzalkonium Chloride 63 
270-325-2 Benzalkonium Chloride 63 
271-536-2 Sodium Borate 670 
275-126-4 Stearalkonium Hectorite 319 
278-928-2 Diazolidinyl Urea 360 
284-634-5 Ceratonia Extract 149 
287-089-1 Benzalkonium Chloride 63 
302-243-0 Attapulgite 57 
303-650-6 Glyceryl Dibehenate 305 
305-633-9 Stearalkonium Hectorite 319 
310-127-6 Albumin 17 
310-127-6 Kaolin 379 
64333-34-2 Sugartab 749 
Appendix III: List of Excipient ‘EINECS’ Numbers 885

Appendix IV: List of Excipient Molecular Weights 
Mol. Weight Excipient 
17.03 Ammonia Solution 44 
18.02 Water 802 
28.01 Nitrogen 488 
36.46 Hydrochloric Acid 328 
40.00 Sodium Hydroxide 683 
40.30 Magnesium Oxide 426 
43.82 Boric Acid (for monohydrate) 74 
44.01 Carbon Dioxide 116 
44.01 Nitrous Oxide 490 
44.10 Propane 325 
46.07 Alcohol 18 
46.07 Dimethyl Ether 246 
56.11 Potassium Hydroxide 605 
58.08 Acetone 8 
58.12 Butane 325 
58.12 2-Methylpropane 325 
58.44 Sodium Chloride 671 
59.99 Aluminum Hydroxide Adjuvant 36 
60.1 Isopropyl Alcohol 371 
60.1 Propan-1-ol 372 
60.05 Acetic Acid, Glacial 6 
60.08 Colloidal Silicon Dioxide 188 
61.08 Monoethanolamine 478 
61.83 Boric Acid (for trihydrate) 74 
66.05 Difluoroethane (HFC) 242 
74.08 Propionic Acid 617 
74.55 Potassium Chloride 600 
76.09 Propylene Glycol 624 
78.13 Dimethyl Sulfoxide 250 
79.88 Titanium Dioxide 782 
82.0 Sodium Acetate (for anhydrous) 654 
84.01 Sodium Bicarbonate 665 
84.31 Magnesium Carbonate 424 
85.11 2-Pyrrolidone 633 
86.47 Chlorodifluoromethane 175 
87.12 Dimethylacetamide 253 
88.1 Ethyl Acetate 268 
88.85 Iron Oxides 364 
90.08 Lactic Acid 381 
92.09 Glycerin 301 
94.11 Phenol 514 
96.06 Anhydrous Sodium Propionate 700 
96.06 Sodium Propionate (for anhydrous) 699 
98.00 Phosphoric Acid 530 
98.08 Sulfuric Acid 758 
99.14 N-Methylpyrrolidone 634 
100.09 Calcium Carbonate 89 
100.11 Potassium Bicarbonate 598 
100.13 Methyl Methacrylate 558 
100.50 Chlorodifluoroethane (HCFC) 174 
101.96 Aluminum Oxide 38 
102.0 Tetrafluoroethane (HFC) 772 
102.09 Propylene Carbonate 622 
102.09 (S)-Propylene Carbonate 623 
104 Methyl Lactate 271 
104.07 Sodium Bisulfite 691 
Mol. Weight Excipient 
105.14 Diethanolamine 238 
108.14 Benzyl Alcohol 69 
108.14 Cresol 208 
108.14 m-Cresol 209 
108.14 o-Cresol 209 
108.14 p-Cresol 209 
108.16 Monothioglycerol 482 
(111.1)n 
. (86.1)m 
Copovidone 201 
112.06 Sodium Lactate 685 
112.13 Sorbic Acid 710 
112.17 Potassium Propionate 700 
114.06 Sodium Propionate (for monohydrate) 699 
116.07 Fumaric Acid 293 
118.13 Ethyl Lactate 270 
119.98 Sodium Phosphate, Monobasic 696 
120.2 Potassium Bisulfite 608 
120.91 Chlorofluorocarbons (CFC) 176 
122.12 Benzoic Acid 66 
122.12 Erythritol 266 
122.17 Phenylethyl Alcohol 519 
126.04 Sodium Sulfite 708 
126.11 Maltol 445 
131.20 DL-Leucine 413 
131.20 Leucine 412 
134.09 D-Malic Acid 437 
134.09 L-Malic Acid 437 
134.09 Malic Acid 436 
134.12 Sodium Sorbate 712 
136.1 Sodium Acetate (for trihydrate) 654 
136.06 Calcium Phosphate, Dibasic Anhydrous 93 
136.09 Monobasic Potassium Phosphate 697 
136.14 Calcium Sulfate 105 
137.37 Chlorofluorocarbons (CFC) 176 
137.99 Sodium Phosphate, Monobasic 696 
138.16 Phenoxyethanol 517 
140.14 Ethyl Maltol 272 
141.96 Sodium Phosphate, Dibasic 693 
142.58 Chlorocresol 171 
144.11 Sodium Benzoate 662 
145.14 Calcium Sulfate Hemihydrate 106 
146.2 n-Butyl Lactate 271 
149.19 Triethanolamine 794 
150.09 Tartaric Acid 770 
150.22 Potassium Sorbate 609 
150.24 Thymol 780 
152.15 Methylparaben 466 
152.15 Vanillin 798 
152.15 Xylitol 824 
152.18 Phenoxypropanol 518 
156.01 Sodium Phosphate, Monobasic 696 
156.27 d-Menthol 460 
156.27 l-Menthol 460 
156.27 Menthol 459 
156.61 Chloroxylenol 180 
159.70 Iron Oxides 364

Mol. Weight Excipient 
159.94 Sodium Phosphate, Dibasic 693 
160.21 Potassium Benzoate 596 
(162.14)n Dextrin 228 
163.94 Tribasic Sodium Phosphate Anhydrous 694 
166.18 Ethyl Vanillin 276 
166.18 Ethylparaben 287 
169.13 Monosodium Glutamate (anhydrous) 480 
170.0 Heptafluoropropane (HFC) 321 
170.92 Chlorofluorocarbons (CFC) 176 
172.2 Capric Acid 407 
172.09 Calcium Phosphate, Dibasic Dihydrate 96 
172.17 Calcium Sulfate 105 
172.60 Chlorophenoxyethanol 518 
174.14 Methylparaben Sodium 469 
174.15 Dibasic Potassium Phosphate 694 
176.13 Ascorbic Acid 48 
176.14 Erythorbic Acid 264 
177.46 Chlorobutanol 168 
177.70 Iron Oxides 364 
177.98 Sodium Phosphate, Dibasic 693 
179.23 Cyclamic Acid 679 
180.16 Dextrose Anhydrous 233 
180.16 Fructose 290 
180.16 Invert Sugar 747 
180.20 Propylparaben 629 
180.25 Butylated Hydroxyanisole 79 
182.17 Mannitol 449 
182.17 Sorbitol 718 
183.18 Saccharin 638 
183.47 Zinc Acetate (for anhydrous) 830 
186.22 Calcium Propionate 700 
187.13 Monosodium Glutamate (monohydrate) 480 
188.17 Ethylparaben Sodium 289 
190.1 Sodium Metabisulfite 690 
190.24 Glycofurol 313 
190.25 Methylparaben Potassium 468 
192.12 Anhydrous Citric Acid 187 
193.16 Ammonium Alginate (calculated) 46 
194.19 Dimethyl Phthalate 248 
194.23 Butylparaben 83 
195.16 Calcium Alginate (calculated) 86 
195.21 Meglumine 457 
198.11 Sodium Ascorbate 659 
198.11 Sodium Erythorbate 265 
198.17 Dextrose 231 
198.17 Ethyl Gallate 620 
200.00 Bronopol 76 
200.2 Saccharin Ammonium 640 
200.32 Lauric Acid 406 
201.2 Sodium Borate Anhydrous 670 
201.22 Sodium Cyclamate 678 
201.24 Acesulfame Potassium 4 
202.20 Propylparaben Sodium 631 
204.28 Ethylparaben Potassium 289 
205.16 Saccharin Sodium 641 
209.24 Eglumine 458 
210.14 Citric Acid Monohydrate 185 
211.52 Zinc Propionate 700 
212.20 Propyl Gallate 619 
212.24 Benzyl Benzoate 72 
214.39 Myristyl Alcohol 484 
216.23 Butylparaben Sodium 85 
217 Ammonium Alginate (actual, average) 46 
217.24 Saccharin Sodium 641 
218.21 Triacetin 790 
218.30 Propylparaben Potassium 631 
219.00 Calcium Alginate (actual, average) 86 
219.50 Zinc Acetate (for dihydrate) 830 
Mol. Weight Excipient 
220.35 Butylated Hydroxytoluene 81 
222.24 Diethyl Phthalate 240 
222.32 Potassium Metabisulfite 607 
222.34 Sodium Laurate 407 
228.37 Myristic Acid 484 
231.54 Iron Oxides 364 
241.19 Saccharin Sodium 641 
242.44 Cetyl Alcohol 155 
251.41 Sodium Myristate 485 
252.15 Sodium Sulfite Heptahydrate 709 
256.42 Palmitic Acid 501 
258.07 Anhydrous Sodium Citrate 677 
258.16 Kaolin 378 
260.86 Magnesium Trisilicate 434 
260.86 Magnesium Trisilicate Anhydrous 435 
262.33 Calcium Sorbate 712 
267.52 Potassium Myristate 484 
268.03 Sodium Phosphate, Dibasic 693 
268.48 Oleyl Alcohol 496 
270.5 Isopropyl Myristate 374 
270.48 Stearyl Alcohol 740 
276.29 Triethyl Citrate 796 
278.23 Diazolidinyl Urea 360 
278.34 Dibutyl Phthalate 234 
278.47 Sodium Palmitate 502 
280.45 Linoleic Acid 414 
282.34 Octyl Gallate 620 
282.47 Oleic Acid 494 
284.47 Purified Stearic Acid 739 
284.47 Stearic Acid 737 
288.38 Sodium Lauryl Sulfate 687 
292.24 Edetic Acid 260 
294.10 Sodium Citrate Dihydrate 675 
294.31 Aspartame 53 
296.33 Shellolic Acid 650 
296.49 Methyl Oleate 275 
298.51 Isopropyl Palmitate 376 
298.62 Octyldodecanol 492 
304.42 Aleuritic Acid 650 
306.40 Potassium Citrate (for anhydrous) 603 
308.35 Dodecyltrimethylammonium Bromide 153 
310.20 Calcium Phosphate, Tribasic 100 
310.51 Ethyl Oleate 274 
314.47 Dibutyl Sebacate 236 
318.3 Acetyltriethyl Citrate 12 
324.41 Potassium Citrate (for monohydrate) 603 
328.60 Ethylene Glycol Palmitostearate 284 
331.44 Alitame (for anhydrous) 28 
336.2 Disodium Edetate (for anhydrous) 255 
336.40 Cetrimide 152 
336.40 Trimethyltetradecylammonium Bromide 153 
336.74 Phenylmercuric Acetate 521 
338.44 Dodecyl Gallate 620 
339.9 Cetylpyridinium Chloride (for anhydrous) 157 
339.61 Hexetidine 323 
342.30 Lactose, Anhydrous 385 
342.30 Lactose, Spray-Dried (for amorphous) 396 
342.30 Sucrose 744 
342.31 Maltose (anhydrous) 447 
342.31 Trehalose (anhydrous) 788 
344.5 Aluminum Monostearate 42 
344.32 Isomalt (for anhydrous) 366 
344.32 Lactitol (anhydrous) 383 
344.32 Maltitol 438 
356.55 Glyceryl Monooleate 306 
358.1 Cetylpyridinium Chloride 
(for monohydrate) 
157 
358.6 Glyceryl Monostearate 308 
Appendix IV: List of Excipient Molecular Weights 887

Mol. Weight Excipient 
358.08 Sodium Phosphate, Dibasic 693 
358.20 Trisodium Edetate 262 
359.16 Bentonite 58 
360 Benzalkonium Chloride 61 
360.31 Lactose, Monohydrate 389 
360.31 Lactose, Spray-Dried (for monohydrate) 396 
360.31 Maltose (monohydrate) 447 
360.5 Tributyl Citrate 792 
362.34 Lactitol (monohydrate) 383 
364.48 Hexadecyltrimethylammonium Bromide 153 
368.46 Dipotassium Edetate 261 
372.2 Disodium Edetate (for dihydrate) 255 
374.28 Edetate Calcium Disodium 261 
376.50 Alitame (for hydrate) 28 
378.33 Trehalose (dihydrate) 788 
380.06 Tribasic Sodium Phosphate 
Dodecahydrate 
694 
380.20 Sodium Edetate 262 
380.32 Isomalt (for dihydrate) 366 
380.35 Lactitol (dihydrate) 383 
381.37 Sodium Borate 669 
383 Hectorite 318 
384.45 Cetylpyridinium Bromide 158 
386.67 Cholesterol 182 
388.29 Imidurea (for anhydrous) 359 
390.31 Calcium Ascorbate 660 
390.5 Sodium Stearyl Fumarate 705 
390.55 Dioctyl Phthalate 235 
397.64 Sucralose 742 
(401.3)n Sodium Hyaluronate 681 
402.5 Acetyltributyl Citrate 10 
402.64 Delta Tocopherol 34 
404.81 Thimerosal 777 
406.33 Imidurea (for monohydrate) 359 
414.54 Ascorbyl Palmitate 51 
416.66 Beta Tocopherol 34 
416.66 Gamma Tocopherol 34 
430.72 Alpha Tocopherol 32 
430.72 d-Alpha Tocopherol 33 
432.57 Calcium Cyclamate 679 
444.56 Docusate Sodium 257 
446.59 Denatonium Benzoate (for anhydrous) 224 
448.10 Benzethonium Chloride 64 
452.37 Sunset Yellow FCF 198 
460.67 Docusate Potassium 258 
464.60 Denatonium Benzoate (for monohydrate) 224 
466.37 Indigo Carmine 197 
467.48 Saccharin Calcium 640 
470–490 Wax, Cetyl Esters 811 
472.73 d-Alpha Tocopherol Acetate 33 
472.73 dl-Alpha Tocopheryl Acetate 33 
480 Saponite 644 
485.65 Magnesium Carbonate Hydroxide 424 
500 Medium-chain Triglycerides 454 
502.32 Calcium Phosphate, Tribasic 100 
504.44 Raffinose (for anhydrous) 635 
505.48 Chlorhexidine 163 
530.8 d-Alpha Tocopheryl Acid Succinate 34 
530.8 dl-Alpha Tocopheryl Acid Succinate 34 
532.9 Oleyl Oleate 497 
Mol. Weight Excipient 
534.39 Tartrazine 198 
536.85 Beta-carotene 196 
578.44 Chlorhexidine Hydrochloride 166 
591.34 Magnesium Stearate 430 
594.52 Raffinose (for pentahydrate) 635 
607.03 Calcium Stearate 102 
610.9 Aluminum Distearate 42 
610.56 Hesperidin 487 
612.58 Neohesperidin Dihydrochalcone 486 
615.2 Phenylmercuric Borate 524 
625.64 Chlorhexidine Acetate 166 
632.33 Zinc Stearate 832 
633.2 Phenylmercuric Borate 524 
634.45 Phenylmercuric Nitrate 526 
807.29 Palmitin 501 
877.39 Aluminum Stearate 42 
883.23 Docusate Calcium 258 
897.88 Chlorhexidine Gluconate 166 
900–9000 Maltodextrin 442 
939.50 Castor Oil, Hydrogenated 130 
972 a-Cyclodextrin 217 
1000 Shellac 649 
1135 b-Cyclodextrin 217 
1200–2000 Polydextrose 542 
1297 g-Cyclodextrin 217 
1331 Dimethyl-b-Cyclodextrin 219 
1429 Trimethyl-b-Cyclodextrin 220 
2000 to 
>100 000 
Aliphatic Polyesters 24 
2163 Sulfobutylether b-Cyclodextrin 754 
2500–3 000 000 Povidone 611 
5000 Inulin 362 
10 000–220 000 Methylcellulose 462 
10 000–1 000 000 Chitosan 159 
10 000–1 500 000 Hypromellose 346 
14 000–21 000 Simethicone 652 
15 000–250 000 Gelatin 295 
20 000–200 000 Hypromellose Phthalate 354 
20 000–200 000 Polyvinyl Alcohol 592 
20 000–240 000 Alginic Acid 21 
30 000–100 000 Pectin 507 
36 000 Cellulose, Microcrystalline 132 
38 000 Zein 828 
50 000–1 250 000 Hydroxypropyl Cellulose 336 
50 000–160 000 Starch 725 
55 000–93 000 Hypromellose Acetate Succinate 350 
66 500 Albumin 16 
80 000–130 000 Hypromellose Phthalate 354 
90 000–700 000 Carboxymethylcellulose Sodium 120 
100 000 Polymethacrylates 553 
220 000 Guar Gum 315 
240 000–580 000 Acacia 1 
243 000 Cellulose, Powdered 136 
310 000 Ceratonia 148 
5105–1106 Sodium Starch Glycolate 701 
840 000 Tragacanth 785 
>1 000 000 Crospovidone 214 
Approximately 
2  106 
Xanthan Gum 821 
106–107 Hyaluronic Acid 682 
888 Appendix IV: List of Excipient Molecular Weights

Index 
Greek characters (a, b, g etc.), numerical prefixes (50-, 1,2- etc.) and prefixes such as para, ortho,O-, N-, D-, L- etc. are excluded from 
alphabetization; page numbers in bold refer to monograph titles. 
905 (mineral hydrocarbons), 474 
A-17, 325 
A-31, 325 
A-46, 326 
A-108, 325 
ABIL, 244–245 
Abrasives 
dibasic anhydrous calcium phosphate, 
93 
dibasic dihydrate calcium phosphate, 96 
Absolute alcohol, 19 
Absorbable dusting powder, 734 
Absorbable gelatin, 295 
Acacia, 1, 34, 149, 316 
Acacia gum, 1 
Acaciae gummi, 1 
Accelerate, 122 
Acconon, 572 
Ac-Di-Sol, 211 
Aceloquat CPB, 158 
Acesulfame K, 4 
Acesulfame potassium, 4, 29 
aspartame synergy, 55 
with sodium cyclamate, 679 
sweetness vs. sucrose, 4 
Acesulfamum kalicum, 4 
(acetato-O)Phenylmercury, 521 
Acetazolamide, 424 
Acetdimethylamide, 253 
Acetic acid, 7 
(2-butenylidene), 710 
dilute, 7 
ethyl ester, 268 
ethylene ester polymer with ethane, 285 
glacial, 6 
sodium salt, 654 
zinc salt, 830 
Acetic acid dimethylamide, 253 
Acetic acid ethenyl ester, polymer with 1- 
ethenyl-2-pyrrolidinone, 201 
Acetic acid vinyl ester, polymer with 1-vinyl- 
2-pyrrolidinone, 201 
Acetic ester, 268 
Acetic ether, 268 
Acetone, 8 
Acetone chloroform, 168 
Acetonum, 8 
Acetoxyethane, 268 
Acetoxyphenylmercury, 521 
Acetyl cellulose, 142 
Acetyl phthalyl cellulose, 145 
Acetylated lanolin, 400 
Acetylbutyl citrate, 10 
Acetylcitric acid, 10 
Acetyldimethylamine, 253 
2-Acetyloxy tributyl ester, 10 
Acetyltributyl citrate, 10, 13, 793, 796–797 
Acetyltriethyl citrate, 11–12, 793, 796–797 
Acid fosforico, 530 
Acid sodium phosphate, 696 
Acide phosphorique, 530 
Acidifying agents, 6 
citric acid monohydrate, 185 
hydrochloric acid, 328 
diluted, 329 
lactic acid, 381 
phosphoric acid, 530 
propionic acid, 617 
sulfuric acid, 758 
tartaric acid, 770 
Acido trimico, 780 
Acidulants 
fumaric acid, 293 
lactic acid, 381 
malic acid, 436 
monobasic sodium phosphate, 696 
phosphoric acid, 530 
tartaric acid, 770 
Acidum aceticum glaciale, 6 
Acidum alginicum, 21 
Acidum ascorbicum, 48 
Acidum benzoicum, 66 
Acidum boricum, 74 
Acidum citricum anhydricum, 187 
Acidum citricum monohydricum, 185 
Acidum edeticum, 260 
Acidum hydrochloricum concentratum, 328 
Acidum hydrochloridum dilutum, 329 
Acidum lacticum, 381 
Acidum malicum, 436 
Acidum methacrylicum et ethylis acrylas 
polymerisatum 1:1, 553 
Acidum methacrylicum et ethylis acrylas 
polymerisatum 1:1 dispersio 30 per 
centum, 553 
Acidum methacrylicum et methylis 
methacrylas polymerisatum 1:1, 553 
Acidum methacrylicum et methylis 
methacrylas polymerisatum 1:2, 553 
Acidum oleicum, 494 
Acidum palmiticum, 501 
Acidum phosphoricum concentratum, 530 
Acidum phosphoricum dilutum, 531 
Acidum sorbicum, 710 
Acidum stearicum, 737 
Acidum sulfuricum, 758 
Acidum tartaricum, 770 
Aclame, 28 
Acriflavine hydrochloride, 60 
Acritamer, 111 
Acryl-EZE, 553 
Acryl-EZE MP, 553 
Acrylic acid polymers, 111 
Actapulgite, 56 
Activated alumina, 38 
Activated aluminum oxide, 38 
Activated attapulgite, 56–57 
Actylol, 270 
Adeps lanae, 399 
Adeps lanae cum aqua, 404 
Adeps lanae hydrogenatus, 400 
Adeps neutralis, 762 
Adeps solidus, 762 
Adhesives 
carbomers, 111, 114 
dextrin, 228 
hypromellose, 346 
poly(methylvinyl ether/maleic 
anhydride), 561 
see also Mucoadhesives 
Adju-Phos, 40 
Adsorbents 
aluminum hydroxide adjuvant, 36 
aluminum oxide, 38 
aluminum phosphate adjuvant, 40 
attapulgite, 56 
bentonite, 58 
cellulose, powdered, 136 
colloidal silicon dioxide, 188 
hectorite, 318 
kaolin, 378 
magnesium aluminum silicate, 418 
magnesium carbonate, 422 
microcrystalline cellulose, 132 
pectin, 507 
polycarbophil, 539 
saponite, 644 
Advantose 100, 447–448 
Advantose FS 95, 290 
Aeropres, 326 
Aeropres 17, 325 
Aeropres 31, 325 
Aeropres 108, 325 
Aerosil, 188 
Aerosol propellants see Propellants 
Aerosol Solvent Extraction Systems (ASES), 
carbon dioxide, 117 
Aethylis acetas, 268 
Aethylium aceticum, 268 
Aextreff CT, 505 
Afrodit, 644 
Agar, 14 
Japan, 14 
Agar-agar, 14

Agaropectin, 14 
Agarose, 14 
Agidol, 81 
Air displacement gases 
carbon dioxide, 116 
nitrogen, 488 
Airvol, 592 
Akofine, 800 
Akosoft, 762 
Akosol, 762 
Akucell, 120 
Alabaster, 105 
Albagel, 58 
Alberger, 671 
Albuconn, 16 
Albumin, 16 
human, 16 
Albumin solution, human, 16 
Albuminar, 16 
Albumini humani solutio, 16 
Albumisol, 16 
Albuspan, 16 
Albutein, 16 
Alcohol, 18 
absolute, 19 
dehydrated, 20 
dilute, 19–20 
Alcohol benzylicus, 69 
Alcohol cetylicus, 155 
Alcohol cetylicus et stearylicus, 150 
Alcohol denaturants 
denatonium benzoate, 224–225 
diethyl phthalate, 240 
Alcohol isopropylicus, 371 
Alcohol oleicus, 496 
Alcohol stearylicus, 740 
Alcoholes adipis lanae, 402 
Alcoholia lanae, 402 
Alcolanum, 402 
Aldo MO, 306 
Aleuritic acid, 650 
Alfadex, 217 
Algaroba, 148 
Algin, 86, 656 
Alginic acid, 21, 46, 86–87, 595, 628, 657 
ammonium salt, 46 
potassium salt, 594 
propylene glycol ester, 627 
sodium salt, 656 
Alhydrogel, 36 
Aliphatic polyesters, 24, 382 
Alitame, 5, 28, 55, 640, 642, 679 
Alkalizing agents 
ammonia solution, 44 
diethanolamine, 238 
monoethanolamine, 478 
potassium bicarbonate, 598 
potassium citrate, 603 
potassium hydroxide, 605 
sodium bicarbonate, 665 
sodium borate, 669 
sodium citrate dihydrate, 675 
sodium hydroxide, 683 
triethanolamine, 794 
Alkyl dimethyl benzyl ammonium chloride, 
61 
Alkylbenzyldimethylammonium chloride, 
61 
Alkyldimethyl(phenylmethyl)ammonium 
chloride, 61 
Alkyltrimethylammonium bromides, 153 
Allomaleic acid, 293 
Allomalenic acid, 293 
Allopurinol, 250 
all-rac-a-Tocopherol, 32 
all-rac-a-Tocopheryl acetate, 33 
Almond oil, 30, 109, 205, 207, 274, 506, 
647 
bitter, 30 
refined, 31 
Alpha aluminum oxide, 38 
Alpha tocopherol, 32–34, 51 
and ascorbyl palmitate, 32 
and lecithin, 32 
and linoleic acid, 32 
and methyl linolenate, 32 
natural, 33 
synthetic, 32 
see also Tocopherol 
dl-Alpha tocopheryl, 32 
(2R,40R,80R)-Alpha-tocopherol, 32 
d-Alpha tocopheryl acetate, 33 
dl-Alpha tocopheryl acetate, 33 
d-Alpha tocopheryl acid succinate, 33 
dl-Alpha tocopheryl acid succinate, 34 
Alpha-cycloamylose, 217 
Alpha-cyclodextrin, 217 
Alpha-dextrin, 217 
Alpha-tocopherolum, 32 
Altalc, 767 
Alumina, 38 
activated, 38 
calcined, 38 
tabular, 38 
Aluminii hydroxidum hydricum ad 
adsorptionem, 36 
Aluminii magnesii silicas, 418 
Aluminium hydroxide adjuvant, 36 
Aluminium hydroxyphosphate, 40 
Aluminium magnesium silicate, 418 
Aluminium oxyhydroxide, 36 
Aluminosilicic acid, 418 
Aluminum, dihydroxy (octadecanoato-O-), 
42 
Aluminum distearate, 42 
Aluminum hydroxide, 426 
Aluminum hydroxide adjuvant, 36, 41 
Aluminum hydroxyphosphate, 40 
Aluminum magnesium salt, 418 
Aluminum magnesium silicate, 418 
Aluminum monobasic stearate, 42 
Aluminum monostearate, 42 
Aluminum oxide, 38 
Aluminum oxide alumite, 38 
Aluminum oxyhydroxide, 36 
Aluminum phosphate, 40 
Aluminum phosphate adjuvant, 37, 40 
Aluminum silicate, 289 
hydrated, 58, 60, 378–379 
hydrous, 378 
Aluminum stearate, 42 
Aluminum trioxide, 38 
Aluminum tristearate, 42 
Aluminum-saponite, 644 
Amalty, 438 
Amberlite IRP-64, 533 
Amberlite IRP-88, 532 
Ambroxol, 507 
Amerchol CAB, 512 
Amerchol L-101, 476 
Amfetamine sulfate, 421 
Amido, 725 
Amidon, 725 
Amilo, 725 
5-Amino-1,3-bis(2-ethylhexyl)hexahydro-5- 
methylpyrimidine, 323 
5-Amino-1,3-di(b-ethylhexyl)hexahydro-5- 
methylpyrimidine, 323 
2-Amino-4-methylpentanoic acid, 412 
2-Amino-4-methylvaleric acid, 412 
g-Aminobutyric acid lactam, 633 
g-Aminobutyric lactam, 633 
g-Aminobutyrolactam, 633 
2-Amino-2-deoxy-(1,4)-b-D-glucopyranan, 
159 
b-(1,4)-2-Amino-2-deoxy-D-glucose, 159 
2-Aminoethanol, 478 
b-Aminoethyl alcohol, 478 
a-Aminoisocaproic acid, 412 
L-a-Aminoisocaproic acid, 412 
a-Amino-g-methylvaleric acid, 412 
3-Amino-N-(a-carboxyphenethyl)succinamic 
acid N-methyl ester, 53 
3-Amino-N-(amethoxycarbonylphenethyl)
succinamic 
acid, 53 
Ammonia, 44 
Ammonia solution, 44–45 
concentrated, 44 
dilute, 45 
strong, 44 
Ammonia water, 45 
Ammoniaca, 44 
Ammoniacum, 44 
Ammoniae solution concentrata, 44 
Ammonio methacrylate copolymer, 553 
Ammonium alginate, 23, 46, 595 
Ammonium polymannuronate, 46 
Amorphous wax, 813 
Amoxicillin, 379 
Ampicillin, 379 
Amygdalae oleum raffinatum, 31 
Amygdalae oleum virginum, 30 
Amylopectin, 729 
a-Amylose, 729 
Amylum, 725 
Amylum pregelificatum, 731 
Anatase, 783 
Anatase titanium dioxide, 782 
Anhydrite, 105 
Anhydrous calcium hydrogen phosphate, 93 
Anhydrous calcium sulfate, 105 
Anhydrous citric acid, 187, 665 
Anhydrous dextrose, 233 
Anhydrous dibasic calcium phosphate, 93 
Anhydrous dibasic sodium phosphate, 693 
Anhydrous disodium hydrogen phosphate, 
693 
Anhydrous ethanol, 19 
Anhydrous ferric oxide, 364 
Anhydrous D-(.)-glucopyranose, 233 
Anhydrous glucose, 233 
Anhydrous gypsum, 105 
Anhydrous iron (III) oxide, 364 
Anhydrous lactose, 385 
Anhydrous Lactose NF 60M, 385 
Anhydrous Lactose NF Direct Tableting, 
385 
Anhydrous lanolin, 399 
Anhydrous monobasic sodium phosphate, 
696 
Anhydrous sodium citrate, 676–677 
Anhydrous sodium dihydrogen phosphate, 
696 
Anhydrous sodium propionate, 700 
Anhydrous sodium sulfite, 708 
Anhydrous sulfate of lime, 105 
Anhydrous trisodium citrate, 677 
Anionic emulsifying wax, 151 
890 Index

Anionic emulsifying wax see Emulsifying 
wax, anionic 
Anionic surfactants see Surfactants, anionic 
Annalin, 106 
Antacid, magnesium carbonate, 422 
Antacids, 424 
Antiadherents, leucine, 412 
Antibacterial agents 
benzoic acid, 67 
chlorocresol, 171 
diazolidinyl urea, 360 
dimethyl sulfoxide, 251 
glacial acetic acid, 6 
imidurea, 359 
iodine/edetic acid, 261 
phenylmercuric acetate, 522 
phenylmercuric borate, 524 
phenylmercuric hydroxide, 527 
potassium sorbate, 609 
sodium hydroxide, 684 
sorbic acid, 609–610 
see also Antiseptics; Disinfectants; 
Preservatives 
Antibacterial preservatives see Antibacterial 
agents; Preservatives 
Antibrowning agents, sodium metabisulfite, 
690 
Anticaking agents 
calcium phosphate, tribasic, 100 
calcium silicate, 435 
colloidal silicon dioxide, 188 
magnesium silicate, 428 
magnesium trisilicate, 434 
talc, 767 
Anticapping agents see ‘Cap locking’ 
preventatives 
Anticoagulants, citric acid monohydrate, 185 
Antidusting agents, polyethylene alkyl ethers, 
565 
Antifoaming agents 
dimethicone, 244 
oleyl alcohol, 496 
polypropylene glycol 2000, 573 
propylene glycol alginate, 627 
simethicone, 652 
Antifungal agents 
benzoic acid, 66 
butylparaben, 83 
chlorocresol, 171–172 
dimethyl sulfoxide, 251 
ethylparaben, 287 
glacial acetic acid, 6 
imidurea, 359 
methylparabens, 466 
phenylmercuric acetate, 522 
phenylmercuric borate, 524 
phenylmercuric hydroxide, 527 
potassium sorbate, 609 
propylparaben, 629 
sodium propionate, 699 
sporocides, chlorocresol, 172 
vanillin, 798 
see also Preservatives 
Antimicrobial preservatives see Antibacterial 
agents; Antifungal agents; Preservatives 
Antioxidants 
alpha tocopherol, 32, 109 
ascorbic acid, 48 
ascorbyl palmitate, 51 
butylated hydroxyanisole, 79, 619 
butylated hydroxytoluene, 81, 619 
carbon dioxide, 116 
chelating agents, 260, 293 
citric acid monohydrate, 185 
erythorbic acid, 264 
ethyl oleate, 274 
fumaric acid, 293 
malic acid, 436 
monothioglycerol, 482 
phosphoric acid, 530 
potassium metabisulfite, 607 
propionic acid, 617 
propyl gallate, 619, 621 
sodium ascorbate, 659 
sodium bisulfite, 691 
sodium metabisulfite, 690–691 
sodium sulfite, 691, 708 
synergists 
citric acid monohydrate, 185 
tartaric acid, 770 
thymol, 780 
tocopherol (see Antioxidants, alpha 
tocopherol) 
vitamin E, 34 
see also Preservatives 
Antiseptics 
benzalkonium chloride, 61 
benzethonium chloride, 64 
bronopol, 76 
cetrimide, 152 
cetylpyridinium chloride, 157 
chlorhexidine, 163 
chloroxylenol, 180 
hexetidine, 323 
phenol, 514 
phenylmercuric acetate, 521 
phenylmercuric borate, 524 
phenylmercuric nitrate, 526 
thimerosal, 777 
thymol, 780 
Antiviral agents 
benzalkonium chloride, 62 
butylated hydroxytoluene, 81 
cellulose acetate phthalate (CAP), 145 
sodium hydroxide, 684 
AnyCoat C, 346 
Apifil, 819 
APM, 53 
Apple acid, 436–437 
Aptal, 171 
Aqoat, 350 
Aqoat AS-HF/HG, 350 
Aqoat AS-LF/LG, 350 
Aqoat AS-MF/MG, 350 
Aqua, 802 
Aqua ammonia, 44 
Aqua purificata, 802 
Aquacoat cPD, 145 
Aquacoat ECD, 278 
Aqualon, 278 
Aquasorb, 120 
Arabic gum, 1 
Araboascorbic acid, 264 
d-Araboascorbic acid, 264 
Arachidic acid 
cottonseed oil, 206 
peanut oil, 505 
sunflower oil, 760 
Arachidis oleum, 505 
Arachis oil, 505 
Araldite 502, 234 
Arbocel, 136 
Arcton, 176 
Arcton 22, 175 
Argilla, 378 
Argobase EU, 512 
Argowax, 402 
Arlatone, 572 
Arosol, 517 
Artificial almond oil, 30 
Artificial sweeteners see Sweetening agents 
Artificial vinegar, 7 
Ascorbic acid, 48, 52, 260, 264–265, 660 
incompatibilities 
sodium starch glycolate, 703 
sucrose, 746 
L-Ascorbic acid 6-hexadecanoate, 51 
L-Ascorbic acid 6-palmitate, 51 
Ascorbic acid ethyl oleate, 274 
L-Ascorbic acid monosodium salt, 659 
Ascorbyl palmitate, 50–51, 660 
and alpha tocopherol, 32 
Ascorbylis palmitas, 51 
Aspartame, 29, 53 
acesulfame potassium synergy, 55 
with saccharin, 640 
with saccharin sodium, 643 
sweetness vs. sucrose, 53 
Aspartamum, 53 
Aspartyl phenylamine methyl ester, 53 
3-(L-Aspartyl-D-alaninamido)-2,2,4,4- 
tetramethylthietane, 28 
L-Aspartyl-D-alanine-N-(2,2,4,4- 
tetramethylthietan-3-yl)amide, 28 
L-a-Aspartyl-N-(2,2,4,4-tetramethyl-3- 
thietanyl)-D-alaninamide anhydrous, 28 
L-a-Aspartyl-N-(2,2,4,4-tetramethyl-3- 
thietanyl)-D-alaninamide hydrate, 28 
N-a-L-Aspartyl-L-phenylalanine 1-methyl 
ester, 53 
Aspasomes, 52 
Aspirin, 430 
A-TAB, 93–94 
ATBC, 10 
ATEC, 12 
Atlas G-695, 306 
Attaclay, 56 
Attacote, 56 
Attagel, 56 
Attapulgite, 56, 319, 421, 645 
activated, 56–57 
colloidal activated, 57 
Attapulgus, 56 
Autism, 778 
Auxite, 644 
Avatech, 471 
Avedex, 228 
Avicel CE-15, 134 
Avicel CL-611, 134 
Avicel PH, 132 
Avicel RC-581, 134 
Avicel RC-591, 134 
Avol, 155 
Avolin, 248 
Aytex P, 725 
Azote, 488 
Bactericides see Antibacterial agents 
Bacteriostatic water for injection, 805 
Baking soda, 665 
Baktol, 171 
Barcroft CS90, 92 
Barcroft CX50, 92 
Barcroft CZ50, 92 
Barrier creams, 815 
Basic phenylmercury nitrate, 526 
Bassorin, 785 
Bayferrox 105M, 364 
Bayferrox 306, 364 
Index 891

Bayferrox 920Z, 364 
Beeswax, 819 
white, 817 
Beet sugar, 744 
Behenic acid 
peanut oil, 505 
sunflower oil, 760 
Benecel, 462 
Benecel MHPC, 346 
Bengal isinglass, 14 
Benne oil, 646 
Bentone 27, 319 
Bentone 38, 319 
Bentonite, 58, 319, 379, 421, 645, 768 
methylparabens incompatibility, 468 
purified, 60 
sol/gel preparation, 59 
Bentonite magma, 60 
Bentonitum, 58 
Benzalkonii chloridum, 61 
Benzalkonium chloride, 61, 65, 153, 528 
adverse effects, 62 
alternatives, thimerosal, 777 
synergists, 260 
Benzenecarboxylic acid, 66 
1,2-Benzenedicarboxylate, 248 
Benzenedicarboxylic acid, 234 
dibutyl ester of, 234 
diethyl ester, 240 
dimethyl ester, 248 
1,2-Benzenedicarboxylic acid bis(2- 
ethylhexyl) ester, 235 
Benzeneethanol, 519 
Benzeneformic acid, 66 
Benzenemethanol, 69 
Benzene-o-dicarboxylic acid di-n-butyl ester, 
234 
Benzethonii chloridum, 64 
Benzethonium chloride, 63–64, 153 
1,2-Benzisothiazol-3(2H)-one 1,1-dioxide, 
638 
sodium salt, 641 
1,2-Benzisothiazolin-3-one 1,1-dioxide, 
638 
sodium salt, 641 
Benzoate of potash, 596 
Benzoate of soda, 662 
Benzoic acid, 66, 436, 597, 663, 799 
benzyl ester, 72 
phenylmethyl ester, 72 
potassium salt, 596 
sodium salt, 662 
Benzoic sulfimide, 638 
Benzosulfimide, 638 
Benzyl alcohol, 69 
Benzyl benzoate, 72 
Benzyl carbinol, 519 
Benzyl phenylformate, 72 
Benzylbenzenecarboxylate, 72 
Benzyldiethyl[(2,6- 
xylylcarbamolyl)methyl]ammonium 
benzoate 
anhydrous, 224 
monohydrate, 224 
Benzyldimethyl-[2-[2-(p-1,1,3,3- 
tetramethylbutylphenoxy) 
ethoxy]ethyl]ammonium chloride, 64 
Benzylis benzoas, 72 
Benzylmethanol, 519 
Bergabest, 454 
Beta tocopherol, 33–34 
Beta-carotene, 196 
Beta-cycloamylose, 217 
Betadex, 217 
Beta-dextrin, 217 
Betadexum, 217 
BHA, 79 
BHT, 81 
Binding agents 
acacia, 1 
agar, 14 
alginic acid, 21, 23 
carbomers, 111 
carboxymethylcellulose sodium, 120 
carrageenan, 125 
cellulose acetate phthalate, 145 
ceratonia, 148 
chitosan, 159 
confectioner’s sugar, 750 
copovidone, 201 
cottonseed oil, 206 
dextrates, 226 
dextrin, 228 
dextrose, 231 
ethylcellulose, 278 
gelatin, 295 
glyceryl behenate, 304 
guar gum, 315 
hydrogenated vegetable oil type I, 800 
hydroxyethyl cellulose, 330 
hydroxyethylmethyl cellulose, 334 
hydroxypropyl cellulose, 336 
low-substituted, 341 
hydroxypropyl starch, 344 
hypromellose, 346 
inulin, 362 
lactose, 389 
anhydrous, 385 
spray dried, 396 
liquid glucose, 299 
magnesium aluminum silicate, 418 
maltodextrin, 442 
maltose, 447 
methylcellulose, 462 
microcrystalline cellulose, 132 
poloxamer, 535 
polycarbophil, 539 
polydextrose, 542 
polyethylene oxide, 551 
polymethacrylates, 554 
povidone, 611 
sodium alginate, 656 
starch, 725 
pregelatinized, 731 
stearic acid, 737 
sucrose, 744 
sunflower oil, 760 
zein, 828 
Bioabsorbables, aliphatic polyesters, 24 
Bioadhesives 
polycarbophil, 539 
see also Adhesives; Mucoadhesives 
Biocompatibles, aliphatic polyesters, 24 
Biodegradable materials 
aliphatic polyesters, 24 
biodegradable polymers, 24 
glyceryl monostearate, 308 
glyceryl palmitostearate, 311 
Biopure 100, 359 
Bio-sorb, 734 
2,6-bis(1,1-Dimethylethyl)-4-methylphenol, 
81 
Bis(2-ethylhexyl) phthalate, 235 
bis(2-Ethylhexyl) sodium sulfosuccinate, 257 
1,4-bis(2-Ethylhexyl) sulfosuccinate, calcium 
salt, 258 
1,3-bis(2-Ethylhexyl)-5-methylhexahydro-5- 
pyrimidinamine, 323 
1,3-bis(2-Ethylhexyl)-5- 
methylhexahydropyrimidin-5-ylamine, 
323 
N,N00-bis(4-Chlorophenyl)-3,12-diimino- 
2,4,11,13- 
tetraazatetradecanediimidamide, 163 
1,3-bis(b-Ethylhexyl)-5-methyl-5- 
aminohexahydropyrimidine, 323 
Bis(hydroxyethyl)amine, 238 
Bismuth nitrate, and glycerin, 302 
1,6-bis[N0-(p-Chlorophenyl)-N5- 
biguanido]hexane, 163 
Bitrex, 224 
Bitter almond oil, 30 
Bitterguard, 224 
BKC, 61 
Black magnetic oxide, 364 
Black oxide, precipitated, 364 
Black rouge, 364 
Blanose, 120 
Bleached shellac, 649 
Bleached wax, 817 
Blood sugar, 231 
Boletic acid, 293 
Bolus alba, 378 
Boracic acid, 74 
Boraic acid, 74 
Borax, 669 
fused, 670 
Borax decahydrate, 669 
Borax glass, 670 
Boric acid, 74, 302, 670 
disodium salt, 669 
Borofax, 74 
Boron trihydroxide, 74 
Bourbonal, 276 
Bovine serum albumin, 17 
Bovine spongiform encephalopathy (BSE), 
183, 297 
Brazil wax, 809 
Brij, 564 
Brij 72, 565 
Brij 97, 565 
British gum, 228 
Bromat, 152 
2-Bromo-2-nitro-1,3-propanediol, 76 
2-Bromo-2-nitropropane-1,3-diol, 76 
Bromocet, 158 
b-Bromo-b-nitrotrimethyleneglycol, 76 
Bronopol, 76 
synergists, 260 
Brookite, 783 
Brookite titanium dioxide, 782 
Brucine, 224 
BSE see Bovine Spongiform 
Encephalopathy 
Buffering agents 
ammonia solution, 44 
calcium carbonate, 89 
calcium phosphate, tribasic, 100 
citric acid monohydrate, 185 
dibasic sodium phosphate, 693 
diethanolamine, 238 
malic acid, 436 
monobasic sodium phosphate, 696 
monoethanolamine, 478 
monosodium glutamate, 480 
phosphoric acid, 530 
potassium citrate, 603 
sodium acetate, 654 
sodium bicarbonate, 665 
892 Index

sodium borate, 669 
sodium citrate dihydrate, 675 
sodium hydroxide, 683 
sodium lactate, 685 
triethanolamine, 794 
Bulking agents 
mannitol, 449 
powdered cellulose, 136 
see also Diluents (tablet/capsule) 
Buminate, 16 
Butane, 325 
(2R,3S)-Butane 1,2,3,4-tetrol, 266 
Butenedioic acid, 293 
2-Butenedioic acid, monooctadecyl ester, 
sodium salt, 705 
(E)-2-Butenedioic acid, 293 
trans-Butenedioic acid, 293 
(2-Butenylidene) acetic acid, 710 
Butyl 4-hydroxybenzoate, 83 
sodium salt, 85 
Di-n-butyl ester, 234 
Butyl hydroxybenzoate, 83 
Butyl a-hydroxypropionate, 271 
n-Butyl lactate, 271 
tert-Butyl-4-methoxyphenol, 79 
Butyl parahydroxybenzoate, 83 
Butyl phthalate, 234 
Butyl sebacate, 236 
Butylated hydroxyanisole, 79, 82, 619 
and ethyl oleate, 274 
Butylated hydroxytoluene, 80–81, 399, 402, 
436, 619 
and hydrous lanolin, 404 
2,6-Di-tert-butyl-p-cresol, 81 
Butylhydroxyanisolum, 79 
Butylhydroxytoluene, 81 
Butylhydroxytoluenum, 81 
Butylis parahydroxybenzoas, 83 
2-tert-Butyl-4-methoxyphenol, 79 
2,6-Di-tert-butyl-4-methylphenol, 81 
Di-n-Butyl phthalate, 234 
Butylparaben, 83, 289, 468, 631 
see also Parabens 
Butylparaben sodium, 85 
g-Butyrolactam, 633 
Byco, 295 
BZT, 64 
C16-alkylpyridinium chloride, 157 
C-97, 48 
C-1297, 406 
CA33, 86 
Cab-O-Sil, 188 
Cab-O-Sil M-5P, 188 
Cachalot, 155, 740 
Caffeine, 798 
Calc algin, 86 
Cal-Carb 4450 PG, 92 
Cal-Carb 4457, 92 
Cal-Carb 4462, 92 
Calchem H-102, 109 
Calchem IVO-114, 722 
Calcii carbonas, 89 
Calcii hydrogenophosphas dihydricus, 96 
Calcii hydrogenphosphas anhydricus, 93 
Calcii stearas, 102 
Calcii sulfas dihydricus, 105 
Calcii sulfas hemihydricus, 106 
Calcinated magnesite, 426 
Calcined gypsum, 106 
Calcined magnesia, 426 
Calcitonin, 682 
Calcium alginate, 23, 46, 86, 595, 657 
Calcium ascorbate, 660 
Calcium L-(.)-ascorbate, 660 
Calcium carbonate, 89 
precipitated, 89 
Calcium carbonate (1:1), 89 
Calcium carboxymethylcellulose, 118 
Calcium CMC, 118 
Calcium cyclamate, 679 
Calcium N-cyclohexylsulfamate dihydrate, 
679 
Calcium dipropionate, 700 
Calcium disodium edetate, 262 
Calcium disodium 
ethylenediaminetetraacetate, 262 
Calcium disodium (ethylenedinitrilo) 
tetraacetate, 262 
Calcium distearate, 102 
Calcium hydrogen orthophosphate dihydrate, 
96 
Calcium hydrogen phosphate, 96 
Calcium hydroxide phosphate, 100 
Calcium monohydrogen phosphate, 93 
Calcium monohydrogen phosphate dihydrate, 
96 
Calcium octadecanoate, 102 
Calcium orthophosphate, 93, 100 
Calcium phosphate, 100 
dibasic anhydrous, 93, 98, 101, 106 
dibasic dihydrate, 94, 96, 101, 106 
precipitated, 100 
tribasic, 94, 98, 100, 106 
Calcium polycarbophil, 540 
Calcium polymannuronate, 86 
Calcium propionate, 700 
Calcium salt, 86 
Calcium silicate, 435 
Calcium sorbate, 712 
Calcium stearate, 102, 431, 452, 739, 833 
Calcium sulfate, 94, 105 
anhydrous, 105 
dihydrate, 105 
dried, 106 
exsiccated, 106 
hemihydrate, 105–106 
native, 105 
precipitated, 105 
Calcium sulphate dihydrate, 105 
Calcium/sodium salt mix, of poly(methylvinyl 
ether/maleic anhydride), 561 
Calginate, 86 
Caloreen, 228, 230 
Calstar, 98 
Cal-Tab, 105 
Canary dextrin, 228 
Canbra oil, 108 
Canderel, 53 
Candex, 226 
Cane sugar, 744 
Canola oil, 31, 108, 205, 207, 506, 647, 723 
erucic acid content, 108 
oleic acid content, 109 
tocopherol content, 109 
CAP, 145 
‘Cap locking’ preventatives 
fructose, 290 
hydroxypropyl cellulose, lowsubstituted, 
341 
sorbitol, 718 
xylitol, 824 
CAP30, 326 
Capmul GMO, 306 
Capmul GMS-50, 308 
Capric acid, 407 
Caprinic acid, 407 
Caprylic/capric triglyceride, 454 
Caprynic acid, 407 
Capsule/tablet diluents see Diluents (tablet/ 
capsule) 
Capsule/tablet disintegrants see Disintegrants 
(tablet/capsule) 
Capsule/tablet lubricants see Lubricants 
(tablet/capsule) 
Capsule/tablet monogramming, shellac, 649 
Captex 300, 454 
Captex 355, 454 
Captex 500, 790 
Captisol, 754 
Caramania gum (hog gum), 786 
Caranda wax, 809 
Carbolic acid, 514 
Carbomer, 111, 540 
Carbomera, 111 
Carbomers, 111, 114 
Carbon dioxide, 116–117, 489, 491 
see also Gas-forming agents 
Carbon dioxide-free water, 805 
Carbonate magnesium, 422 
Carbonei dioxidum, 116 
Carbonic acid, 622 
calcium salt (1:1), 89 
magnesium salt 
hydrate, 424 
mixture with magnesium hydroxide 
and magnesium hydrate, 424 
magnesium salt (1:1), 422 
magnesium salt anhydrous, 424 
Carbonic acid calcium salt 1:1, 89 
Carbonic acid gas, 116 
Carbonic acid monopotassium salt, 598 
Carbonic acid monosodium salt, 665 
Carbonic anhydride, 116 
Carbopol, 111 
Carbowax, 545 
Carbowax Sentry, 545 
Carboxy polymethylene, 111 
Carboxybenzene, 66 
Carboxyethane, 617 
Carboxylic acid C10, 407 
Carboxymethyl cellulose, 352 
Carboxymethyl starch, sodium salt, 701 
Carboxymethylamylum natricum, 701 
Carboxymethylcellulose, 827 
Carboxymethylcellulose calcium, 118, 122, 
212 
Carboxymethylcellulose sodium, 119–120, 
212 
crosslinked, 211 
and microcrystalline cellulose, 134 
[(o-Carboxyphenyl)thio]ethylmercury sodium 
salt, 777 
Carboxyvinyl polymer, 111 
Caridex, 231 
Carmellose calcium, 118 
Carmellose sodium, 120 
Carmellosum calcicum, 118 
Carmellosum natricum, 120 
Carmellosum natricum conexum, 211 
Carnallite, 601 
Carnauba wax, 809 
Carob, extract of, 149 
Carob bean gum, 148–149 
Carob flour, 148 
Carob gum, 148 
b-Carotene, 196 
Carrageenan, 124 
and microcrystalline cellulose, 134 
Index 893

Carrisorb, 418 
C*Ascend, 788 
Cassava (tapioca) starch, 725, 729 
Castor oil, 128, 131 
hydrogenated, 129–130, 801 
hydrogenated polyoxyl, 572 
polyethoxylated, 572 
polyoxyethylene derivatives, 572 
polyoxyl, 572 
polyoxyl 35, 572–573 
polyoxyl 40 hydrogenated, 572–573 
Castorwax, 130 
Castorwax MP 70, 130 
Castorwax MP 80, 130 
Cathkinite, 644 
Cationic emulsifying wax see Emulsifying 
wax cationic 
Cationic surfactants see Surfactants, 
cationic 
Caustic potash, 605 
Caustic soda, 683 
Cavamax W6 Pharma, 217 
Cavamax W7 Pharma, 217 
Cavamax W8 Pharma, 217 
Cavitron, 217 
CCal-97, 660 
C*Dry MD, 442 
Cecavon, 832 
Ceftazidime, 522 
Cefuroxime, 522 
Celex, 132 
Cellacefate, 145 
Cellacephate, 145 
Cellosize HEC, 330 
Celluflex DBP, 234 
Cellulose, 132, 136 
acetate, 1,2-benzenedicarboxylate, 145 
carboxymethyl ether 
calcium salt, 118 
sodium salt, 120 
sodium salt, crosslinked, 211 
colloidal, 134 
crystalline, 132 
dispersible, 134 
hydrogen 1,2-benzenedicarboxylate, 2- 
hydroxypropyl methyl ether, 354 
hydroxyethyl, 330 
2-hydroxyethyl ether, 330 
2-hydroxyethyl methyl ester, 334 
hydroxyethylmethyl, 334 
hydroxypropyl ether, 336 
2-hydroxypropyl ether (low-substituted), 
341 
2-hydroxypropyl methyl ether, acetate 
succinate, 350 
2-hydroxypropylmethyl ether, acetate 
hydrogen butanedioate, 350 
microcrystalline, 132, 137, 140, 352 
and carboxymethylcellulose sodium, 
134 
and carrageenan, 134 
and guar gum, 134 
powdered, 134, 136 
silicified, microcrystalline, 134, 139 
Cellulose acetate, 142, 146, 248, 352 
solvents, diethyl phthalate, 240 
Cellulose acetate benzene-1,2-dicarboxylate, 
145 
Cellulose acetate hydrogen 1,2- 
benzenedicarboxylate, 145 
Cellulose acetate hydrogen phthalate, 145 
Cellulose acetate monophthalate, 145 
Cellulose acetate phthalate, 145 
Cellulose acetate phthalate (CAP), 144–145, 
352, 357, 589–590 
compatible plasticizers, 145 
Cellulose acetate-butyrate, 248 
Cellulose acetophthalate, 145 
Cellulose acetylphthalate, 145 
Cellulose diacetate, 142 
Cellulose ethyl ether, 278 
Cellulose gel, 132 
Cellulose gum, 120 
modified, 211 
Cellulose hydroxyethyl ether, 330 
Cellulose hydroxyethylate, 330 
Cellulose hydroxypropyl methyl ether, 346 
Cellulose methyl ether, 462 
Cellulose phthalate hydroxypropyl methyl 
ether, 354 
Cellulose triacetate, 142 
Cellulosi acetas, 142 
Cellulosi acetas phthalas, 145 
Cellulosi pulvis, 136 
Cellulosum microcristallinum, 132 
Celphere, 132, 135 
Ceolus KG, 132 
Cepacol, 157 
Cepacol chloride, 157 
Cera alba, 817 
Cera carnauba, 809 
Cera cetyla, 811 
Cera flava, 819 
Cera lanae, 399 
Ceratonia, 2, 148, 822 
Ceratonia extract, 149 
Ceratonia gum, 148 
Ceratonia siliqua, 148 
Ceratonia siliqua extract, 149 
Ceratonia siliqua gum, 148 
C*Eridex, 266 
CertiSeal, 649 
Cetab, 152 
Cetamiun, 157 
Cetanol, 155 
Cetapharm, 158 
Cetasol, 158 
Cetavlon, 152 
Cetearyl alcohol, 150 
Ceteth-N, 564 
Cetomacrogol 1000, 564 
Cetomacrogol emulsifying ointment BP, 815 
Cetomacrogol emulsifying wax, 815 
Cetostearyl alcohol, 150, 156, 689, 741, 808, 
816 
polyoxyethylene alkyl ethers, 578 
Cetraol, 152 
Cetrimide, 61, 63–65, 152, 165 
synergists, 260 
Cetrimide BP 1953, 153 
Cetrimide emulsifying wax, 816 
Cetrimidum, 152 
Cetrimonium bromide, 153 
Cetyl alcohol, 151, 155, 689, 741 
Cetyl esters wax, 811 
Cetyl pyridium chloride, 157 
Cetylacetic acid, 737 
Cetylic acid, 501 
Cetylpridinii chloridum, 157 
Cetylpyridinium bromide, 158 
Cetylpyridinium chloride, 157 
Cetyltrimethylammonium bromide, 153 
Cevitamic acid, 48 
Ceylon isinglass, 14 
CFCs see Chlorofluorocarbons (CFCs) 
Chalk, precipitated, 89 
Chelating agents 
antioxidants, 260, 293 
citric acid monohydrate, 185 
dipotassium edetate, 261 
disodium edetate, 255 
edetate calcium disodium, 261 
edetic acid, 260 
fumaric acid, 293 
malic acid, 436 
maltol, 446 
sodium edetate, 262 
trisodium edetate, 262 
Chelation therapy, 262 
Cheshire gum, 148 
Chewable tablet formulations 
mannitol, 449 
microcrystalline cellulose and guar gum, 
134 
xylitol, 824 
see also Medicated confectionery bases 
China clay, 378 
Chinese isinglass, 14 
Chinese Restaurant Syndrome, 480 
Chinese seasoning, 480 
Chitin, deacetylated, 159 
Chitosan, 159, 508 
Chitosan hydrochloride, 159 
Chitosani hydrochloridum, 159 
Chlorbutanol, 168 
Chlorbutol, 168 
Chlorhexidine, 163 
and surfactants, 165 
Chlorhexidine acetate, 163, 166, 705 
Chlorhexidine cream BP, 815 
Chlorhexidine diacetate, 166 
Chlorhexidine digluconate, 166 
Chlorhexidine dihydrochloride, 166 
Chlorhexidine gluconate, 166 
Chlorhexidine gluconate solution, 163 
Chlorhexidine hydrochloride, 163, 166 
Chlorhexidini acetas, 166 
Chlorhexidini diacetas, 163 
Chlorhexidini digluconatis, 166 
Chlorhexidini digluconatis solutio, 163 
Chlorhexidini dihydrochloridum, 163 
Chlorhexidini hydrochloridum, 166 
Chloride of potash, 600 
Chlorobutanol, 168, 518, 520 
Chlorobutanolum anhydricum, 168 
Chlorocresol, 171, 181, 209 
Chlorocresolum, 171 
p-Chloro-m-cresol, 171 
1-Chloro-1,1-difluoroethane, 174, 243 
Chlorodifluoroethane (HCFC), 174 
Chlorodifluoromethane, 175 
with chlorodifluoroethane, 174, 243 
4-Chloro-3,5-dimethylphenol, 180 
Chlorofluorocarbons (CFCs), 176, 772 
dichlorodifluoromethane, 176, 178 
essential use status, 178 
dichlorotetrafluoroethane, 176 
essential use exemptions, 178 
Montreal Protocol, 178 
nomenclature, 178 
trichloromonofluoromethane, 176 
Chlorohydric acid, 328 
1-Chloro-4-hydroxy-2-methylbenzene, 171 
2-Chloro-5-hydroxytoluene, 171 
4-Chloro-m-cresol, 171 
4-Chloro-3-methylphenol, 171 
p-Chloro-m-xylenol, 180 
Chlorophenoxyethanol, 518 
Chloropotassuril, 600 
894 Index

Chloroquine, 507 
Chloroquine phosphate, 428 
Chloroxylenol, 173, 180 
synergists, 260 
Chlorphenamine maleate, 819 
Chlorpheniramine maleate, 339 
Chlorpromazine, 208 
Chlorure de sodium, 671 
Cholest-5-en-3b-ol, 182 
Cholesterin, 182 
Cholesterol, 182, 400, 403, 405 
lanolin alcohols, 402 
Cholesterolum, 182 
Choline, 409 
Chondrus extract, 124 
CI 77492, 364 
CI 77499, 364 
Ciclosporin, 250, 274 
Cimetidine, 379 
Citation, 474 
Citrate of potash, 603 
Citric acid, 79, 185, 187, 437, 598, 792 
anhydrous, 187, 665 
effervescent tablet formulations, 665 
ethyl ester, 796 
and polydextrose, 543 
sodium bicarbonate neutralization, 667 
Citric acid monohydrate, 185, 294, 676, 771 
Citric acid potassium salt, 603 
Citric acid trisodium salt, 675 
Citric acid trisodium salt anhydrous, 677 
Citroflex 2, 796 
Citroflex 4, 792 
Citroflex A-2, 12 
Citroflex A-4, 10 
Citrofol AI, 796 
Citrosa, 486 
Citrus pectin, 507 
Clindamycin, 379 
Clinoenstatite, 429 
CMC sodium, 120 
Coal tar, 476, 512 
Coateric, 590 
Coating agents 
acetyltributyl citrate, 10 
acetyltriethyl citrate, 12 
calcium carbonate, 89 
carboxymethylcellulose sodium, 120 
carnauba wax, 809 
cellulose acetate, 142 
cellulose acetate phthalate (CAP), 145 
cetyl alcohol, 155 
chitosan, 159 
ethylcellulose, 278 
fructose, 290 
gelatin, 295 
glycerin, 301 
glyceryl behenate, 304 
glyceryl palmitostearate, 311 
hydroxyethyl cellulose, 330 
hydroxyethylmethyl cellulose, 334 
hydroxypropyl cellulose, 336 
hypromellose, 346 
hypromellose phthalate, 354 
isomalt, 366 
latex particles, 147 
liquid glucose, 299 
maltitol, 438 
maltodextrin, 442 
methylcellulose, 462 
microcrystalline wax, 813 
paraffin, 503 
poloxamer, 535 
polydextrose, 542 
polyethylene glycol, 546–547 
polyvinyl acetate phthalate, 589 
polyvinyl alcohol, 592 
potassium chloride, model drug, 600 
povidone, 611 
shellac, 649 
shellac with stearic acid, 737 
sucrose, 299, 744 
surface color agents, 194 
titanium oxide, 782, 784 
tributyl citrate, 792 
triethyl citrate, 796 
vanillin, 798 
white wax, 817 
xylitol, 824 
yellow wax, 819 
zein, 828 
see also Film-forming agents; Lubricants 
(tablet and capsule) 
Cocoa butter, 765 
Coemulsifying agents, poloxamer, 535 
Colamine, 478 
Colemanite, 74 
Colloidal, 418 
Colloidal anhydrous silica, 188 
Colloidal cellulose, 134 
Colloidal silica, 188 
Colloidal silicon dioxide, 139–140, 188 
Collone HV, 807 
Collone NI, 815 
Colonic drug delivery 
chitosan, 159 
guar gum, 315 
Color index number 77891, 782 
Colorants, coloring agents, 193 
Coloring adjuvants, trehalose, 788 
Coloring agents, 192, 784 
classifications, 194 
iron oxides, 364 
lakes, 194 
see also Pigments 
Colza oil, 109 
low erucic acid, 108 
Colzao CT, 108 
Common salt, 671 
Compactrol, 105 
Complex colloidal, 418 
Complexing agents, poly(methylvinyl ether/ 
maleic anhydride), 561 
Compound Thymol Glycerin BP, 780 
Compressible starch, 731 
Compressible sugar, 747–748, 751, 753 
Compressible tablet excipients, lactose 
anhydrous, 385 
spray dried, 396 
Compritol 888 ATO, 304 
Concentrated ammonia solution, 44 
Concentrated glycerin, 301 
Concentrated hydrochloric acid, 328 
Confectionary bases, medicate, isomalt, 366 
Confectioner’s sugar, 747, 749–750, 753 
Confectionery bases, medicate 
polydextrose, 542 
sucrose, 744 
xylitol, 824 
Contact lenses 
benzalkonium chloride, 62 
cetrimide, 152 
chlorhexidine, 163 
chlorobutanol, 169 
edetic acid, 260 
poloxamers, 535 
thimerosal, 777 
Controlled-release agents 
acetyltributyl citrate, 10 
acetyltriethyl citrate, 12 
aliphatic polyesters, 24 
bentonite, 58, 60 
biodegradable polymers, 24 
carbomers, 111 
carrageenan, 124–125 
cellulose acetate, 142 
cellulose acetate phthalate with ethyl 
cellulose, 145 
ceratonia, 148 
cetyl alcohol, 155 
cetyl esters wax, 811 
chitosan, 159 
dibutyl sebacate, 236 
ethylcellulose, 278, 282 
glycerin monostearate, 308 
glyceryl behenate, 304 
glyceryl monooleate, 306 
glyceryl monostearate, 308 
glyceryl palmitostearate, 311 
guar gum, 315 
hydrogenated vegetable oil type I, 800 
hydroxypropyl cellulose, 336 
hypromellose acetate succinate, 350 
isopropyl palmitate, 376 
magnesium aluminum silicate, 418 
magnesium oxide, 427 
methylcellulose, 462 
microcrystalline wax, 813 
paraffin, 503 
peanut oil, 505 
polacrilin potassium, 532 
polycarbophil, 539 
polyethylene oxide, 551 
polymethacrylates, 554 
potassium chloride model drug, 600 
povidone, 615 
sesame oil, 646 
sodium bicarbonate, 665 
sodium chloride, 671 
stearic acid, 737 
stearyl alcohol, 740 
talc, 767 
tributyl citrate, 792 
triethyl citrate, 796 
urethane hydrogels, 546 
white wax, 817 
xanthan gum, 822 
yellow wax, 819–820 
zein, 828 
see also Enteric formulations/coating 
agents; Sustained-release agents 
Cooling agents, thymol, 780 
Copherol F1300, 32 
Copolymer, of 1-vinyl-2-pyrrolidinone and 
vinyl acetate, 201 
Copolyvidone, 201 
Copovidone, 201, 215 
Copovidonum, 201 
Cordycepic acid, 449 
Corn oil, 31, 109, 204, 207, 506, 621, 647, 
723, 761 
refined, 204 
Corn starch, 725, 729, 750 
sterilizable, 732, 734 
Corn sugar, 231 
Corn sugar gum, 821 
Corn syrup, 299 
Corn syrup solids, 444 
Cornmint oil, 460 
Index 895

Cosmetic ingredients, hectorite, 318 
CoTran, 285 
Cotton oil, 206 
Cottonseed oil, 31, 109, 205–206, 506, 621, 
647, 723, 761 
hydrogenated, 131, 800 
refined, 206 
C*Pharm Maltidex, 438 
C*PharmDex, 231 
C*PharmDry, 442 
C*PharmGel, 725 
C*PharmMannidex, 449 
C*PharmSorbidex, 718 
C*PharmSweet, 299 
Cream bases see Ointment bases 
Cremao CS-34, 762 
Cremao CS-36, 762 
Cremophor, 572 
Cremophor A, 564, 578 
Cresol, 173, 208–209 
m-Cresol, 209 
o-Cresol, 209 
ortho-Cresol, 209 
p-Cresol, 209 
para-Cresol, 209 
Cresylic acid, 208–209 
m-Cresylic, 209 
o-Cresylic, 209 
Cresylol, 208 
Creta preparada, 89 
Crodacid, 737 
Crodacol C70, 155 
Crodacol C90, 155 
Crodacol C95, 155 
Crodacol CS90, 150 
Crodacol S95, 740 
Crodamol GTC/C, 454 
Crodamol IPM, 374 
Crodamol IPP, 376 
Crodamol SS, 811 
Croderol, 301 
Crodex A, 807 
Crodex C, 816 
Crodex N, 815 
Crodolene, 494 
Croduret, 130 
Croscarmellose sodium, 119, 211 
Crospovidone, 202, 214, 615 
Crospovidonum, 214 
Crossential 094, 494 
Crosslinked carboxymethylcellulose sodium, 
211 
Crosslinked povidone, 214 
Crotylidene acetic acid, 710 
Crude olive-pomace oil, 499 
Cryogel, 295 
Cryoprotectants 
albumin, 16 
dimethyl sulfoxide, 250 
see also Freeze-drying stabilizers 
Crystal Gum, 228, 230 
Crystalline cellulose, 132 
Crystalline maltose, 447–448 
Crystallization modifiers, raffinose, 635 
Crystallose, 641 
CTAB, 153 
Culminal MC, 462 
Culminal MHEC, 334 
Cumotocopherol, 34 
Cutina CP, 811 
Cutina GMS, 308 
Cutina HR, 130 
Cyclamate, 679 
Cyclamic acid, 679 
Cyclan, 679 
Cyclic methylethylene carbonate, 622 
Cyclic oligosaccharide, 217 
Cyclic propylene carbonate, 622 
Cyclic propylene ester, 622 
Cycloamylose, 217 
alpha-Cycloamylose, 217 
beta-Cycloamylose, 217 
b-Cyclodextrin, 217, 756 
b-Cyclodextrin sulfobutylether, sodium salt, 
754 
Cyclodextrins, 217 
alpha-Cyclodextrin, 217 
Cycloglucan, 217 
Cyclogol 1000, 564 
Cycloheptaamylose, 217 
Cycloheptaglucan, 217 
Cyclohexaamylose, 217 
Cyclohexanesulfamic acid, 679 
Cyclohexanesulfamic acid calcium salt, 679 
N-Cyclohexylsulfamic acid, 679 
Cyclohexylsulfamic acid calcium salt, 679 
Cyclohexylsulfamic acid monosodium salt, 
678 
Cyclomaltoheptose, 217 
Cyclomaltohexose, 217 
Cyclomethicone, 222, 245, 653 
Cyclonette Wax, 807 
Cyclooctaamylose, 217 
Cyclopolydimethylsiloxane, 222 
g-Cycylodextrin, 217 
p-Cymen-3-ol, 780 
3-p-Cymenol, 780 
Cysteine hydrochloride, 77 
Dalpac, 81 
d-Alpha tocopherol, 33 
d-Alpha tocopheryl acetate, 33 
d-Alpha tocopheryl acid succinate, 34 
DBP, 234 
DEA, 238 
Deacetylated chitin, 159 
Deacetylchitin, 159 
De-aerated water, 805 
Decanedioic acid, 236 
di-n-butyl ester, 236 
Decanoic acid, 407 
Decoic acid, 407 
Decyclic acid, 407 
n-Decylic acid, 407 
DEHP, 235 
Dehydrated alcohol, 19–20 
Delayed-release agents see Colonic drug 
delivery; Controlled-release agents; Enteric 
formulations/coating agents 
Delivery systems, sulfobutylether bcyclodextrin, 
754 
Delta tocopherol, 33–34 
see also Tocopherol 
Deltan, 250 
Denatonium benzoate, 224 
Denatured alcohol, 19–20 
Denaturing agents, 20 
methanol, 20 
methyl isobutyl ketone, 20 
Dendritic salt, 673 
1-Deoxy-1-(ethylamino)-D-glucitol, 458 
1-Deoxy-1-(methylamino)-D-glucitol, 457 
(2S)-7-[[6-O-(6-Deoxy-a-L-mannopyranosyl)- 
b-D-glucopyranosyl]oxy]-2,3-dihydro-5- 
hydroxy-2-(3-hydroxy-4-methoxyphenyl)- 
4H-1-benzopyran-4-one, 487 
1-[4-[[2-O-(6-Deoxy-a-L-mannopyranosyl)-b- 
D-glucopyranosyl]oxy]-2,6- 
dihydroxyphenyl]-3-(3-hydroxy-4- 
methoxyphenyl)propan-1-one, 486 
1-[4-[[2-O-6-Deoxy-a-L-mannopyranosyl)-b- 
D-glycopyranosyl]oxy]-2,6- 
dihydroxyphenyl]-3-(3-hydroxy-4- 
methoxyphenyl), 486 
DEP, 240 
Desiccants, calcium sulfate anhydrous, 105 
Destab, 89, 105, 426 
Detergents 
polyethylene alkyl ethers, 565 
sodium lauryl sulfate, 687 
see also Surfactants; Wetting agents 
Dewaxed orange shellac, 649 
Dextrates, 226, 229, 233, 444 
Dextrimaltose, 230 
Dextrin, 228, 233, 300, 444 
alpha-Dextrin, 217 
beta-Dextrin, 217 
see also Cyclodextrins 
Dextrinum, 228 
Dextrinum album, 228 
Dextrofin, 231 
Dextrose, 227, 229, 231, 292, 300, 543 
anhydrous, 233 
invert sugar, 747 
monohydrate, 233 
sweetness vs.fructose, 290 
see also Polydextrose 
Dextrose equivalent (DE) values, definition, 
444 
Dextrose solutions, 233 
Dextrosum anhydricum, 233 
Di(2-ethyl-hexyl)phthalate, 235 
1,6-Di(40-chlorophenyldiguanido)hexane, 163 
1,2-Diacyl-sn-glycero-3-phosphocholine, 409 
Diagnostic aids, inulin, 362 
Diazepam, 421, 423 
Diazolidinyl urea, 360 
Dibasic anhydrous calcium phosphate, 93 
Dibasic calcium phosphate, 93, 96 
dihydrate, 96 
Dibasic dihydrate calcium phosphate, 96 
Dibasic potassium phosphate, 694 
Dibasic sodium phosphate, 693, 697 
dihydrate, 693 
dodecahydrate, 693 
heptahydrate, 693 
hydrate, 693 
monohydrate, 693 
Dibasic zinc stearate, 832 
Dibutyl 1,2-benzenedicarboxylate, 234 
Dibutyl 1,8-octanedicarboxylate, 236 
Dibutyl benzene 1,2-dicarboxylate, 234 
Dibutyl benzene-1,2-dicarboxylate, 234 
Dibutyl decanedioate, 236 
Dibutyl ester, 236 
of 1,2-benzenedicarboxylic acid, 234 
Dibutyl phthalate, 234, 241, 249 
Dibutyl sebacate, 236 
Dibutylated hydroxytoluene, 81 
Dibutylis phthalas, 234 
Dibutyl-o-phthalate, 234 
Di-Cafos, 96, 98 
Di-Cafos AN, 93–94 
Dicalcium orthophosphate, 93, 96 
Dicarbomethoxy zinc, 830 
1,2-Dichloro-1,1,2,2-tetrafluoroethane, 176 
1,6-Dichloro-1,6-dideoxy-b-Dfructofuranosyl-
4-chloro-4-deoxy-a-Dgalactopyranoside, 
742 
896 Index

Dichlorodifluoromethane, 176, 178, 322, 773 
essential use status, 178 
Montreal Protocol, 178 
Dichlorotetrafluoroethane, 176, 322, 773 
Montreal Protocol, 178 
D-2,3-Didehydroerythro-hexono-1,4-lactone, 
264 
2,3-Didehydro-L-threo-hexono-1,4-lactone, 
48 
Dietary supplements 
calcium phosphate, tribasic, 100 
linoleic acid, 414 
Diethanolamine, 238, 479, 795 
Diethyl phthalate, 235, 240, 249, 589 
Diethylene glycol monopalmitostearate, 283– 
284 
Diethylene glycol palmitostearate, 284 
Diethyleneglycoli monopalmitostearas, 284 
Diethylis phthalas, 240 
Diethylolamine, 238 
1,1-Difluoro-1-chloroethane, 174 
Difluorochloromethane, 175 
Difluoroethane, 242, 322, 773 
with chlorodifluoroethane, 174 
Montreal Protocol, 242 
Digoxin, 379 
(
)-3,4-Dihydro-2,8-dimethyl-2-(4,8,12- 
trimethyltridecyl)-2H-1-benzopyran-6-ol, 
34 
1,2-Dihydro-2-ketobenzisosulfonazole, 638 
2,3-Dihydro-3-oxobenzisosulfonazole, 638 
(dihydrogen borato)Phenylmercury, 524 
2-(1,3-Dihydro-3-oxo-5-sulfo-2H-indol-2- 
ylidene)-2,3-dihydro-3-oxo-1H-indole-5- 
sulfonic acid disodium salt, 197 
4,5-Dihydro-5-oxo-1-(4-sulfophenyl)-4-[(4- 
sulfophenyl)azo]-1H-pyrazole-3- 
carboxylic acid trisodium salt, 198 
(
)-3,4-Dihydro-2,5,7,8-tetramethyl-2- 
(4,8,12-trimethyltridecyl)-2H-1- 
benzopyran-6-ol, 32 
(
)-3,4-Dihydro-2,5,7,8-tetramethyl-2- 
(4,8,12-trimethyltridecyl)-2H-1- 
benzopyran-6-ol acetate, 33 
(
)-3,4-Dihydro-2,7,8-trimethyl-2-(4,8,12- 
trimethyltridecyl)-2H-1-benzopyran-6-ol, 
34 
Dihydroxyaluminum monostearate, 42 
L-(.)-2,3-Dihydroxybutanedioic acid, 770 
10b,13-Dihydroxycedr-8-ene-12,15-dioic 
acid, 650 
2,20-Dihydroxydiethylamine, 238 
3,5-Dihydroxy-4-(3-hydroxy-4- 
methoxyhydrocinnamoyl)phenyl-2-O-(6- 
deoxy-a-Lmannopyranosyl)-b-Dglucopyranoside, 
486 
1,2-Dihydroxypropane, 624 
2,3-Dihydroxypropyl docosanoate, 304 
2,3-Dihydroxypropyl octadecanoate, 308 
2,3-Dihydroxysuccinic acid, 770 
Diiron trioxide, 364 
Diisobutylphenoxyethoxyethyl dimethyl 
benzyl ammonium chloride, 64 
Diluents (dry powder inhalers) 
lactose, 389 
mannitol, 449 
Diluents (liquids) 
maltitol, 438 
sunflower oil, 760 
Diluents (medicated powders), starch, 
sterilizable maize, 734–735 
Diluents (tablet/capsule) 
ammonium alginate, 46 
calcium carbonate, 89, 92 
calcium phosphate 
dibasic anhydrous, 93 
dibasic dihydrate, 96 
tribasic, 100 
calcium phosphate, tribasic, 100 
calcium sulfate, 105 
cellulose 
powdered, 136 
silicified microcrystalline, 139 
cellulose acetate, 142 
compressible sugar, 748 
confectioner’s sugar, 750 
dextrates, 226 
dextrin, 228 
dextrose, 231 
erythritol, 266 
ethylcellulose, 278 
fructose, 290 
fumaric acid, 293 
glyceryl palmitostearate, 311 
hydrogenated vegetable oil type I, 800 
isomalt, 366 
kaolin, 378 
lactitol, 383 
lactose, 389 
anhydrous, 385 
spray dried, 396 
lyphilized preparations, mannitol, 449 
magnesium carbonate, 422 
magnesium oxide, 426 
maltodextrin, 442 
maltose, 447 
mannitol, 449 
medium-chain triglycerides, 454 
microcrystalline cellulose, 132 
polydextrose, 542 
polymethacrylates, 554 
simethicone, 652 
sodium alginate, 656 
sodium chloride, 671, 673 
sorbitol, 718 
starch, 725 
pregelatinized, 731 
sterilizable maize, 734–735 
sucrose, 744 
sugar spheres, 752 
sulfobutylether b-cyclodextrin, 754 
talc, 767 
tragacanth, 785 
trehalose, 788 
xylitol, 824 
Dilute acetic acid, 7 
Dilute alcohol, 19–20 
Dilute ammonia solution, 45 
Dilute ethanol, 20 
Dilute hydrochloric acid, 329 
Dilute phosphoric acid, 531 
Dilute sulfuric acid, 759 
Diluted glycerin solutions, 303 
Diluted hydrochloric acid, 329 
Diluted phosphoric acid, 531 
Dimethicone, 223, 244, 653 
Dimethyl 1,2-benzenedicarboxylate, 248 
Dimethyl benzene-o-dicarboxylate, 248 
Dimethyl benzeneorthodicarboxylate, 248 
Dimethyl carbinol, 371 
Dimethyl ether, 246, 326 
Dimethyl ketone, 8 
Dimethyl o-phthalate, 248 
Dimethyl oxide, 246 
Dimethyl phthalate, 234–235, 241, 248 
o-Dimethyl phthalate, 248 
Dimethyl sulfoxide, 250 
Dimethyl sulphoxide, 250 
Dimethylacetamide, 253 
Dimethylacetamidum, 253 
Dimethylacetone amide, 253 
Dimethylamide acetate, 253 
Dimethyl-b-cyclodextrin, 219, 756 
Dimethylcyclopolysiloxane, 222 
1,1-Dimethylethyl-4-methoxyphenol, 79 
Dimethylformaldehyde, 8 
Dimethylis sulfoxidum, 250 
Dimethylmethane, 325 
N-[2-(2,6-Dimethylphenyl)amino]-2- 
oxoethyl]-N,Ndiethylbenzenemethanaminium 
benzoate 
monohydrate, 224 
Dimethylpolysiloxane, 244 
Dimethylsilicone fluid, 244 
Dimethylsiloxane, 244 
N,N-Dimethyl-N-[2-[2-[4-(1,1,3,3- 
tetramethylbutyl)phenoxy]ethoxy]ethyl] 
benzene-methanaminium chloride, 64 
5,8-Dimethyltocol, 34 
Dimeticone, 244 
Dimeticonum, 244 
Dimexide, 250 
Dinatrii edetas, 255 
Dinatrii phosphas anhydricus, 693 
Dinatrii phosphas dihydricus, 693 
Dinatrii phosphas dodecahydricus, 693 
Dinitrogen monoxide, 490 
Dinitrogen oxide, 490 
Dinitrogenii oxidum, 490 
Dioctyl calcium sulfosuccinate, 258 
Dioctyl phthalate, 235 
Dioctyl potassium sulfosuccinate, 258 
Dioctyl sodium sulfosuccinate, 257 
Diolamine, 238 
Di-Pac, 748 
Dipotassium dichloride, 600 
Dipotassium edathamil, 261 
Dipotassium edetate, 261 
Dipotassium ethylenediaminetetraacetate, 261 
Dipotassium hydrogen orthophosphate, 694 
Dipotassium hydrogen phosphate, 694 
Dipotassium phosphate, 694 
Dipotassium pyrosulfite, 607 
Direct compacting sucrose, 748 
Disinfectants 
alcohol, 18 
benzalkonium chloride, 61 
benzethonium chloride, 64 
benzyl alcohol, 69 
cetrimide, 152 
cetylpyridinium chloride, 157 
chlorhexidine, 163 
chlorocresol, 171 
chloroxylenol, 180 
cresol, 208 
isopropyl alcohol, 371 
phenol, 514 
phenoxyethanol, 517 
phosphoric acid, 531 
potassium metabisulfite, 607 
povidone-iodine, 615 
propylene glycol, 624 
sodium borate, 669 
sodium hydroxide, 684 
thymol, 780 
see also Antibacterial agents 
Disintegrants, hydroxypropyl starch, 344 
Disintegrants (tablet/capsule), 532 
alginic acid, 21 
Index 897

Disintegrants (tablet/capsule) (cont.) 
calcium alginate, 86 
carboxymethylcellulose calcium, 118 
carboxymethylcellulose sodium, 120 
cellulose, powdered, 136 
chitosan, 159 
colloidal silicon dioxide, 188 
croscarmellose sodium, 211–212 
crospovidone, 214–215 
docusate sodium, 257 
guar gum, 315 
hydroxypropyl cellulose, 336 
low-substituted, 341 
magnesium aluminum silicate, 418 
methylcellulose, 462 
microcrystalline cellulose, 132 
polacrilin potassium, 532 
povidone, 611 
sodium alginate, 656 
sodium starch glycolate, 701 
starch, 725 
pregelatinized, 731 
Disodium 5,50-indigotin disulfonate, 197 
Disodium disulfite, 690 
Disodium edetate, 61, 255, 260–261 
Disodium EDTA, 255 
Disodium ethylenediaminetetraacetate, 255 
dihydrate, 255 
Disodium hydrogen citrate, 675 
Disodium hydrogen phosphate, 693 
anhydrous, 693 
dodecahydrate, 693 
Disodium phosphate, 693 
Disodium pyrosulfite, 690 
Disodium sulfite, 708 
disodium tetraborate anhydrous, 670 
Disodium tetraborate decahydrate, 669 
Dispersible cellulose, 134 
Dispersing agents 
aluminum oxide, 38 
diethanolamine, 238 
ethylene glycol palmitostearate, 283 
glycerin monostearate, 308 
hypromellose acetate succinate, 350 
lecithin, 409 
poloxamers, 535, 537 
polyethylene alkyl ethers, 565 
poly(methylvinyl ether/maleic 
anhydride), 561 
sorbitan esters, 714 
Dissolution enhancers 
calcium carbonate, 89 
crospovidone, 214–215 
cyclodextrins, 217 
fructose, 290 
macrogol 15 hydroxystearate, 416 
oleyl alcohol, 496 
povidone, 611 
see also Solubilizing agents 
Dissolution-enhancing agents, sulfobutylether 
b-cyclodextrin, 754 
Dissolvine, 260 
Distilled water, 805 
Disulfurous acid 
dipotassium salt, 607 
disodium salt, 690 
DI-TAB, 96, 98 
DMA, 253 
DMAC, 253 
DM-b-CD, 219 
DME, 246 
DMP, 248 
DMSO, 250 
Dobendan, 157 
Docosanoic acid 
diester with glycerin, 304 
2,3-dihydroxypropyl ester, 304 
monoester with glycerin, 304 
triester with glycerin, 304 
Docusate calcium, 258 
Docusate potassium, 258 
Docusate sodium, 257 
Docusatum natricum, 257 
Dodecanoic acid, 406 
Dodecoic acid, 406 
Dodecyl 3,4,5-trihydroxybenzoate, 620 
Dodecyl gallate, 620 
Dodecyl sodium sulfate, 687 
Dodecylis gallas, 620 
Dodecyltrimethylammonium bromide, 153 
Dolomite, 423 
DOP, 235 
Double-dressed, white maize starch, 734 
Dow Corning 245 Fluid, 222 
Dow Corning 246 Fluid, 222 
Dow Corning 345 Fluid, 222 
Dow Corning Q7-2243 LVA, 652 
Dow Corning Q7-2587, 652 
Dow Corning Q7-9120, 244 
Dracylic acid, 66 
Drakeol, 471 
Dried calcium sulfate, 106 
Dried gypsum, 106 
Dried sodium sulfite, 708 
Drierite, 105 
Dry ice, 116 
DSS, 257 
DTAB, 153 
Duodecylic acid, 406 
Dusting powders 
absorbable, 734 
chlorhexidine salts, 163 
starch, 726 
starch-derivative, 734 
talc, 767 
zinc stearate, 832 
Dymel, 176 
Dymel 134a/P, 772 
Dymel 142b, 174 
Dymel 152a, 242 
Dymel 227 EA/P, 321 
Dymel A, 246 
Dypingite, 424 
Dyriel 22, 175 
Ear wax softeners, 30 
Earthnut oil, 505 
Eastacryl 30D, 553–554 
Eastman Vitamin E TPGS, 32 
ECG 505, 118 
Eco-Lac, 381 
Edathamil, 260 
Edathamil calcium disodium, 262 
Edathamil dipotassium, 261 
Edathamil disodium, 255 
Edenor, 737 
Edenor C14 98-100, 484 
Edenor C16 98-100, 501 
Edetate calcium disodium, 260–261 
Edetate dipotassium, 261 
Edetate disodium, 255 
Edetate sodium, 262 
Edetate trisodium, 262 
Edetic acid, 180, 256, 260 
dipotassium salt, 261 
disodium salt, 255 
tetrasodium salt, 262 
and thimerosal, 778 
trisodium salt, 262 
Edetic acid calcium, disodium salt, 262 
EDTA, 260 
EDTA calcium, 262 
EDTA dipotassium, 261 
EDTA tetrasodium, 262 
EDTA trisodium, 262 
Effer-Soda, 665 
Effervescent tablet formulations 
citric acid, anhydrous, 185 
citric acid monohydrate, 185 
dextrates, 226 
fumaric acid, 293 
potassium bicarbonate, 598 
sodium bicarbonate, 665 
sodium citrate dihydrate, 675 
tartaric acid, 770 
Egg lecithin, 409 
Egg yolk lecithin, 409 
Eglumine, 458 
Elaic acid, 494 
Elaol, 234 
Elcema, 136 
Elfan 240, 687 
Elvanol, 592 
Embanox BHT, 81 
Embanox tocopherol, 34 
Emcocel, 132 
Emcompress, 96, 98 
Emcompress Anhydrous, 93–94 
EmCon CO, 128 
Emdex, 226 
Emerescence 1160, 517 
Emerest 2316, 376 
Emersol, 494, 737 
Emersol 140, 501 
Emersol 143, 501 
Emersol 310, 414 
Emersol 315, 414 
Emollients 
almond oil, 30 
aluminum stearate, 42 
castor oil, 128 
ceratonia extract, 149 
cetostearyl alcohol, 150 
cetyl alcohol, 155 
cetyl esters wax, 811 
cholesterol, 182 
cottonseed oil, 206 
cyclomethicone, 222 
dibutyl sebacate, 237 
dimethicone, 244 
ethylene glycol palmitostearate, 283 
glycerin, 301 
glycerin monostearate, 308 
glyceryl monooleate, 306 
glyceryl monostearate, 310 
isopropyl myristate, 374 
isopropyl palmitate, 376 
lanolin, 399 
lecithin, 409 
light mineral oil, 474 
medium-chain triglycerides, 454 
mineral oil, 471 
mineral oil and lanolin alcohols, 476 
octyldodecanol, 492 
oleyl alcohol, 496 
petrolatum, 509 
petrolatum and lanolin alcohols, 512 
soybean oil, 722 
starch, 726 
898 Index

stearyl alcohol, 740 
sunflower oil, 760–761 
xylitol, 824 
zinc acetate, 830 
Empilan KB, 564 
Empilan KM, 564 
Emulgade 1000NI, 815 
Emulgen, 564 
Emulsifying agents 
acacia, 1 
agar, 14 
ammonium alginate, 46 
anionic emulsifying wax, 807 
calcium alginate, 86 
calcium stearate, 102 
carbomers, 111 
carrageenan, 124 
cetostearyl alcohol, 150 
cetyl alcohol, 155 
cholesterol, 182 
diethanolamine, 238 
ethylene glycol palmitostearate, 283 
glycerin monostearate, 308 
glyceryl monooleate, 306 
hectorite, 318 
hydroxypropyl cellulose, 336 
hydroxypropyl starch, 344 
hypromellose, 346 
lanolin, 399 
hydrous, 404 
lanolin alcohols, 402 
lauric acid, 406 
lecithin, 409 
linoleic acid, 414 
medium-chain triglycerides, 454 
methylcellulose, 462 
mineral oil and lanolin alcohols, 476 
monobasic sodium phosphate, 696 
monoethanolamine, 478 
myristic acid, 484 
nonionic emulsifying wax, 815 
octyldodecanol, 492 
oleic acid, 494 
oleyl alcohol, 496 
palmitic acid, 501 
pectin, 507 
poloxamer, 535 
poloxamers, 537 
polycarbophil, 539 
polyoxyethylene alkyl ethers, 565 
polyoxyethylene castor oil derivatives, 
573 
polyoxyethylene sorbitan fatty acid 
esters, 581 
polyoxyethylene stearates, 586 
potassium alginate, 594 
propylene glycol alginate, 627 
saponite, 644 
self-emulsifying glyceryl monostearate, 
310 
sodium borate, 669 
sodium citrate dihydrate, 675 
sodium lactate, 685 
sodium lauryl sulfate, 687 
sorbitan esters, 714 
stearic acid, 737 
sunflower oil, 760 
tragacanth, 785 
triethanolamine, 794 
xanthan gum, 821 
Emulsifying ointment BP, 807–808 
Emulsifying wax, 807, 815 
anionic, 807, 816 
incompatibilities, quaternary 
ammonium compounds, 807 
with white soft paraffin, 807 
cationic, 816 
cetrimide emulsifying wax, 816 
incompatibilities, anionic surfactants/ 
drugs, 816 
nomenclature, 808, 816 
nonionic, 566, 808, 815 
cetomacrogol emulsifying wax, 815 
phenol, 815 
quaternary ammonium compounds, 
815 
surfactants, 808, 816 
Emulsifying wax BP, 808, 816 
Emulsifying wax USP, 808, 816 
Emulsion stabilizers 
colloidal silicon dioxide, 188 
polyethylene glycol, 545 
poly(methylvinyl ether/maleic 
anhydride), 561 
zinc acetate, 830 
Encapsin, 217 
Enstatite, 429 
Enteric formulations/coating agents 
acetyltributyl citrate, 10 
carbomers, 111 
cellulose acetate phthalate, 145 
colonic drug delivery, 315 
guar gum, 315 
hypromellose acetate succinate, 350 
hypromellose phthalate, 354 
polymethacrylates, 554 
polyvinyl acetate phthalate, 589 
potassium chloride as model drug, 600 
shellac, 649, 651 
Sureteric, 589 
tributyl citrate, 792 
triethyl citrate, 796 
white wax, 817 
zein, 828 
see also Controlled-release agents 
Entonox, 491 
Equal, 53 
Ergoplast FDB, 234 
Erucic acid 
canola oil, 108 
colza oil, 108 
rapeseed oil, 108–109 
Erycorbin, 264 
Erythorbic acid, 50, 264 
sodium salt, 265 
d-Erythorbic acid, 264 
Erythrite, 266 
Erythritol, 266 
Erythritolum, 266 
Erythroglucin, 266 
D-erythro-Hex-2-enoic acid, sodium salt, 265 
D-erythro-3-Ketohexonic acid lactone, 264 
DL-erythro-9,10,16,-Trihydroxyhexadecanoic 
acid, 650 
Erythromycin stearate, 428 
Essential oils, 260, 468 
solubilizing agents 
polyethylene alkyl ethers, 565 
polyoxyethylene castor oil derivatives, 
573 
polyoxyethylene sorbitan fatty acid 
esters, 581 
Esterifying agents, propionic acid, 617 
Esterifying agents, propionic acid, 617 
Estol IPM, 374 
Ethal, 155 
Ethanecarboxylic acid, 617 
N,N0-1,2-Ethanediylbis[N- 
(carboxymethyl)glycine, dipotassium salt, 
261 
N,N-1,2-Ethanediylbis[N- 
(carboxymethyl)glycine], 260 
tetrasodium salt, 262 
trisodium salt, 262 
Ethanoic acid, 6 
Ethanol, 18–20 
anhydrous, 19 
dilute, 20 
Ethanol (96%), 18 
Ethanolamine, 478 
Ethanolic acid, 6 
Ethanolum (96 per centum), 18 
1,2-Ethenedicarboxylic acid, 293 
Ethenol, homopolymer, 592 
1-Ethenyl-2-pyrrolidinone homopolymer, 
214, 611 
Ethiops iron, 364 
Ethispheres, 132 
Ethocel, 278 
Ethol, 155 
3-Ethoxy-4-hydroxybenzaldehyde, 276 
Ethoxylated fatty acid esters, 585 
Ethyl acetate, 268 
Ethyl alcohol, 18 
Ethyl benzene-1,2-dicarboxylate, 240 
Ethyl cellulose, with cellulose acetate 
phthalate, 145 
Ethyl ethanoate, 268 
Ethyl gallate, 620 
Ethyl hydroxide, 18 
Ethyl hydroxybenzoate, 287 
Ethyl 4-hydroxybenzoate potassium salt, 289 
Ethyl 4-hydroxybenzoate sodium salt, 289 
Ethyl a-hydroxypropionate, 270 
Ethyl lactate, 270 
Ethyl linoleate, 414 
Ethyl maltol, 272, 446 
Ethyl (2-mercaptobenzoato-S)-mercury, 
sodium salt, 777 
Ethyl 9-octadecenoate, 274 
Ethyl oleate, 274, 495 
Ethyl parahydroxybenzoate, 287 
Ethyl parasept, 287 
Ethyl phthalate, 240 
2-Ethyl pyromeconic acid, 272 
Ethyl (sodium o-mercaptobenzoato)mercury, 
777 
Ethyl 3,4,5-trihydroxybenzoate, 620 
Ethyl vanillin, 276, 799 
2-Ethyl-3-hydroxy-4H-pyran-4-one, 272 
Ethylan C, 564 
Ethylcellulose, 278, 335, 352, 464 
Ethylcellulose, compatible plasticizers, 281 
Ethylcellulosum, 278 
Ethylene fluoride, 242 
Ethylene glycol monopalmitate, 283–284 
Ethylene glycol monopalmitostearate, 283 
Ethylene glycol monostearate, 283–284 
Ethylene glycol palmitostearate, 283 
Ethylene glycol stearate, 284 
Ethylene glycoli monostearas, 284 
Ethylene vinyl acetate, 285 
Ethylene vinyl acetate copolymer, 285 
Ethylenebis(iminodiacetic acid) 
dipotassium salt, 261 
tetrasodium salt, 262 
Ethylenediaminetetraacetic acid, 260 
calcium disodium chelate, 262 
dipotassium salt, 261
Index 899

Ethylenediaminetetraacetic acid (cont.) 
disodium salt, 255 
tetrasodium salt, 262 
trisodium salt, 262 
trans-1,2-Ethylenedicarboxylic acid, 293 
[(Ethylenedinitrilo)tetraacetato]calciate(2-) 
disodium, 262 
(ethylenedinitrilo)Tetraacetic acid, 260 
dipotassium salt, 261 
tetrasodium salt, 262 
trisodium salt, 262 
Ethyleneglycol monophenyl ether, 517 
Ethylene/vinyl acetate copolymer, 285 
Ethylenglycoli monopalmitostearas, 283 
Ethyleni glycoli stearas, 284 
Ethylformic acid, 617 
sodium salt, hydrate, 699 
N-Ethylglucamine, 458 
Ethylhydroxy cellulose, 330 
Ethyl-2-hydroxypropanoate, 270 
Ethyl-2-hydroxypropionate, 270 
Ethyl-S-(–)-2-hydroxypropionate, 270 
Ethylic acid, 6 
Ethylis acetas, 268 
Ethylis oleas, 274 
Ethylis parahydroxybenzoas, 287 
Ethyl[2-mercaptobenzoato(2-)-O,S]- 
mercurate(1-) sodium, 777 
Ethylolamine, 478 
Ethylose, 330 
Ethylparaben, 85, 287, 468, 631 
see also Parabens 
Ethylparaben potassium, 289 
Ethylparaben sodium, 289 
Ethylprotal, 276 
Ethylprotocatechuic aldehyde, 276 
Etocas, 572 
Eudragit, 553 
Eudragit E, 554 
Eudragit FS, 554 
Eudragit L, 554 
Eudragit L 30 D-55, 554 
Eudragit L 30D, 589 
Eudragit L 100-55, 554 
Eudragit NE 30, 554 
Eudragit NE 30D, 554 
Eudragit NE 400, 554 
Eudragit RD 100, 554 
Eudragit RL, 554 
Eudragit RS, 427, 554 
Eudragit S, 554 
Eumulgin, 572 
Eutanol G PH, 492 
EVA, 285 
EVA copolymer, 285 
EVM, 285 
Explocel, 211 
Explosol, 701 
Explotab, 701 
Expressed almond oil, 30 
Exsiccated calcium sulfate, 106 
Exsiccated sodium sulfite, 708 
Extended-release agents see Sustained-release 
agents 
Extra virgin olive oil, 499 
Extract of carob, 149 
Extractants, propylene glycol, 624 
Famotidine, 783 
Fancol, 130 
Fatty acid esters, ethoxylated, 585 
FD&C blue #2, 197 
FD&C yellow #5, 198 
FD&C yellow #6, 198 
Fermine, 248 
Ferric ferrous oxide, 364 
Ferric hydrate, 364 
Ferric hydroxide, 364 
Ferric hydroxide oxide, 364 
Ferric oxide hydrated, 364 
Ferroan saponite, 644 
Ferrosoferric oxide, 364 
Fibrocel, 132 
Fillers see Diluents (tablet/capsule) 
Film-forming agents 
ammonium alginate, 46 
chitosan, 159 
chlorpheniramine maleate, 339 
copovidone, 201 
dibutyl phthalate, 234 
dibutyl sebacate, 236 
diethyl phthalate, 240 
dimethyl phthalate, 248 
ethyl lactate, 270 
ethylcellulose, 278 
gelatin, 295 
hydroxyethyl cellulose, 330 
hydroxypropyl cellulose, 336, 339 
hypromellose, 346 
hypromellose acetate succinate, 350 
maltodextrin, 442 
opacifiers, calcium carbonate, 89 
polydextrose, 542 
polyethylene glycol, 546–547 
polyethylene oxide, 551 
polymethacrylates, 554 
poly(methylvinyl ether/maleic 
anhydride), 561 
polyvinyl acetate phthalate, 589 
triethyl citrate, 796 
vanillin, 798 
see also Coating agents 
Fine virgin olive oil, 499 
Finetose, 447 
Finetose F, 447 
Finlac DC, 383–384 
Finmalt L, 440 
Finnfix, 120 
Fixatives, perfume, diethyl phthalate, 240 
Flavinol, 780 
Flavor enhancers 
acesulfame potassium, 4 
aspartame, 53 
citric acid monohydrate, 185 
dibutyl sebacate, 236 
ethyl maltol, 272 
ethylcellulose, 278 
fructose, 290 
maltol, 445 
monosodium glutamate, 480 
neohesperidin dihydrochalcone, 486 
saccharin, 638 
saccharin sodium, 641 
sodium cyclamate, 678 
tartaric acid, 770 
thaumatin, 775 
trehalose, 788 
xylitol, 824 
Flavoring agents 
confectioner’s sugar, 750 
denatonium benzoate, 224 
dibutyl sebacate, 236 
ethyl acetate, 268 
ethyl lactate, 270 
ethyl maltol, 272 
ethyl vanillin, 276 
fumaric acid, 293 
leucine, 412 
malic acid, 436 
maltol, 445 
menthol, 459 
phosphoric acid, 530 
propionic acid, 618 
propylene glycol alginate, 627 
sodium acetate, 654 
sodium lactate, 685 
sodium propionate, 699 
thymol, 780 
triethyl citrate, 796 
vanillin, 798 
Flavoring fixatives, ethylcellulose, 278 
Flolys, 299 
FlowLac 100, 396 
Fluftex W, 725 
Fluidamid R444P, 734 
Fluorocarbon 134a, 772 
Fluorocarbon emulsifying agents, poloxamer, 
535 
Foaming agents, polyethylene alkyl ethers, 
565 
Folic acid, 428 
Forlan 500, 512 
Formaldehyde, 423 
Forsterite, 429 
Freeze-drying stabilizers/carriers 
albumin, 16 
lactose, anhydrous, 385 
mannitol, 449 
sodium bicarbonate, 665 
trehalose, 788 
see also Cryoprotectants 
French chalk, purified, 767 
Freon, 176 
Frigen, 176 
Frigen 22, 175 
Frigen 134a, 772 
Fructamyl, 290 
b-D-Fructofuranosyl-O-a-D-galactopyranosyl- 
(1!6)-a-D-glucopyranoside 
anhydrous, 635 
pentahydrate, 635 
b-D-Fructofuranosyl-a-D-glucopyranoside, 
744 
D-(-)-Fructopyranose, 290 
Fructose, 233, 290 
furanose form, 292 
high-fructose syrup, 292 
invert sugar, 747 
liquid, 292 
with povidone, 290 
powdered, 292 
pyranose form, 292 
with silicon dioxide, 292 
sweetness vs.dextrose, 290 
sweetness vs.sucrose, 290, 292 
b-D-Fructose, 290 
Fructosum, 290 
Fruit sugar, 290 
Frutafit, 362 
Fujicalin, 93–94 
Fumaric acid, 187, 293, 437, 705, 771 
Fumed silica, 188 
Fuming sulfuric acid, 759 
Fungicides see Antifungal agents 
Fused borax, 670 
Fused sodium borate, 670 
Galactomannan, 148 
Galactomannan polysaccharide, 315 
900 Index

Galactomannans, guar gum, 315 
Galactomannoglycone, ceratonia, 149 
O-b-D-Galactopyranosyl-(1!4)-b-Dglucopyranose, 
385 
O-b-D-Galactopyranosyl-(1!4)-a-Dglucopyranose 
monohydrate, 389, 396 
4-O-(b-D-Galactopyranosyl)-D-glucitol, 383 
dihydrate, 383 
monohydrate, 383 
b-Galactosido-sorbitol, 383 
Galactosol, 315 
Galen IQ, 366 
Gallic acid propyl ester, 619 
Gallotox, 521 
Gamma cyclodextrin, 217 
Gamma tocopherol, 33–34 
Gantrez AN-119, 561 
Gantrez AN-139, 561 
Gantrez AN-149, 561 
Gantrez AN-169, 561 
Gantrez AN-179, 561 
Gantrez AN-903, 561 
Gantrez ES-225, 561 
Gantrez ES-425, 561 
Gantrez MS-955, 561 
Gantrez S-95, 561 
Gantrez S-96, 561 
Gantrez S-97, 561 
Garantose, 638 
Gas-forming agents 
potassium bicarbonate, 598 
sodium bicarbonate, 665 
Gelatin, 34, 295, 452 
absorbable, 295 
hard capsules, 295, 800 
plasticizers 
glycerin, 295, 301 
mannitol, 449 
sorbitol, 295, 718 
soft capsules, 295 
Gelatin sponge, 295 
Gelatina, 295 
Gelatine, 295 
Gelcarin, 124 
Gelling agents 
aluminum stearate, 42 
calcium silicate, 435 
carbomers, 114 
carboxymethylcellulose sodium, 120 
carrageenan, 124 
chitosan, 159 
colloidal silicon dioxide, 188 
gelatin, 295 
glyceryl monooleate, 306 
glyceryl palmitostearate, 311 
guar gum, 316 
hydroxyethyl cellulose, 333 
microcrystalline cellulose and 
carboxymethylcellulose sodium, 134 
pectin, 507 
polyethylene alkyl ethers, 565 
polyethylene glycol, 546 
polyethylene oxide, 551 
polymethacrylates, 554 
propylene carbonate, 622 
sodium ascorbate, 659 
sorbitol, 719 
zinc acetate, 830 
see also Hydrogels; Stiffening agents; 
Thickening agents; Viscosity-increasing 
agents 
Gelosa, 14 
Gelose, 14 
Gelsorb, 418 
Gelvatol, 592 
Genetron, 176 
Genetron 134a, 772 
Genetron 142b, 174 
Genetron 152a, 242 
Genoplast B, 234 
Genu, 124 
Germall 115, 359 
Germall II, 360 
Ghassoulite, 318 
Gingelly oil, 646 
Gingili oil, 646 
Ginseng, Korean red, 446 
Glacial acetic acid, 6 
Glaze, pharmaceutical, 650 
Glidants 
calcium phosphate, tribasic, 100 
calcium silicate, 435 
cellulose, powdered, 136 
colloidal silicon dioxide, 188 
magnesium silicate, 428 
magnesium trisilicate, 434 
silicon dioxide, 292 
starch, 725 
talc, 767 
Glipizide, 458 
Glucens, substituted, 161 
Glucidex, 442 
D-Glucitol, 718 
Glucodry, 442 
Glucomalt, 299 
D-(.)-Glucopyranose, anhydrous, 233 
D-(.)-Glucopyranose monohydrate, 231 
a-D-glucopyranosyl-b-D-Fructofuranoside, 
744 
4-O-a-D-Glucopyranosyl-D-glucitol, 438 
4-O-a-D-Glucopyranosyl-b-D-glucopyranose 
anhydrous, 447 
4-O-a-D-Glucopyranosyl-b-D-glucopyranose 
monohydrate, 447 
a-D-Glucopyranosyl-a-D-glucopyranoside 
anhydrous, 788 
a-D-Glucopyranosyl-a-D-glucopyranoside 
dihydrate, 788 
4-O-a-D-Glucopyranosyl-b-D-glucose, 447 
1-O-a-D-glucopyranosyl-D-mannitol 
dihydrate (1,1-GPM), 366 
6-O-a-D-glucopyranosyl-D-sorbitol (1,6-GPS), 
366 
Glucosaccharonic acid, 264 
Glucose, 231 
anhydrous, 233 
liquid, 229, 233, 299, 448 
D-Glucose, and polydextrose, 543 
Glucose monohydrate, 231 
D-(.)-Glucose monohydrate, 231 
Glucose syrup, 299 
hydrogenated, 440 
4-(a-D-Glucosido)-D-glucose, 447 
(a-D-Glucosido)-a-D-glucoside, 788 
Glucosum liquidum, 299 
Glucosum monohydricum, 231 
Glucosweet, 299 
Gluside, 638 
soluble, 641 
Glutamic acid monosodium salt, 480 
Glutamic acid monosodium salt 
monohydrate, 480 
Glutamic acid, sodium salt, 480 
Glycerides 
almond oil, 30 
hydrogenated vegetable, 762 
Glycerin, 301, 624, 765 
concentrated, 301 
Glycerin monostearate, 308 
Glycerin palmitostearate, 311 
Glycerin solutions, diluted, 303 
Glycerine, 301 
Glycerine monostearate, 308 
Glycerol, 301 
Glycerol (85 per cent), 303 
Glycerol behenate, 304 
Glycerol dibehenate, 304 
Glycerol mono-oleates, 306 
Glycerol monostearate, 308 
Glycerol palmitostearate, 311 
Glycerol stearate, 308 
Glycerol triacetate, 790 
Glyceroli dibehenas, 304 
Glyceroli mono-oleates, 306 
Glyceroli monostearas 40-55, 308 
Glycerol-1-oleate, 306 
Glycerolum, 301 
Glycerolum tricacetas, 790 
Glyceryl behenate, 304, 312 
Glyceryl dibehenate, 304 
Glyceryl monobehenate, 304 
Glyceryl monooleate, 306, 310 
Glyceryl monostearate, 283, 307–308, 312 
self-emulsifying, 310 
Glyceryl monostearate 40-55, 308 
Glyceryl palmitostearate, 283, 305, 310–311 
Glyceryl stearate, 308 
Glyceryl triacetate, 790 
Glyceryl tribehenate, 304 
Glyceryl tricaprylate/caprate, 454 
Glyceryl-tri-(12-hydroxystearate), 130 
Glycofurol, 313 
Glycofurol 75, 313–314 
Glycolys, 701 
Glycon, 494 
Glycon G-100, 301 
Glypesin, 323 
GMS, 308 
Goat’s thorn, 785 
Gohsenol, 592 
Gomenoleo oil, 498 
Gomme de caroube, 148 
Gossypol, 206 
Gossypose, 635 
Grain alcohol, 18 
Granulating agents 
copovidone, 201 
glucose, liquid, 299 
isomalt, 366 
maltitol, 438 
polydextrose, 542 
sucrose, 744 
Grape sugar, 231 
Griffithite, 644 
Groco, 494 
Groundnut oil, 505 
Guar acetate, 316 
Guar acetate phthalate, 316 
Guar flour, 315 
Guar galactomannan, 315 
Guar galactomannanum, 315 
Guar gum, 2, 315–316, 822 
and microcrystalline cellulose, 134 
oxidized, 316 
Guar phthalate, 316 
3-oxo-L-Gulofuranolactone 6-palmitate, 51 
3-oxo-L-Gulofuranolactone, enol form, 48 
3-oxo-L-Gulofuranolactone sodium enolate, 
659 
Index 901

L-Gulo-D-mannoglycuronan, 21 
Gum acacia, 1 
Gum arabic, 1 
Gum benjamin, 785 
Gum dragon, 785 
Gum tragacanth, 785 
Gummi africanum, 1 
Gummi arabicum, 1 
Gummi mimosae, 1 
Gypsum, 105 
calcined, 106 
dried, 106 
Halite, 673 
Halocarbon 152a, 242 
Halofantrine, 424 
Halon, 176 
Haloperidol, 798 
Hard fat, 762 
Hard fat suppository bases, 456, 762 
additives, 762 
chemical reactivity, 762 
melting characteristics, 762 
rheology, 762 
Hard fat triglyceride esters, 762 
Hard paraffin, 503 
Hard water, 805 
Hard wax, 503 
alternatives, 800 
Hardening agents (suppositories) 
hydrogenated vegetable oil, 800 
stearic acid, 737 
Hartolan, 402 
Hatcol DBP, 234 
HCFCs 
HCFC 22, 175 
HCFC 142b, 174 
see also Hydrochlorofluorocarbons 
(HCFCs) 
HD-Eutanol V PH, 496 
HE cellulose, 330 
Heavy kaolin, 378 
Heavy liquid petrolatum, 471 
Heavy magnesium carbonate, 422 
Heavy magnesium oxide, 426 
Heavy mineral oil, 471 
HEC, 330 
2-HE-b-CD, 219 
Hectabrite AW, 318 
Hectabrite DP, 318 
Hector clay, 318 
Hectorite, 318, 645 
Helianthi annui oleum raffinatum, 760 
HEMC, 334 
Heptafluoropropane, 321, 773 
Hermesetas, 638 
Hesperetin-7-rutinoside, 487 
Hesperidin, 487 
Hesperitin 7-rhamnoglucoside, 487 
(E,E)-Hexa-2,4-dienoic acid, 710 
Hexadecan-1-ol, 155 
Hexadecanoic acid, 501 
Hexadecanoic acid 1-methylethyl ester, 376 
Hexadecanoic acid isopropyl ester, 376 
1-Hexadecanol, 155 
n-Hexadecoic acid, 501 
n-Hexadecyl alcohol, 155 
Hexadecylic acid, 501 
Hexadecylpyridinium chloride, 157 
1-Hexadecylpyridinium chloride 
monohydrate, 157 
Hexadecyltrimethylammonium bromide, 
152–153 
Hexadecyltrimethylammonium hydroxide, 
152 
Hexadexylpyridinium bromide, 158 
Hexadienic acid, 710 
Hexadienoic acid, 710 
(E,E)-Hexa-2,4-dienoic acid, 710 
2,4-Hexadienoic acid (E,E)-potassium salt, 
609 
2,4-Hexadienoic acid potassium salt, 609 
2,3,4,7,8,8a-Hexahydro-4-hydroxy-8- 
(hydroxymethyl)-8-methyl-1H-3a,7- 
methanoazulene-3,6-dicarboxylic acid, 
650 
Hexahydrothymol, 459 
1,10-Hexamethylenebis[5-(4- 
chlorophenyl)biguanide] diacetate, 166 
1,10-Hexamethylenebis[5-(4- 
chlorophenyl)biguanide] digluconate, 166 
1,10-Hexamethylenebis[5-(4- 
chlorophenyl)biguanide]dihydrochloride, 
166 
Hexamic acid, 679 
1,2,3,4,5,6-Hexanehexol, 718 
Hexaplast M/B, 234 
D-erythro-Hex-2-enoic acid, 264 
Hexetidine, 323 
Hexetidinum, 323 
Hexigel, 323 
Hexocil, 323 
Hexoral, 323 
Hextril, 323 
HFA 134a, 772 
HFA227, 321 
HFCs
HFC 134a, 772 
HFC 152a, 242 
HFC227, 321 
see also Hydrofluorocarbons (HFCs) 
Hibiclens, 166 
Hibiscrub, 166 
Hibitane, 166 
Hibitane diacetate, 166 
High-fructose syrup, 292 
Hog gum (caramania gum), 786 
Hopper salt, 671 
HP-50, 357 
HP-55, 357 
HP-55S, 357 
2-HP-b-CD, 219 
HPMC, 346 
HPMCAS, 350 
HPMCP, 354 
HSA, 16 
Huile d’amande, 30 
Huile de tournesol, 760 
Human albumin solution, 16 
Human serum albumin, 16 
Humectants 
ammonium alginate, 46 
cyclomethicone, 222 
glycerin, 301 
polydextrose, 542 
propylene glycol, 624 
sodium hyaluronate, 681 
sodium lactate, 685 
sorbitol, 718 
trehalose, 788 
triacetin, 790 
triethanolamine, 794 
xylitol, 824 
Hyaluronan, 681 
Hyaluronate sodium, 681 
Hyaluronic acid, 682 
Hyamine 1622, 64 
Hyamine 3500, 61 
Hydagen CAT, 796 
Hydrated ferric oxide, 364 
Hydrazine yellow, 198 
Hydrocarbons (HC), 247, 325 
Hydrochloric acid, 328 
concentrated, 328 
dilute, 329 
Hydrochlorofluorocarbons (HCFCs) 
chlorodifluoroethane, 174 
nomenclature, 178 
Hydrocortisone, 56 
Hydrofluoroalkanes (HFAs), 
tetrafluoroethane, 772 
Hydrofluorocarbons (HFCs) 
difluoroethane, 242 
heptafluoropropane, 321 
tetrafluoroethane, 772 
Hydrofol, 501 
Hydrofol acid 1255, 406 
Hydrofol acid 1295, 406 
Hydrogels 
hydroxyethyl cellulose, 333 
sodium alginate, 656 
urethane, 546 
Hydrogen oxide, 802 
Hydrogen phosphate, 530 
Hydrogen sulfate, 758 
Hydrogenated castor oil, 130, 801 
Hydrogenated cottonseed oil, 800 
Hydrogenated isomaltulose, 366 
Hydrogenated lanolin, 400 
Hydrogenated maltose, 438 
Hydrogenated oil, 800 
Hydrogenated palatinose, 366 
Hydrogenated palm oil, 800 
Hydrogenated polyoxyl castor oil, 572 
Hydrogenated soybean oil, 800 
Hydrogenated vegetable glycerides, 762 
Hydrogenated vegetable oil, 800 
type I, 207 
type II, 801 
applications, 801 
Hydrogenated vegetable oil, type I, 131, 800 
Hydrogenated wool fat, 400 
a-Hydro-o-hydroxypoly(oxy-1,2-ethanediyl), 
545 
a-Hydro-o-hydroxypoly(oxyethylene)poly 
(oxypropylene) poly(oxyethylene) block 
copolymer, 535 
Hydromagnesite, 422 
2-Hydroperfluoropropane, 321 
Hydrous lanolin, 404 
Hydrous magnesium calcium silicate, 767 
Hydrous magnesium silicate, 767 
Hydrous wool fat, 404 
Hydroxyaluminum distearate, 42 
4-Hydroxy-m-anisaldehyde, 798 
Hydroxybenzene, 514 
4-Hydroxybenzoic acid butyl ester, 83 
4-Hydroxybenzoic acid ethyl ester, 287 
4-Hydroxybenzoic acid methyl ester, 466 
4-Hydroxybenzoic acid propyl ester, 629 
2-Hydroxy-1,4-butanedioic acid, 436 
3-Hydroxy-p-cymene, 780 
1-Hydroxy-1,2-ethanedicarboxylic acid, 436 
4-Hydroxy-3-ethoxybenzaldehyde, 276 
b-Hydroxyethyl benzene, 519 
Hydroxyethyl cellulose, 281, 330, 335, 339, 
348, 352, 464 
2-Hydroxyethyl cellulose ether, 330 
2-Hydroxyethyl-b-cyclodextrin, 219 
902 Index

2-Hydroxyethyl ester stearic acid, 284 
Hydroxyethyl ether cellulose, 330 
Hydroxyethyl methylcellulose, 334 
b-Hydroxyethyl phenyl ether, 517 
Hydroxyethyl starch, 330 
b-Hydroxyethylamine, 478 
Hydroxyethylcellulose, 330 
Hydroxyethylcellulosum, 330 
2-Hydroxyethyl-b-cyclodextrin, 219, 756 
Hydroxyethylmethyl cellulose, 281, 333–334, 
348, 464 
Hydroxyethylmethylcellulose, 334 
3-Hydroxy-2-ethyl-4-pyrone, 272 
Hydroxylapatite, 100–101 
Hydroxylpropyl starch, 344 
p-Hydroxy-m-methoxybenzaldehyde, 798 
3-Hydroxy-2-methyl-4H-pyran-4-one, 445 
3-Hydroxy-1-methyl-4-isopropylbenzene, 780 
N-(Hydroxymethyl)-N-(1,3-dihydroxymethyl- 
2,5-dioxo-4-imidazolidinyl)-N0- 
(hydroxymethyl)urea, 360 
3-Hydroxy-2-methyl-(1,4-pyran), 445 
3-Hydroxy-2-methyl-4-pyrone, 445 
12-Hydroxyoctadecanoic acid polymer, with 
a-hydro-o-hydroxypoly(oxy-1,2- 
ethanediyl), 416 
1-Hydroxy-2-phenoxyethane, 517 
2-Hydroxypropane 1,2,3-tricarboxylic acid, 
187 
2-Hydroxypropane-1,2,3-tricarboxylic acid, 
monohydrate, 185 
2-Hydroxypropane-1,2,3-tricarboxylic acid 
monohydrate, 185 
2-Hydroxy-b-1,2,3-propanetricarboxylic acid, 
187 
monohydrate, 185 
triethyl ester, 796 
2-Hydroxy-1,2,3-propanetricarboxylic acid 
tripotassium salt 
anhydrous, 603 
monohydrate, 603 
2-Hydroxypropanoic acid, 381 
ethyl ester, 270 
2-Hydroxypropanoic acid monosodium salt, 
685 
2-Hydroxypropanol, 624 
a-Hydroxypropionic acid, 381 
(RS)-(
)-2-Hydroxypropionic acid, 381 
(S)-(.)-2-Hydroxypropionic acid, 381 
Hydroxypropyl alginate, 627 
Hydroxypropyl cellulose, 333, 336, 342, 348, 
352 
low-substituted, 339, 341 
2-Hydroxypropyl-b-cyclodextrin, 219, 756 
3-Hydroxypropyl-b-cyclodextrin, 219 
Hydroxypropyl methylcellulose, 346 
Hydroxypropyl methylcellulose benzene-1,2- 
dicarboxylate, 354 
2-Hydroxypropyl methylcellulose phthalate, 
354 
Hydroxypropyl starch, 344 
Hydroxypropylcellulose, 336 
Hydroxypropylcellulosum, 336 
Hydroxypropylmethylcellulose, 346 
Hydroxypropylmethylcellulose phthalate, 354 
Hydroxysuccinic acid, 436 
6-Hydroxy-5-[(4-sulfophenyl)azo]-2- 
naphthalenesulfonic acid disodium salt, 
198 
a-Hydroxytoluene, 69, 208–209 
butylated, 399, 402, 404 
Hyetellose, 330 
Hyfatol 16-95, 155 
Hyfatol 16-98, 155 
Hyfatol 18-95, 740 
Hyfatol 18-98, 740 
Hygum TP-1, 124 
Hymetellose, 334 
Hy-Phi, 494 
Hyprolose, 336 
low-substituted, 341 
Hypromellose, 333, 335, 339, 346, 352, 357, 
464 
Hypromellose acetate succinate, 350 
Hypromellose phthalate, 146, 348, 352, 354, 
590 
film coat splitting, 354, 357 
plasticizers, 354 
Hypromellosi phthalas, 354 
Hypromellosum, 346 
HyQual, 102, 832 
Hystrene, 737 
Hystrene 9016, 501 
Hystrene 9512, 406 
Ibuprofen, 156 
Ichthammol, 476, 512 
Icing sugar, 750 
Idoxuridine, 250 
Imidazolidinyl urea, 359 
Imidurea, 359 
and methylparabens, 466 
synergists, 260 
2,20-Iminobisethanol, 238 
2,20-Iminodiethanol, 238 
Implantable drug delivery systems 
aliphatic polyesters, 24 
gelatin, 295 
glyceryl monostearate, 308 
Improved Kelmar, 594 
Impruvol, 81 
Imwitor 191, 308 
Imwitor 900, 308 
Indigo blue, soluble, 197 
Indigo carmine, 196–197 
Indigotine, 197 
Industrene, 494, 737 
Industrene 4516, 501 
Industrial methylated spirit, 20 
Inhalers, dry powder diluents/carrier 
mannitol, 449 
see also Metered-dose inhalant 
formulations 
Insect repellents 
dibutyl phthalate, 234 
dimethyl phthalate, 248 
Instagel, 295 
Instant Pure-Cote, 725 
Instastarch, 731 
Intense sweeteners see Sweetening agents 
Intrasol, 780 
Inulin, 362 
Invert sugar, 747 
Iodine, 261 
Ionol CP, 81 
IPA, 371 
Irish moss extract, 124 
Iron hydrate, 364 
Iron hydroxide, 364 
Iron hydroxide oxide, 364 
Iron (II, III) oxide, 364 
Iron (II) oxide, black, 364 
Iron (III) oxide, 364 
Iron (III) oxide hydrated, 364 
Iron (III) oxide monohydrate, yellow, 364 
Iron oxide, 364, 760 
Iron oxide black, 364 
Iron oxide red, 364 
Iron oxide yellow monohydrate, 364 
Iron oxides, 193, 196, 364 
Iron oxides (Fe3O4), 364 
Isceon, 176 
Isceon 22, 175 
Isceon 134a, 772 
Isinglas 
Bengal, 14 
Ceylon, 14 
Chinese, 14 
Japan, 14 
Isoarachidyl alcohol, 492 
DIsoascorbic acid, 264 
Isobutane, 325 
Isoeicosyl alcohol, 492 
Isomalt, 366 
Isomalt, with polydextrose, 542 
Isomaltidex 16500, 366 
Isomaltulose, hydrogenated, 366 
Isomaltum, 366 
Isopropanol, 371 
Isopropyl alcohol, 19, 371 
Isopropyl cresol, 780 
Isopropyl-m-cresol, 780 
Isopropyl ester, of myristic acid, 374 
Isopropyl hexadecanoate, 376 
Isopropyl lanolate, 400 
Isopropyl metacresol, 780 
4-Isopropyl-1-methylcyclohexan-3-ol, 459 
2-Isopropyl-5-methylcyclohexanol, 459 
2-Isopropyl-5-methylphenol, 780 
Isopropyl myristate, 374, 377 
Isopropyl palmitate, 375–376 
Isopropylis myristas, 374 
Isopropylis palmitas, 376 
Isotrehalose, 789 
Isotron, 176 
Isovitamin C, 264 
Jaguar gum, 315 
Japan agar, 14 
Japan isinglass, 14 
Jarcol 1-20, 492 
Jeechem, 572 
Jeecol ODD, 492 
Jeweller’s borax, 670 
Jinjili oil, 646 
Kainite, 601 
Kali disulfis, 607 
Kalii chloridum, 600 
Kalii citras, 603 
Kalii hydrogenocarbonas, 598 
Kalii hydroxidum, 605 
Kalii sorbas, 609 
Kalipol 32, 696 
Kalium benzoat, 596 
Kalium hydroxydatum, 605 
Kaltostat, 86 
Kaolin, 60, 67, 319, 378, 421, 645 
heavy, 378 
light, 378 
light (natural), 378 
Kaolinite, 378–379 
Kaolinosis, 379 
Kaolinum ponderosum, 378 
Karstenite, 105 
Karvol, 781 
Katchung oil, 505 
Kelacid, 21 
Kelcoloid, 627 
Kelcosol, 656 
Index 903

Keltone, 656 
Keltose, 46 
Keltrol, 821 
Kemsol, 250 
Kemstrene, 301 
Keoflo ADP, 734 
Kessco CA, 155 
Kessco EO, 274 
Kessco GMO, 306 
Kessco GMS, 308 
Kessco IPM 95, 374 
Kessco IPP, 376 
Ketoprofen, 311 
b-Ketopropane, 8 
Klea 134a, 772 
Kleptose, 217 
Kleptose HPB, 219 
Klinit, 824 
Klucel, 336 
Kodaflex DBP, 234 
Kodaflex DBS, 236 
Kodaflex DEP, 240 
Kodaflex DMP, 248 
Kollicoat MAE 30 D, 553–554 
Kollicoat MAE 30 DP, 553–554 
Kollidon, 611 
Kollidon CL, 214 
Kollidon CL-M, 214 
Kollidon VA 64, 201 
Kortacid 1895, 737 
Kronos 1171, 782 
Krystar, 290 
Labrafac CC, 454 
Labrasol, 18 
Lac, 649 
Lacca, 649 
Lacolin, 685 
Lactic acid, 27, 381, 686 
ethyl ester, 270 
racemic, 381 
DL-Lactic acid, 381 
Lactic acid butyl ester, 271 
Lactic acid monosodium salt, 685 
Lactic acid sodium salt, 685 
Lactil, 383 
Lactite, 383 
Lactitol, 383 
with lactose, 383 
monohydrate, 383 
with polydextrose, 542 
sweetness vs.sucrose, 384 
Lactitolum monohydricum, 383 
Lactobiosit, 383 
g-Lactone, 264 
Lactopress Anhydrous, 385 
Lactopress Spray-Dried, 396 
Lactose, 293, 389, 396 
anhydrous, 385, 394, 397 
with lactitol, 383 
monohydrate, 387, 389, 397 
spray dried, 387, 394, 396 
Lactose monohydrate, 389 
Lactosit, 383 
Lactosum, 385 
Lactosum anhydricum, 385 
Lactosum monohydricum, 389 
Lacty, 383 
Laevulose, 290 
Lakes (coloring agents), 194 
Lampante virgin olive oil, 499 
Lanalcolum, 402 
Lanette 16, 155 
Lanette 18, 740 
Lanette O, 150 
Lanette wax SX BP, 807 
Lanolin, 183, 399, 403, 405 
acetylated, 400 
anhydrous, 399 
hydrogenated, 400 
hydrous, 400, 403–404 
liquid, 400 
modified, 400 
purified, 399 
water-soluble, 400 
Lanolin alcohols, 183, 400, 402, 405, 476, 
512–513 
mineral oil and, 476 
Lanolin alcohols ointment, 512 
Lanolin hydrous, 183 
Lanolin oil, 400 
Lanolin wax, 400 
Lanolina, 399 
Lansoprazole, 423 
Laponite, 318 
Larixinic acid, 445 
Latex particle coating agents, 147 
Lattios, 385 
Laughing gas, 490 
Laureth-N, 564 
Lauric acid, 406, 484, 501 
Lauric acid, shellac films, 651 
Lauromacrogol, 564 
Laurostearic acid, 406 
Lauryl gallate, 620 
N-Lauryl-N,N,N-trimethylammonium 
bromide, 153 
Layor carang, 14 
Leavening agents, potassium bicarbonate, 
598 
Lecithin, 409 
and alpha tocopherol, 32 
solvents, glycerin monostearate, 308 
unpurified, 410 
vegetable, 409 
Leinoleic acid, 414 
Lemol, 592 
Leu, 412 
Leucine, 412–413 
l-Leucine, 412 
DL-Leucine, 412 
Leucinum, 412 
Levomenthol, 460 
Levomentholum, 460 
Levulose, 290 
Lexalt L, 381 
Lexgard B, 83 
Lexol IPM-NF, 374 
Lexol IPP-NF, 376 
LH-21, 341 
LH-22, 341 
LH-31, 341 
LH-32, 341 
L-HPC, 341 
Lichenic acid, 293 
Licianite, 644 
Ligalub, 306 
Light anhydrous silicic acid, 188 
Light kaolin, 378 
Light kaolin (natural), 378 
Light liquid paraffin, 474 
Light liquid petrolatum, 474 
Light magnesium carbonate, 422 
Light magnesium oxide, 426 
Light mineral oil, 472, 474, 504, 510 
Light spar, 105 
Light white mineral oil, 474 
Lignocaine benzyl benzoate, 224 
Lignoceric acid, peanut oil, 505 
Lincomycin, 379 
Linoleic acid, 414 
and almond oil, 30 
and alpha tocopherol, 32 
castor oil, 128 
and corn oil, 204 
and cottonseed oil, 206 
ethyl ester, 414 
peanut oil, 505 
sunflower oil, 760 
Linolenic acid 
canola oil, 109 
and corn oil, 204 
Linolic acid, 414 
Lion, 378 
Lipex 107, 722 
Lipex 108, 108 
Lipex 200, 722 
Lipex 204, 108 
Lipo GMS 410, 308 
Lipo GMS 450, 308 
Lipo GMS 600, 308 
Lipocol, 572 
Lipocol C, 155 
Lipocol S, 740 
Lipocol S-DEO, 740 
Lipolan, 404 
Liponate IPP, 376 
Liponate SPS, 811 
Liponic 70-NC, 718 
Liponic 76-NC, 718 
Lipovol CAN, 108 
Lipovol CO, 128 
Lipovol HS-K, 800 
Lipovol SES, 646 
Lipoxol, 545 
Liquefied phenol, 515 
Liquid fructose, 292 
Liquid glucose, 299 
Liquid lanolin, 400 
Liquid maltitol, 440 
Liquid paraffin, 471 
Liquid paraffin and lanolin alcohols, 476 
Liquid petrolatum, 471 
heavy, 471 
Liquiphene, 521 
Lissolamine V, 152 
Litesse, 542 
Locust bean gum, 148–149 
Locust tree extract, 149 
Loperamide, 56 
LoSalt, 601 
Low erucic acid colza oil, 108 
Low erucic acid rapeseed oil, 108 
Low-substituted hydroxypropyl cellulose, 341 
Low-substituted hydroxypropylcellulose, 341 
Low-substituted hyprolose, 341 
LSC 5050, 409 
Lubricants 
octyldodecanol, 492 
sodium hyaluronate, 681 
Lubricants (general) 
canola oil, 108 
hydroxyethyl cellulose, 330 
lauric acid, 406 
leucine, 412 
mineral oil, 471 
poloxamers, 535 
polyvinyl alcohol, 592 
talc, 767 
904 Index

Lubricants (surgeons’/exam gloves) 
sterilizable maize starch, 734–735 
triethanolamine, 794 
Lubricants (tablet/capsule) 
calcium stearate, 102 
glycerin monostearate, 308 
glyceryl behenate, 304 
glyceryl palmitostearate, 311 
hydrogenated castor oil, 130 
hydrogenated vegetable oil type I, 800 
light mineral oil, 474 
magnesium lauryl sulfate, 689 
magnesium stearate, 430, 442 
medium-chain triglycerides, 454 
mineral oil, 471 
myristic acid, 484 
palmitic acid, 501 
poloxamer, 535 
polyethylene glycol, 545–546 
potassium benzoate, 596 
sodium benzoate, 662 
sodium chloride, 671 
sodium lauryl sulfate, 687 
sodium stearyl fumarate, 705 
stearic acid, 731, 737 
talc, 767 
zinc stearate, 832 
see also Coating agents 
Lubritab, 800 
Lucianite, 644 
Lustre Clear, 134 
Lutrol, 535, 537 
Lutrol E, 545 
Luviskol VA, 201 
Luzenac Pharma, 767 
Lycadex PF, 231 
Lycasin 80/55, 440 
Lycasin 80/55 (Roquette), 440 
Lycasin HBC, 440 
Lycatab C, 731 
Lycatab DSH, 442, 444 
Lycatab PGS, 731 
Lye, 683 
Lyophilization see Freeze-drying stabilizers/ 
carriers 
Macrogel 400, 545 
Macrogel 1500, 545 
Macrogel 4000, 545 
Macrogel 6000, 545 
Macrogel 20000, 545 
Macrogol 15 Hydroxystearate, 416 
Macrogol cetostearyl ether, 564 
Macrogol ethers, 564 
Macrogol lauryl ether, 564 
Macrogol oleyl ether, 564 
Macrogol stearate 400, 585 
Macrogol stearates, 585 
Macrogol stearyl ether, 564 
Macrogola, 545 
Macrogolglyceroli hydroxystearas, 572 
Macrogolglyceroli ricinoleas, 572 
Macrogoli 15 hydroxystearas, 416 
Macrogoli aether cetostearylicus, 564 
Macrogoli aether stearylicus, 564 
Macrogoli aetherum laurilicum, 564 
Macrogoli aetherum oleicum, 564 
Macrogols, 545 
Magcal, 426 
Magchem 100, 426 
MagGran CC, 89 
Maglite, 426 
Magnabite, 418 
Magnabrite, 58 
Magnesia, 426 
calcined, 426 
Magnesia monoxide, 426 
Magnesia usta, 426 
Magnesii oxidum leve, 426 
Magnesii oxidum ponderosum, 426 
Magnesii stearas, 430 
Magnesii subcarbonas levis, 422 
Magnesii subcarbonas ponderosus, 422 
Magnesii trisilicas, 434 
Magnesite, 424 
calcinated, 426 
Magnesium aluminosilicate, 418 
Magnesium aluminum silicate, 56, 60, 319, 
379, 418, 429, 645, 768, 821–822 
activated attapulgite, 57 
hydrated, 56 
and propylparaben, 631 
Magnesium calcium silicate, hydrous, 767 
Magnesium carbonate, 422, 601 
anhydrous, 422, 424 
heavy, 422 
light, 422 
normal, 424 
normal hydrate, 424 
Magnesium carbonate hydroxide, 424 
Magnesium hydrogen metasilicate, 767 
Magnesium lauryl sulfate, 689 
Magnesium mesotrisilicate, 434 
Magnesium metasilicate, 429 
Magnesium octadecanoate, 430 
Magnesium orthosilicate, 429 
Magnesium oxide, 426, 735 
heavy, 426 
light, 426 
Magnesium salt, 418 
Magnesium silicate, 428, 435, 768 
hydrous, 767 
synthetic, 428 
Magnesium stearate, 103–104, 430, 442, 
452, 731, 739, 833 
crystalline forms, 431 
dextrates, 226 
incompatibilities, 558 
Magnesium trisilicate, 60, 421, 429, 434, 768 
anhydrous, 435 
methylparabens incompatibility, 468 
preservative inactivation, 434 
and propylparaben, 631 
Magnesium trisilicate 02, 434 
Magnetite, 364 
Magnyox, 426 
Magsil Osmanthus, 767 
Magsil Star, 767 
Maize oil, 204 
refined, 204 
Maize starch, 725, 729 
sterilizable, 729, 734 
Majsao CT, 204 
Malbit, 438 
Maldex, 442 
Malic acid, 187, 294, 436–437, 771 
D-Malic acid, 436 
L-Malic acid, 436 
DL-Malic acid, 436 
Malt sugar, 447 
Malta*Gran, 442 
Maltisorb, 438 
Maltisorb 75/75, 440 
Maltisweet 3145, 440 
Maltit, 438 
Maltitol, 438, 441 
with polydextrose, 542 
D-Maltitol, 438 
Maltitol solution, 440, 720 
Maltitol syrup, 440 
Maltitolum, 438 
Maltitolum liquidum, 440 
Maltobiose, 447 
Maltodextrin, 229, 442, 729 
Maltodextrinum, 442 
Maltodiose, 447 
Maltol, 272, 445 
Maltose, 300, 447 
crystalline, 447–448 
dextrimaltose, 230 
hydrogenated, 438 
Maltose HH, 447 
Maltose HHH, 447 
Maltrin, 442, 444 
Maltrin QD, 442 
Manna sugar, 449 
D-Mannite, 449 
Mannitol, 267, 449, 720 
recommended lubricants, 452 
sweetness vs. xylitol, 827 
vs.sorbitol, 452 
Mannitolum, 449 
Mannogem, 449 
Mantrolac R-49, 649 
Manucol ester, 627 
Mapeg, 572 
Mapico red, 364 
Mapico yellow, 364 
Margarine, oleomargarine, 760 
Marine Colloids, 124 
Marlosol, 585 
Marlowet, 564, 572 
Marmag, 426 
Massa estarinum, 762 
Massupol, 762 
Maydis amylum, 725 
Maydis oleum raffinatum, 204 
MCT oil, 454 
Mebeverine hydrochloride, 428 
Medicated confectionery bases 
polydextrose, 542 
sucrose, 744 
xylitol, 824 
see also Chewable tablet formulations 
Medilave, 157 
Medium-chain triglycerides, 454, 765, 801 
Medophyll, 780 
Meerschaum, 428 
Meglumine, 457 
Megluminum, 457 
Melibiose, 636 
Melitose, 635 
Melitriose, 635 
Melojel, 725 
Membranes, ethylene vinyl acetate, 285 
p-Menthan-3-ol, 459 
3-p-Menthanol, 459 
Menthol, 459–460, 781 
d-Menthol, 460 
dl-Menthol, 460 
l-Menthol, 460 
racemic, 459–460 
Mentholum racemicum, 459 
3-Mercapto-1,2-propanediol, 482 
1-Mercapto-2,3-propanediol, 482 
1-Mercaptoglycerol, 482 
Mercuriphenyl nitrate, 526 
Mercurothiolate, 777 
Merigel, 731 
Index 905

Meritena, 725, 734 
Meritol, 718 
Merkur, 509 
Merphenyl nitrate, 526 
meso-Erythritol, 266 
Meso-xylitol, 824 
Metaboric acid, 74 
Metacetonic acid, 617 
Metaupon, 494 
Metered-dose inhalant formulations, 176 
CFC-free, 179, 772 
heptafluoropropane, 321 
tetrafluoroethane, 772–773 
see also Inhalers, dry powder diluents/ 
carriers; Propellants 
Methacrylic acid copolymer, 553 
Methacrylic acid copolymer dispersion, 553 
Methacrylic acid, methyl ester, 558 
Methacrylic acid polymer with 
divinylbenzene, 533 
potassium salt, 532 
Methacrylic acid-ethyl acrylate coploymer 
(1:1), 553 
Methane carboxylic acid, 6 
Methanebis[N,N0 (5-ureido-2,4- 
diketotetrahydroimidazole)-N,Ndimethylol], 
359 
Methanol, 20 
Methocel, 336, 346, 462 
Methopectin, 507 
3-Methoxy-4-hydroxybenzaldehyde, 798 
Methoxymethane, 246 
Methyl -a-L-aspartyl-L-phenylalaninate, 53 
Methyl benzene-1,2-dicarboxylate, 248 
Methyl carbinol, 18 
Methyl cellulose, 334 

-4-Methyl-1,3-dioxolan-2-one, 622 
Methyl ether, 246 
Methyl ethylene glycol, 624 
Methyl glycol, 624 
Methyl hydroxy propionate, 271 
Methyl hydroxybenzoate, 466 
potassium salt, 469 
sodium salt, 469 
soluble, 469 
Methyl hydroxypropylcellulose, 346 
Methyl isobutyl ketone, 20 
Methyl lactate, 271 
Methyl linoleate, 414 
Methyl linolenate, 32 
Methyl methacrylate, 558 
Methyl methacrylate polymer, 559 
Methyl 2-methylpropenoate, 558 
Methyl 9-octadecenoate, 275 
Methyl oleate, 275 
Methyl parahydroxybenzoate, 466 
Methyl pectin, 507 
Methyl pectinate, 507 
Methyl polysiloxane, 244 
2-Methyl pyromeconic acid, 445 
Methylacetic acid, 617 
sodium salt, hydrate, 699 
1-Methylamino-1-deoxy-D-glucitol, 457 
Methylated spirit, industrial, 20 
Methylcellulose, 281, 333, 335, 348, 352, 
452, 462 
alternatives, guar gum, 315 
Methylcellulose propylene glycol ether, 346 
Methylcellulosum, 462 
3-Methyl-4-chlorophenol, 171 
6-Methyl-3,4-dihydro-1,2,3-oxathiazin- 
4(3H)-one 2,2-dioxide potassium salt, 4 
4-Methyl-2-oxo-1,3-dioxolane, 622 
Methyldopa, 798 
1,10-Methylenebis{3-[3-(hydroxymethyl)-2,5- 
dioxo-4-imidazolidinyl]urea}, 359 
N,N00-Methylenebis{N0-[3-(hydroxymethyl)- 
2,5-dioxo-4-imidazolidinyl]urea}, 359 
1-Methylethyl hexadecanoate, 376 
1-Methylethyl tetradecanoate, 374 
N-Methylglucamine, 457 
Methylhydroxyethylcellulose, 334 
Methylhydroxyethylcellulosum, 334 
1-Methyl-3-hydroxy-4-isopropylbenzene, 780 
Methylhydroxypropylcellulose phthalate, 354 
2-Methyl-3-hydroxy-4-pyrone, 445 
Methylis parahydroxybenzoas, 466 
5-Methyl-2-isopropylphenol, 780 
5-Methyl-2-(1-methylethyl) phenol, 780 
(1RS,2RS,5RS)-(
)-5-Methyl-2-(1- 
methylethyl)cyclohexanol, 459–460 
4-Methylnorvaline, 412 
6-Methyl-1,2,3-oxathiazin-4(3H)-one-2,2- 
dioxide potassium salt, 4 
Methylparaben, 85, 289, 359, 466, 631 
and propylene glycol, 466, 468 
and propylparaben, 629 
see also Parabens 
Methylparaben potassium, 468–469 
Methylparaben sodium, 468–469 
Methylphenol, 208–209 
2-Methylpropane, 325 
2-Methyl-2-propenoic acid polymer with 
divinylbenzene, 533 
potassium salt, 532 
Methylprotocatechuic aldehyde, 798 
1-Methyl-2-pyrrolidinone, 634 
N-Methylpyrrolidone, 634 
N-Methylpyrrolidonum, 634 
Methylsulfoxide, 250 
8-Methyltocol, 34 
Metolose, 346, 462 
Mexpectin, 507 
Meyprodor, 315 
Meyprofin, 315 
Meyprofleur, 148 
Meyprogat, 315 
MHEC, 334 
Micol, 152 
Microcrystalline cellulose, 132 
and carboxymethylcellulose sodium, 
134 
and carrageenan, 134 
and guar gum, 134 
silicified, 134 
Microcrystalline wax, 504, 813 
Micromite, 89 
Miglyol 810, 454 
Miglyol 812, 454 
Milk acid, 381 
Milk sugar, 385 
Mineral jelly, 509 
Mineral oil, 471, 475–476, 510, 513 
heavy, 471 
light, 472, 474, 504, 510 
white, 471 
Mineral oil and lanolin alcohols, 472, 475– 
476, 512 
Mineral oils, 403 
Mineral soap, 58 
Mineral white, 105 
Mipax, 248 
Mixed soybean phosphatides, 409 
MME, 558 
Modified cellulose gum, 211 
Modified lanolin, 400 
Modified starch dusting powder, 734 
Monestriol EN-A, 284 
Monobasic potassium phosphate, 697 
Monobasic sodium phosphate, 694, 696 
anhydrous, 696 
dihydrate, 696 
monohydrate, 696 
Monobutyl/monoethyl ester mix, of 
poly(methylvinyl ether/maleic acid), 561 
Monocizer DBP, 234 
Monoester with 1,2,3-propanetriol, 308 
Monoethanolamine, 239, 478, 795 
Monoethyl ester, of poly(methylvinyl ether/ 
maleic acid), 561 
Monoethyl/monobutyl ester mix, of 
poly(methylvinyl ether/maleic acid), 561 
Monogramming, tablet/capsule, shellac, 649 
Monolan, 535 
Monolein, 306 
Monomuls 90-O18, 306 
Mono-olein, 306 
a-Mono-olein glycerol, 306 
Monopotassium carbonate, 598 
Monopotassium phosphate, 697 
Monosodium L-(.)-ascorbate, 659 
Monosodium carbonate, 665 
Monosodium glutamate, 480 
Monosodium L-glutamate monohydrate, 480 
Monosodium orthophosphate, 696 
Monosodium phosphate, 696 
Monostearin, 308 
Monothioglycerin, 482 
Monothioglycerol, 482 
Monthyle, 284 
Montmorillonite, 58, 418, 421 
Montreal Protocol, 178 
difluoroethane, 242 
essential use exemptions, 178 
Morpan CHSA, 152 
Morphans, 152 
Mowiol, 592 
MSG (monosodium glutamate), 480 
Mucoadhesives 
chitosan, 159 
ethylcellulose backing membranes, 281 
glyceryl monooleate, 306 
polyethylene oxide, 551 
see also Adhesives; Bioadhesives 
Muriacite, 105 
Myacide, 76 
Mycose, 788 
Mylose, 299 
Myreth-N, 564 
Myristic acid, 206, 407, 484, 501 
isopropyl ester, 374 
Myristyl alcohol, 484 
Myristyltrimethylammonium bromide, 153 
Myritol, 454 
Myvaplex 600P, 308 
Myvatex, 308 
Naproxen, 738 
National 78-1551, 731 
Native calcium sulfate, 105 
Natrii acetas trihydricus, 654 
Natrii alginas, 656 
Natrii ascorbas, 659 
Natrii benzoas, 662 
Natrii chloridum, 671 
Natrii citras, 675 
Natrii cyclamas, 678 
Natrii dihydrogenophosphas dihydricus, 696 
Natrii disulfis, 690 
906 Index

Natrii glutamas, 480 
Natrii hyaluronas, 681 
Natrii hydrogenocarbonas, 665 
Natrii hydroxidum, 683 
Natrii lactatis solutio, 685 
Natrii laurilsulfas, 687 
Natrii metabisulfis, 690 
Natrii propionas, 699 
Natrii stearylis fumaras, 705 
Natrii sulfis anhydricus, 708 
Natrii sulfis heptahydricus, 709 
Natrii tetraboras, 669 
Natrium benzoicum, 662 
Natrosol, 330 
Natural alpha tocopherol, 33 
Natural halite, 671 
Natural trehalose, 788 
Neobee M5, 454 
Neo-Fat, 494 
Neo-fat 12, 406 
Neohesperidin DC, 486 
Neohesperidin DHC, 486 
Neohesperidin dihydrochalcone, 486 
Neohesperidin dihydrochalconum, 486 
Neohesperidine dihydrochalcone, 486 
Neomycin sulfate, 276 
Neosorb, 718, 720 
Neotocopherol, 34 
Neotrehalose, 789 
Nesatol, 454 
Neusilin, 418 
NF Lactose–315, 396 
NF Lactose–316 Fast Flo, 396 
NHDC, 486 
Nikkol, 572 
Ninol AA62 Extra, 406 
Nipabutyl, 83 
Nipacide PC, 171 
Nipacide PX, 180 
Nipagin M, 466 
Nipanox BHA, 79 
Nipanox BHT, 81 
Nipantiox 1-F, 79 
Nipasol M, 629 
Nisso HPC, 336 
(nitrato-O)Phenylmercury, 526 
Nitratophenylmercury, 526 
2,20,200-Nitrilotriethanol, 794 
Nitrogen, 117, 488, 491 
aerosol propellant, 116 
Nitrogen monoxide, 490 
Nitrogenium, 488 
Nitrogenol, 158 
Nitrous oxide, 117, 489–490 
aerosol propellant, 116 
N-Methylpyrrolidone, 634 
NMP (N-methylpyrrolidone), 634 
N,N00-Bis(4-chlorophenyl)-3,12-diimino- 
2,4,11,13- 
tetraazatetradecanediimidamide, 163 
1-Nonanecarboxylic acid, 407 
Nonionic emulsifying wax see Emulsifying 
wax, nonionic 
Nonionic surfactant, macrogol 15 
hydroxystearate, 416 
Nonionic surfactants see Surfactants, 
nonionic 
Nonoxynol 10, 566 
Non-pareil, 752 
Non-pareil seeds, 752 
Normal human serum albumin, 16 
Normal magnesium carbonate, 424 
Novata, 762 
Noveon AA-1, 539 
Noveon CA-1, 540 
Noveon CA-2, 540 
NPTAB, 752 
NSC-2752, 293 
Nu-Core, 752 
Nu-Pareil PG, 752 
Nut oil, 505 
NutraSweet, 53 
Nymcel, 120 
Nymcel ZSC, 118 
Nymcel ZSX, 211 
Ocenol, 496 
9,12-Octadecadienoic acid 
ethyl ester, 414 
methyl ester, 414 
cis,cis-9,12-Octadecadienoic acid, 414 
Octadecanoic acid, 737, 739 
2,3-dihydroxypropyl ester mixed with 
3-hydroxy-2-[(1-oxohexadecyl)-oxy] 
propyl octadecanoate, 311 
aluminum salt, 42 
calcium salt, 102 
magnesium salt, 430 
monoester with 1,2,3-propanetriol, 308 
zinc salt, 832 
N-Octadecanol, 740 
(Z)-9-Octadecenoic acid, ethyl ester, 274 
9-Octadecenoic acid (Z), monoester with 
1,2,3-propanetriol, 306 
cis-9-Octadecen-1-ol; oleic alcohol, 496 
9,10-Octadecenoic acid, 494 
cis-9-Octadecenoic acid, 494 
Octadecyl alcohol, 740 
Octadecyl ester, sodium salt, 705 
Octildodecanol, 492 
Octoil, 235 
Octyl 3,4,5-trihydroxybenzoate, 621 
Octyl gallate, 620 
2-Octyl-1-dodecanol, 492 
2-Octyldecyl alcohol, 492 
Octyldodecanol, 492 
Octyldodecanolum, 492 
Odor enhancing agents, menthol, 459 
OHS28890, 81 
Oil of vitriol, 758 
Ointment bases 
lanolin, 399 
hydrous, 404 
lanolin alcohols, 402 
paraffin, 503 
petrolatum, 509 
petrolatum and lanolin alcohols, 512 
poloxamer, 535 
polyethylene glycol, 545 
stearic acid, 737 
Olea europaea oil, 498 
Oleaginous vehicles 
almond oil, 30 
canola oil, 108 
castor oil, 128 
corn oil (maize), 204 
cottonseed oil, 206 
ethyl oleate, 274 
isopropyl myristate, 374 
isopropyl palmitate, 376 
light mineral oil, 474 
mineral oil, 471 
olive oil, 498 
peanut oil, 505 
sesame oil, 646 
soybean oil, 722 
Oleic acid, 275, 494, 497, 772 
almond oil, 30 
canola oil, 109 
castor oil, 128 
and corn oil, 204 
and cottonseed oil, 206 
ethyl ester, 274 
peanut oil, 505 
sunflower oil, 760–761 
Oleic alcohol, 496 
Oleinic acid, 494 
Oleo alcohol, 496 
Oleo de ame.ndoas, 30 
Oleol, 496 
Oleomargarine, 760 
Oleum, 759 
Oleum cacao, 765 
Oleum helianthi, 760 
Oleum neutrale, 454 
Oleum olivae, 498 
Oleum ricini, 128 
Oleum theobromatis, 765 
Oleum vegetable tenue, 454 
Oleyl alcohol, 496 
Oleyl oleate, 497 
Oligofructose, 362 
Oligosaccharides, cyclic, 217 
Olio di mandorla, 30 
Olivae oleum raffinatum, 498 
Olive oil, 498 
alternatives, rapeseed oil, 109 
refined, 498 
Olive-pomace oil, 499–500 
Opacifing agents 
calcium carbonate, 89 
zinc acetate, 830 
Opacifying agents 
aluminum stearate, 42 
calcium carbonate, 89 
coloring agents, 193 
ethylene glycol palmitostearate, 283 
titanium oxide, 782 
zinc stearate, 832 
Opaseal, 589 
Optim, 301 
Oraldene, 323 
Orange shellac, 649 
[Orthoborato(3-)-O]-phenylmercurate(2- 
)dihydrogen, 524 
Orthoboric acid, 74 
Orthophosphoric acid, 530 
Oryzae amylum, 725 
Osmotic agents, sulfobutylether bcyclodextrin, 
754 
Overloading syndrome, 207 
Ovolecithin, 409 
2-Oxopyrrolidine, 633 
Oxybenzene, 514 
Oxybismethane, 246 
Oxycellulose, 330 
Oxymag, 426 
Oxypropylated cellulose, 336 
P-22, 175 
P-142b, 174 
P-152a, 242 
P-227, 321 
Pal Sweet, 53 
Pal Sweet Diet, 53 
Palanitol C, 234 
Palatinit, 366 
Palatinol M, 248 
Palatinose, hydrogenated, 366 
Index 907

Palatone, 445 
Palm oil, 109 
hydrogenated, 800 
Palmitic acid, 336, 484, 501 
almond oil, 30 
castor oil, 128 
and corn oil, 204 
and cottonseed oil, 206 
peanut oil, 505 
sunflower oil, 760 
Palmitic acid isopropyl ester, 376 
Palmitin, 501 
Palmityl alcohol, 155 
Palygorscite, 56 
Palygorskite, 56 
Pamolyn, 414 
Parabens, 359, 428, 441 
antimicrobial activity and chain length, 
466 
incompatibilities 
methylcellulose, 464 
nonionic surfactants, 468 
poloxamer, 536 
polyethylene alkyl ethers, 566 
polyethylene glycols, 547 
polysorbates, 584 
paraben paradox, 468 
synergists, 260 
see also Butylparaben; Ethylparaben; 
Methylparaben; Propylparaben 
Paracetamol, 428, 507 
Parachlorometacresol, 171 
Parachlorometaxylenol, 180 
Paraffin, 472, 475, 503, 510, 512, 814 
anhydrous ointment bases, 807 
hard, 503 
liquid, 471 
and lanolin alcohols, 476 
synthetic, 504 
white soft, 510 
and anionic emulsifying wax, 807 
yellow soft, 509 
Paraffin oil, 471 
Paraffin wax, 503, 813 
Paraffinum durum, 503 
Paraffinum liquidum, 471 
Paraffinum perliquidum, 474 
Paraffinum solidum, 503 
Parasepiolite, 428 
Paselli MD10 PH, 442 
Patlac LA, 381 
Paygel 55, 725 
PCMC, 171 
PCMX, 180 
PEA (phenylethyl alcohol), 519 
Peanut oil, 31, 109, 205, 207, 274, 505, 647, 
722–723, 761 
Pearl Steric, 737 
Pearling agents, ethylene glycol 
palmitostearate, 283 
Pearlitol, 449 
Peceol, 306 
Pectin, 507 
Pectina, 507 
Pectinic acid, 507 
PEG, 545 
PEG fatty acid esters, 585 
PEG stearates, 585 
Pemulen, 111 
Penetration enhancers 
alcohol, 18 
dimethyl sulfoxide, 250–251 
glyceryl monooleate, 306 
glycofurol, 313 
isopropyl myristate, 374 
isopropyl palmitate, 376 
lanolin, 399 
light mineral oil, 474 
linoleic acid, 414 
menthol, 459 
myristic acid, 484 
oleic acid, 494 
oleyl alcohol, 496 
palmitic acid, 501 
polyoxyethylene alkyl ethers, 565 
2-pyrrolidone, 633 
sodium lauryl sulfate, 687 
thymol, 780 
see also Transdermal delivery agents 
Penicillin V, 316 
1-pentadecanecarboxylic acid, 501 
1,3-Pentadiene-1-carboxylic acid, 710 
Pentonium, 61 
Peppermint camphor, 459 
Peppermint oil, 460 
Perfectamyl D6PH, 725 
Perfume fixatives, diethyl phthalate, 240 
Periclase, 426 
Permulgin D, 815 
Persian tragacanth, 785 
Petrohol, 371 
Petrolatum, 472, 475, 504, 509, 512–513 
and lanolin alcohols, 402 
white, 510, 513 
yellow, 513 
Petrolatum and lanolin alcohols, 403, 476, 
510, 512 
Petrolatum and wool alcohols, 512 
Petroleum ceresin, 813 
Petroleum jelly, 509 
white, 510 
Petroleum wax (microcrystalline), 813 
pH-adjusting agents 
acetic acid, glacial, 6 
ammonia solution, 44 
diethanolamine, 238 
meglumine, 457 
sodium citrate dihydrate, 675 
see also Acidifying agents; Alkalizing 
agents; Buffering agents 
Pharma-Carb, 89 
Pharmacel, 132 
Pharmacel XL, 211 
Pharmaceutical glaze, 650 
Pharmacoat, 346 
Pharma-Gel, 731 
Pharmasolve, 634 
Pharmatose DCL 11, 396 
Pharmatose DCL 14, 396 
Pharmatose DCL 21, 385 
Pharmatose DCL 22, 385 
Pharmsorb, 418 
Pharmsorb Regular, 56 
Phe-Mer-Nite, 526 
Phenethanol, 519 
Phenic acid, 514 
Phenobarbital sodium, 423 
Phenol, 209, 476, 512, 514 
incompatibilities 
carbomers, 113 
nonionic emulsifying wax, 815 
poloxamer, 536 
polyoxyethylene castor oil derivatives, 
574 
liquefied, 515 
Phenolum, 514 
Phenoxen, 517 
Phenoxyethano, 517 
Phenoxyethanol, 169, 517 
Phenoxyethanolum, 517 
b-Phenoxyethyl alcohol, 517 
1-Phenoxypropan-2-ol, 518 
Phenoxypropanol, 518 
Phenyl cellulose, 517 
Phenyl hydrate, 514 
Phenyl hydroxide, 514 
Phenylcarbinol, 69 
Phenylcarboxylic acid, 66 
Phenyldriargyri acetas, 521 
2-Phenylethanol, 171, 519 
Phenylethyl alcohol, 169, 519 
Phenylformic acid, 66 
Phenylhydrargyri boras, 524 
Phenylhydrargyri nitras, 526 
Phenylic acid, 514 
Phenylic alcohol, 514 
Phenylmercuriborate, 524 
Phenylmercuric acetate, 521, 524–526, 528, 
778 
Phenylmercuric borate, 521–522, 524, 526, 
528, 778 
Phenylmercuric hydroxide, 524, 526 
Phenylmercuric metaborate, 524 
Phenylmercuric nitrate, 261, 521–522, 524– 
526, 778 
Phenylmercuric orthoborate, 524 
Phenylmercury acetate, 521 
Phenylmercury borate, 524 
Phenylmercury nitrate, 526 
Phenylmethanol, 69 
Phenytoin, 379 
Phosal 53 MCT, 409 
Phosphatides, mixed soybean, 409 
Phosphatidylcholine, 409 
Phospholipids 
solvents, glycerin monostearate, 308 
soybean, 409 
Phospholipon 100 H, 409 
Phosphoric acid, 530 
dilute, 531 
diluted, 531 
disodium salt, 693 
monosodium salt, 696 
Phosphoric acid calcium salt (1:1), 93 
Phosphoric acid calcium salt (1:1) dihydrate, 
96 
Phosphoric acid calcium salt (2:3), 100 
Phosphorite, 694 
Photostabilizers, vanillin, 798 
Phthalavin, 589 
Phthalic acid, 589–590 
Phthalic acid dibutyl ester, 234 
Phthalic acid diethyl ester, 240 
Phthalic acid dimethyl ester, 248 
Phthalic acid methyl ester, 248 
Phycite, 266 
Pigment black 11, 364 
Pigment white 6, 782 
Pigment yellow 42, 364 
Pigments, 193 
classifications, 194 
dispersing agents, glycerin 
monostearate, 308 
titanium oxide, 782, 784 
see also Coloring agents 
Plasbumin, 16 
Plasdone, 611 
Plasdone S-630, 201 
Plasma albumin, 16 
908 Index

Plaster of Paris, 105–106 
Plasticizers 
acetyltributyl citrate, 10, 796 
acetyltriethyl citrate, 12, 796 
benzyl benzoate, 72 
cellulose acetate phthalate compatible, 
145–146 
chlorbutanol, 168 
dextrin, 228 
dibutyl phthalate, 234 
dibutyl sebacate, 236 
diethyl phthalate, 240 
dimethyl phthalate, 248 
glycerin, 301 
glycerin monostearate, 308 
hypromellose phthalate compatible, 354 
mannitol, 449 
mineral oil and lanolin alcohols, 476 
palmitic acid, 336 
polyethylene glycol, 545–546 
polymethacrylate compatible, 559 
polyvinyl acetate phthalate, 589 
propylene glycol, 624 
2-pyrrolidone, 633 
sorbitol, 718 
stearic acid, 336 
triacetin, 790 
tributyl citrate, 792, 796 
triethanolamine, 794 
triethyl citrate, 796 
Pluracare, 537 
Plurafac, 564 
Pluriol E, 545 
Pluronic, 535, 537 
Pluronic F-68, 537 
PMA (phenylmercuric acetate), 521 
PMAC, 521 
PMAS, 521 
PMB (phenylmercuric borate), 524 
PMMA, 559 
PMN (phenylmercuric nitrate), 526 
Polacrilin, 533 
Polacrilin potassium, 532 
Polacrilinum kalii, 532 
Polargel, 58 
Polawax, 815 
Polishing agents 
yellow wax, 819 
see also Coating agents 
Poloxalkol, 535 
Poloxamer, 535 
Poloxamer 188, 535–536 
Poloxamer 338, 535 
Poloxamer 407, 535 
Poloxamera, 535 
Poloxamers, 535 
nomenclature, 537 
Poloxyl 8 stearate, 585 
Poly (ethylene-co-vinyl acetate), 285 
Poly[1-(2-oxo-1-pyrrolidinyl)ethylene], 611 
Polyacrylic acid, 111 
Polycarbophil, 114, 539 
Polycizer DBP, 234 
Polydextrose, 233, 542, 827 
Polydextrose A, 542 
Polydextrose K, 542 
Polydextrose see also Dextrose 
Poly(dimethylsiloxane), 244 
Polydimethylsiloxane-silicon dioxide mixture, 
652 
Polyesters, aliphatic, 24 
Polyethoxylated castor oil, 572 
Polyethylene glycol, 545, 552, 584, 587, 765 
incompatibilities, sorbitol, 719 
and macrogol 15 hydroxystearate, 417 
Polyethylene glycol 660 12-hydroxystearate, 
416 
Polyethylene glycol distearate, 585 
Polyethylene glycol monocetyl ether, 564 
Polyethylene glycol monolauryl ether, 564 
Polyethylene glycol monooleyl ether, 564 
Polyethylene glycol monostearyl ether, 564 
Polyethylene glycol stearate, 585 
Polyethylene glycol stearates, 585 
Polyethylene glycol-15-hydroxystearate, 416 
Polyethylene oxide, 550–551 
Polyethylene-propylene glycol copolymer, 
535 
Polyfructose, 362 
Poly-(1,4-b-D-glucopyranosamine), 159 
b-1,4-Poly-D-glucosamine, 159 
Polylactic acids, 382 
Polylactide acetyltributyl citrate, 11 
Polylin No. 515, 414 
Polymannuronic acid, 21 
Polymeric methacrylates, 553 
Polymers acrylic acid see Carbomer 
Polymers, biodegradable, aliphatic polyesters, 
24 
Polymethacrylates, 553, 590 
compatible plasticizers, 559 
Poly(methyl methacrylate), 558–559 
Poly(methyl vinyl ether/maleic anhydride), 
561 
Poly(methylvinyl ether/maleic acid), 561 
Poly(methylvinyl ether/maleic anhydride), 
561 
Polyox, 551 
Polyoxirane, 551 
Poly(oxy-1,2-ethanediyl)a-hydro-ohydroxyoctadecanoate, 
585 
Polyoxyethylene, 551 
Polyoxyethylene 8 stearate, 585 
Polyoxyethylene alkyl ethers, 550, 564, 578, 
816 
nomenclature, 564 
Polyoxyethylene castor oil derivatives, 572 
Polyoxyethylene glycol, 545 
Polyoxyethylene glycol 400 stearate, 585 
Polyoxyethylene glycol stearates, 585 
Polyoxyethylene sorbitan fatty acid esters, 
550, 580, 717 
Polyoxyethylene stearates, 550, 578, 585, 
739 
nomenclature, 585 
Polyoxyethylene-polyoxypropylene 
copolymer, 535 
Polyoxyl 10 oleyl ether, 564 
Polyoxyl 20 cetostearyl ether, 564 
Polyoxyl 35 castor oil, 572–573 
Polyoxyl 40 hydrogenated castor oil, 572– 
573 
Polyoxyl 40 stearate, 585 
Polyoxyl castor oil, 572 
Polyoxyl lanolin, 400 
Polyoxyl lauryl ether, 564 
Polyoxyl stearyl ether, 564 
Polyplasdone XL, 214 
Polyplasdone XL-10, 214 
Polypropylene glycol 2000, 573 
Polysaccharide B-1459, 821 
Polysorbate 80, 468, 580 
Polysorbates 20, 40, 60, and 80, 580 
Polysorbates 20, 60, and 80, 580 
Polysorbatum 20, 60, and 80, 580 
Polythiazide, 798 
Polyvidone, 611 
Polyvinol, 592 
Polyvinyl acetate phthalate, 146, 589, 650 
Polyvinyl alcohol, 592 
Poly(vinylis acetas), 592 
Polyvinylpolypyrrolidone, 214 
Polyvinylpyrrolidone, 611 
Poly(1-vinylpyrrolidone–co-vinyl acetate), 
201 
Polyvinylpyrrolidone–vinyl acetate 
copolymer, 201 
Poorly crystalline boehmite, 36 
Porcelain clay, 378 
Potash lye, 605 
Potassium acid carbonate, 598 
Potassium acid phosphate, 697 
Potassium acid sulfite, 608 
Potassium alginate, 23, 46, 87, 594, 657 
Potassium benzoate, 67, 596, 663 
Potassium bicarbonate, 598, 667 
Potassium biphosphate, 697 
Potassium 1,4-bis(2-ethylhexyl) 
sulfosuccinate, 258 
Potassium bisulfite, 608 
Potassium bisulphite, 608 
Potassium chloride, 600, 673 
Potassium citrate, 603 
Potassium citrate anhydrous, 604 
Potassium citrate monohydrate, 604 
Potassium dihydrogen orthophosphate, 697 
Potassium (E,E)-hexa-2,4-dienoate; 
potassium (E,E)-sorbate, 609 
Potassium ethyl hydroxybenzoate, 289 
Potassium hydrate, 605 
Potassium hydrogen carbonate, 598 
Potassium hydrogen sulfite, 608 
Potassium hydroxide, 605, 684 
Potassium metabisulfite, 607, 691 
Potassium methyl hydroxybenzoate, 469 
Potassium monochloride, 600 
Potassium myristate, 484 
Potassium phosphate, 694 
dibasic, 694 
monobasic, 697 
Potassium polymannuronate, 594 
Potassium propionate, 700 
Potassium propyl hydroxybenzoate, 631 
Potassium pyrosulfite, 607 
Potassium salt trihydrate, 596 
Potassium sorbate, 609, 712 
Potato starch, 725 
Povidone, 202, 215, 452, 611 
crosslinked, 214 
and fructose, 290 
Povidone-iodine, 615 
Povidonum, 611 
Powdered cellulose, 134, 136 
Powdered fructose, 292 
Powdered sugar, 750 
Powdered talc, 767 
Powdered tragacanth, 786 
Precipitated calcium carbonate, 89 
Precipitated calcium phosphate, 100 
Precipitated calcium sulfate, 105 
Precipitated carbonate of lime, 89 
Precipitated chalk, 89 
Precirol ATO 5, 311 
Pregelatinized starch, 92, 703, 729, 731 
Prejel, 731 
Preservatives 
alcohol, 18 
benzalkonium chloride, 61–62 
benzethonium chloride, 64–65 
Index 909

Preservatives (cont.) 
benzoic acid, 66–67 
benzyl alcohol, 69–70 
boric acid, 74 
bronopol, 76–77 
butylated hydroxyanisole, 79 
butylparaben, 83–84 
carbon dioxide, 116 
cationic, and bentonite, 60 
cetrimide, 152 
cetylpyridinium chloride, 157 
chlorbutanol, 168 
chlorhexidine, 163 
chlorobutanol, 168–169 
chlorocresol, 171 
chloroxylenol, 180 
cresol, 208 
dimethyl ether, 247 
ethylparaben, 287–288 
glycerin, 301 
hexetidine, 323 
imidurea, 359 
inactivation by magnesium trisilicate, 
434 
isopropyl alcohol, 371 
lactic acid, 381 
methylparaben, 359, 466 
monothioglycerol, 482 
parabens, 359 
alkyl chain length, 466 
phenol, 514 
phenoxyethanol, 517–518 
phenylethyl alcohol, 519 
phenylmercuric acetate, 521–522 
phenylmercuric borate, 524 
phenylmercuric nitrate, 526–528 
potassium benzoate, 596 
potassium metabisulfite, 607 
potassium sorbate, 609–610 
propionic acid, 617 
propyl gallate, 619 
propylene glycol, 624 
propylparaben, 359, 629–631 
sodium acetate, 654 
sodium benzoate, 662 
sodium borate, 669 
sodium lactate, 685 
sodium metabisulfite, 690 
sodium propionate, 699 
sodium sulfite, 708 
sorbic acid, 609, 710 
synergists, edetic acid, 260–261 
thimerosal, 777 
xylitol, 824 
see also Antibacterial agents; Antifungal 
agents; Antioxidants 
Pricerine, 301 
Primary sodium phosphate, 696 
Primellose, 211 
Primogran W, 228 
Primojel, 701 
Printing inks, pharmaceutical, shellac, 649 
Priolene, 494 
Priolube 1408, 306 
Pristacin, 157 
Pristerene, 737 
ProBenz PG, 596 
Pro-Bumin, 16 
Procol, 564 
Progallin P, 619 
Prolamins, zein, 828 
Promethazine hydrochloride, 710 
Pronova, 627 
Propagin, 629 
Propan-1-ol, 372 
Propan-2-ol, 371 
Propane, 325 
Propane-1,2-diol, 624 
Propane-1,2-diol alginate, 627 
Propane-1,2,3-triol, 301 
glycerin solutions, 303 
(-)-1,2-Propanediol, 624 
1,2-Propanediol, 624 
1,2-Propanediol cyclic carbonate, 622 
2-[(1-oxohexadecyl)-oxy]-1,3-Propanediyl 
dioctadecanoate and 1,2,3-propane triol, 
311 
1,2,3-Propanetricarboxylic acid, 10 
2-acetyloxy, triethyl ester, 12 
2-hydroxy, tributyl ester, 792 
1,2,3-Propanetriol, 301 
1,2,3-Propanetriol octadecanoate, 308 
1,2,3-Propanetriol triacetate, 790 
Propanoic acid, 617, 700 
calcium salt, 700 
potassium salt, 700 
sodium salt, anhydrous, 700 
zinc salt, 700 
Propanoic acid 2-hydroxy butyl ester, 271 
Propanoic acid 2-hydroxy-ethyl ester, 270 
2-Propanol, 371–372 
2-Propanone, 8, 486 
Propellant 11(trichloromonofluoromethane), 
176 
Propellant 12 (dichlorodifluoromethane), 
176 
Propellant 12 (dichlorodifluoromethane ), 
178 
Propellant 22, 175 
Propellant 114 (dichlorotetrafluoroethane), 
176, 178 
Propellant 134a, 772 
Propellant 142b, 174 
Propellant 152a, 242 
Propellant 227, 321 
Propellants 
butane, 325 
carbon dioxide, 116–117 
chlorodifluoroethane, 174 
chlorodifluoromethane, 175 
chlorofluorocarbons (CFCs), 176 
difluoroethane, 242–243 
dimethyl ether, 246 
fluorocarbon nomenclature, 176, 178 
heptafluoropropane, 321 
hydrocarbons, 325 
isobutane, 325 
nitrogen, 116, 488 
nitrous oxide, 116, 490 
propane, 325 
solubility enhancers, polyoxyl 40 
hydrogenated castor oil, 573 
tetrafluoroethane, 772 
2-Propenylacrylic acid, 710 
Propionic acid, 617, 700 
calcium salt, 700 
potassium salt, 700 
sodium salt 
anhydrous, 699 
hydrate, 699 
zinc salt, 700 
Propyl 3,4,5-trihydroxybenzoate, 619 
Propyl 4-hydroxybenzoate, 629 
Propyl 4-hydroxybenzoate potassium salt, 
631 
Propyl 4-hydroxybenzoate sodium salt, 631 
Propyl alcohol, 372 
Propyl gallate, 619 
ethyl oleate, 274 
Propyl hydride, 325 
Propyl hydroxybenzoate, 629 
soluble, 631 
Propyl parahydroxybenzoate, 629 
Propyl parasept, 629 
Propyl p-hydroxybenzoate, 629 
Propylene carbonate, 622 
(S)-Propylene carbonate, 623 
Propylene glycol, 624, 628 
and methylparabens, 466, 468 
Propylene glycol alginate, 23, 46, 87, 595, 
625, 627, 657 
Propylenglycolum, 624 
Propylic alcohol, 372 
Propylis gallas, 619 
Propylis parahydroxybenzoas, 629 
Propylparaben, 85, 289, 468, 629 
and methylparabens, 466 
see also Parabens 
Propylparaben potassium, 631 
Propylparaben sodium, 631 
Proserum, 16 
ProSolv, 139 
Protachem, 572 
Protachem GMS-450, 308 
Protachem IPP, 376 
Protachem MST, 811 
Protacid, 21 
Protalan anhydrous, 399 
Protalan M-16, 476 
Protalan M-26, 476 
Protanal, 627, 656 
Protoenstatite, 429 
Pruv, 705 
Pseudoacetic acid, 617 
Pseudoboehmite, 36 
Purac 88 PH, 381 
Purasolv BL, 271 
Purasolv EL, 270 
Purasolv ML, 271 
Pure olive oil, 498 
Pure-Bind, 725 
Pure-Cote, 725 
Pure-Dent, 725 
Pure-Dent B851, 734 
Pure-Gel, 725 
Pure-Set, 725 
Purified bentonite, 60 
Purified French chalk, 767 
Purified lanolin, 399 
Purified shellac, 649 
Purified stearic acid, 739 
Purified talc, 767 
Purified water, 802, 805 
Purity 21, 725 
Purity 826, 725 
Purtalc, 767 
PVA, 592 
PVAP (polyvinyl acetate phthalate), 589 
PVP, 611 
PVPP, 214 
PVP/VA, 201 
PVP/VA copolymer, 201 
PX 104, 234 
Pyrisept, 157 
Pyroacetic ether, 8 
Pyroborax, 670 
m-Pyrol, 634 
2-Pyrol, 633 
a-Pyrrolidinone, 633 
910 Index

Pyrrolidone, 633 
2-Pyrrolidone, 633 
Quammonium, 152 
Quassin, 224 
Quaternary ammonium compounds 
benzalkonium chloride, 61 
benzethonium chloride, 64 
cetrimide, 152 
imidurea, 359 
incompatibilities 
anionic emulsifying wax, 807 
nonionic emulsifying wax, 815 
talc, 768 
Quaternium 18-hectorite, 319 
(R)-(-)-2-Hydroxypropionic acid, 381 
R-227, 321 
Racementhol, 459 
Racemic lactic acid, 381 
Racemic menthol, 459–460 
Raffinose, 635 
D-Raffinose, 635 
Raftiline, 362 
Rape oil, 109 
Rapeseed oil, 109 
alternatives, olive oil, 109 
erucic acid, 108–109 
Rayon, 790 
RC Plasticizer DBP, 234 
Red ferric oxide, 364 
Refined almond oil, 31 
Refined bleached shellac, 649 
Refined corn oil, 204 
Refined cottonseed oil, 206 
Refined maize oil, 204 
Refined olive oil, 498 
Refined olive-pomace oil, 499 
Refined sesame oil, 646 
Refined soya oil, 722 
Refined soya-bean oil, 722 
Refined sugar, 744 
Refined sunflower oil, 760 
Refined wax, 819 
Refined wool fat, 399 
Refrigerants 
dimethyl ether, 246 
nomenclature, 176 
refrigerant 22, 175 
refrigerant 134a, 772 
refrigerant 142b, 174 
refrigerant 152a, 242 
Regular bleached shellac, 649 
Rehydragel, 36 
Rehydraphos, 40 
Repeftal, 248 
Resorcinol, 476, 512 
Rhodiarome, 276 
Rhodigel, 821 
Rhovanil, 798 
(R)-(.)-Hydroxybutanedioic acid, 437 
Riboflavin, 56 
Rice starch, 725 
Rice*Trin, 442 
Ricini oleum hydrogenatum, 130 
Ricini oleum virginale, 128 
Ricinoleic acid, 128 
Ricinoleum, 128 
Ricinus communis, 128 
Ricinus oil, 128 
Rimso-50, 250 
Rita CA, 155 
Rita GMS, 308 
RITA HA C-1-C, 681 
Rita IPM, 374 
RITA IPP, 376 
Rita SA, 740 
Ritaceti, 811 
Ritachol 2000, 815 
Ritachol SS, 811 
Ritawax, 402 
Rock salt, 671 
Roclys, 299 
Roferose, 231 
Roquette (Lycasin 80/55), 440 
Rubefacients, ammonia solution, 44 
Rutile, 783 
Rutile titanium dioxide, 782 
SA-99, 659 
Sacarina, 638 
Sacchari spheri, 752 
Saccharin, 29, 638, 642 
and sodium cyclamate, 678 
soluble, 641 
sweetness vs.sucrose, 638 
Saccharin ammonium, 640 
Saccharin calcium, 640 
Saccharin insoluble, 638 
Saccharin sodium, 29, 640–641 
sweetness vs. sucrose, 641 
Saccharinum, 638 
Saccharinum natricum, 641 
Saccharose, 744 
Saccharosonic acid, 264 
Saccharum, 744 
Saccharum lactis, 385 
Sal de Vichy, 665 
Salicylic acid, 66, 436 
Saline, 671 
Salt, 671 
Sanacel, 136 
Sanecta, 53 
Saponite, 319, 418, 421, 644 
Sassolite, 74 
Satialgine H8, 21 
Satin spar, 105 
Satinite, 105 
SBE7-b-CD, 754 
(SBE)7m-beta-CD, 754 
SBECD, 754 
SC-18862, 53 
Scabies, treatment of, 72 
Schardinger dextrin, 217 
SCMC, 120 
SDS (sodium dodecyl sulfate), 687 
Sea salt, 671 
SeaSpen PF, 124 
Sebacic acid, 293 
Secondary calcium phosphate, 93, 96 
Secondary sodium phosphate, 693 
sec-Propyl alcohol, 371 
Selenite, 105 
Self-emulsifying glyceryl monostearate, 310 
Semisynthetic glycerides, 762 
Sentry, 244 
Sentry Simethicone, 652 
Sepiolite, 428 
Sepistab ST 200, 731–732 
Seprison, 158 
Sequestering agents 
citric acid, 79 
citric acid monohydrate, 185 
dibasic sodium phosphate, 693 
monobasic sodium phosphate, 696 
phosphoric acid, 530 
potassium citrate, 603 
sodium citrate dihydrate, 675 
tartaric acid, 770 
Sequestrene AA, 260 
Sequestrene NA3, 262 
Sequestrene NA4, 262 
Serum albumin, 16 
Sesame oil, 31, 109, 205, 207, 506, 646, 723, 
761 
refined, 646 
Sesami oleum raffinatum, 646 
SHCa-1, 318 
Shellac, 589–590, 649 
bleached, 649 
dewaxed orange, 649 
orange, 649 
purified, 649 
refined bleached, 649 
regular bleached, 649 
with stearic acid, 737 
white, 649 
Shellolic acid, 650 
Shogun CT, 722 
(S)-(-)-Hydroxybutanedioic acid, 437 
Silica, 188 
colloidal, 188 
fumed, 188 
Silica colloidalis anhydrica, 188 
Silicic acid, 418 
light anhydrous, 188 
magnesium salt, 428 
magnesium salt (1: 2), hydrate, 434 
Silicic anhydride, 188 
Silicified microcrystalline cellulose, 134 
Silicon dioxide 
colloidal, 139–140, 188 
and fructose, 292 
fumed, 188 
and a-(trimethysilyl-o-methylpoly[oxy 
(dimethylsilylene)], 652 
Silicones, cyclomethicone, 222 
Silicosis, 379 
Silkolene, 509 
Siloxanes, 222 
dimethicone, 244 
Sim 90, 378 
Simethicone, 223, 244–245, 652 
Simeticone, 652 
Simeticonum, 652 
Simulsol, 572 
Simulsol 1293, 130 
Sirius, 471 
Skin-penetration enhancers see Penetration 
enhancers; Transdermal delivery agents 
Snow White, 105, 509 
Soap clay, 58 
Soapstone, 767 
Sobenate, 662 
Soda lye, 683 
Sodii benzoas, 662 
Sodium 1,4-bis(2-ethylhexyl) sulfosuccinate, 
257 
Sodium acetate, 6, 654 
Sodium acetate anhydrous, 654 
Sodium acetate trihydrate, 654 
Sodium acid carbonate, 665 
Sodium acid sulfite, 690 
Sodium alginate, 23, 46, 87, 595, 628, 656 
methylparabens incompatibility, 468 
Sodium ascorbate, 50, 52, 659 
Sodium benzoate, 67, 441, 597, 662 
alternatives to, 596 
Sodium benzoic acid, 662 
Sodium biborate decahydrate, 669 
Index 911

Sodium bicarbonate, 599, 665 
alternatives, potassium bicarbonate, 
598 
citric acid neutralization, 667 
tartaric acid neutralization, 667 
Sodium biphosphate, 696 
Sodium bisulfite, 691 
Sodium borate, 75, 669 
fused, 670 
Sodium borate anhydrous, 670 
Sodium bromide, 153 
Sodium butylhydroxybenzoate, 85 
Sodium calcium edetate, 262 
Sodium carboxymethyl guar, 316 
Sodium carboxymethyl starch, 701 
Sodium carboxymethylcellulose, 120 
Sodium cellulose glycolate, 120 
Sodium chloride, 601, 671 
Sodium citrate anhydrous, 676–677 
Sodium citrate dihydrate, 187, 675 
Sodium citrate tertiary, 675 
Sodium CMC, 120 
Sodium cyclamate, 29, 678 
with acesulfame potassium, 679 
and saccharin, 678 
with saccharin sodium, 679 
sweetness vs.sucrose, 678 
Sodium cyclohexanesulfamate, 678 
Sodium N-cyclohexylsulfamate, 678 
Sodium dihydrogen orthophosphate, 696 
Sodium dihydrogen phosphate, 696 
anhydrous, 696 
dihydrate, 696 
monohydrate, 696 
Sodium dioctyl sulfosuccinate, 257 
Sodium dodecyl sulfate, 687 
Sodium edetate, 261–262 
Sodium erythorbate, 265 
Sodium ethanoate, 654 
Sodium ethyl hydroxybenzoate, 289 
Sodium ethylmercurithiosalicylate, 777 
Sodium L-glutamate, 480 
Sodium glutamate monohydrate, 480 
Sodium (E,E)-hexa-2,4-dienoate, 712 
Sodium hyaluronate, 681 
Sodium hydrate, 683 
Sodium hydrogen L-(.)-2-aminoglutarate 
monohydrate, 480 
Sodium hydrogen carbonate, 665 
Sodium hydrogen sulfite, 691 
Sodium hydroxide, 606, 683 
Sodium a-hydroxypropionate, 685 
Sodium indigotin disulfonate, 197 
Sodium iodide, 673 
Sodium lactate, 382, 685 
Sodium lactate solution, 685 
Sodium laurate, 407 
Sodium laurilsulfate, 687 
Sodium lauryl sulfate, 151, 687, 808 
and cationic surfactants, 688 
gelatin capsule formation, 295 
Sodium metabisulfite, 608, 690, 709 
Sodium metabisulphite, 690 
Sodium methyl hydroxybenzoate, 469 
Sodium monododecyl sulfate, 687 
Sodium monolauryl sulfate, 687 
Sodium monostearyl fumarate, 705 
Sodium myristate, 484–485 
Sodium nitrite, sodium ascorbate, 659 
Sodium o-benzosulfimide, 641 
Sodium orthophosphate, 693 
Sodium palmitate, 501–502 
Sodium phosphate 
dibasic, 693, 697 
dihydrate, 693 
dodecahydrate, 693 
heptahydrate, 693 
hydrate, 693 
monohydrate, 693 
monobasic, 694, 696 
secondary, 693 
tribasic, 694 
Sodium phosphate dihydrate, monobasic, 696 
Sodium phosphate monohydrate, monobasic, 
696 
Sodium polymannuronate, 656 
Sodium propanoate hydrate, 699 
Sodium propionate, 618, 699 
anhydrous, 700 
Sodium propionate hydrate, 699 
Sodium propyl hydroxybenzoate, 631 
Sodium pyroborate, 670 
Sodium pyroborate decahydrate, 669 
Sodium pyrosulfite, 690 
Sodium sorbate, 712 
Sodium starch glycolate, 701, 703 
Sodium stearyl fumarate, 705 
Sodium sulfate, 690 
Sodium sulfite, 690–691, 708 
dried, 708 
Sodium sulfite anhydrous, 708 
Sodium sulfite heptahydrate, 709 
Sodium sulphite anhydrous, 708 
Sodium tetraborate anhydrous, 670 
Sodium tetraborate decahydrate, 669 
Sodium/calcium salt mix, of poly(methylvinyl 
ether/maleic anhydride), 561 
Soft water, 805 
Soft white, 509 
Softisan 154, 800 
Soiae oleum raffinatum, 722 
Soja bean oil, 722 
Solactol, 270 
Solani amylum, 725 
Solbrol A, 287 
Solbrol P, 629 
Solka-Floc, 136 
Solkane 134a, 772 
Solkane 142b, 174 
Solkane 152a, 242 
Solkane 227, 321 
Solubilizing agent, macrogol 15 
hydroxystearate, 416 
Solubilizing agents 
benzalkonium chloride, 61 
benzethonium chloride, 64 
benzyl alcohol, 69 
benzyl benzoate, 72 
cetylpyridinium chloride, 157 
cyclodextrins, 217–218 
glycerin monostearate, 308 
lecithin, 409 
meglumine, 457 
perfume bases, 573 
poloxamer, 535 
polyethylene alkyl ethers, 565 
polyoxyethylene alkyl ethers, 565 
polyoxyethylene castor oil derivatives, 
573 
polyoxyethylene sorbitan fatty acid 
esters, 581 
polyoxyethylene stearates, 586 
povidone, 611 
2-pyrrolidone, 633 
sodium bicarbonate, 665 
sorbitan esters, 714 
stearic acid, 737 
sulfobutylether b-cyclodextrin, 754 
see also Dissolution enhancers; Solvents; 
Surfactants; Wetting agents 
Soluble gluside, 641 
Soluble indigo blue, 197 
Soluble methyl hydroxybenzoate, 469 
Soluble propyl hydroxybenzoate, 631 
Soluble saccharin, 641 
Solugel, 295 
Soluphor P, 633 
Solutab, 211 
Solutol HS 15, 416 
Solvanom, 248 
Solvarone, 248 
Solvent, acetone, 8 
Solvents 
albumin, 16 
alcohol, 18 
almond oil, 30 
benzyl alcohol, 69 
benzyl benzoate, 72 
carbon dioxide, 116 
castor oil, 128 
corn oil (maize), 204 
cottonseed oil, 206 
dibutyl phthalate, 234 
diethyl phthalate, 240 
dimethyl ether, 246 
dimethyl phthalate, 248 
dimethyl sulfoxide, 250 
dimethylacetamide, 253 
ethyl acetate, 268 
ethyl lactate, 270 
ethyl oleate, 274 
glycerin, 301 
glycofurol, 313 
isopropyl alcohol, 371 
isopropyl myristate, 374 
isopropyl palmitate, 376 
light mineral oil, 474 
medium-chain triglycerides, 454 
mineral oil, 471 
monoethanolamine, 478 
octyldodecanol, 492 
olive oil, 498 
peanut oil, 505 
polyethylene glycol, 545–546 
polyoxyl 35 castor oil, 573 
propylene carbonate, 622 
propylene glycol, 624 
2-pyrrolidone, 633 
sesame oil, 646 
soybean oil, 722 
sunflower oil, 760 
triacetin, 790 
triethanolamine, 794 
water, 802 
water-miscible, 624 
see also Solubilizing agents 
Sorbic acid, 359, 609–610, 710 
(E,E)-Sorbic acid, 710 
Sorbic acid potassium salt, 609 
Sorbistat K, 710 
Sorbitan diisostearate, 717 
Sorbitan dioleate, 717 
Sorbitan, esters monodecanoate (sorbitan 
monolaurate), 713–714 
Sorbitan esters (sorbitan fatty acid esters), 
584, 713 
Sorbitan laurate, 713, 717 
Sorbitan monolaurate (sorbitan, esters 
monodecanoate), 713–714 
912 Index

Sorbitan monooleate, 713 
Sorbitan monopalmitate, 713–714 
Sorbitan monostearate, 713 
Sorbitan oleate, 713, 717 
Sorbitan palmitate, 713, 717 
Sorbitan sesquiolate, 717 
Sorbitan sesquioleate, 713, 772 
Sorbitan sesquistearate, 717 
Sorbitan stearate, 713, 717 
Sorbitan triisostearate, 717 
Sorbitan trioleate, 713–714, 717, 772 
Sorbitan tristearate, 717 
Sorbitani lauras, 713 
Sorbitani oleas, 713 
Sorbitani palmitas, 713 
Sorbitani sesquioleas, 713 
Sorbitani stearas, 713 
Sorbitani trioleas, 713 
Sorbite, 718 
Sorbitol, 267, 439–441, 452, 718 
incompatibilities 
methylparabens, 468 
polyethylene glycols, 719 
vs.mannitol, 452 
and polydextrose, 543 
D-Sorbitol, 440 
Sorbitol Instant, 718 
Sorbitol liquid, 720 
Sorbitol solution 70%, 720 
Sorbitolum, 718 
Sorbo, 720 
Sorbogem, 718 
Soya lecithin, 772 
Soya oil, refined, 722 
Soyabean oil, 722 
hydrogenated, 722 
refined, 722 
Soybean lecithin, 409 
Soybean oil, 31, 109, 205, 207, 506, 647, 
722, 761 
hydrogenated, 800 
Soybean phosphatides, mixed, 409 
Soybean phospholipids, 409 
Spectracel, 346 
Spermaceti, synthetic, 811 
Spermaceti wax, 812 
Spermaceti wax replacement, 811 
Spirit of hartshorn, 44 
Splenda, 742 
Sporocides, chlorocresol, 172 
Spress B820, 731 
St. John’s bread, 148 
Stabilizers, glyceryl monooleate, 306 
Stabilizing agents 
acacia, 1 
agar, 14 
albumin, 16 
alginic acid, 21 
aluminum stearate, 42 
ammonium alginate, 46 
ascorbic acid, 48 
ascorbyl palmitate, 51 
bentonite, 58 
butylated hydroxytoluene, 81 
calcium alginate, 86 
calcium stearate, 102 
carboxymethylcellulose calcium, 118 
carboxymethylcellulose sodium, 120 
carrageenan, 124 
ceratonia, 148 
colloidal silicon dioxide, 188 
cyclodextrins, 217–218 
diethanolamine, 238 
edetates, 260 
ethylcellulose, 278 
ethylene glycol palmitostearate, 283 
glycerin monostearate, 308 
guar gum, 315 
hydroxypropyl cellulose, 336 
hypromellose, 346 
invert sugar, 747 
lecithin, 409 
magnesium aluminum silicate, 418 
mineral oil and lanolin alcohols, 476 
monoethanolamine, 478 
pectin, 507 
polacrilin potassium, 532 
poloxamer, 535 
polyvinyl alcohol, 592 
potassium alginate, 594 
potassium chloride, 600 
povidone, 611 
propyl gallate, 619 
propylene glycol, 624 
propylene glycol alginate, 627 
raffinose, 635 
sodium acetate, 654 
sodium alginate, 656 
sodium borate, 669 
sodium stearyl fumarate, 707 
sorbitol, 718 
stearyl alcohol, 740 
sulfobutylether b-cyclodextrin, 754 
trehalose, 788 
white wax, 817 
xanthan gum, 821 
xylitol, 824 
yellow wax, 819 
zinc acetate, 830 
Stachyose, 636 
Staflex DBP, 234 
Starch, 444, 452, 703, 725, 732, 735, 753 
corn, 725, 729 
sterilizable, 732, 734 
maize, 725, 729 
sterilizable, 729, 732, 734 
modified, dusting powder, 734 
potato, 725 
pregelatinized, 92, 703, 729, 731, 735 
sterilizable maize, 729, 732, 734 
wheat, 725 
Starch 1500 G, 731 
Starch 1500 LM, 732 
Starch carboxymethyl ether, sodium salt, 
701 
Starch gum, 228 
Starch sugar, 231 
Starch syrup, 299 
Starch-derivative dusting powder, 734 
Star-Dri, 442, 444 
Starfol Wax CG, 811 
Stearalkonium hectorite, 319 
Steareth-20, 564 
Steareth-N, 564 
Stearic acid, 103, 336, 407, 431, 484, 501, 
587, 589, 731, 737, 833 
aluminum dihydroxide salt, 42 
aluminum salt, 42 
calcium salt, 102 
castor oil, 128 
and corn oil, 204 
and cottonseed oil, 206 
magnesium salt, 430 
monoester with glycerol, 308 
peanut oil, 505 
polyethoxylated, 585 
purified, 739 
sunflower oil, 760 
zinc salt, 832 
Stearic monoglyceride, 308 
Stearol, 740 
Stearyl alcohol, 151, 156, 740 
Stearylamine, 111 
Steatite, 767 
Stenol, 740 
Stepan GMO, 306 
Stepan GMS, 308 
Stepan IPM, 374 
Stepan IPP, 376 
Stereophanic acid, 737 
Sterile water 
for inhalation, 805 
for injection, 805 
for irrigation, 805 
Sterile water for inhalation, 805 
Sterile water for injection, 805 
Sterile water for irrigation, 805 
Sterilizable corn starch, 734 
Sterilizable maize starch, 729, 734 
Sterilizing agents 
potassium metabisulfite, 607 
see also Disinfectants 
Sterisil, 323 
Steri/Sol, 323 
Sternpur, 409 
Sterogenol, 158 
Sterotex, 800 
Sterotex HM, 800 
Sterotex K, 131 
Stiffening agents 
anionic emulsifying wax, 807 
carnauba wax, 810 
cetyl alcohol, 155 
cetyl esters wax, 811 
dextrin, 228 
hydrogenated castor oil, 130 
microcrystalline wax, 813 
nonionic emulsifying wax, 815 
paraffin, 503 
stearyl alcohol, 740 
white wax, 817 
yellow wax, 819 
see also Gelling agents; Thickening 
agents; Viscosity-increasing agents 
Strese & Hofmann’s Hectorite, 318 
Strong ammonia solution, 44 
Stronger ammonia water, 44 
Substituted glucens, 161 
Sucaryl, 679 
Sucaryl calcium, 679 
Sucaryl sodium, 641 
Succinylsulfathiazole, 276 
Sucralfate, 428 
Sucralose, 742 
Sucrose, 233, 292, 299, 636, 743–744, 749, 
751, 753 
alternatives to see Sweetening agents 
direct compacting, 748 
gelatin capsule formation, 295 
sweetness 
vs. acesulfame potassium, 4 
vs. aspartame, 53 
vs. fructose, 290, 292 
vs. lactitol, 384 
vs. saccharin, 638 
vs. saccharin sodium, 641 
vs. xylitol, 827 
vs. artificial sweetening agents, 640, 642 
see also Sugar 
Index 913

Sucrose syrup, 440 
Sucticide, 152 
Sugar, 744 
alternatives to see Sweetening agents 
compressible, 747–748, 753 
confectioner’s, 747, 750, 753 
icing, 750 
powdered, 750 
refined, 744 
see also Sucrose 
Sugar coating adjuncts, 750 
sucrose, 744 
Sugar seeds, 752 
Sugar spheres, 747, 749, 751–752 
Sugar-free lozenges, 542 
Sugartab, 749 
Suglets, 752 
Sukor, 486 
Sulfate of lime, 106 
anhydrous, 105 
Sulfinylbismethane, 250 
o-Sulfobenzimide, 638 
o-Sulfobenzoic acid imide, 638 
Sulfo-butanedioic acid 1,4-bis(2-ethylhexyl) 
ester, sodium salt, 257 
Sulfobutylether b-cyclodextrin, 754 
sodium salt, 754 
1-p-Sulfophenylazo-2-naphthol-6-sulfonic 
acid disodium salt, 198 
Sulfuric acid, 758 
dilute, 759 
fuming, 759 
monododecyl ester sodium salt, 687 
Sulfurous acid disodium salt, 708 
Sulphinylbismethane, 250 
Sulphuric acid, 758 
Sunett, 4 
Sunflower oil, 205, 207, 506, 647, 723, 
760 
refined, 760 
Sunflowerseed oil, 760 
Sunmalt, 447 
Sunmalt S, 447 
Sunscreens, 761 
Sunset yellow FCF, 196, 198 
Superiore, 767 
Super-Tab Anhydrous, 385 
Super-Tab Spray-Dried, 396 
Suppocire, 762 
Suppository bases, 550, 801 
agar, 14 
factors affecting drug release, 762 
hard fat, 456, 762 
additives, 762 
chemical reactivity, 762 
melting characteristics, 762 
rheology, 762 
poloxamer, 535 
polyethylene glycol, 545 
Supronic, 535 
Surelease, 278 
Sureteric, 589 
Surfactants 
anionic 
docusate sodium, 257 
emulsifying wax BP, 808, 816 
and self-emulsifying glyceryl 
monooleate, 306 
sodium lauryl sulfate, 687 
cationic 
benzethonium chloride, 64 
cetrimide, 152 
cetylpyridinium chloride, 157 
sodium lauryl sulfate incompatibility, 
688 
chlorhexidine activity, 165 
and emulsifying waxes, 808, 816 
lauric acid, 406 
nonionic 
and butylparaben, 84 
and ethylparaben, 288 
and methylparaben, 468 
and propylparaben, 630 
and sorbic acid, 710–711 
emulsifying wax USP, 808, 816 
glyceryl monooleate, 306 
polyoxyethylene alkyl ethers, 564–565 
polyoxyethylene castor oil derivatives, 
573 
polyoxyethylene sorbitan fatty acid 
esters, 581 
polyoxyethylene stearates, 585 
polysorbate 80, 468 
sorbitan esters, 714 
triethyl citrate, 796 
see also Solubilizing agents; Wetting 
agents 
Surgical spirit, 20 
Suspending agents 
acacia, 1 
agar, 14 
alginic acid, 21 
bentonite, 58 
calcium stearate, 102 
carbomers, 111 
carboxymethylcellulose calcium, 118 
carboxymethylcellulose sodium, 120 
carrageenan, 124 
cellulose, powdered, 136 
cellulose, powdered, 136 
ceratonia, 148 
colloidal silicon dioxide, 188 
dextrin, 228 
gelatin, 295 
guar gum, 315 
hydroxyethyl cellulose, 330 
hydroxyethylmethyl cellulose, 334 
hydroxypropyl cellulose, 336 
hypromellose, 346 
kaolin, 378 
magnesium aluminum silicate, 418 
maltitol solution, 440 
medium-chain triglycerides, 454 
methylcellulose, 462 
microcrystalline cellulose, 132 
microcrystalline cellulose and 
carboxymethylcellulose sodium, 134 
polycarbophil, 539 
polyethylene glycol, 545 
potassium alginate, 594 
povidone, 611 
propylene glycol alginate, 627 
sesame oil, 646 
sodium alginate, 656 
sodium starch glycolate, 701 
sorbitan esters, 714 
sucrose, 744 
tragacanth, 785 
xanthan gum, 821 
Sustained-release agents 
acetyltributyl citrate, 10 
agar, 14 
alginic acid, 21 
carbomers, 111 
carnauba wax, 809 
carrageenan, 124 
cellulose acetate, 142 
glycerin monostearate, 308 
glyceryl monooleate, 306 
glyceryl palmitostearate, 311 
guar gum, 315 
hydrogenated castor oil, 130 
hydroxypropyl cellulose, 336 
hypromellose, 346 
hypromellose acetate succinate, 350 
hypromellose phthalate, 354 
mannitol, 449 
methylcellulose, 462 
oleyl alcohol, 496 
peanut oil, 505 
polacrilin potassium, 532 
polyethylene oxide, 551 
polyvinyl alcohol, 592 
sesame oil, 646 
sodium alginate, 656 
sodium hyaluronate, 681 
stearic acid, 737 
sugar spheres, 752 
tributyl citrate, 792 
triethyl citrate, 796 
white wax, 817 
xanthan gum, 821–822 
yellow wax, 819 
zein, 828 
see also Controlled-release agents 
Sustane, 81 
Suva 134a, 772 
Swanlac, 649 
Sweet almond oil, 30 
Sweet One, 4 
Sweetening agents 
acesulfame potassium, 4–5 
alitame, 28 
artificial vs.sucrose, 640, 679 
aspartame, 53, 55 
compressible sugar, 748 
confectioner’s sugar, 750 
dextrose, 231 
erythritol, 266 
fructose, 290 
glycerin, 301 
inulin, 362 
isomalt, 366 
lactitol, 383 
liquid glucose, 299 
maltitol, 438 
maltitol solution, 440 
maltose, 447 
mannitol, 449 
neohesperidin dihydrochalcone, 486 
polydextrose, 542 
relative sweetness, 292 
saccharin, 638 
saccharin sodium, 641 
sodium cyclamate, 678 
sorbitol, 718, 720 
sucralose, 742 
sucrose, 744 
synergistic effects, 640, 643, 679 
thaumatin, 775 
trehalose, 788 
xylitol, 824 
Sylvine, 601 
Sylvinite, 601 
Sylvite, 601 
Synaceti 116, 811 
Syncal CAS, 640 
Synperonic, 535 
Synthetic alpha tocopherol, 32 
914 Index

Synthetic magnesium silicate, 428 
Synthetic paraffin, 504 
Synthetic spermaceti, 811 
Syrupy phosphoric acid, 530 
Tabfine D-100, 231 
Table salt, 671 
Tablet binders/binding agents see Binding 
agents 
Tablet coating agents see Coating agents 
Tablet film former see Film-forming agents 
Tablet White, 725 
Tablet/capsule diluents see Diluents (tablet/ 
capsule) 
Tablet/capsule disintegrants see Disintegrants 
(tablet/capsule) 
Tablet/capsule lubricants see Lubricants 
(tablet/capsule) 
Tablet/capsule monogramming, shellac, 649 
Tablets, chewable see Chewable tablet 
formulations; Medicated confectionery 
bases 
Tablitz, 731 
Tablo, 701 
Tabulose, 132 
Talc, 60, 178, 319, 421, 429, 435, 645, 767, 
800 
methylparabens incompatibility, 468 
powdered, 767 
Talcum, 767 
Talha gum, 1 
Talin, 775 
Tangantangan, 128 
Tannic acid, 14 
Tapi, 442 
Tapioca, 725 
Tapioca (cassava) starch, 725, 729 
Tartaric acid, 187, 294, 437, 598, 770 
effervescent tablet formulations, 665 
sodium bicarbonate neutralization, 
667 
d-Tartaric acid, 770 
L-(+)-Tartaric acid, 770 
Tartrazine, 196, 198 
Taste masking agents, erythritol, 266 
taste-masking agents, glyceryl 
palmitostearate, 311 
Taumatin, 775 
Taylorite, 58 
TBC, 792 
TEA, 794 
Tealan, 794 
TEC, 796 
Teel oil, 646 
Tegin, 306, 308 
Tegin 503, 308 
Tegin 515, 308 
Tegin 4100, 308 
Tegin M, 308 
Tego Alkanol 16, 155 
Tego Alkanol 18, 740 
Tego Alkanol 1618, 150 
Tego Alkanol 6855, 150 
Tegosept B, 83 
Tegosept E, 287 
Tegosoft M, 374 
Tegosoft P, 376 
Tegostearic, 737 
Telfairic acid, 414 
Tenox BHA, 79–80 
Tenox BHT, 81 
Tenox PG, 619 
Terra alba, 105 
Tertiary calcium phosphate, 100 
Tetracemate dipotassium, 261 
Tetracemate tetrasodium, 262 
Tetracemic acid, 260 
Tetracemin, 262 
Tetracycline, 379, 428 
n-Tetradecanoic acid, 484 
1-methylethyl ester, 374 
Tetradecyltrimethylammonium bromide, 
153 
Tetrafluoroethane, 243, 322, 772 
Tetraglycol, 313 
a-[(Tetrahydro-2-furanyl)methyl]-o-hydroxypoly(
oxy-1,2-ethanediyl), 313 
a-(tetrahydrofuranyl)-o-Hydroxypoly(
oxyethylene), 313 
Tetrahydrofurfuryl alcohol, 313 
Tetrahydrofurfuryl alcohol polyethylene 
glycol ether, 313 
Tetrahydroxybutane, 266 
(.)-(2R,40R,80R)-2,5,7,8-Tetramethyl-2- 
(4,080,120-trimethyltridecyl)-6-chromanol, 
33 
(.)-(2R,40R,80R)-2,5,7,8-Tetramethyl-2- 
(4,080,120-trimethyltridecyl)-6-chromanyl 
acetate, 33 
(
)-(2RS,40 RS,80 RS)-2,5,7,8-Tetramethyl-2- 
(40 ,80 ,120 -trimethyltridecyl)-6- 
chromanol, 32 
(
)-(2RS, 40RS, 80RS)- 2,5,7,8-Tetramethyl-2- 
(4,0 80, 120-trimethyltridecyl)-6-chromanyl 
acetate, 33 
Tetrasodium edetate, 262 
Tetrasodium ethylenebis(iminodiacetate), 
262 
Tetrasodium ethylenediaminetetraacetate, 
262 
Texapon K12P, 687 
Texofor A, 564 
Texofor A10, 564 
TGS, 742 
Thalin, 775 
Thaumatin, 775 
Thaumatine, 775 
Thaumatins, 775 
Thaumatins protein, 775 
Theobroma oil, 765, 807 
Therapeutic agents 
albumin, 16 
alginic acid, 21 
almond oil, 30–31 
alpha tocopherol, 32 
aluminum hydroxide, 426 
ammonia solution, 44 
anionic emulsifying wax, 807 
ascorbic acid, 48 
aspartame, 53 
attapulgite, 56 
bentonite, 58 
benzethonium chloride, 65 
benzoic acid, 66 
benzyl alcohol, 69 
benzyl benzoate, 72 
butylated hydroxytoluene, 81 
calcium carbonate, 89 
calcium sulfate, 105 
cellulose acetate, 142 
cellulose acetate phthalate (CAP), 145 
chlorbutanol, 168 
chloroxylenol, 180 
citric acid monohydrate, 185 
cottonseed oil, 206 
dextrin, 228 
dextrose, 231 
dibasic sodium phosphate, 693 
diluted hydrochloric acid, 329 
dimethicone, 244 
dimethyl sulfoxide, 250–251 
docusate sodium, 257–258 
edetic acid, 260 
fumaric acid, 293 
gelatin, 295 
glycerin, 301 
guar gum, 315 
hexetidine, 323 
hydrochloric acid, 328 
isopropyl alcohol, 371 
isopropyl myristate, 374 
kaolin, 378 
lactic acid, 381 
lactitol, 383 
lecithin, 409 
light mineral oil, 474 
magnesium carbonate, 422 
magnesium oxide, 426 
magnesium silicate, 429 
magnesium trisilicate, 434 
malic acid, 436 
maltodextrin, 442 
maltol, 446 
mannitol, 449 
medium-chain triglycerides, 454 
menthol, 459 
methylcellulose, 462 
mineral oil, 471–472, 474 
monobasic sodium phosphate, 696 
monoethanolamine, 478 
monothioglycerol, 482 
nitrous oxide, 490 
olive oil, 498 
peanut oil, 505 
petrolatum, 509 
phenol, 514 
phosphoric acid, 530 
poloxamers, 535 
potassium benzoate, 596 
potassium bicarbonate, 598 
potassium chloride, 600 
potassium citrate, 603–604 
potassium hydroxide, 605 
propylene glycol, 625 
simethicone, 652 
sodium alginate, 656 
sodium ascorbate, 659 
sodium bicarbonate, 665 
sodium citrate dihydrate, 675 
sodium propionate, 699–700 
sorbitol, 718 
soybean oil, 722 
starch, 726 
sucrose, 744 
sulfuric acid, 758 
sunflower oil, 760 
thymol, 780 
titanium oxide, 782 
triethanolamine, 794 
trisodium edetate, 262 
vanillin, 798 
xylitol, 824 
Thermal stabilizers, colloidal silicon dioxide, 
188 
Thiamin (vitamin B1), 608 
Thickening agents 
agar, 14 
ammonium alginate, 46 
calcium alginate, 86 
Index 915

Thickening agents (cont.) 
colloidal silicon dioxide, 188 
dextrin, 228 
ethylcellulose, 278 
ethylene glycol palmitostearate, 283 
hydroxyethyl cellulose, 330 
hydroxyethylmethyl cellulose, 334 
hydroxypropyl cellulose, 336 
hydroxypropyl starch, 344 
hypromellose, 346 
methylcellulose, 462 
octyldodecanol, 492 
pectin, 507 
polycarbophil, 539 
polyethylene glycol, 545 
polyethylene oxide, 551 
potassium alginate, 594 
trehalose, 788 
xanthan gum, 821 
zinc stearate, 832 
see also Gelling agents; Stiffening agents; 
Viscosity-increasing agents 
Thimerosal, 61, 261, 522, 525, 528, 777 
Thimerosal Sigmaultra, 777 
Thin vegetable oil, 454 
Thioglycerin, 482 
1-Thioglycerol, 482 
Thiomersal, 777 
Thiomersalate, 777 
Thiomersalum, 777 
Thiothixene, 798 
Thyme camphor, 780 
Thymic acid, 780 
Thymol, 780 
and menthol, 460 
m-Thymol, 780 
Thymolum, 780 
TIC Pretested, 627 
Timol, 780 
Timolol, 250, 609 
Tioxide, 782 
TiPure, 782 
Titanic anhydride, 782 
Titanii dioxidum, 782 
Titanium dioxide, 193, 196, 199, 357, 782 
anatase, 782 
Titanium oxide, 782 
TM-b-CD, 220 
Tocopherol, 32–34 
(2R,40R ,80R)-alpha-Tocopherol, 32 
alpha Tocopherol, 32–34, 51 
and ascorbyl palmitate, 32 
and lecithin, 32 
and linoleic acid, 32 
and methyl linolenate, 32 
natural, 33 
synthetic, 32 
alpha-Tocopherolum, 32 
d-alpha Tocopherol, 32–33 
d-alpha Tocopheryl acetate, 33 
d-alpha Tocopheryl acid succinate, 33– 
34 
dl-alpha Tocopherol, 32 
dl-alpha Tocopheryl acetate, 33 
dl-alpha Tocopheryl acid succinate, 33– 
34 
beta Tocopherol, 33–34 
and canola oil, 109 
delta Tocopherol, 33–34 
d-a-Tocopherol, 32–34 
dl-a-Tocopherol, 32–34 
(
)-a-Tocopherol acetate, 33 
(.)-a-Tocopherol hydrogen succinate, 34 
dl-a-Tocopherol succinate, 34 
a-Tocopheroli acetas, 33 
Tocopherols excipient, 33–34 
a-Tocopherolum, 32 
d-a-Tocopheryl acetate, 33 
dl-a-Tocopheryl acetate, 33 
d-a-Tocopheryl acid succinate, 34 
dl-a-Tocopheryl acid succinate, 34 
Tolbutamide, 421 
a-Toluenol, 69 
Tonicity agents 
dextrose, 231 
glycerin, 301 
mannitol, 449 
potassium chloride, 600 
sodium chloride, 671 
Topanol, 81 
Trag, 785 
Tragacanth, 2, 148–149, 316, 785 
and acacia, 1 
and guar gum, 316 
methylparabens incompatibility, 468 
powdered, 786 
Tragacantha, 785 
Tragacantha gum, 785 
Tragant, 785 
Transdermal delivery agents 
acetyltributyl citrate, 10 
dimethyl sulfoxide, 250 
ethylene vinyl acetate, 285 
glyceryl monooleate, 306 
isopropyl myristate, 374 
isopropyl palmitate, 376 
light mineral oil, 474 
polymethacrylates, 554 
polyvinyl alcohol, 592 
sesame oil, 646 
sodium carboxymethyl guar, 316 
stearyl alcohol, 740 
see also Penetration enhancers 
Transmissible Spongiform Encephalopathy 
(TSE), 297 
Trehalose, 788–789 
Trehalose dihydrate, 788 
Triacetin, 790 
Triacetyl glycerine, 790 
Tribasic calcium phosphate, 100 
Tribasic sodium phosphate, 694 
Tribehenin, 304 
Tributyl acetylcitrate, 10 
Tributyl citrate, 11, 13, 792, 796–797 
Tri-n-butyl citrate, 792 
Tributyl citrate acetate, 10 
Tributyl ester, 10, 792 
Tributyl 2-hydroxy-1,2,3- 
propanetricarboxylate, 792 
Tributyl O-acetylcitrate, 10 
Tributylis acetylcitras, 10 
Tri-Cafos, 100 
TRI-CALWG, 100 
Tricalcii phosphate, 100 
Tricalcium diorthophosphate, 100 
Tricalcium orthophosphate, 100 
Tricalcium phosphate, 100 
1,1,1-Trichloro-2-methyl-2-propanol, 168 
Trichlorofluoromethane, 176 
10,4 ,06 0-Trichlorogalactosucrose, 742 
Trichloromonofluoromethane, 176 
Montreal Protocol, 178 
4,10,60-Trichloro-4,1,060-trideoxy-galactosucrose, 
742 
Trichloro-tert-butanol, 168 
b,b,b-Trichloro-tert-butyl alcohol, 168 
Tricresol, 208 
1-Tridecanecarboxylic acid, 484 
Triethanolamine, 239, 479, 794 
Triethyl acetylcitrate, 12 
Triethyl citrate, 11, 13, 793, 796 
Triethyl citrate acetate, 12 
Triethyl O-acetylcitrate, 12 
Triethylis citras, 796 
Triethylolamine, 794 
Triglycerida saturata media, 454 
Triglyceride, caprylic/capric, 454 
Triglycerides, medium-chain, 454, 765, 801 
3,4,5-Trihydroxybenzoic acid propyl ester, 
619 
Trihydroxyborene, 74 
9,10,16-Trihydroxypalmitic acid, 650 
8,9,15-Trihydroxypentadecane-1-carboxylic 
acid, 650 
Trihydroxypropane glycerol, 301 
Trihydroxytriethylamine, 794 
Triiron tetraoxide, 364 
N,N,N-Trimethyl-1-tetradecanaminium 
bromide, 153 
Trimethyl-b-cyclodextrin, 219–220, 756 
N,N,N-Trimethyldodecylammonium 
bromide, 153 
N,N,N-Trimethylhexadecylammonium 
bromide, 153 
a-(trimethylsilyl)-o- 
Methylpoly[oxy(dimethylsilylene)], 244 
Trimethyltetradecylammonium bromide, 
152–153 
5,7,8-Trimethyltocol, 32 
a-(Trimethysilyl-omethylpoly[
oxy(dimethylsilylene)] mixture 
with silicon dioxide, 652 
Tri-n-butyl citrate, 792 
Tripotassium citrate monohydrate, 603 
TriseptB, 83 
Tris(hydroxyethyl)amine, 794 
Trisodium 2-hydroxypropane-1,2,3- 
tricarboxylate dihydrate, 675 
Trisodium citrate, 675 
anhydrous, 677 
Trisodium edetate, 261–262 
Trisodium ethylenediaminetetraacetate, 262 
Trisodium 2-hydroxy-1,2,3- 
propanetricarboxylic acid, 677 
Trisodium orthophosphate, 695 
Trisodium phosphate, 695 
Tri-Stat IU, 359 
Tri-Sweet, 53 
TRI-TAB, 100 
Tritici amylum, 725 
Trolamine, 794 
Trolaminum, 794 
Tronox, 782 
TSE see Transmissable Spongiform 
Encephalopathy 
TSP, 695 
T-Wax, 815 
Tylopur, 346 
Tylopur MH, 334 
Tylopur MHB, 334 
Tylose CB, 120 
Tylose MB, 334 
Tylose MH, 334 
Tylose MHB, 334 
Tylose PHA, 330 
U-1149, 293 
Ultramarine blue 
and butylparaben, 84 
916 Index

and ethylparaben, 289 
and propylparaben, 631 
Ultrez, 111 
1-Undecanecarboxylic acid, 406 
Unimate GMS, 308 
Unimate IPP, 376 
Unimoll DB, 234 
Unimoll DM, 248 
Uniphen P-23, 83, 466, 629 
Unipure LD, 731 
Unipure WG220, 731 
Unisept, 166 
Unisept B, 83 
Urethane hydrogels, 546 
USAF EK-P-583, 293 
USG Terra Alba, 105 
Vaccine adjuvants 
aluminum hydroxide adjuvant, 36 
aluminum phosphate adjuvant, 40 
VA/ethylene copolymer, 285 
Vanillal, 276 
Vanillic aldehyde, 798 
Vanillin, 276–277, 798 
Vanillinum, 798 
Vanzan NF, 821 
Vaselinum album, 510 
Vaselinum flavum, 509 
Veegum, 418 
Veegum HS, 58 
Vegetable glycerides, hydrogenated, 762 
Vegetable lecithin, 409 
Vegetable oil 
hydrogenated, 456, 800 
type I, 131, 207, 800 
type II, 801 
thin, 454 
Veltol, 445 
Veltol Plus, 272 
Versene, 262 
Versene Acid, 260 
Versene CA, 262 
Versene-9, 262 
Vestimol C, 234 
Vianol, 81 
Vinegar, artificial, 7 
Vinegar acid, 6 
Vinegar, artificial, 7 
Vinegar naphtha, 268 
Vinyl acetate, copolymer with 1-vinyl-2- 
pyrrolidinone, 201 
Vinyl acetate/ethylene copolymer, 285 
Vinyl alcohol polymer, 592 
1-Vinyl-2-pyrrolidinone 
copolymer with vinyl acetate, 201 
homopolymer, 214 
1-Vinyl-2-pyrrolidinone polymer, 611 
Virgin almond oil, 30 
Virgin castor oil, 128 
Virgin olive oil, 499 
Viricides see Antiviral agents 
Viscarin, 124 
Viscosity-increasing agents 
acacia, 1 
agar, 14 
alginic acid, 21 
bentonite, 58 
carbomers, 111 
carboxymethylcellulose calcium, 118 
carboxymethylcellulose sodium, 120 
carrageenan, 124 
ceratonia, 148 
cetostearyl alcohol, 150 
chitosan, 159 
colloidal silicon dioxide, 188 
cyclomethicone, 222 
ethylcellulose, 278 
gelatin, 295 
glycerin, 301 
glyceryl behenate, 304 
guar gum, 315 
hectorite, 318 
hydrogenated vegetable oil type I, 800 
hydroxyethyl cellulose, 330 
hydroxyethylmethyl cellulose, 334 
hydroxypropyl cellulose, 336 
hydroxypropyl starch, 344 
hypromellose, 346 
magnesium aluminum silicate, 418 
maltodextrin, 442 
methylcellulose, 462 
polydextrose, 542 
polyethylene glycol, 545 
poly(methylvinyl ether/maleic 
anhydride), 561 
polyvinyl acetate phthalate, 589 
polyvinyl alcohol, 592 
potassium chloride, 600 
povidone, 611 
propylene glycol alginate, 627 
saponite, 644 
sodium alginate, 656–657 
sodium chloride, 671 
stearyl alcohol, 740 
sucrose, 744 
sulfobutylether b-cyclodextrin, 754 
tragacanth, 785 
xanthan gum, 148, 821–822 
see also Gelling agents; Stiffening agents; 
Thickening agents 
Vitamins 
solubilizing agents 
polyoxyethylene castor oil derivatives, 
573 
polyoxyethylene sorbitan fatty acid 
esters, 581 
vitamin A palmitate, 573 
vitamin A propionate, 573 
vitamin B1 (thiamin), 608 
vitamin C, 48, 478 
vitamin C palmitate, 51 
vitamin C sodium, 659 
vitamin D, 573 
vitamin E, 32–34 
vitamin E acetate, 573 
vitamin F, 414 
vitamin K1, 573 
Vivapress Ca, 89 
Vivapress Ca 740, 92 
Vivapress Ca 800, 92 
Vivapur, 132 
Vivasol, 211 
Vivastar P, 701 
Voelicherite, 101 
Volpo, 564 
Vulvic acid, 406 
Wacker HDK, 188 
Waglinol 3/9280, 454 
Waglinol 6014, 374 
Waglinol 6016, 376 
Warfarin, 379 
Warfarin sodium, 421 
Water, 802 
for injection, 805 
Water for injection, 805 
Water softeners, edetic acid, 260 
Water-absorbing agents 
carboxymethylcellulose calcium, 118 
carboxymethylcellulose sodium, 120 
Water-repelling agents 
dimethicone, 244 
simethicone, 652 
Water-soluble lanolin, 400 
Wax 
anionic emulsifying, 689, 807 
see also Emulsifying wax, anionic) 
bleached, 817 
carnauba, 809 
cetyl esters, 811 
hard, 503 
alternatives to, 800 
microcrystalline, 504, 813 
nonionic emulsifying, 815 
refined, 819 
white, 817 
yellow, 817–819 
Wecobee, 762 
Wecoline 1295, 406 
Weisserton, 378 
Wetting agents 
benzalkonium chloride, 61 
benzethonium chloride, 64 
cetylpyridinium chloride, 157 
docusate sodium, 257 
hypromellose, 346 
poloxamer, 535 
polyethylene alkyl ethers, 565 
polyoxyethylene alkyl ethers, 565 
polyoxyethylene castor oil derivatives, 
573 
polyoxyethylene sorbitan fatty acid 
esters, 581 
polyoxyethylene stearates, 586 
sodium lauryl sulfate, 687 
sorbitan esters, 714 
see also Solubilizing agents; 
Surfactants 
Wheat starch, 725 
White beeswax, 817 
White bole, 378 
White dextrin, 228 
White mineral oil, 471 
White petrolatum, 510, 513 
White petroleum jelly, 510 
White shellac, 649 
White soft paraffin, 510 
and anionic emulsifying wax, 807 
and lanolin alcohols, 512 
White wax, 817, 820 
Whitfield’s ointment, 66 
Whitlockite, 101 
Wickenol 111, 376 
Wilkinite, 58 
Witcarb, 89 
Witcizer 300, 234 
Witepsol, 762 
Wood ether, 246 
Wool alcohols, 402 
Wool alcohols ointment, 512 
Wool fat, 399 
hydrogenated, 400 
hydrous, 404 
refined, 399 
Wool wax alcohols, 402 
Xanthan gum, 148–149, 316, 418, 821 
Xanthani gummi, 821 
Xantural, 821 
Index 917

Xilitol, 824 
Xylifin, 824 
Xylisorb, 824 
Xylit, 824 
Xylitab, 824 
Xylitab 100, 827 
Xylitab 200, 827 
Xylitab 300, 827 
Xylite, 824 
Xylitol, 267, 451, 720, 824 
cooling effect, 827 
sweetness vs. mannitol, 827 
sweetness vs. sucrose, 827 
Xylitolo, 824 
Xylitolum, 824 
xylo-Pentane-1,2,3,4,5-pentol, 824 
o-Xylotocopherol, 34 
p-Xylotocopherol, 34 
Yellow beeswax, 819 
Yellow dextrin, 228 
Yellow ferric oxide, 364 
Yellow iron oxide, 364 
and butylparaben, 84 
and ethylparaben, 289 
and propylparaben, 631 
Yellow ochre, 364 
Yellow orange S, 198 
Yellow petrolatum, 509, 513 
Yellow petroleum jelly, 509 
Yellow soft paraffin, 509 
and lanolin alcohols, 512 
Yellow wax, 817–819 
Yeso Blanco, 106 
(Z)-9-Octadecen-1-ol, 496 
(Z)-9-Octadecenoic acid, 494 
methyl ester, 275 
Zein, 828 
Zephex 134a, 772 
Zephex 227 EA, 321 
Zephiran, 61 
Zinc acetas dihydricus, 830 
Zinc acetate, 830 
Zinc acetate anhydrous, 830 
Zinc acetate dihydrate, 830 
Zinc diacetate, 830 
Zinc distearate, 832 
Zinc ethanoate, 830 
Zinc (II) acetate, 830 
Zinc oxide, 302, 760 
Zinc propionate, 700 
Zinc soap, 832 
Zinc stearate, 103, 431, 739, 832 
Zinci stearas, 832 
(Z,Z)-9,12-Octadecadienoic acid, 414 
918 Index