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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 1 Taylor A, Bagley A. Tailoring closely packed gel-particles systems for use as thickening agents. J Appl Polym Sci 1975; 21: 113–122. 2 Taylor A, Bagley A. Rheology of dispersions of swollen gel particles. J Polym Sci 1975; 13: 1133–1144. 3 Nae HN, Reichert WW. Rheological properties of lightly crosslinked carboxy copolymers in aqueous solutions. Rheol Acta 1992; 31: 351–360. 4 Carnali JO, Naser MS. The use of dilute solution viscosity to characterize the network properties of carbopol microgels. Colloid Polym Sci 1992; 270: 183–193. 5 Amin PD, Bhogte CP, Deshpande MA. Studies on gel tears. Drug Dev Ind Pharm 1996; 22(7): 735–739. 6 U. nlu. N, Ludwig A, van Ooteghem M, et al. Formulation of carbopol 940 ophthalmic vehicles, and in vitro evaluation of the influence of simulated lacrimal fluid on their physico-chemical 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 suppositories with lipophilic excipient. Part 1: use of polyacrylic acids. Farmaco 1991; 46: 1459–1474. 9 Morimoto K, Morisaka K. In vitro release and rectal absorption of barbital and aminopyrine from aqueous polyacrylic acid gel. Drug Dev Ind Pharm 1987; 13(7): 1293–1305. 10 Green JT, Rhodes J, Thomas GA, Evans BK, et al. Nicotine carbomer enemas–pharmacokinetics of a revised formulation. Ital J Gastroenterol Hepatol 1998; 30: 260–265. 11 Tamburic S, Craig DQM. Investigation into the rheological, dielectric and mucoadhesive properties of poly(acrylic acid) gel systems. J Control Release 1995; 37: 59–68. 12 Ferrari F, Bertoni M, Caramella C, et al. Description and validation of an apparatus for gel strength measurements. Int J Pharm 1994; 109: 115–124. 13 Chu JS, Yu DM, Amidon GL, et al. Viscoelastic properties of polyacrylic acid gels in mixed solvents. Pharm Res 1992; 9: 1659– 1663. 14 Amsellem E, Derrien F, Lanquetin M, Paris J, et al. In vitro studies on the influence of carbomers on the availability and acceptability of estradiol gels. Arzneimittelforschung 1998; 48: 492–496. 15 Jimenez-Kairuz A, Allemandi D, Manzo RH. Mechanism of lidocaine release from carbomer-lidocaine hydrogels. J Pharm Sci 2002; 91: 267–272. 16 Tanna S, Sahota T, Clark J, Taylor MJ. Covalent coupling of concanavalin to a carbopol 934P and 941P carrier in glucosesensitive gels for delivery of insulin. J Pharm Pharmacol 2002; 54: 1461–1469. 17 Tas C, Ozkan Y, Savaser A, Baykara T. In vitro and ex vivo permeation studies of chlorpheniramine maleate gels prepared by carbomer derivatives. Drug Dev Ind Pharm 2004; 30: 637–647. 18 Meshali MM, El-Sayed GM, El-Said Y, et al. Preparation and evaluation of theophylline sustained release tablets. Drug Dev Ind Pharm 1996; 22(4): 373–376. 19 Huang LL, Schwartz JB. Studies on drug release from a carbomer tablet matrix. Drug Dev Ind Pharm 1995; 21(13): 1487–1501. 20 Pe.rez-Marcos B, Iglesias R, Gomez-Amoza JL, et al. Mechanical and drug-release properties of atenolol–carbomer hydrophilic matrix tablets. J Control Release 1991; 17: 267–276. 21 Graf E, Tsaktanis I, Fawzy AA. Studies on the direct compression of pharmaceuticals part 20: timed release of tablets of diphenhydramine and dexachlorpheniramine. Pharm Ind 1986; 48: 661– 665. 22 Choulis NH, Papadopoulos H, Choulis M. Long acting methadone. Pharmazie 1976; 31: 466–470. 23 Neau SH, ChowMY. Fabrication and characterization of extruded and spheronized beads containing Carbopol 974P NF resin. Int J Pharm 1996; 131: 47–55. 24 Luessen HL, De-Leeuw BJ, Perard D, et al. Mucoadhesive polymers in peroral peptide drug delivery. Part 1: influence of mucoadhesive excipients on the proteolytic activity of intestinal enzymes. Eur J Pharm Sci 1996; 4: 117–128. 25 Luessen HL, Verhoef JC, Borchard G, et al. Mucoadhesive polymers in peroral peptide drug delivery. Part 2: carbomer and polycarbophil are potent inhibitors of the intestinal proteolytic enzyme trypsin. Pharm Res 1995; 12: 1293–1298. 26 Woolfson AD, McCafferty DF, McCarron PA. Bioadhesive patch cervical drug delivery system for the administration of 5- fluorouracil to cervical tissue. J Control Release 1995; 35: 49–58. 27 Vidgren P, Vidgren M, Arppe J, et al. In vitro evaluation of spraydried mucoadhesive microspheres for nasal administration. Drug Dev Ind Pharm 1992; 18(5): 581–597. 28 Ito R, Machida Y, Sannan T, et al. Magnetic granules: novel system for specific drug delivery to esophageal mucosa in oral administration. Int J Pharm 1990; 61: 109–117. 29 Singla AK, Chawla M, Singh A. Potential applications of carbomer in oral mucoadhesive controlled drug delivery system: a review. Drug Dev Ind Pharm 2000; 26: 913–924. 30 Llabot JM, Manzo RH, Allemandi DA. Drug release from carbomer:carbomer sodium salt matrices with potential use as mucoadhesive drug delivery system. Int J Pharm 2004; 276: 59– 66. 31 Wang HT, Schmitt E, Flanagan DR, et al. Influence of formulation methods on the in vitro controlled release of protein from poly(ester) microspheres. J Control Release 1991; 17: 23–32. 32 Sullivan LJ, McCurrach F, Lee S, Taylor HR, et al. Efficacy and safety of 0.3% carbomer gel compared to placebo in patients with moderate-to-severe dry eye syndrome. Ophthalmology 1997; 104: 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 between calcium, a model divalent cation, and a range of poly(acrylic acid) resins as a function of solution pH. Drug Dev 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 lubricant. J Pharm Pharmacol 1972; 24(Suppl.): 178P. 37 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 71. 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. Islam MT, Rodriguez-Hornedo N, Ciotti S, Ackermann C. Rheological characterization of topical carbomer gels neutralized to different pH. Pharm Res 2004; 21: 1192–1199. Jimenez-Kairuz AF, Llabot JM, Allemandi DA, Manzo RH. Swellable drug-polyelectrolyte matrices (SDPM). Characterization and delivery properties. Int J Pharm 2005; 288: 87–99. Pe.rez-Marcos B, Martinez-Pacheco R, Gomez-Amoza JL, et al. Interlot variability of carbomer 934. Int J Pharm 1993; 100: 207–212. 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. 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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. 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