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01 Excipients Prelims 1..8

Handbook ofPharmaceuticalExcipientsFifth EditionEdited byRaymond C Rowe, Paul J Sheskey and Sin C OwenHandbook ofPharmaceutical Excipients

Handbook ofPharmaceutical ExcipientsFIF TH EDITION Edited byRaymond C RoweBPharm, PhD, DSc, FRPharmS, CChem, FRSC, CPhys, MInstP

Chief Scientist Intelligensys Ltd Billingham, UK

Paul J SheskeyBSc, RPh

Technical Services LeaderThe Dow Chemical CompanyMidlandMI, USA

Sia n C OwenBSc, MA

Development Editor

Royal Pharmaceutical Society of Great Britain

London, UK

London . Chicago Published by the Pharmaceutical PressPublications division of the Royal Pharmaceutical Society of Great Britain

1 Lambeth High Street, London SE1 7JN, UK

100 South Atkinson Road, Suite 206, Grayslake, IL 60030-7820, USA

and the American Pharmacists Association2215 Constitution Avenue, NW, Washington, DC 20037-2985, USA

# Pharmaceutical Press and American Pharmacists Association 2006is a trademark of Pharmaceutical PressFirst published 1986Second edition published 1994Third edition published 2000Fourth edition published 2003Fifth edition published 2006Printed in Great Britain by Butler & Tanner, Frome, SomersetTypeset by Data Standards Ltd, Frome, SomersetISBN 0 85369 618 7 (UK) ISBN 1 58212 058 7 (USA)

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, without the prior written permissionof the copyright holder.The publisher makes no representation, express or implied, with regard to the accuracy of the information contained in this book and cannot accept any legal responsibility or liability for any errors or omissions that may be made.A catalogue record for this book is available from the British LibraryLibrary of Congress Cataloging-in-Publication DataHandbook of pharmaceutical excipients.5th ed. / edited by Raymond C. Rowe, Paul J. Sheskey, Sia n C. Owen.p. ; cm.Includes bibliographical references and index.ISBN 1-58212-058-7 (USA) ISBN 0-85369-618-7 (UK)

1. ExcipientsHandbooks, manuals, etc.[DNLM: 1. ExcipientsHandbooks. 2. Technology, PharmaceuticalHandbooks. QV 735 H236 2006] I. Rowe, Raymond C. II. Sheskey, Paul J. III. Owen, Sia n C. IV. American Pharmacists Association.RS201.E87H36 20066150 .19dc22

2005028523ContentsInternational 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

MonographsAcacia 1Acesulfame Potassium 4Acetic Acid, Glacial 6Acetone 8Acetyltributyl Citrate 10Acetyltriethyl Citrate 12Agar 14Albumin 16Alcohol 18Alginic Acid 21Aliphatic Polyesters 24Alitame 28Almond Oil 30Alpha Tocopherol 32Aluminum Hydroxide Adjuvant 36Aluminum Oxide 38Aluminum Phosphate Adjuvant 40Aluminum Stearate 42Ammonia Solution 44Ammonium Alginate 46Ascorbic Acid 48

Ascorbyl Palmitate 51Aspartame 53Attapulgite 56Bentonite 58Benzalkonium Chloride 61Benzethonium Chloride 64Benzoic Acid 66Benzyl Alcohol 69Benzyl Benzoate 72Boric Acid 74Bronopol 76Butylated Hydroxyanisole 79Butylated Hydroxytoluene 81Butylparaben 83Calcium Alginate 86Calcium Carbonate 89Calcium Phosphate, Dibasic Anhydrous 93Calcium Phosphate, Dibasic Dihydrate 96Calcium Phosphate, Tribasic 100Calcium Stearate 102Calcium Sulfate 105Canola Oil 108Carbomer 111Carbon Dioxide 116Carboxymethylcellulose Calcium 118Carboxymethylcellulose Sodium 120Carrageenan 124Castor Oil 128Castor Oil, Hydrogenated 130Cellulose, Microcrystalline 132Cellulose, Powdered 136Cellulose, Silicified Microcrystalline 139Cellulose Acetate 142Cellulose Acetate Phthalate 145Ceratonia 148Cetostearyl Alcohol 150vi ContentsCetrimide152Ethyl Oleate274

Cetyl Alcohol155Ethyl Vanillin276

Cetylpyridinium Chloride157Ethylcellulose278

Chitosan159Ethylene Glycol Palmitostearate283

Chlorhexidine163Ethylene Vinyl Acetate285

Chlorobutanol168Ethylparaben287

Chlorocresol171Fructose290

Chlorodifluoroethane (HCFC)174Fumaric Acid293

Chlorofluorocarbons (CFC)176Gelatin295

Chloroxylenol180Glucose, Liquid299

Cholesterol182Glycerin301

Citric Acid Monohydrate185Glyceryl Behenate304

Colloidal Silicon Dioxide188Glyceryl Monooleate306

Coloring Agents192Glyceryl Monostearate308

Copovidone201Glyceryl Palmitostearate311

Corn Oil204Glycofurol313

Cottonseed Oil206Guar Gum315

Cresol208Hectorite318

Croscarmellose Sodium211Heptafluoropropane (HFC)321

Crospovidone214Hexetidine323

Cyclodextrins217Hydrocarbons (HC)325

Cyclomethicone222Hydrochloric Acid328

Denatonium Benzoate224Hydroxyethyl Cellulose330

Dextrates226Hydroxyethylmethyl Cellulose334

Dextrin228Hydroxypropyl Cellulose336

Dextrose231Hydroxypropyl Cellulose, Low-substituted341

Dibutyl Phthalate234Hydroxypropyl Starch344

Dibutyl Sebacate236Hypromellose346

Diethanolamine238Hypromellose Acetate Succinate350

Diethyl Phthalate240Hypromellose Phthalate354

Difluoroethane (HFC)242Imidurea359

Dimethicone244Inulin362

Dimethyl Ether246Iron Oxides364

Dimethyl Phthalate248Isomalt366

Dimethyl Sulfoxide250Isopropyl Alcohol371

Dimethylacetamide253Isopropyl Myristate374

Disodium Edetate255Isopropyl Palmitate376

Docusate Sodium257Kaolin378

Edetic Acid260Lactic Acid381

Erythorbic Acid264Lactitol383

Erythritol266Lactose, Anhydrous385

Ethyl Acetate268Lactose, Monohydrate389

Ethyl Lactate270Lactose, Spray-Dried396

Ethyl Maltol272Lanolin399

Contents vii Lanolin Alcohols402Petrolatum and Lanolin Alcohols512

Lanolin, Hydrous404Phenol514

Lauric Acid406Phenoxyethanol517

Lecithin409Phenylethyl Alcohol519

Leucine412Phenylmercuric Acetate521

Linoleic Acid414Phenylmercuric Borate524

Macrogol 15 Hydroxystearate416Phenylmercuric Nitrate526

Magnesium Aluminum Silicate418Phosphoric Acid530

Magnesium Carbonate422Polacrilin Potassium532

Magnesium Oxide426Poloxamer535

Magnesium Silicate428Polycarbophil539

Magnesium Stearate430Polydextrose542

Magnesium Trisilicate434Polyethylene Glycol545

Malic Acid436Polyethylene Oxide551

Maltitol438Polymethacrylates553

Maltitol Solution440Poly(methyl vinyl ether/maleic anhydride)561

Maltodextrin442Polyoxyethylene Alkyl Ethers564

Maltol445Polyoxyethylene Castor Oil Derivatives572

Maltose447Polyoxyethylene Sorbitan Fatty Acid Esters580

Mannitol449Polyoxyethylene Stearates585

Medium-chain Triglycerides454Polyvinyl Acetate Phthalate589

Meglumine457Polyvinyl Alcohol592

Menthol459Potassium Alginate594

Methylcellulose462Potassium Benzoate596

Methylparaben466Potassium Bicarbonate598

Mineral Oil471Potassium Chloride600

Mineral Oil, Light474Potassium Citrate603

Mineral Oil and Lanolin Alcohols476Potassium Hydroxide605

Monoethanolamine478Potassium Metabisulfite607

Monosodium Glutamate480Potassium Sorbate609

Monothioglycerol482Povidone611

Myristic Acid484Propionic Acid617

Neohesperidin Dihydrochalcone486Propyl Gallate619

Nitrogen488Propylene Carbonate622

Nitrous Oxide490Propylene Glycol624

Octyldodecanol492Propylene Glycol Alginate627

Oleic Acid494Propylparaben629

Oleyl Alcohol4962-Pyrrolidone633

Olive Oil498Raffinose635

Palmitic Acid501Saccharin638

Paraffin503Saccharin Sodium641

Peanut Oil505Saponite644

Pectin507Sesame Oil646

Petrolatum509Shellac649

viii Contents

Simethicone652Thymol780

Sodium Acetate654Titanium Dioxide782

Sodium Alginate656Tragacanth785

Sodium Ascorbate659Trehalose788

Sodium Benzoate662Triacetin790

Sodium Bicarbonate665Tributyl Citrate792

Sodium Borate669Triethanolamine794

Sodium Chloride671Triethyl Citrate796

Sodium Citrate Dihydrate675Vanillin798

Sodium Cyclamate678Vegetable Oil, Hydrogenated800

Sodium Hyaluronate681Water802

Sodium Hydroxide683Wax, Anionic Emulsifying807

Sodium Lactate685Wax, Carnauba809

Sodium Lauryl Sulfate687Wax, Cetyl Esters811

Sodium Metabisulfite690Wax, Microcrystalline813

Sodium Phosphate, Dibasic693Wax, Nonionic Emulsifying815

Sodium Phosphate, Monobasic696Wax, White817

Sodium Propionate699Wax, Yellow819

Sodium Starch Glycolate701Xanthan Gum821

Sodium Stearyl Fumarate705Xylitol824

Sodium Sulfite708Zein828

Sorbic Acid710Zinc Acetate830

Sorbitan Esters (Sorbitan Fatty Acid Esters)713Zinc Stearate832

Sorbitol718

Soybean OilStarch722725Appendix I: Suppliers Directory835

Appendix II: List of Excipient E Numbers 882

Starch, Pregelatinized 731 Appendix III: List of Excipient EINECS Numbers884

Starch, Sterilizable Maize 734 Appendix IV: List of Excipient Molecular Weights886

Stearic Acid 737 Index 889

International Steering CommitteeGregory E Amidon Pharmacia Corporation Kalamazoo, MI, USAStephen W HoagUniversity of Maryland at BaltimoreBaltimore, MD, USAAnthony Palmieri III University of Florida Gainesville, FL, USA

Graham Buckton University of London London, UKArthur H Kibbe Wilkes University Wilkes-Barre, PA, USARaymond C Rowe Intelligensys Ltd Billingham, UK

Colin G CableWestern General HospitalEdinburgh, UKWilliam J LambertEisai IncResearch Triangle Park, NC, USAShirish A ShahWatson PharmaceuticalsCorona, CA, USA

Brian A Carlin FMC Biopolymer Princeton, NJ, USAM Jayne LawrenceKings College, University of LondonLondon, UKBob Sherwood JRS Pharma Patterson, NY, USA

Walter Cook AstraZeneca Loughborough, UKJohn MacLaineBoots Contract ManufacturingNottingham, UKPaul J Sheskey

The Dow Chemical CoMidland, MI, USA

Henk J de JongServier International Research InstituteCourbevoie, FranceColin P McCoyQueens University Belfast

Belfast, UKKamalinder K SinghSNDT Womens UniversityMumbai, India

Stephen EdgeDMV InternationalVeghel, The NetherlandsRoger T GuestGlaxoSmithKlineWare, Hertfordshire, UK

Bruno HancockPfizer IncGroton, CT, USAR Christian Moreton Idenix Pharmaceuticals Cambridge, MA, USA

Sandeep NemaPfizer IncChesterfield, MO, USA

Sia n C OwenRoyal Pharmaceutical Society of GreatBritainLondon, UKPaul J WellerRoyal Pharmaceutical Society of GreatBritainLondon, UK

Tim WoodGlaxoSmithKlineWare, Hertfordshire, UK

Mukund Yelvigi

Wyeth ResearchPearl River, NY, USA

Editorial Staff

Editorial Staff of the Pharmaceutical Press: Laurent Y GalichetLouise ME McIndoeSia n C OwenPaul J WellerContributorsO AbuBakerPfizer IncAnn Arbor, MI, USAR ChenPfizer IncGroton, CT, USAB Fritzsching Palatinit GmbH Mannheim, Germany

KS Alexander University of Toledo Toledo, OH, USAJH ChuPfizer IncGroton, CT, USAG FrunziBristol-Myers SquibbNew Brunswick, NJ, USA

LV Allen

International Journal of PharmaceuticalCompoundingEdmond, OK, USA

GE AmidonPharmacia CorporationKalamazoo, Michigan, USA

GP AndrewsThe Queens University of Belfast

Belfast, UK

NA ArmstrongHarpenden, Hertfordshire, UKJH CollettUniversity of ManchesterManchester, UK

JT ColvinPfizer IncGroton, CT, USA

W Cook AstraZeneca Loughborough, UK

DQM CraigThe University of East AngliaNorwich, UKLY GalichetRoyal Pharmaceutical Society of GreatBritainLondon, UK

SR GoskondaSunnyvale, CA, USA

JL GrayThe Queens University of Belfast

Belfast, UK

RT GuestGlaxoSmithKlineWare, Hertfordshire, UK

ME AultonDe Montford UniversityLeicester, UKTC DahlGilead Sciences

Foster City, CA, USARR GuptaSNDT Womens UniversityMumbai, India

S Behn AstraZeneca Macclesfield, UKA Day AstraZeneca Loughborough, UKVK GuptaTyco HealthCare MallinckrodtSt Louis, MO, USA

M BondDanisco Sweeteners LtdRedhill, Surrey, UKHJ de JongServier International Research InstituteCourbevoie, FranceG HaestCargill Cerestar BVBA Mechelen, Belgium

CG CableWestern General HospitalEdinburgh, UKSP DenyerUniversity of CardiffCardiff, UKBC HancockPfizer IncGroton, CT, USA

E Cahill AstraZeneca Macclesfield, UKX Duriez Roquette Fre` res Lestrem, FranceRJ HarwoodBensalem, PA, USA

W CamarcoISP CorpWayne, NJ, USAS EdgeDMV InternationalVeghel, The NetherlandsS HemPurdue UniversityWest Lafayette, IN, USA

WG Chambliss University of Mississippi University, MS, USAK FowlerSchering-Plough Healthcare ProductsMemphis, TN, USAL Hendricks Rhodia Inc Cranbury, NJ, USA

RK ChangShire LaboratoryRockville, MD, USASO FreersGrain Processing CorporationMuscatine, IA, USASE HepburnBristol Royal InfirmaryBristol, UK

Contributors xi NA HodgesUniversity of BrightonBrighton, UK

JT IrwinPerrigo CorporationMI, USA

BR JastiUniversity of the Pacific

Stockton, CA, USA

R Johnson AstraZeneca Loughborough, UK

DS JonesThe Queens University of Belfast

Belfast, UK

AS KearneyGlaxoSmithKlineKing-of-Prussia, PA, USA

SW Kennedy Morflex Inc Greensboro, NC, USA

VL KettThe Queens University of Belfast

Belfast, UK

AH KibbeWilkes University

MG Lee

Medicines and Healthcare productsRegulatory Agency

London, UK

X Li

University of the Pacific

Stockton, CA, USA

EB Lindblad Brenntag Biosector Frederikssund, DenmarkO LuhnPalatinit GmbH Mannheim, GermanyPE LunerPfizer IncGroton, CT, USA

HJ MawhinneyThe Queens University of Belfast

Belfast, UK

CP McCoyThe Queens University of Belfast

Belfast, UK

OS McGarveyThe Queens University of Belfast

Belfast, UK

MP MullarneyPfizer IncGroton, CT, USA

S MurdandePfizer IncGroton, CT, USA

RA NashSt Johns UniversityJamaica, NY, USA

S NemaPfizer IncChesterfield, MO, USA

SC OwenRoyal Pharmaceutical Society of GreatBritainLondon, UK

A PalmieriUniversity of FloridaGainesville, FL, USA

D Parsons ConvaTec Ltd Clwyd, UK

Y PengUniversity of TennesseeMemphis, TN, USA

xii ContributorsJJ SciarraSciarra Laboratories IncHicksville, NY, USA

SA ShahWatson PharmaceuticalsCorona, CA, USA

RM ShankerPfizer IncGroton, CT, USA

PJ Sheskey

The Dow Chemical CoMidland, MI, USA

AJ ShuklaUniversity of TennesseeMemphis, TN, USA

KK SinghSNDT Womens UniversityMumbai, IndiaR Steer AstraZeneca Loughborough, UK

JT StewartUniversity of GeorgiaAthens, GA, USA

Y SunUniversity of TennesseeMemphis, TN, USA

AK TaylorBaton Rouge, LA, USA

MS TesconiWyeth ResearchPearl River, NY, USA

D ThassuUCB Pharma IncRochester, NY, USA

BF TruittPfizer IncGroton, CT, USA

CK TyePfizer IncKalamazoo, MI, USA

HM UnvalaBayer CorporationMyerstown, PA, USA

KD VaughanBoots Healthcare InternationalNottingham, UK

H WangPfizer IncGroton, CT, USA

PJ WellerRoyal Pharmaceutical Society of GreatBritainLondon, UK

AJ WinfieldAberdeen, UK

AW WoodGlaxoSmithKlineResearch Triangle Park, NC, USA

M Yelvigi

Wyeth ResearchPearl River, NY, USA

PM YoungUniversity of SydneySydney, AustraliaAbout the Editors

Raymond C RoweBPharm, 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 Pharmaceu- tics at the School of Pharmacy, University of Bradford, UK. He was formerly Senior Principal Scientist at AstraZeneca, UK. In1998 he was awarded the Chiroscience Industrial Achievement Award, and in 1999 he was the British Pharmaceutical Conference Science Chairman. He has contributed to over350 publications in the pharmaceutical sciences including a book and eight patents.Paul J SheskeyBSc, RPhPaul Sheskey has been involved in the Handbook of Pharma- ceutical 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.Sian C OwenBSc, 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.

New MonographsThe following new monographs have been added to the Handbook of Pharmaceutical Excipients, 5th edition.AcetoneAgarAluminum Hydroxide AdjuvantAluminum OxideAluminum Phosphate AdjuvantAmmonium AlginateAluminum StearateBoric Acid Calcium Alginate Cetylpyridinium ChlorideCopovidoneDimethylacetamide Disodium Edetate Erythorbic AcidErythritolEthyl LactateEthylene Vinyl AcetateHectoriteHydroxypropyl Starch Hypromellose Acetate Succinate InulinIron OxidesIsomaltLactose, AnhydrousLactose, MonohydrateLactose, Spray-Dried

Lauric Acid Leucine Linoleic AcidMacrogol 15 HydroxystearateMyristic AcidNeohesperidin DihydrochalconeOctyldodecanolOleyl Alcohol Palmitic Acid PectinPolycarbophilPoly(methylvinyl ether/maleic anhydride) Potassium Alginate2-PyrrolidoneRaffinose Saponite Sodium Acetate Sodium BorateSodium HyaluronateSodium LactateSodium Sulfite

Sulfobutylether b-CyclodextrinThaumatinThymolZinc AcetateAcetic acidActivated attapulgiteAleuritic acidd-Alpha tocopherold-Alpha tocopheryl acetatedl-Alpha tocopheryl acetated-Alpha tocopheryl acid succinate dl-Alpha tocopheryl acid succinate Aluminum distearateAluminum monostearateAmylopectina-AmyloseAnhydrous citric acidAnhydrous sodium citrate Anhydrous sodium propionate Artificial vinegarBacteriostatic water for injectionBentonite magma Beta tocopherol Beta-carotenen-Butyl lactateButylparaben sodium Calcium ascorbate Calcium cyclamate Calcium polycarbophilCalcium propionateCalcium silicateCalcium sorbateCalcium sulfate hemihydrateCapric acidCarbon dioxide-free waterCationic emulsifying waxCeratonia extract Cetylpyridinium bromide Chlorhexidine acetate Chlorhexidine gluconateChlorhexidine hydrochlorideChlorodifluoromethaneChlorophenoxyethanolCorn syrup solidsm-Cresol o-Cresol p-CresolCrude olive-pomace oilCyclamic acidDe-aerated waterDehydrated alcoholDelta tocopherol Denatured alcohol Dextrose anhydrousDiazolidinyl ureaDibasic potassium phosphate Diethylene glycol monopalmitostearate Dilute acetic acidDilute 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 gallateDodecyltrimethylammonium bromideEdetate calcium disodiumEglumineEthyl gallateEthylene glycol monopalmitate Ethylene glycol monostearate Ethyl linoleateEthylparaben potassiumEthylparaben sodium Extra virgin olive oil Fine virgin olive oilFuming sulfuric acidGamma tocopherol Hard water HesperidinHexadecyltrimethylammonium bromideHigh-fructose syrupHyaluronic acidHydrogenated lanolinHydrogenated vegetable oil, type II

2-Hydroxyethyl-b-cyclodextrin2-Hydroxypropyl-b-cyclodextrin3-Hydroxypropyl-b-cyclodextrinIndigo carmine Invert sugar IsotrehaloseLampante virgin olive oilLanolin alcohols ointmentDL-LeucineLiquefied phenolLiquid fructoseMagnesium carbonate anhydrousMagnesium carbonate hydroxideMagnesium lauryl sulfate Magnesium metasilicate Magnesium orthosilicate Magnesium trisilicate anhydrousD-Malic acidL-Malic acidd-Mentholl-Menthol Methyl lactate Methyl linoleate Methyl methacrylateMethyl oleateRelated Substances xv Methylparaben potassiumMethylparaben sodiumN-MethylpyrrolidoneMicrocrystalline cellulose and carboxymethylcellulose sodiumMicrocrystalline cellulose and carrageenanMicrocrystalline cellulose and guar gumModified lanolinMonobasic potassium phosphateMontmorilloniteMyristyl alcoholNeotrehaloseNormal magnesium carbonateOctyl gallateOleyl oleateOlive-pomace oil Palmitin Pharmaceutical glazePhenoxypropanolPolacrilinPoly(methyl methacrylate) Potassium bisulfitePotassium myristatePotassium propionatePowdered fructosePropan-1-ol(S)-Propylene carbonate Propylparaben potassium Propylparaben sodiumPurified bentonitePurified stearic acid Quaternium 18-hectorite Rapeseed oilRefined almond oilRefined olive-pomace oil

Saccharin ammoniumSaccharin calciumSelf-emulsifying glyceryl monostearateShellolic acidSodium bisulfiteSodium borate anhydrousSodium edetate Sodium erythorbate Sodium laurate Sodium myristateSodium palmitateSodium sorbateSodium sulfite heptahydrateSoft waterSorbitol solution 70% Spermaceti wax Stearalkonium hectoriteSterile water for inhalationSterile water for injection Sterile water for irrigation Sunset yellow FCFSynthetic paraffinDL-( )-Tartaric acidTartrazineTheobroma oil Tocopherols excipient Tribasic sodium phosphate Trimethyl-b-cyclodextrinTrimethyltetradecylammonium bromideTrisodium edetate Virgin olive oil Water for injectionWhite petrolatumZinc propionatePharmaceutical dosage forms contain both pharmacologically active compounds and excipients added to aid the formulation and manufacture of the subsequent dosage form for adminis- tration 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 devel- oped 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 topicsThe 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 in2003 containing 249 monographs. Since 2000, the data has also been available on CD-ROM, updated annually, and from2004 online. This new printed edition with its companion CD- ROM, Pharmaceutical Excipients 5, contains 300 monographscompiled by over 120 experts in pharmaceutical formulation or excipient manufacture from Australia, Europe, India and theUSA. All the monographs have been reviewed and revised in thelight of current knowledge. There has been a greater emphasis on including published data from primary sources although some data from laboratory projects included in previouseditions have been retained where relevant. Variations in testmethodology 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-absorp- tion isotherms, particle size distribution, rheology, specific surface area, and solubility. Scanning electron microphoto- graphs (SEMs) are also included for many of the excipients. The Handbook contains information from various international sources and personal observation and comments from mono- graph 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 compre- hensive, 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 phar- maceutical 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.The information consists of monographs that are divided into22 sections to enable the reader to find the information of interest easily. Although it was originally intended that eachmonograph 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 suchmonographs as Coloring Agents and Hydrocarbons. Inaddition, some materials have more than one monograph depending on the physical characteristics of the material, e.g. Starch versus Pregelatinized Starch. Regardless of the complex-ity of the monograph they are all divided into 22 sections asfollows:

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 compo- sition 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, emulsi- fying agent, etc.1Nonproprietary NamesSection 7, Applications in Pharmaceutical Formulation or Tech- nology, describes the various applications of the excipient.

2Synonyms

3Chemical Name and CAS Registry NumberSection 8, Description, includes details of the physical appear-

4Empirical Formula and Molecular Weightance of the excipient, e.g., white or yellow flakes, etc.

5Structural Formula

6Functional CategorySection 9, Pharmacopeial Specifications, briefly presents the

7Applications in Pharmaceutical Formulation orcompendial standards for the excipient. Information included

Technologyis obtained from the British Pharmacopoeia (BP), European

8DescriptionPharmacopeia (PhEur), Japanese Pharmacopeia (JP), and the

9Pharmacopeial SpecificationsUnited States Pharmacopeia/National Formulary (USP/

10Typical PropertiesUSPNF). Information from the JP, USP and USPNF are

11Stability and Storage Conditionsincluded if the substance is in those compendia. Information

12Incompatibilitiesfrom the PhEur is also included. If the excipient is not in the

13Method of ManufacturePhEur but is included in the BP, information is included from

14Safetythe BP. Pharmacopeias are continually updated with most

15Handling Precautionsnow being produced as annual editions. However, although

16Regulatory Statusefforts were made to include up-to-date information at the

17Related Substancestime of publication of this edition, the reader is advised to

18Commentsconsult the most current pharmacopeias or supplements.

19Specific References

20General ReferencesSection 10, Typical Properties, describes the physical proper-

21Authorsties of the excipient which are not shown in Section 9. All

22Date of Revisiondata are for measurements made at 208C unless otherwise

indicated. Where the solubility of the excipient is described in

Descriptions of the sections appear below with informationfrom an example monograph if needed.Section 1, Nonproprietary Names, lists the excipient names used in the current British Pharmacopoeia, European Pharma- copeia, Japanese Pharmacopeia, and the United States Phar- macopeia/National Formulary.Section 2, Synonyms, lists other names for the excipient, including trade names used by suppliers (shown in italics). The inclusion of one suppliers trade name and the absence of others should in no way be interpreted as an endorsement of one suppliers 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, indi- cates the unique Chemical Abstract Services number for an

words, the following terms describe the solubility ranges:Very soluble 1 part in less than 1Freely soluble 1 part in 110Soluble 1 part in 1030Sparingly soluble 1 part in 30100Slightly soluble 1 part in 1001000Very slightly soluble 1 part in 100010 000Practically insoluble 1 part in more than 10 000 or insolubleWhere 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 methodsxviii Arrangementused to generate the data readers should consult the appro- priate 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 con- tain the excipient.Section 12, Incompatibilities, describes the reported incompat- ibilities 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 pro- duct.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 recommen- dations 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. Com- ments 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 mono- graph 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.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 OwenAugust 2005Notice to ReadersThe 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 incompat- ibilities or adverse reactions to an excipient, in a particular application, may not necessarily prevent its use in other applications. Formulators should perform suitable experimen- tal 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 errorsor 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 berepresentative of other batches or samples.Relevant data and constructive criticism are welcome and may be used to assist in the preparation of any future editionsor 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, 1Lambeth High Street, London SE1 7JN, UK, or Editor,Handbook of Pharmaceutical Excipients, American Pharma- cists Association, 2215 Constitution Avenue, NW, Washington,DC 20037-2985, USA.

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 FormDesign, 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 Character- ization by IR, Raman, and NMR Spectroscopy. New York: Marcel Dekker, 1999.European Pharmacopoeia, 5th edn. and supplements. Stras-bourg: Council of Europe, 2005.Florence AT, Salole EG, eds. Formulation Factors in AdverseReactions. 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: NationalAcademy Press, 1996.Health and Safety Executive. EH40/2002: OccupationalExposure Limits 2002. Sudbury: Health and Safety Execu- tive, 2001.Health Canada. Canadian List of Acceptable Non-medicinal Ingredients. http://www.hc-sc.gc.ca/hpfb-dgpsa/nhpd-dpsn/ nmi_list1_e.html (accessed 11 July 2005)Hoepfner E, Reng A, Schmidt PC, eds. Fiedler Encyclopedia ofExcipients for Pharmaceuticals, Cosmetics and RelatedAreas. Aulendorf, Germany: Editio Cantor, 2002.Japan Pharmaceutical Excipients Council. Japanese Pharma- ceutical 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 CosmeticIngredients. Aulendorf, Germany: Editio Cantor, 2000. Lewis RJ, ed. Saxs Dangerous Properties of IndustrialMaterials, 11th edn. New York: John Wiley, 2004.Lund W, ed. The Pharmaceutical Codex: Principles andPractice of Pharmaceutics, 12th edn. London: Pharmaceu- tical Press, 1994.National Library of Medicine. TOXNET. http://toxnet.nlm.nih.gov (accessed 11 July 2005)ONeil MJ, Smith A, Heckelman PE, eds.The Merck Index: anEncyclopedia of Chemicals, Drugs, and Biologicals, 13th edn. Whitehouse Station, NJ: Merck, 2001.Smolinske SC. Handbook of Food, Drug and CosmeticExcipients. Boca Raton, FL: CRC Press, 1992.Swarbrick J, Boylan JC, eds. Encyclopedia of PharmaceuticalTechnology, 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 Pharmaco-peial 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 Formula-tion Agents: a Handbook of Excipients. New York: MarcelDekker, 1989.Weiner ML, Kotkoskie LA, eds. Excipient Toxicity and Safety.New York: Marcel Dekker, 2000.AbbreviationsSome 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).

Abbreviations xxi DSC differential scanning calorimetry.EC European Community.e.g. exemplit gratia, for example.EINECS European Inventory of Existing CommercialChemical Substances.et al et alii, and others.EU European Union.FAO Food and Agriculture Organization of the UnitedNations.FAO/ Food and Agriculture Organization of the UnitedWHO 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 DrugAdministration of the USA.

HC hydrocarbon.HCFC hydrochlorofluorocarbon.HFC hydrofluorocarbon.HIV human immunodeficiency virus.HLB hydrophiliclipophilic 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 Excipientskcal 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.SIStatutory Instrument or SystU me International dUnites (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 NationalFormulary.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.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 appro- priate, imperial units reported in parentheses.Area1 square inch (in2) = 6.4516 104 square meter (m2)1 square foot (ft2) = 9.29030 102 square meter (m2)1 square yard (yd2) = 8.36127 101 square meter (m2)Density1 pound per cubic foot (lb/ft3) = 16.0185 kilograms per cubic meter (kg/m3)Energy1 kilocalorie (kcal) = 4.1840 103 joules (J)

Force1 dyne (dynes) = 1 105 newton (N)Length1 angstrom (a ) = 1010 meter (m)1 inch (in) = 2.54 102 meter (m)1 foot (ft) = 3.048 101 meter (m)1 yard (yd) = 9.144 101 meter (m)Pressure1 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 tension1 dyne per centimeter (dyne/cm) = 1 millinewton per meter(mN/m)TemperatureCelsius (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)Volume1 cubic inch (in3) = 1.63871 105 cubic meter (m3)1 cubic foot (ft3) = 2.83168 102 cubic meter (m3)1 cubic yard (yd3) = 7.64555 101 cubic meter (m3)1 pint (UK) = 5.68261 104 cubic meter (m3)1 pint (US) = 4.73176 104 cubic meter (m3)1 gallon (UK) = 4.54609 103 cubic meter (m3)1 gallon (US) = 3.78541 103 cubic meter (m3)Acacia1 Nonproprietary NamesBP: AcaciaJP: AcaciaPhEur: Acaciae gummiUSPNF: Acacia2 SynonymsAcacia gum; arabic gum; E414; gum acacia; gummi africanum;gum arabic; gummi arabicum; gummi mimosae; talha gum.3 Chemical Name and CAS Registry NumberAcacia [9000-01-5]4 Empirical Formula and Molecular WeightAcacia is a complex, loose aggregate of sugars and hemi- celluloses with a molecular weight of approximately240 000580 000. The aggregate consists essentially of an

8 DescriptionAcacia 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 SpecificationsThe PhEur 2005 provides monographs on acacia and spray- dried 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 23Identification Characters Microbial limit 4104/g Water 417.0% 415.0% 415.0%arabic acid nucleus to which are connected calcium, mag-

415.0%(a)

410.0%(b)

nesium, and potassium along with the sugars arabinose, galactose, and rhamnose.5 Structural FormulaSee Section 4.6 Functional CategoryEmulsifying agent; stabilizing agent; suspending agent; tablet binder; viscosity-increasing agent.7 Applications in Pharmaceutical Formulation or TechnologyAcacia 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 disin- tegration time. Acacia has also been evaluated as a bioad-hesive;(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 1020Pastille base 1030Suspending agent 510Tablet binder 15

Total ash 44.0% 44.0% 44.0%Acid-insoluble ash 40.5% 40.5% Insoluble residue 40.2% 40.5% 450 mg 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 PropertiesAcidity/alkalinity: pH = 4.55.0 (5% w/v aqueous solution)Acid value: 2.5Hygroscopicity: at relative humidities of 2565%, the equili- brium moisture content of powdered acacia at 258C is

813% 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 ofwater leaving only a very small residue of powder. Thesolution is colorless or yellowish, viscous, adhesive, and translucent. Spray-dried acacia dissolves more rapidly, in about 20 minutes.Specific gravity: 1.351.49Viscosity (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,2 Acaciastorage 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 ConditionsAqueous 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 sodiumbenzoate, or a mixture of 0.17% w/v methylparaben and0.03% propylparaben. Powdered acacia should be stored in an airtight container in a cool, dry place.12 IncompatibilitiesAcacia is incompatible with a number of substances including amidopyrine, apomorphine, cresol, ethanol (95%), ferric salts, morphine, phenol, physostigmine, tannins, thymol, and vanil- lin.An oxidizing enzyme present in acacia may affect prepara- tions 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 solu- tions 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 ManufactureAcacia 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 SafetyAcacia 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/kg15 Handling PrecautionsObserve 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 StatusGRAS listed. Accepted for use in Europe as a food additive. Included in the FDA Inactive Ingredients Guide (oral prepara- tions 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 SubstancesCeratonia; guar gum; tragacanth.18 CommentsConcentrated 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 (1215% w/w) can be used to make an oil/water emulsion with similar rheological character- istics 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 References1 Attama AA, Adiknu MV, Okoli ND. Studies on bioadhesive granules. STP Pharma Sci 2003; 13(3): 177181.2 Streubel A, Siepmann J, Bodmeier R. Floating matrix tablets based on low density foam powder. Eur J Pharm Sci 2003; 18: 3745.3 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): 10251038.4 Buffo R, Reineccius G. Optimization of gum acacia/modifiedstarch/maltodextrin blends for spray drying of flavors. Perfumer & Flavorist 2000; 25: 4554.5 Richards RME, Al Shawa R. Investigation of the effect of microwave irradiation on acacia powder. J Pharm Pharmacol1980; 32: 45P.6 Maytum CK, Magath TB. Sensitivity to acacia. J Am Med Assoc1932; 99: 2251.7 Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipi- ents. Boca Raton, FL: CRC Press, 1992: 711.8 FAO/WHO. Evaluation of certain food additives and contami- nants. 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. Saxs 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): 669671.11 I-Achi A, Greenwood R, Akin-Isijola A. Experimenting with a new emulsifying agent (tahini) in mineral oil. Int J Pharm Compound2000; 4(4): 315317.20 General ReferencesAnderson DMW, Dea ICM. Recent advances in the chemistry of acacia gums. J Soc Cosmet Chem 1971; 22: 6176.Anderson DM, Douglas DM, Morrison NA, Wang WP. Specifications for gum arabic (Acacia Senegal): analytical data for samplescollected between 1904 and 1989. Food Add Contam 1990; 7:303321.Aspinal GO. Gums and mucilages. Adv Carbohydr Chem Biochem1969; 24: 333379.Whistler RL. Industrial Gums. New York: Academic Press, 1959.

21 AuthorsAH Kibbe.22 Date of Revision20 August 2005.1 Nonproprietary NamesPhEur: Acesulfamum kalicum2 SynonymsAcesulfame 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 Number6-Methyl-1,2,3-oxathiazin-4(3H)-one-2,2-dioxide potassium salt [55589-62-3]4 Empirical Formula and Molecular WeightC4H4KNO4S 201.245 Structural Formula

6 Functional CategorySweetening agent.7 Applications in Pharmaceutical Formulation or TechnologyAcesulfame 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 180200 times that of sucrose. It enhances flavor systems and can be used to mask some unpleasant taste characteristics.8 DescriptionAcesulfame potassium occurs as a colorless to white-colored, odorless, crystalline powder with an intensely sweet taste.

Table I: Pharmacopeial specifications for acesulfame potassium.Test PhEur 2005Characters 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 99.0101.0%SEM: 1Excipient: Acesulfame potassiumMagnification: 150 Voltage: 5 kV

10 Typical PropertiesBonding index: 0.007Brittle 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: 4000 MPa(3) Melting point: 2508CSolubility: see Table II.9 Pharmacopeial SpecificationsSee Table I.

Specific volume: 0.538 cm3/g Tensile strength: 0.5 MPa(3) Viscoelastic index: 2.6(3)

(4)Table II: Solubility of acesulfame potassium.Solvent Solubility at 208Cunless otherwise statedEthanol 1 in 1000Ethanol (50%) 1 in 100Water 1 in 7.1 at 08C1 in 3.71 in 0.77 at 1008C11 Stability and Storage ConditionsAcesulfame potassium possesses good stability. In the bulk form it shows no sign of decomposition at ambient temperature over many years. In aqueous solutions (pH 3.03.5 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 pasteur-ization 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 ManufactureAcesulfame potassium is synthesized from acetoacetic acid tert- butyl 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 potas- sium is formed.14 SafetyAcesulfame 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 potas- sium 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): 6.98.0 g/kg15 Handling PrecautionsObserve normal precautions appropriate to the circumstances and quantity of material handled. Eye protection, gloves, and a dust mask are recommended.16 Regulatory StatusIncluded 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 SubstancesAlitame.18 CommentsThe 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 beenreported, e.g., acesulfame potassium with aspartame or sodium cyclamate. A ternary combination of sweeteners that includes acesulfame potassium and sodium saccharin has a greaterdecrease 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 theFood Chemicals Codex (FCC).19 Specific References1 Kloesel L. Sugar substitutes. Int J Pharm Compound 2000; 4(2):8687.2 Schmidt R, Janssen E, Haussler O, et al. Evaluating toothpaste sweetening. Cosmet Toilet 2000; 115: 4953.3 Mullarney MP, Hancock BC, Carlson GT, Ladipo DD. The powder flow and compact mechanical properties of sucrose andthree high-intensity sweeteners used in chewable tablets. Int J Pharm 2003; 257: 227236.4 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: 429435.5 Lipinski G-WvR, Huddart BE. Acesulfame K. Chem Ind 1983; 11:427432.6 FAO/WHO. Evaluation of certain food additives and contami- nants. 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 tertiarymixtures of sweetness. Chem Senses 2003; 28: 219229.20 General ReferencesAnonymous. Artificial sweetners. Can Pharm J 1996; 129: 22. Lipinski G-WvR, Lu ck E. Acesulfame K: a new sweetener for oralcosmetics. Manuf Chem 1981; 52(5): 37.Marie S. Sweeteners. In: Smith J, ed. Food Additives Users Handbook.Glasgow: Blackie, 1991: 4774.Nutrinova. Technical literature: Sunett in Pharmaceuticals, 1998.21 AuthorsJH Chu.22 Date of Revision12 August 2005.1 Nonproprietary NamesBP: Glacial acetic acidJP: Glacial acetic acidPhEur: Acidum aceticum glacialeUSP: Glacial acetic acid2 SynonymsE260; ethanoic acid; ethylic acid; methane carboxylic acid;vinegar acid.

Table I: Pharmacopeial specifications for glacial acetic acid.Test JP 2001 PhEur 2005 USP 28Identification Characters Freezing point 514.58C 514.88C 515.68C Nonvolatile matter 41.0 mg 40.01% 41.0 mg Sulfate Chloride Heavy metals 410 ppm 45 ppm 45 ppmIron 45 ppm

See also Sections 17 and 18.

Readily oxidizable

impurities

Assay 599.0% 99.5100.5% 99.5100.5%3 Chemical Name and CAS Registry NumberEthanolic acid [64-19-7]4 Empirical Formula and Molecular WeightC2H4O2 60.055 Structural Formula

6 Functional CategoryAcidifying agent.7 Applications in Pharmaceutical Formulations or TechnologyGlacial 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 DescriptionGlacial acetic acid occurs as a crystalline mass or a clear, colorless volatile solution with a pungent odor.9 Pharmacopeial SpecificationsSee Table I.

10 Typical PropertiesAcidity/alkalinity:pH = 2.4 (1 M aqueous solution);pH = 2.9 (0.1 M aqueous solution);pH = 3.4 (0.01 M aqueous solution).Boiling point: 1188CDissociation constant: pKa = 4.76Flash point: 398C (closed cup); 578C (open cup).Melting point: 178CRefractive index: n20 = 1.3718Solubility: miscible with ethanol, ether, glycerin, water, and other fixed and volatile oils.Specific gravity: 1.04511 Stability and Storage ConditionsAcetic acid should be stored in an airtight container in a cool, dry place.12 IncompatibilitiesAcetic acid reacts with alkaline substances.13 Method of ManufactureAcetic 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 SafetyAcetic 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/kg15 Handling PrecautionsObserve 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 StatusGRAS listed. Accepted as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (injections, nasal, ophthal- mic, and oral preparations). Included in parenteral and nonparenteral preparations licensed in the UK.

17 Related SubstancesAcetic acid; artificial vinegar; dilute acetic acid.Acetic acidComments: a diluted solution of glacial acetic acid containing3037% w/w of acetic acid. See Section 18.Artificial vinegarComments: a solution containing 4% w/w of acetic acid.

Dilute acetic acidComments: a weak solution of acetic acid which may contain between 610% w/w of acetic acid. See Section 18.18 CommentsIn 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 36.037.0% 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 32.533.5% w/w of acetic acid. Acetic acid (6%)BP 2004 contains 5.76.3% w/w of acetic acid. The JP 2001 also contains a monograph for acetic acid that specifies that it contains 30.032.0% w/w of acetic acid.A specification for glacial acetic acid is contained in theFood Chemicals Codex (FCC).The EINECS number for acetic acid is 200-580-7.19 Specific References1 Sweetman SC, ed. Martindale: The Complete Drug Reference,34th edn. London: Pharmaceutical Press, 2005: 1645.2 Fenner PJ, Williamson JA. Worldwide deaths and severe enveno- mation from jellyfish stings. Med J Aust 1996; 165: 658661.3 Milner SM. Acetic acid to treat Pseudomonas aeruginosa in superficial wounds and burns. Lancet 1992; 340: 61.4 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials,11th edn. New York: Wiley, 2004: 1516.5 Health and Safety Executive. EH40/2002: Occupational ExposureLimits 2002, Sudbury: Health and Safety Executive, 2002.20 General References

21 AuthorsWG Chambliss.22 Date of Revision8 August 2005.1 Nonproprietary Names

Table I: Pharmacopeial specifications for acetone.BP: Acetone PhEur: Acetonum USPNF: Acetone

Test PhEur 2005 (Suppl. 5.1)

USPNF 232 SynonymsDimethylformaldehyde; dimethyl ketone; b-ketopropane; pyro- acetic ether.3 Chemical Name and CAS Registry Number2-Propanone [67-64-1]4 Empirical Formula and Molecular WeightC3H6O 58.085 Structural Formula

6 Functional CategorySolvent.7 Applications in Pharmaceutical Formulation or TechnologyAcetone is used as a solvent or cosolvent in topical prepara- tions, and as an aid in wet granulation.(1,2) It has also been used when formulating tablets with water-sensitive active ingredi- ents, 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 DescriptionAcetone is a colorless volatile, flammable, transparent liquid, with a sweetish odor and pungent sweetish taste.9 Pharmacopeial SpecificationsSee Table I.

Identification Characters Appearance of solution Acidity or alkalinity Relative density 0.7900.793 40.789Related substances Matter insoluble in water Reducing substances Residue on evaporation 450 ppm 40.004% Water 43 g/L Assay 599.0%10 Typical PropertiesBoiling point: 56.28C Flash point: 208C Melting point: 94.38CRefractive index: n20 = 1.359Solubility: soluble in water; freely soluble in ethanol (95%)Vapor pressure: 185 mmHg at 208C11 Stability and Storage ConditionsAcetone should be stored in a cool, dry, well-ventilated place out of direct sunlight.12 IncompatibilitiesAcetone 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 ManufactureAcetone 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 SafetyAcetone 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/kgLD50 (rat, IV): 5.5 g/kgLD50 (rat, oral): 5.8 g/kg15 Handling PrecautionsObserve 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 StatusIncluded 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 CommentsA specification for acetone is included in the Japanese Pharmaceutical Excipients (JPE).(7) The EINECS number for acetone is 200-662-2.

19 Specific References1 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. Bio-materials 2004; 25(19): 47414748.3 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. Biomaterials2003; 24(27): 50375044.4 Todd RG, Wade A, eds. The Pharmaceutical Codex, 11th edn.London: Pharmaceutical Press, 1979: 6.5 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials,11th edn. New York: Wiley, 2004: 2223.6 Health and Safety Executive: EH40/2002: Occupational ExposureLimits 2002. Sudbury: Health and Safety Executive, 2002.7 Japan Pharmaceutical Excipients Council. Japanese Pharmaceu- tical Excipients 2004. Tokyo: Yakuji Nippo, 2004: 3536.20 General References

21 AuthorsAH Kibbe, SC Owen.22 Date of Revision23 August 2005.1 Nonproprietary NamesUSPNF: Acetyltributyl citratePhEur: Tributylis acetylcitras2 SynonymsAcetylbutyl citrate; acetylcitric acid, tributyl ester; ATBC; Citroflex A-4; tributyl acetylcitrate; tributyl O-acetylcitrate; tributyl citrate acetate.3 Chemical Name and CAS Registry Number1,2,3-Propanetricarboxylic acid, 2-acetyloxy, tributyl ester[77-90-7]4 Empirical Formula and Molecular WeightC20H34O8 402.55 Structural Formula

6 Functional CategoryPlasticizer.7 Applications in Pharmaceutical Formulation or TechnologyAcetyltributyl citrate is used to plasticize polymers in for- mulated pharmaceutical coatings,(15) including capsules, tablets, beads, and granules for taste masking, immediate release, sustained-release and enteric formulations.

Table I: Pharmacopeial specifications for acetyltributyl citrate.Test PhEur 2005 USPNF 23Identification Appearance Characters Specific gravity 1.0451055

Refractive index 1.44101.4425 1.4421.445Sulfated ash 40.10% Acidity Water 40.25% 40.25% Heavy metals 40.001% 40.001% Assay (anhydrous basis) 599.0% 99.0101.0%10 Typical PropertiesAcid value: 0.02Boiling point: 3268C (decomposes)Flash point: 2048CPour point: 598CSolubility: miscible with acetone, ethanol, and vegetable oil;practically insoluble in water.Viscosity (dynamic): 33 mPa s (33 cP) at 258C11 Stability and Storage ConditionsAcetyltributyl citrate should be stored in a well-closed container in a cool, dry location at temperatures not exceeding388C. When stored in accordance with these conditions, acetyltributyl citrate is a stable product.12 IncompatibilitiesAcetyltributyl citrate is incompatible with strong alkalis and oxidizing materials.13 Method of ManufactureAcetyltributyl citrate is prepared by the esterification of citric acid with butanol followed by acylation with acetic anhydride.14 SafetyAcetyltributyl citrate is used in oral pharmaceutical formula- tions 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.8 Description

LD50

(cat, oral): >50 mL/kg(7)Acetyltributyl citrate is a clear, odorless, practically colorless,oily liquid.9 Pharmacopeial SpecificationsSee Table I.

LD50 (mouse, IP): >4 g/kgLD50 (rat, oral): >31.5 g/kg15 Handling PrecautionsObserve normal precautions appropriate to the circumstances and quantity of material handled. Acetyltributyl citrate is

Acetyltributyl Citrate 11 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 StatusIncluded 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 SubstancesAcetyltriethyl citrate; tributyl citrate; triethyl citrate.18 CommentsAcetyltributyl 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 beeninvestigated as a biodegradable barrier for use in guided-tissue regeneration therapy.(9)The EINECS number for acetyltributyl citrate is 201-067-0.19 Specific References1 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: 293301.2 Lehmann K. Chemistry and application properties of polymetha- crylate coating systems. In: McGinity JW, ed. Aqueous PolymericCoatings for Pharmaceutical Dosage Forms. New York: MarcelDekker, 1989: 153245.

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: 161.4 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 Pharm1993; 19(3): 315332.5 Repka MA, Gerding TG, Repka SL. Influence of plasticisers and drugs on the physical-mechanical properties of hydroxypropylcel-lulose films prepared by hot melt extrusion. Drug Dev Ind Pharm1999; 25(5): 625633.6 Lieb S, Szeimies RM, Lee G. Self-adhesive thin films for topical delivery of 5-aminolevulinic acid. Eur J Pharm Biopharm 2002;53(1): 99106.7 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials,11th edn. New York: Wiley, 2004: 3512.8 Goulas AE, Riganakos KA, Ehlermann DA, et al. Effect of high- dose 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): 720724.9 Dorfer CE, Kim TS, Steinbrenner H, et al. Regenerative period-ontal surgery in interproximal intrabony defects with biodegrad- able barriers. J Clin Peridontol 2000; 27(3): 162168.20 General References

21 AuthorsSW Kennedy.22 Date of Revision15 August 2005.1 Nonproprietary NamesUSPNF: Acetyltriethyl citrate2 SynonymsATEC; Citroflex A-2; triethyl acetylcitrate; triethyl O-acetyl- citrate; triethyl citrate acetate.3 Chemical Name and CAS Registry Number1,2,3-Propanetricarboxylic acid, 2-acetyloxy,