Handbook of pharmaceutical excipients 6th

Related SubstancesAcetic acid see Acetic Acid, Glacial Activated attapulgite see Attapulgite Aleuritic acid see Shellac d-Alpha tocopherol see Alpha Tocopherol d-Alpha tocopheryl acetate

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Handbook of Pharmaceutical Excipients

Application Development Leader

The Dow Chemical Company, Midland, MI, USA

Marian E Quinn BSc, MSc

Development Editor

Royal Pharmaceutical Society of Great Britain, London, UK

London Chicago

Published by the Pharmaceutical Press

An imprint of RPS Publishing

1 Lambeth High Street, London SE1 7JN, UK

100 South Atkinson Road, Suite 200, Grayslake, IL 60030-7820, USA

and the American Pharmacists Association

2215 Constitution Avenue, NW, Washington, DC 20037-2985, USA

# Pharmaceutical Press and American Pharmacists Association 2009

is a trade mark of RPS Publishing

RPS Publishing is the publishing organisation of the Royal Pharmaceutical Society of Great Britain First published 1986

Second edition published 1994

Third edition published 2000

Fourth edition published 2003

Fifth edition published 2006

Sixth edition published 2009

Typeset by Data Standards Ltd, Frome, Somerset

Printed in Italy by L.E.G.O S.p.A.

ISBN 978 0 85369 792 3 (UK)

ISBN 978 1 58212 135 2 (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 permission

of 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 Library

Preface x

Arrangement xi

Acknowledgments xiii

Notice to Readers xiii

International Steering Committee xiv

Editorial Staff xv

Contributors xvi

About the Editors xx

New Monographs xxi

Related Substances xxii

Lactose, Monohydrate and Microcrystalline Cellulose 371

Polymethacrylates 525

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 coprocessed

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

The fifth edition with its companion CD-ROM, Pharmaceutical

Excipients 5, contained 300 monographs and was published in

2006 This new edition contains 340 excipient monographs with a

new text design and enhanced online features, compiled by over 140

experts in pharmaceutical formulation or excipient manufacture

from Australia, Europe, India, Japan, 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 wasconsidered relevant to the behavior of a material in practice Overthe past few years, there has been an increased emphasis on theharmonization of excipients For information on the current statusfor each excipient selected for harmonization, the reader is directed

to the General Information Chapter<1196> in the USP32–NF27,the General Chapter 5.8 in PhEur 6.0, along with the ‘State ofWork’ document on the PhEur EDQM website (http://www.edq-m.eu), and also the General Information Chapter 8 in the JP XV.The Suppliers Directory (Appendix I) has also been completelyupdated with many more international suppliers included

In a systematic and uniform manner, the Handbook ofPharmaceutical Excipients collects essential data on the physicalproperties of excipients such as: boiling point, bulk and tap density,compression characteristics, hygroscopicity, flowability, meltingpoint, moisture content, moisture-absorption isotherms, particlesize distribution, rheology, specific surface area, and solubility.Scanning electron microphotographs (SEMs) are also included formany of the excipients This edition contains over 130 near-infrared(NIR) spectra specifically generated for the Handbook TheHandbook contains information from various international sourcesand personal observation and comments from monograph authors,steering committee members, and the editors

All of the monographs in the Handbook are thoroughly referenced and indexed so that excipients may be identified by either

cross-a chemiccross-al, cross-a nonproprietcross-ary, or cross-a trcross-ade ncross-ame Most monogrcross-aphslist related substances to help the formulator to develop a list ofpossible materials for use in a new dosage form or product Relatedsubstances are not directly substitutable for each other but, ingeneral, 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 pharmaceuticalexcipients, and is an essential reference source for those involved inthe development, production, control, or regulation of pharmaceu-tical preparations Since many pharmaceutical excipients are alsoused in other applications, the Handbook of PharmaceuticalExcipients will also be of value to persons with an interest in theformulation or production of confectionery, cosmetics, and foodproducts

x

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

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,

includ-ing 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

pro-duct 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 ent is generally thought to perform, e.g., diluent, emulsifyingagent, etc

excipi-Section 7, Applications in Pharmaceutical Formulation or ogy, Describes the various applications of the excipient

Technol-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 pendial standards for the excipient Information included isobtained from the British Pharmacopoeia (BP), European Pharma-copeia (PhEur), Japanese Pharmacopeia (JP), and the UnitedStates Pharmacopeia/National Formulary (USP/USP–NF) Infor-mation from the JP, USP and USP–NF are included if the sub-stance is in those compendia Information from the PhEur is alsoincluded If the excipient is not in the PhEur but is included in the

com-BP, information is included from the BP Pharmacopeias are nually updated with most now being produced as annual editions.However, although efforts were made to include up-to-date infor-mation at the time of publication of this edition, the reader isadvised to consult the most current pharmacopeias or supple-ments

conti-Section 10, Typical Properties, Describes the physical properties ofthe excipient which are not shown in Section 9 All data are formeasurements made at 208C unless otherwise indicated Wherethe solubility of the excipient is described in words, the followingterms describe the solubility ranges:

Very soluble 1 part in less than 1

Sparingly soluble 1 part in 30–100Slightly soluble 1 part in 100–1000Very slightly soluble 1 part in 1000–10 000Practically insoluble or insoluble 1 part in more than 10 000For this edition, near-infrared (NIR) reflectance spectra of samples

as received (i.e the samples were not dried or reduced in particlesize) were measured using a FOSS NIRSystems 6500 spectro-photometer (FOSS NIRSystems Inc., Laurel, MD, USA) fitted with aRapid Content Analyser against a ceramic standard supplied withthe instrument The instrument was controlled by Vision (version2.22) software Spectra were recorded over the wavelength range1100–2498 nm (700 data points) and each saved spectrum was theaverage of 32 scans Solid powdered samples were measured in glassvials of approximately 20 mm diameter Each sample was measured

in triplicate and the mean spectrum taken When more than onebatch of a material was available, the mean of all the batches ispresented Liquid samples were measured by transflectance using agold reflector (2 0.5 mm optical path-length, FOSS) placed in a

45 mm silica reflectance cell against air as the reference Spectra arepresented as plots of (a) log(1/R) vs wavelength (dashed line, scale

on right-hand side) and (b) second-derivative log(1/R) vs length (solid line, scale on left-hand side) R is the reflectance andlog(1/R) represents the apparent absorbance Second-derivativespectra were calculated from the log(1/R) values using an 11 pointSavitzky-Golay filter with second-order polynomial smoothing

wave-xi

Note, peak positions and amplitudes in the second-derivative

spectrum are very sensitive to the method used to calculate the

second-derivative

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

Hand-book

Section 11, Stability and Storage Conditions, Describes the

condi-tions 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

incompatibil-ities 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

incompatibil-ities prior to use in a commercial product

Section 13, Method of Manufacture, Describes the common

meth-ods of manufacture and additional processes that are used to give

the excipient its physical characteristics In some cases the

possibi-lity 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

con-cerning possible hazards and adverse reactions that have been

reported Relevant animal toxicity data are also shown

Section 15, Handling Precautions, Indicates possible hazards ciated with handling the excipient and makes recommendationsfor suitable containment and protection methods A familiaritywith current good laboratory practice (GLP) and current goodmanufacturing practice (GMP) and standard chemical handlingprocedures is assumed

asso-Section 16, Regulatory Status, Describes the accepted uses infoods and licensed pharmaceuticals where known However, thestatus of excipients varies from one nation to another, and appro-priate regulatory bodies should be consulted for guidance

Section 17, Related Substances, Lists excipients similar to theexcipient discussed in the monograph

Section 18, Comments, Includes additional information and vations relevant to the excipient Where appropriate, the differentgrades of the excipient available are discussed Comments are theopinion of the listed author(s) unless referenced or indicatedotherwise

obser-Section 19, Specific References, Is a list of references cited withinthe monograph

Section 20, General References, Lists references which have eral information about this type of excipient or the types ofdosage forms made with these excipients

gen-Section 21, Authors, Lists the current authors of the monograph

in alphabetical order Authors of previous versions of the graph are shown in previous printed editions of the text

mono-Section 22, Date of Revision, Indicates the date on which changeswere 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 140 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.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 We extend our thanks to all for their support Thanks are also

extended to Roger Jee, Kelly Palmer, and Tony Moffat at The School

of Pharmacy, University of London for supplying the NIR spectra,

to Pfizer PGRD, Sandwich, UK for supplying SEMs, and to

excipient manufacturers and suppliers who provided helpfulinformation on their products

Thanks are also gratefully extended to the staff of thePharmaceutical Press and American Pharmacists Association whowere involved in the production of the Handbook: Tamsin Cousins,Simon Dunton, Rebecca Garner, Julian Graubart, Karl Parsons,Linda Paulus, Jo Watts, Paul Weller, and John Wilson The diligentcopy-editing and proofreading by Len Cegielka and Janet Pascoe,respectively, helped the authors and editors, we hope, to expresstheir thoughts clearly, concisely, and accurately

Raymond C Rowe, Paul J Sheskey, Marian E Quinn

July 2009

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

incompat-ibilities or adverse reactions to an excipient, in a particular

application, may not necessarily prevent its use in other

applica-tions 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 productsand, similarly, the unintentional omission of a supplier or productfrom the directory is not intended to reflect adversely on thatsupplier or its product

Although diligent effort was made to use the most recentcompendial information, compendia are frequently revised andthe reader is urged to consult current compendia, or supplements,for up-to-date information, particularly as efforts are currently inprogress to harmonize standards for excipients

Data presented for a particular excipient may not be tive of other batches or samples

representa-Relevant data and constructive criticism are welcome and may beused to assist in the preparation of any future editions or electronicversions of the Handbook The reader is asked to send anycomments to the Editor, Handbook of Pharmaceutical Excipients,Royal Pharmaceutical Society of Great Britain, 1 Lambeth HighStreet, London SE1 7JN, UK, or Editor, Handbook of Pharmaceu-tical Excipients, American Pharmacists Association, 2215 Consti-tution Avenue, NW, Washington, DC 20037-2985, USA

xiii

International Steering Committee

Wilkes University School of Pharmacy

Wilkes-Barre, PA, USA

Bruce R KinseyAshland Aqualon Functional IngredientsHarleysville, PA, USA

William J LambertPacira Pharmaceuticals, Inc

San Diego, CA, USAJian-Xin Li

Evonik Degussa CorporationPiscataway, NJ, USABrian R MatthewsAlcon Laboratories (UK) LtdHertfordshire, UK

R Christian MoretonFinnBrit ConsultingWaltham, MA, USAGary Moss

University of HertfordshireHertfordshire, UK

Marian E QuinnRoyal Pharmaceutical Society of Great BritainLondon, UK

Raymond C RoweIntelligensys LtdStokesley, UKNiklas SandlerUniversity of HelsinkiHelsinki, FinlandShirish A ShahICON Development SolutionsPhoenix, AZ, USA

Catherine M SheehanUnited States PharmacopeiaRockville, MD, USAPaul J SheskeyThe Dow Chemical CompanyMidland, MI, USA

Kamalinder K SinghSNDT Women’s UniversityMumbai, India

Hirofumi TakeuchiGifu Pharmaceutical UniversityGifu, Japan

Paul J WellerRoyal Pharmaceutical Society of Great BritainLondon, UK

xiv

International Journal of Pharmaceutical Compounding

Edmond, OK, USA

W CookPfizer Global R&DKent, UK

A CramPfizer Global R&DKent, UK

TC DahlGilead SciencesFoster City, CA, USA

PD DaugherityPfizer IncGroton, CT, USA

A DayAstraZenecaMacclesfield, Cheshire, UK

HJ de JongPuteaux, France

E DraganoiuLubrizol Advanced Materials IncCleveland, OH, USA

D DubashSolvay Pharmaceuticals IncMarietta, GA, USA

S EdgeNovartis Pharma AGBasel, Switzerland

C EggerRockwood PigmentsTurin, Italy

T FarrellColorcon IncWest Point, PA, USA

RA FerrainaPfizer Global R&DGroton, CT, USA

RT ForbesUniversity of BradfordBradford, UK

SO FreersGrain Processing CorporationMuscatine, IA, USA

B FritzschingBENEO-Palatinit GmbHMannheim, Germany

xvi

GP Frunzi

Time-Cap Labs Inc

Farmingdale, NY, USA

WL HulseUniversity of BradfordBradford, UK

JT IrwinPerrigo CompanyAllegan, MI, USA

M IsrebUniversity of BradfordBradford, UK

H ItoNOF CorporationHyogo-ken, Japan

BR JastiUniversity of the PacificStockton, CA, USA

BA JohnsonPfizer IncGroton, CT, USA

DS JonesThe Queen’s University BelfastBelfast, UK

M JulienGattefosse SASSaint-Priest, France

MA KabirSchering-Plough Consumer HealthcareMemphis, TN, USA

JS KaergerAeropharm GmbHRudolstadt, Germany

AS KearneyGlaxoSmithKline IncKing of Prussia, PA, USA

VL KettThe Queen’s University of BelfastBelfast, UK

AH KibbeWilkes University School of PharmacyWilkes-Barre, PA, USA

PB KlepakReheis IncBerkeley Heights, NJ, USA

DD LadipoPfizer Global R&DGroton, CT, USA

WJ LambertPacira Pharmaceuticals IncSan Diego, CA, USA

University of the Pacific

Stockton, CA, USA

MP MullarneyPfizer IncGroton, CT, USA

K MurakamiTomita Pharmaceutical Co LtdTokushima-ken, Japan

S MurdandePfizer IncGroton, CT, USA

BJ MurphyPfizer IncGroton, CT, USA

RG NausePfizer IncGroton, CT, USA

S NemaPfizer Global R&DChesterfield, MO, USA

S ObaraShin-Etsu Chemical Co LtdNiigata, Japan

A PalmieriUniversity of FloridaGainesville, FL, USA

MA PellettWyeth Consumer HealthcareHavant, Hampshire, UK

L PeltonenUniversity of HelsinkiHelsinki, Finland

Y PengAstraZeneca PharmaceuticalsWilmington, DE, USA

M PenningMainz, Germany

JD PipkinCyDex Pharmaceuticals IncLenexa, KS, USA

P PlumbAstraZenecaMacclesfield, Cheshire, UK

F PodczeckTyne and Wear, UK

P PopleSNDT Women’s UniversityMumbai, India

W QuUniversity of TennesseeMemphis, TN, USA

Pacira Pharmaceuticals Inc

San Diego, CA, USA

Pacira Pharmaceuticals Inc

San Diego, CA, USA

HC ShahSNDT Women’s UniversityMumbai, India

SA ShahICON Development SolutionsPhoenix, AZ, USA

U ShahSolvay Pharmaceuticals IncMarietta, GA, USA

RM ShankerPfizer IncGroton, CT, USA

JJ ShengAstraZenecaWilmington, DE, USA

PJ SheskeyThe Dow Chemical CompanyMidland, MI, USA

AJ ShuklaUniversity of TennesseeMemphis, TN, USA

J ShurUniversity of BathBath, UK

D SimonRoquette Fre`resLestrem, France

A SinghUniversity of Mississippi

MS, USA

KK SinghSNDT Women’s UniversityMumbai, India

JLP SohPfizer Global R&DKent, UK

RA StoreyAstraZenecaMacclesfield, Cheshire, UK

C SunUniversity of Minnesota College of PharmacyMinneapolis, MN, USA

AK TaylorBaton Rouge

LA, USA

J TeckoeColorcon LtdDartford, Kent, UK

MS Tesconi

Wyeth Research

Pearl River, NY, USA

D Thassu

UCB Pharma Inc

Rochester, NY, USA

D WallickThe Dow Chemical CompanyMidland, MI, USA

PJ WellerRoyal Pharmaceutical Society of Great BritainLondon, UK

P YingPacira Pharmaceuticals IncSan Diego, CA, USA

PM YoungUniversity of SydneySydney, NSW, Australia

D ZhangMerck Co IncRahway, NJ, USA

About the Editors

Raymond C Rowe

BPharm, PhD, DSC, FRPharmS, FRSC, CPhys, MInstP

Raymond Rowe has been involved in the Handbook of

Pharma-ceutical 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 an Application Development Leader in

the Dow-Wolff Cellulosics R&D Group at The Dow ChemicalCompany 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 formdevelopment at the Perrigo Company and the Upjohn (Pfizer)Company Paul has authored numerous journal articles in the area

of pharmaceutical technology He is a member of the AAPS and theControlled Release Society

Marian E QuinnBSc, MSc

Marian Quinn joined the publications department of the RoyalPharmaceutical Society of Great Britain in 2007 for the sixth edition

of the Handbook of Pharmaceutical Excipients, having previouslyworked on the 34th and 35th editions of Martindale: The CompleteDrug Reference She has also previously worked at the NationalInstitute for Medical Research, Blackwell Publishing, and Elsevier.Marian received her BSc (Hons) degree in microbiology from theUniversity of Surrey, and her MSc in molecular genetics from theUniversity of Leicester

Lactose, Monohydrate and Corn Starch

Lactose, Monohydrate and Microcrystalline Cellulose

Lactose, Monohydrate and Povidone

Lactose, Monohydrate and Powdered Cellulose

Maleic AcidMethionineMyristyl AlcoholNeotamePentetic AcidPhospholipidsPoly(DL-Lactic Acid)PolyoxylglyceridesPotassium AlumPropylparaben SodiumSafflower Oil

Sodium CarbonateSodium Formaldehyde SulfoxylateSodium Thiosulfate

Sucrose OctaacetateSulfur DioxideTagatoseTricaprylinTrioleinVitamin E Polyethylene Glycol Succinate

xxi

Related Substances

Acetic acid see Acetic Acid, Glacial

Activated attapulgite see Attapulgite

Aleuritic acid see Shellac

d-Alpha tocopherol see Alpha Tocopherol

d-Alpha tocopheryl acetate see Alpha Tocopherol

dl-Alpha tocopheryl acetate see Alpha Tocopherol

d-Alpha tocopheryl acid succinate see Alpha Tocopherol

dl-Alpha tocopheryl acid succinate see Alpha Tocopherol

Aluminum distearate see Aluminum Monostearate

Aluminum tristearate see Aluminum Monostearate

Anhydrous citric acid see Citric Acid Monohydrate

Anhydrous sodium citrate see Sodium Citrate Dihydrate

Anhydrous sodium propionate see Sodium Propionate

Aqueous shellac solution see Shellac

Artificial vinegar see Acetic Acid, Glacial

Aspartame acesulfame see Aspartame

Bacteriostatic water for injection see Water

Bentonite magma see Bentonite

Beta tocopherol see Alpha Tocopherol

Beta-carotene see Coloring Agents

n-Butyl lactate see Ethyl Lactate

Butylparaben sodium see Butylparaben

Calcium acetate monohydrate see Calcium Acetate

Calcium ascorbate see Sodium Ascorbate

Calcium cyclamate see Sodium Cyclamate

Calcium diorthosilicate see Calcium Silicate

Calcium polycarbophil see Polycarbophil

Calcium propionate see Sodium Propionate

Calcium sorbate see Sorbic Acid

Calcium sulfate hemihydrate see Calcium Sulfate

Calcium trisilicate see Calcium Silicate

Calcium trisodium pentetate see Pentetic Acid

Capric acid see Lauric Acid

Carbon dioxide-free water see Water

Cationic emulsifying wax see Wax, Nonionic Emulsifying

Ceratonia extract see Ceratonia

Cetylpyridinium bromide see Cetylpyridinium Chloride

Chlorhexidine acetate see Chlorhexidine

Chlorhexidine gluconate see Chlorhexidine

Chlorhexidine hydrochloride see Chlorhexidine

Chlorodifluoromethane see Chlorodifluoroethane (HCFC)

Chlorophenoxyethanol see Phenoxyethanol

Corn syrup solids see Maltodextrin

m-Cresol see Cresol

o-Cresol see Cresol

p-Cresol see Cresol

Crude olive-pomace oil see Olive Oil

Cyclamic acid see Sodium Cyclamate

De-aerated water see Water

Dehydrated alcohol see Alcohol

Delta tocopherol see Alpha Tocopherol

Denatured alcohol see Alcohol

Dextrose anhydrous see Dextrose

Diazolidinyl urea see Imidurea

Dibasic potassium phosphate see Sodium Phosphate, Dibasic

Diethylene glycol monopalmitostearate see Ethylene Glycol

Stea-rates

Dilute acetic acid see Acetic Acid, Glacial

Dilute alcohol see Alcohol

Dilute ammonia solution see Ammonia Solution

Dilute hydrochloric acid see Hydrochloric Acid

Dilute phosphoric acid see Phosphoric Acid

Dilute sulfuric acid see Sulfuric AcidDimethyl-b-cyclodextrin see CyclodextrinsDioctyl phthalate see Dibutyl PhthalateDipotassium edetate see Edetic AcidDocusate calcium see Docusate SodiumDocusate potassium see Docusate SodiumDodecyl gallate see Propyl GallateDodecyltrimethylammonium bromide see CetrimideEdetate calcium disodium see Edetic Acid

Eglumine see MeglumineEthyl gallate see Propyl GallateEthyl linoleate see Linoleic AcidEthylene glycol monopalmitate see Ethylene Glycol StearatesEthylene glycol monostearate see Ethylene Glycol StearatesEthylparaben potassium see Ethylparaben

Ethylparaben sodium see EthylparabenExtra virgin olive oil see Olive OilFine virgin olive oil see Olive OilFuming sulfuric acid see Sulfuric AcidGamma tocopherol see Alpha TocopherolGlyceryl triisooctanoate see TricaprylinGlycine hydrochloride see GlycineHard water see Water

Hesperidin see Neohesperidin DihydrochalconeHexadecyltrimethylammonium bromide see CetrimideHigh-fructose syrup see Fructose

Hyaluronic acid see Sodium HyaluronateHydrogenated lanolin see LanolinHydrogenated vegetable oil, type II see Vegetable Oil, Hydro-genated

2-Hydroxyethyl-b-cyclodextrin see Cyclodextrins3-Hydroxypropyl-b-cyclodextrin see Hydroxypropyl BetadexIndigo carmine see Coloring Agents

Invert sugar see SucroseIsotrehalose see TrehaloseLaccaic acid B see ShellacLampante virgin olive oil see Olive OilLanolin alcohols ointment see Petrolatum and Lanolin Alcohols

DL-Leucine see LeucineLiquefied phenol see PhenolLiquid fructose see FructoseMagnesium carbonate anhydrous see Magnesium CarbonateMagnesium carbonate hydroxide see Magnesium CarbonateMagnesium lauryl sulfate see Sodium Lauryl SulfateMagnesium metasilicate see Magnesium SilicateMagnesium orthosilicate see Magnesium SilicateMagnesium trisilicate anhydrous see Magnesium Trisilicate

D-Malic acid see Malic Acid

L-Malic acid see Malic Acidd-Menthol see Mentholl-Menthol see Menthol

D-Methionine see Methionine

DL-Methionine see MethionineMethyl lactate see Ethyl LactateMethyl linoleate see Linoleic AcidMethyl methacrylate see PolymethacrylatesMethyl oleate see Ethyl Oleate

Methylparaben potassium see MethylparabenMethylparaben sodium see MethylparabenN-Methylpyrrolidone see PyrrolidoneMicrocrystalline cellulose and carrageenan see Cellulose, Micro-crystalline

xxii

Microcrystalline cellulose and guar gum see Cellulose,

Microcrys-talline

Microcrystalline cellulose spheres see Sugar Spheres

Modified lanolin see Lanolin

Monobasic potassium phosphate see Sodium Phosphate,

Mono-basic

Montmorillonite see Magnesium Aluminum Silicate

Neotrehalose see Trehalose

Normal magnesium carbonate see Magnesium Carbonate

NPTAB see Sugar Spheres

Octyl gallate see Propyl Gallate

Oleyl oleate see Oleyl Alcohol

Olive-pomace oil see Olive Oil

Palmitin see Palmitic Acid

Pentasodium pentetate see Pentetic Acid

Pharmaceutical glaze see Shellac

Phenoxypropanol see Phenoxyethanol

Polacrilin see Polacrilin Potassium

Poly(methyl methacrylate) see Polymethacrylates

Potassium bisulfite see Potassium Metabisulfite

Potassium myristate see Myristic Acid

Potassium propionate see Sodium Propionate

Powdered fructose see Fructose

Propan-1-ol see Isopropyl Alcohol

(S)-Propylene carbonate see Propylene Carbonate

Propylparaben potassium see Propylparaben

Purified bentonite see Bentonite

Purified stearic acid see Stearic Acid

Quaternium 18-hectorite see Hectorite

Rapeseed oil see Canola Oil

Refined almond oil see Almond Oil

Refined olive-pomace oil see Olive Oil

Saccharin ammonium see Saccharin

Saccharin calcium see Saccharin

Safflower glycerides see Safflower Oil

Self-emulsifying glyceryl monostearate see Glyceryl Monostearate

Sodium bisulfite see Sodium Metabisulfite

Sodium borate anhydrous see Sodium BorateSodium carbonate decahydrate see Sodium CarbonateSodium carbonate monohydrate see Sodium CarbonateSodium edetate see Edetic Acid

Sodium erythorbate see Erythorbic AcidSodium glycinate see Glycine

Sodium laurate see Lauric AcidSodium myristate see Myristic AcidSodium palmitate see Palmitic AcidSodium sorbate see Sorbic AcidSodium sulfite heptahydrate see Sodium SulfiteSoft water see Water

Spermaceti wax see Wax, Cetyl EstersStearalkonium hectorite see HectoriteSterile water for inhalation see WaterSterile water for injection see WaterSterile water for irrigation see WaterSugartab see Sugar, CompressibleSunset yellow FCF see Coloring AgentsSynthetic paraffin see Paraffin

DL-Tagatose see Tagatose

L-Tagatose see TagatoseTartrazine see Coloring AgentsTheobroma oil see Suppository Bases, Hard FatTocopherols excipient see Alpha TocopherolTribasic sodium phosphate see Sodium Phosphate, DibasicTrimethyl-b-cyclodextrin see Cyclodextrins

Trimethyltetradecylammonium bromide see CetrimideTrisodium edetate see Edetic Acid

Virgin olive oil see Olive OilWater for injection see WaterWhite petrolatum see PetrolatumZinc formaldehyde sulfoxylate see Sodium Formaldehyde Sulfox-ylate

Zinc propionate see Sodium PropionateZinc trisodium pentetate see Pentetic Acid

A selection of publications and websites which contain useful information on pharmaceutical excipients is listed below:

Ash M, Ash I Handbook of Pharmaceutical Additives, 3rd edn,

Endicott, NY: Synapse Information Resources, 2007

Aulton ME Aulton’s Pharmaceutics: The Design and Manufacture

of Medicines, 3rd edn, Edinburgh: Churchill Livingstone, 2007

Banker GS Rhodes CT Modern Pharmaceutics, 4th edn, New

York: Marcel Dekker, 2002

British Pharmacopoeia 2009, London: The Stationery Office, 2009

Bugay DE, Findlay WP Pharmaceutical Excipients

Characteriza-tion by IR, Raman, and NMR Spectroscopy, New York: Marcel

Health and Safety Executive EH40/2005: Workplace Exposure

Limits Sudbury: HSE Books, 2005 (updated 2007) http://

www.hse.gov.uk/coshh/table1.pdf (accessed 5 February 2009)

Health Canada Canadian List of Acceptable Non-medicinal

Ingredients

http://www.hc-sc.gc.ca/dhp-mps/prodnatur/legisla-tion/docs/nmi-imn_list1-eng.php (accessed 5 February 2009)

Hoepfner E, et al 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, 15th edn, Tokyo: Yakuji Nippo, 2006

Kemper FH, et al Blue List Cosmetic Ingredients, Aulendorf,Germany: Editio Cantor, 2000

Lewis RJ Sax’s Dangerous Properties of Industrial Materials, 11thedn, New York: John Wiley, 2004

Lund W The Pharmaceutical Codex: Principles and Practice ofPharmaceutics, 12th edn, London: Pharmaceutical Press, 1994.Matthews BR Pharmaceutical Excipients: A Manufacturer’s Hand-book, Bethesda, MD: PDA Books, 2005

National Library of Medicine TOXNET http://toxnet.nlm.nih.gov(accessed 5 February 2009)

O’Neil MJ, et al The Merck Index: an Encyclopedia of Chemicals,Drugs, and Biologicals, 14th edn, Whitehouse Station, NJ:Merck, 2006

Smolinske SC Handbook of Food, Drug and Cosmetic Excipients,Boca Raton, FL: CRC Press, 1992

Swarbrick J Boylan JC Encyclopedia of Pharmaceutical ogy, 2nd edn, New York: Marcel Dekker, 2002

Technol-Sweetman SC Martindale: the Complete Drug Reference, 36th edn,London: Pharmaceutical Press, 2009

United States Pharmacopeia 32 and National Formulary 27,Rockville, MD: United States Pharmacopeial Convention, 2009.University of the Sciences in Philadelphia, Remington: the Scienceand Practice of Pharmacy, 21st edn, Baltimore: LippincottWilliams and Wilkins, 2005

Weiner M, Bernstein IL Adverse Reactions to Drug FormulationAgents: A Handbook of Excipients, New York: Marcel Dekker,1989

Weiner ML Kotkoskie LA Excipient Toxicity and Safety, NewYork: Marcel Dekker, 2000

xxiv

BS British Standard (specification).

BSI British Standards Institution

cmc critical micelle concentration

CNS central nervous system

cP centipoise(s)

cSt centistoke(s)

CTFA Cosmetic, Toiletry, and Fragrance Association

d particle diameter (d10at 10 percentile; d50at 50

percentile; d90at 90 percentile)

D&C designation applied in USA to dyes permitted for

use in drugs and cosmetics

DoH Department of Health (UK)

DSC differential scanning calorimetry

e.g exemplit gratia, ‘for example’

EINECS European Inventory of Existing Commercial

FAO/WHO Food and Agriculture Organization of the United

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

GMP Good Manufacturing Practice

GRAS generally recognized as safe by the Food and Drug

Administration of the USA

HSE Health and Safety Executive (UK)

i.e id est, ‘that is’

LAL Limulus amoebocyte lysate

LC50 a concentration in air lethal to 50% of the specified

MIC minimum inhibitory concentration

min minute(s) or minimum

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

SI Statutory Instrument or Syste`me International

d’Unites (International System of Units)

TDLo lowest toxic dose for the specified animals or

microorganisms

TPN total parental nutrition

TWA time weighted average

US or USA United States of America

USAN United States Adopted Name

USP The United States Pharmacopeia

USP–NF The United States Pharmacopeia National

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 10–4square meter (m2)

1 square foot (ft2) = 9.29030 10–2square meter (m2)

1 square yard (yd2) = 8.36127 10–1square meter (m2)

1 angstrom (A˚) = 10–10meter (m)

1 inch (in) = 2.54 10–2meter (m)

1 foot (ft) = 3.048 10–1meter (m)

1 yard (yd) = 9.144 10–1meter (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)

TemperatureCelsius (8C) = (1.8  8C) þ 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 10–5cubic meter (m3)

1 cubic foot (ft3) = 2.83168 10–2cubic meter (m3)

1 cubic yard (yd3) = 7.64555 10–1cubic meter (m3)

1 pint (UK) = 5.68261 10–4cubic meter (m3)

1 pint (US) = 4.73176 10–4cubic meter (m3)

1 gallon (UK) = 4.54609 10–3cubic meter (m3)

1 gallon (US) = 3.78541 10–3cubic meter (m3)

xxvii

Acaciae gummi; 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

formula-tions 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.

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 SpecificationsThe PhEur 6.3 provides monographs on acacia and spray-driedacacia, while the USP32–NF27 describes acacia in a singlemonograph that encompasses tears, flakes, granules, powder, andspray-dried powder The USP32–NF27 also has a monograph onacacia syrup The JP XV has monographs on acacia and powderedacacia See Table II

Table II: Pharmacopeial specifications for acacia.

(a) Powdered acacia.

(b) Spray-dried acacia.

10 Typical PropertiesAcidity/alkalinity pH = 4.5–5.0 (5% w/v aqueous solution)Acid value 2.5

Hygroscopicity At relative humidities of 25–65%, the equilibriummoisture content of powdered acacia at 258C is 8–13% w/w, but

at relative humidities above about 70% it absorbs substantialamounts of water

NIR spectra see Figure 1

Solubility Soluble 1 in 20 of glycerin, 1 in 20 of propylene glycol,

1 in 2.7 of water; practically insoluble in ethanol (95%) Inwater, acacia dissolves very slowly, although almost completelyafter two hours, in twice the mass of water leaving only a verysmall residue of powder The solution is colorless or yellowish,viscous, adhesive, and translucent Spray-dried acacia dissolvesmore rapidly, in about 20 minutes

Specific gravity 1.35–1.49Viscosity (dynamic) 100 mPa s (100 cP) for a 30% w/v aqueoussolution at 208C The viscosity of aqueous acacia solutionsvaries depending upon the source of the material, processing,storage conditions, pH, and the presence of salts Viscosityincreases slowly up to about 25% w/v concentration andexhibits Newtonian behavior Above this concentration, viscos-ity increases rapidly (non-Newtonian rheology) Increasingtemperature or prolonged heating of solutions results in adecrease of viscosity owing to depolymerization or particleagglomeration See also Section 12

A

1

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

follow-ing 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)

16 Regulatory StatusGRAS listed Accepted for use in Europe as a food additive.Included in the FDA Inactive Ingredients Database (oral prepara-tions and buccal or sublingual tablets) Included in the CanadianList of Acceptable Non-medicinal Ingredients Included in nonpar-enteral medicines licensed in the UK

17 Related SubstancesCeratonia; guar gum; tragacanth

Concentrated aqueous solutions are used to prepare pastilles since

on drying they form solid rubbery or glasslike masses dependingupon the concentration used Foreign policy changes and politicallyunstable conditions in Sudan, which is the principal supplier ofacacia, has created a need to find a suitable replacement.(10)Poloxamer 188 (12–15% w/w) can be used to make an oil/wateremulsion with similar rheological characteristics to acacia Othernatural by-products of foods can also be used.(11)Acacia is also used

in the food industry as an emulsifier, stabilizer, and thickener Aspecification for acacia is contained in the Food Chemicals Codex(FCC).(12)

The EINECS number for acacia is 232-519-5

3 Bahardwaj TR et al 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 et al Experimenting with a new emulsifying agent (tahini) in mineral oil Int J Pharm Compound 2000; 4(4): 315–317.

12 Food Chemicals Codex, 6th edn Bethesda, MD: United States Pharmacopeia, 2008; 425.

20 General ReferencesAnderson DMW, Dea ICM Recent advances in the chemistry of acacia gums J Soc Cosmet Chem 1971; 22: 61–76.

2323 2467 2262

1928 1435

1201

Figure 1: Near-infrared spectrum of acacia measured by reflectance.

A

Anderson DM et al Specifications for gum arabic (Acacia Senegal):

analytical data for samples collected between 1904 and 1989 Food

PhEur: Acesulfame Potassium

USP-NF: Acesulfame Potassium

Acesulfame K; ace K; acesulfamum kalicum; E950;

6-methyl-3,4-dihydro-1,2,3-oxathiazin-4(3H)-one-2,2-dioxide potassium salt;

potassium 6-methyl-2,2-dioxo-oxathiazin-4-olate; Sunett; Sweet

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, similar to aspartame, about one-third as sweet as sucralose,

one-half as sweet as sodium saccharin, and about 4-5 times sweeter

than sodium cyclamate.(3)It enhances flavor systems and can beused to mask some unpleasant taste characteristics

8 DescriptionAcesulfame potassium occurs as a colorless to white-colored,odorless, crystalline powder with an intensely sweet taste

9 Pharmacopeial SpecificationsSee Table I

10 Typical PropertiesAcidity/alkalinity pH = 5.5–7.5 (1% w/v aqueous solution)Bonding index 0.007(4)

Brittle fracture index 0.08(4)Density (bulk) 1.04 g/cm3 (4)Density (tapped) 1.28 g/cm3 (4)Elastic modulus 4000 MPa(4)Flowability 19% (Carr compressibility index)(4)Melting point 2508C

NIR spectra see Figure 1

Solubility see Table II

SEM 1: Excipient: acesulfame potassium; magnification: 150 ; voltage:

5 kV.

A

Table II: Solubility of acesulfame potassium (3)

Solvent Solubility at 208C unless otherwise stated

Surface tension 73.2 mN/m(6)(1% w/v aqueous solution at 208C

Tensile strength 0.5 MPa(4)

Viscoelastic index 2.6(4)

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

decom-position was noted following storage at 408C for several months

Sterilization and pasteurization do not affect the taste of acesulfame

potassium.(7)

The bulk material should be stored in a well-closed container in a

cool, dry place and protected from light

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 isthen cyclized in the presence of potassium hydroxide to form theoxathiazinone dioxide ring system Because of the strong acidity ofthis compound, the potassium salt is produced directly.(8)

An alternative synthesis route for acesulfame potassium startswith the reaction between diketene and amidosulfonic acid In thepresence of dehydrating agents, and after neutralization withpotassium hydroxide, acesulfame potassium is formed

14 SafetyAcesulfame potassium is widely used in beverages, cosmetics, foods,and pharmaceutical formulations, and is generally regarded as arelatively nontoxic and nonirritant material Pharmacokineticstudies have shown that acesulfame potassium is not metabolizedand is rapidly excreted unchanged in the urine Long-term feedingstudies in rats and dogs showed no evidence to suggest acesulfamepotassium is mutagenic or carcinogenic.(9)

The WHO has set an acceptable daily intake for acesulfamepotassium of up to 15 mg/kg body-weight.(9) The ScientificCommittee for Foods of the European Union has set a daily intakevalue of up to 9 mg/kg of body-weight.(3)

LD50(rat, IP): 2.2 g/kg(7)

LD50(rat, oral): 6.9–8.0 g/kg

15 Handling PrecautionsObserve normal precautions appropriate to the circumstances andquantity of material handled Eye protection, gloves, and a dustmask are recommended

16 Regulatory StatusIncluded in the FDA Inactive Ingredients Database for oral andsublingual preparations Included in the Canadian List of Accep-table Non-medicinal Ingredients Accepted for use in Europe as afood additive It is also accepted for use in certain food products inthe USA and several countries in Central and South America, theMiddle East, Africa, Asia, and Australia

17 Related SubstancesAlitame

The perceived intensity of sweeteners relative to sucrose dependsupon their concentration, temperature of tasting, and pH, and onthe flavor and texture of the product concerned

Intense sweetening agents will not replace the bulk, textural, orpreservative characteristics of sugar, if sugar is removed from aformulation

Synergistic effects for combinations of sweeteners have beenreported, e.g acesulfame potassium with aspartame or sodiumcyclamate; see also Aspartame A ternary combination of sweet-eners that includes acesulfame potassium and sodium saccharin has

a greater decrease in sweetness upon repeated tasting than othercombinations.(10)

Note that free acesulfame acid is not suitable for use as asweetener

A specification for acesulfame potassium is contained in theFood Chemicals Codex (FCC).(11)

19 Specific References

1 Kloesel L Sugar substitutes Int J Pharm Compound 2000; 4(2): 86–87.

2 Schmidt R et al Evaluating toothpaste sweetening Cosmet Toilet 2000; 115: 49–53.

3.0

0.0

2482 2282 2251 2134 1699

1646

16591685

2268 2294 2466 1711

25002100

190017001300

Table I: Pharmacopeial specifications for acesulfame potassium.

Assay (dried basis) 99.0–101.0% 99.0–101.0%

(a) Impurity B is 5-chloro-6-methyl-1,2,3-oxathiazin-4(3H)-one 2,2-dioxide.

A

3 Wilson R, ed Sweeteners, 3rd edn Oxford, UK: Blackwell Publishing,

2007; 3–19.

4 Mullarney MP et al The powder flow and compact mechanical

properties of sucrose and three high-intensity sweeteners used in

chewable tablets Int J Pharm 2003; 257: 227–236.

5 Birch GG et al Apparent specific volumes and tastes of cyclamates,

other sulfamates, saccharins and acesulfame sweeteners Food Chem

2004; 84: 429–435.

6 Hutteau F et al Physiochemical and psychophysical characteristics of

binary mixtures of bulk and intense sweeteners Food Chem 1998;

9 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.

10 Schiffman SS et al Effect of repeated presentation on sweetness intensity

of binary and tertiary mixtures of sweetness Chem Senses 2003; 28:

219–229.

11 Food Chemicals Codex, 6th edn Bethesda, MD: United States Pharmacopeia, 2008; 9.

20 General ReferencesAnonymous Artificial sweetners Can Pharm J 1996; 129: 22.

Lipinski G-WvR, Lu¨ck E Acesulfame K: a new sweetener for oral cosmetics.

BP: Glacial Acetic Acid

JP: Glacial Acetic Acid

PhEur: Acetic Acid, Glacial

USP: Glacial Acetic Acid

Acidum aceticum glaciale; E260; ethanoic acid; ethylic acid;

methane carboxylic acid; vinegar acid

See also Sections 17 and 18

3 Chemical Name and CAS Registry Number

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 andantifungal properties

8 DescriptionGlacial acetic acid occurs as a crystalline mass or a clear, colorlessvolatile solution with a pungent odor

9 Pharmacopeial SpecificationsSee Table I

Table I: Pharmacopeial specifications for glacial acetic acid.

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= 1.3718

A

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 1470mg/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

recom-mended

16 Regulatory Status

GRAS listed Accepted as a food additive in Europe Included in the

FDA Inactive Ingredients Database (injections, nasal, ophthalmic,

and oral preparations) Included in parenteral and nonparenteralpreparations licensed in the UK

17 Related SubstancesAcetic acid; artificial vinegar; dilute acetic acid

Acetic acidComments A diluted solution of glacial acetic acid containing30–37% w/w of acetic acid See Section 18

Artificial vinegarComments A solution containing 4% w/w of acetic acid.Dilute acetic acid

Comments A weak solution of acetic acid which may containbetween 6–10% w/w of acetic acid See Section 18

In addition to glacial acetic acid, many pharmacopeias containmonographs for diluted acetic acid solutions of various strengths.For example, the USP32–NF27 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 2009 contains separatemonographs for glacial acetic acid, acetic acid (33%), and aceticacid (6%) Acetic acid (33%) BP 2009 contains 32.5–33.5% w/w ofacetic acid Acetic acid (6%) BP 2009 contains 5.7–6.3% w/w ofacetic acid The JP XV also contains a monograph for acetic acidthat specifies that it contains 30.0–32.0% w/w of acetic acid

A specification for glacial acetic acid is contained in the FoodChemicals Codex (FCC).(5)

The EINECS number for acetic acid is 200-580-7 The PubChemCompound ID (CID) for glacial acetic acid is 176

Acetonum; dimethylformaldehyde; dimethyl ketone;

b-ketopro-pane; pyroacetic ether

3 Chemical Name and CAS Registry Number

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 See also Section 18

Table I: Pharmacopeial specifications for acetone.

Refractive index nD20= 1.359Solubility Soluble in water; freely soluble in ethanol (95%)

Vapor pressure 185 mmHg at 208C

11 Stability and Storage ConditionsAcetone should be stored in a cool, dry, well-ventilated place out ofdirect 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 shouldnot be used as a solvent for iodine, as it forms a volatile compoundthat is extremely irritating to the eyes.(4)

13 Method of ManufactureAcetone is obtained by fermentation as a by-product of n-butylalcohol manufacture, or by chemical synthesis from isopropylalcohol; from cumene as a by-product in phenol manufacture; orfrom propane as a by-product of oxidation-cracking

14 SafetyAcetone is considered moderately toxic, and is a skin irritant andsevere eye irritant Skin irritation has been reported due to itsdefatting action, and prolonged inhalation may result in headaches

Inhalation of acetone can produce systemic effects such asconjunctival irritation, respiratory system effects, nausea, andvomiting.(5)

1681

1723 2214

2441 2482 2304 2259

2319 2425

Figure 1: Near-infrared spectrum of acetone measured by transflectance (1 mm path-length).

A

7

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) workplace

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 Database (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

—

A specification for acetone is included in the Japanese

Pharmaceu-tical Excipients (JPE).(7)

The EINECS number for acetone is 200-662-2 The PubChem

Compound ID (CID) for acetone is 180

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 EH40/2005: Workplace Exposure Limits Sudbury: HSE Books, 2005 (updated 2007) http://www.hse.gov.uk/ coshh/table1.pdf (accessed 5 February 2009).

7 Japan Pharmaceutical Excipients Council Japanese Pharmaceutical Excipients 2004 Tokyo: Yakuji Nippo, 2004; 35–36.

USP-NF: Acetyltributyl Citrate

PhEur: Tributyl Acetylcitrate

Acetylbutyl citrate; acetylcitric acid, tributyl ester; ATBC; Citroflex

A-4; tributyl acetylcitrate; tributylis acetylcitras; tributyl

O-acetylcitrate; tributyl citrate acetate

3 Chemical Name and CAS Registry Number

1,2,3-Propanetricarboxylic acid, 2-acetyloxy, tributyl ester

7 Applications in Pharmaceutical Formulation orTechnology

Acetyltributyl citrate is used to plasticize polymers in formulatedpharmaceutical coatings,(1–5)including capsules, tablets, beads, andgranules for taste masking, immediate release, sustained-releaseand enteric formulations

8 DescriptionAcetyltributyl citrate is a clear, odorless, practically colorless, oilyliquid

9 Pharmacopeial SpecificationsSee Table I

10 Typical PropertiesAcid value 0.02

Boiling point 3268C (decomposes)Flash point 2048C

Pour point 598CSolubility Miscible with acetone, ethanol, and vegetable oil;practically insoluble in water

Viscosity (dynamic) 33 mPa s (33 cP) at 258CA

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

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

recom-mended when using acetyltributyl citrate at elevated temperatures

16 Regulatory Status

Included in FDA Inactive Ingredients Database (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

Acetyltributyl citrate is used as a plasticizer in food contact films,although it has been known to migrate from food-grade PVC filmsinto high-fat foods such as olive oil.(8)

Polylactide plasticized with acetyltributyl citrate has beeninvestigated as a biodegradable barrier for use in guided-tissueregeneration therapy.(9)

The EINECS number for acetyltributyl citrate is 201-067-0 ThePubChem Compound ID (CID) for acetyltributyl citrate is 6505

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 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 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 mechanical properties of acrylic resin films cast from aqueous dispersions and organic solutions Drug Dev Ind Pharm 1993; 19(3):

physical-315–332.

5 Repka MA et al Influence of plasticisers and drugs on the mechanical properties of hydroxypropylcellulose films prepared by hot melt extrusion Drug Dev Ind Pharm 1999; 25(5): 625–633.

physical-6 Lieb S et al Self-adhesive thin films for topical delivery of aminolevulinic acid Eur J Pharm Biopharm 2002; 53(1): 99–106.

5-7 Lewis RJ, ed Sax’s Dangerous Properties of Industrial Materials, 11th edn New York: Wiley, 2004; 3512.

8 Goulas AE 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):

Table I: Pharmacopeial specifications for acetyltributyl citrate.

Acetyltriethyl Citrate

1 Nonproprietary Names

USP-NF: Acetyltriethyl Citrate

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

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)

Boiling point 2948C (decomposes)Flash point 1888C

Pour point 438CSolubility 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 ConditionsAcetyltriethyl citrate should be stored in dry, closed containers attemperatures not exceeding 388C When stored in accordance withthese conditions, acetyltriethyl citrate is a stable product

12 IncompatibilitiesAcetyltriethyl citrate is incompatible with strong alkalis andoxidizing materials

13 Method of ManufactureAcetyltriethyl citrate is prepared by the esterification of citric acidwith ethanol followed by acylation with acetic anhydride

14 SafetyAcetyltriethyl citrate is used in oral pharmaceutical formulationsand 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 PrecautionsObserve normal precautions appropriate to the circumstances andquantity of material handled Acetyltriethyl citrate may be irritating

to the eyes or the respiratory system as a mist or at elevatedtemperatures Gloves and eye protection are recommended fornormal handling and a respirator is recommended if used atelevated temperatures

16 Regulatory StatusApproved in the USA for direct food contact in food films

17 Related SubstancesAcetyltributyl citrate; tributyl citrate; triethyl citrate

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 McGinity JW, ed Aqueous Polymeric Coatings for

A

10

Pharmaceutical Dosage Forms New York: Marcel Dekker, 1989; 153–

245.

4 Steurnagel CR Latex emulsions for controlled drug delivery McGinity

JW, ed Aqueous Polymeric Coatings for Pharmaceutical Dosage

Forms New York: Marcel Dekker,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 et al Diffusion-controlled drug delivery systems:

calcula-tion of the required composicalcula-tion 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.

PhEur: Adipic Acid

USP-NF: Adipic Acid

Acidum adipicum; acifloctin; acinetten; adilactetten; asapic;

1,4-butanedicarboxylic acid; E355; 1,6-hexanedioic acid; Inipol DS

3 Chemical Name and CAS Registry Number

Acidifying agent; buffering agent; flavoring agent

7 Applications in Pharmaceutical Formulation or

Technology

Adipic acid is used as an acidifying and buffering agent in

intramuscular, intravenous and vaginal formulations It is also

used in food products as a leavening, pH-controlling, or flavoring

agent

Adipic acid has been incorporated into controlled-release

formulation matrix tablets to obtain pH-independent release for

both weakly basic(1,2)and weakly acidic drugs.(3,4)It has also been

incorporated into the polymeric coating of hydrophilic monolithic

systems to modulate the intragel pH, resulting in zero-order release

of a hydrophilic drug.(5)The disintegration at intestinal pH of theenteric polymer shellac has been reported to improve when adipicacid was used as a pore-forming agent without affecting release inthe acidic media.(6) Other controlled-release formulations haveincluded adipic acid with the intention of obtaining a late-burstrelease profile.(7)

8 DescriptionAdipic acid occurs as a white or almost white, odorless nonhygro-scopic crystalline powder The crystal structure of adipic acid ismonoclinic holohedral

9 Pharmacopeial SpecificationsSee Table I

Table I: Pharmacopeial specifications for adipic acid.

Boiling point 337.58CDissociation constant

pKa1: 4.418 at 258C;

pKa2: 5.412 at 258C

Density 1.360 g/cm3Flash point 1968C (closed cup)

A