*m%____'=__._
`
`_
`
`,
`
`THIRD EDITION
`THIRD EDITION
`
`
`
`HANDBOOKe;
`
`PHARMACEUTICAL
`
`
`~ 6IRIENTS
`EXCIPIENTS
`
`
`
`.
`EDITED BY
`E n I
`‘- E n
`B '
`ARTHUR H. KIBBE
`ARTHUR H. KIBBE
`
`GSK Exhibit 1032 - Page 1 of 49
`
`'
`
`Association
`
` P
`
`

`

`Handbook of
`PHARMACEUTICAL
`EXCIPIENTS
`
`

`

`Handbook of
`PHARMACEUTICAL
`· EXCIPIENTS
`
`Third Edition
`
`Edited by
`Arthur H. Kibbe, Ph.D.
`Professor and Chair
`Department of Pharmaceutical Sciences
`Wilkes University School of Pharmacy
`Wilkes-Barre, Pennsylvania
`
`~ APltA
`
`American Pharmaceutical Association
`Washington, D.C.
`
`(RP)
`
`Pharmaceutical Press
`London, United Kingdom
`
`

`

`Published by the American Pharmaceutical Association
`2215 Constitution Avenue NW, Washington, DC 20037-2985, USA
`www.aphanet.org
`and the Pharmaceutical Press
`1 Lambeth High Street, London SEl 7JN, UK
`www.pharmpress.com
`© 1986, 1994, 2000 American Pharmaceutical Association and Pharmaceutical Press
`
`First edition 1986
`Second edition 1994
`Third edition 2000
`
`Printed in the United States of America
`
`ISBN: 0-85369-381-1 (UK)
`ISBN: 0-917330-96-X (USA)
`Library of Congress Cataloging-in-Publication Data
`Handbook of pharmaceutical excipients / edited by Arthur H. Kibbe.--3rd ed.
`p.; cm.
`Includes bibliographical references and index.
`ISBN 0-917330-96-X
`I. Kibbe, Arthur H. II. American
`1. Excipients--Handbooks, manuals, etc.
`Pharmaceutical Association.
`[DNLM: 1. Excipients--Handbooks. QV 735 H236 2000]
`RS201.E87 H36 2000
`615' .19--dc21
`A catalogue record for this book is available from the British Library.
`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 lhe 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.
`
`99-044554
`
`Managing Editor:
`Copy editor:
`Indexer:
`Compositor:
`Cover Designer:
`
`Melanie Segala
`Paul Gottebrer
`Lillian Rodberg
`Roy Barnhill
`Tim Kaage
`
`

`

`Contents
`
`Committees
`Contributors
`Additions to the Third Edition
`Related Substances
`Preface
`Acknowledgments
`Notice to Readers
`Selected Bibliography
`Abbreviations
`Units of Measurement
`
`Monographs
`Acacia
`Acesulfame Potassium
`Albumin
`Alcohol
`Alginic Acid
`Aliphatic Polyesters
`Alpha Tocopherol
`Ascorbic Acid
`Ascorbyl Palmitate
`Aspartame
`Bentonite
`Benzalkonium Chloride
`Benzethonium Chloride
`Benzoic Acid
`Benzyl Alcohol
`Benzyl Benzoate
`Bronopol
`Butylated Hydroxyanisole
`Butylated Hydroxytoluene
`Butylparaben
`Calcium Carbonate
`Calcium Phosphate, Dibasic Anhydrous
`Calcium Phosphate, Dibasic Dihydrate
`Calcium Phosphate, Tribasic
`Calcium Stearate
`Calcium Sulfate
`Canola Oil
`Carbomer
`Carbon Dioxide
`Carboxymethylcellulose Calcium
`Carboxymethylcellulose Sodium
`Carrageenan
`Castor Oil, Hydrogenated
`Cellulose Acetate
`Cellulose Acetate Phthalate
`Cellulose, Microcrystalline
`Cellulose, Powdered
`Cellulose, Silicified Microcrystalline
`Cetostearyl Alcohol
`Cetrimide
`Cetyl Alcohol
`Chlorhexidine
`Chlorobutanol
`Chlorocresol
`Chlorodi fluoroethane (HCFC)
`Chlorofluorocarbons (CFC)
`
`Contents v
`
`138
`140
`143
`146
`154
`156
`158
`160
`163
`165
`169
`172
`175
`178
`180
`182
`184
`186
`188
`191
`195
`201
`203
`205
`208
`210
`213
`215
`218
`220
`223
`225
`228
`230
`232
`234
`236
`238
`240
`244
`249
`252
`256
`261
`263
`265
`267
`269
`272
`274
`276
`286
`288
`290
`292
`295
`299
`303
`305
`309
`
`vii
`ix
`xii
`xiii
`xv
`xvii
`xviii
`xviii
`xix
`xx
`
`1
`3
`5
`7
`10
`13
`18
`21
`25
`27
`30
`33
`36
`38
`41
`44
`46
`49
`51
`53
`56
`60
`63
`68
`70
`73
`77
`79
`83
`85
`87
`91
`94
`96
`99
`102
`107
`110
`112
`114
`117
`121
`126
`129
`132
`134
`
`Cholesterol
`Citric Acid Monohydrate
`Colloidal Silicon Dioxide
`Coloring Agents
`Corn Oil
`Cottonseed Oil
`Cresol
`Croscarmellose Sodium
`Crospovidone
`Cyclodextrins
`Dextrates
`Dextrin
`Dextrose
`Dibutyl Sebacate
`Diethanolamine
`Diethyl Phthalate
`Difluoroethane (HFC)
`Dimethyl Ether
`Docusate Sodium
`Edetic Acid
`Ethylcellulose
`Ethyl Maltol
`Ethyl Oleate
`Ethylparaben
`Ethyl Vanillin
`Fructose
`Fumaric Acid
`Gelatin
`Glucose, Liquid
`Glycerin
`Glyceryl Monooleate
`Glyceryl Monostearate
`Glyceryl Palmitostearate
`Glycofurol
`Guar Gum
`Heptafluoropropane (HFC)
`Hydrocarbons (HC)
`Hydrochloric Acid
`Hydroxyethyl Cellulose
`Hydroxypropyl Cellulose
`Hydroxypropyl Cellulose, Low-substituted
`Hydroxypropyl Methylcellulose
`Hydroxypropyl Methylcellulose Phthalate
`Imidurea
`Isopropyl Alcohol
`Isopropyl Myristate
`Isopropyl Palmitate
`Kaolin
`Lactic Acid
`Lactitol
`Lactose
`Lanolin
`Lanolin Alcohols
`Lanolin, Hydrous
`Lecithin
`Magnesium Aluminum Silicate
`Magnesium Carbonate
`Magnesium Oxide
`Magnesium Stearate
`Magnesium Trisilicate
`
`

`

`vi Contents
`
`Malic Acid
`Maltitol
`Maltitol Solution
`Maltodextrin
`Maltol
`Maltose
`Mannitol
`Medium Chain Triglycerides
`Meglumine
`Menthol
`Methylcellulose
`Methylparaben
`Mineral Oil
`Mineral Oil, Light
`Mineral Oil and Lanolin Alcohols
`Monoethanolamine
`Nitrogen
`Nitrous Oxide
`Oleic Acid
`Paraffin
`Peanut Oil
`Petrolatum
`Petrolatum and Lanolin Alcohols
`Phenol
`Phenoxyethanol
`Phenylethyl Alcohol
`Phenylmercuric 'Acetate
`Phenylmercuric Borate
`Phenylmercuric Nitrate
`Polacrilin Potassium
`Poloxamer
`Polydextrose
`Polyethylene Glycol
`Polyethylene Oxide
`Polymethacrylates
`Polyoxyethylene Alkyl Ethers
`Polyoxyethylene Castor Oil Derivatives
`Polyoxyethylene Sorbitan Fatty Acid Esters
`Polyoxyethylene Stearates
`Polyvinyl Alcohol
`Potassium Chloride
`Potassium Citrate
`Potassium Sorbate
`Povidone
`Propylene Carbonate
`Propylene Glycol
`Propylene Glycol Alginate
`Propyl Gallate
`Propy lparaben
`Saccharin
`Saccharin Sodium
`Sesame Oil
`Shellac
`Sodium Alginate
`
`311
`313
`315
`317
`320
`322
`324
`329
`332
`334
`336
`340
`345
`347
`349
`350
`352
`354
`356
`358
`360
`362
`365
`367
`370
`372
`374
`377
`379
`383
`386
`389
`392
`399
`401
`407
`412
`416
`420
`424
`426
`429
`431
`433
`440
`442
`445
`447
`450
`454
`457
`460
`462
`465
`
`Sodium Ascorbate
`Sodium Benzoate
`Sodium Bicarbonate
`Sodium Chloride
`Sodium Citrate Dihydrate
`Sodium Cyclamate
`Sodium Laury! Sulfate
`Sodium Metabisulfite
`Sodium Phosphate, Dibasic
`Sodium Phosphate, Monobasic
`Sodium Propionate
`Sodium Starch Glycolate
`Sodium Stearyl Fumarate
`Sorbic Acid
`Sorbitan Esters (Sorbitan Fatty Acid Esters)
`Sorbitol
`Soybean Oil
`Starch
`Starch, Pregelatinized
`Starch, Steri!izable Maize
`Stearic Acid
`Stearyl Alcohol
`Sucrose
`Sugar, Compressible
`Sugar, Confectioner's
`Sugar Spheres
`Suppository Bases, Hard Fat
`Talc
`Tartaric Acid
`Tetrafluoroethane (HFC)
`Thimerosal
`Titanium Dioxide
`Tragacanth
`Triacetin
`Triethanolamine
`Triethyl Citrate
`Vanillin
`Vegetable Oil, Hydrogenated, Type I
`Water
`Wax, Anionic Emulsifying
`Wax, Carnauba
`Wax, Cetyl Esters
`Wax, Microcrystalline
`Wax, Nonionic Emulsifying
`Wax, White
`Wax, Yellow
`Xanthan Gum
`Xylitol
`Zein
`Zinc Stearate
`
`Appendix I: Suppliers' Directory
`Appendix II: HPE Laboratory Methods
`Index
`
`468
`471
`474
`478
`482
`485
`487
`490
`493
`496
`498
`501
`505
`508
`511
`515
`519
`522
`528
`531
`534
`537
`539
`544
`546
`548
`550
`555
`558
`560
`562
`565
`568
`570
`572
`574
`576
`578
`580
`585
`587
`589
`591
`593
`595
`597
`599
`602
`606
`608
`
`611
`641
`645
`
`

`

`Related Substances
`
`Related Substances xiii
`
`Acetyltributyl Citrate
`Acetyltriethyl Citrate
`Aleuritic Acid
`d-Alpha Tocopherol
`d-Alpha Tocopheryl Acetate
`dl-Alpha Tocopberyl Acetate
`d-Alpha Tocopheryl Acid Succinate
`di-Alpha Tocopheryl Acid Succinate
`Amylopectin
`a-Amy lose
`Anhydrous Citric Acid
`Anhydrous Sodium Citrate
`Anhydrous Sodium Propionate
`Bacteriostatic Water for Injection
`Bentonite Magma
`Beta-Carotene
`Beta-Tocopherol
`Butylparaben Sodium
`Calcium Alginate
`Calcium Ascorbate
`Calcium Cyclamate
`Calcium Propionate
`Calcium Silicate
`Calcium Sorbate
`Calcium Sulfate Hemihydrate
`Carbon Dioxide-Free Water
`Carboxymethylcellulose Sodium 12
`Castor Oil
`Cationic Emulsifying Wax
`Chlorhexidine Acetate
`Chlorhexidine Gluconate
`Chlorhexidine Hydrochloride
`Chlorodifluoromethane
`Chlorophenoxyethanol
`Chloroxy lenol
`Corn Syrup Solids
`m-Cresol
`o-Cresol
`p-Cresol
`· Cyclamic Acid
`Dehydrated Alcohol
`Delta-Tocopherol
`Denatured Alcohol
`Dextrose Anhydrous
`Diazolidinyl Urea
`Dibasic Sodium Phosphate
`Dibutyl Pbthalate
`Dilute Alcohol
`Dilute Hydrochloric Acid
`Dimethyl-P-Cyclodextrin
`Dimethyl Phthalate
`Dipotassium Edetate
`Disodium Edetate
`Docusate Calcium
`Docusate Potassium
`Dodecyl GaJlate
`Dodecyltrimethylammonium Bromide
`Edetate Calcium Disodium
`Eglumine
`
`Ethyl Gallate
`Ethylparaben Potassium
`Ethylparaben Sodium
`Fructose Liquid
`Fructose Milled
`Fructose Pyrogen-Free
`Gamma-Tocopherol
`Glyceryl Behenate
`Hard Water
`Hexadecyltrimethylammonium Bromide
`High Fructose Syrup
`Hydrogenated Vegetable Oil, Type II
`2-Hydroxyethyl-P-Cyclodexti:in
`2-Hydroxypropyl-P-Cyclodextrin
`Indigo Carmine
`Invert Sugar
`Iron Oxides
`Liquified Phenol
`Magnesium Carbonate Anhydrous
`Magnesium Carbonate Hydroxide
`Magnesium Laury! Sulfate
`Magnesium Silicate
`Magnesium Trisilicate Anhydrous
`o-Malic Acid
`L-Malic Acid
`d-Menthol
`!-Menthol
`Methyl Methacrylate
`Methyl Oleate
`Methylparaben Potassium
`Methylparaben Sodium
`Microcrystalline Cellulose and Carboxymethylcellulose Sodium
`Monobasic Potassium Phosphate
`Montmorillonite
`Normal Magnesium Carbonate
`Octyl Gallate
`Palmitic Acid
`Pharmaceutical Glaze
`Phenoxypropanol
`Polacrilin
`Poly (Methyl Methacrylate)
`Potassium Alginate
`Potassium Benzoate
`Potassium Bicarbonate
`Potassium Bisulfite
`Potassium Citrate Anhydrous
`Potassium Metabisulfite
`Potassium Propionate
`Powdered Fructose
`Propan-1-ol
`Propionic Acid
`(S)-Propylene Carbonate
`Propylparaben Potassium
`Propylparaben Sodium
`Purified Stearic Acid
`Rapeseed Oil
`Saccharin Ammortium
`Saccharin Calcium
`Saponite.
`
`

`

`xiv Related Substances
`
`Self-emulsifying Glyceryl Monostearate
`Shellolic Acid
`Sodium Bisulfite
`Sodium Edetate
`Sodium Sorbate
`Sodium Sulfite
`Soft Water
`Sorbitol Solution 70%
`Spermaceti Wax
`Sterile Water for Inhalation
`Sterile Water for Injection
`Sterile Water for Irrigation
`Sugartab
`Sunset Yellow FCF
`
`Synthetic Paraffin
`o-(-)-Tartaric Acid
`DL-(±)-Tartaric Acid
`Tartrazine
`Theobroma Oil
`Tocopherols Excipients
`Tribasic Sodium Phosphate
`Tributyl Citrate
`Trimethy 1-~-Cyclodextrin
`Trimethyltetradecylammonium Bromide
`Trisodium Edetate
`Water for Injection
`White Petrolatum
`Zinc Propionate
`
`

`

`Benzalkonium
`Chloride
`
`1. Nonproprietary Names
`BP: Benzalkonium chloride
`JP: Benzalkonium chloride
`PhEur: Benzalkonii chloridum
`USP: Benzalkonium chloride
`
`2. Synonyms
`Alkylbenzyldimethylammonium chloride; ·alkyl dimethyl benzyl
`ammonium chloride; BKC; Catigene DC 100; Exameen 3580;
`Hyamine 3500; Pentonium; Rocca[; Zephiran.
`
`3. Chemical Name and CAS Registry Number
`Alkyldimethyl(phenylmethyl)ammonium chloride [8001-54-5]
`
`4. Empirical Formula Molecular Weight
`The USP describes benzalkonium chloride as a mixture of
`alkylbenzyldimethylammonium chlorides of the general for(cid:173)
`mula [C6H5CH2N(CH3hR]Cl, where R represents a mixture
`of alkyls, including all or some of the group beginning with
`n-C8H 17 and extending through higher homologs, with n(cid:173)
`C12H25, n-C 14H29, and n-C 16H33 comprising the major portion.
`The average molecular weight of benzalkonium chloride is
`360.
`
`5. Structural Formula
`
`R = mixture of alkyls: n-C 8H 17 to n-C 18H37 ; mainly n-C 12H25
`(dodecyl), n-C 14H29 (tetradecyl), and n-C 16H33 (hexadecyl).
`
`6. Functional Category
`Antimicrobial preservative; antiseptic; disinfectant; solubiliz(cid:173)
`ing agent; wetting agent.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Benzalkonium chloride is a quaternary ammonium compound
`used in pharmaceutical formulations as an antimicrobial pre(cid:173)
`servative in applications similar to other cationic surfactants,
`such as cetrimide.
`In ophthalmic preparations, benzalkonium chloride is one of
`the most widely used preservatives, at a concentration of
`0.01-0.02% w/v. Often it is used in combination with other
`preservatives or excipients, particularly 0.1 % w/v disodium
`
`Benzalkonium Chloride 33
`
`edetate, to enhance its antimicrobial activity against strains
`of Pseudomonas.
`In nasal and otic formulations a concentration of 0.002-0.02%
`is used, sometimes in combination with 0.002-0.005% w/v
`thimerosal. Benzalkonium chloride 0.01 % w/v is also em(cid:173)
`ployed as a preservative in small-volume parenteral products.
`Benzalkonium chloride is additionally used as a preservative
`in cosmetics.
`
`8. Description
`Benzalkonium chloride occurs as a white or yellowish-white
`amorphous powder, a thick gel, or gelatinous flakes. It is hy(cid:173)
`groscopic, soapy to the touch, and has a mild aromatic odor
`and very bitter taste.
`
`9. Pharmacopeial Specifications
`
`Test
`
`Identification
`Characters
`Acidity or alkalinity
`Appearance of solution
`Water
`Residue on ignition
`Sulfated ash
`Water-insoluble matter
`Foreign amines
`Ratio of alkyl components
`Assay (dried basis)
`Of n-C 12H25
`Of n-C 14H29
`Of n-C12H25 & n-C14H29
`For total alkyl content
`
`JP
`
`+
`
`+
`~ 15.0%
`~ 0.2%
`
`PhEur
`
`+
`+
`+
`+
`~ 10.0%
`
`~ 0.1%
`
`+
`
`USP
`+
`
`~ 15.0%
`~ 2.0%
`
`+
`+
`+
`
`;:>: 40.0%
`;:>: 20.0%
`;:>: 70.0%
`95.0-105.0% 95.0-104.0% 97.0-103.0%
`
`10. Typical Properties
`Acidity/alkalinity: pH = 5-8 for a 10% w/v aqueous solution.
`Antimicrobial activity: benzalkonium chloride solutions are
`active against a wide range of bacteria, yeasts, and fungi.
`Activity is more marked against Gram-positive than Gram(cid:173)
`negative bacteria and minimal against bacterial endospores
`and acid-fast bacteria. The antimicrobial activity of ben(cid:173)
`zalkonium chloride is significantly dependent upon the
`alkyl composition of the homolog mixture.<1) Benzalko(cid:173)
`nium chloride is ineffective against some Pseudomonas
`aeruginosa strains, Mycobacterium tuberculosis, Tricho(cid:173)
`phyton interdigitale, and T. rubrum. However, combined
`with disodium edetate (0.01-0.1 % w/v), benzyl alcohol,
`phenylethanol, or phenylpropanol, the activity against
`Pseudomonas aeruginosa is increased. (Z) Antimicrobial
`activity may also be enhanced by the addition of phenylm(cid:173)
`ercuric acetate, phenylmercuric borate, chlorhexidine, cet(cid:173)
`rimide, or m-cresol. (3.4) In the presence of citrate and
`phosphate buffers (but not borate), activity against
`Pseudomonas can be reduced. See also Sections 11 and
`12. BenzaJkonium chloride is relatively inactive against
`spores and molds, but is active against some viruses,
`including HIV.(5) Inhibitory activity· increases with pH
`although antimicrobial activity occurs between pH 4-10.
`Typical minimum inhibitory concentrations (MICs) are
`shown in Table I.
`
`

`

`34 Benzalkonium Chloride
`
`Table I: Minimum inhibitory concentrations (MICs) of
`benzalkonium chloride.
`
`Microorganism
`
`Aerobacter aerogenes
`Clostridium histolyticum
`Clostridium oedematiens
`Clostridium tetani
`Clostridium welchii
`Escherichia coli
`Pneumococcus II
`Proteus vulgaris
`Pseudomonas aeruginosa
`Salmonella enteritidis
`Salmonella paratyphi
`Salmonella typhosa
`Shigella dysenteriae
`Staphylococcus aureus
`Streptococcus pyrogenes
`Vibrio cholerae
`
`MIC (µg/mL)
`
`64
`5
`5
`5
`5
`16
`5
`64
`30
`30
`16
`4
`2
`1.25
`1.25
`2
`
`Density: "' 0.98 g/cm3 at 20°C
`Melting point: "' 40°C
`Partition coefficients: the octanol: water partition coefficient
`varies with the alkyl chain length of the homolog; 9.98
`for C 12, 32.9 for C14, and 82.5 for C 16.
`Solubility: practically insoluble in ether; very soluble in ace(cid:173)
`tone, ethanol (95%), methanol, propanol, and water. Aque(cid:173)
`ous solutions of benzalkonium chl6ride foam when shaken,
`have a low surface tension and possess detergent and emul(cid:173)
`sifying properties.
`
`11. Stability and Storage Conditions
`Benzalkonium chloride is hygroscopic and may be affected
`by light, air, and metals.
`Solutions are stable over a wide pH and temperature range
`and may be sterilized by autoclaving without loss of effec(cid:173)
`tiveness. Solutions may be stored for prolonged periods at
`room temperature. Dilute solutions stored in polyvinyl chlo(cid:173)
`ride or polyurethane foam containers may lose antimicrobial
`activity.
`The bulk material should be stored in an airtight container,
`protected from light and contact with metals, in a cool, dry,
`place.
`
`12. Incompatibilities
`Incompatible with aluminum, anionic surfactants, citrates, cot(cid:173)
`ton, fluorescein, hydrogen peroxide, hydroxypropyl methyl(cid:173)
`cellulose, <6l iodides, kaolin, lanolin, nitrates, nonionic
`surfactants in high . concentration, permanganates, protein, sal(cid:173)
`icylates, silver salts, soaps, sulfonamides, tartrates, zinc oxide,
`zinc sulfate, some rubber mixes, and some plastic mixes.
`Benzalkonium chloride has been shown to be adsorbed to var(cid:173)
`ious filtering membranes especially those that are hydrophobic
`or anionic. <7l
`
`13. Method of Manufacture
`Benzalkonium chloride is formed by the reaction of a solution
`of N-alkyl-N-methyl-benzamine with methyl chloride in an
`organic solvent suitable for precipitating the quaternary com(cid:173)
`pound as it is formed.
`
`14. Safety
`Benzalkonium chloride is usually nonirritating, nonsensttlz(cid:173)
`ing, and well tolerated in the dilutions normally employed on
`the skin and mucous membranes. However, benzalkonium
`chloride has been associated with adverse effects when used
`in some pharmaceutical formulations. (S)
`Ototoxicity can occur when benzalkonium chloride is applied
`to the ear<9l and prolonged contact with the skin can occa(cid:173)
`sionally cause irritation and hypersensitivity. Benzalkonium
`chloride is also known to cause bronchoconstriction in some
`asthmatics when used in nebulizer solutions.0°-14)
`Toxicity experiments with rabbits have shown benzalkonium
`chloride, in concentrations higher than that normally used as
`a preservative, to be harmful to the eye. However, the human
`eye appears to be l<;ss affected than the rabbit eye and many
`ophthalmic products have been formulated with benzalkonium
`chloride 0.01 % w/v as the preservative. Benzalkonium chlo(cid:173)
`ride is not suitable for use as a preservative in solutions used
`for storing and washing hydrophilic soft contact lenses, as the
`benzalkonium chloride can bind to the lenses and may later
`produce ocular toxicity when the lenses are worn.0 5) Solutions
`stronger than 0.03% w/v concentration entering the eye re(cid:173)
`quire prompt medical attention.
`Local irritation of the throat, esophagus, stomach, and intes(cid:173)
`tine can occur following contact with strong solutions (> 0.1 %
`w/v). The fatal oral dose of benzalkonium chloride in humans
`is estimated to be 1-3 g. Adverse effects following oral in(cid:173)
`gestion include vomiting, c_ollapse, and coma. Toxic doses
`lead to paralysis of the respiratory muscles, dyspnea, and cy(cid:173)
`anosis.
`LD50 (guinea pig, oral): 200 mg/kg0 6J
`LD50 (mouse, IP): 10 mg/kg
`LD50 (mouse, IV): 10 mg/kg
`LD50 (mouse, oral): 175 mg/kg
`LD50 (mouse, SC): 64 mg/kg
`LD50 (rat, IP): 14.5 mg/kg
`LD50 (rat, IV): 13.9 mg/kg
`LD50 (rat, oral): 240 mg/kg
`LD50 (rat, SC): 400 mg/kg
`LD50 (rat, skin): 1.56 g/kg
`
`15. Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Benzalkonium chloride is
`irritant to the skin and eyes and repeated exposure to the skin
`may cause hypersensitivity. Concentrated benzalkonium chlo(cid:173)
`ride solutions accidentally spilled on the skin may produce
`corrosive skin lesions with deep necrosis and scarring, and
`should be washed immediately with water, followed by soap
`solutions applied freely. Gloves, eye protection, and suitable
`protective clothing should be worn.
`
`16. Regulatory Status
`Included in the FDA Inactive Ingredients Guide (inhalations,
`IM injections, nasal, ophthalmic, otic, and topical prepara(cid:173)
`tions). Included in nonparenteral medi~ines licensed in the
`UK.
`
`17. Pharmacopeias
`Eur, Int, Jpn, Pol, and US.
`
`

`

`18. Related Substances
`Benzethonium chloride; cetrimide.
`
`19. Comments
`
`20. Specific References
`I. Euerby MR. High performance liquid chromatography of
`benzalkonfom chlorides - variation in commercial prepara(cid:173)
`tions. J Clin Hosp Pharm 1985; 10: 73-77.
`2. Richards RME, McBride RJ . Enhancement of benzalkonium
`chloride and chlorhexidine acetate activity against
`Pseudomonas aeruginosa by aromatic alcohols . J Pharm Sci
`1973; 62: 2035-2037.
`3. Hugbo PG. Additivity and synergisrn in vitro as displayed
`by mixtures of some commonly employed antibacterial pre(cid:173)
`servatives. Can J Pharm Sci I 976; 11: 17-20.
`4. McCarthy TJ, Myburgh JA, Butler N. Further studies on the
`influence of formulation on preservative activity. Cosmet Toi(cid:173)
`let 1977; 92(3) : 33-36.
`5. Chermann JC, Barre-Sinoussi F, Henin Y, Marechal V. HIV
`inactivation by a spermicide containing benzalkonium. AIDS
`Forsch 1987; 2: 85-86.
`6. Richards RME. Effect of hypromellose on the antibacterial
`activity of benzalkonium chloride. J Pharm Pharmacol 1976;
`28: 264.
`7. Bin T, Kulshreshtha AK, Al-Shakhshir R, Hem SL. Adsorp(cid:173)
`tion of benzalkonium chloride by filter membranes: mecha(cid:173)
`nisms and effect of formulation and processing parameters.
`Pharm Dev Technol 1999; 4(2), 151-165.
`8. Smolinske SC. Handbook of Food, Drug, and Cosmetic
`Excipients. Boca Raton, FL, CRC Press Inc, 1992; 31-39.
`9. Honigman JL. Disinfectant ototoxicity [letter]. Pharm J
`1975; 215: 523.
`I 0. Beasley CRW, Rafferty P, Holgate ST. Bronchoconstrictor
`properties of preservatives in ipratropium bromide (Atrovent)
`nebuliser solution. Br Med J 1987; 294: 1197- 1198.
`11 . Miszkiel KA, Beasley R, Rafferty P, Holgate ST. The con(cid:173)
`tribution of histamine release to bronchoconstriction pro(cid:173)
`voked by inhaled benzalkonium chloride in asthma. Br J Clin
`·
`Pharmacol 1988; 25: 157-163.
`12. Miszkiel KA , Beasley R, Holgate ST. The influence of ipra(cid:173)
`tropium bromide and sodium cromoglycate on benzalkonium
`chloride-induced bronchoconstriction in asthma. Br J Clin
`Pharmacol 1988; 26: 295 -30 I.
`
`Benzalkonium Chloride 35
`
`13. Worthington I. Bronchoconstriction due to benzalkonium
`chloride in nebulizer solutions. Can J Hosp Pharm 1989; 42:
`165-166.
`14. Boucher M, Roy MT, Henderson J. Possible association of
`benzalkonium chloride in nebulizer solutions with respiratory
`arrest. Ann Pharmacother 1992; 26: 772-774.
`15. Gasset AR. Benzalkonium chloride toxicity to the human cor(cid:173)
`nea. Am J Ophthalmol 1977; 84: 169-171.
`16. Sweet DV, editor. Registry of Toxic Effects of Chemical Sub(cid:173)
`stances. Cincinnati, US Department of Health, 1987
`
`21. General References
`Cowen RA, Steiger B. Why a preservative system must be tailored
`to a specific product. Cosmet Toilet 1977; 92(3): 15-20.
`El-Falaha BMA, Rogers DT, Furr JR, Russell AD. Surface
`changes in Pseudomonas aeruginosa exposed to chlorhexidine
`diacetate and benzalkonium chloride. Int J Pharmaceutics
`1985; 23: 239-243.
`El-Falaha BMA, Russell AD, Furr JR, Rogers DT. Activity of
`benzalkonium chloride and chlorhexidine diacetate against
`wild-type and envelope mutants of Escherichia coli and
`Pseudomonas aeruginosa. Int J Pharmaceutics 1985; 23:
`239-243.
`Karabit MS, Juneskans OT, Lundgre11 P. Studies on the evaluation
`of preservative efficacy III: the determinatio11 of antimicrobial
`characteristics of benzalkonium chloride. Int J Pharmaceutics
`1988; 46: 141-147.
`Lien EJ, Perrin JH. Effect of chain length on critical micelle
`formation and protein binding of quaternary ammonium com(cid:173)
`pounds. J Med Chem 1976; 19: 849-850.
`Martin AR. Anti-infective agents. In: Doerge RF, editor. Wilson
`and Gisvold's Textbook of Organic, Medicinal and Pharma(cid:173)
`ceutical Chemistry. Philadelphia, J.B. Lippincott Company,
`1982; 141-142.
`Pense AM, Vauthier C, Puisieux F, Benoit JP. Microencapsulation
`of benzalkonium chloride. Int J Pharmaceutics 1992; 81:
`111-117.
`Prince HN, Nonemaker WS, Norgard RC, Prince DL. Drug resis(cid:173)
`tance studies with topical antiseptics . J Pharm Sci 1978; 67:
`1629-1631.
`Wallhausser KH. Benzalkonium chloride. In: Kabara JJ, editor.
`Cosmetic and Drug Preservation Principles and Practice. New
`York, Marcel Dekker Inc, 1984; 731-734.
`
`22. Authors
`AH Kibbe.
`
`

`

`Carboxymethylcellulose Sodium 87
`
`Higher concentrations, usually 3-6%, of the medium viscosity
`grade is used to produce gels which can be used as the base
`for applications and pastes; glycols are often included in such
`gels to prevent drying out. Carboxymethylcellulose sodium is
`additionally one of the main ingredients of self-adhesive os(cid:173)
`tomy, wound care, and dermatological patches where it is used
`to absorb wound exudate or transepidermal water and sweat.
`Carboxymethylcellulose sodium is also used in cosmetics, toi(cid:173)
`letries,<6l incontinence, personal hygiene, and food products_
`
`Use
`
`Emulsifying agent
`Gel-forming agent
`Injections
`Oral solutions
`Tablet binder
`
`Concentration(%)
`
`0.25-1.0
`3.0-6.0
`0.05-0.75
`0.1-1.0
`1.0-6.0
`
`8. Description
`Carboxymethylcellulose sodium occurs as a white to almost
`white colored, odorless, granular powder. See also Section 19.
`
`9. Pharmacopeial Specifications
`
`Carboxymethylcellulose
`Sodium
`
`1. Nonproprietary Names
`BP: Carmellose sodium
`JP: Carmellose sodium
`PhEur: Carboxymethylcellulosum natricum
`USP: Carboxymethylcellulose sodium
`
`2. Synonyms
`Akucell; Aquasorb; Blanose; Cekol; cellulose gum; CMC
`sodium; E466; Finnfix; Nymcel; SCMC; sodium carboxyme(cid:173)
`thylcellulose; sodium cellulose glycolate; sodium CMC;
`Tylose CB.
`
`3. Chemical Name and CAS Registry Number
`Cellulose, carboxymethyl ether, sodium salt [9004-32-4]
`
`4. Empirical Formula Molecular Weight
`The USP describes carboxymethylcellulose sodium as the so(cid:173)
`dium salt of a polycarboxymethyl ether of cellulose. Typical
`molecular weight is 90 000-700 000.
`
`5. Structural Formula
`
`~~c:N•
`c_J'4'
`
`OH
`
`OH
`
`CHPC1½COONa
`
`Test
`
`Identification
`Characters
`pH (I% w/v solution)
`Degree of substitution
`Appearance of solution
`Viscosity
`Loss on drying
`Heavy metals
`Chloride
`Arsenic
`Sulfate
`Silicate
`Sodium glycolate
`Starch
`Sulfated ash
`Organic volatile impurities
`Assay (of sodium)
`
`JP
`
`+
`+
`6.0-8.0
`
`PhEur
`
`+
`+
`6.0-8 .0
`
`+
`+
`~ 10.0%
`~ 20 ppm
`~ 0.25%
`
`+
`+
`~ 10.0%
`~ 20 ppm
`~ 0.640%
`~ 10 ppm
`~ 0.960%
`~ 0.5%
`
`+
`
`USP
`
`+
`
`6.5-8.5
`1.15-1.45
`
`+
`~ 10.0%
`~ 20 ppm
`
`~0.4%
`
`~ 0.5%
`
`20.0-33.3%
`
`6.5-8.5%
`
`6.5-10.8%
`
`+
`10.5-12.0%
`
`Structure shown with a degree of substitution (DS) of 1.0.
`
`6. Functional Category
`Coating agent; tablet and capsule disintegrant; tablet binder;
`stabilizing agent; suspending agent; viscosity-increasing
`agent; water absorbing agent.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Carboxymethylcellulose sodium is widely used in oral and
`topical pharmaceutical formulations primarily for its viscosi(cid:173)
`ty-increasing properties. Viscous aqueous solutions are used
`to suspend powders intended for either topical application or
`oral and parenteral administration. <ll Carboxymethylcellulose
`sodium may also be used as a tablet binder and disinte(cid:173)
`grant, <2-4> and to stabilize emulsions.<5>
`
`10. Typical Properties
`Compaction data: See Fig. 1.<•l
`Density (bulk): 0.520 g/cm3
`Density (tapped): 0.783 g/cm3
`Dissociation constant: pK. = 4.30
`Melting point: browns at approximately 227°C, chars at
`approximately 252°C.
`Moisture content: typically, contains less than 10% of water.
`However, carboxymethylcellulose sodium is hygroscopic
`and absorbs significant amounts of water at temperatures
`up to 37°C at relative humidities of about 80%. See Section
`11. See also Fig. 2. <•l
`Solubility: practically insoluble in acetone, ethanol, ether, and
`tol.uene. Easily dispersed in water at all temperatures ,
`forming clear, colloidal solutions. The aqueous solubility
`varies with the degree of substitution (DS) - See Section 19.
`
`

`

`88 Carboxymethylcellulose Sodium
`
`SEM: 1
`Excipienc: Carboxymethylcellulose sodium
`Manufacturer: Buckeye Cellulose Corp
`Lot No: 9247 AP
`Magnification: l20x
`Voltage: IO kV
`
`SEM: 2
`Excipient: Carboxymethylcellulose sodium
`Manufacturer: Hercules Ltd
`Lot No: 21 A-I (44390)
`Magnifiction: 600x
`Voltage: kV
`
`1.3
`
`1.2
`
`1.1
`
`91.0
`
`~
`
`~
`
`E 0.9
`
`0.8
`
`0.7
`
`11.00
`
`9.00
`
`7.00
`
`5.00
`
`3.00
`
`1.00
`
`:::l
`
`I
`ill a
`(1) "' "'
`
`~
`~
`
`60.--- - - - -- -- - -- - -- -- --,
`
`50
`
`@
`::::i 40
`t5
`·5
`E
`~ 30
`~ ·s
`
`0-
`LJ.J 20
`'if.
`
`10
`
`0.620
`
`40
`
`60
`
`100
`80
`Pressure (MPa)
`
`120
`
`140
`
`-1.00
`
`Fig. 1: Heckel plot carboxymethylcellulose sodium.
`0: Inl/(1-D)
`■: Hardness
`
`Viscosity: various grades of carboxymethylcellulose sodium
`are commercially available which have differing aqueous
`viscosities; aqueous I% w/v solutions with viscosities of
`5-13 000 mPa s (5-13 000 cP) may be obtained. An
`increase in concentration results in an increase in aqueous
`solution viscosity.<6> Prolonged heating at high tempera(cid:173)
`tures will depolymerize the gum and permanently decrease
`
`0 o
`
`10
`
`20
`
`70 80
`60
`40 50
`30
`% Relative Humidity
`
`90
`
`100
`
`Fig. 2: Sorption-desorption isotherm of carboxymethylcellulose
`sodium.
`0: Sorption
`■ : Desorption
`the viscosity. The viscosity of sodium carboxymethylcel(cid:173)
`lulose solutions is fairly stable over a pH range of 4 to
`l 0. The optimum pH range is neutral. Viscosities of three
`grades of sodium carboxymethylcellulose are shown in
`Table 1. See also Section 11.
`
`(a) Results of laboratory project for third edition.
`
`

`

`Table I: Viscosity of aqueous carboxymethylcellulose sodium
`solutions<•) (Measurements taken with a Brookfield LVT viscometer
`at 25°C).
`
`Grade
`
`Concen. Viscosity
`(% w/v) (mPa s)
`
`Spindle Speed
`
`Low viscosity
`
`Medium
`viscosity
`High viscosity
`
`Akucell
`AF 0305
`Akucell
`AF 2785
`Akucell
`AF 3085
`
`1%
`
`1%
`
`1%
`
`10-15
`
`1500-2500
`
`8000-1200
`
`#1
`
`#3
`
`#4
`
`60 rpm
`
`30 rpm
`
`30 rpm
`
`(a) Ashland Chemical Company technical literature.
`
`11. Stability and Storage Conditions
`Carboxymethylcellulose sodium is a stable, though hygro(cid:173)
`scopic material. Under high humidity conditions carboxyme(cid:173)
`thylcellulose sodium can absorb a large quantity (> 50%) of
`water. In tablets, this has been associated with a decrease in
`tablet hardness and an incn::ase in disintegration time.(7)
`Aqueous solutions are stable between pH 2-10; below pH 2
`precipitation can occur while above pH 10 solution viscosity
`rapidly decreases. Generally, solutions exhibit maximum vis(cid:173)
`cosity and stability at pH 7-9.
`Carboxymethylcellulose sodium may be sterilized in the dry
`state by maintaining it at a temperature of 160°C for 1 hour.
`However, this process results in a significant decrease in vis(cid:173)
`cosity and some deterioration in the properties of solutions
`prepared from the sterilized material.
`Aqueous solutions may similarly be sterilized by heating although
`this also results in some reduction in viscosity. After.autoclaving,
`viscosity is reduced by about 25% although this reduction is less
`marked than for solutions prepared from material sterilized in the
`dry state. The extent of the reduction is dependent on the molec(cid:173)
`ular weight and degree of substitution; higher molecular weight
`grades generally undergo a greater percentage reduction in vis(cid:173)
`cosity. Sterilization of solutions by gamma irradiation also results
`in a reduction in viscosity.
`Aqueous solutions stored for prolonged periods should contain
`an antimicrobial preservative.<8)
`The bulk material should be stored in a well-closed container
`in a cool, dry, place.
`
`12. Incompatibilities
`Carboxymethylcellulose sodium is incompatible with strongly
`acidic solutions and with the soluble salts of iron and some
`other metals, such as aluminum, mercury, and zinc. Precipi(cid:173)
`tation can occur at pH < 2 and when mixed with ethanol
`(95%).
`Carboxymethylcellulose sodium also forms complex coacer(cid:173)
`vates with gelatin and pectin. It additionally forms a complex
`with collagen and is capable of precipitating certain positively
`charged proteins.
`
`13. Method of Manufacture
`Alkali cellulose is prepared by steeping cellulose obtained
`from wood pulp or cotton fibers in sodium hydroxide solution.
`The alkali cellulose is then reacted with sodium monochloro(