Handbook of
`
`PHARMACEUTICAL
`
`EXCIPIEN TS
`
`Third Edition
`
`Edited by
`
`Arthur H. Kibbe, Ph.D.
`Professor and Chair
`
`Department of Pharmaceutical Sciences
`Wilkes University School of Pharmacy
`Wi1kes—Barre, Pennsylvania
`
`$2
`
`American Pharmaceutical Association
`
`Washington, D.C.
`
`(RP)
`
`Phunnucwlical Puss
`
`London, United Kingdom
`
`|PR2015—01099
`
`|PR2015—01097
`
`|PR2015—01100
`
`|PR2015—01105
`
`Lupin EX1161
`Page 1
`
`

`
`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 SE1 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
`1. Excipients--Handbooks, manuals, etc.
`Pharmaceutical Association.
`
`I. Kibbe, Arthur H. II. American
`
`[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.
`
`
`
`,Lr..__--_T-.1.4..__L»
`
`99-044554
`
`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.
`
`Managing Editor: Melanie Segala
`Copyeditor:
`Paul Gottehrer
`Indexer:
`Lillian Rodberg
`Compositor:
`Roy Barnhill
`Cover Designer:
`Tim Kaage
`
`x -
`
`Page 2
`
`Page 2
`
`

`
`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; Roccal; Zephiran.
`
`3. Chemical Name and CAS Registry Number
`
`Alkyldimethyl(phenylmethyl)ammonium chloride [8001—54—5]
`
`Molecular Weight
`4. Empirical Formula
`The USP describes benzalkonium chloride as a mixture of
`alkylbenzyldimethylammonium chlorides of the general for-
`mula [C6H5CH2N(CH3)2R]Cl, where R represents a mixture
`of alkyls, including all or some of the group beginning with
`n—C8H,7 and extending through higher homologs, with n-
`C121-I25, n—C,4H29, and fl-C16H33 comprising the major portion.
`
`The average molecular weight of benzalkonium chloride is
`360.
`
`5. Structural Formula
`
`CH,
`—CH2—N‘;—R Cl
`I
`CH3
`
`R = mixture of alkyls: n-C8H,7 to n-CISH37; mainly It-C12H25
`(dodecyl), n—C,4H29 (tetradecyl), and n-C16H33 (hexadecyl).
`
`6. Functional Category
`
`Antimicrobial preservative; antiseptic; disinfectant; solubiliz—
`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-
`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
`
`to enhance its antimicrobial activity against strains
`edetate,
`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-
`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 ye11owish—white
`amorphous powder, a thick gel, or gelatinous flakes. It is hy-
`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-C12H25
`2 20.0%
`—
`—
`Of n-CMH29
`2 70.0%
`—
`Of n—C,2H25 & n—C,4H29 —
`For total alkyl content
`95.0—105.0% 95.0-104.0% 97.0-103.0%
`
`10. Typical Properties
`Acidity/alkalinity: pH = 5-8 for a 10% w/v aqueous solution.
`Antimicrobial activity: benzalkonium chloride solutions are
`active against a wide range of bacteria, yeasts, and fungi.
`Activity is more marked against Gram-positive than Gram-
`negative bacteria and minimal against bacterial endospores
`and acid-fast bacteria. The antimicrobial activity of ben-
`zalkonium chloride is significantly dependent upon the
`alkyl composition of the homolog mixturef‘) Benzalko-
`nium chloride is ineffective against some Pseudomonas
`aeruginosa strains, Mycobacterium tuberculosis, Tricho-
`phyton irtterdigitale, 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”) Antimicrobial
`activity may also be enhanced by the addition of phenylm-
`ercuric acetate, phenylmercuric borate, chlorhexidine, cet-
`rimide, or m-cresol.(3v4) In the presence of citrate and
`phosphate buffers (but not borate), activity against
`Pseudomonas can be reduced. See also Sections 11 and
`12. Benzalkonium chloride is relatively inactive against
`spores and molds, but
`is active against some viruses,
`including HIVX5) Inhibitory activity increases with pH
`although antimicrobial activity occurs between pH 4-10.
`Typical minimum inhibitory concentrations (MICs) are
`shown in Table I.
`
`Page 3
`
`Page 3
`
`

`
`34 Benzalkonium Chloride
`
`Table 1: Minimum inhibitory concentrations (MICs) of
`benzalkonium chloride.
`
`14. Safety
`
`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 (pg/mL)
`
`64
`5
`5
`5
`5
`16
`5
`64
`30
`30
`16
`4
`2
`
`Density: = 0.98 g/cm3 at 20°C
`Melting point: = 40°C
`Partition coefiicientsz the octanol: water partition coefficient
`varies with the alkyl chain length of the homolog; 9.98
`for C12, 32.9 for C14, and 82.5 for C16.
`Solubility: practically insoluble in ether; very soluble in ace-
`tone, ethanol (95%), methanol, propanol, and water. Aque-
`ous solutions of benzalkonium chloride foam when shaken,
`have a low surface tension and possess detergent and emul-
`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-
`tiveness. Solutions may be stored for prolonged periods at
`room temperature. Dilute solutions stored in polyvinyl chlo-
`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-
`ton, fluorescein, hydrogen peroxide, hydroxypropyl methyl-
`cellulose,(5)
`iodides, ' kaolin,
`lanolin, nitrates, nonionic
`surfactants in high concentration, permanganates, protein, sal-
`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-
`ious filtering membranes especially those that are hydrophobic
`or anionic.(7>
`
`13. Method of Manufacture
`
`Benzalkonium chloride is usually nonirritating, nonsensitiz-
`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“)
`
`Ototoxicity can occur when benzalkonium chloride is applied
`to the ear(9) and prolonged contact with the skin can occa-
`sionally cause irritation and hypersensitivity. Benzalkonium
`chloride is also known to cause bronchoconstriction in some
`asthmatics when used in nebulizer solutions.(‘°"“)
`
`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 less affected than the rabbit eye and many
`ophthalmic products have been formulated with benzalkonium
`chloride 0.01% w/v as the preservative. Benzalkonium chlo-
`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.”5’ Solutions
`stronger than 0.03% w/v concentration entering the eye re-
`quire prompt medical attention.
`
`Local irritation of the throat, esophagus, stomach, and intes-
`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-
`gestion include vomiting, collapse, and coma. Toxic doses
`lead to paralysis of the respiratory muscles, dyspnea, and cy-
`anosis.
`
`LD50 (guinea pig, oral): 200 mg/kg“)
`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-
`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-
`tions). Included in nonparenteral medicines licensed in the
`UK.
`
`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-
`pound as it is formed.
`
`17. Pharmacopeias
`
`Eur, Int, Jpn, P01, and US.
`
`Page 4
`
`

`
`18. Related Substances
`
`Benzethonium chloride; cetrimide.
`
`19.
`
`Comments
`
`20.
`
`Specific References
`. Euerby MR. High performance liquid chromatography of
`benzalkonium chlorides - variation in commercial prepara-
`tions. J Clin Hosp Pharm 1985; 10: 73-77.
`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.
`Hugbo PG. Additivity and synergism in vitro as displayed
`by mixtures of some commonly employed antibacterial pre-
`servatives. Can J Pharm Sci 1976; 11: 17-20.
`McCarthy TJ, Myburgh JA, Butler N. Further studies on the
`influence of formulation on preservative activity. Cosmet Toi-
`let 1977; 92(3): 33-36.
`Chermann JC, Barre-Sinoussi F, Henin Y, Marechal V. HIV
`inactivation by a spermicide containing benzalkonium. AIDS
`Forsch 1987; 2: 85-86.
`Richards RME. Effect of hypromellose on the antibacterial
`activity of benzalkonium chloride. J Pharm Pharmacol 1976;
`28: 264.
`Bin T, Kulshreshtha AK, Al-Shakhshir R, Hem SL. Adsorp-
`tion of benzalkonium chloride by filter membranes: mecha-
`nisms and effect of formulation and processing parameters.
`Pharm Dev Technol 1999; 4(2), 151-165.
`Smolinske SC. Handbook of Food, Drug, and Cosmetic
`Excipients. Boca Raton, FL, CRC Press Inc, 1992; 31-39.
`Honigman JL. Disinfectant ototoxicity [letter]. Pharm J
`1975;215:523.
`Beasley CRW, Rafferty P, Holgate ST. Bronchoconstrictor
`properties of preservatives in ipratropium bromide (Atrovent)
`nebuliser solution. Br Med J 1987; 294: 1197-1198.
`Miszkiel KA, Beasley R, Rafferty P, Holgate ST. The con-
`tribution of histamine release to bronchoconstriction pro-
`voked by inhaled benzalkonium chloride in asthma. Br J Clin
`Pharmacol 1988; 25: 157-163.
`Miszkiel KA, Beasley R, Holgate ST. The influence of ipra-
`tropium bromide and sodium cromoglycate on benzalkonium
`chloride-induced bronchoconstriction in asthma. Br J Clin
`Pharmacol 1988; 26: 295-301.
`
`10.
`
`ll.
`
`12.
`
`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-
`nea. Am J Ophthalmol 1977; 84: 169-171.
`16. Sweet DV, editor. Registry of Toxic Effects of Chemical Sub-
`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.
`E1-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, Lundgren P. Studies on the evaluation
`of preservative efficacy III: the determination 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-
`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-
`ceutical Chemistry. Philadelphia, J.B. Lippincott Company,
`1982; 141-142.
`Pensé 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-
`tance studies with topical antiseptics. J Pharm Sci 1978; 67:
`1629-1631.
`In: Kabara JJ, editor.
`Wallhausser KH. Benzalkonium chloride.
`Cosmetic and Drug Preservation Principles and Practice. New
`York, Marcel Dekker Inc, 1984; 731-734.
`
`22. Authors
`
`AH Kibbe.
`
`Page 5
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`Page 5