(cid:61)(cid:86)(cid:99)(cid:89)(cid:87)(cid:100)(cid:100)(cid:96)(cid:21)(cid:100)(cid:91)(cid:21)
`(cid:69)(cid:93)(cid:86)(cid:103)(cid:98)(cid:86)(cid:88)(cid:90)(cid:106)(cid:105)(cid:94)(cid:88)(cid:86)(cid:97)(cid:21)(cid:58)(cid:109)(cid:88)(cid:94)(cid:101)(cid:94)(cid:90)(cid:99)(cid:105)(cid:104)
`
`(cid:72)(cid:94)(cid:109)(cid:105)(cid:93)(cid:21)(cid:90)(cid:89)(cid:94)(cid:105)(cid:94)(cid:100)(cid:99)
`
`(cid:58)(cid:89)(cid:94)(cid:105)(cid:90)(cid:89)(cid:21)(cid:87)(cid:110)(cid:21)
`(cid:71)(cid:86)(cid:110)(cid:98)(cid:100)(cid:99)(cid:89)(cid:21)(cid:56)(cid:21)(cid:71)(cid:100)(cid:108)(cid:90)(cid:33)(cid:21)(cid:69)(cid:86)(cid:106)(cid:97)(cid:21)(cid:63)(cid:21)(cid:72)(cid:93)(cid:90)(cid:104)(cid:96)(cid:90)(cid:110)(cid:21)(cid:86)(cid:99)(cid:89)(cid:21)(cid:66)(cid:86)(cid:103)(cid:94)(cid:86)(cid:99)(cid:21)(cid:58)(cid:21)(cid:70)(cid:106)(cid:94)(cid:99)(cid:99)
`
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`

`

`Handbook of Pharmaceutical Excipients
`
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`

`Handbook of
`Pharmaceutical Excipients
`
`S I X T H E D I T I O N
`
`Edited by
`Raymond C Rowe BPharm, PhD, DSC, FRPharmS, FRSC, CPhys, MInstP
`Chief Scientist
`Intelligensys Ltd, Stokesley, North Yorkshire, UK
`
`Paul J Sheskey BSc, RPh
`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
`
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`

`

`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
`
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`

`

`Benzalkonium Chloride
`
`B
`
`Nonproprietary Names
`1
`BP: Benzalkonium Chloride
`JP: Benzalkonium Chloride
`PhEur: Benzalkonium Chloride
`USP-NF: Benzalkonium Chloride
`
`Synonyms
`2
`Alkylbenzyldimethylammonium chloride; alkyl dimethyl benzyl
`ammonium chloride; benzalkonii chloridum; BKC; Hyamine 3500;
`Pentonium; Zephiran.
`
`Chemical Name and CAS Registry Number
`3
`Alkyldimethyl(phenylmethyl)ammonium chloride [8001-54-5]
`
`Empirical Formula and Molecular Weight
`4
`The USP32–NF27 describes benzalkonium chloride as a mixture of
`alkylbenzyldimethylammonium chlorides of the general formula
`[C6H5CH2N(CH3)2R]Cl, where R represents a mixture of alkyls,
`including all or some of the group beginning with n-C8H17 and
`extending through higher homologs, with n-C12H25, n-C14H29, and
`n-C16H33 comprising the major portion.
`The average molecular weight of benzalkonium chloride is 360.
`
`5
`
`Structural Formula
`
`R = mixture of alkyls: n-C8H17 to n-C18H37; mainly n-C12H25
`(dodecyl), n-C14H29 (tetradecyl), and n-C16H33 (hexadecyl).
`
`Functional Category
`6
`Antimicrobial preservative; antiseptic; disinfectant; solubilizing
`agent; wetting agent.
`
`7
`
`Applications in Pharmaceutical Formulation or
`Technology
`Benzalkonium chloride is a quaternary ammonium compound used
`in pharmaceutical formulations as an antimicrobial preservative in
`applications similar to other cationic surfactants, such as cetrimide.
`In ophthalmic preparations, benzalkonium chloride is one of the
`most widely used preservatives,(1) at a concentration of
`0.01–0.02% w/v. Often it is used in combination with other
`preservatives or excipients, particularly 0.1% w/v disodium edetate,
`to enhance its antimicrobial activity against strains of Pseudomo-
`nas.
`In nasal,(2)
`a concentration of
`formulations
`and otic
`in combination with
`sometimes
`0.002–0.02% w/v is used,
`0.002–0.005% w/v thimerosal. Benzalkonium chloride 0.01%
`w/v is also employed as a preservative in small-volume parenteral
`products. Benzalkonium chloride was also shown to enhance the
`topical penetration of lorazepam.(3)
`
`56
`
`Benzalkonium chloride is additionally used as a preservative in
`cosmetics.
`
`Description
`8
`Benzalkonium chloride occurs as a white or yellowish-white
`amorphous powder, a thick gel, or gelatinous flakes.
`It
`is
`hygroscopic, soapy to the touch, and has a mild aromatic odor
`and very bitter taste.
`
`Pharmacopeial Specifications
`9
`See Table I.
`
`Table I: Pharmacopeial specifications for benzalkonium chloride.
`
`JP XV
`þ
`þ
`—
`þ
`
`41.0%
`
`—
`—
`—
`
`PhEur 6.4
`þ
`þ
`þ
`þ
`
`410.0%
`—
`40.1%
`—
`þ
`þ
`
`—
`
`40.5%
`40.15%
`40.05%
`
`—
`—
`—
`
`USP32–NF27
`þ
`—
`—
`—
`
`415.0%
`42.0%
`—
`þ
`þ
`þ
`
`—
`
`—
`—
`—
`
`540.0%
`520.0%
`570.0%
`
`Test
`Identification
`Characters
`Acidity or alkalinity
`Appearance of
`solution
`415.0%
`Water
`40.2%
`Residue on ignition
`—
`Sulfated ash
`Water-insoluble matter —
`Foreign amines
`—
`Ratio of alkyl
`—
`components
`Petroleum ether-soluble
`substances
`—
`Benzyl alcohol
`—
`Benzaldehyde
`Chloromethylbenzene —
`Assay (dried basis)
`of n-C12H25
`of n-C14H29
`of n-C12H25 and n-
`C14H29
`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, see Table II. The antimicrobial activity of
`benzalkonium chloride is significantly dependent upon the alkyl
`composition of the homolog mixture.(4) Benzalkonium chloride
`is ineffective against some Pseudomonas aeruginosa strains,
`Mycobacterium tuberculosis, Trichophyton interdigitale, and T.
`rubrum. However, combined with disodium edetate (0.01–0.1%
`w/v), benzyl alcohol, phenylethanol, or phenylpropanol, the
`activity against Pseudomonas aeruginosa is increased.(5) Anti-
`microbial activity may also be enhanced by the addition of
`phenylmercuric acetate, phenylmercuric borate, chlorhexidine,
`cetrimide, or m-cresol.(6,7)
`In the presence of citrate and
`phosphate buffers (but not borate), activity against Pseudomo-
`nas can be reduced. See also Sections 11 and 12. Benzalkonium
`chloride is relatively inactive against spores and molds, but is
`active against some viruses, including HIV.(8) Inhibitory activity
`
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`

`B
`
`Benzalkonium Chloride
`
`57
`
`12 Incompatibilities
`Incompatible with aluminum, anionic surfactants, citrates, cotton,
`fluorescein, hydrogen peroxide, hypromellose,(9) iodides, kaolin,
`lanolin, nitrates, nonionic surfactants in high concentration,
`permanganates, protein, salicylates, silver salts, soaps, sulfona-
`mides, tartrates, zinc oxide, zinc sulfate, some rubber mixes, and
`some plastic mixes.
`Benzalkonium chloride has been shown to be adsorbed to
`various filtering membranes, especially those that are hydrophobic
`or anionic.(10)
`
`13 Method of Manufacture
`Benzalkonium chloride is formed by the reaction of a solution of N-
`alkyl-N-methylbenzamine with methyl chloride in an organic
`solvent suitable for precipitating the quaternary compound as it is
`formed.
`
`14 Safety
`Benzalkonium chloride is usually nonirritating, nonsensitizing, and
`is well tolerated in the dilutions normally employed on the skin and
`mucous membranes. However, benzalkonium chloride has been
`associated with adverse effects when used in some pharmaceutical
`formulations.(11)
`Ototoxicity can occur when benzalkonium chloride is applied to
`the ear(12) and prolonged contact with the skin can occasionally
`cause irritation and hypersensitivity. Benzalkonium chloride is also
`known to cause bronchoconstriction in some asthmatics when used
`in nebulizer solutions.(13–17)
`Toxicity experiments with rabbits have shown benzalkonium
`chloride to be harmful to the eye in concentrations higher than that
`normally used as a preservative. However, the human eye appears to
`be less affected than the rabbit eye and many ophthalmic products
`have been formulated with benzalkonium chloride 0.01% w/v as
`the preservative.
`Benzalkonium chloride is not suitable for use as a preservative in
`solutions used for storing and washing hydrophilic soft contact
`lenses, as the benzalkonium chloride can bind to the lenses and may
`later produce ocular toxicity when the lenses are worn.(18) Solutions
`stronger than 0.03% w/v concentration entering the eye require
`prompt medical attention.
`Local irritation of the throat, esophagus, stomach, and intestine
`can occur following contact with strong solutions (>0.1% w/v).
`The fatal oral dose of benzalkonium chloride in humans is estimated
`to be 1–3 g. Adverse effects following oral
`ingestion include
`vomiting, collapse, and coma. Toxic doses lead to paralysis of the
`respiratory muscles, dyspnea, and cyanosis.
`LD50 (mouse, oral): 150 mg/kg(19)
`LD50 (rat, IP): 14.5 mg/kg
`LD50 (rat, IV): 13.9 mg/kg
`LD50 (rat, oral): 300 mg/kg
`LD50 (rat, skin): 1.42 g/kg
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances and
`quantity of material handled. Benzalkonium chloride is irritant to
`the skin and eyes and repeated exposure to the skin may cause
`hypersensitivity. Concentrated benzalkonium chloride solutions
`accidentally spilled on the skin may produce corrosive skin lesions
`with deep necrosis and scarring, and should be washed immediately
`with water, followed by soap solutions applied freely. Gloves, eye
`protection, and suitable protective clothing should be worn.
`
`16 Regulatory Status
`Included in the FDA Inactive Ingredients Database (inhalations, IM
`injections, nasal, ophthalmic, otic, and topical preparations).
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`1.0
`
`log(1/R)
`
`1745
`
`1651
`
`2128 2292 2324
`2175
`
`1.6
`
`0.0
`
`1214
`
`1475
`
`1968 2002
`
`2164
`
`2348
`
`1672
`
`1728
`−0.1
`1300 1500 1700 1900 2100 2300 2500
`Wavelength/nm
`
`2141
`
`2309
`
`000 × [2nd deriv. log(1/R)
`
`−2.51
`1100
`
`Figure 1: Near-infrared spectrum of benzalkonium chloride measured by
`reflectance.
`
`increases with pH, although antimicrobial activity occurs at pH
`4–10.
`
`Table II: Minimum inhibitory concentrations (MICs) of benzalkonium
`chloride.
`
`MIC (mg/mL)
`64
`5
`5
`5
`5
`16
`5
`64
`30
`30
`16
`4
`2
`1.25
`1.25
`2
`
`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
`Density 0.98 g/cm3 at 208C
`Melting point 408C
`NIR spectra see Figure 1.
`Partition coefficients The octanol : water partition coefficient
`varies with the alkyl chain length of the homolog: 9.98 for C12,
`32.9 for C14, and 82.5 for C16.
`Solubility Practically insoluble in ether; very soluble in acetone,
`ethanol
`(95%), methanol, propanol, and water. Aqueous
`solutions of benzalkonium chloride foam when shaken, have a
`low surface tension and possess detergent and emulsifying
`properties.
`
`11 Stability and Storage Conditions
`Benzalkonium chloride is hygroscopic and may be affected by light,
`air, and metals.
`Solutions are stable over a wide pH and temperature range and
`may be sterilized by autoclaving without loss of effectiveness.
`Solutions may be stored for prolonged periods at room tempera-
`ture. Dilute solutions stored in polyvinyl chloride or polyurethane
`foam containers may lose antimicrobial activity.
`The bulk material should be stored in an airtight container,
`protected from light and contact with metals, in a cool, dry place.
`
`

`

`B
`
`58
`
`Benzalkonium Chloride
`
`Included in nonparenteral medicines licensed in the UK. It is also
`included in the Canadian List of Acceptable Non-medicinal
`Ingredients.
`
`17 Related Substances
`Benzethonium chloride; cetrimide.
`
`18 Comments
`Benzalkonium chloride has been used in antiseptic wipes and has
`been shown to produce significantly less stinging or burning than
`isopropyl alcohol and hydrogen peroxide.(20)
`The EINECS numbers for benzalkonium chloride are 264-151-
`6; 260-080-8; 269-919-4; 270-325-2; 287-089-1. The PubChem
`Compound ID (CID) for benzalkonium chloride is 3014024
`
`19 Specific References
`1 Sklubalova Z. Antimicrobial substances in ophthalmic drops. Ceska
`Slov Form 2004; 53(3): 107–116.
`2 Pisal SS et al. Pluronic gels for nasal delivery of vitamin B. Int J Pharm
`2004; 270(1–2): 37–45.
`3 Nokodchi A et al. The enhancement effect of surfactants in the
`penetration of lorazepam through rat skin. Int J Pharm 2003; 250(2):
`359–369.
`4 Euerby MR. High performance liquid chromatography of benzalk-
`onium chlorides – variation in commercial preparations. J Clin Hosp
`Pharm 1985; 10: 73–77.
`5 Richards RME, McBride RJ. Enhancement of benzalkonium chloride
`and chlorhexidine acetate activity against Pseudomonas aeruginosa by
`aromatic alcohols. J Pharm Sci 1973; 62: 2035–2037.
`6 Hugbo PG. Additivity and synergism in vitro as displayed by mixtures
`of some commonly employed antibacterial preservatives. Can J Pharm
`Sci 1976; 11: 17–20.
`7 McCarthy TJ et al. Further studies on the influence of formulation on
`preservative activity. Cosmet Toilet 1977; 92(3): 33–36.
`8 Chermann JC et al. HIV inactivation by a spermicide containing
`benzalkonium. AIDS Forsch 1987; 2: 85–86.
`9 Richards RME. Effect of hypromellose on the antibacterial activity of
`benzalkonium chloride. J Pharm Pharmacol 1976; 28: 264.
`10 Bin T et al. Adsorption of benzalkonium chloride by filter membranes:
`mechanisms and effect of formulation and processing parameters.
`Pharm Dev Technol 1999; 4(2): 151–165.
`11 Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients.
`Boca Raton, FL: CRC Press, 1992; 31–39.
`12 Honigman JL. Disinfectant ototoxicity [letter]. Pharm J 1975; 215: 523.
`13 Beasley CR et al. Bronchoconstrictor properties of preservatives in
`ipratropium bromide (Atrovent) nebuliser solution. Br Med J 1987;
`294: 1197–1198.
`14 Miszkiel KA et al. The contribution of histamine release to broncho-
`constriction provoked by inhaled benzalkonium chloride in asthma. Br
`J Clin Pharmacol 1988; 25: 157–163.
`
`15 Miszkiel KA et al. The influence of ipratropium bromide and sodium
`cromoglycate on benzalkonium chloride-induced bronchoconstriction
`in asthma. Br J Clin Pharmacol 1988; 26: 295–301.
`16 Worthington I. Bronchoconstriction due to benzalkonium chloride in
`nebulizer solutions. Can J Hosp Pharm 1989; 42: 165–166.
`17 Boucher M et al. Possible association of benzalkonium chloride in
`nebulizer solutions with respiratory arrest. Ann Pharmacother 1992;
`26: 772–774.
`18 Gasset AR. Benzalkonium chloride toxicity to the human cornea. Am J
`Ophthalmol 1977; 84: 169–171.
`19 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th
`edn. New York: Wiley, 2004; 104.
`20 Pagnoni A et al. Lack of burning and stinging from a novel first-aid
`formulation applied to experimental wounds. J Cosmet Sci 2004; 55(2):
`157–162.
`
`20 General References
`Cowen RA, Steiger B. Why a preservative system must be tailored to a
`specific product. Cosmet Toilet 1977; 92(3): 15–20.
`El-Falaha BM et al. Surface changes in Pseudomonas aeruginosa exposed to
`chlorhexidine diacetate and benzalkonium chloride. Int J Pharm 1985;
`23: 239–243.
`El-Falaha BM et al. Activity of benzalkonium chloride and chlorhexidine
`diacetate against wild-type and envelope mutants of Escherichia coli and
`Pseudomonas aeruginosa. Int J Pharm 1985; 25: 329–337.
`Karabit MS et al. Studies on the evaluation of preservative efficacy III: the
`determination of antimicrobial characteristics of benzalkonium chloride.
`Int J Pharm 1988; 46: 141–147.
`Lien EJ, Perrin JH. Effect of chain length on critical micelle formation and
`protein binding of quaternary ammonium compounds. J Med Chem
`1976; 19: 849–850.
`Martin AR. Anti-infective agents. Doerge RF, ed. Wilson and Gisvold’s
`Textbook of Organic, Medicinal and Pharmaceutical Chemistry.
`Philadelphia: JB Lippincott, 1982; 141–142.
`Pense´ AM et al. Microencapsulation of benzalkonium chloride. Int J Pharm
`1992; 81: 111–117.
`Prince HN et al. Drug resistance studies with topical antiseptics. J Pharm Sci
`1978; 67: 1629–1631.
`Wallha¨usser KH. Benzalkonium chloride. Kabara JJ, ed. Cosmetic and Drug
`Preservation Principles and Practice. New York: Marcel Dekker, 1984;
`731–734.
`
`21 Author
`AH Kibbe.
`
`22 Date of Revision
`15 January 2009.
`
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`

`

`1000 × [2nd deriv. log(1/R)]
`
`Benzethonium Chloride
`
`Nonproprietary Names
`1
`BP: Benzethonium Chloride
`JP: Benzethonium Chloride
`PhEur: Benzethonium Chloride
`USP: Benzethonium Chloride
`
`Synonyms
`2
`benzyldimethyl-[2-[2-(p-1,1,3,3-tetra-
`Benzethonii
`chloridum;
`methylbutylphenoxy) ethoxy]ethyl]ammonium chloride; BZT; dii-
`sobutylphenoxyethoxyethyl dimethyl benzyl ammonium chloride;
`Hyamine 1622.
`
`Chemical Name and CAS Registry Number
`3
`N,N-Dimethyl-N-[2-[2-[4-(1,1,3,3-tetramethylbutyl)phenox-
`y]ethoxy]ethyl]benzene-methanaminium chloride [121-54-0]
`
`Empirical Formula and Molecular Weight
`4
`C27H42ClNO2
`448.10
`
`5
`
`Structural Formula
`
`Functional Category
`6
`Antimicrobial preservative; antiseptic; disinfectant.
`
`7
`
`Applications in Pharmaceutical Formulation or
`Technology
`Benzethonium chloride is a quaternary ammonium compound used
`in pharmaceutical formulations as an antimicrobial preservative.
`Typically, it is used for this purpose in injections, ophthalmic and
`otic preparations at concentrations 0.01–0.02% w/v. Benzethonium
`chloride may also be used as a wetting and solubilizing agent, and as
`a topical disinfectant.(1,2)
`In cosmetics such as deodorants, benzethonium chloride may be
`used as an antimicrobial preservative in concentrations up to 0.5%
`w/v.
`The physical properties and applications of benzethonium
`chloride are similar to those of other cationic surfactants such as
`cetrimide.
`
`Description
`8
`Benzethonium chloride occurs as a white crystalline material with a
`mild odor and very bitter taste.
`
`B
`
`Table I: Pharmacopeial specifications for benzethonium chloride.
`
`Test
`Identification
`Characters
`Appearance of
`solution
`Acidity or alkalinity
`Melting range
`Loss on drying
`Residue on ignition
`Sulfated ash
`Ammonium
`compounds
`Assay (dried basis)
`
`JP XV
`þ
`—
`—
`
`—
`158–1648C
`45.0%
`40.1%
`—
`þ
`
`PhEur 6.0
`þ
`þ
`þ
`þ
`158–1648C
`45.0%
`—
`40.1%
`450 ppm
`
`USP 32
`þ
`—
`—
`
`—
`158–1638C
`45.0%
`40.1%
`—
`þ
`
`597.0%
`
`97.0–103.0% 97.0–103.0%
`
`10 Typical Properties
`Acidity/alkalinity pH = 4.8–5.5 for a 1% w/v aqueous solution.
`Antimicrobial activity Optimum antimicrobial activity occurs
`between pH 4–10. Preservative efficacy is enhanced by ethanol
`and reduced by soaps and other anionic surfactants. For typical
`minimum inhibitory concentrations (MICs) see Table II.(3)
`
`Table II: Minimum inhibitory concentration (MIC) for benzethonium
`chloride.
`
`Microorganism
`Aspergillus niger
`Candida albicans
`Escherichia coli
`Penicillium notatum
`Proteus vulgaris
`Pseudomonas aeruginosa
`Pseudomonas cepacia
`Pseudomonas fluorescens
`Staphylococcus aureus
`Streptococcus pyogenes
`
`MIC (mg/mL)
`128
`64
`32
`64
`64
`250
`250
`250
`0.5
`0.5
`
`NIR spectra see Figure 1.
`Solubility Soluble 1 in less than 1 of acetone, chloroform, ethanol
`(95%), and water; soluble 1 in 6000 of ether. Dissolves in water
`to produce a foamy, soapy solution.
`
`2149 2175 2440
`2214
`2125
`2286
`
`0.30.3
`
`1652
`
`log(1/R)
`log(1/R)
`
`1669
`
`1983
`
`2320
`
`0.8
`
`0.0
`
`1194
`
`−0.2−0.2
`−1.2
`1100 1300 1500 1700 1900 2100 2300 2500
`Wavelength/nm
`
`2138
`
`2162
`
`2474
`
`Pharmacopeial Specifications
`9
`See Table I.
`
`Figure 1: Near-infrared spectrum of benzethonium chloride measured by
`reflectance.
`
`59
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`

`60
`
`Benzethonium Chloride
`
`11 Stability and Storage Conditions
`Benzethonium chloride is stable. Aqueous solutions may be
`sterilized by autoclaving.
`The bulk material should be stored in an airtight container
`protected from light, in a cool, dry place.
`
`B
`
`12 Incompatibilities
`Benzethonium chloride is incompatible with soaps and other
`anionic surfactants and may be precipitated from solutions greater
`than 2% w/v concentration by the addition of mineral acids and
`some salt solutions.
`
`13 Method of Manufacture
`p-Diisobutylphenol is condensed in the presence of a basic catalyst
`with b,b0
`-dichlorodiethyl ether
`to yield 2-[2-[4-(1,1,3,3-tetra-
`methylbutyl)phenoxy]ethoxy]ethyl chloride. Alkaline dimethylami-
`nation then produces the corresponding tertiary amine which, after
`purification by distillation, is dissolved in a suitable organic solvent
`and treated with benzyl chloride to precipitate benzethonium
`chloride.(4)
`
`14 Safety
`Benzethonium chloride is readily absorbed and is generally
`regarded as a toxic substance when administered orally. Ingestion
`may cause vomiting, collapse, convulsions, and coma. The probable
`lethal human oral dose is estimated to be 50–500 mg/kg body-
`weight.
`The topical use of solutions containing greater than 5% w/v
`benzethonium chloride can cause irritation although benzethonium
`chloride is not regarded as a sensitizer. The use of 0.5% w/v
`benzethonium chloride in cosmetics is associated with few adverse
`effects. A maximum concentration of 0.02% w/v benzethonium
`chloride is recommended for use in cosmetics used in the eye area
`and this is also the maximum concentration generally used in
`pharmaceutical formulations such as injections and ophthalmic
`preparations.(5)
`See also Benzalkonium Chloride.
`LD50 (mouse, IP): 15.5 mg/kg(6)
`LD50 (mouse, IV): 30 mg/kg
`LD50 (mouse, oral): 338 mg/kg
`LD50 (rat, IP): 16.5 mg/kg
`LD50 (rat, IV): 19 mg/kg
`LD50 (rat, oral): 368 mg/kg
`LD50 (rat, SC): 119 mg/kg
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances and
`quantity of material handled. Eye protection and gloves are
`recommended.
`
`16 Regulatory Status
`Included in the FDA Inactive Ingredients Database (IM and IV
`injections; nasal, ophthalmic and otic preparations). Included in the
`Canadian List of Acceptable Non-medicinal Ingredients.
`
`17 Related Substances
`Benzalkonium chloride; cetrimide.
`
`18 Comments
`Benzethonium chloride has been used therapeutically as a disin-
`fectant and topical anti-infective agent. However, its use in these
`applications has largely been superseded by other more effective
`antimicrobials and it is now largely used solely as a preservative in a
`limited number of pharmaceutical and cosmetic formulations.
`The EINECS number for benzethonium chloride is 204-479-9.
`The PubChem Compound ID (CID) for benethonium chloride
`includes 8478 and 547429.
`
`19 Specific References
`1 Shintre MS et al. Efficacy of an alcohol-based healthcare hand rub
`containing synergistic combination of farnesol and benzethonium
`chloride. Int J Hyg Environ Health 2006; 209: 477–487.
`2 Bearden DT et al. Comparative in vitro activities of topical wound care
`products against community-associated methicillin-resistant Staphylo-
`coccus aureus. J Antimicrob Chemother 2008; 62: 769–772.
`3 Wallha¨usser KH. Benzethonium chloride. Kabara JJ, ed. Cosmetic and
`Drug Preservation Principles and Practice. New York: Marcel Dekker,
`1984; 734–735.
`4 Gennaro AR, ed. Remington: The Science and Practice of Pharmacy,
`20th edn. Baltimore: Lippincott Williams and Wilkins, 2000; 1508.
`5 The Expert Panel of the American College of Toxicology. Final report
`on the safety assessment of benzethonium chloride and methylben-
`zethonium chloride. J Am Coll Toxicol 1985; 4: 65–106.
`6 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th
`edn. New York: Wiley, 2004; 407.
`
`20 General References
`Lonza. Product data sheet: Hyamine 1622 crystals, April 2005.
`
`21 Author
`ME Quinn.
`
`22 Date of Revision
`27 January 2009.
`
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`

`

`Benzyl Alcohol
`
`B
`
`Nonproprietary Names
`1
`BP: Benzyl Alcohol
`JP: Benzyl Alcohol
`PhEur: Benzyl Alcohol
`USP-NF: Benzyl Alcohol
`
`Synonyms
`2
`Alcohol benzylicus; benzenemethanol; a-hydroxytoluene; phenyl-
`carbinol; phenylmethanol; a-toluenol.
`
`Chemical Name and CAS Registry Number
`3
`Benzenemethanol [100-51-6]
`
`Empirical Formula and Molecular Weight
`4
`C7H8O
`108.14
`
`5
`
`Structural Formula
`
`Description
`8
`A clear, colorless, oily liquid with a faint aromatic odor and a sharp,
`burning taste.
`
`Pharmacopeial Specifications
`9
`See Table I. See also Section 18.
`
`Table I: Pharmacopeial specifications for benzyl alcohol.
`
`PhEur 6.5
`þ
`þ
`þ
`þ
`þ
`
`USP32–NF27
`þ
`—
`—
`þ
`þ
`
`JP XV
`þ
`þ
`þ
`þ
`þ
`
`Test
`Identification
`Characters
`Solubility
`Acidity
`Clarity and color of
`solution
`1.043–1.049 —
`1.043–1.049
`Specific gravity
`1.538–1.541
`1.538–1.541
`1.538–1.541
`Refractive index
`40.05%
`40.05%
`Residue on evaporation 40.05%
`þ
`þ
`þ
`Related substances
`þ
`þ
`0.05–0.15
`Benzaldehyde
`45
`45
`45
`Peroxide value
`Assay
`98.0–100.5% 98.0–100.5% 98.0–100.5%
`
`Functional Category
`6
`Antimicrobial preservative; disinfectant; solvent.
`
`7
`
`Applications in Pharmaceutical Formulation or
`Technology
`Benzyl alcohol is an antimicrobial preservative used in cosmetics,
`foods, and a wide range of pharmaceutical formulations,(1–4)
`including oral and parenteral preparations, at concentrations up
`to 2.0% v/v. The typical concentration used is 1% v/v, and it has
`been reported to be used in protein, peptide and small molecule
`products, although its frequency of use has fallen from 48 products
`in 1996, 30 products in 2001, to 15 products in 2006.(5) In
`cosmetics, concentrations up to 3.0% v/v may be used as a
`preservative. Concentrations of 5% v/v or more are employed as a
`solubilizer, while a 10% v/v solution is used as a disinfectant.
`Benzyl alcohol 10% v/v solutions also have some local anesthetic
`properties, which are exploited in some parenterals, cough
`products, ophthalmic solutions, ointments, and dermatological
`aerosol sprays.
`Although widely used as an antimicrobial preservative, benzyl
`alcohol has been associated with some fatal adverse reactions when
`administered to neonates. It is now recommended that parenteral
`products preserved with benzyl alcohol, or other antimicrobial
`preservatives, should not be used in newborn infants if at all
`possible; see Section 14.
`
`64
`
`10 Typical Properties
`Acidity/alkalinity Aqueous solutions are neutral to litmus.
`Antimicrobial activity Benzyl alcohol is bacteriostatic and is used
`as an antimicrobial preservative against Gram-positive bacteria,
`molds, fungi, and yeasts, although it possesses only modest
`bactericidal properties. Optimum activity occurs at pH below 5;
`little activity is shown above pH 8. Antimicrobial activity is
`reduced in the presence of nonionic surfactants, such as
`polysorbate 80. However, the reduction in activity is less than
`is the case with either hydroxybenzoate esters or quaternary
`ammonium compounds. The activity of benzyl alcohol may also
`be reduced by incompatibilities with some packaging materials,
`particularly polyethylene; see Section 12.
`See Table II for reported minimum inhibitory concentrations
`(MICs).
`
`Table II: Minimum inhibitory concentrations (MICs) of benzyl
`alcohol.(4)
`
`Microorganism
`Aspergillus niger
`Candida albicans
`Escherichia coli
`Pseudomonas aeruginosa
`Staphylococcus aureus
`
`MIC (mg/mL)
`5000
`2500
`2000
`2000
`25
`
`is moderately active against most
`Bacteria Benzyl alcohol
`Gram-positive organisms (typical MICs are 3–5 mg/mL),
`although some Gram-positive bacteria are very sensitive
`(MICs 0.025–0.05 mg/mL). In general, benzyl alcohol is less
`active against Gram-negative organisms.
`Fungi Benzyl alcohol is effective against molds and yeasts;
`typical MICs are 3–5 mg/mL.
`Spores Benzyl alcohol is inactive against spores, but activity
`may be enhanced by heating. Benzyl alcohol 1% v/v, at pH
`5–6, has been claimed to be as effective as phenylmercuric
`nitrate 0.002% w/v against Bacillus stearothermophilus at
`1008C for 30 min.
`
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`

`B
`
`Benzyl Alcohol
`
`65
`
`14 Safety
`is used in a wide variety of pharmaceutical
`Benzyl alcohol
`formulations. It is metabolized to benzoic acid, which is further
`metabolized in the liver by conjugation with glycine to form
`hippuric acid, which is excreted in the urine.
`Ingestion or inhalation of benzyl alcohol may cause headache,
`vertigo, nausea, vomiting, and diarrhea. Overexposure may result
`in CNS depression and respiratory failure. However, the concentra-
`tions of benzyl alcohol normally employed as a preservative are not
`associated with such adverse effects.
`Reports of adverse reactions to benzyl alcohol(9,10) used as an
`excipient
`include
`toxicity following intravenous administra-
`tion;(11–13) neurotoxicity in patients administered benzyl alcohol
`in intrathecal preparations;(14,15) hypersensitivity,(16–18) although
`relatively rare; and a fatal
`toxic
`syndrome
`in premature
`infants.(19–22)
`The fatal toxic syndrome in low-birth-weight neonates, which
`includes symptoms of metabolic acidosis and respiratory depres-
`sion, was attributed to the use of benzyl alcohol as a preservative in
`solutions used to flush umbilical catheters. As a result of this, the
`FDA has recommended that benzyl alcohol should not be used in
`such flushing solutions and has advised against the use of medicines
`containing preservatives in the newborn.(23,24)
`The WHO has set the estimated acceptable daily intake of the
`benzyl/benzoic moiety at up to 5 mg/kg body-weight daily.(25)
`LD50 (mouse, IV): 0.32 g/kg(26)
`LD50 (mouse, oral): 1.36 g/kg
`LD50 (rat, IP): 0.4 g/kg
`LD50 (rat, IV): 0.05 g/kg
`LD50 (rat, oral): 1.23 g/kg
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances and
`quantity of material handled. Benzyl alcohol (liquid and vapor) is
`irritant to the skin, eyes, and mucous membranes. Eye protection,
`gloves, and protective clothing are recommended. Benzyl alcohol
`should be handled in a well-ventilated environment; a self-
`contained breathing apparatus is recommended in areas of poor
`ventilation. Benzyl alcohol is flammable.
`
`16 Regulatory Status
`Included in the FDA Inactive Ingredients Database (dental
`injections, oral capsules, solutions and tablets, topical, and vaginal
`preparations). Included in parenteral and nonparenteral medicines
`licensed in the UK. Included in the Canadian List of Acceptable
`Non-medicinal Ingredients.
`
`17 Related Substances
`
`— 1
`
`8 Comments
`Benzyl alcohol is one of the materials that have been selected for
`harmonization by the Pharmacopeial Discussion Group. For further
`information see the General Information Chapter <1196> in the
`USP32–NF27, the General Chapter 5.8 in PhEur 6.0, along with the
`‘State of Work’ document on the PhEur EDQM website, and also
`the General Information Chapter 8 in the JP XV.
`The EINECS number for benzyl alcohol
`is 202-859-9. The
`PubChem Compound ID (CID) for benzyl alcohol is 244.
`
`19 Specific References
`1 Croshaw B. Preservatives for cosmetics and toiletries. J Soc Cosmet
`Chem 1977; 28: 3–16.
`
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`Autoignition temperature 436.58C
`Boiling point 204.78C
`Flammability Flammable. Limits in air 1.7–15.0% v/v.
`Flash point
`100.68C (closed cup);
`104.58C (open cup).
`Freezing point 158C
`Partition coefficients
`Liquid paraffin : water = 0.2;
`Octanol : water = 1.10;
`Peanut oil : water = 1.3.
`Solubility see Table III.
`
`Table III: Solubility of benzyl alcohol.
`
`Solvent
`Chloroform
`Ethanol
`Ethanol (50%)
`Ether
`Fixed and volatile oils
`Water
`
`Solubility at 208C unless otherwise stated
`Miscible in all proportions
`Miscible in all proportions
`1 in 1.5
`Miscible in all proportions
`Miscible in all proportions
`1 in 25 at 258C
`1 in 14 at 908C
`
`Surface tension 38.8 mN/m (38.8 dynes/cm)
`Vapor density (relative) 3.72 (air = 1)
`Vapor pressure
`13.3 Pa (0.1 mmHg) at 308C;
`1.769 kPa (13.3 mmHg) at 1008C.
`Viscosity (dynamic) 6 mPa s (6 cP) at 208C
`
`11 Stability and Storage Conditions
`Benzyl alcohol oxidizes slowly in air to benzaldehyde and benzoic
`acid;
`it does not react with water. Aqueous solutions may be
`sterilized by filtration or autoclaving; some solutions may generate
`benzaldehyde during autoclaving.
`Benzyl alcohol may be stored in metal or glass containers. Plastic
`containers
`should not be used;