Petitioner |nnoPharma EX 1108
`
`|PR2015—00902, |PR2015—00903
`
`Page 1
`
`

`
`
`
`Handbook of
`
`Pl1a.rn1aceutical Excipients
`
`FOURTH ED TION
`
`//
`
`Edited by
`
`Raymond C Rowe
`BPl1orm, PhD, DSC, FRPl1armS, CCl'1em, FRSC, CPl1ys, MlnsIP
`
`Senior Principal Scientist
`AstraZeneca
`Maccleslield, UK
`
`Paul J Sheskey
`BSC, RPh
`
`Technical Service Leader
`Water Soluble Polymers R&D
`The Dow Chemical Company
`Midland
`
`Ml, USA
`
`Paul J Weller
`BSC, MSC, CChem, MRSC
`
`Publisher — Science and Practice
`
`Royal Pharmaceutical Society of Great Britain
`London, UK
`
`(RP)
`
`London o Chicago Pharmaceutical Press
`
`This material was copied
`at t:-he N LM 5 rid may be
`S~|.K'l}‘j€::t US‘ Copyright Laws
`
`A9414;
`American
`Pharmaceutical
`Association
`
`Page 2
`
`Page 2
`
`

`
`'
`'
`I
`Published by the Pharmaceutical Press
`Publications division of the Royal Pharmaceutical Society of Great Britain
`
`l Lambeth High Street, London SE1 7JN, UK
`100 South Atkinson Road, Suite 206, Graysloke, lL 60030-7820, USA
`
`and the American Pharmaceutical Association
`2215 Constitution Avenue N‘/\/, Washington, DC 20037-2985, USA
`
`(7; Phzirmaceutical Press and American Pharniaceutlcal Association 2003
`
`is a trade mark of Pharmaceutical Press
`First edition published 1986
`Second edition published 1994
`Third edition published 2000
`Fourth edition published 2003
`
`Text design by Barker Hilsdon, Lyme Regis
`Typeset by Bibliocraft Ltd, Dundee
`Primed in Great Britain by The Bath Press, Bath
`
`ISBN 0 85369 472 9 (UK)
`ISBN 1 58212 022 6 (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
`Library of Congress Cataloging-in-Publication Data
`Handbook of pharmaceutical eXCipi(:ntS.— 4th ed. /edited by Raymond C.
`Rowe, Paul J. Sheskey, Paul]. Weller.
`p. ,- cm.
`Includes bibliographical references and index.
`ISBN 1-58212~022~6 (alk. paper) -ISBN O-85369-472-9 (alk. paper)
`1. Excipier1ts—Handbooks, manuals, etc.
`[DNI,M: 1. Excipients—Handbooks. QV 735 H236 2003] I. Rowe, Raymond
`C. II. Sheskey, Paul I. III. Weller, Paul J.
`RS201.I_"87H36 2003
`615’.l94ic2‘l
`
`
`
`This material was copriad
`at the NLM and may be
`S«u't>js~:t US Copyright; Laws
`
`2003002641
`
`Page 3
`
`Page 3
`
`

`
`
`
`Benzalkonium Chloride
`
`0.0l—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
`Pseudomonas.
`In nasal and otic formulations a concentration of 0.002-
`0.02°o is used, sometimes in combination with 0.00Z—0.005%
`w/v thimerosal. Benzalkonium chloride 0.01% w/v is also
`employed as a preservative in small-volume parenteral pro-
`ducts.
`Benzalkonium chloride is additionally used as a preserva-
`tive in cosmetics.
`
`8 Description
`Ben7;.1ll<onium 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.
`
`9 Pharmacopeial Specifications
`See Table I.
`
`Table l:
`
`Phcirmocopeiol specifications for benzalkonium chloride.
`
`Test
`
`JP 200i
`
`Pl1Eur 2002
`
`USPNF 20
`
`+
`+
`+
`+
`
`< 10.0%
`.—
`<0.l%
`—
`+
`—
`
`—
`
`——
`—
`—
`
`+
`-
`—
`—
`
`s l5.0°/o
`<2~O%
`—
`+
`+
`+
`
`—
`
`240.0%
`220.0%
`370-0%
`
`95.0~iO5.0% 95.0-104.0% 97.0—lO3.0%
`
`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 surfac-
`tants, such as cetrimide.
`In ophthalmic preparations, benzalkoiiiuin chloride is one
`of the most widely used preservatives, at a concentration of
`
`10 Typical Properties
`Acidity/alkalinity: pH = 5-8 for a 10% w/v aqueous solution.
`Antimicrobial activity: benzalltonium 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 acti-
`vity of benzalkonium chloride is significantly dependent
`
`This material was »:>t1«piei:l
`atthe HLM and may lane
`Eu bjeizt US? 5o«py1righ‘t Laws
`
`Page 4
`
`Identification
`Characters
`Acidiiy or alkalinity
`Appearance of
`solution
`< l5.0°/o
`Water
`<0.2°/0
`Residue on ignition
`—
`Sulfoiecl ash
`Waier-insoluble mcifier —
`Foreign amines
`—
`Ratio of o|l<y|
`—
`components
`Petroleum eiher-
`soluble subsionces
`Assay [dried basis)
`Ol I7-C12l'l25
`of i7'C14l'l2Q
`OF Vi-C12l‘l25 and
`H-Ci4l‘l29
`for total olkyl
`content
`
`+
`—
`—
`+
`
`< l .O%
`
`—
`—
`—
`
`I Nonproprieta ry Names
`BI’: Benzalkonium chloride
`JP: Benzalkonium chloride
`I’hEur: P)en7,all<onii cliloridum
`USPNF; Benzalkonium chloride
`
`2
`
`Synonyms
`
`Alkylbenzyldimethylammonium chloride; alltyl dimethyl hen-
`zyl ammonium chloride; BKC; Hymnine 3500; Pem‘om'z1m;
`Zap/yiran.
`
`3 Chemical Name and CAS Registry Number
`Alkyldiinethyl(phenyhuethyl)ammonium chloride [8001-54-5]
`
`Molecular Weight
`4
`Empirical Formula
`The USPNF 20 describes benzallconium chloride as a mixture
`of alkylbenzyldiniethylammonium chlorides of the general
`formula [C(,H5CI-I3N(Cl-I3);R]Cl, where R represents a mix-
`ture of all<yls, including all or some of the group beginning
`with 1l‘CgH]7 and extending through higher homologs, with
`n~C1;I-I35, n—C,.,I-Ila, and n—C1(,I-I37; coniprising the major
`portion.
`The average molecular weight of benzalkonium chloride is
`360.
`
`5
`
`Structural Formula
`
`Cl
`
`H (
`
`l3—-—N—-R
`i.
`
`Iz—C3I~I.7 to n—C.3H;,7; mainly
`R = mixture of alkyls:
`n—C12H3;
`(dodecyl), n—CHI-I39 (tetradecyl), and ll-C](,l'l_i3
`(hexaclecyl).
`
`Functional Category
`6
`Antimicrobial preservative; antiseptic; disinfectant; solubiliz-
`ing agent; wetting agent.
`
`Page 4
`
`

`
`‘' “~15:
`
`46
`
`Benzolkonium Chloride
`
`upon the alkyl composition of the honiolog mixture.“
`Benzalkonium chloride is ineffective against sotne Pseudo-
`monzis aeruginosa strains, Mycobzzcterum-z tuberculosis,
`Triclaoplvyton iuterdigitale, and T. rubrum. However, com-
`bined with disodiurn edetate (0.01—0.l"o w/v), benzyl
`alcohol, phenylethanol, or phenylpropanol,
`the activity
`against Pseudomomzs aeruginoszz is increasedlll Antimicro-
`bial activity may also be enlianced by the addition of
`phenylmercuric acetate, phenylmercuric borate, chlorhex—
`idine, cetrimide, or m—cresol.(""ll In the presence of citrate
`and phosphate buffers (but not borate), activity against
`Pseudomomzs 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.l5l Inhibitory activity increases with pH,
`although aiitiinicrobial activity occurs between pH 4
`and 10.
`
`Incompatibilities
`‘I2
`incompatible with aluminum, anionic surfactants, citrates
`cotton,
`fluorescein, hydrogen peroxide,
`hypromellose,l(’l
`iodides, kaolin, lanolin, nitrates, nonionic surfactants in high
`concentration, permanganates, protein, salicylates, silver salts,
`soaps, sulfonamides, tartrates, zinc oxide, zinc sulfate, some
`rubber mixes, and some plastic mixes.
`llenzalkoniuni chloride has been shown to be adsorbed to
`various filtering membranes, especially those that are hydro-
`phobic or anionic.(7'
`
`13 Method of Manufacture
`
`Benzalkoniuin chloride is formed by the reactioti of a solution
`of N—alkyl—N-methylbenzamine \vith methyl chloride in art
`organic solvent suitable for precipitating the quaternary com-
`pound as it is formed.
`
`Table II: Minimum inhibitory concentrations lM|Cs] of beiizolkonium
`chloride.
`
`1 4 Safety
`
`Microorganism
`
`MIC (pg/ml)
`
`Aerobocter aerogenes
`Clostridium histolyticurn
`Clostridium oedematiens
`Clostriclium tctani
`Clostridium welchii
`Escherichia coli
`Pneumococcus ll
`Proteus vulgciris
`Pseudomonas aeruginosa
`Salmonella enteritidis
`Salmonella pciratyplii
`Salmonella typhosa
`Sliigella dysenterioe
`Staphylococcus aureus
`Streptococcus pyrogenes
`Vibrio cholerae
`
`64
`5
`5
`5
`.5
`l6
`5
`64
`30
`30
`lo
`4
`2
`1 .25
`L25
`2
`
`Density: z0.98 g/cm3 at 20 “C
`Melting point: :40 “C
`Partition coefficients: the octanolzwater partition coefficient
`varies with the alkyl chain length of the homolog; 9.98 for
`C12, 32.9 for C1,), and 82.5 for C16.
`Solubility: practically insoluble in ether; very soluble in
`acetone, ethanol (95%), methanol, propanol, and water.
`Aqueous solutions of bcnzalkonium chloride foam when
`shaken, have a low surface tension and possess detergent
`and emulsifying properties.
`
`1 1
`
`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 effective-
`ness. Solutions may be stored for prolonged periods at room
`temperature. Dilute solutions stored in polyvinyl chloride or
`polyurethane foam containers may lose antimicrobial activity,
`1 he bulk material should be stored in an airtight container,
`protected from light and contact with metals, in a cool, dry
`place.
`
`
`
`Benzalkonium chloride is usually nonirritating, nonsensitizing,
`and well tolerated in the dilutions normally employed on the
`skin and mucous membranes. However, benzalkonium chlor-
`ide has been associated with adverse effects when used in some
`pharmaceutical f()l‘n11ll21[l()I1S.(s)
`Ototoxicity can occur when benzalkonium chloride is
`applied to the earl” and prolonged contact with the skin can
`occasionally cause irritation and hypersensitivity. Benzal—
`konium chloride is also known to cause bronchoconstriction
`in some asthmatics when used in nebulizer st)iiitioiis."m"4l
`Toxicity experinients with rabbits have shown benzalko-
`niuni 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 benzalkoninm
`Chloride ().0l"u w/V as the preservative.
`Benzalkonium chloride is not suitable for use as a preserva-
`tive in solutions used for storing and washing hytlrophilic soft
`contact lenses, as the benzalkoniuin chloride can bind to the
`lenses and may later produce ocular toxicity when the lenses
`are worn.l15l 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
`(>O.1“u w/v). The fatal oral dose of benzalkoniuni 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.
`
`LD5n (mouse, oral): 150I11g/l(g(l6)
`LD5;, (rat, ll’): l4.5mg/kg
`LD.sri (rat, lV): 'l3.9mg/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 chlor-
`ide solutions accidentally spilled oii
`the skin may produce
`corrosive skin lesions with deep necrosis and scarring, and
`should be washed immediately with water, followed by soap
`
`This material wascopied
`atttie NLM and may be
`3t.l’l}j-Evif US £’a-pwigtit; Laws
`
`Page 5
`
`Page 5
`
`

`
`
`
`solutions applied freely. Gloves, eye protection, and suitable
`protective clothing should be worn.
`
`'16 Regulatory Status
`Included in the FDA Inactive Ingredients Guide (1I1l'l€ll:l[1()l]S,
`HV1 injections,
`ll(1S1ll, oplithalinic, otic, and topical p1'epm‘21~
`tions).1ncludcd in n(mpnrcnter-.11 medicines licensed in the UK.
`
`17 Related Substances
`Benzethonium chloride; cetrimitle.
`
`18 Comments
`The EINECS numbers for benz'.1ll<0niu1n chloride are 264-151»
`6; Z60-080-8; 269-9194; 270-3253.; 287-089-'1.
`
`19
`1
`
`[.2
`
`3
`
`Specific References
`Euerby MR. High performance liquid climinntogtapliy of
`l)C11ZZlll(()I‘llUlll chlorides - variation in C()1111l1C1’C1;1l prepai‘in'.im1s.
`] Clin H0511 I’/mm; 1985; 10: 73-77.
`Riclmrcls RME,
`l\*1cl3ride R]. Enliunceinent of lienmlkoiiiuin
`chloride and chlorlicxidine acetate activity agairist I’sezido/umms
`aeruginosa hy 21r0n1flt1C alcohols. ] I’/mrm Sci 1973; 62: 2035-
`2037.
`1~1ugl)0 PG. Additivity and syncrgisiu in Liilru as displayed hy
`mixtures of sonic coinnmnly cniployccl aiitibactcrial preserva-
`tives. Cr:/1] P/mrm Sci 1976; 11: 17-20.
`4 McCarthy '1‘_], Mylnngli JA, Butler N. Iiurther studies on the
`influence of formulation on preservative activity. Cosmcr Toilet
`1977; 92(3): 33-36.
`5 Cherniann JC, BZIITK3-S1ll()Ll$S1 F, Ilenin Y, Mareclial V. HIV
`inactivation by .1 spermicide containing l)enzall<oniun1. AIDS
`Fmsc/7 1987; 2: 85-86.
`6 Riclidrds RNIE. Effect of hyproinellose on the antil)acte1‘i;1l
`activity of benzulkuniuin chlorii1c.] Plmrm P/}fl7‘I1I(l('rJi 1976; 28:
`264.
`7 Bin T, Knlshreshtha AK, Al~Sl1al<hshir R, Hem SL. Adsorption of
`hcnzalkoniuin Cl‘ll()l'1(‘l€ by filter ineiiibrzliics: meclianisins and
`effect of fnrinnlarinn and processing ]'7(1l'z1l1lC1€l‘S.
`I’/mrm DUN
`lilac/111011999;-’l(l): 151-165.
`l)rIrg, and Cosmetic
`Smnlinske SC. Hmxdbotile of Fund,
`Ext!/I/£’lI!S. 1500.1 Raton, FL: CRC Press, 1992: 31-39.
`9 Honigman _|L. Disinfectzint ototnxicity [letter]. P/mrm _] 1975;
`215: 523.
`10 Beasley CRW, Rafferty 1’, Hnlgatc ST. Broiiclioeoiistrictor
`[n'opei'ties of preservatives in iprarrnpiiun hroniitle (Atrnvent)
`nel)ulise1' S()ll1tl(tl1. Br Med] 1987; 294: 1197-1198.
`M15’/.l<iel KA, llezlslcy R, Rafferty P, fltilgiite ST. The cL)ntrilm-
`riun of histamine release to l)1'(}llCll()C0l‘lSU‘lCtifln provoked by
`
`8
`
`11
`
`Berizolkoniuni Chloride
`
`47
`
`1l'll1LllL‘Ll l)enzall<0niuin chloride in 1'lStlllIl£|. Br] Cfifl I’l7c1mmcoi
`1988; 25: 157-163.
`Mis7.l<icl KA, Ueasley R, Hnlgate ST. The influence of
`ipr.1tmpiLun hmmide and sodium eromoglyczite on henzul~
`kuniuin chltiritle-induczed l)r()iIcliocrmstriction in asthma. Br ]
`C/iii P/)LIl'lJ1(IC()1 1988; 26: 295-301.
`13 Wnrtliingtun 1.
`ljronelinctmsrriction due to hcn7,all<<miinn
`Cl‘Il(\I‘l(l€
`in nehuli'/.er S()lltI1(}l1S. Ctm ] Hos]? I’/Jarm 1989; 42:
`165-166.
`14 Boucliet M, Roy 1\/1'1’, Ilenderson _|. Possible association of
`henz21ll<0nium Cl1l()l'1(lC in nehuli7.ci' solutions with respiratorv
`‘.'ll‘1‘CSl'. Aim I’/mmmcul/yer 1992; 26: 772-774.
`'
`Gusset AR. BCl1Z1lll(()nlLIl]I chloride toxicity to the human cornea.
`Am] Ofiiitlmliiioi 1977; 84: 169-171.
`Lewis R], ed. SzIx's Dimgerozzs l’ropertie5 oflriditslriai Materials,
`10th etln. New York: Wiley, 2000: 360.
`
`16
`
`20 General References
`Cowcn RA, Steigcr B. Why :1 preservative system I1‘11lStl)6 tailored to a
`specilic product. Cosme! Toilet 1977; 92(3): 15-20.
`17.1-13al:1l1:1 BM/\, Rogers DT, Furr JR, Russell AD. Surface clianges in
`i’$c'IItI'0m07m5 (1El‘l!gi7I()S(I exposed to clilorhexidine diacetnte and
`
`henzalknniuin Clll()1'1(lC. 1111] 1’/mrm 1985; 2
`39-243.
`1”.l—l-"alalia EMA, Russell AD, Furr JR, Rogcis DT. Activity uf
`heiimlkoiiiuni cliloritle and Cl1l()l‘l]€X1(l1I‘l(:‘ diacetate against wild-
`type and envelope mutants of Esc/ieric/Jiri mix‘ and Psmtdrmzonas
`ilcrzzgittoszi. Inl] I’/mrm 1985; 25: 329-337.
`Kiwahir l\/lS,]iiiiesl-211115 0'1’, Lundgren P. Studies (in the cvuluzltiun of
`preservative efficacy III:
`the determination of antiniicrohial
`cliarucleristics of l7K:‘I1Zflll(()111lln1 chloride. Int ] I’/mm; 1988; 46:
`141447.
`Lien E], Perrin JH. Effect nf chain length on critical micelle formation
`and protein hintling (1f(]llLl[C1'l121l'y '.\min<>niuin compounds. ] Med
`Chem 1976; 19: 849-850.
`Martin AR. Anti—infective agents. In: Doerge RF, ed. Wilson and
`Gist/uidk Textbook of Orgmiic,
`il/1t'dicimi/ and Plyimmzcenticzvi
`Cimriistry. Philadelphia: JB Lippincott, 1982: 141-142.
`Pensé AM, Vciuthiet C, Puisienx F, 15cnuirJP. .\/1ict0eiieapsLila1ioii of
`hen7.all<0ninin chloride. Int] Plmrm 1992; 81: 111-117.
`Prince HN, Ntinciiiaker \X/S, Notgard RC, Prince DL. Drug resistance
`studies with topical antiseptics]1’/mrmSci 1978; 67: 1629-1631.
`\‘</allliiiusser KH. l.$enzall<onium chloride. In: K;1l3Jl'flJ_1, ed. Cosmetic
`and Drug I’reseri/zitirm l’rinci[2/es and Practice. New York: Marcel
`l.)6l<1(Cl', 1984: 731-734.
`
`21 Authors
`AH Kihbc.
`
`22 Date of Revision
`26 June 2002.
`
`
`
`This material was zepiecl
`atthe NLM and may be
`S«i.i—l:ijEvz:‘c US 4C’x;i';egtig1'it Laws
`
`Page 6
`
`Page 6
`
`

`
`Benzethonium Chloride
`
`1 Nanproprietciry Names
`Bl’: Benzethonium chloride
`JP: Benzethonium chloride
`PhEur: Benzethonii chloridum
`USP: Benzetlioniurn chloride
`
`8 Description
`
`Beiizerlioiiiiiiii chloride occurs as a white crystalline material
`with a mild odor and very bitter taste.
`
`2 Synonyms
`
`Benzyldimethyl-[2-[2-(fr1,1,3,3—tetramethylbutylplienoxy)
`etlioxylethylIammonium chloride;
`ISZT; diisobutylplienoxy-
`ethoxyetliyl dimetliyl benzyl ammonium chloride; Hyamine
`1622.
`
`PharmacopeialSpecifications
`9
`See Table I.
`
`Table I:
`
`Pharmcicopeial specitications ior benzethonium chloride.
`
`Test
`
`JP 200i
`
`PhEur 2002
`
`USP 25
`
`
`
`3 Chemical Name and CAS Registry Number
`N,N—Dimetliyl-N-[2—[2—l4-(‘1,‘l,3,3—teti'ametliylbutyl)
`phenoxy|ethoxy]ethyl]benzene—mcthaiiaminium
`[12'l—54-O]
`
`chloride
`
`4 Empirical Formula
`Cg7H43ClNO1
`
`Molecular Weight
`448.10
`
`5
`
`H,c
`
`Structural Formula
`CH3
`
`CH3
`
`H36
`
`CH3
`
`o\/\0/W er
`
`H3C—-N’
`H c
`3
`
`Functional Category
`6
`Antimicrobial preservative; antiseptic; disinfeetaiit.
`
`7 Applications in Pharmaceutical Formulation
`or Technology
`
`Benzethonium chloride is a quaternary ammonium compound
`used in pharmaceutical forinulatioiis as an
`is used for this
`it
`antimicrobial preservative. Typically,
`purpose in injections, ophthalmic and otic preparations at
`conceiitrations 0.0l—0.02“u w/v. Benzethoiiium chloride may
`also be used as a wetting and solubilizing agent, and as a
`topical disinfectant.
`In cosmetics such as deodorants, benzetlionium chloride
`may be used as an antimicrobial preservative in concentrations
`up to 0.5% w/v.
`The physical properties and applications of beiizetlioniuin
`chloride are similar to those of other cationic surfactants such
`as cetrimide.
`
`+
`—
`—
`
`Identification
`Characters
`Appearance of
`solution
`Acidity or alkalinity —
`Melting range
`l58—l 64"C
`Loss on drying
`<.5.0%
`Residue on ignition
`<O.l°/o
`Sultated ash
`—
`Ammonium
`+
`compounds
`Assciy (dried basis)
`
`297.0%
`
`+
`+
`+
`
`+
`_
`__
`
`+
`l58—l 64 "C
`§5.0°/a
`—
`<01"/D
`$50 ppm
`
`_
`l58—l 63 “C
`g5_O°/0
`<o_]%
`_
`+
`
`97.0—l 03.0% 97.0—l 03.0%
`
`10 Typical Properties
`
`Acidity/alkalinity: plrl = 4.8-5.5 for a 1% W/v aqueous solu-
`tion.
`
`Antimicrobial activity: optimum antiiiiierobial activity occurs
`between pH 4-10. Prescrvative efficacy is enhanced by
`ethanol and reduced by soaps and other anionic surfac-
`rants. For
`typical
`ipiiiiniiiiii
`inhibitory concentrations
`(MICS) see Table ll.("
`
`Table II: Minimum inhibitory concentration (MIC) For benzethonium
`chloride.
`
`Microorganism
`
`MIC (pg/mu
`
`Aspergillus niger
`Candida olbicans
`Escherichia coli
`Penicillium notalum
`Proteus vulgaris
`Pseudomonas aeruginoszi
`Pseudomonas cepacia
`Pseudomonas fluorescens
`Staphylococcus aureus
`Streptococcus pyogenes
`
`1'28
`64
`32
`64
`()4
`250
`250
`250
`0,5
`0_5
`
`in less than 1 of acetone, chloroform,
`Solubility: soluble '1
`ethanol (95%), and water; soluble 1
`in 6000 of ether.
`Dissolves in water to produce a foamy, soapy solution.
`
`48
`
`This mate rial was capiecl
`at t‘;l'tE N LM ya rm may be
`Subject Ufitiapgvright Laws
`
`Page 7
`
`Page 7
`
`

`
`
`
`Stability and Storage Conditions
`1 ‘I
`Bcnzethonium 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.
`
`lncompatibilities
`12
`Benzerhoriium 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
`[},[}'-dichlorodicthyl
`ether
`to
`yield
`2-[2~
`[4-(1,l,3,3—tetramethylbntyl)phenoxyjethoxylerhyl
`chloride.
`Alkaline dimethylamination then produces the corresponding
`tertiary amine which, after purification by distillation,
`is
`clissolved in a suitable organic solvent and treated with benzyl
`chloride to precipitate benzethonium chloride.(2l
`
`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 benzetlio-
`nium chloride is not regarded as a sensiti7.er. The use of
`0.5% w/v henzethonium chloride in cosmetics is associated
`with few adverse effects. A maximum concentration of 0.02%
`w/v benzcthonium chloride is recommended for use in cos-
`metics used in the eye area and this is also the maximum
`concentration generally used in pharmaceutical formulations
`such as injections and ophthalmic prepar-ations.l3’
`See also Beuzalkonium Chloride.
`
`LD50 (mouse, ll’): 15.5 mg/l<g(4)
`LD50 (mouse, IV): 30mg/l<g
`LD;o (mouse, oral): 338 mg/kg
`LD;0 (rat, IP): 16.5mg/kg
`[D50 (rat, IV): 19mg/kg
`LD50 (rat, oral): 368111;;/ltg
`LD50 (rat, SC): 1 19mg/kg
`
`Benzelhonium Chloride
`
`49
`
`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 Guide (IM and IV
`injections, ophthalmic and otic preparations).
`
`17 Related Substances
`Benzallconiuin chloride; cetriniide.
`
`'| 8 Comments
`
`Benzetlmnium chloride has been used therapeutically as 3
`disinfectant and topical anti—i11fectiVe 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 C05-
`metic formulations.
`The EINECS number for benzethonium chloride is 204-
`479-9.
`
`Specific References
`19
`.3d_
`In: Kabara H,
`1 Wallhiiusser KII. Benzethonium chloride.
`Cosmetic and Drug I’r:zsr>r1/arinn l’r1'nci[)les and Practice. New
`York: Marcel DL‘l(l{€l‘, 1984: 734—735.
`2 Gcnuaro AR, ed. Remington: The Science and Practice of
`Plmrmacy, 20th edn, Baltimore: Lippincott Williams and Wilkim
`2000: 1508.
`i’
`The Expert Panel of the American College of Toxicology. Final
`report on the safety assessment of benzethonium chloride and
`methylbenzcthoninm chloride. ] Am Coll Toxicol 1985; 4; 55_
`106.
`4 Lewis R], ed. S:Ix’s Dm1gcrous I’roperties of lmiuslrial Materials
`10th edn. New York; Wiley, 2000, 416.
`
`L.»
`
`’
`
`20 General References
`
`21 Authors
`LME W/ykes.
`
`22 Date of Revision
`5 March 2002.
`
`
`
`This !'f!ET\E'FlEl was copied
`atthe HLM and may Ere
`Ezrmject US /Copyright Law:
`
`Page 8
`
`Page 8
`
`

`
`
`
`
`
`440
`
`Phenylmercuric Nitrate
`
`Phenylmercuric salts are incompatible with halldefi Patti‘
`cularly bromides and iodides, as they form less-soluble.halot';en
`compounds. At Concentrations of 0.002?/u W/v precipitation
`may not occur in the presence of chlorides. Phenylmercuric
`salts are also incompatible with aluminum and other metals,
`ammonia and ammonium salts, atnino acids, and with some
`sulfur compounds, e.g., in rubber.
`Phenylmercuric salts are absorbed by rubber stoppers and
`some types of plastic packaging components; uptake is usually
`greatest
`to natural rubbers and polyethylene and least
`to
`Polypropyleiledlliml
`'
`Incompatibilities with some types of filter membranes may
`also result in loss [of plicnylmercuric salts following steriliza-
`tion by filtration.‘ ’)
`
`16 Regulatory Status
`Included in the FDA Inactive Ingredients Guide (IM and
`ophthalmic preparations). Included in nonparenteral medi-
`cines liccnsed in the UK. In the UK, the use of phenylmercuric
`salts in cosmetics is limited to 0.003% (calculated as mercury,
`equivalent
`to approximately 0,0047% of phenyltnercuric
`nitrate) as a preservative in shampoos and hair creams,
`which contain nonionic emulsifiers that would render other
`preservatives ineffective. Total perrnitted concentr-.1tion, as
`mercury, when mixed with other mercury compounds is
`0.007% (equivalent up to approximately 0.011% of phenyl-
`mercuric nitrate).“"’l
`
`17 Related Substances
`
`13 Method of Manufacture
`
`Plienylniercuric acetate; phcnylmcrcuric borate; thimerosal.
`
`18 Comments
`
`Phenylmercuric salts should be used in preference to benz-.1lk»
`onium chloride as a preservative for salicylates and nitrates and
`in solutions of salts of physostigmine and epinephrine that
`contain 0.1% sodium sulfite.
`
`Phenylrnercuric nitrate is readily formed by heating benzene
`with mercuric acetate, and treating the resulting acetate with
`an alkali nitrate.“
`
`I4 Safely
`Phenylmercuric nitrate and other phenylmercuric salts are
`widely used as antimicrobial preservatives in parenteral and
`topical pharmaceutical formulations. However, concern over
`the use of phenylmercuric salts
`in pharmaceuticals has
`increased as a result of greater awareness of the toxicity of
`mercury and other mercury compounds. This concern must,
`however, be balanced by the effectiveness of these materials as
`antimicrobial preservatives and the low concentrations in
`which they are employed.
`Phenylmercnric salts are irritant to the skin at 0.1% w/w
`Concentration in petrolatumfw’ In solution, they may give rise
`to erythcma and blistering 6-12 hours after administration. In
`a modified repeated insult patch test, a 2% w/v solution was
`found to produce extreme sensitization of the skii1.‘l°*2“
`Eye drops containing phenylmercuric nitrate as a preserva-
`tive should not be used continuously for prolonged periods as
`mercurialentis, a brown pigmentation of the anterior capsule
`of the lens may occur. Incidence is 6% in patients using eye
`drops for greater than 6 years; however, the condition is not
`associated with visual
`iinp:iirment.U‘2‘“l Cases of atypical
`band keratopathy have also been attributed to phenylmercuric
`nitrate preservative in eye drops.(24)
`Concern that the absorption of mercury from the vagina
`may be harmful has led to the recommendation that phenyl-
`trons.
`mercuiztgc nitrate sl'1ould not be used in intravaginal formula-
`
`LD50 (mouse, IV): 27ing/kgizm
`LD50 (mouse, oral): 50 mg/kg
`LD50 (rat, SC): 63 mg/kg
`
`‘I5 Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity ofmaterial handled. Phenylinercuric nitrate may
`be irritant to the skin, eyes, and mucous membranes. Eye
`protection, gloves, and :1 respirator are recommended. In the
`UK, the occupational exposure limit for mercury containing
`compounds, calculated as mercury,
`is 0.012mg/m3 long-term
`(8—hour TWA) and 0.03 mg/m3 short—term.‘ 7)
`
`
`
`4
`
`7
`
`Specific References
`19
`1 Buckles J, Brown MW, Porter G5. The inactivation of
`phenylmercuric nitrate by sodium metabisulphite. ] I’/mrm
`Plmrnmcol 1971; Z3(Suppl.): 2375-2385,
`2 Richards RME, Reary ]l\/IE. Changes in antibacterial activity of
`thiomersal and l’MN on anmclaving with certain adjuv-ants.
`] P/7£!Y‘H1 Pbzirmacol 1972; 24(Suppl.): S4l’—89I’.
`3 Richards RME, Fell AF, Butehart JME. Interaction between
`sodium met-abisulpliite and I’MN.] 1’/mrm 1’/zarrnzicol 1972; 24:
`999-1000.
`Parker MS. The preservation of pharmacetiticuls and cosmetic
`products. In: Russell AD, Hugo WE, Ayliffe GA], eds. I’rinci';2/es
`and I’mcIicc of Dz'sinfecz1'ovz, Preserz/ation and Sterilizatimi.
`5 Oxford: Blackwell Scientific, 1982: 287-305.
`lIart /\. Antibacterial activity of phenylmercurie nitrate in zinc
`sulphate and adrenaline eye drops BPC 1968. ] Plmrm
`Phzlrmacol 1973; 25: 507—508,
`6 Miezitis E0, Polnck AE, Roberts MS. Concentration changes
`during autoclaving of aqueous solutions in polyethylene containi-
`ers: an examination of some methods for reduction of solute loss.
`A1151] I’/Jrirm Sci 1979; 8(3): 72-76.
`Parkin JE, Marshall
`(IA. The iiist-ability of phenylinercuric
`nitrate in APF ophthalmic products containing sodium metabi-
`sulfitc. Aust] Hosp Plmrm 1991; 20: 4344436.
`8 Collins A], Lingliam I’, Burbridge TA, Bain R. Incompatibility of
`plionyliiieiuiric acetate with sodium metabisulphite in eye drop
`forniulations. ] Plmrm I’barnmcol 1985; 37(Suppl.): 1231’.
`9 Yousef RT, El~Nakecb MA, Salnma 5. Effect of some pharma-
`ceutical materials on the bactericidal activities of preservatives.
`Cmi] Plmrm Sci 1973; 8: 54-56.
`Interactions between
`10 Horn NR, McCarthy T}, Ramsted E.
`powder suspensions and selected quaternary ammonium and
`organomcrcurial preservatives. Cosme! Toilet 1980; 95(2): 69-
`73.
`Ingversen J, Andersen VS. Transfer of plicnylmcrcuric com-
`pounds from dilute aqueous solutions to vials and rubber
`Closures. Drmsle Tidssler Fmm 1968; 42: 264-271.
`12 Etiksson K. Loss of organomercurial preservatives from medica-
`ments in different kinds of containers. Acm Plmrm Site: 1967; 4:
`261-264.
`13 Cliristensen K, Dauv E. Absorption of preservatives by drip
`attaclinients in eye drop packages. ] Mond I’/mrm 1969; 12(1):
`5-11.
`
`11
`
`This material was copied
`attire NLM and may be
`Sutzjeirt US Ctcip-yrigtit Laws
`
`Page 9
`
`Page 9
`
`

`
`
`
`
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`22
`
`23
`
`25
`26
`
`27
`
`I’/mm: ]
`
`Aspinall _lA, Duffy '11), Saunders MB, Taylor CG. The effect of
`low density polyethylene containers on some hospital—manufac-
`tnrerl eye drop formulations I: sorption of phenylmercnric
`acetate. ] Cliu Hos]: Plmrm 1980; 5: 21-29.
`McCarthy T].
`lnteraction hetween aqueous preservative solu-
`tions and their plastic containers, III. 1"/mm: Wcekbi 1972; 107:
`1-7.
`Aspinall JA, Duffy TD, Taylor CG. The effect of low density
`polyethylene containers on some hospital-manufactured eye drop
`formulations ll:
`inhilvitiou of the sorption of phenylmercuric
`acetate. ] Clin Hosp Plmrm 1983; 8: 223-240.
`Naido NT, Price CH, McCarthy T]. Preservative loss from
`ophthalmic solutions during filtration sterilization. Aust] P/mrm
`Sci1972; 1(1): 16-18.
`Pyinan FL, btevensott HA. Pltetiylmereurie nitrate.
`1934; 133: 269.
`Kohy GA, Fisher AA. Phenylmcrcnric acetate as primary irritant.
`/lrc/7 Dermatol 1972; 106: 129.
`Kligman AM. The identification of contact allergens by human
`assay, 111. The maximization test: a procedure for screening and
`rating contact sensitizers. ] Int/est l)ernu1tol 1966; 47: 3934109.
`Galindo PA, Feo I7, Garcia R, et :11. Metcurochrome allergy:
`immediate and delayed hypersensitivity. Allergy 1997; 52(11):
`1 138-1 141.
`:1]. A Clinical and
`Garron LK, Wood 15, Spencer WH, at
`pathologic study of mercnrialentiq mcdicamentosus. Tums Am
`Ophz/mlmol Soc 1977; 74: 295.
`\X/intler AF, Astbury N], Sheraidah GAK, Ruben 1V1. Penetration
`of mercury from ophthalmic preservatives into the human eye.
`Lcmcel 1980; ii: 237-239.
`Brazier D], Hitehings RA. Atypical band ketatopathy following
`long—term pilocarpine treatment. Br] Oplatlm/mol
`I989; 73:
`294-296.
`Lohr L. Mercury controversy heats up. A771 P/mrm "1978; 18(9):
`23.
`Sweet DV, ed. Registry of Toxic Effects of Cl)emical Substances.
`Cincinnati: US Department of Health, 1987: 306047093.
`Health and Safety Executive. EH40/2002: Occupziiiumzl Expo-
`sure Limits 2002. Sudhnry: Health and Safety Executive, 2002.
`
`Phenylmercuric Nilrole
`
`441
`
`28
`
`Statutory Instrument (S1) 1989: No. 2233. Consumer Protection:
`The Consumer Products (Safety) Regulations 1989. London:
`HMSO, 1989.
`
`20 General References
`Abtlelaziz AA, El-Nakeeh MA. Sporieidal activity of local anaesthetics
`and their hinary combinations with preservatives. ] Cliu Plmrm
`The? 1988; 13: 249-256.
`Barlcman R, Germanis M, Karpe G, Malmlmrg AS. Preservatives in
`eye drops. Acm Opbtlmlmol 1969; 47: 461-475.
`Grier N. Mereurials inorganic and organic.
`In: Block 55, ed.
`Disinfectirm, Sterilizatioli nIx(i1’resert/tttimz, 3rd edn. Pliiladclphia:
`Lea and Febiger, 1983: 346-374.
`Hecht G. Ophthalmic preparations. in: Gennaro AR, cd. Remhigtozz:
`The Science and Practice of I’/zmvzmcy, 20th edn. Baltimore:
`Lippincott \Williams and Wilkiiis, 2000: 821-835.
`Parkin ]E. The decomposition of phenylmcrcuric nitrate in sulph-
`acetamide drops during hear sterilization. ] P/mrm I’/mrmacol
`1993; 45: 1024-1027.
`Parltin JE, Button KL. Maroudas PA. The decomposition of
`phenylmercuric nitrate caused hy disodium ecletate in nemnycin
`eye drops during the process of heat sterilization. ] Clin Plmrm
`T/IET1992; 17: 191-196.
`Parkin JE, Duffy MB, Loo CN. The chemical degradation of
`phenylmercuric nitrate by disodinm edetate during heat steriliza-
`tion at pH values commonly encountered in ophthalmic products.
`] Ci/'11 P/mrm