Handbook of
`PHARMACEUTICAL
`EXCIPIENTS
`
`Second Edition
`
`Edited by
`Ainley Wade and Paul J Weller
`
`American Pharmaceutical Association (cid:9)
`Washington
`
`1994
`
`The Pharmaceutical Press
`London
`
`Exhibit 1026
`ARGENTUM
`IPR2018-00080
`
`000001
`
`(cid:9)
`

`

`Copyright 1986, 1994 by the American Pharmaceutical Association, 2215 Constitution Avenue NW, Washington,
`DC 20037-2985, USA, and The Pharmaceutical Press, Royal Pharmaceutical Society of Great Britain, 1 Lambeth High
`Street, London, SE1 TIN, England.
`
`A catalogue record for this book is available from the British Library.
`
`Library of Congress Catalog Card Number: 94-79492.
`
`International Standard Book Number (ISBN) in the UK: 0 85369 305 6
`International Standard Book Number (ISBN) in the USA: 0 91730 66 8
`
`No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical,
`including photocopy, recording, or any information storage or retrieval system, without prior written permission from
`the joint publishers.
`
`Typeset in Great Britain by Alden Multimedia, Northampton.
`Printed and bound in Great Britain by
`
`000002
`
`

`

`Acacia
`
`1. Nonproprietary Names
`BP: Acacia
`PhEur: Acaciae gummi
`USPNF: Acacia
`
`2. Synonyms
`E414; gum acacia; gum arabic; talha gum.
`
`3. Chemical Name and CAS Registry Number
`Acacia [9000-01-5]
`
`4. Empirical Formula Molecular Weight
`Acacia is a complex, loose aggregate of sugars and hemi-
`celluloses with a molecular weight of approximately 240 000-
`580 000. The aggregate consists essentially of an arabic acid
`nucleus to which are connected calcium, magnesium and
`potassium along with the sugars arabinose, galactose and
`rhamnose.
`
`5. Structural Formula
`See Section 4.
`
`6. Functional Category
`Emulsifying agent; stabilizing agent; suspending agent; tablet
`binder; viscosity-increasing agent.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Acacia is mainly used in oral and topical pharmaceutical
`formulations as a suspending and emulsifying agent, often in
`combination with tragacanth. It is also used in the preparation
`of pastilles and lozenges, and as a tablet binder, although used
`incautiously it can produce tablets with a prolonged
`disintegration time.
`Acacia is also used in cosmetics, confectionery and food
`products.
`See also Section 19.
`
`Use (cid:9)
`
`Emulsifying agent
`Pastille base
`Suspending agent
`Tablet binder
`
`Concentration (%)
`
`5-10
`10-30
`5-10
`1-5
`
`8. Description
`Acacia occurs as white or yellowish-white colored thin flakes,
`spheroidal tears, granules or powder. It is odorless and has a
`bland taste.
`
`9. Pharmacopeial Specifications
`The BP 1993 includes monographs on acacia, powdered acacia
`and spray-dried acacia which differ only in their physical
`characteristics. The PhEur 1992 similarly has monographs on
`acacia and spray-dried acacia, while the USPNF XVII
`describes acacia in a single monograph which encompasses
`tears, flakes, granules and spray-dried powder.
`
`Acacia 1
`
`Test (cid:9)
`
`PhEur 1992 (cid:9)
`
`USPNF XVII
`
`Identification
`Botanic characteristics
`Microbial limit
`Water
`
`Total ash
`Acid-insoluble ash
`Insoluble residue
`Arsenic
`Lead
`Heavy metals
`Starch or dextrin
`Tannin-bearing gums
`Agar & tragacanth
`Agar & sterculia gum
`Sucrose & fructose
`
`Note: a. Spray-dried acacia.
`
`0.5%
`
`• 15%
`
`4.0%
`• 0.5%
`• 1.0%
`▪ 3 ppm
`0.001%
`0.004%
`
`10. Typical Properties
`Acidity/alkalinity:
`pH = 4.5-5.0 (5% w/v aqueous solution)
`Acid value: 2.5
`Hygroscopicity: at relative humidities between 25-65%, the
`equilibrium moisture content of powdered acacia at 25°C is
`between 8-13% w/w, but at relative humidities above about
`70% it absorbs substantial amounts of water.
`Moisture content: see HPE Data.
`Solubility: soluble 1 in 20 of glycerin, 1 in 20 of propylene
`glycol, 1 in 2.7 of water; practically insoluble in ethanol (95%).
`Specific gravity: 1.35-1.49
`Viscosity (dynamic): 100 mPa s (100 cP) for a 30% w/v
`aqueous solution at 20°C.
`The viscosity of aqueous acacia solutions varies depending
`upon the source of the material, processing, storage condi-
`tions, pH and the presence of salts. Viscosity increases slowly
`up to about 25% w/v concentration and exhibits Newtonian
`behavior. Above this concentration, viscosity rapidly increases.
`Increasing temperature or prolonged heating of solutions
`results in a decrease of viscosity due to depolymerization or
`particle agglomeration. See also Section 12.
`
`Moisture content (cid:9)
`
`HPE Laboratory Project Data
`
`Method Lab # (cid:9)
`MC-1 (cid:9)
`5 (cid:9)
`MC-1 (cid:9)
`5 (cid:9)
`MC-1 5 (cid:9)
`
`Results
`
`10.75%"
`12.54')/o(b)
`3.92%"
`
`Supplier: a. Penick; b. EM Industries Inc; c. Fisher Scientific.
`
`11. Stability and Storage Conditions
`Aqueous solutions are subject to bacterial or enzymatic
`degradation but may be preserved by initially boiling the
`solution for a short time to inactivate any enzymes present;
`microwave irradiation can also be used.(I) Aqueous solutions
`may also be preserved by the addition of an antimicrobial
`preservative such as 0.1% w/v benzoic acid, 0.1% w/v sodium
`benzoate or a mixture of 0.17% w/v methylparaben and 0.03%
`propylparaben.
`Powdered acacia should be stored in an airtight container in a
`cool, dry, place.
`
`000003
`
`

`

`2 Acacia
`
`12. Incompatibilities
`Acacia is incompatible with a number of substances including
`amidopyrine, cresol, ethanol (95%), ferric salts, morphine,
`phenol, physostigmine, tannins, thymol, and vanillin.
`An oxidizing enzyme is present in acacia which may affect
`preparations containing easily oxidizable substances. The
`enzyme may however be inactivated by heating at 100°C for
`a short time, see Section 11.
`Many salts reduce the viscosity of aqueous acacia solutions,
`while trivalent salts may initiate coagulation. Aqueous
`solutions carry a negative charge and will form coacervates
`with gelatin and other substances. In the preparation of
`emulsions, solutions of acacia are incompatible with soaps.
`
`13. Method of Manufacture
`Acacia is the dried gummy exudate obtained from the stems
`and branches of Acacia senegal (Lime) Willdenow or other
`related species of Acacia (Fam. Leguminosae) which grow
`mainly in the Sudan and Senegal regions of Africa.
`The bark of the tree is incised and the exudate allowed to dry
`on the bark. The dried exudate is then collected, processed to
`remove bark, sand and other particulate matter, and graded.
`Various acacia grades differing in particle size and other
`physical properties are thus obtained. A spray-dried powder is
`also commercially available.
`
`14. Safety
`Acacia is used in cosmetics, foods, and oral and topical
`pharmaceutical formulations. Although generally regarded as
`an essentially nontoxic material, there have been a limited
`number of reports of hypersensitivity to acacia after inhalation
`or ingestion.(2'3) Severe anaphylactic reactions have occurred
`following the parenteral administration of acacia and it is now
`no longer used for this purpose.(2)
`The WHO has not set an acceptable daily intake for acacia as a
`food additive since the levels necessary to achieve a desired
`effect were not considered to represent a hazard to health.(4)
`LD50 (rabbit, oral): 8.0 g/kg(5)
`
`15. Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Acacia can be irritant to the
`eyes, skin, and upon inhalation. Gloves, eye protection and a
`dust respirator are recommended.
`
`16. Regulatory Status
`GRAS listed. Accepted for use in Europe as a food additive.
`Included in the FDA Inactive Ingredients Guide (oral
`preparations). Included in nonparenteral medicines licensed
`in the UK.
`
`17. Pharmacopeias
`Aust, Br, Cz, Egypt, Eur, Fr, Ger, Ind, It, Jpn, Neth, Nord,
`Port, Rom, Swiss, USPNF and Yug.
`See also Section 9.
`
`18. Related Substances
`Tragacanth.
`
`19. Comments
`Concentrated aqueous solutions are used to prepare pastilles
`since on drying they form solid rubbery, or glass-like masses
`depending upon the concentration used.
`
`20. Specific References
`1. Richards RME, Al Shawa R. Investigation of the effect of
`microwave irradiation on acacia powder. J Pharm Pharmacol
`1980; 32: 45P.
`2. Maytum CK, Magath TB. Sensitivity to acacia. JAMA 1932; 99:
`2251.
`3. Smolinske SC. Handbook of food, drug, and cosmetic excipients.
`Boca Raton, FL: CRC Press Inc, 1992: 7-11.
`4. FAO/WHO. Evaluation of certain food additives and contami-
`nants: thirty-fifth report of the joint FAO/WHO expert committee
`on food additives. Tech Rep Ser Wld Hlth Org 1990; No. 789.
`5. Sweet DV, editor. Registry of toxic effects of chemical substances.
`Cincinnati: US Department of Health, 1987.
`
`21. General References
`Anderson DMW, Dea ICM. Recent advances in the chemistry of
`acacia gums. J Soc Cosmet Chem 1971; 22: 61-76.
`Anderson DM, Douglas DM, Morrison NA, Wang WP. Specifications
`for gum arabic (Acacia Senegal): analytical data for samples
`collected between 1904 and 1989. Food Add Contam 1990; 7: 303-
`321.
`Aspinal GO. Gums and Mucilages. Adv Carbohydrate Chem Biochem
`1969; 24: 333-379.
`Whistler RL. Industrial gums. New York: Academic Press, 1959.
`
`22. Authors
`USA: E Shefter.
`
`000004
`
`

`

`Benzalkonium Chloride 27
`
`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
`employed 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
`hygroscopic, soapy to the touch and has a mild aromatic odor
`and very bitter taste.
`
`9. Pharmacopeia! Specifications
`
`Test
`Identification
`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
`of n-C14H29
`of n-C12H2.5 & n-C 141129
`for total alkyl content
`
`PhEur 1985
`
`USPNF
`
`10.0%
`
`0.1%
`
`15.0%
`2.0%
`
`7--
`
`95.0-104.0%
`
`40.0%
`20.0%
`70.0%
`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 benzalk-
`onium chloride is significantly dependent upon the alkyl
`composition of the homolog mixture.(1) Benzalkonium
`chloride is ineffective against some Pseudomonas aeruginosa
`strains, Mycobacterium tuberculosis, Trichophyton intetdigitale
`and T. rubrum. However, combined with disodium edetate
`(0.01-0.1% w/v), benzyl alcohol, phenylethanol or phenylpro-
`panol, the activity against Pseudomonas aeruginosa is
`increased.t21 Antimicrobial activity may also be enhanced by
`the addition of phenylmercuric acetate,phenylmercuric borate,
`chlorhexidine, cetrimide 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.
`Benzalkonium chloride is relatively inactive against spores and
`molds, but is active against some viruses, including HW.(5)
`Inhibitory activity increases with pH although antimicrobial
`activity occurs between pH 4-10. Typical minimum inhibitory
`concentrations (MICs) are shown in Table I.
`
`Benzalkonium Chloride
`
`1. Nonproprietary Names
`BP: Benzalkonium chloride
`PhEur: Benzalkonii chloridum
`USPNF: Benzalkonium chloride
`
`2. Synonyms
`Alkylbenzyldimethylammonium chloride; alkyl dimethyl ben-
`zyl ammonium chloride; BKC; Catigene DC 100; Exameen
`3580; Hyamine 3500; Pentonium; Roccal; Zephiran.
`
`3. Chemical Name and CAS Registry Number
`Alkyldimethyl(phenylmethypammonium chloride
`[8001-54-5]
`
`4. Empirical Formula Molecular Weight
`The USPNF XVII describes benzalkonium chloride as a
`mixture of alkylbenzyldimethylammonium chlorides of the
`general formula [C61-15CH2N(CH3)2R]C1, where R represents a
`mixture of alkyls, including all or some of the group beginning
`with n-05H17 and extending through higher homologs, with n-
`C 12E125, n-C14H29, and n-C16H33 comprising the major portion.
`The average molecular weight of benzalkonium chloride is 360.
`
`5. Structural Formula
`
`Cl .
`
`CH,
`I —R
`
`
`cI
`
`R — mixture of alkyls: n-C8H17 to n-C15H37; mainly n-C12H25
`(dodecyl), n-C14H29 (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
`preservative in applications similar to other cationic surfac-
`tants, 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
`edetate, to enhance its antimicrobial activity against strains of
`Pseudomonas.
`
`000005
`
`

`

`28 Benzalkonium Chloride
`
`Table I: Minimum inhibitory concentrations (MICs) of benzalkonium
`chloride.
`
`Microorganism
`
`MIC (p.g/mL)
`
`Aerobacter aerogenes
`Clostridium histolyticum
`Clostridium oedematiens
`Clostridium tetani
`Clostridium welchii
`Escherichia coli
`Pneumococcus II
`Proteus vulgaris
`Pseudomonas aeruginosa
`Salmonella enterilidis
`Salmonella paratyphi
`Salmonella typhosa
`Shigella dysenteriae
`Staphylococcus aureus
`Streptococcus pyrogenes
`Vibrio cholerae
`
`64
`5
`5
`5
`5
`16
`5
`64
`30
`30
`16
`4
`2
`1.25
`1.25
`2
`
`0.98 g/cm3 at 20°C
`Density: (cid:9)
`Melting point: .^ 40°C
`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
`temperature. 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.
`
`12. Incompatibilities
`Incompatible with aluminum, anionic surfactants, citrates,
`cotton, fluorescein, hydrogen peroxide, hydroxypropyl
`methylcellulose,(6) 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.
`
`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
`compound as it is formed.
`
`14. Safety
`Benzalkonium chloride is usually nonirritating, nonsensitizing
`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(8) and prolonged contact with the skin can
`occasionally cause irritation and hypersensitivity. Benzalk-
`onium chloride is also known to cause bronchoconstriction in
`some asthmatics when used in nebulizer solutions(9-13)
`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 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." 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 (guinea pig, oral): 200 mg/kg(15)
`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 benzalkoniurn
`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 Guide (inhalations,
`IM injections, nasal, ophthalmic, otic and topical prepara-
`tions). Included in nonparenteral medicines licensed in the
`UK.
`
`17. Pharmacopeias
`Aust, Br, Braz, Egypt, Eur, Fr, Gr, Hung, It, Jpn, Mex, Neth,
`Port, Swiss, Turk, Yug and USPNF. Also in BP Vet.
`
`18. Related Substances
`
`BenzPthonium Chloride; Cetrimide.
`
`19. Comments
`
`000006
`
`

`

`20. Specific References
`1. Euerby MR. High performance liquid chromatography of
`benzalkonium chlorides - variation in commercial prepara-
`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 synergism in vitro as displayed by
`mixtures of some commonly employed antibacterial preserva-
`tives. Can .1 Pharm Sci 1976; 11: 17-20.
`4. McCarthy TJ, Myburgh JA, Butler N. Further studies on the
`influence of formulation on preservative activity. Cosmet Toilet
`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. Smolinske SC. Handbook of food, drug, and cosmetic excipients.
`Boca Raton, FL: CRC Press Inc, 1992: 31-39.
`8. Honigman JL. Disinfectant ototoxicity [letter]. Pharm .1 1975;
`215: 523.
`9. Beasley CRW, Rafferty P, Holgate ST. Bronchoconstrictor
`properties of preservatives in ipratropium bromide (Atrovent)
`nebuliser solution. Br Med J 1987; 294: 1197-1198.
`10. Miszkiel KA, Beasley R, Rafferty P, Holgate ST. The
`contribution of histamine release to bronchoconstriction pro-
`voked by inhaled benzalkonium chloride in asthma. Br J Clin
`Pharmacol 1988; 25: 157-163.
`11. Miszkiel KA, Beasley R, Holgate ST. The influence of
`ipratropium bromide and sodium cromoglycate on benzalko-
`nium chloride-induced bronchoconstriction in asthma. Br .1 Clin
`Pharmacol 1988; 26: 295-301.
`12. Worthington I. Bronchoconstriction due to benzalkonium
`chloride in nebulizer solutions. Can J Hosp Pharm 1989; 42:
`165-166.
`13. Boucher M, Roy MT, Henderson J. Possible association of
`
`Benzalkonium Chloride 29
`
`benzalkonium chloride in nebulizer solutions with respiratory
`arrest. Ann Pharmacother 1992; 26: 772-774.
`14. Gasset AR. Benzalkonium chloride toxicity to the human cornea.
`Am J Ophthalmol 1977; 84: 169-171.
`15. Sweet DV, editor. Registry of toxic effects of chemical
`substances. 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 colt 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 ET, Perrin HI. 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. In: Doerge RF, editor. Wilson and
`Gisvold's textbook of organic, medicinal and pharmaceutical
`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 resistance
`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
`USA: NM Vemuri.
`
`000007
`
`

`

`30 Benzethonium Chloride
`
`Benzethonium Chloride
`
`1. Nonproprietary Names
`USP: Benzethonium chloride
`
`2. Synonyms
`Berizyldimethyl[242-(p-1,1,3,3-tetramethylbutylphe-
`noxy)ethoxyjethyllammonium chloride; BZT; diisobutylphe-
`noxyethoxyethyl dimethyl benzyl ammonium chloride;
`Hyamine 1622.
`
`3. Chemical Name and CAS Registry Number
`N,N-Dimethyl-N424244-(1,1,3,3-tetramethylbu-
`tyl)phenoxylethoxylethyl]benzene-methanaminium chloride
`[121-54-0]
`
`4. Empirical Formula Molecular Weight
`448.10
`C27H42C1NO2 (cid:9)
`
`5. Structural Formula
`
`CH, CH,
`1 (cid:9)
`I
`CH,CCH,C
`I (cid:9)
`I
`CH, CH,
`
`7H,
`
`OCH,CH,OCH,CHTCH
`
`CH,
`
`6. Functional Category
`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
`between 0.01-0.02% w/v. Benzethonium chloride may also be
`used as a wetting and solubilizing agent, and as a topical
`disinfectant.
`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 other cationic surfactants such as
`cetrimide.
`
`8. Description
`Benzethonium chloride occurs as a white crystalline material
`with a mild odor and very bitter taste.
`
`9. Pharmacopeial Specifications
`
`Test
`Identification
`Melting range (cid:9)
`Loss on drying (cid:9)
`Residue on ignition (cid:9)
`Ammonium compounds
`Assay (dried basis)
`
`USP XXII
`
`158-163°C
`5.0%
`0.1%
`
`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. Typical
`minimum inhibitory concentrations (MICs) are shown
`belowP)
`
`Microorganism
`Aspergillus niger
`Candida albicans
`Escherichia colt
`Penicillium notatum
`Proteus vulgaris
`Pseudomonas aeruginosa
`Pseudomonas cepacia
`Pseudomonas fluorescens
`Staphylococcus aureus
`Streptococcus pyogenes
`
`MIC (fig/mL)
`128
`64
`32
`64
`64
`250
`250
`250
`0.5
`0.5
`
`CI-
`
`Solubility: soluble I in less than 1 of acetone, chloroform,
`ethanol (95%) and water; soluble I in 6000 of ether. Dissolves
`in water to produce a foamy, soapy solution.
`
`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.
`
`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 fl,Or-dichlorodiethyl ether to yield 2424441,1,3,3-
`tetramethylbutyl)phenoxyjethoxylethyl chloride. Alkaline di-
`methylamination 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.(2)
`
`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.
`
`000008
`
`(cid:9)
`

`

`The topical use of solutions containing greater than 5% w/v
`benzethonium chloride can cause irritation although benzetho-
`nium 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.(3)
`See also Benzalkonium Chloride.
`LDso (mouse, IP): 8 mg/kg(4)
`LD50 (mouse, IV): 30 mg/kg
`LD50 (mouse, oral): 340 mg/kg
`LD50 (rat, IP): 17 mg/kg
`LD50 (rat, IV): 19 mg/kg
`LD50 (rat, oral): 370 mg/kg
`LD50 (rat, SC): 120 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 Guide (IM and IV
`injections, ophthalmic and otic preparations).
`
`17. Pharmacopeias
`Egypt, Jpn, Nord and US.
`
`Benzethonium Chloride 31
`
`18. Related Substances
`Benzalkonium Chloride; Cetrimide.
`
`19. Comments
`Benzethonium chloride has been used therapeutically in the
`past as a disinfectant 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.
`
`20. Specific References
`1. Wallhausser KR. Benzethonium chloride. In: Kabara II, editor.
`Cosmetic and drug preservation principles and practice. New York:
`Marcel Dekker Inc, 1984: 734-735.
`2. Remington's pharmaceutical sciences, 15th edition. Easton, PA:
`Mack Publishing Co, 1975: 1089.
`3. The Expert Panel of the American College of Toxicology. Final
`report on the safety assessment of benzethonium chloride and
`methylhenzethonium chloride. I Am Coll Toxicol 1985; 4: 65-106.
`4. Sweet DV, editor. Registry of toxic effects of chemical substances.
`Cincinnati: US Department of Health, 1987.
`
`21. General References
`
`22. Authors
`UK: P.1 Weller.
`
`000009
`
`

`

`r."
`
`Calcium Stearate 63
`
`SEM: 1
`Excipient Calcium stearate (Standard)
`Manufacturer: Durham Chemicals
`Lot No.: 0364
`Voltage: 20 kV
`
`SEM: 2
`Excipient: Calcium stearate (Precipitated)
`Manufacturer: Witco Corporation
`Lot No.: 0438
`Voltage: 12 kV
`
`Calcium Stearate
`
`1. Nonproprietary Names
`USPNF: Calcium stearate
`
`2. Synonyms
`Calcium distearate; HyQual; stearic acid, calcium salt.
`
`3. Chemical Name and CAS Registry Number
`Octadecanoic acid calcium salt [1592-23-0]
`
`4. Empirical Formula Molecular Weight
`607.03
`C36H70CaO4
`(for pure material)
`The USPNF XVII describes calcium stearate as a compound
`of calcium with a mixture of solid organic acids obtained from
`fats and consists chiefly of variable proportions of calcium
`stearate and calcium palmitate (C32H62CaO4). It contains the
`equivalent of 9.0-10.5% of calcium oxide.
`
`5. Structural Formula
`ICH3(CH2)16C0012Ca
`
`6. Functional Category
`Tablet and capsule lubricant.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Calcium stearate is primarily used in pharmaceutical formula-
`tions as a lubricant in tablet and capsule manufacture at
`concentrations up to 1.0% w/w. Although it has good
`antiadherent and lubricant properties, calcium stearate has
`poor glidant properties.
`Calcium stearate is also employed as an emulsifier, stabilizing
`agent and suspending agent. It is also used in cosmetics and
`food products.
`
`8. Description
`Calcium stearate occurs as a fine, white to yellowish white-
`colored, bulky powder having a slight, characteristic odor. It is
`unctuous and free from grittiness.
`
`9. Pharmacopeial Specifications
`
`Test (cid:9)
`Identification
`Loss on drying (cid:9)
`Arsenic (cid:9)
`Heavy metals (cid:9)
`Assay (as CaO)
`
`USPNF XVII (Suppl 5)
`
`4.0%
`3 ppm
`0.001%
`9.0-10.5%
`
`10. Typical Properties
`Acid value: 191-203
`Ash: 9.9-10.3%
`Chloride: < 200 ppm
`Density: 1.04 &in'
`
`000010
`
`(cid:9)
`(cid:9)
`

`

`64 Calcium Stearate
`
`SEM: 3
`Excipient: Calcium stearate (EA)
`Manufacturer: Witco Corporation
`Voltage: 12 kV
`
`SEM: 5
`Excipient: Calcium stearate
`Manufacturer: Mallinckrodt Speciality Chemicals Co
`Lot No.: JMP
`Magnification: 600x
`Voltage: 5 kV
`
`SEM: 4
`Excipient: Calcium stearate (Fused)
`Manufacturer: Witco Corporation
`Voltage: 15 kV
`
`SEM: 6
`Excipient: Calcium stearate
`Manufacturer: Mallinckrodt Speciality Chemicals Co
`Lot No.: JMP
`Magnification: 2400x
`Voltage: 5 kV
`
`000011
`
`

`

`Density (bulk & tapped):
`
`Bulk Density
`date
`
`Tapped Density
`gicon3
`
`Durham Chemicals
`(Standard)
`(A)
`(AM)
`Witco Corporation
`(EA)
`(Fused)
`(Precipitated)
`
`0.21
`0.38
`0.16
`
`0.26
`0.45
`0.33
`
`0.27
`0.48
`0.20
`
`Flowability: 21.2-22.6% (Carr compressibility index)
`Free fatty acid: 0.3-0.5%
`Melting point: 149-160°C
`Moisture content: see HPE Data.
`Particle size distribution: 1.7-60 ',Lin.
`100% through a 73.7 pm (#200 mesh); 99.5% through a
`44.5 pm (#325 mesh).
`Shear strength: 14.71 MPa
`Softening point: 160°C
`Solubility: practically insoluble in ethanol (95%), ether and
`water.
`Specific surface area: 5.76-7.44 m2/g
`Sulfate: < 0.25%
`
`HPE Laboratory Project Data
`Lab # (cid:9)
`Results
`Method (cid:9)
`2.96% (')
`MC-23 (cid:9)
`21 (cid:9)
`18 (cid:9)
`MC-12 (cid:9)
`2.97% (b)
`Supplier: a. Witco Corporation; b. Mallinckrodt Speciality Chemicals
`Co.
`
`Moisture content (cid:9)
`Moisture content (cid:9)
`
`Calcium Stearate 65
`
`13. Method of Manufacture
`Calcium stearate is prepared by the reaction of calcium
`chloride with a mixture of the sodium salts of stearic and
`palmitic acids. The calcium stearate formed is collected and
`washed with water to remove any sodium chloride.
`
`14. Safety
`Calcium stearate is used in oral pharmaceutical formulations
`and is generally regarded as a nontoxic and nonirritant
`material.
`
`15. Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Calcium stearate should be
`used in a well-ventilated environment; eye protection, gloves
`and a respirator are recommended.
`
`16. Regulatory Status
`GRAS listed. Included in the FDA Inactive Ingredients Guide
`(oral capsules and tablets). Included in nonparenteral
`medicines licensed in the UK.
`
`17. Pharmacopeias
`Jpn and USPNF.