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. Benzal- konium chloride is also known to cause bronchoconstriction in some asthmatics when used in nebulizer solutions.(13–17)

Toxicity experiments with rabbits have shown benzalk- onium 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 benzal- konium 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

Density: ≈0.98 g/cm at 208C

Melting point: ≈408C

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.

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.

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

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Benzalkonium chloride is

Benzalkonium Chloride 63 

irritant to the skin and eyes and repeated exposure to the skin may cause hypersensitivity. Concentrated benzalkonium chlor- ide 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.

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. It is also included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

Benzethonium chloride; cetrimide.

Comments

Benzalkonium chloride has been used in antiseptic wipes and has been shown to produce significantly less stinging or burn- ing 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.

Specific References

Sklubalova Z. Antimicrobial substances in ophthalmic drops.

Ceska Slov Form 2004; 53(3): 107–116.

Pisal SS, Poradkar AR, Mahadik KR, Kadam SS. Pluronic gels for nasal delivery of vitamin B. Int J Pharm 2004; 270(1–2): 37–45.

Nokodchi A, Shokri J, Dashbolaphi A, et al. The enhancement effect of surfactants in the penetration of lorazepam through rat skin. Int J Pharm 2003; 250(2): 359–369.

Euerby MR. High performance liquid chromatography of benzalkonium chlorides – variation in commercial preparations. J Clin Hosp Pharm 1985; 10: 73–77.

Richards RME, McBride RJ. Enhancement of benzalkonium chloride and chlorhexidine acetate activity against Pseudomonas aeruginosa by aromatic alcohols. J Pharm Sci 1973; 62: 2035– 2037.

Hugbo PG. Additivity and synergism in vitro as displayed by mixtures of some commonly employed antibacterial preservatives. Can J Pharm Sci 1976; 11: 17–20.

McCarthy TJ, Myburgh JA, Butler N. Further studies on the influence of formulation on preservative activity. Cosmet Toilet 1977; 92(3): 33–36.

Chermann JC, Barre-Sinoussi F, Henin Y, Marechal V. HIV inactivation by a spermicide containing benzalkonium. AIDS Forsch 1987; 2: 85–86.

Richards RME. Effect of hypromellose on the antibacterial activity of benzalkonium chloride. J Pharm Pharmacol 1976; 28: 264.

Bin T, Kulshreshtha AK, Al-Shakhshir R, Hem SL. Adsorption of benzalkonium chloride by filter membranes: mechanisms and effect of formulation and processing parameters. Pharm Dev Technol 1999; 4(2): 151–165.

Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipi- ents. Boca Raton, FL: CRC Press, 1992: 31–39.



Honigman JL. Disinfectant ototoxicity [letter]. Pharm J 1975; 215:

523.

Beasley CRW, Rafferty P, Holgate ST. Bronchoconstrictor proper- ties of preservatives in ipratropium bromide (Atrovent) nebuliser solution. Br Med J 1987; 294: 1197–1198.

Miszkiel KA, Beasley R, Rafferty P, Holgate ST. The contribution of histamine release to bronchoconstriction provoked by inhaled benzalkonium chloride in asthma. Br J Clin Pharmacol 1988; 25: 157–163.

Miszkiel KA, Beasley R, Holgate ST. The influence of ipratropium bromide and sodium cromoglycate on benzalkonium chloride- induced bronchoconstriction in asthma. Br J Clin Pharmacol 1988; 26: 295–301.

Worthington I. Bronchoconstriction due to benzalkonium chloride in nebulizer solutions. Can J Hosp Pharm 1989; 42: 165–166.

Boucher M, Roy MT, Henderson J. Possible association of benzalkonium chloride in nebulizer solutions with respiratory arrest. Ann Pharmacother 1992; 26: 772–774.

Gasset AR. Benzalkonium chloride toxicity to the human cornea.

Am J Ophthalmol 1977; 84: 169–171.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 104.

Pagnoni A, Spinelli G, Berger RS, 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.

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 Pharm 1985; 23: 239–243.

El-Falaha BMA, Russell AD, Furr JR, Rogers DT. Activity of benzalkonium chloride and chlorhexidine diacetate against wild- type and envelope mutants of Escherichia coli and Pseudomonas aeruginosa. Int J Pharm 1985; 25: 329–337.

Karabit MS, Juneskans OT, Lundgren P. Studies on the evaluation of preservative efficacy III: the determination of antimicrobial char- acteristics 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. In: Doerge RF, ed. Wilson and Gisvold’s Textbook of Organic, Medicinal and Pharmaceutical Chemistry. Philadelphia: JB Lippincott, 1982: 141–142.

Pense´ AM, Vauthier C, Puisieux F, Benoit JP. Microencapsulation of benzalkonium chloride. Int J Pharm 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. Wallha¨ usser KH. Benzalkonium chloride. In: Kabara JJ, ed. Cosmetic and Drug Preservation Principles and Practice. New York: Marcel

Dekker, 1984: 731–734.

Authors

AH Kibbe.

Date of Revision

12 August 2005.

Benzethonium Chloride

Nonproprietary Names

BP: Benzethonium chloride JP: Benzethonium chloride PhEur: Benzethonii chloridum USP: Benzethonium chloride

Synonyms

Benzyldimethyl-[2-[2-(p-1,1,3,3-tetramethylbutylphenoxy) ethoxy]ethyl]ammonium chloride; BZT; diisobutylphenoxy- ethoxyethyl dimethyl benzyl ammonium chloride; Hyamine 1622.

Chemical Name and CAS Registry Number

N,N-Dimethyl-N-[2-[2-[4-(1,1,3,3-tetramethylbutyl)phenoxy] ethoxy]ethyl]benzene-methanaminium chloride [121-54-0]

Empirical Formula and Molecular Weight

C27H42ClNO2 448.10

Structural Formula

 

Functional Category

Antimicrobial preservative; antiseptic; disinfectant.

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. 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

Benzethonium chloride occurs as a white crystalline material with a mild odor and very bitter taste.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for benzethonium chloride.

 

Test JP 2001 PhEur 2005 USP 28    

Identification + + +    

Characters — + —    

Appearance of — + —    

solution    

Acidity or alkalinity — + —    

Melting range 158–1648C 158–1648C 158–1638C    

Loss on drying 45.0% 45.0% 45.0%    

Residue on ignition 40.1% — 40.1%    

Sulfated ash — 40.1% —    

Ammonium

compounds + 450 ppm +    

Assay (dried basis) 597.0% 97.0–103.0% 97.0–103.0%  

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.(1)

Table II: Minimum inhibitory concentration (MIC) for benzethonium chloride.

Microorganism MIC (mg/mL)

Proteus vulgaris 64

Pseudomonas aeruginosa 250

Pseudomonas cepacia 250

Pseudomonas fluorescens 250

Staphylococcus aureus 0.5

Streptococcus pyogenes 0.5

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.

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.

Benzethonium Chloride 65 

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.

Method of Manufacture

p-Diisobutylphenol is condensed in the presence of a basic catalyst with b,b'-dichlorodiethyl ether to yield 2-[2-[4- (1,1,3,3-tetramethylbutyl)phenoxy]ethoxy]ethyl chloride. Alkaline dimethylamination 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)

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 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 injec- tions and ophthalmic preparations.(3)

See also Benzalkonium Chloride.

LD50 (mouse, IP): 15.5 mg/kg(4) 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

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and gloves are recommended.



Regulatory Status

Included in the FDA Inactive Ingredients Guide (IM and IV injections, ophthalmic and otic preparations). Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Benzalkonium chloride; cetrimide.

Comments

Benzethonium chloride has been used therapeutically 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.

The EINECS number for benzethonium chloride is 204- 479-9.

Specific References

Wallha¨ usser KH. Benzethonium chloride. In: Kabara JJ, ed. Cosmetic and Drug Preservation Principles and Practice. New York: Marcel Dekker, 1984: 734–735.

Gennaro AR, ed. Remington: The Science and Practice of Pharmacy, 20th edn. Baltimore: Lippincott Williams and Wilkins, 2000: 1508.

The Expert Panel of the American College of Toxicology. Final report on the safety assessment of benzethonium chloride and methylbenzethonium chloride. J Am Coll Toxicol 1985; 4: 65–106.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 407.

General References

—

Authors

LME McIndoe.

Date of Revision

12 August 2005.

Benzoic Acid

Nonproprietary Names

BP: Benzoic acid JP: Benzoic acid

PhEur: Acidum benzoicum USP: Benzoic acid

Synonyms

Benzenecarboxylic acid; benzeneformic acid; carboxybenzene;

Description

Benzoic acid occurs as feathery, light, white or colorless crystals or powder. It is essentially tasteless and odorless or with a slight characteristic odor suggestive of benzoin.

Pharmacopeial Specifications

See Table II.

Table II:  Pharmacopeial specifications for benzoic acid.

dracylic acid; E210; phenylcarboxylic acid; phenylformic acid.

Test JP 2001 PhEur 2005 USP 28

Chemical Name and CAS Registry Number

Benzoic acid [65-85-0]

Empirical Formula and Molecular Weight

C7H6O2 122.12

Structural Formula

 

Functional Category

Antimicrobial preservative; therapeutic agent.

Applications in Pharmaceutical Formulation or Technology

Benzoic acid is widely used in cosmetics, foods, and pharma- ceuticals (see Table I), as an antimicrobial preservative.(1–3) Greatest activity is seen at pH values between 2.5–4.5; see Section 10.

Benzoic acid also has a long history of use as an antifungal agent(4) in topical therapeutic preparations such as Whitfield’s ointment (benzoic acid 6% and salicylic acid 3%).

Table I: Uses of benzoic acid.

Use Concentration (%)

IM and IV injections 0.17

Oral solutions 0.01–0.1

Oral suspensions 0.1

Oral syrups 0.15

Topical preparations 0.1–0.2

Vaginal preparations 0.1–0.2



compounds and halides

Appearance of solution — + —

Assay 599.5% 99.0–100.5%  99.5–100.5%

Typical Properties

Acidity/alkalinity: pH = 2.8 (saturated aqueous solution at 258C)

Antimicrobial activity: only the undissociated acid shows antimicrobial properties, the activity therefore depends on the pH of the medium. Optimum activity occurs at pH values below 4.5; at values above pH 5, benzoic acid is almost inactive.(5) It has been reported that antimicrobial activity is enhanced by the addition of protamine, a basic protein.(6)

Bacteria: moderate bacteriostatic activity against most species of Gram-positive bacteria. Typical MIC is 100 mg/mL. Activity is less, in general, against Gram- negative bacteria. MIC for Gram-negative bacteria may be up to 1600 mg/mL.

Molds: moderate activity. Typical MICs are 400–1000 mg/mL at pH 3; 1000–2000 mg/mL at pH 5.

Spores: inactive against spores.

Yeasts: moderate activity. Typical MIC is 1200 mg/mL. The addition of propylene glycol may enhance the fungistatic activity of benzoic acid.

Autoignition temperature: 5708C

Boiling point: 249.28C

Density:

1.311 g/cm3 for solid at 248C;

1.075 g/cm3 for liquid at 1308C.

Dissociation constant: the dissociation of benzoic acid in mixed solvents is dictated by specific solute–solvent interactions as

Benzoic Acid 67 

well as by relative solvent basicity. Increasing the organic solvent fraction favors the free acid form.(7)

pKa = 4.19 at 258C;

pKa = 5.54 in methanol 60%.

Flash point: 121–1318C

Melting point: 1228C (begins to sublime at 1008C).

Moisture content: 0.17–0.42% w/w

Partition coefficients:

Benzene : water = 0.0044;(8) Cyclohexane : water = 0.30;(9) Octanol : water = 1.87.(10)

Refractive index:

n15 = 1.5397 for solid;

n132 = 1.504 for liquid.

Solubility: apparent aqueous solubility of benzoic acid may be enhanced by the addition of citric acid or sodium acetate to the solution; see Table III.

Table III: Solubility of benzoic acid.

Solvent Solubility at 258C unless otherwise stated

Acetone 1 in 2.3

Benzene 1 in 9.4

Carbon disulfide 1 in 30

Carbon tetrachloride 1 in 15.2

Chloroform 1 in 4.5

Cyclohexane 1 in 14.6(9)

Ethanol 1 in 2.7 at 158C

1 in 2.2

Ethanol (76%) 1 in 3.72(11)

Ethanol (54%) 1 in 6.27(11)

Ethanol (25%) 1 in 68(11)

Ether 1 in 3

Fixed oils Freely soluble

Methanol 1 in 1.8

Toluene 1 in 11

Water 1 in 300

Stability and Storage Conditions

Aqueous solutions of benzoic acid may be sterilized by autoclaving or by filtration.

A 0.1% w/v aqueous solution of benzoic acid has been reported to be stable for at least 8 weeks when stored in polyvinyl chloride bottles, at room temperature.(12)

When added to a suspension, benzoic acid dissociates, with the benzoate anion adsorbing onto the suspended drug particles. This adsorption alters the charge at the surface of the particles, which may in turn affect the physical stability of the suspension.(13)

The bulk material should be stored in a well-closed container in a cool, dry place.

Incompatibilities

Undergoes typical reactions of an organic acid, e.g. with alkalis or heavy metals. Preservative activity may be reduced by interaction with kaolin.(14)

Method of Manufacture

Although benzoic acid occurs naturally, it is produced commercially by several synthetic methods. One process involves the continuous liquid-phase oxidation of toluene in



the presence of a cobalt catalyst at 150–2008C and 0.5–5.0 MPa (5.0–50.0 atm) pressure to give a yield of approximately 90% benzoic acid.

Benzoic acid can also be produced commercially from benzotrichloride or phthalic anhydride. Benzotrichloride, produced by chlorination of toluene, is reacted with 1 mole of benzoic acid to yield 2 moles of benzoyl chloride. The benzoyl chloride is then converted to 2 moles of benzoic acid by hydrolysis. Yield is 75–80%.

In another commercial process, phthalic anhydride is converted to benzoic acid, in about an 85% yield, by hydrolysis in the presence of heat and chromium and disodium phthalates. Crude benzoic acid is purified by sublimation or recrystalli-

zation.

Safety

Ingested benzoic acid is conjugated with glycine in the liver to yield hippuric acid, which is then excreted in the urine;(15) care should be taken when administering benzoic acid to patients with chronic liver disease.(16) Benzoic acid is a gastric irritant, and a mild irritant to the skin.(17–19) It is also a mild irritant to the eyes and mucous membranes.(20) Allergic reactions to benzoic acid have been reported, although a controlled study indicated that the incidence of urticaria in patients given benzoic acid is no greater than in those given a lactose placebo.(21)

The WHO acceptable daily intake of benzoic acid and other benzoates, calculated as benzoic acid, has been set at up to 5 mg/kg body-weight.(22,23) The minimum lethal human oral dose of benzoic acid is 500 mg/kg body-weight.(24)

LD50 (cat, oral): 2 g/kg(24) LD50 (dog, oral): 2 g/kg LD50 (mouse, IP): 1.46 g/kg

LD50 (mouse, oral): 1.94 g/kg LD50 (rat, oral): 1.7 g/kg

See also Sodium benzoate.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Benzoic acid may be harmful by inhalation, ingestion, or skin absorption and may be irritant to the eyes, skin, and mucous membranes. Benzoic acid should be handled in a well-ventilated environment; eye protection, gloves, and a dust mask or respirator are recommended. Benzoic acid is flammable.

Regulatory Status

GRAS listed. Accepted as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (IM and IV injections, irrigation solutions, oral solutions, suspensions, syrups and tablets, rectal, topical, and vaginal preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Potassium benzoate; sodium benzoate.

Comments

Benzoic acid is known to dimerize in many nonpolar solvents. This property, coupled with pH-dependent dissociation in

68 Benzoic Acid

aqueous media, comprises a classic textbook example of the effects of dissociation and molecular association on apparent partitioning behavior. The principles involved may be practi- cally applied in determination of the total concentration of benzoate necessary to provide a bacteriostatic level of benzoic acid in the aqueous phase of an oil-in-water emulsion.

A specification for benzoic acid is contained in the Food Chemicals Codex (FCC).

The EINECS number for benzoic acid is 200-618-2.

Specific References

Buzzi MM, Marth EH. Characteristics of sodium benzoate injury of Listeria monocytogenes. Microbios 1992; 700: 199–207.

Elder DJ, Kelly DJ. The bacterial degradation of benzoic acid and benzenoid compounds under anaerobic conditions: unifying trends and new perspectives. FEMS Microbiol Rev 1994; 13(4): 441–468.

Hwang CA, Beuchat LR. Efficacy of a lactic acid/sodium benzoate wash solution in reducing bacterial contamination in raw chicken. Int J Food Microbiol 1995; 27(1): 91–98.

Burlini N, Pellegrine R, Facheris P, et al. Metabolic effects of benzoate and sorbate in the yeast Saccharomyes cerevisiae at neutral pH. Arch Microbiol 1993; 159(3): 220–224.

Hurwitz SJ, McCarthy TJ. The effect of pH and concentration on the rates of kill of benzoic acid solutions against E. coli. J Clin Pharm Ther 1987; 12: 107–115.

Boussard P, Devleeschouwer MJ, Dony J. In vitro modification of antimicrobial efficacy by protamine. Int J Pharm 1991; 72: 51–55.

Ghosh SK, Hazra DK. Solvent effects on the dissociation of benzoic acid in aqueous mixtures of 2-methoxyethanol and 1,2- dimethoxyethane at 258C. J Chem Soc Perkin Trans 1989; 2: 1021–1024.

Pawlowski W, Wieckowska E. Hydration of benzoic acid in benzene solution II: calculation of hydration constant. Z Phys Chem 1990; 168: 205–215.

Dearden JC, Roberts MJ. Cyclohexane–water partition coeffi- cients of some pharmaceuticals. J Pharm Pharmacol 1989; 41: 102P.

Yalkowsky SH, Valvani SC, Roseman TJ. Solubility and partition- ing VI: octanol solubility and octanol–water partition coefficients. J Pharm Sci 1983; 72: 866–870.

Pal A, Lahiri SC. Solubility and the thermodynamics of transfer of benzoic acid in mixed solvents. Indian J Chem 1989; 28A: 276– 279.

The Pharmaceutical Society of Great Britain, Department of Pharmaceutical Sciences. Plastic medicine bottles of rigid PVC. Pharm J 1973; 210: 100.

Gallardo V, Salcedo J, Parera A, Delgado A. Effect of the preservatives antipyrin, benzoic acid and sodium metabisulfite

on properties of the nitrofurantoin/solution interface. Int J Pharm

1991; 71: 223–227.

Clarke CD, Armstrong NA. Influence of pH on the adsorption of benzoic acid by kaolin. Pharm J 1972; 209: 44–45.

Tremblay GC, Qureshi IA. The biochemistry and toxicology of benzoic acid metabolism and its relationship to the elimination of waste nitrogen. Pharmacol Ther 1993; 60(1): 63–90.

Yamada S, Yamamota T, Suou T, et al. Clinical significance of benzoate-metabolizing capacity in patients with chronic liver disease: pharmacokinetic analysis. Res Commun Chem Pathol Pharmacol 1992; 76(1): 53–62.

Downward CE, Roberts LJ, Morrow JD. Topical benzoic acid induces the increased biosynthesis of PGD2 in human skin in vivo. Clin Pharmacol Ther 1995; 57(4): 441–445.

Lahti A, Pylvanen V, Hannuksels M. Immediate irritant reactions to benzoic acid are enhanced in washed skin areas. Contact Dermatitis 1996; 35(1): 51.

Munoz FJ, Bellido J, Moyano JC, et al. Perioral contact urticaria from sodium benzoate in a toothpaste. Contact Dermatitis 1996; 35(1): 51.

Takeichi Y, Kimura T. Improvement of aqueous solubility and rectal absorption of 6-mercaptopurine by addition of sodium benzoate. Biol Pharm Bull 1994; 17(10): 1391–1394.

Lahti A, Hannuksela M. Is benzoic acid really harmful in cases of atopy and urticaria? Lancet 1981; ii: 1055.

FAO/WHO. Toxicological evaluation of certain food additives with a review of general principles and of specifications. Seventeenth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1974; No. 539.

FAO/WHO. Evaluation of certain food additives and contami- nants. Twenty-seventh report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1983; No. 696.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials,

11th edn. New York: Wiley, 2004: 379.

General References

Garrett ER, Woods OR. The optimum use of acid preservatives in oil– water systems: benzoic acid in peanut oil–water. J Am Pharm Assoc (Sci) 1953; 42: 736–739.

Authors

PJ Weller.

Date of Revision

14 August 2005.

Benzyl Alcohol

Nonproprietary Names

BP: Benzyl alcohol JP: Benzyl alcohol

PhEur: Alcohol benzylicus USPNF: Benzyl alcohol

Synonyms

Benzenemethanol; a-hydroxytoluene; phenylcarbinol; phenyl- methanol; a-toluenol.

Chemical Name and CAS Registry Number

Benzenemethanol [100-51-6]

Empirical Formula and Molecular Weight

C7H8O 108.14

Structural Formula

 

Functional Category

Antimicrobial preservative; disinfectant; solvent.

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. 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 derma- tological 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 recom- mended 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.

Description

A clear, colorless, oily liquid with a faint aromatic odor and a sharp, burning taste.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for benzyl alcohol.

 

Test JP 2001 PhEur 2005 USPNF 23    

Identification + + +    

Characters + + —    

Solubility — + —    

Acidity + + +    

Clarity of solution + + —    

Specific gravity 1.043–1.053 1.043–1.049 1.042–1.047    

Distilling range 202.5–206.58C — —    

Refractive index 1.538–1.541 1.538–1.541 1.539–1.541    

Residue on ignition 40.005% — 40.005%    

Nonvolatile matter — 40.05% 41 mg    

Chlorinated + — 40.03%    

compounds    

Benzaldehyde + + 40.2%    

Peroxide value — 45 —    

Organic volatile — — +    

impurities    

Assay 598.0% 98.0–100.5% 97.0–100.5%  

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 hydroxybenzo- ate esters or quaternary ammonium compounds. The activity of benzyl alcohol may also be reduced by incompatibilities with some packaging materials, particu- larly polyethylene; see Section 12.

See Table II for reported minimum inhibitory concentra- tions (MICs).

Table II: Minimum inhibitory concentrations (MICs) of benzyl alcohol.(4)

Microorganism MIC (mg/mL)

Aspergillus niger 5000

Candida albicans 2500

Escherichia coli 2000

Pseudomonas aeruginosa 2000

Staphylococcus aureus 25

Bacteria: benzyl alcohol is moderately active against most Gram-positive organisms (typical MICs are 3–5 mg/mL), although some Gram-positive bacteria are very sensitive

70 Benzyl Alcohol

(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.

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; Peanut oil : water = 1.3.

Solubility: see Table III.

Table III: Solubility of benzyl alcohol.

Solvent Solubility at 208C unless otherwise stated

Chloroform Miscible in all proportions

Ethanol Miscible in all proportions

Ethanol (50%) 1 in 2.5

Ether Miscible in all proportions Fixed and volatile oils Miscible in all proportions Water 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

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; exceptions to this include polypropylene containers or vessels coated with inert fluori- nated polymers such as Teflon; see Section 12.

Benzyl alcohol should be stored in an airtight container, protected from light, in a cool, dry place.

Incompatibilities

Benzyl alcohol is incompatible with oxidizing agents and strong acids. It can also accelerate the autoxidation of fats.

Although antimicrobial activity is reduced in the presence of nonionic surfactants, such as polysorbate 80, the reduction is less than is the case with hydroxybenzoate esters or quaternary ammonium compounds.

Benzyl alcohol is incompatible with methylcellulose and is only slowly sorbed by closures composed of natural rubber, neoprene, and butyl rubber closures, the resistance of which can be enhanced by coating with fluorinated polymers.(5)



However, a 2% v/v aqueous solution in a polyethylene container, stored at 208C, may lose up to 15% of its benzyl alcohol content in 13 weeks.(6) Losses to polyvinyl chloride and polypropylene containers under similar conditions are usually negligible. Benzyl alcohol can damage polystyrene syringes by extracting some soluble components.(7)

Method of Manufacture

Benzyl alcohol is prepared commercially by the distillation of benzyl chloride with potassium or sodium carbonate. It may also be prepared by the Cannizzaro reaction of benzaldehyde and potassium hydroxide.

Safety

Benzyl alcohol is used in a wide variety of pharmaceutical 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 head- ache, vertigo, nausea, vomiting, and diarrhea. Overexposure may result in CNS depression and respiratory failure. However, the concentrations of benzyl alcohol normally employed as a preservative are not associated with such adverse effects.

Reports of adverse reactions to benzyl alcohol(8,9) used as an excipient include toxicity following intravenous administra- tion;(10,11) neurotoxicity in patients administered benzyl alcohol in intrathecal preparations;(12) hypersensitivity,(13,14) although relatively rare; and a fatal toxic syndrome in premature infants.(15–17)

The fatal toxic syndrome in low-birth-weight neonates, which includes symptoms of metabolic acidosis and respiratory depression, 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.(18,19)

The WHO has set the estimated acceptable daily intake of the benzyl/benzoic moiety at up to 5 mg/kg body-weight daily.(20)

LD50 (mouse, IV): 0.32 g/kg(21) 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

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 environ- ment; a self-contained breathing apparatus is recommended in areas of poor ventilation. Benzyl alcohol is flammable.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (dental injections, oral capsules, solutions and tablets, topical, and vaginal preparations). Included in parenteral and nonparent- eral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Benzyl Alcohol 71 

Related Substances

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Comments

The EINECS number for benzyl alcohol is 202-859-9.

Specific References

Croshaw B. Preservatives for cosmetics and toiletries. J Soc Cosmet Chem 1977; 28: 3–16.

Karabit MS, Juneskans OT, Lundgren P. Studies on the evaluation of preservative efficacy II: the determination of antimicrobial characteristics of benzyl alcohol. J Clin Hosp Pharm 1986; 11: 281–289.

Shah AK, Simons KJ, Briggs CJ. Physical, chemical, and bioavailability studies of parenteral diazepam formulations con- taining propylene glycol and polyethylene glycol 400. Drug Dev Ind Pharm 1991; 17: 1635–1654.

Wallha¨ usser KH. Benzyl alcohol. In: Kabara JJ, ed. Cosmetic and Drug Preservation Principles and Practice. New York: Marcel Dekker, 1984: 627–628.

Royce A, Sykes G. Losses of bacteriostats from injections in rubber-closed containers. J Pharm Pharmacol 1957; 9: 814–823.

Roberts MS, Polack AE, Martin G, Blackburn HD. The storage of selected substances in aqueous solution in polyethylene containers: the effect of some physicochemical factors on the disappearance kinetics of the substances. Int J Pharm 1979; 2: 295–306.

Doull J, Klaassen CD, Amdur MO, eds. Casarett and Doull’s Toxicology: The Basic Science of Poisons. New York: Macmillan, 1980.

Reynolds RD. Nebulizer bronchitis induced by bacteriostatic saline [letter]. J Am Med Assoc 1990; 264: 35.

Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipi- ents. Boca Raton, FL: CRC Press, 1992: 47–54.

Evens RP. Toxicity of intravenous benzyl alcohol [letter]. Drug Intell Clin Pharm 1975; 9: 154–155.

Lo´ pez-Herce J, Bonet C, Meana A, Albajara L. Benzyl alcohol poisoning following diazepam intravenous infusion [letter]. Ann Pharmacother 1995; 29: 632.

Hahn AF, Feasby TE, Gilbert JJ. Paraparesis following intrathecal chemotherapy. Neurology 1983; 33: 1032–1038.

Grant JA, Bilodeau PA, Guernsey BG, Gardner FH. Unsuspected benzyl alcohol hypersensitivity [letter]. N Engl J Med 1982; 306: 108.

Wilson JP, Solimando DA, Edwards MS. Parenteral benzyl alcohol-induced hypersensitivity reaction. Drug Intell Clin Pharm 1986; 20: 689–691.