med 11

FAO/WHO. Evaluation of certain food additives. Twenty-third report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1980; No. 648.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 398–399.

General References

Akers MJ. Considerations in selecting antimicrobial preservative agents for parenteral product development. Pharm Technol 1984; 8(5): 36–40, 43, 44, 46.

Bloomfield SF. Control of microbial contamination part 2: current problems in preservation. Br J Pharm Pract 1986; 8: 72, 74–76, 78,

80.

Carter DV, Charlton PT, Fenton AH, et al. The preparation and the antibacterial and antifungal properties of some substituted benzyl alcohols. J Pharm Pharmacol 1958; 10 (Suppl.): 149T–159T.

Harrison SM, Barry BW, Dugard PH. Benzyl alcohol vapour diffusion through human skin: dependence on thermodynamic activity in the vehicle. J Pharm Pharmacol 1982; 34 (Suppl.): 36P.

Russell AD, Jenkins J, Harrison IH. The inclusion of antimicrobial agents in pharmaceutical products. Adv Appl Microbiol 1967; 9: 1–

38.

Sklubalova Z. Antimicrobial substances in ophthalmic drops. Ceska Slov Form 2004; 53(3): 107–116.

BP: Benzyl benzoate JP: Benzyl benzoate

PhEur: Benzylis benzoas USP: Benzyl benzoate

Synonyms

Benzoic acid benzyl ester; benzylbenzenecarboxylate; benzyl phenylformate.

Chemical Name and CAS Registry Number

Benzoic acid phenylmethyl ester [120-51-4]

9 Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for benzyl benzoate.

Test JP 2001 PhEur 2005 USP 28

Identification + + +

Characters + + —

Specific gravity ≈1.123 1.118–1.122 1.116–1.120

Congealing ≈178C 517.08C 518.08C

temperature

Boiling point ≈3238C ≈3208C —

Refractive index 1.568–1.570 1.568–1.570 1.568–1.570

Aldehyde — — 40.05%

Acidity + + +

Sulfated ash 40.05% 40.1% —

Empirical Formula and Molecular Weight

Assay 599.0% 99.0–100.5% 99.0–100.5%

Structural Formula

Functional Category

Plasticizer; solubilizing agent; solvent; therapeutic agent.

Applications in Pharmaceutical Formulation or Technology

Benzyl benzoate is used as a solubilizing agent and nonaqueous solvent in intramuscular injections at concentrations of 0.01–46.0% v/v,(1) and as a solvent and plasticizer for cellulose and nitrocellulose. It is also used in the preparation of spray- dried powders using nanocapsules.(2)

However, the most widespread pharmaceutical use of benzyl benzoate is as a topical therapeutic agent in the treatment of scabies.(3) Benzyl benzoate is also used therapeutically as a parasiticide in veterinary medicine.(4)

Other applications of benzyl benzoate include its use as a pediculicide and as a solvent and fixative for flavors and perfumes in cosmetics and food products.

Description

Benzyl benzoate is a clear, colorless, oily liquid with a slightly aromatic odor. It produces a sharp, burning sensation on the tongue. At temperatures below 178C it exists as clear, colorless crystals.

Typical Properties

Autoignition temperature: 4818C

Boiling point: 3238C Flash point: 1488C Freezing point: 178C

Refractive index: n21 = 1.5681

Solubility: practically insoluble in glycerin and water; miscible with chloroform, ethanol (95%), ether, and with fatty acids and essential oils.

Specific gravity: 1.12

Vapor density (relative): 7.3 (air = 1)

Stability and Storage Conditions

Benzyl benzoate is stable when stored in tight, well-filled, light- resistant containers. Exposure to excessive heat (above 408C) should be avoided.

Incompatibilities

Benzyl benzoate is incompatible with alkalis and oxidizing agents.

Method of Manufacture

Benzyl benzoate is a constituent of Peru balsam and occurs naturally in certain plant species. Commercially, benzyl benzoate is produced synthetically by the dry esterification of sodium benzoate and benzoyl chloride in the presence of triethylamine or by the reaction of sodium benzylate with benzaldehyde.

Benzyl Benzoate 73

Safety

Benzyl benzoate is metabolized by rapid hydrolysis to benzoic acid and benzyl alcohol. Benzyl alcohol is then further metabolized to hippuric acid, which is excreted in the urine.

Benzyl benzoate is widely used as a 25% v/v topical application in the treatment of scabies and as an excipient in intramuscular injections and oral products. Adverse reactions to benzyl benzoate include skin irritation and hypersensitivity reactions. Oral ingestion may cause harmful stimulation of the CNS and convulsions.

LD50 (cat, oral): 2.24 g/kg(5–7) LD50 (guinea pig, oral): 1.0 g/kg LD50 (mouse, oral): 1.4 g/kg LD50 (rabbit, oral): 1.68 g/kg LD50 (rabbit, skin): 4.0 g/kg LD50 (rat, oral): 0.5 g/kg

LD50 (rat, skin): 4.0 g/kg

Handling Precautions

Benzyl benzoate may be harmful if ingested and is irritating to the skin, eyes, and mucous membranes. Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection, gloves, and a respirator are recommended. It is recommended that benzyl benzoate is handled in a fume cupboard. Benzyl benzoate is flammable.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (IM injections and oral capsules). Included, as an active ingredient, in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

—

Comments

The EINECS number for benzyl benzoate is 204-402-9.

Specific References

Spiegel AJ, Noseworthy MM. Use of nonaqueous solvents in parenteral products. J Pharm Sci 1963; 52: 917–927.

Guterres SS, Weiss V, de Lucca Freitas L, Pohlmann AR. Influence of benzyl benzoate as oil core on the physicochemical properties of spray-dried powders from polymeric nanocapsules containing indomethacin. Drug Deliv 2000; 7(4): 195–199.

Gilman AG, Rall TW, Nies AS, et al, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 8th edn. New York: Pergamon Press, 1990: 1630.

Bishop Y, ed. The Veterinary Formulary, 6th edn. London: Pharmaceutical Press, 2005: 56.

Graham BE, Kuizenga MH. Toxicity studies on benzyl benzoate and related benzyl compounds. J Pharmacol Exp Ther 1945; 84: 358–362.

Draize JH, Alvarez E, Whitesell MF, et al. Toxicological investiga- tions of compounds proposed for use as insect repellents. J Pharmacol Exp Ther 1948; 93: 26–39.

Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. Cincinnati: US Department of Health, 1987: 965.

General References

Gupta VD, Ho HW. Quantitative determination of benzyl benzoate in benzyl benzoate lotion NF. Am J Hosp Pharm 1976; 33: 665–666. Hassan MMA, Mossa JS. Benzyl benzoate. In: Florey K, ed. Analytical Profiles of Drug Substances, volume 10. New York: Academic

BP: Boric acid JP: Boric acid

PhEur: Acidum boricum

Table I: Pharmacopeial specifications for boric acid.

Test JP 2001 PhEur 2005 USPNF 23

Identification + + +

USPNF: Boric acid

Synonyms

Boracic acid; boraic acid; Borofax; boron trihydroxide; E284; orthoboric acid; trihydroxyborene.

Appearance of solution

+ + —

Chemical Name and CAS Registry Number

Orthoboric acid [10043-35-3]

Metaboric acid [13460-50-9]

Empirical Formula and Molecular Weight

H3BO3 61.83 (for trihydrate) HBO2 43.82 (for monohydrate)

Structural Formula

H3BO3

Functional Category

Antimicrobial preservative.

Applications in Pharmaceutical Formulation or Technology

Boric acid is used as an antimicrobial preservative in eye drops,(1,2) cosmetic products,(3) ointments,(4,5) and topical creams.(6) It is also used as an antimicrobial preservative in foods.

Boric acid has also been used therapeutically in the form of suppositories to treat yeast infections,(7–9) and in dilute concentrations as a mild antiseptic, although it has been superseded by more effective and less toxic disinfectants.(10) See Section 14.

Boric acid and borate have good buffering capacity and are used to control pH; they have been used for this purpose in external preparations such as eye drops.(11)

Description

Boric acid occurs as a hygroscopic, white crystalline powder, colorless shiny plates, or white crystals.

Pharmacopeial Specifications

See Table I.

Typical Properties

Acidity/alkalinity: pH = 3.5–4.1 (5% w/v aqueous solution)

Density: 1.435

Melting point: 170.98C. When heated slowly to 181.08C, boric acid loses water to form metaboric acid (HBO2); at 1408C, tetraboric acid (H2B4O7) is formed; and at higher tempera- tures, boron trioxide (B2O3) is formed.(12)

Solubility: miscible with ethanol, ether, glycerin, water, and other fixed and volatile oils. Solubility in water is increased by addition of hydrochloric, citric, or tartaric acids.

Specific gravity: 1.517

Stability and Storage Conditions

Boric acid is hygroscopic and should therefore be stored in an air-tight, sealed container. The container must be labeled ‘Not for Internal Use’.

Incompatibilities

Boric acid is incompatible with water, strong bases and alkali metals. It reacts violently with potassium and acid anhydrides. It also forms a complex with glycerin, which is a stronger acid than boric acid.

Method of Manufacture

Boric acid occurs naturally as the mineral sassolite. However, the majority of boric acid is produced by reacting inorganic borates with sulfuric acid in an aqueous medium. Sodium borate and partially refined calcium borate (colemanite) are the principal raw materials. When boric acid is made from colemanite, the fine-ground ore is vigorously stirred with mother liquor and sulfuric acid at about 908C. The by-product calcium sulfate is removed by filtration, and the boric acid is crystallized by cooling the filtrate.

Safety

Boric acid is a weak bacteriostatic and antimicrobial agent, and has been used in topical preparations such as eye lotions,

Boric Acid 75

mouthwashes and gargles. It has also been used in US- and Japanese-approved intravenous products. Solutions of boric acid were formerly used to wash out body cavities, and as applications to wounds and ulcers, although the use of boric acid for these purposes is now regarded as inadvisable owing to the possibility of absorption.(13) Boric acid is not used internally owing to its toxicity. It is poisonous by ingestion and moderately toxic by skin contact. Experimentally it has proved to be toxic by inhalation and subcutaneous routes, and moderately toxic by intraperitoneal and intravenous routes.

Boric acid is absorbed from the gastrointestinal tract and from damaged skin, wounds, and mucous membranes, although it does not readily permeate intact skin. The main symptoms of boric acid poisoning are abdominal pain, diarrhea, erythematous rash involving both skin and mucous membrane, and vomiting. These symptoms may be followed by desquamation, and stimulation or depression of the central nervous system. Convulsions, hyperpyrexia, and renal tubular damage have been known to occur.

Death has occurred from ingestion of less than 5 g in young children, and of 5–20 g in adults. Fatalities have occurred most frequently in young children after the accidental ingestion of solutions of boric acid, or after the application of boric acid powder to abraded skin.

The permissible exposure limit (PEL) of boric acid is 15 mg/m3 total dust, and 5 mg/m3 respirable fraction for nuisance dusts.(14)

LD50 (mouse, oral): 3.45 g/kg(15) LD50 (mouse, IV): 1.24 g/kg LD50 (mouse, SC): 1.74 g/kg LD50 (rat, oral): 2.660 g/kg

LD50 (rat, IV): 1.33 g/kg LD50 (rat, SC): 1.4 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Boric acid is irritating to the skin and is potentially toxic by inhalation. Gloves, eye protection, protective clothing, and a respirator are recom- mended.

Regulatory Status

Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (IV injections; ophthalmic preparations; otic solutions; topical preparations). Reported in the EPA TSCA Inventory. In the UK, the use of boric acid in cosmetics and toiletries is restricted. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Sodium borate.

Comments

Boric acid has been used experimentally as a model oxo-acid to retard mannitol crystallization in the solid state.(16)

The EINECS number for boric acid is 233-139-2.

Specific References

Kodym A, Marcinkowski A, Kukula H. Technology of eye drops containing aloe (Aloe arborescens M–Liliaceae) and eye drops containing both aloe and neomycin sulphate. Acta Pol Pharm 2003; 60(1): 31–39.

Tromp TFJ, Nusman-Schoterman Z, et al. Preservation of eye drops. Pharm Weekbl 1975; 110(465–472): 485–492.

Seller R, Caldini O, Orzalesi G, et al. Preservation of cosmetic products: protection of the talc powders. Boul Chim Farm 1974; 113(Dec): 617–627.

Allen LV, Stiles ML. Compound’s corner: diaper rash paste.

Maryland Pharm 1986: 62(Dec): 30.

Dawson CR, Daghfous T, Whitcher J, et al. Intermittent trachoma chemotherapy: controlled trial of tetracycline or erythromycin. Bull World Health Organ 1981; 59: 91–97.

Shaw K. Vaginal yeast infections. Pharm Times 1998; 64(Dec): 57–

58, 60.

Allen LV. Boric acid suppositories. US Pharm 1996; 21(Jan): 92– 93.

Van Slyke KK, Michel VP, Rein MF. Treatment of vulvovaginal candidaisis with boric acid powder. Am J Obstet Gynecol 1981; 141: 145.

Allen ES. Multiple-ingredient drug for use in the treatment of vaginitis. Clin Med 1971; 78: 31–32.

Sweetman SC, ed. Martindale: The Complete Drug Reference, 34th edn. London: Pharmaceutical Press, 2005: 1662.

Lund W, ed. The Pharmaceutical Codex: Principles and Practice of Pharmaceutics, 12th edn. London: Pharmaceutical Press, 1994: 67.

Lund W, ed. The Pharmaceutical Codex: Principles and Practice of Pharmaceutics, 12th edn. London: Pharmaceutical Press, 1994: 109.

Zabka M, Vitkova Z, Burelova A, Mandak M. Formulation and local anesthetic activity of carbizocaine in collyria. Cesk Farm 1988; 37(10): 457–460.

Dean JA, ed. Lang’s Handbook of Chemistry, 13th edn. New York: McGraw-Hill, 1985: 4–57.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 536.

Yoshinari T, Forbes RT, York P, et al. Crystallisation of amorphous mannitol is retarded using boric acid. Int J Pharm 2003; 258: 109–

2-Bromo-2-nitro-1,3-propanediol; b-bromo-b-nitrotrimethyl- eneglycol; Myacide.

Chemical Name and CAS Registry Number

2-Bromo-2-nitropropane-1,3-diol [52-51-7]

Empirical Formula and Molecular Weight

C3H6BrNO4 200.00

Structural Formula

Functional Category

Antimicrobial preservative; antiseptic.

Applications in Pharmaceutical Formulation or Technology

Bronopol 0.01–0.1% w/v is used as an antimicrobial pre- servative either alone or in combination with other preserva- tives in topical pharmaceutical formulations, cosmetics, and toiletries; the usual concentration is 0.02% w/v.

Description

Bronopol is a white or almost white crystalline powder; odorless or with a faint characteristic odor.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for bronopol.

Test BP 2004

Identification +

Characters +

Acidity or alkalinity (1% w/v solution) 5.0–7.0

Related substances +

Sulfated ash 40.1%

Water 40.5%

Assay (anhydrous basis) 99.0–101.0%

Typical Properties

Antimicrobial activity: bronopol is active against both Gram- positive and Gram-negative bacteria including Pseudomo- nas aeruginosa, with typical minimum inhibitory concen- trations (MICs) between 10–50 mg/mL;(1–8) see also Table II. At room temperature, a 0.08% w/v aqueous solution may reduce the viability of culture collection strains of Escher- ichia coli and Pseudomonas aeruginosa by 100-fold or more in 15 minutes. Antimicrobial activity is not markedly influenced by pH in the range 5.0–8.0, nor by common anionic and nonionic surfactants, lecithin, or proteins.(2,5,6) Bronopol is less active against yeasts and molds, with typical MICs of 50–400 mg/mL or more, and has little or no useful activity against bacterial spores. See also Section 12.

Table II: Minimum inhibitory concentrations (MICs) of bronopol.(2,9)

Microorganism MIC (mg/mL)

Aspergillus niger 3200

Bacillus subtilis 12.5

Burkholderia (Pseudomonas) cepacia 25

Candida albicans 1600

Escherichia coli 12.5–50

Klebsiella aerogenes 25

Legionella pneumophilia 50

Penicillium roqueforti 400

Penicillium funiculosum 1600

Pityrosporum ovale 125

Proteus mirabilis 25–50

Proteus vulgaris 12.5–50

Pseudomonas aeruginosa 12.5–50

Saccharomyces cerevisiae 3200

Salmonella gallinarum 25

Staphylococcus aureus 12.5–50

Staphylococcus epidermidis 50

Streptococcus faecalis 50

Trichophyton mentagrophytes 200

Trichoderma viride 6400

Melting point: 128–1328C

Partition coefficients:

Mineral oil : water = 0.043 at 22–248C; Peanut oil : water = 0.11 at 22–248C.

Solubility: see Table III.

Table III: Solubility of bronopol.

Solvent Solubility at 208C

Cottonseed oil Slightly soluble

Ethanol (95%) 1 in 2

Glycerol 1 in 100

Isopropyl myristate 1 in 200

Mineral oil Slightly soluble

Propan-2-ol 1 in 4

Propylene glycol 1 in 2

Water 1 in 4

Bronopol 77

Stability and Storage Conditions

Bronopol is stable and its antimicrobial activity is practically unaffected when stored as a solid at room temperature and ambient relative humidity for up to 2 years.(3)

The pH of a 1.0% w/v aqueous solution is 5.0–6.0 and falls slowly during storage; solutions are more stable in acid conditions. Half-lives of bronopol in buffered aqueous solu- tions at 0.03% w/v are shown in Table IV.(9)

Microbiological assay results indicate longer half-lives than those obtained by HPLC and thus suggest that degradation products may contribute to antimicrobial activity. Formalde- hyde and nitrites are among the decomposition products, but formaldehyde arises in such low concentrations that its antimicrobial effect is not likely to be significant. On exposure to light, especially under alkaline conditions, solutions become yellow or brown-colored but the degree of discoloration does not directly correlate with loss of antimicrobial activity.

The bulk material should be stored in a well-closed, non- aluminum container protected from light, in a cool, dry place.

Table IV: Half-lives of bronopol under different storage conditions.

tions containing amines may be reduced by limiting the concentration of bronopol to 0.01% w/v and including an antioxidant such as 0.2% w/v alpha tocopherol or 0.05% w/v butylated hydroxytoluene;(14) other inhibitor systems may also be appropriate.(15)

LD50 (dog, oral): 250 mg/kg (16) LD50 (mouse, IP): 15.5 mg/kg LD50 (mouse, IV): 48 mg/kg LD50 (mouse, oral): 270 mg/kg LD50 (mouse, SC): 116 mg/kg LD50 (mouse, skin): 4.75 g/kg LD50 (rat, IP): 26 mg/kg

LD50 (rat, IV): 37.4 mg/kg LD50 (rat, oral): 180 mg/kg LD50 (rat, SC): 170 mg/kg LD50 (rat, skin): 1.6 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances

and quantity of material handled. Bronopol may be harmful

upon inhalation and the solid or concentrated solutions can be

irritant to the skin and eyes. Eye protection, gloves, and dust

respirator are recommended. Bronopol burns to produce toxic fumes.

Incompatibilities

Sulfhydryl compounds cause significant reductions in the activity of bronopol, and cysteine hydrochloride may be used as the deactivating agent in preservative efficacy tests; lecithin/ polysorbate combinations are unsuitable for this purpose.(5) Bronopol is incompatible with sodium thiosulfate, with sodium metabisulfite, and with amine oxide or protein hydrolysate surfactants. Owing to an incompatibility with aluminum, the use of aluminum in the packaging of products that contain bronopol should be avoided.

Method of Manufacture

Bronopol is synthesized by the reaction of nitromethane with paraformaldehyde in an alkaline environment, followed by bromination. After crystallization, bronopol powder may be milled to produce a powder of the required fineness.

Safety

Bronopol is used widely in topical pharmaceutical formulations and cosmetics as an antimicrobial preservative.

Although bronopol has been reported to cause both irritant and hypersensitivity adverse reactions following topical use,(10–13) it is generally regarded as a nonirritant and nonsensitizing material at concentrations up to 0.1% w/v. At a concentration of 0.02% w/v, bronopol is frequently used as a preservative in ‘hypoallergenic’ formulations.

Animal toxicity studies have shown no evidence of phototoxicity or tumor occurrence when bronopol is applied to rodents topically or administered orally; and there is no in vitro or in vivo evidence of mutagenicity;(1) this is despite the demonstrated potential of bronopol to liberate nitrite on decomposition, which in the presence of certain amines may generate nitrosamines. Formation of nitrosamines in formula-

Regulatory Status

Included in topical pharmaceutical formulations licensed in Europe. Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

—

Comments

Bronopol owes its usefulness as a preservative largely to its activity against Pseudomonas aeruginosa, and its affinity for polar solvents, which prevents the loss of preservative into the oil phase of emulsions that is seen with some other preserva- tives. Other advantages include a low incidence of microbial resistance; low concentration exponent;(17) and good compat- ibility with most surfactants, other excipients, and preserva- tives, with which it can therefore be used in combination.

The major disadvantages of bronopol are relatively poor activity against yeasts and molds, instability at alkaline pH, and the production of formaldehyde and nitrite on decomposition, although there is no evidence of serious toxicity problems associated with bronopol that are attributable to these compounds.

The EINECS number for bronopol is 200-143-0.

Specific References

Croshaw B, Groves MJ, Lessel B. Some properties of bronopol, a new antimicrobial agent active against Pseudomonas aeruginosa. J Pharm Pharmacol 1964; 16 (Suppl.): 127T–130T.

Anonymous. Preservative properties of bronopol. Cosmet Toilet

1977; 92(3): 87–88.

Bryce DM, Croshaw B, Hall JE, et al. The activity and safety of the antimicrobial agent bronopol (2-bromo-2-nitropropane-1,3-diol). J Soc Cosmet Chem 1978; 29: 3–24.

78 Bronopol

Moore KE, Stretton RJ. A method for studying the activity of preservatives and its application to bronopol. J Appl Bacteriol 1978; 45: 137–141.

Myburgh JA, McCarthy TJ. Effect of certain formulation factors on the activity of bronopol. Cosmet Toilet 1978; 93(2): 47–48.

Moore KE, Stretton RJ. The effect of pH, temperature and certain media constituents on the stability and activity of the preservative bronopol. J Appl Bacteriol 1981; 51: 483–494.

Sondossi M. The effect of fifteen biocides on formaldehyde resistant strains of Pseudomonas aeruginosa. J Ind Microbiol 1986; 1: 87–96.

Kumanova R, Vassileva M, Dobreva S, et al. Evaluating bronopol.

Manuf Chem 1989; 60(9): 36–38.

BASF Corp. Technical literature: Bronopol products, 2000.

Maibach HI. Dermal sensitization potential of 2-bromo-2- nitropropane-1,3-diol (bronopol). Contact Dermatitis 1977; 3: 99.

Elder RL. Final report on the safety assessment for 2-bromo-2- nitropropane-1,3-diol. J Environ Pathol Toxicol 1980; 4: 47–61.

Storrs FJ, Bell DE. Allergic contact dermatitis to 2-bromo-2- nitropropane-1,3-diol in a hydrophilic ointment. J Am Acad Dermatol 1983; 8: 157–170.

Grattan CEH, Harman RRM. Bronopol contact dermatitis in a milk recorder. Br J Dermatol 1985; 113 (Suppl. 29): 43.

Dunnett PC, Telling GM. Study of the fate of bronopol and the effects of antioxidants on N-nitrosamine formation in shampoos and skin creams. Int J Cosmet Sci 1984; 6: 241–247.

Challis BC, Trew DF, Guthrie WG, Roper DV. Reduction of nitrosamines in cosmetic products. Int J Cosmet Sci 1995; 17: 119–

131.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 566.

Denyer SP, Wallha¨ usser KH. Antimicrobial preservatives and their properties. In: Denyer SP, Baird RM, eds. Guide to Microbiological Control in Pharmaceuticals. London: Ellis Horwood, 1990: 251– 273.

General References

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

Rossmore HW, Sondossi M. Applications and mode of action of formaldehyde condensate biocides. Adv Appl Microbiol 1988; 33: 223–273.

Shaw S. Patch testing bronopol. Cosmet Toilet 1997; 112(4): 67, 68,

71–73.

Toler JC. Preservative stability and preservative systems. Int J Cosmet Sci 1985; 7: 157–164.

Wallha¨ usser KH. Bronopol. In: Kabara JJ, ed. Cosmetic and Drug Preservation Principles and Practice. New York: Marcel Dekker, 1984: 635–638.

Authors

SP Denyer, NA Hodges.

Date of Revision

15 August 2005.

Butylated Hydroxyanisole

Nonproprietary Names

BP: Butylated hydroxyanisole PhEur: Butylhydroxyanisolum USPNF: Butylated hydroxyanisole

Synonyms

BHA; tert-butyl-4-methoxyphenol; 1,1-dimethylethyl-4-meth- oxyphenol; E320; Nipanox BHA; Nipantiox 1-F; Tenox BHA.

Chemical Name and CAS Registry Number

2-tert-Butyl-4-methoxyphenol [25013-16-5]

Empirical Formula and Molecular Weight

C11H16O2 180.25

The PhEur 2005 describes butylated hydroxyanisole as 2-(1,1- dimethylethyl)-4-methoxyphenol containing not more than 10% of 3-(1,1-dimethylethyl)-4-methoxyphenol.

Structural Formula

Functional Category

Antioxidant.

Applications in Pharmaceutical Formulation or Technology

Butylated hydroxyanisole is an antioxidant (see Table I) with some antimicrobial properties.(1) It is used in a wide range of cosmetics, foods, and pharmaceuticals. When used in foods, it is used to delay or prevent oxidative rancidity of fats and oils and to prevent loss of activity of oil-soluble vitamins.

Butylated hydroxyanisole is frequently used in combination with other antioxidants, particularly butylated hydroxytoluene and alkyl gallates, and with sequestrants or synergists such as citric acid.

FDA regulations direct that the total content of antioxidant in vegetable oils and direct food additives shall not exceed 0.02% w/w (200 ppm) of fat or oil content or essential (volatile) oil content of food.

USDA regulations require that the total content of antioxidant shall not exceed 0.01% w/w (100 ppm) of any

one antioxidant or 0.02% w/w combined total of any antioxidant combination in animal fats.

Japanese regulations allow up to 1 g/kg in animal fats.

Table I: Antioxidant uses of butylated hydroxyanisole.

Antioxidant use Concentration (%)

b-Carotene 0.01

Essential oils and flavoring agents 0.02–0.5

IM injections 0.03

IV injections 0.0002–0.0005

Oils and fats 0.02

Topical formulations 0.005–0.02

Vitamin A 10 mg per million units

Description

Butylated hydroxyanisole occurs as a white or almost white crystalline powder or a yellowish-white waxy solid with a faint, characteristic aromatic odor.

Pharmacopeial Specifications

See Table II.

Table II: Pharmacopeial specifications for butylated hydroxyanisole.

Test PhEur 2005 USPNF 23

Identification + +

Characters + —

Appearance of solution + —

Residue on ignition — 40.01%

Sulfated ash 40.1% —

Related substances + —

Heavy metals 410 ppm 40.001%

Organic volatile impurities — +

Assay — 598.5%

10 Typical Properties

Antimicrobial activity: activity is similar to that of the p-hydroxybenzoate esters (parabens). The greatest activity is against molds and Gram-positive bacteria, with less activity against Gram-negative bacteria.

Boiling point: 2648C at 745 mmHg

Density (true): 1.117 g/cm3

Flash point: 1308C

Melting point: 478C (for pure 2-tert-butyl-4-methoxyphenol);

med 11

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