166 Chlorobutanol

30 Honigman JL. Disinfectant ototoxicity [letter]. Pharm J 1975; 215: 523. McCarthy TJ. The influence of insoluble powders on preservatives in 31 Addy M et al. Extrinsic tooth discoloration by metals and chlorhexidine solution. J Mond Pharm 1969; 12: 321–328. I: surface protein denaturation or dietary precipitation? Br Dent J 1985; Senior N. Some observations on the formulation and properties of 159: 281–285. chlorhexidine. J Soc Cosmet Chem 1973; 24: 259–278. 32 Addy M, Moran J. Extrinsic tooth discoloration by metals and Sweetman SC, ed. Martindale: the Complete Drug Reference, 36th edn. chlorhexidine II: clinical staining produced by chlorhexidine, iron and London: Pharmaceutical Press, 2009; 1635. tea. Br Dent J 1985; 159: 331–334. C 33 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004; 471. 21 Author L Peltonen. 20 General References 0 Davies GE et al. 1,6-Di-4 -chlorophenyldiguanidohexane (Hibitane): 22 Date of Revision laboratory investigation of a new antibacterial agent of high potency. Br J Pharmacol Chemother 1954; 9: 192–196. 10 March 2009.

Chlorobutanol

1 Nonproprietary Names especially useful as an antibacterial agent in nonaqueous formula- BP: Chlorobutanol tions. Chlorobutanol is also used as a preservative in cosmetics (see Section 16); as a plasticizer for cellulose esters and ethers; and has JP: Chlorobutanol been used therapeutically as a mild and local analgesic in PhEur: Chlorobutanol, Anhydrous dentistry. USP-NF: Chlorobutanol 8 Description 2 Synonyms Volatile, colorless or white crystals with a musty, camphoraceous ; anhydrous chlorbutol; chlorbutanol; chlor- odor. obutanolum anhydricum; chlorbutol; chloretone; Coliquifilm; Methaform; Sedaform; trichloro-tert-butanol; b,b,b-trichloro-tert- 9 Pharmacopeial Specifications butyl ; trichloro-t-butyl alcohol. See Table I.

3 Chemical Name and CAS Registry Number Table I: Pharmacopeial specifications for chlorobutanol. 1,1,1-Trichloro-2-methyl-2-propanol [57-15-8] Test JP XV PhEur 6.0 USP32–NF27 1,1,1-Trichloro-2-methyl-2-propanol hemihydrate [6001-64-5] Identification þþþ þþ 4 Empirical Formula and Molecular Weight Characters — Appearance of solution — þ — C4H7Cl3O 177.46 (for anhydrous) 5768C þ — 1= 8 C4H7Cl3O 2H2O 186.46 (for hemihydrate) Anhydrous — 95 C— Hemihydrate — 788C— þþþ 5 Structural Formula Acidity Water (anhydrous form) 46.0% 41.0% 41.0% Hemihydrate — 4.5–5.5% 46.0% Chloride 40.071% þ 40.07% Anhydrous — 4300 ppm — Hemihydrate — 4100 ppm — Residue on ignition 40.10% — — Sulfated ash — 40.1% — Assay (anhydrous basis) 598.0% 98.0–101.0% 98.0–100.5%

6 Functional Category Note: the JP XV and USP32–NF27 allow either the anhydrous form or the hemihydrate; the PhEur includes them as separate monographs. Antimicrobial preservative; plasticizer.

7 Applications in Pharmaceutical Formulation or 10 Typical Properties Technology Antimicrobial activity Chlorobutanol has both antibacterial and Chlorobutanol is primarily used in ophthalmic or parenteral dosage antifungal properties. It is effective against Gram-positive and forms as an antimicrobial preservative at concentrations up to 0.5% Gram-negative bacteria and some fungi, e.g. Candida albicans, w/v; see Section 10. It is commonly used as an antibacterial agent for Pseudomonas aeruginosa, and Staphylococcus albus. Antimi- epinephrine solutions, posterior pituitary extract solutions, and crobial activity is bacteriostatic, rather than bactericidal, and is ophthalmic preparations intended for the treatment of miosis. It is considerably reduced above pH 5.5. In addition, activity may Chlorobutanol 167

1.0 (4) 3.0 1697 2273 immediately. There is also appreciable loss of chlorobutanol 2311 through stoppers in parenteral vials. 1740 1659 2232 The bulk material should be stored in an airtight container at a 2368 temperature of 8–158C. 1191 1411

0.0 12 Incompatibilities Owing to problems associated with sorption, chlorobutanol is C 1349 1958 (4–8) (9) 1370 1754 incompatible with plastic vials, rubber stoppers, bentonite, log(1/R) (9) 1175 magnesium trisilicate, polyethylene, and polyhydroxyethylmetha- 2384 (10) 1722 crylate, which has been used in soft contact lenses. To a lesser 2258 extent, carboxymethylcellulose and polysorbate 80 reduce anti- 1683 2294 microbial activity by sorption or complex formation.

1000 × [2nd deriv. log(1/R)] −4.0 −0.1 1100 1300 1500 1700 1900 2100 2300 2500 13 Method of Manufacture Wavelength/nm Chlorobutanol is prepared by condensing acetone and chloroform in the presence of solid . Figure 1: Near-infrared spectrum of chlorobutanol measured by reflectance. 14 Safety Chlorobutanol is widely used as a preservative in a number of also be reduced by increasing heat and by incompatibilities pharmaceutical formulations, particularly ophthalmic prepara- between chlorobutanol and other excipients or packaging tions. Although animal studies have suggested that chlorobutanol materials; see Sections 11 and 12. However, activity may be may be harmful to the eye, in practice the widespread use of increased by combination with other antimicrobial preserva- chlorobutanol as a preservative in ophthalmic preparations has tives; see Section 18. Typical minimum inhibitory concentrations been associated with few reports of adverse reactions. A study of the m (MICs) are: Gram-positive bacteria 650 g/mL; Gram-negative irritation potential of a on the murine cornea m m m bacteria 1000 g/mL; yeasts 2500 g/mL; fungi 5000 g/mL. indicated significant corneal surface damage in the presence of 8 Boiling point 167 C 0.5% w/v chlorobutanol, which may be related to the preservative’s Melting point effective concentration.(11) Reported adverse reactions to chloro- 76–788C for the hemihydrate; butanol include: cardiovascular effects following intravenous 95–978C for the anhydrous form. administration of heparin sodium injection preserved with chlor- (12) NIR spectra see Figure 1. obutanol; neurological effects following administration of a (13) Partition coefficient Octanol : water log kow = 2.03 large dose of infusion preserved with chlorobutanol; Refractive index n 25 = 1.4339 and hypersensitivity reactions, although these are regarded as D (14–16) see Table II. rare. The lethal human dose of chlorobutanol is estimated to be (17) Table II: Solubility of chlorobutanol. 50–500 mg/kg. (18,19) Solvent Solubility at 208C unless otherwise LD50 (dog, oral): 0.24 g/kg stated LD50 (mouse, oral): 0.99 g/kg Acetic acid, glacial Freely soluble LD50 (rabbit, oral): 0.21 g/kg Acetone Freely soluble Chloroform Freely soluble 15 Handling Precautions Ethanol (95%) 1 in 1 Ether Freely soluble Observe normal precautions appropriate to the circumstances and Glycerin 1 in 10 quantity of material handled. Chlorobutanol may be irritant to the Freely soluble skin, eyes, and mucous membranes. Eye protection and gloves are Volatile oils Freely soluble recommended along with a respirator in poorly ventilated environ- Water 1 in 125 ments. There is a slight fire hazard on exposure to heat or flame. Freely soluble in hot water 16 Regulatory Status Included in the FDA Inactive Ingredients Database (IM, IV, and SC 11 Stability and Storage Conditions injection; inhalations; nasal, otic, ophthalmic, and topical prepara- Chlorobutanol is volatile and readily sublimes. In aqueous solution, tions). Labeling must state ‘contains chlorobutanol up to 0.5%.’ degradation to carbon monoxide, acetone and chloride ion is Included in nonparenteral and parenteral medicines licensed in the catalyzed by hydroxide ions. Stability is good at pH 3 but becomes UK. Included in the Canadian List of Acceptable Non-medicinal progressively worse with increasing pH.(1) The half-life at pH 7.5 Ingredients. for a chlorobutanol solution stored at 258C was determined to be In the UK, the maximum concentration of chlorobutanol approximately 3 months.(2) In a 0.5% w/v aqueous chlorobutanol permitted for use in cosmetics, other than foams, is 0.5%. It is solution at room temperature, chlorobutanol is almost saturated not suitable for use in aerosols. and may crystallize out of solution if the temperature is reduced. Losses of chlorobutanol also occur owing to its , with 17 Related Substances appreciable amounts being lost during autoclaving; at pH 5 about Phenoxyethanol; phenylethyl alcohol. 30% of chlorobutanol is lost.(3) Porous containers result in losses from solutions, and polyethylene containers result in rapid loss. Losses of chlorobutanol during autoclaving in polyethylene 18 Comments containers may be reduced by pre-autoclaving the containers in a It has been reported that a combination of chlorobutanol and solution of chlorobutanol; the containers should then be used phenylethanol, both at 0.5% w/v concentration, has shown greater 168 Chlorocresol

antibacterial activity than either compound alone. An advantage of 11 Kalin P et al. Influence of preservatives on the irritation potential of a the use of this combination is that chlorobutanol dissolves in the local anaesthetic on murine cornea. Eur J Pharm Biopharm 1996; 42: alcohol; the resulting liquid can then be dissolved in an aqueous 402. pharmaceutical preparation without the application of heat. 12 Bowler GMR et al. Sharp fall in blood pressure after injection of The EINECS number for chlorobutanol is 200-317-6. The heparin containing chlorbutol [letter]. Lancet 1986; i: 848–849. PubChem ID Compound (CID) for chlorobutanol is 5977. 13 DeChristoforo R et al. High-dose morphine infusion complicated by chlorobutanol-induced somnolence. Ann Intern Med 1983; 98: 335– C 336. 19 Specific References 14 Dux S et al. Hypersensitivity reaction to chlorobutanol-preserved 1 Patwa NV, Huyck CL. Stability of chlorobutanol. J Am Pharm Assoc heparin [letter]. Lancet 1981; i: 149. 1966; NS6: 372–373. 15 Itabashi A et al. Hypersensitivity to chlorobutanol in DDAVP solution 2 Nair AD, Lach JL. The kinetics of degradation of chlorobutanol. JAm [letter]. Lancet 1982; i: 108. Pharm AssocSci 1959; 48: 390–395. 16 Hofmann H et al. Anaphylactic shock from chlorobutanol-preserved 3 Lang JC et al. Design and evaluation of ophthalmic pharmaceutical oxytocin. Contact Dermatitis 1986; 15: 241. products. Banker GS, Rhodes CT, eds. Modern Pharmaceutics, 4th edn. 17 Gosselin RE et al. Clinical Toxicology of Commercial Products, 4th New York: Marcel Dekker, 2002; 415–478. edn. Baltimore: Williams & Wilkins, 1976; II-119. 4 Blackburn HD et al. The effect of container pre-treatment on the 18 Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. interaction between chlorbutol and polyethylene during autoclaving. Cincinnati: US Department of Health, 1987; 3838. Aust J Hosp Pharm 1983; 13: 153–156. 5 Lachman L et al. Stability of antibacterial preservatives in parenteral 19 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th solutions I: factors influencing the loss of antimicrobial agents from edn. New York: Wiley, 2004; 784. solutions in rubber-stoppered containers. J Pharm Sci 1962; 51: 224– 232. 6 Friesen WT, Plein EM. The antibacterial stability of chlorobutanol 20 General References stored in polyethylene bottles. Am J Hosp Pharm 1971; 28: 507–512. Summers QA et al. A non-bronchoconstrictor, bacteriostatic preservative for 7 Blackburn HD et al. Preservation of ophthalmic solutions: some nebuliser solutions. Br J Clin Pharmacol 1991; 31: 204–206. observations on the use of chlorbutol in plastic containers [letter]. J Pharm Pharmacol 1978; 30: 666. 8 Holdsworth DG et al. Fate of chlorbutol during storage in polyethylene dropper containers and simulated patient use. J Clin Hosp Pharm 1984; 21 Author 9: 29–39. BA Hanson. 9 Yousef RT et al. Effect of some pharmaceutical materials on the bactericidal activities of preservatives. Can J Pharm Sci 1973; 8: 54–56. 10 Richardson NE et al. The interaction of preservatives with polyhy- 22 Date of Revision droxyethylmethacrylate (polyHEMA). J Pharm Pharmacol 1978; 30: 469–475. 2 February 2009.

Chlorocresol

1 Nonproprietary Names 5 Structural Formula BP: Chlorocresol PhEur: Chlorocresol USP-NF: Chlorocresol

2 Synonyms Aptal; Baktol; chlorocresolum; 4-chloro-m-cresol; p-chloro-m- cresol; 1-chloro-4-hydroxy-2-methylbenzene; 2-chloro-5-hydroxy- ; 6-chloro-3-hydroxytoluene; 4-chloro-3-methylphenol; 3- methyl-4-chlorophenol; Nipacide PC; parachlorometacresol; PCMC. 6 Functional Category Antimicrobial preservative; disinfectant. 3 Chemical Name and CAS Registry Number 7 Applications in Pharmaceutical Formulation or 4-Chloro-3-methylphenol [59-50-7] Technology Chlorocresol is used as an antimicrobial preservative in cosmetics and pharmaceutical formulations. It is generally used in concentra- 4 Empirical Formula and Molecular Weight tions up to 0.2% in a variety of preparations except those intended C7H7ClO 142.58 for oral administration or that contact mucous membrane.