Nonproprietary Names

USP:Ethanol (96%) JP: Ethanol
PhEur:Ethanol (96 per cent)
USP:Alcohol

Synonyms

Ethanolum (96 per centum); ethyl alcohol; ethyl hydroxide; grain alcohol; methyl carbinol.

Chemical Name and CAS Registry Number

Ethanol [64-17-5]

Empirical Formula and Molecular Weight

C2H6O 46.07

Structural Formula

Functional Category

Antimicrobial preservative; disinfectant; skin penetrant; solvent.

Applications in Pharmaceutical Formulation or Technology

Technology Ethanol and aqueous ethanol solutions of various concentrations (see Sections 8 and 17) are widely used in pharmaceutical formulations and cosmetics; see Table I. Although ethanol is primarily used as a solvent, it is also employed as a disinfectant, and in solutions as an antimicrobial preservative.(1,2) Topical ethanol solutions are used in the development of transdermal drug delivery systems as penetration enhancers.(3–10) Ethanol has also been used in the development of transdermal preparations as a co-surfac- tant.(11–13) Table I: Uses of alcohol. Use Concentration (% v/v) Antimicrobial preservative 510 Disinfectant 60–90 Extracting solvent in galenical manufacture Up to 85 Solvent in film coating Variable Solvent in injectable solutions Variable Solvent in oral liquids Variable Solvent in topical products 60–90

Description

In the BP 2009, the term ‘ethanol’ used without other qualification refers to ethanol containing 599.5% v/v of C2H6O. The term ‘alcohol’, without other qualification, refers to ethanol 95.1–96.9% v/v. Where other strengths are intended, the term ‘alcohol’ or ‘ethanol’ is used, followed by the statement of the strength. In the PhEur 6.0, anhydrous ethanol contains not less than 99.5% v/v of C2H6O at 208C. The term ethanol (96%) is used to describe the material containing water and 95.1–96.9% v/v of C2H6O at 208C. In the USP 32, the term ‘dehydrated alcohol’ refers to ethanol 599.5% v/v. The term ‘alcohol’ without other qualification refers to ethanol 94.9–96.0% v/v. In the JP XV, ethanol (alcohol) contains 95.1–96.9% v/v (by specific gravity) of C2H6O at 158C. In the Handbook of Pharmaceutical Excipients, the term ‘alcohol’ is used for either ethanol 95% v/v or ethanol 96% v/v. Alcohol is a clear, colorless, mobile, and volatile liquid with a slight, characteristic odor and burning taste. See also Section 17.

Pharmacopeial Specifications

See Table II. See also Sections 17 and 18. Table II: Pharmacopeial specifications for alcohol. Test JP XV PhEur 6.0 USP 32 Identification Characters Specific gravity þ— 0.809–0.816 þ þ 0.805–0.812 þ — 0.812–0.816 Acidity or alkalinity Clarity and color of solution þ þ þ þ þ þ Nonvolatile residue 42.5 mg 425 ppm 42.5 mg Volatile impurities Absorbance at 240 nm þ þ40.40 þ þ 40.40 þ þ 40.40 at 250–260 nm 40.30 40.30 40.30 at 270–340 nm 40.10 40.10 40.10 Assay 95.1–96.9% 95.1–96.9% 92.3–93.8% by weight 94.9–96.0% by volume

Typical Properties

Antimicrobial activity Ethanol is bactericidal in aqueous mixtures at concentrations between 60% and 95% v/v; the optimum concentration is generally considered to be 70% v/v. Antimicrobial activity is enhanced in the presence of edetic acid or edetate salts.(1) Ethanol is inactivated in the presence of nonionic surfactants and is ineffective against bacterial spores. Boiling point 78.158C Flammability Readily flammable, burning with a blue, smokeless flame. Flash point 148C (closed cup) NIR spectra see Figures 1 and 2. Solubility Miscible with chloroform, ether, glycerin, and water (with rise of temperature and contraction of volume). Specific gravity 0.8119–0.8139 at 208C Note The above typical properties are for alcohol (ethanol 95% or 96% v/v). See Section 17 for typical properties of dehydrated alcohol.

Stability and Storage Conditions

Aqueous ethanol solutions may be sterilized by autoclaving or by filtration and should be stored in airtight containers, in a cool place.

Incompatibilities

In acidic conditions, ethanol solutions may react vigorously with oxidizing materials. Mixtures with alkali may darken in color owing to a reaction with residual amounts of aldehyde. Organic 17 Figure 1: Near-infrared spectrum of alcohol (96%) measured by Figure 2: Near-infrared spectrum of alcohol (absolute) measured by transflectance (1 mm path-length). salts or acacia may be precipitated from aqueous solutions or dispersions. Ethanol solutions are also incompatible with aluminum containers and may interact with some drugs.

Method of Manufacture

Ethanol is manufactured by the controlled enzymatic fermentation of starch, sugar, or other carbohydrates. A fermented liquid is produced containing about 15% ethanol; ethanol 95% v/v is then obtained by fractional distillation. Ethanol may also be prepared by a number of synthetic methods.

Safety

Ethanol and aqueous ethanol solutions are widely used in a variety of pharmaceutical formulations and cosmetics. It is also consumed in alcoholic beverages. Ethanol is rapidly absorbed from the gastrointestinal tract and the vapor may be absorbed through the lungs; it is metabolized, mainly in the liver, to acetaldehyde, which is further oxidized to acetate. Ethanol is a central nervous system depressant and ingestion of low to moderate quantities can lead to symptoms of intoxication including muscle incoordination, visual impairment, slurred speech, etc. Ingestion of higher concentrations may cause depression of medullary action, lethargy, amnesia, hypothermia, hypoglycemia, stupor, coma, respiratory depression, and cardiovascular collapse. The lethal human blood-alcohol concentration is generally estimated to be 400–500mg/100mL. Although symptoms of ethanol intoxication are usually encountered following deliberate consumption of ethanol-containing beverages, many pharmaceutical products contain ethanol as a solvent, which, if ingested in sufficiently large quantities, may cause adverse symptoms of intoxication. In the USA, the maximum quantity of alcohol included in OTC medicines is 10% v/v for products labeled for use by people of 12 years of age and older, 5% v/v for products intended for use by children aged 6–12 years of age, and 0.5% v/v for products for use by children under 6 years of age.(14) Parenteral products containing up to 50% of alcohol (ethanol 95 or 96% v/v) have been formulated. However, such concentrations can produce pain on intramuscular injection and lower concentrations such as 5–10% v/v are preferred. Subcutaneous injection of alcohol (ethanol 95% v/v) similarly causes considerable pain followed by anesthesia. If injections are made close to nerves, neuritis and nerve degeneration may occur. This effect is used therapeutically to cause anesthesia in cases of severe pain, although the practice of using alcohol in nerve blocks is controversial. Doses of 1mL of absolute alcohol have been used for this purpose.(15) Preparations containing more than 50% v/v alcohol may cause skin irritation when applied topically. LD50 (mouse, IP): 0.93g/kg(16) LD50 (mouse, IV): 1.97g/kg LD50 (mouse, oral): 3.45g/kg LD50 (mouse, SC): 8.29g/kg LD50 (rat, IP): 3.75g/kg LD50 (rat, IV): 1.44g/kg LD50 (rat, oral): 7.06g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Ethanol and aqueous ethanol solutions should be handled in a well-ventilated environment. In the UK, the long-term 8-hour TWA workplace exposure limit for ethanol is 1920mg/m3 (1000ppm).(17) Ethanol may be irritant to the eyes and mucous membranes, and eye protection and gloves are recommended. Ethanol is flammable and should be heated with care. Fixed storage tanks should be electrically grounded to avoid ignition from electrostatic discharges when ethanol is transferred.

Regulatory Status

Included in the FDA Inactive Ingredients Database (dental preparations; inhalations; IM, IV, and SC injections; nasal and ophthalmic preparations; oral capsules, solutions, suspensions, syrups, and tablets; rectal, topical, and transdermal preparations). Included in the Canadian List of Acceptable Non-medicinal Ingredients. Included in nonparenteral and parenteral medicines licensed in the UK. 17 Related Substances Dehydrated alcohol; denatured alcohol; dilute alcohol; isopropyl alcohol. Dehydrated alcohol Synonyms Absolute alcohol; anhydrous ethanol; ethanol. Autoignition temperature 3658C Boiling point 78.58C Explosive limits 3.5–19.0% v/v in air Flash point 128C (closed cup) Melting point 1128C Moisture content Absorbs water rapidly from the air. Refractive index n 20D = 1.361 Specific gravity 0.7904–0.7935 at 208C Surface tension 22.75mN/m at 208C (ethanol/vapor) Vapor density (relative) 1.59 (air = 1) Alcohol 19 Vapor pressure 5.8Pa at 208C Viscosity (dynamic) 1.22mPas (1.22cP) at 208C Comments Dehydrated alcohol is ethanol 599.5% v/v. See Section 8. Dehydrated alcohol is one of the materials that have been selected for harmonization by the Pharmacopeial Discussion Group. For further information see the General Information Chapter <1196> in the USP32–NF27, the General Chapter 5.8 in PhEur 6.0, along with the ‘State of Work’ document on the PhEur EDQM website, and also the General Information Chapter 8 in the JP XV. Denatured alcohol Synonyms Industrial methylated spirit; surgical spirit. Comments Denatured alcohol is alcohol intended for external use only. It has been rendered unfit for human consumption by the addition of a denaturing agent such as methanol or methyl isobutyl ketone. Dilute alcohol Synonyms Dilute ethanol. Specific gravity see Table III. Table III: Specific gravity of alcohol. Strength of alcohol (% v/v) Specific gravity at 208C 90 0.8289–0.8319 80 0.8599–0.8621 70 0.8860–0.8883 60 0.9103–0.9114 50 0.9314–0.9326 45 0.9407–0.9417 25 0.9694–0.9703 20 0.9748–0.9759 Comments The term ‘dilute alcohol’ refers to a mixture of ethanol and water of stated concentration. The USP32–NF27 lists diluted alcohol. The BP 2009 lists eight strengths of dilute alcohol ( dilute ethanol) containing 90%, 80%, 70%, 60%, 50%, 45%, 25%, and 20% v/v respectively of ethanol.

Comments

Alcohol is one of the materials that have been selected for harmonization by the Pharmacopeial Discussion Group. For further information see the General Information Chapter <1196> in the USP32–NF27, the General Chapter 5.8 in PhEur 6.0, along with the ‘State of Work’ document on the PhEur EDQM website, and also the General Information Chapter 8 in the JP XV. Possession and use of nondenatured alcohols are usually subject to close control by excise authorities. A specification for alcohol is contained in the Food Chemicals Codex (FCC).(18) The EINECS number for alcohol is 200-578-6. The PubChem Compound ID (CID) for alcohol is 702. 19 Specific References 1 Chiori CO, Ghobashy AA. A potentiating effect of EDTA on the bactericidal activity of lower concentrations of ethanol. Int J Pharm 1983; 17: 121–128. 2 Karabit MS et al. Studies on the evaluation of preservative efficacy. IV. The determination of antimicrobial characteristics of some pharmaceutical compounds in aqueous solutions. Int J Pharm 1989; 54: 51–56. 3 Liu P et al. Quantitative evaluation of ethanol effects on diffusion and metabolism of b-estradiol in hairless mouse skin. Pharm Res 1991; 8(7): 865–872. 4 Verma DD, Fahr A. Synergistic penetration enhancement of ethanol and phospholipids on the topical delivery of cyclosporin A. J Control Release 2004; 97(1): 55–66. 5 Gwak SS et al. Transdermal delivery of ondansetron hydrochloride: effects of vehicles and penetration enhancers. Drug Dev Ind Pharm 2004; 30(2): 187–194. 6 Williams AC, Barry BW. Penetration enhancers. Adv Drug Delivery Rev 2004; 56(5): 603–618. 7 Heard CA et al. Skin penetration enhancement of mefenamic acid by ethanol and 1,8-cineole can be explained by the ‘pull’ effect. Int J Pharm 2006; 321: 167–170. 8 Rhee YS et al. Effects of vehicles and enhancers on transdermal delivery of clebopride. Arch Pharm Res 2007; 30: 1155–1161. 9 Fang C et al. Synergistically enhanced transdermal permeation and topical analgesia of tetracaine gel containing menthol and ethanol in experimental and clinical studies. Eur J Pharm Biopharm 2008; 68: 735–740. 10 Krishnaiah YS et al. Penetration-enhancing effect of ethanolic solution of menthol on transdermal permeation of ondansetron hydrochloride across rat epidermis. Drug Deliv 2008; 15: 227–234. 11 Kweon JH et al. Transdermal delivery of diclofenac using microemulsions. Arch Pharmacol Res 2004; 27(3): 351–356. 12 Huang YB et al. Transdermal delivery of capsaicin derivative-sodium nonivamide acetate using microemulsions as vehicles. Int J Pharm 2008; 349: 206–211. 13 El Maghraby GM. Transdermal delivery of hydrocortisone from eucalyptus oil microemulsion: effects of cosurfactants. Int J Pharm 2008; 355: 285–292. 14 Jass HE. Regulatory review. Cosmet Toilet 1995; 110(5): 21–22. 15 Lloyd JW. Use of anaesthesia: the anaesthetist and the pain clinic. Br Med J 1980; 281: 432–434. 16 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004; 1627–1628. 17 Health and Safety Executive. EH40/2005: Workplace Exposure Limits. Sudbury: HSE Books, 2005 (updated 2007). http://www.hse.gov.uk/ coshh/table1.pdf (accessed 5 February 2009). 18 Food Chemicals Codex, 6th edn. Bethesda, MD: United States Pharmacopeia, 2008; 303.

General References

European Directorate for the Quality of Medicines and Healthcare (EDQM). European Pharmacopoeia – State Of Work Of International Harmonisation. Pharmeuropa 2009; 21(1): 142–143. http://www.edqm.eu/site/-614.html (accessed 3 February 2009). Lund W, ed. The Pharmaceutical Codex: Principles and Practice of Pharmaceutics, 12th edn. London: Pharmaceutical Press, 1994; 694– 695. Spiegel AJ, Noseworthy MN. Use of nonaqueous solvents in parenteral products. J Pharm Sci 1963; 52: 917–927. Wade A, ed. Pharmaceutical Handbook, 19th edn. London: Pharmaceutical Press, 1980; 227–230.

Author

ME Quinn.

Date of Revision

5 February 2009.