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By Melissa Merrell Rhoads, PharmD, PCCA Director of Formulation Development; Fabiana Banov, RPh, MS, PCCA Senior Formulation Pharmacist; Emily Kay Hanners, B.S. Biomedical Sciences
The definition of alcohol is: “ An organic molecule that contains a hydroxyl group bonded to a saturated carbon atom. A hydroxyl group is an oxygen molecule bonded with hydrogen, written as -OH. ” Alcohols are commonly used in compounded preparations and their characteristics will determine which one is appropriate.
Ethanol and aqueous ethanol solutions are used in pharmaceutical formulations and cosmetics. It is primarily used as a solvent, however, it also acts as an antimicrobial preservative at concentrations of 10% or greater.
Topically ethanol may also be used as a penetration enhancer.
Ethanol and Ethanol dehydrated have been utilized in over 1000 PCCA formulas. The uses in compounding have a wide range: solvent, stock solution, topical vehicle, penetration enhancer, preservative, to disinfectant.
Isopropyl alcohol is not as readily used in compounding, but when used it is often as a solvent or disinfectant in a topical formulation. Isopropyl alcohol is not appropriate for use in oral preparations.
Both ethanol and isopropyl alcohol can be used as disinfectants and were commonly used in compounding hand sanitizers during the shortage.
Ethanol can be consumed, where isopropyl or denatured alcohol cannot. Therefore, ethanol would be the only option for oral compounded preparations.
When alcohol is a component of the formulation, it is important to note that the preparation should be stored in an air-tight container to reduce exposure to air and causing evaporation, which can over time cause your compound to increase in potency. Another alternative to reduce the evaporation process is storage of the preparation in the refrigerator.
When to choose alcohol as the preferred solvent (over Propylene Glycol USP or Diethylene Glycol Monoethyl Ether NF) in your compounded formulation primarily depends on the API being used and desired characteristics compatible with the vehicle. We suggest referring to the PCCA formula database for reference to similar formulas to determine the ideal solvent.
Ethanol (ethyl alcohol) is a clear, colorless, mobile, volatile, and flammable liquid with a burning taste. Ethanol is miscible with all organic solvents (ether, chloroform, glycerin) including water. It is naturally produced by yeasts when they ferment sugars.
Ethanol should be stored in air-tight containers at controlled room temperature and protected from light.
Ethanol has considerably good bactericidal activity at concentrations ranging from 20-70%, acting quickly with very little residual lasting effect. At concentrations above 80% ethanol loses its bactericidal activity, going from good to low activity. Ethanol works by denaturing cellular proteins of microorganisms, which lowers surface tension and facilitates their removal. Ethanol also has a solvent effect on oily, wax-coated skin around sebaceous glands. It is important to note that ethanol is not an effective sporicidal nor anti-viral. High concentrations of topical ethanol may cause dehydration of the stratum corneum and excessive ingestion can lead to alcohol intoxication symptoms and severe GI distress.
Functionally used as an antimicrobial preservative, disinfectant, skin penetrant, and solvent. Ethanol and its various diluted solutions are commonly used in pharmaceutical formulations and cosmetics as a solvent, but also for its antimicrobial effects. Topical ethanol can also be used to enhance penetration. Ethanol ≥ 10% may be used as an antimicrobial preservative in compounded preparations. Ethanol in concentrations ranging from 60-90% may be used as a disinfectant. Ethanol’s use as a solvent may have varying concentrations depending on the formula and use.
In USP “dehydrated alcohol” which may also be referred as anhydrous or absolute alcohol, contains ethanol ≥ 99.5%, and “alcohol” contains ethanol 94.9-96.0% v/v. 1, 5
Dehydrated alcohol should be stored in tight containers and protected from light. 5
Acidic conditions may create a vigorous reaction among ethanol and oxidizing agents. Substances that create hydroxide ions (alkali) may turn the solution with ethanol a darker color due to excess residual amounts of aldehydes. Ethanol solutions may cause precipitation of organic salts. Ethanol solutions are also deemed incompatible with aluminum containers.
Incompatibilities of ethanol include acacia gums; it will cause precipitation of the gum. Albumin and starch are insoluble with ethanol which makes ethanol a very useful “selective” solvent. Alcohols have high dielectric constants when compared to other solvents but considered low when compared to water. High dielectric constants are parallel to dissolving salts, so the higher constants the more likely to dissolve salts. This can come into importance with compounding elixirs and spirits. 3
Ethanol is rapidly absorbed through the GI tract and can also be absorbed via vapors in the lung. It is metabolized into acetaldehyde then into acetate, mainly in the liver. Ethanol is a CNS depressant and when ingested in moderate quantities produces intoxication symptoms such as slurred speech, and incoordination. Ingestion in higher amounts and concentrations may lead to lethargy, amnesia, hypothermia, hypoglycemia, coma, respiratory depression, and even cardiovascular collapse. Ethanol’s lethal human BAC is usually around 400-500 mg/100 mL. Ethanol should be handled in a well-ventilated room and have an 8-hour total weight average exposure limit of 1000 ppm. Ethanol may cause irritation to skin, eyes, and mucous membranes; therefore, eye protection and gloves are recommended while handling.
Alcohol, USP (Ethanol 190 proof) Properties:1
Dehydrated Alcohol, USP (Ethanol 200 proof) Properties:1
Isopropyl alcohol (IPA) is a clear, colorless, mobile, volatile, and flammable liquid with an odor similar to ethanol and acetone.
Isopropyl alcohol is also commonly called “rubbing alcohol.” Its molecular structure contains one more carbon and two more hydrogen molecules than ethyl alcohol. Its formula is written as C3H7OH.
Like ethanol, it’s commonly used as an antiseptic and disinfectant. It’s also found in lotions, cosmetics, and face washes.
Between the concentrations of 60% and 90%, Isopropyl alcohol is a very effective agent against microbial bacteria, fungi, and viruses. Higher concentrations don’t generate a much more desirable effectiveness against bacteria, fungi and viruses. This is because, there has to be a significant enough presence of water with the Isopropyl alcohol in order to be effective. And this percentage of water needs to be at least more than 10% within the solution.
IPA 99% is not as commonly used as a disinfectant, but as a solvent or cleaning agent for industries that produce products that are sensitive to water. Hence, it makes sense to use a hydrophobic solvent. It also has a very low flash point and hence, evaporates rapidly. This is useful in computer and electronics manufacturing industries that prefer immediate evaporation of cleaning agents for their work.
Functionally used as a disinfectant or a solvent. Can be used in cosmetics and pharmaceutical preparations, most commonly as a solvent in topicals. It is not recommended to be used in oral formulations due to toxicity.
The degreasing property of IPA may limit its use in lotions that are to be used repeatedly.
Isopropyl alcohol is miscible with benzene, chloroform, ethanol, ether, glycerin, and water; it is soluble in acetone, and insoluble/incompatible in salt solutions (sodium hydroxide, sodium chloride, sodium sulfate). Isopropyl alcohol is considered incompatible with oxidizing agents (hydrogen peroxide, nitric acid) which causes decomposition.
Regarding the safety of IPA, it is readily absorbed through the GI tract and slowly absorbed through the skin. Once absorbed, IPA is metabolized more slowly than ethanol and is primarily metabolized to acetone with metabolites and any unchanged IPA excreted in the urine. Isopropyl alcohol is twice as toxic as ethanol and should NOT be administered orally. Symptoms of IPA toxicity are similar to ethanol toxicity minus any euphoric effects and greater gastritis/vomiting.
Due to its irritant properties (skin, eyes, mucous membranes), eye protection and gloves are recommended, and IPA should be handled in well-ventilated rooms. OSHA standards have an 8-hour time weighted average airborne level that cannot exceed 400 ppm.1
Isopropyl alcohol contains 99.0% to 100.5% by weight of C3H8O and is a transparent, colorless, mobile, volatile liquid with a characteristic odor and a slightly bitter taste. It has a specific gravity of 0.783 to 0.787 and is miscible with water, alcohol (ethanol), ether, and chloroform. It is used for disinfection of medical and surgical equipment and supplies and as a skin antiseptic. As a skin antiseptic in concentrations greater than 70%, it has effectiveness similar to ethanol.
This strength of isopropyl rubbing alcohol is 70% and has some antimicrobial activity and is used as a topical disinfectant.1 USP monograph of Isopropyl rubbing alcohol defines the strength of 68-72% as isopropyl alcohol. USP recommends Isopropyl rubbing alcohol be stored in tight containers and away from heat sources. It should be properly labeled as a flammable liquid.6
Isopropyl Alcohol is incompatible with oxidizing agents, such as hydrogen peroxide and nitric acid, which cause decomposition. It maybe salted out from aqueous mixtures by the addition of sodium chloride, sodium sulfate, and other salts or by the addition of sodium hydroxide.
Properties:1
Denatured ethanol has the addition of chemicals that make the alcohol unpalatable and unsafe for ingestion.
Denatured alcohol can also be referred to as industrial methylated spirits, or surgical spirits and should be used for external use only since they have been deemed unfit for human consumption due to the addition of a denaturing agent such as methanol or methyl isobutyl ketone which are unsafe for human consumption.1
Denatured alcohols or specially denatured (SD) alcohols are commonly used in the cosmetic industry. Denaturants in this industry may include brucine, brucine sulfate, denatonium benzoate, and quassin. The Cosmetic Ingredient Review Expert Panel determined that the use of denaturants in ethanol products make the ethanol unpotable and therefore the cosmetic products should not be listed with the genotoxic, and reproductive warnings of ethanol if it was ingested.7
Common denaturants include methanol, gasoline, benzene, chloroform, pyridine, and naphthalene which can all cause severe damage to the CNS and respiratory system. Patients with alcohol use disorder may resort to these desperate measures to maintain their needs.8
Melissa Merrell Rhoads, PharmD, PCCA Director of Formulation Development, received her pharmacy degree from Mercer University in Atlanta, Georgia, in 1995. She currently is involved with and oversees the development and implementation of new formulas at PCCA.
Fabiana Banov, RPh, MS, PCCA Senior Formulation Pharmacist and flavors expert, earned her pharmacy degree from the College of Pharmaceutical Science of the University of Mogi das Cruzes in Brazil. She also obtained specialization in cosmetic science from São Paulo State University and completed post-graduate work in the technology of cosmetic products from Osvaldo Cruz College.
Emily Kay Hanners has her B.S. in Biomedical Sciences from Western Michigan University. She is currently attending pharmacy school in Chicago, Illinois.
1. Kibbe AH. Handbook of Pharmaceutical Excipients. 3rd ed. American Pharmaceutical Association; 2000: p 7-9, p 41-43, p 263-264,
2. Covington TR. Handbook of Nonprescription Drugs. 10 th ed. American Pharmaceutical Association; 1993: p 55, p 500-501
3. Allen, LV. Remington: The Science and Practice of Pharmacy. 22 nd ed. Pharmaceutical Press; 2013: p 594, p 1837
4. Trissel LA. Stability of Compounded Formulations. 6 th ed. American Pharmacists Association; 2018: p 234-235.
5. United States Pharmacopeia and National Formulary (USP-NF). United States Pharmacopeial Convention; 2020. Accessed February 21, 2022. https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/revisions/dehydrated-alcohol-rb-notice-20200817.pdf
6. United States Pharmacopeia and National Formulary (USP-NF). United States Pharmacopeial Convention; 2020. Accessed February 21, 2022. http://www.pharmacopeia.cn/v29240/usp29nf24s0_m43150.html#:~:text=USP%20Monographs%3A%20Isopropyl%20Rubbing%20Alcohol&text=%C2%BB%20Isopropyl%20Rubbing%20Alcohol%20contains%20not,FDA%20for%20use%20in%20drugs .
7. Cosmetic Ingredient Review Expert Panel. Final report of the safety assessment of Alcohol Denat., including SD Alcohol 3-A, SD Alcohol 30, SD Alcohol 39, SD Alcohol 39-B, SD Alcohol 39-C, SD Alcohol 40, SD Alcohol 40-B, and SD Alcohol 40-C, and the denaturants, Quassin, Brucine Sulfate/Brucine, and Denatonium Benzoate. Int J Toxicol. 2008;27 Suppl 1:1-43. doi:10.1080/10915810802032388
8. Bastani JB, Blose IL. Neuropsychiatric studies of drinkers of denatured alcohol. Dis Nerv Syst. 1976;37(12):683-686.
9. https://doh.sd.gov/boards/pharmacy/assets/Temporary-Policy-Compounding-Hand-Sanitizer-Guidance.pdf Accessed February 22, 2022.