Ethanol

Two separate safety questions live on this page, and blending them is how both get answered badly.

The first is ethanol as a laboratory and formulation liquid. It is flammable and has a low flash point, so an open container near an ignition source is the most likely way it hurts someone. It defats and dries skin on repeated contact, and it is absorbed through skin, so a topical preparation is a route of exposure to the ethanol as well as to whatever is dissolved in it. Because it enhances skin permeation by extracting stratum corneum lipids and loosening the ones that remain ^[1], anything dissolved in it gets further in than it would from water. That is the reason to use it and equally the reason not to be casual about what is in the bottle. Denatured alcohol is not interchangeable with food or pharmaceutical grade; denaturants are added specifically to make it undrinkable and can include methanol, and isopropyl alcohol is a different molecule entirely.

Stability is an under-appreciated hazard with this particular solvent, because ethanol is chemically reactive as well as volatile. In an injectable conivaptan solution built on a 40% alcohol cosolvent system with lactic acid added to improve solubility, the pH rose steadily across storage, driven both by hydrolysis of lactic acid oligomers and by ester formation between the lactic acid and the alcohols in the vehicle; an uncontrolled pH rise threatened to reduce solubility and precipitate the drug ^[6]. A solution built with ethanol can change its own composition on the shelf rather than simply losing potency.

The second question is ethanol as a substance that goes into people, and here the record is one of the largest in epidemiology. In the Global Burden of Disease analysis for 2016, alcohol was the seventh leading risk factor for both deaths and disability-adjusted life years worldwide, and the leading risk factor of any kind among people aged 15 to 49, accounting for 3.8% of female deaths and 12.2% of male deaths in that age group; the level of consumption that minimised overall health loss across all outcomes was zero ^[11]. For cancer specifically, an estimated 741,300 new cancer cases in 2020, 4.1% of all new cancers, were attributable to alcohol, led by cancers of the oesophagus, liver and breast, and roughly 14% of that burden came from moderate rather than heavy drinking ^[12]. The pharmacology side gives a consistent list of chronic effects: liver disorders, carcinogenicity, cardiovascular and neuropsychiatric disorders, addiction and a withdrawal syndrome, haematological effects, reproductive toxicity and osteoporosis, with acetaldehyde doing much of the damage ^[14].

Those two questions meet in exactly one place. Food and pharmaceutical grade ethanol is the same molecule as the ethanol in a drink; reagent and denatured grades are not the same substance and are more dangerous rather than less. Neither fact makes ethanol a bad solvent. It makes it a solvent that should be bought at the right grade, kept away from flame, and not treated as consumable merely because it happens to be pure.

Ethanol is the oldest solvent in pharmacy. Distillation produced a liquid that would extract and hold plant constituents water could not, and the tincture, the elixir and the fluid extract were all built on that single property centuries before anyone could explain it. A large part of the traditional materia medica exists in the form it does because ethanol was the only cosolvent available.

Its modern role is documented rather than assumed. The survey of commercially available oral and injectable solution formulations lists ethanol among the standard water-soluble organic solvents used to get poorly soluble drugs into solution, beside PEG-300, PEG-400, propylene glycol and glycerin ^[9]. Newer skin delivery systems went further and made the ethanol structural rather than incidental: ethosomes are vesicles built around a high ethanol content, 20 to 45%, specifically so that they deform and penetrate more deeply than conventional liposomes ^[5]. Microemulsions and volatile spray vehicles followed the same logic from different directions ^{[8] [7]}.

The scientific account of what happens to alcohol in the body arrived far later than the drinking did. The alcohol dehydrogenase and aldehyde dehydrogenase pathway, and the discovery that common coding variants in both enzymes change how quickly acetaldehyde accumulates and therefore how much people drink and what risk they run, is a comparatively recent chapter ^[13].

Ethanol carries the strangest reputation of the four carriers here, because almost everyone meets it socially before they ever meet it as a solvent. That produces two opposite errors. One is treating a bottle of solvent-grade ethanol as drinkable because it is pure; reagent and denatured grades are neither food nor pharmaceutical grade, and denaturants are chosen precisely to be harmful. The other is treating the health record of drinking as irrelevant to a solvent because the intent is different; the molecule does not know the intent, and skin absorbs it.

Among people who make things themselves, ethanol's reputation as the reliable choice is largely earned. Its solubilization power for a given compound is predictable from that compound's partition coefficient ^[2], it follows the log-linear cosolvent model ^[3], it evaporates rather than lingering, and it is the best characterised of the group on skin ^[1]. Where it disappoints is in mixtures, since combining it with a surfactant can raise or sharply lower solubility depending on which surfactant ^[3], and on the shelf, where it can esterify with acidic excipients and shift a formulation's pH over time ^[6].

Set beside the others: PEG-400 is less volatile, less flammable and gentler, but a weaker solubilizer ^[2]. DMSO takes up more and carries more through skin, and is correspondingly less forgiving. MCT oil is not further along the same scale at all; it is on the other side of the polarity line ^[9] and is the right answer only for compounds that are fat-soluble to begin with.