496 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Zn and Hg, while cadmium occupied an intermediate position. Non- electrolytes are influenced by other factors which will be dealt with in a subsequent section. pH The pH of the solution influences percutaneous absorption principally by determining the state of ionization of a particular compound. Samitz et al (97) found that the absorption of chromium from chloride, sulphate or nitrate solutions in vitro was less at a pH of 7 than at pH 5 or pH 9. Later studies in vivo by Arita et al (106) confirmed that altering the pH of the skin to either side of neutrality increased absorption. Thus, absorption of salicylic acid was less at a pH 5 or higher than that at more acidic pH values while with carbinoxamine, absorption was lowest at pH 7 and increased as the pH became more alkaline. In both these investigations the authors attribute the low absorption at neutral pH to a higher degree of ionization at this pH than at more acid or alkaline pH values. If the solution is strongly acid or alkaline an irreversible destructive effect on the keratin occurs which will render the skin more permeable (1). Water/lipid solubility A much wider variation in the rate of absorption has been demonstrated in studies of some non-electrolytes. Skin permeability to a homologue series of normal primary alcohols CwC8 applied in dilute aqueous solutions were studied by Blank (46). He found that methanol and ethanol (0.1-0.4 s0 penetrated the epidermal barrier in vitro to the same extent as water. The rate of penetration of propanol was greater than that of water by a factor of 1.4. The higher alcohols in this series penetrated the skin much more rapidly octanol, the alcohol with the highest molecular weight in the series, passed through the barrier 52 times as fast as water. The lipid solu- bility of these alcohols also increased with increasing molecular weight, and according to Scheuplein (39) the increased rate of absorption is accounted for by the increased lipid solubility. At higher concentrations, the rate of penetration of the alcohols is greatly increased, and does not follow the pattern of absorption from weak solutions. According tO Blank and Scheuplein (116) this may be due to one or other of two reasons: at high concentrations, the alcohol content of the stratum corneum increases and this 'acts as an added pathway'. Secondly, high concentrations may damage the stratum corneum impairing its 'barrier' properties.

PERCUTANEOUS ABSORPTION 497 An even greater difference in percutaneous absorption was shown by the series of non-electrolytes studied by Treherne (117). This author deter- mined the permeability of skin to ethyliodide, methanol, ethanol, thiourea glycerol, urea and glucose and found that it decreased in this order. He also found that the permeability of ethyliodide was a hundred times that of glucose. Since the rates of transepidermal diffusion agreed with the calcu- lated rates of diffusion from water into lipid, the author concluded that the principal factor determining the rate of diffusion was the degree of lipid solubility. As in the case of the alcohols, molecular volume appears to have little effect, for example, the molar volume (expressed in ml) of ethyliodide is 25.23 while that of urea is 13.67. The influence of lipid solubility on percutaneous absorption was studied by Wurster and Kramer (26) using the three salicylate esters: ethyl-, methyl-, and ethylene-glycol esters. They showed that under conditions of normal hydration of the stratum corneum, the in vivo absorption for ethyl- and ethylene-glycol salicylate was 1.5 M X 10 a 100 cm -x h-:. Absorption was about twice this rate for methyl-salicylate which had a greater water/lipid partition coefficient than the other two esters. Since the compounds studied by Blank (46), Treherne (117) and Wurster and Kramer (26) possessed different degrees of water solubility in addition to their lipid solubility, it would appear that the water/lipid partition coefficient, rather than lipid solubility as such, is the important factor. The work carried out by Clen- denning and Stoughton (118) and Marzulli, Callahan and Brown (95) supports this view. Clendenning et al (118) studied carefully the relation between the percutaneous absorption and water/lipid partition coeffic- ient of phenylboronic acid and seven substituted derivatives. Four of of the compounds had a water/benzene partition coefficient between 1 and 6 and the other four had a coefficient 50. The penetration of the compounds with the lower coefficients was seven-fold better than that of the other four. Marzulli et a1(95), employing a series of organophosphorus compounds also found that the closer to unity the water/lipid solubility, the greater the rate of penetration. These results are in agreement with the opinion expressed by Hadgraft and Somers (1) that percutaneous absorp- tion occurs optimally 'when the medicament combines lipid solubility with a moderate solubility in water'. Chemical structure In the three series of experiments mentioned, chemical structure did not appear to influence the rate of absorption but Scheuplein, Blank,