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,

498 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Brauner and McFarlane (119) showed that it has some relevance in the absorption of steroids. The steroids were chosen to span as wide a range as possible in the presence of polar groups within a restricted range of molecular weights (oestrone mw 270.3 to hydrocorfisone mw 360.4). Nevertheless, a thousand- fold difference between these two compounds was observed in permeability studies in vitro with human cadaver skin. Skin permeability of the other steroids in the series (progesterone, pregnenolone, hydroxypregnenolone, hydroxyprogesterone, cortexone, testosterone, cortexolone, corticosterone, cortisone, hydro-cortisone and aldosterone) were of an intermediate degree between that of oestrone and hydrocortisone. The rate of permeability in this series, as in the examples quoted in previous paragraphs, correlated with the lipid solubility of the compounds and was inversely related to the polarity. But the difference in lipid solubility between the extremes in this series of steroids was 50-fold which is in strong contrast to the 1 000- fold difference in permeability so that the authors could attribute only a small part of this difference to their lipid solubility. They postulated that the more polar molecules possessed a decreased mobility not only because they were less lipid soluble but also because of a stronger chemical binding with the stratum corneum. Thus, in the case of steroids, the chemical structure influenced to a significant extent the absorption through the stratum corneum. This possibility of a chemical binding with components of the stratum corneum may explain the formation of a corticosteroid 'reservoir' in this layer (120). Chemical binding may also explain the failure of a series of synthetic artionic surfactants to penetrate the stratum corneum from low concentra- tions of aqueous solutions (121-123). The slower rates of absorption of trivalent compared with hexavalent chromium at concentrations of 0.017-0.239 M (124) is also probably due to a difference in the ability of these two compounds to interact with the proteins of the stratum corneum. In the trivalent form, chromium binds with the proteins of the stratum corneum three times as much as its hexa- valent form (125, 126). Hexavalent chromium is, however, reduced to the trivalent form in the skin (125) and it is thought likely that any Cr bound to the stratum corneum on the application of hexavalent compounds is largely in the trivalent form. Molecular size The percutaneous absorption of molecules much larger than those of