EPIDERMAL PERMEABILITY - PENETRANT STRUCTURE RELATIONSHIPS .2. THE EFFECT OF H-BONDING GROUPS IN PENETRANTS ON THEIR DIFFUSION THROUGH THE STRATUM-CORNEUM

The permeability coefficients of solutes through stratum corneum (SC) have previously been related to the presence of H-bonding groups on th e penetrant. This study suggests that, whereas lipophilicity of a solu te is the major determinant for solute partitioning into SC from aqueo us solutions, the H-bonding of the solute is the main determinant of s olute diffusion across SC. The diffusion is related to the number of H -bonding groups on the solute, with the presence of zero to two groups having the most pronounced effect on the magnitude of the diffusion c oefficient. Diffusion was estimated from the permeability coefficient (k(p)) and SC/water partition coefficient (K-sc) using the expression: log(D/h) = log k(p) - log K-sc where D is the diffusion coefficient a nd h the path length for diffusion. For. a set of 45 compounds the fol lowing regression is found: log(D/h) = - 2.47 - 0.191 Sigma H - 0.0853 Sigma C, r(2) = 0.709 where Sigma H is the number of H-bonding group s present and Sigma C the number of carbons not involved in a C=O bon d in the penetrant. Better regressions are obtained when Sigma C is u sed rather than size of the molecule as defined by molecular weight. A n improved regression was obtained by using the solvatochromic paramet ers for individual H-bonding groups instead of Sigma H: log(D/h) = - 1 .86 - 0.605 alpha - 2.09 beta, r(2) = 0.904. Similar relationships bet ween lag time, an independent estimate of diffusivity, and H-bonding p arameters validate the dominant effect of H-bonding as a major determi nant of diffusion coefficient.