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 the penetrant. This study suggests that, whereas lipophilicity of a solute is the major determinant for solute partitioning into SC from aqueous solutions, the H-bonding of the solute is the main determinant of solute 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 coefficient. 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 and h the path length for diffusion. For. a set of 45 compounds the following 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 groups present and Sigma C* the number of carbons not involved in a C=O bond in the penetrant. Better regressions are obtained when Sigma C* is used rather than size of the molecule as defined by molecular weight. An improved regression was obtained by using the solvatochromic parameters 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 between lag time, an independent estimate of diffusivity, and H-bonding parameters validate the dominant effect of H-bonding as a major determinant of diffusion coefficient.