Epidermal permeability - Penetrant structure relationships .3. The effect of hydrogen bonding interactions and molecular size on diffusion across the stratum corneum

The permeability coefficient, k(p), is the product of partition into (K-SC) and diffusion across (D/h) the stratum corneum (SC). From water, log K-SC = -0.024 + 0.59 log K-octanol. H-bonding between permeant and SC is a major negative determinant of D/h. SC is predominantly a H-bond donor (alpha), rather than acceptor (beta), with alpha(SC):beta(SC) = 0.6:0.4. Chemical groups have characteristic H-bonding potentials to the SC which slow diffusion and are quantified as 'retardation coefficients' (RC). For penetrants of known alpha and beta, RC = 0.0024 + 1:36 (alpha - beta) + 3.18 Sigma beta. For polyfunctionals of unknown alpha and beta, an apparent retardation coefficient (RC*) is first estimated from 0.0024 + 1.36 (Sigma alpha - Sigma beta) + 3.18 Sigma beta, where Sigma alpha, Sigma beta are summed fragmental values, and RC calculated from - 0.0678 + 1.17RC* - 0.0807(RC*)(2). The maximal diffusion (D-o/h) attainable by small, non-bonding molecules is about 0.03 cm/h, declining rapidly as H-bonding groups are introduced to a very low minimum (D-m/h) after about four groups. The D/h versus RC plot resembles an adsorption isotherm and the data can be fitted by Langmuir's equation. The effect of molecular weight on diffusion is lower than previously reported.