The Factors that Influence Skin Penetration of Solutes*

Abstract

In this study, human skin permeation data are analysed using a number of physicochemical descriptors. It is shown that the equilibrium distribution of compounds between the stratum corneum and water (log Km) can be correlated with either water-octanol partition coefficients (log Poct) or Abraham solute descriptors. The latter reveals that partitioning of compounds is governed by solute size and hydrogen-bond acidity that favour the stratum corneum, and solute dipolarity/polarizability, and hydrogen-bond basicity that favour water. For water-skin permeation coefficient (log kp) data it is demonstrated that log Poct cannot be used as a descriptor across a wide range of chemical families, but that log kp can be correlated using Abraham solute descriptors. These disclose that log kp values are increased by solute size and decreased by solute dipolarity/polarizability, hydrogen-bond acidity and hydrogen-bond basicity. It is suggested that different solutes travel through the stratum corneum by the same route, which cannot be distinguished as an intercellular or transcellular mechanism. Backward skin permeation is examined and it is demonstrated that factors governing this process can be rationalized. Furthermore, it is shown that using the Abraham analysis, log Poct can be corrected to correlate log kp over a wide range of compounds. The determination of solute descriptors is also described, indicating that Abraham solute descriptors can be obtained by substructure summation and partition coefficient measurements, so that dermatological properties can be predicted for solutes without the necessity for synthesis.