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Human skin permeation of neutral species and ionic species: Extended linear free-energy relationship analyses



The permeability, Kp, of some ionized solutes (including nine acids and nine bases) through human epidermis membrane was measured in this work. Combined with the experimental Kp data set for neutral species created by Abraham and Martins and reliable Kp data for ionic species from the literature, a linear free-energy relationship (LFER) analysis was conducted. The values of log Kp for 118 compounds have been correlated with solute descriptors to yield an LFER equation that incorporates neutral species and ionic species, with R2 = 0.861 and SD = 0.462 log units. The equation can be used to predict Kp for neutral species and ionic species, as well as partly ionized solutes. Predicted values for the passive permeation of the sodium ion and the tetraethylammonium ion are in good accord with the experimental values. It was observed that neutral acids and bases are more permeable than their ionized forms, and that the ratio depends on the actual structure. The correlation between human skin permeation and water–organic solvent/artificial membrane partitions was investigated by comparison of the coefficients in the LFER equations. Partition into cerasome is a reasonable model for partition into skin, and using cerasome as a surrogate for the partitioning process, we separate permeation into partition and diffusion processes. We show that the poor permeability of ionic species is largely due to slow diffusion through the stratum corneum. This is especially marked for a number of protonated base cations. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:2034–2044, 2012

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