Modeling the percutaneous absorption of solvent-deposited solids over a wide dose range: II. Weak electrolytes.

Dermal absorption of weak electrolytes applied to skin from pharmaceutical and cosmetic compositions is an important consideration for both their efficacy and skin safety. We developed a mechanistic, physics-based framework that simulates this process for leave on applications following solvent deposition. We incorporated this framework into our finite dose computational skin permeation model previously tested with nonelectrolytes to generate quantitative predictions for weak electrolytes. To test the model, we analyzed experimental data from an in vitro human skin permeation study of a weak acid (benzoic acid) and a weak base (propranolol) and their sodium and hydrochloride salts from simple, ethanol/water vehicles as a function of dose and ionization state. Key factors controlling absorption are the pH and buffer capacity of the dose solution, the dissolution rate of precipitated solids into a lipid boundary layer and the rate of conversion of the deposited solid to its conjugate form as the nonionized component permeates and (sometimes) evaporates from the skin surface. The resulting framework not only describes the current test data but has the potential to predict the absorption of other weak electrolytes following topical application.