Alcohol enhanced permeation in model membranes. Part II. Thermodynamic analysis of membrane partitioning.

The role of solvents in drug transport has not been properly addressed in the literature, despite its well known influence on drug permeation. Previously we have conducted thermodynamic and kinetic analyses to probe the molecular mechanisms of alcohol enhanced permeation. In the present study, the influence of temperature on the partitioning of methyl paraben into silicone membranes is investigated. In line with previous membrane transport studies of methyl paraben in silicone membranes, butanol and heptanol are used as representative alcohols. The results show higher amounts of methyl paraben extracted from the silicone membrane following equilibration with butanol, at all experimental temperatures. This was in line with alcohol uptake data. In fact, a linear correlation (r(2) ∼0.97) was found between the amount of methyl paraben in the silicone membrane and the corresponding alcohol uptake. Calculated "specific" vehicle-membrane partition coefficients for both alcohols were approximately one, suggesting that the effective concentrations of methyl paraben inside and outside the membrane were the same. Thermodynamic analysis of the alcohol-membrane partition coefficients as a function of temperature showed no apparent trend for butanol, with an associated enthalpy change of approximately zero. Conversely, there was a positive trend in the van't Hoff plot for methyl paraben in heptanol, indicative of an exothermic process. Moreover, the partitioning trends of methyl paraben in silicone membranes obtained from membrane transport and equilibrium experiments were not the same. This reflects the fundamental differences between the calculated vehicle-membrane partition coefficients in the two studies. Finally, the findings from membrane transport and equilibrium experiments support a model of alcohol enhanced permeation where high solvent sorption promotes high solute concentrations in the overall volume of the membrane (i.e. K), thus leading to modified solute transport (i.e. increased flux). The same model also accounts for changes in membrane diffusivity (i.e. D) related to the properties of the imbibed alcohol.