Effects of ionization on the percutaneous absorption of drugs: partitioning of nicotine into organic liquids and hydrated stratum corneum.

To gain further insight into the disposition of ionizable drugs in the stratum corneum, the partitioning of nicotine as a function of pH was studied in excised, hydrated, human stratum corneum (SC) and the organic liquids n-butanol, n-octanol, isopropyl myristate, and Miglyol 812. Partitioning in n-octanol, isopropyl myristate, and Miglyol 812 was consistent with the pH-partition hypothesis, while partitioning in n-butanol agreed with agreed with a model for the partitioning of the free base and an ion pair which dissociates in the organic phase. The results in SC also suggested the partitioning of ion pairs. Binding studies indicated that neither the un-ionized nor the ionized species is bound significantly in the stratum corneum. Trichloroacetate (TCA) anion increased partitioning of ionized nicotine in n-butanol, but had no effect in stratum corneum. Delipidization of the stratum corneum decreased the partition coefficient for the free base, but had no effect on the ionized species. Thermodynamic parameters determined from van't Hoff plots were consistent with the entry of un-ionized nicotine into ordered lipids. These results suggest that the un-ionized form is found within the lipid regions of the stratum corneum, while the ionized form is located in aqueous regions.