Oil-Water Partitioning of Chlorpromazine and Other Phenothiazine Derivatives Using Dodecane and n-Octanol

Abstract

The apparent partition coefficients of chlorpromazine and some other phenothiazine derivatives in dodecane-water and n-octanol-water systems were measured at 30°. Results in the dodecane system at various pH values demonstrated that only the free base form partitions. Intrinsic partition coefficients for all derivatives, except the very polar metabolite chlorpromazine sulfoxide, range from 104 to 105, indicating the remarkable hydrophobicity of these molecules. Partitioning measurements in n-octanol indicate significant extraction of these drugs as ion-pairs, as well as higher intrinsic partition coefficients than in dodecane. Measurement of partitioning at various salt concentrations, utilizing different anions, allowed the calculation of extraction constants. Correlations between intrinsic partition coefficients in dodecane and extraction constants in n-octanol are presented. From these studies, it is clear that quantitative studies involving the pheno-thiazines in heterogeneous systems such as membranes must consider their extreme hydrophobicity and the various factors that influence such behavior.