PARTITION-COEFFICIENTS IN-VITRO - ARTIFICIAL MEMBRANES AS A STANDARDIZED DISTRIBUTION MODEL

The lipophilicity of beta-adrenoceptor antagonists (RS)-propranolol and (S)-dihydroalprenolol is characterized in a standardized liposomal partition system at 37-degrees-C. Apparent partition coefficients in the range of pH 2 to pH 12 were determined by a two-chamber equilibrium dialysis between small unilamellar phosphatidylcholine liposomes (lipophilic phase) and universal buffer solutions adjusted in ionic strength and osmolality (hydrophilic phase). Above pH 4.5, the partition behavior of both compounds ideally follows the pH-dependent degree of dissociation of the drug. Data analysis as performed by a nonlinear curve fitting procedure revealed a perfect correspondence between the fitted pK(a) values and the respective thermodynamic dissociation constants at 37-degrees-C. The fitted true partition coefficient was 1892.8 +/- 58.1 for (RS)-propranolol and 1105.9 +/- 31.6 for (S)-dihydroalprenolol. Below pH 4.5, drug partitioning was influenced by an acid-induced change in the lipophilic phase.