Theoretical and experimental exploration of the lipophilicity of zwitterionic drugs in the 1,2-dichloroethane/water system.

Purpose: This work examines the lipophilic behavior of various zwitterions and shows how distribution profiles in biphasic systems and ionic partition diagrams may improve our understanding of pH-absorption profiles of drugs.

Methods: The lipophilicity of various zwitterionic drugs was examined by potentiometry and cyclic voltammetry in the 1,2-dichloroethane/water system to study the intramolecular interactions and conformational effects affecting absorption and activity of zwitterions, as well as to draw their theoretical and experimental ionic partition diagrams.

Results: Different theoretical partition diagrams are reported according to the tautomeric constant of the zwitterion. Shifts of apparent PKa are obtained in the ionic partition diagrams of raclopride and eticlopride and compared to the deviations from pH-absorption profile described in the literature for lipophilic drugs. The physicochemical origin of these shifts is discussed.

Conclusions: The comparison between pH-absorption profiles and ionic partition diagrams of zwitterions is shown here to be of value for a better mechanistic understanding of absorption processes, thus opening new perspectives in studying pH-absorption profiles of ionizable drugs.