Impact of pH and membrane nature on distribution and permeability processes of nortriptyline hydrochloride

Partitioning/distribution and permeability are key parameters determining successful drug absorption. In the present work the distribution thermodynamics of nortryptiline hydrochloride (NTT) - an antidepressant drug of BCS II class was studied in the three partition systems: 1-octanol/buffer, n-hexane/buffer and isopropyl myristate (IPM)/buffer (pH 2.0, pH 4.0, and pH 6.8). The studies revealed rather low values of D-app(Org/buf) ionized state of the majority of the NTT molecules. The following sequence of the distribution coefficients in all the systems was estimated: D-app(Org/buf(pH6.8))> DDappOrg/buf(pH4.0)> DDappOrg/buf(pH2.0) the entropy as the main driving force for the buffer -> 1-octanol and buffer pH 6.8 -> IPM transfer. In order to select the optimal membrane for simulating the cells of different tissues, three artificial barriers were tested for NTT permeability: cellulose (RC), PermeaPad (PP) and polydimethylsiloxane-polycarbonate (PDS). A 4.7-fold enhancing effect of IPM as a known "percutaneous permeability enhancer" was demonstrated on PDS membrane. The distribution-permeability interrelations were discussed. We expected the results to be applicable for the improvement of tricyclic antidepressants peroral and transdermal use.