Lipophilicity measurement of drugs by reversed phase HPLC over Wide pH range using an alkaline-resistant silica-based stationary phase, XBridge Shield RP(18).

We propose a reversed phase HPLC (RP-HPLC) with an alkaline-resistant silica-based stationary phase, XBridge Shield RP(18), for the determination of the lipophilicity of drugs with diverse chemical nature ranging from acidic to basic. A set of 40 model compounds with well-defined solvatochromic parameters was selected to allow a broad distribution of structural properties. The chromatographic results showed that the lipophilicity index log k(w) obtained with XBridge Shield RP(18) was well correlated with experimental log P(oct) values (r(2)=0.96). Linear solvation free-energy relationship (LSER) analyses revealed that the retention mechanism of the stationary phase and 1-octanol/water partitioning were controlled by almost the same balance of intermolecular forces (hydrophobicity as expressed by the van der Waals volume V(w), H-bond acceptor basicity beta, and dipolarity/polarizability pi*). The results showed that XBridge Shield RP(18) phase overcomes the shortcomings of the silica-based stationary phases, the application of which to lipophilicity measurements had been limited to neutral and acidic compounds.