CHROMATOGRAPHIC HYDROPHOBICITY INDEX BY FAST-GRADIENT RP HPLC - A HIGH-THROUGHPUT ALTERNATIVE TO LOG-P LOG-D

A new chromatographic hydrophobicity index (CHI) is described which ca n be used as part of a protocol for high-throughput (50-100 compounds/ day) physicochemical property profiling for rational drug design. The index is derived from retention times (t(R)) observed in a fast gradie nt reversed-phase HPLC method. The isocratic retention factors (log k' ) were measured for a series of 76 structurally unrelated compounds by using various concentrations of acetonitrile in the mobile phase. By plotting the log k' as a function of the acetonitrile concentration, t he slope (S) and the intercept (log k'(w)) values were calculated. The previously validated index of hydrophobicity phi(0) was calculated as -log k'(w)/S. A good linear correlation was obtained between the grad ient retention time values, t(R) and the isocratically determined phi( 0) values for the 76 compounds. The constants of this linear correlati on can be used to calculate CHI. For most compounds, CHI is between 0 and 100 and in this range it approximates to the percentage (by volume ) of acetonitrile required to achieve an equal distribution of compoun d between the mobile and the stationary phases, CHI values can be meas ured using acidic, neutral, or slightly basic eluents, Values correspo nding to the neutral form of molecules could be measured for 52 of the compounds and showed good correlation (r = 0.851) to the calculated o ctanol/water partition coefficient (0 log P) values.