Prediction of the octanol-water partition constant of neutral compounds by reversed-phase liquid chromatography using alternative organic solvent modifiers

Abstract

Reversed-phase liquid chromatography (RPLC) offers significant advantages over traditional methods for estimating octanol-water partition constants, which are a critical parameter in drug discovery. In contrast to classical methods for determining the octanol-water partition constant, such as shake-flask techniques, RPLC is less time-consuming and easier to automate. In this study, we explored three alternative organic solvent modifiers: acetone, 2-propanol, and tetrahydrofuran for the indirect determination of the octanol-water partition constant for neutral compounds by RPLC using either isocratic retention factors or retention factors extrapolated to 100 % water for several stationary phases. The Kinetex XB C18 column with acetone-water mobile phase compositions gave the best results for the construction of correlation models for the prediction of the octanol-water partition constant of varied compounds employing isocratic retention factors for 20 % (v/v) acetone-water and retention factors extrapolated to 100 % water. Retention factors extrapolated to 100 % water were nearly as good as the isocratic retention factors with a standard error of 0.136 and Fisher statistic of 1446 for the correlation model compared with a standard error of 0.122 and Fisher statistic of 1456 for the 20 % (v/v) acetone-water model. An XTerra MS C18 column with 10 % (v/v) tetrahydrofuran-water gave the best model for predicting the octanol-water partition constants with a standard error of 0.106 and Fisher statistic of 2806.