Prediction of pH Effect on the Octanol–Water Partition Coefficient of Ionizable Pharmaceuticals

Abstract

The octanol–water partition coefficient (KOW) is a measure of the relative hydrophobicity and hydrophilicity of a chemical. Knowledge regarding how this value changes with the acidity (pH value) in the aqueous phase is important for understanding many biological activities. In this work, we develop a computational method to predict the effect of pH on the partition coefficient of ionizable drugs. In particular, three dissociation mechanisms were examined based on four relevant properties: the acid dissociation constant (pKa), and the octanol–water partition coefficient of the molecule in the neutral form (KOW,N), in the form of free ions (KOW,I) and in the form of an ion pair (KOW,IP). The values of KOW,N, KOW,I, and KOW,IP are predicted based on the COSMO-SAC activity coefficient model, and the value of pKa is determined using the SMD solvation model. The root-mean-square (RMS) error in the predicted log KOW,N, log KOW,IP, and pKa for 41 pharmaceuticals are found to be 0.636, 0.816, and 2.59, respectivel...