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

The octanol-water partition coefficient (K-OW) 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 (pK(a)), and the octanol-water partition coefficient of the molecule in the neutral form (K-OW,K-N), in the form of free ions (K-OW,K-I) and in the form of an ion pair (K-OW,K-IP). The values of K-OW,K-N, K-OW,K-I, and K-OW,K-IP are predicted based on the COSMO-SAC activity coefficient model, and the value of pK(a) is determined using the SMD solvation model. The root-mean-square (RMS) error in the predicted log K-OW,K-N, log K-OW,K-IP, and pK(a) for 41 pharmaceuticals are found to be 0.636, 0.816, and 2.59, respectively. The predicted overall partition coefficient, as a function of pH, is also compared to experimental values whenever available. Our results show that the proposed method can provide satisfactory a priori prediction of pH dependency of K-OW without input of any experimental data. This method can serve as a useful tool for modern drug delivery.