Computational Prediction of Drug Solubility in Fasted Simulated and Aspirated Human Intestinal Fluid

Purpose To develop predictive models of apparent solubility (S app ) of lipophilic drugs in fasted state simulated intestinal fluid (FaSSIF) and aspirated human intestinal fluid (HIF). Methods Measured S app values in FaSSIF, HIF and phosphate buffer pH 6.5 (PhB pH6.5 ) for 86 lipophilic drugs were compiled and divided into training (Tr) and test (Te) sets. Projection to latent structure (PLS) models were developed through variable selection of calculated molecular descriptors. Experimentally determined properties were included to investigate their contribution to the predictions. Results Modest relationships between S app in PhB pH6.5 and FaSSIF (R 2 = 0.61) or HIF (R 2 = 0.62) were found. As expected, there was a stronger correlation obtained between FaSSIF and HIF (R 2 = 0.78). Computational models were developed using calculated descriptors alone (FaSSIF, R 2 = 0.69 and RMSE te of 0.77; HIF, R 2 = 0.84 and RMSE te of 0.81). Accuracy improved when solubility in PhB pH6.5 was added as a descriptor (FaSSIF, R 2 = 0.76 and RMSE Te of 0.65; HIF, R 2 = 0.86 and RMSE Te of 0.69), whereas no improvement was seen when melting point (Tm) or logD pH 6.5 were included in the models. Conclusion Computational models were developed, that reliably predicted S app of lipophilic compounds in intestinal fluid, from molecular structures alone. If experimentally determined pH-dependent solubility values were available, this further improved the accuracy of the predictions.