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 (R² = 0.61) or HIF (R² = 0.62) were found. As expected, there was a stronger correlation obtained between FaSSIF and HIF (R² = 0.78). Computational models were developed using calculated descriptors alone (FaSSIF, R² = 0.69 and RMSE^te of 0.77; HIF, R² = 0.84 and RMSE_te of 0.81). Accuracy improved when solubility in PhB_pH6.5 was added as a descriptor (FaSSIF, R² = 0.76 and RMSE_Te of 0.65; HIF, R² = 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.