Contribution of solid-state properties to the aqueous solubility of drugs

This study investigates the influence of the solid-state properties melting point (T-m), enthalpy of melting (Delta H-m) and entropy of melting (Delta S-m) of a drug on its intrinsic solubility (S-0). For this purpose, 26 chemically and structurally diverse drugs covering the oral drug space were selected and the S-0, T-m, Delta H-m and Delta S-m were determined experimentally. The influence of T-m, Delta(H), and Delta S-m on S-0 was studied using regression analysis. The overall improvement of the predictions were 0.3 log units, however, five compounds (astemizole, glyburide, fenbufen, gliclazide and griseofulvin) were improved by more than one log unit. Tm and AHm had a larger effect than Delta S-m on the solubility predictions. The well-known general solubility equation (GSE) and the Darmenfelser semi-empirical equation for the calculation of AS. were evaluated using our data set. While predictions of drug solubility obtained using the GSE were acceptable, the use of the experimental AS values instead of the constant 56.5J mol(-1) K-1 improved the accuracy of the prediction. The Darmenfelser equation underestimated the Delta S-m for most compounds with on average 15J mol(-1) K-1. Our results show that solid-state properties should be considered for improved performance of future models for prediction of drug solubility. In addition our study provides accurate experimental data on intrinsic solubility for 26 compounds, supplying a useful external data set for validation of drug solubility models. (c) 2006 Elsevier B.V. All rights reserved.