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

Abstract

This study investigates the influence of the solid-state properties melting point (Tm), enthalpy of melting (ΔHm) and entropy of melting (ΔSm) of a drug on its intrinsic solubility (S0). For this purpose, 26 chemically and structurally diverse drugs covering the oral drug space were selected and the S0, Tm, ΔHm and ΔSm were determined experimentally. The influence of Tm, ΔHm and ΔSm on S0 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 ΔHm had a larger effect than ΔSm on the solubility predictions. The well-known general solubility equation (GSE) and the Dannenfelser semi-empirical equation for the calculation of ΔSm were evaluated using our data set. While predictions of drug solubility obtained using the GSE were acceptable, the use of the experimental ΔSm values instead of the constant 56.5Jmol−1K−1 improved the accuracy of the prediction. The Dannenfelser equation underestimated the ΔSm for most compounds with on average 15Jmol−1K−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.