Hydrophobic and solvation effects on the solubility of hydroxysteroids in various solvents: Quantitative and qualitative assessment by application of the mobile order and disordr theory

摘要

Following the preliminary discussion outlining the relative difficulty of the experimental determination of solubilities versus the lack of general applicability and sound theoretical basis of most current predictive approaches for solubility, we look closely at the recently developed pure thermodynamic model for solubility in real solutions: that derived from mobile order and disorder theory. With successful estimates of the solubility of 62 hydroxysteroids and related drugs in common organic solvents of differing polarities and H-bonding capacity, the model has proved to be a valuable tool in predicting the solubility of complex solutes such as polyfunctional drugs. Free of any adjusted regression coefficients and based on a limited number of readily available parameters, the proposed model is a time-saving alternative procedure to experimentation. By properly quantifying the enthalpic and entropic contributions involved in the overall solubility process, the model furthermore assesses the factors that determine solubility differences between steroids and solubility changes upon solvent properties. Therefore, the poor solubility of hydroxysteroids in aliphatic hydrocarbons results from the negative effects due to the change in non-specific cohesion forces upon mixing and due to steroid self-association in solution. In water, the low solubilities are mainly due to the large negative value of the hydrophobic effect which cannot be overcome by steroid-water functional group associations, i.e., the solvation effect. The relatively good solubility of hydroxysteroids in polar non-associated solvents (ketones, ethers, esters) and in alcohols is explained by the fact that, in both kinds of solvents, steroid self-association is rather well counterbalanced by the formation of a more or less important number of steroid-solvent interactions without being penalized by a strong negative hydrophobic effect in the case of alcohols. Some practical rules regarding how some parameters like the molar volume or the substitution may affect solubility are finally derived, which might help the pharmaceutical scientist to orient the choice of a solvent for liquid pharmaceutical forms.