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

Following the preliminary discussion outlining the relative difficulty of t he experimental determination of solubilities versus the lack of general ap plicability and sound theoretical basis of most current predictive approach es for solubility, we look closely at the recently developed pure thermodyn amic model for solubility in real solutions: that derived from mobile order and disorder theory. With successful estimates of the solubility of 62 hyd roxysteroids and related drugs in common organic solvents of differing pola rities and H-bonding capacity, the model has proved to be a valuable tool i n predicting the solubility of complex solutes such as polyfunctional drugs . Free of any adjusted regression coefficients and based on a limited numbe r of readily available parameters, the proposed model is a time-saving alte rnative 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 differenc es between steroids and solubility changes upon solvent properties. Therefo re, the poor solubility of hydroxysteroids in aliphatic hydrocarbons result s from the negative effects due to the change in non-specific cohesion forc es upon mixing and due to steroid self-association in solution. In water, t he low solubilities are mainly due to the large negative value of the hydro phobic effect which cannot be overcome by steroid-water functional group as sociations, i.e., the solvation effect. The relatively good solubility of h ydroxysteroids in polar non-associated solvents (ketones, ethers, esters) a nd in alcohols is explained by the fact that, in both kinds of solvents, st eroid self-association is rather well counterbalanced by the formation of a more or less important number of steroid-solvent interactions without bein g 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 liq uid pharmaceutical forms.