Descriptors and Modeling Methods for Developing Solubility Models

Descriptors and Modeling Methods for Developing Solubility Models 

The choice of descriptors is not always clear-cut. The time required to calculate elaborate descriptors by quantum methods is not always justified compared to the results obtained with simpler and more rapidly calculated descriptors. For example, Bergstrom [12] compared 2D polar surface area (PSA) with 3D PSA and static, instead of dynamic, calculations. No definitive gain was obtained by using the most sophisticated method(s) of calculating PSA descriptors. 

There is no such clear-cut judgment about the statistical methods of modeling solubility. There are models as simple as the relationship between log Pand melting point (MP), established some time ago by Yalkowsky and coworkers, and the very complex linear solvation energy relationships (LSERs). The limitation of the simple Yalkowsky relationship is that it uses two variables, obtained with accuracy only by measurement, and thus the simple relationship turns out to be very complicated when calculated log P and MP are used. 

Among the recent reviews, the most comprehensive one is by Dearden [15]. In his review, he discusses the fundamentals of aqueous solubility, which lead to the Yalkowsky equation. Dearden also reviews the oldest approaches of predicting aqueous solubility, from a very simple fragment-based approach of 1924 to the numerous approaches post-1990, for which he made an extensive tabular comparison. 

Delaney [13] describes the solubilization mechanism as controlled by a double phenomenon the affinity of the compound for itself and the affinity of the compound for the solvent. The latter effect is simply described either by the log P property or by very sophisticated methods such as statistical thermodynamic or quantum mechanical techniques. These very intensive calculation methods have not yet proved their superiority over the simpler and faster methods that tend to mimic the successful log P fragment calculator. 

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