(602e) Predicting the Solubility Limit of Drug Molecules by Molecular Simulation

Understanding the solubility behavior of crystalline solids in different solvents is of immense practical interest. For instance, in the formulation of pharmaceuticals, a molecule that has promising activity but is poorly soluble in water may end up being abandoned or may require substantial modification. Different crystalline polymorphs of a particular molecule can have vastly different solubilities, and hence different pharmacological activities. Failure to understand how the solubility is related to the crystalline structure can have dire health and economic consequences.

Recently, we have formulated an adaptable method to compute the solubility limit of solids by molecular simulation, which avoids the difficulty of reference state calculations (Paluch et al. 2010). In this way, application to molecules of complex topology is straightforward. The method combines the pseudo-supercritical path integration and expanded ensemble methodologies to calculate the free energy of the solid and solution respectfully. In this talk, we will demonstrate the application of the method to predict the solubility limit of ibuprofen in light alcohols.