(496d) Solubility Prediction of Organic Molecules Using Atomistic Simulations

More than 90% of small molecule drugs are delivered in crystalline form. The "bioperformance" and manufacturing of these crystalline molecules is a strong function of their polymorphic form, shape, and size. To engineer crystals into their most bioavailable form and with least processing difficulty, we must be able to model their form, shape, and size as a function of practical design parameters. Solubility is a crucial physical property for bioavailability, for growth rates, and nucleation rates. We have developed a new chemical potential route to solubilities, based on absolute chemical potentials in the solid and solution phases. Our gas phase chemical potential calculations begin from a novel centroid reference system, which we convert to the real molecule and then to a solvated molecule via thermodynamic perturbation and/or thermodynamic integration. The solid chemical potential is obtained by transforming the Einstein crystal to a molecular crystal (Frenkel-Ladd calculations). We illustrate the calculations by predicting the solubility of succinic acid (with GAFF force field and TIP3P water). We use direct coexistence simulations to make a self-consistent test of our chemical potential calculations.