Absolute Organic Crystal Thermodynamics: Growth of the Asymmetric Unit into a Crystal via Alchemy.

The solubility of organic molecules is of critical importance to the pharmaceutical industry; however, robust computational methods to predict this quantity from first-principles are lacking. Solubility can be computed from a thermodynamic cycle that decomposes standard state solubility into the sum of solid–vapor sublimation and vapor–liquid solvation free energies ΔGsolubility° = ΔGsub° + ΔGsolv°. Over the past few decades, alchemical simulation methods to compute solvation free energy using classical force fields have become widely used. However, analogous methods for determining the free energy of the sublimation/deposition phase transition are currently limited by the necessity of a priori knowledge of the atomic coordinates of the crystal. Here, we describe progress toward an alternative scheme based on growth of the asymmetric unit into a crystal via alchemy (GAUCHE). GAUCHE computes deposition free energy ΔGdep° = −ΔGsub° = −kBT ln(Vc/Vg) + ΔGAU + ΔGAU→UC as the sum of an entropic term to account ...