Polymorph-Specific Solubility Prediction using Constant Chemical Potential Molecular Dynamics

Molecular Dynamics (MD) simulations offer a robust approach to understanding material properties within a system. Solubility is defined as the analytical composition of a saturated solution expressed as a proportion of designated solute in a designated solvent, according to IUPAC. It is a critical property of compounds and holds significance across numerous fields. Various computational techniques have been explored for determining solubility, including methods based on chemical potential determination, enhanced sampling simulation, and direct coexistence simulation, and lately, machine learning-based methods have shown promise. In this investigation, we aim to find the solubility values of a compound through Constant Chemical Potential Molecular Dynamics, a method rooted in direct coexistence simulation. The primary purpose of using this method is to overcome the limitation of the direct simulation method by maintaining a constant chemical potential for a sufficiently long time. Urea is chosen as a prototypical system for our study, with a particular focus on three of its polymorphs. Our approach effectively discriminates between the polymorphs of urea based on their respective solubility values; polymorph III is found to have the highest solubility followed by form IV and I.