(468a) Two-Step Nucleation Mechanism Drives Crystal Structure Formation By Selective Desolvation

Nucleation rate and crystal structure can be predicted using two disjointed yet popular theoretical approaches, two-step nucleation theory (TSN) and crystal structure prediction (CSP). The TSN theory is widely used to explain nucleation in crystalline materials in a wide range of solvents. Despite this, the model has not been expanded to predict crystal structures or polymorphisms. CSP techniques, on the other hand, only empirically consider solvent effects. Thus, TSN theory and CSP techniques continue to evolve as separate methods of predicting two critical characteristics of nucleation – rate, and structure. In this study, we resolve this gap by demonstrating for the first time how crystals are formed through the use of TSN theory. In TSN, a sequential desolvation mechanism is proposed, where partial desolvation leads to dense clusters, and selective desolvation of functional groups leads to crystal structure formation. Molecular simulations are used to investigate the effect of specific interactions on the degree of solvation around different functional groups of glutamic acid molecules. Energy landscape and activation barriers, from these molecular simulations indicate sequential and selective desolvation as supersaturation increases. Through a combination of computational and experimental approaches, we demonstrate that crystallization and polymorph selection is governed by a previously unknown phenomenon associated with supersaturation-induced asymmetric desolvation.