Molecular Motions During Nucleation and Crystallization from Organic Solvents: An All-atom Molecular Dynamics Perspective

Crystallization from solution is ubiquitous. Solvents play a crucial role in the determination of the crystal habit and solvent-surface interactions lead to different morphologies for a crystal. During crystallization, solvents structured on the solute as well as growth sites are removed. Therefore, solvent structure and dynamics at the crystal-solvent interface, which depends on crystal-surface interactions, becomes essential for understanding of the growth mechanisms. In recent years, organic solvents have been commonly used as a crystal growth medium in numerous applied settings. Experiments have been crucial in understanding of the crystal growth from the aqueous solution, however, a full mechanistic understanding of the influence of mixed-aqueous and pure organic solvents on various aspects of crystal growth, such as solvent structure and dynamics in the interfacial region, and fundamental thermodynamics and growth kinetics remains elusive.

We employed atomistic molecular dynamic (MD) simulations and advanced sampling techniques to study various aspects of the growth of the crystals of current technological interest from complex solvent compositions: mixed-aqueous and pure organic solvents. We investigated the structure, dynamics, and energetics which determine the growth mechanism of the molecular crystals. We demonstrated a correlation between solvent structure and dynamics at the interface and anisotropic growth rates of different faces of hematin, which is central to the survival of the malaria parasite. Next, we elucidated a novel non-classical growth mechanism through the incorporation of a dimer for olanzapine, an antipsychotic drug, and showed that its symmetry breaks in solution prior to crystallization. Further, we put forward a novel mechanism for etioporphyrin I, an organic semiconductor candidate, from pure organic solvents. We showed that incorporation of etioporphyrin I happen via an intermediate state, in contrast to classical theories, which is stabilized by the solvent dynamics in the kink pocket. The molecular level insights our work offers will help to design crystallization processes in the chemical and pharmaceutical industries and understand biomineralization and crystallization in geological and live systems, including pathological crystallization.