(542g) Molecular Simulations Reveal Underlying Mechanism of Cooling and Antisolvent Crystallization to Predict the Polymorphism and Growth of Organic Crystals

Understanding the self-assembly of molecules driven by increased chemical potential is a fundamental aspect of materials science. Crystallization of organic molecules is one such process where the increase in supersaturation is used to obtain the crystal of the desired molecule. However, the highly stochastic nature of molecular motion and the presence of multiple energy minima in the crystal energy landscape makes it difficult to predict the outcome of crystallization. This problem is more significant for the pharmaceutical industries, where multiple energy minima in the crystal energy landscape lead to polymorphism. To understand the molecular events which lead to polymorphism, we have employed molecular simulations of cooling and antisolvent crystallization processes. The simulations reveal that the rapid exchange of solvent molecules in the solvation shell and the configuration of the solvent molecules around different functional groups of the organic molecule can be used to predict the polymorphic form obtained at the end of the crystallization. In cooling crystallization simulations of glutamic acid molecules, the density of the solvent molecule in the solvation shell influences the polymorph formation. However, in the case of antisolvent crystallization of Histidine in the mixture of Water and Ethanol molecules, the rupture of the solvation shell due to the interaction with the Ethanol molecule influences the polymorphism. Furthermore, knowledge of per-molecule energy contribution in the solvation shell allows calculating the growth rates of the crystals, which can be used to control the morphology of the crystals. Overall, the knowledge of solvation shell dynamics explains and unifies the traditional empirical observations and opens up possibilities for better control strategies for crystallization.