Study of solvent induced polymorphism and crystal nucleation from solution

Abstract

Crystal polymorphism is the existence of different crystal structures for the same compound. Different polymorphs will have different physical properties, such as solubility and dissolution rate. The early stage of crystallization, called nucleation, plays a vital in determining the structure of the crystal formed. Understanding the molecular mechanism of nucleation enables us to produce specific polymorphs. Unlike nucleation from the melt, nucleation from solution involves many complexities. Two critical issues with simulating nucleation from solution are the slow diffusion of solute molecules from the bulk solution to the nucleus's surface and the need to simulate many solvent molecules to observe a reasonable nucleus size. First, we used the classical nucleation theory to analyze the role of solvent on polymorph formation. In most cases, the polymorph with the lowest free energy barrier that nucleates fi rst. Compounding the free energy barrier requires the knowledge of the solids' free energy and interfacial free energy of the solidsolvent system. In this context, we have developed methods to compute both the free energy of solids described by flexible models and the interfacial free energy of solid-liquid systems. Using the calculated values, we study the role of solvent in determining the polymorph formation. The predictions are qualitatively consistent with the experimental results. Many studies in the literature showed that nucleation proceeds in a nonclassical pathway. To understand the nucleation mechanism, we have formulated a rigorous statistical mechanics-based theory called a molecular theory. We have tested the proposed theory's ability and accuracy by applying it to study Lennard Jones crystal nucleation from the vapour phase. Our analysis reveals that diffusion anisotropy also plays a vital role in deciding the nucleation pathway in addition to the underlying free energy. Then we applied it to study NaCl nucleation from an aqueous solution to understand the nucleation pathway.