Study of Solvent Induced Crystal Polymorphism via Molecular Simulations of Crystal Nucleation

Abstract

The ability of a compound to exist in different crystal structures is called crystal polymorphism and such crystals of varied spatial arrangement are called polymorphs. The polymorphic forms can differ in their properties such as dissolution rate, solubility, stability etc. Crystal polymorphism is of particular importance in the pharmaceutical industry where the differing properties of the polymorphs of an API (Active Pharmaceutical Ingredient) can affect its bioavailability and consequently the performance of the drug. Since solution crystallization is one of the crucial steps for the separation and purification of drugs, control of the formation of a polymorph during crystallization is important in various pharmaceutical applications. Polymorph selectivity depends strongly on the operating conditions of crystallization such as the supersaturation of the solution, solvent composition, external surfaces, additives and impurities. The first step towards crystal formation is nucleation, which is the formation of a microscopic nucleus of the crystalline phase from a supersaturated solution. Since the rate of nucleation depends on the properties of the crystal nucleus, study of crystal nucleation can help us understand the role of various factors that affect polymorph selectivity during crystallization. The focus of our work is to study the role of solvents in polymorph selectivity during crystal nucleation using molecular simulations. Directly simulating crystal nucleation from solutions is quite challenging as it involves diffusion of the solute molecules from the solution to form a nucleus. Furthermore, it requires simulating a large number of solvent molecules which is computationally expensive. To simplify this problem, we study crystal nucleation using an indirect approach which reduces the computational burden involved in simulating the solvent molecules. In our work, we investigate the phenomenon of crystal nucleation of two anhydrous polymorphs (Form I and Form II) of a molecular solid, Orcinol. Form I and Form II are obtained during crystallization from solutions having chloroform and nitromethane as solvents respectively. In this thesis, we report our calculations of the free energies of formation of nuclei of both the polymorphs from a supersaturated Orcinol vapor as well as from a supersaturated solution of chloroform. The results help us identify the most likely polymorph that can nucleate during crystallization.