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.