Solution crystallization is a commonly used technique to separate and purify APIs (Active Pharmaceutical Ingredients) in the pharmaceutical industry. The selection of the solvent is of great importance in solution crystallization. Solvent affects many properties of the crystal product, including polymorph form, morphology, size distribution, flowability, and compressibility. It therefore has consequences for the dissolution rate and bioavailability of the final drug product. Current solvent selection techniques for solution crystallization remain ad hoc, and typically do not have a theoretical underpinning. In this study, computer simulations are applied to elucidate the interactions between solvent and solute molecules at molecular level and also the mechanism underlying the solvent effects on the properties of the crystal product. By doing this, we want to pave the way to the rational selection of solvent for solution crystallization.

Molecular dynamics was applied to study the solvent effects on the molecular self-assembly of a model compound tetrolic acid (TTA) in four different solvents and implications on the polymorph formed during crystallization. TTA has two polymorphic forms (form I and form II) and a solvate form, which are known to form from chloroform, ethanol and dioxane respectively. A hypothesis in literature states that there is a link between the solution chemistry and the solid state polymorphic outcome: the most stable motif (growth synthon) in the solution has the highest probability of crystallizing into the crystal as the structural synthon. This link hypothesis was investigated using molecular simulations in our study. Our results suggest that the strong interactions between TTA and solvent molecules (ethanol or dioxane) prevent the formation of a carboxylic acid dimer in solution and thus promote the crystallization of TTA in a catemer based form or a solvate form. However weak interactions between TTA and solvent molecules (carbon tetrachloride or chloroform) facilitate the formation of carboxylic acid dimers in solution and thus promote the crystallization of a dimer based crystal. Detailed solvent structure plays an important role in determining the relative stability of various growth synthons in solution and also the barriers along the pathway connecting them. Moreover, a procedure to study the solvent-solute interactions in solution and the initial solvent screening for the desired polymorph is proposed, a procedure which can be extended easily to other polymorphic systems.