(357r) Screening Solvents for Desired Polymorph Selection: A Solution Thermodynamics Study

Polymorphism is defined as the ability of a compound to exist in multiple crystal structures due to the ability of molecules comprising the crystal to arrange themselves in multiple lattice structures. When water or solvent molecules become part of the crystal lattice, the resulting structures are known as hydrates or solvates, respectively. These hydrated or solvated crystal structures are commonly referred to as pseudo-polymorphs. Pharmaceutical drugs can exist as various polymorphs or pseudo-polymorphs, which can have a significant impact on the drug's solubility, and therefore its bioavailability. Hence, understanding the polymorphic landscape and occurrence domain of a pharmaceutically relevant compound is critical for polymorph selection during drug development and scale-up.

In the present work, the solubilities of a drug (BMS-817399) in several solvents (ethanol, isopropanol, acetonitrile, and acetone) were determined utilizing polythermal crystallization studies on a small scale (0.5-1 mL). The compound exists as a hydrate (starting raw material), however the anhydrous form is desirable. Hence, to identify suitable solvents for crystallization of the desired form, dissolution thermodynamics of the compound was estimated by modeling the solubility data using the van’t Hoff equation. Initial results suggest that dissolution properties such as enthalpy of dissolution (DH_diss) can be utilized as a descriptor to identify solvents that may be conducive for crystallization of a different polymorph. For example, the enthalpy of dissolution in acetonitrile was estimated to be around 40 kJ/mole which was almost three times higher when compared to dissolution in ethanol or iso-propanol (Fig. 1). Interestingly, during studies of cooling crystallization in acetonitrile at a larger scale (100 mL), a novel polymorph (Form X) was identified. A higher dissolution enthalpy indicates that homogeneous intermolecular interactions (solute-solute and solvent-solvent) are preferred with respect to heterogeneous intermolecular interactions (solute-solvent) in solution. Hence, it is possible that an altered molecular assembly during nucleation may have led to a distinct polymorph due to enhanced solute-solute interactions.