On the Formation of Droperidol Solvates: Characterization of Structure and Properties

A solvate screening and characterization of the obtained solvates was performed to rationalize and understand the solvate formation of active pharamaceutical ingredient droperidol. The solvate screening revealed that droperidol can form 11 different solvates. The analysis of the crystal structures and molecular properties revealed that droperidol solvate formation is mainly driven by the inability of droperidol molecules to pack efficiently. The obtained droperidol solvates were characterized by X-ray diffraction and thermal analysis. It was found that droperidol forms seven nonstoichiometric isostructural solvates, and the crystal structures were determined for five of these solvates. To better understand the structure of these five solvates, their solvent sorption–desorption isotherms were recorded, and lattice parameter dependence on the solvent content was determined. This revealed a different behavior of the nonstoichiometic hydrate, which was explained by the simultaneous insertion of two hydrogen-bonded water molecules. Isostructural solvates were formed with sufficiently small solvent molecules providing effective intermolecular interactions, and solvate formation was rationalized based on already presented solvent classification. The lack of solvent specificity in isostructural solvates was explained by the very effective interactions between droperidol molecules. Desolvation of stoichiometric droperidol solvates produced one of the four droperidol polymorphs, whereas that of nonstoichiometic solvates produced an isostructural desolvate