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

Abstract

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.

Prediction of Hydrate and Solvate Formation Using Statistical Models

“…The size and branching of molecules was found to be the most important factor in each of the five solvents studied, while the presence of hydrogen bonding groups came second. Large, branched molecules optimize their close packing through interspersed solvent molecules, [68][69][70] while hydrogen bonding groups are responsible for inclusion of solvents via strong, specific interactions. 68,71 The present work expands on earlier research by quantifying the relative importance of these effects.…”

Solid-state NMR and computational investigation of solvent molecule arrangement and dynamics in isostructural solvates of droperidol

“…The identity of all droperidol solvates was confirmed using PXRD [20]. 15 N spectra were recorded at ambient temperature, whereas 13 C and 2 H spectra were recorded at controlled temperatures from 20 o C down to -45 o C. Note that these are set temperatures that do not attempt to correct for sample heating under magicangle spinning; these are estimated to be of the order of +5, +8 and +15 °C for the 2 H, 15 N and 13 C spectra respectively.…”

“…The water molecules occupy two nearby hydrogen-bonded positions in the channel, forming hydrogen bonds with the carboxyl group in the benzimidazolone moiety of droperidol. The isotropic displacement parameter for the water oxygen at 120 K is three times higher than for other non-hydrogen atoms, and it was not possible to locate all the water hydrogen atoms for structures determined at 173 K or above [20], suggesting that the water molecules are slightly disordered. Secondly, the S Me and S Et structures refine with centrosymmetry, with one droperidol and half a disordered alcohol molecule in the asymmetric unit.…”

“…Chemical shift calculations were carried out using the GIPAW method implemented in CASTEP [48; 49; 50; 51], after geometry optimization of the droperidol crystal structures determined at 173 K [20]. Since the first principles calculations cannot be applied to disordered structures, starting structures of S Me and S Et without disorder were prepared in two ways: (a) both structures were solved in the P1 space group with ordered solvent and (b) P1 structures were derived from the reported P structures by discarding one of the solvent molecule orientations.…”

“…The solvates with methanol, ethanol, acetonitrile, nitromethane, chloroform, dichloromethane as well as the nonstoichiometric hydrate (S Me , S Et , S ACN , S NM , S CLF , S DCM and NSH respectively) are isostructural, as observed by PXRD, and crystallize in the P1 or P space group (depending on the solvent symmetry and ordering), with two droperidol molecules in the unit cell. It has not, however, been possible to obtain diffraction quality crystals for S CLF and S DCM [20]. Although non-stoichiometric in that the solvent content is dependent on the partial pressure of solvent in the atmosphere -up to one equivalent of water per droperidol for NSH, and 0.5 equivalents of solvent for the other solvates -samples produced from crystallization are always fully solvated and are relatively stable with respect to desolvation if stored in closed containers.…”