New Salt and Cocrystal of Mequitazine: Impact of Coformer Flexibility and Hydrogen Bond Donors on Polymorphism

New multicomponent crystals of mequitazine
(MQZ) with succinic
acid (SUC), fumaric acid (FUM), glycolic acid (GLC), and glycolamide
(GLA) were obtained after liquid-assisted grinding. The hydrate/anhydrate
availability in the crystals differed owing to slight differences
in the coformer structure. Therefore, the causes of these differences
in the crystal structure were investigated. The structures of crystals,
for which single crystals were difficult to obtain, were obtained
using powder diffraction crystal structure analyses. The crystal structures,
including the disordered structure and the structure in which the
H atom position could not be identified, were validated via dispersion-corrected
density functional theory calculations using the Quantum ESPRESSO
code. MQZ-SUC and MQZ-FUM formed isostructural anhydrates, but only
MQZ-SUC formed a hydrate by twisting the alkyl straight chain; hence,
the difference between the dihedral angles that the coformer can form
led to a small change in polymorphism. MQZ-GLC hydrate and MQZ-GLA
anhydrate had no isomorphic crystals, MQZ-GLC formed a hydrate, and
MQZ-GLA formed an anhydrate. Differences in the number of hydrogen
bond donors in the coformer led to major changes in polymorphism.
The results of this study might be useful for coformer selection and
controlling multicomponent crystal polymorphism.