Conformational Trimorphism in an Ionic Cocrystal of Hesperetin

We report the existence of conformational polymorphism in an ionic cocrystal (ICC) of the nutraceutical compound hesperetin (HES) in which its tetraethylammonium (TEA+) salt serves as a coformer. Three polymorphs, HESTEA-alpha, HESTEA-beta and HESTEA-gamma, were characterized by single-crystal X-ray diffraction (SCXRD). Each polymorph was found to be sustained by phenol center dot center dot center dot phenolate supramolecular heterosynthons that self-assemble with phenol center dot center dot center dot phenol supramolecular homosynthons into C32(7) H-bonded motifs. Conformational variability in HES moieties and different relative orientations of the H-bonded motifs resulted in distinct crystal packing patterns: HESTEA-alpha and HESTEA-beta exhibit H-bonded sheets; HESTEA-gamma is sustained by bilayers of H-bonded tapes. All three polymorphs were found to be stable upon exposure to humidity under accelerated stability conditions for 2 weeks. Under competitive slurry conditions, HESTEA-alpha was observed to transform to the beta or gamma forms. Solvent selection impacted the relationship between HESTEA-beta (favored in EtOH) and HESTEA-gamma (favored in MeOH). A mixture of the beta and gamma forms was found to be present following H2O slurry.