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-α, HESTEA-β and HESTEA-γ, were characterized by single-crystal X-ray diffraction (SCXRD). Each polymorph was found to be sustained by phenol···phenolate supramolecular heterosynthons that self-assemble with phenol···phenol supramolecular homosynthons into C 3 2(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-α and HESTEA-β exhibit H-bonded sheets; HESTEA-γ 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-α was observed to transform to the β or γ forms. Solvent selection impacted the relationship between HESTEA-β (favored in EtOH) and HESTEA-γ (favored in MeOH). A mixture of the β and γ forms was found to be present following H2O slurry.
© 2022 The Authors. Published by American Chemical Society.