Conformational Trimorphism in an Ionic Cocrystal of Hesperetin

Abstract

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.

Crystal engineering of ionic cocrystals comprising Na/K salts of hesperetin with hesperetin molecules and solubility modulation

“…No cyclic dimers were found between HES molecules. When HES is deprotonated, the results reported here and in our previous study on polymorphic ICCs of HES with its tetraethylammonium salt (Jin, Haskins et al, 2022) reveal that HES À anions may form infinite chains with (in HESTEA-) or without (in HESTEA-, HESTEA-) HES molecules. They may also self-assemble into cyclic dimers which were found in four out of the seven structures reported in this work.…”

“…It has been suggested that symmetric [PhOÁ Á ÁHÁ Á ÁPhO] À hydrogen bonds can be classified as quasicovalent bonds in nature due to incomplete proton transfer (Steiner, 2002). The [PhOÁ Á ÁHÁ Á ÁPhO] À hydrogen bonds observed in HESNAH [2.4618 (18) A ˚] and HESKHEÁ2H 2 O [2.451 (2) A ˚], reported here, HESTEA-[2.4256 (19) A ˚] reported by us recently (Jin, Haskins et al, 2022), and bis(4-Nitrophenoxide) dihydrate [2.434 (6) A ˚] reported by Kreevoy et al (1998), are shorter than other PhOHÁ Á ÁPhO À hydrogen bonds [2.479 (3) A ˚to 2.660 (3) A ˚] observed in this work.…”

Polymorphism in cocrystals of metronidazole benzoate

“…44 However, as the number of reports on polymorphic cocrystals continues to rise, most of these reports focus on structural characterization. [45][46][47][48][49] Solubility studies, on the other hand, are still relatively scarce. Upon examining the available data, it becomes clear that the BZMDSLC and BZMDFMA polymorphic cocrystals can serve as representative examples for many of the other reported cases.…”