Enantioselectivity of chiral dihydromyricetin in multicomponent solid solutions regulated by subtle structural mutation

Abstract

Multicomponent crystals of a chiral drug with non-chiral components have attracted increasing attention in the application of enantiomer purification and regulation of the physicochemical properties of crystalline materials. Crystalline solid solutions provide opportunities for fine-tuning material properties because of continuously adjustable component stoichiometry ratios. The synthesis, crystal structure, thermodynamics and solid-state enantioselectivity of a series of multicomponent crystals of chiral dihydromyricetin (DMY) with caffeine (CAF) or theophylline (THE) were investigated and the results reveal how the subtle change of molecular structure of the coformer dictates the enantiomer selectivity in multicomponent cocrystals. A series of multicomponent cocrystal solvates of chiral DMY with CAF and THE were synthesized by the slurry cocrystallization method in acetonitrile. Although most racemic mixtures crystallize as racemic compounds or conglomerates, both DMY–CAF and DMY–THE crystallize as chiral solid solutions, unveiled by pseudo-binary melt phase diagrams and pseudo-ternary solution phase diagrams. Crystal structures of Rac-DMY–CAF, R,R-DMY–CAF, Rac-DMY–THE and R,R-DMY–THE are reported for the first time via single-crystal X-ray diffraction, displaying two distinct types of solid solution differing in mixing scale of enantiomers spanning several orders of magnitude. Surprisingly, this remarkable impact on enantiomer discrimination was simply achieved by the reduction of a methyl group of CAF to the THE coformer, which was further rationalized from their crystal structures and intermolecular interactions. Collectively, this work has demonstrated that a subtle change in the molecular structure of a coformer can regulate enantioselectivity in crystalline materials, guiding the purification of chiral racemic compounds via the cocrystallization method and the design of solid-solution crystalline materials.

Bifunctional Chiral Agent Enables One‐pot Spontaneous Deracemization of Racemic Compounds

“…Finally, the racemization reaction must be compatible with the crystallization process required for deracemization. Unfortunately, DMY crystallizes as a stable racemic crystal rather than as a conglomerate [28] . In addition, it contains two stereocenters, making the racemization of this molecule challenging.…”

“…Unfortunately, DMY crystallizes as a stable racemic crystal rather than as a conglomerate. [28] In addition, it contains two stereocenters, making the racemization of this molecule challenging. Furthermore, all known crystal structures of DMY cocrystals are racemic-compound-forming systems.…”

“…Furthermore, all known crystal structures of DMY cocrystals are racemic-compound-forming systems. [28] Therefore, the direct deracemization of DMY or its cocrystal forms using attrition-enhanced or temperature-cycling induced methods is impossible. Multiple stereocenters account for more than 60 % of clinically chiral drugs.…”

Double Trouble: A Peculiar Case of Solid Solution Cocrystals Involving Two Chiral Compounds

“…A first technique focuses on resolution by cocrystallization with an achiral compound aiming to form conglomerate cocrystals which can then be separated by preferential crystallization. − Care has to be taken, as for some systems solid solutions are formed instead of conglomerate cocrystals. ,− In a second approach an enantiopure coformer can be combined with a racemate of the target compound, with the goal of developing either an enantiospecific or diastereomeric cocrystal resolution process . Enantiospecific cocrystallization occurs when a chiral coformer interacts with only one of the enantiomers of the target compound whereas diastereomeric cocrystallization occurs when a pair of diastereomeric cocrystals can be formed. − In a third and final approach, a racemic resolution agent can be used.…”

“…Solid solution cocrystals involving chiral compounds often occur due to a change in the enantiomeric ratio of the chiral compound . If the counter enantiomers are partially miscible, the term partial solid solution − is used, whereas a complete solid solution is obtained if substitution occurs over the whole range of enantiomeric ratios. − Cappuccino et al investigated such systems looking into the cocrystallization of praziquantel with malic acid and tartaric acid . In their study racemic praziquantel and an equivalent amount of malic acid and/or tartaric acid formed complete solid-solution cocrystals with a freely varying enantiomeric ratio of tartaric acid or malic acid.…”