Competitive cocrystallization and its application in the separation of flavonoids

Abstract

Recently, cocrystallization has been widely employed to tailor physicochemical properties of drugs in the pharmaceutical field. In this study, cocrystallization was applied to separate natural compounds with similar structures. Three flavonoids [baicalein (BAI), quercetin (QUE) and myricetin (MYR)] were used as model compounds. The coformer caffeine (CAF) could form cocrystals with all three flavonoids, namely BAI–CAF (cocrystal 1), QUE–CAF (cocrystal 2) and MYR–CAF (cocrystal 3). After adding CAF to methanol solution containing MYR and QUE (or QUE and BAI), cocrystal 3 (or cocrystal 2) preferentially formed rather than cocrystal 2 (or cocrystal 1), indicating that flavonoid separation could be achieved by competitive cocrystallization. After co-mixing the slurry of two flavonoids with CAF followed by centrifugation, the resolution ratio that could be achieved was 70–80% with purity >90%. Among the three cocrystals, cocrystal 3 showed the lowest formation constant with a negative Gibbs free energy of nucleation and the highest energy gap. Hirshfeld surface analysis and density of states analysis found that cocrystal 3 had the highest strong interaction contribution and the closest electronic density, respectively, followed by cocrystal 2 and cocrystal 1, suggesting CAF could competitively form a cocrystal with MYR much more easily than QUE and BAI. Cocrystallization is a promising approach for green and effective separation of natural products with similar chemical structures.

Uncovering Cocrystal Formation and Competition Mechanism of Polyhydroxy Natural Products: Cases of Quercetin, Hesperidin, Resveratrol, and Curcumin

“…It is necessary to clarify the premises of cocrystal competition experiments . First, the components in the system should not undergo chemical reactions under the experimental conditions . Second, cocrystal research focuses on the entire system, encompassing the majority or even all of the molecules involved .…”

“…Calculations of molecular electrostatic potential surfaces can identify potential sites within a molecule where hydrogen bonds may form, typically associated with the electronegativity of the ligand atom or group . Generally, the strength of the electrostatic potential is positively correlated with the electronegativity of the atom or group, and sites with higher absolute values of electrostatic potential are more prone to forming hydrogen bonds .…”

“…Polyhydroxy natural products belong to a class of plant compounds that contain multiple phenolic hydroxyl or hydroxyl groups. These compounds, which include flavonoids, tannins, phenolic acids, and anthocyanins, are found in numerous common plant foods like cacao nibs, tea, soybeans, red wine, vegetables, and fruits. − These natural medicines have various health-promoting effects, such as antioxidantion, promotion of vasodilation, and prevention of diseases like atherosclerosis, coronary heart disease, and myocardial infarction. − However, these drugs suffer from poor water solubility, instability, and low bioavailability and hence have limited applications. , Cocrystallization is an effective strategy for modifying the physicochemical properties of such natural medicines. ,, …”

Natural Products as Cocrystal Constituents

“…Intriguingly, one natural product family that has more quickly exploited the power of cocrystallization are the flavonoids. Besides enhanced biological availability, cocrystal methodology has also recently assisted in the separation of the flavonoids baicalein, quercetin, and myricetin from each other 4 as well as facilitating the first x-ray crystal characterization of syringic acid. 5 Furthermore, the dextrose cocrystal of curcumin not only improved its solubility but also its stability in water.…”