Apigenin Cocrystals: From Computational Prescreening to Physicochemical Property Characterization

Apigenin (4′,5,7-trihydroxyflavone, APG) has many potential therapeutic benefits; however, its poor aqueous solubility has limited its clinical applications. In this work, a large scale cocrystal screening has been conducted, aiming to discover potential APG cocrystals for enhancement of its solubility and dissolution rate. In order to reduce the number of the experimental screening tests, three computational prescreening tools, i.e., molecular complementarity (MC), hydrogen bond propensity (HBP), and hydrogen bond energy (HBE), were used to provide an initial selection of 47 coformer candidates, leading to the discovery of seven APG cocrystals. Among them, six APG cocrystal structures have been determined by successful growth of single crystals, i.e., apigenin–carbamazepine hydrate 1:1:1 cocrystal, apigenin–1,2-di(pyridin-4-yl)ethane hydrate 1:1:1 cocrystal, apigenin–valerolactam 1:2 cocrystal, apigenin-(dl) proline 1:2 cocrystal, apigenin-(d) proline/(l) proline 1:1 cocrystal. All of the APG cocrystals showed improved dissolution performances with the potential to be formulated into drug products.