Simultaneously Improving the Physicochemical Properties, Dissolution Performance, and Bioavailability of Apigenin and Daidzein by Co-Crystallization With Theophylline.

Co-crystals have received increasing attention during the past decades for their ability to modify the solubility and other physicochemical properties of active pharmaceutical ingredients. Apigenin (Agn) and Daidzein (Dai) are flavonoid compounds with a variety of biological effects. However, the bioavailability and clinical applications of flavonoid compounds are usually limited by their poor aqueous solubilities. In this study, theophylline (Thp) is used as a coformer to co-crystallize with Agn and Dai. The solid-state properties of the co-crystals of Thp with Agn and Dai are characterized by powder X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, Raman spectroscopy, and nuclear magnetic resonance experiments. In addition, both co-crystals show a greater resistance to hydration than Thp alone. The solubilities, intrinsic dissolution rates, and permeabilities of Agn-Thp co-crystal and Dai-Thp co-crystal are improved compared with those of parent flavonoids. The pharmacokinetic study shows that the bioavailabilities of both co-crystals are enhanced in comparison with the corresponding physical mixtures and parent flavonoids. This study demonstrates that the co-crystallization by using theophylline is a promising strategy to improve physicochemical properties and bioavailability of flavonoid compounds.