Journal
JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 108, Issue 9, Pages 2982-2993Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.xphs.2019.04.017
Keywords
flavonoids; co-crystal; solid-state; physicochemical properties; bioavailability
Funding
- National Science Foundation of China [81872813]
- State Project for Essential Drug Research and Development [2017ZX09301075]
- Program of State Key Laboratory of Natural Medicines-China Pharmaceutical University [SKLNMZZCX201826]
- Graduate Innovative Research Project of Jiangsu Province [KYCX18_0757]
- 111 project [B16046]
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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. (c) 2019 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.
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