Han Jiawei, Sun Wen, Chen Jiaxin, Yue Zhimin, Fang Weitao, Liu Xiaoqian, Wang Jue, Wu Gaorong
School of Pharmacy & School of Biological and Food Engineering, Changzhou University, Changzhou 213164, P. R. China.
Changzhou Pharmaceutical Factory Co., LTD, Changzhou 213018, P. R. China.
Mol Pharm. 2025 Jun 2;22(6):3045-3060. doi: 10.1021/acs.molpharmaceut.4c01536. Epub 2025 Apr 29.
Flavonoids represent an extensive group of phenolic substances in vegetables, fruits, grains, tea, flowers, etc., which show a variety of biological activities in various nutraceutical, cosmetic, and medicinal fields. Despite demonstrating multifunctional bioactive properties relevant to nutraceutical and pharmaceutical applications, their clinical utilization faces challenges due to their generally low water solubility. This study established a systematic methodology combining computational modeling and experimental validation for developing flavonoid-meglumine (MEG) coamorphous formulations. The initial screening identified 13 flavonoid compounds exhibiting favorable miscibility with MEG from 15 candidates through Hansen solubility parameter analysis. Subsequent molecular dynamics simulations revealed potential hydrogen bond formation in six selected flavonoids (BAI, HES, NAR, KAE, QUE, and ISO) with MEG. Then, six flavonoid coamorphous systems were successfully prepared via the melt-quenching method and characterized by PLM, PXRD, and differential scanning calorimetry. FTIR and radial distribution function analysis results collectively confirmed intermolecular hydrogen bond interactions within these binary systems. In vitro dissolution studies revealed significant solubility/dissolution enhancement in both pH 1.2 HCl and pH 6.8 phosphate buffers, maintaining long-term supersaturation for all six coamorphous formulations. Meanwhile, six flavonoid coamorphous systems had superior stability over individual flavonoid amorphous components, which were attributed to the stronger intermolecular interactions by higher binding energy calculation. These results indicated that the obtained flavonoid coamorphous systems performed a promising application potential in functional products. Importantly, this study presents a novel design framework integrating computational prediction, molecular modeling, and experimental validation for systematic screening of flavonoid coamorphous formulations.
黄酮类化合物是蔬菜、水果、谷物、茶叶、花卉等中广泛存在的一类酚类物质，在各种营养保健、化妆品和医药领域具有多种生物活性。尽管黄酮类化合物具有与营养保健和制药应用相关的多功能生物活性特性，但由于其普遍较低的水溶性，其临床应用面临挑战。本研究建立了一种结合计算建模和实验验证的系统方法，用于开发黄酮类化合物-葡甲胺（MEG）共无定形制剂。通过汉森溶解度参数分析，初步筛选从15种候选物中确定了13种与MEG具有良好混溶性的黄酮类化合物。随后的分子动力学模拟揭示了六种选定的黄酮类化合物（白藜芦醇、橙皮苷、芦丁、山奈酚、槲皮素和异黄酮）与MEG之间可能形成氢键。然后，通过熔融淬火法成功制备了六种黄酮类共无定形体系，并通过偏光显微镜、粉末X射线衍射和差示扫描量热法进行了表征。傅里叶变换红外光谱和径向分布函数分析结果共同证实了这些二元体系内的分子间氢键相互作用。体外溶出度研究表明，在pH 1.2盐酸和pH 6.8磷酸盐缓冲液中，溶解度/溶出度均显著提高，所有六种共无定形制剂均保持长期过饱和状态。同时，六种黄酮类共无定形体系比单个黄酮类无定形成分具有更好的稳定性，这归因于通过更高的结合能计算得出的更强的分子间相互作用。这些结果表明，所获得的黄酮类共无定形体系在功能性产品中具有广阔的应用潜力。重要的是，本研究提出了一种新颖的设计框架，将计算预测、分子建模和实验验证相结合，用于系统筛选黄酮类共无定形制剂。
