Han Jiawei, Sun Wen, Yao Yongxu, Li Shuo, Yue Zhimin, Fang Weitao, Liu Xiaoqian, Wang Jue, Chen Jiaxin
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.
AAPS PharmSciTech. 2025 Mar 5;26(3):78. doi: 10.1208/s12249-025-03077-9.
Flavonoids are a large class of compounds with a variety of biological activities. Nevertheless, their therapeutic application remains limited due to the generally low water solubility. In the present study, an integrated approach was provided to guide the design of flavonoid co-amorphous systems co-formed with piperine (PIP). Firstly, 7 flavonoid compounds showed good miscibility with PIP from 13 flavonoid candidates. Then, molecular dynamics simulation confirmed hydrogen bond formation between 5 flavonoid compounds (i.e., BAI, HES, ISO, NAR and KAE) and PIP. Herein, 5 flavonoid compounds were successfully co-amorphized with PIP by the melting and quench cooling method, which were proved via PLM, PXRD and DSC measurements. FTIR results showed the potential hydrogen bond interactions between -OH of flavonoid molecules and C = O of PIP molecule in the formed co-amorphous systems, which were consistent with RDF analyses in molecular models. For dissolution tests, 4 co-amorphous systems (i.e., BAI-PIP CM, HES-PIP CM, ISO-PIP CM and NAR-PIP CM) appeared abnormally reduced dissolution compared to their original crystalline counterparts arising from the formation of gels during dissolution, while only KAE-PIP CM displayed significantly enhanced dissolution (5.83-fold of crystalline KAE at 12 h) with long-time supersaturated concentration. Meanwhile, KAE-PIP CM kept physically stable at least 3 months under 25°C and 40°C conditions, and possessed excellent physical stability over individual amorphous components, which was attributed to the stronger intermolecular interaction by higher binding energy analysis. Therefore, this study provides a design strategy to guide the screening of flavonoid co-amorphous systems through combining theory-model-experiment techniques.
黄酮类化合物是一类具有多种生物活性的化合物。然而，由于其普遍较低的水溶性，它们的治疗应用仍然有限。在本研究中，提供了一种综合方法来指导与胡椒碱（PIP）共形成的黄酮类共无定形体系的设计。首先，从13种黄酮类候选物中筛选出7种与PIP具有良好混溶性的黄酮类化合物。然后，分子动力学模拟证实了5种黄酮类化合物（即BAI、HES、ISO、NAR和KAE）与PIP之间形成了氢键。在此，通过熔融和骤冷冷却法成功地将5种黄酮类化合物与PIP共无定形化，通过偏光显微镜（PLM）、粉末X射线衍射（PXRD）和差示扫描量热法（DSC）测量得到了证实。傅里叶变换红外光谱（FTIR）结果表明，在形成的共无定形体系中，黄酮类分子的-OH与PIP分子的C=O之间存在潜在的氢键相互作用，这与分子模型中的径向分布函数（RDF）分析结果一致。对于溶出试验，4种共无定形体系（即BAI-PIP CM、HES-PIP CM、ISO-PIP CM和NAR-PIP CM）与其原始结晶对应物相比，溶出度异常降低，这是由于溶出过程中形成了凝胶，而只有KAE-PIP CM表现出显著增强的溶出度（12小时时为结晶KAE的5.83倍），且具有长时间的过饱和浓度。同时，KAE-PIP CM在25°C和40°C条件下至少3个月保持物理稳定，并且比单个无定形成分具有优异的物理稳定性，这归因于通过更高结合能分析得到的更强分子间相互作用。因此，本研究提供了一种设计策略，通过结合理论-模型-实验技术来指导黄酮类共无定形体系的筛选。
