目的 以氧化苦参碱（oxymatrine，OMT）/苦参碱（matrine，MT）为配体，分别与黄芩素（baicalein，BE）制备成不同比例的共无定形体系（coamorphous system，CM），并考察该体系对黄芩素溶解度、物理稳定性的改善效果，并对其潜在增溶机制进行初步探讨。方法 利用旋转蒸发法分别制备不同物质的量比例的黄芩素-氧化苦参碱/苦参碱共无定形体系（BE-OMT/MT CM）；采用偏光显微镜观察、X射线粉末衍射分析、差示扫描量热分析和傅里叶变换红外光谱分析等对其进行固态表征；根据其在不同pH值缓冲液中的表观溶解度、粉末过饱和溶出速率及其引湿性和物理稳定性等综合考察黄芩素与不同配体间的最优配比；并结合分子动力学模拟不同配体对其增溶的潜在分子机制进行关联分析。结果 固态表征结合分子动力学模拟结果显示，OMT/MT与黄芩素均存在分子间氢键相互作用，具有单一玻璃化转变温度；溶解度结果显示，在BE-MT/OMT CM（1∶1、2∶1、3∶1）中，黄芩素的溶解度均高于其原料药及其物理混合物，且在pH 7.4缓冲体系中不同比例的BE-OMT/MT CM的溶解度均提升明显，BE-OMT CM提高至3.9～5.6倍，BE-MT CM提高至5.1～9.1倍；BE-OMT CM在不同pH值介质下维持过饱和状态及抑制药物转晶能力均优于BE-MT CM；不同比例BE-MT/OMT CM在25 ℃、60%相对湿度条件下均十分稳定，可稳定放置达9个月。结论 BE-OMT/MT CM可显著提高黄芩素溶解度、溶出度及物理稳定性，OMT是一种更加理想的CM配体，其机制与形成分子间氢键有关。

Objective Co-amorphous systems (CM) of baicalein (BE) with oxymatrine (OMT) or matrine (MT) at various molar ratios were prepared, aiming to evaluate their effects on improving the solubility and physical stability of baicalein, and to preliminarily explore the underlying solubilization mechanisms. Methods BE-OMT/MT CM with various molar ratios were prepared by rotary evaporation method. Solid-state characterization was characterized by polarized light microscopy, X-ray powder diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopy. The optimal molar ratio between baicalein and each coformer was determined by systematically evaluating the apparent solubility in buffer solutions with different pH values, supersaturation dissolution profiles, hygroscopicity, and physical stability. Furthermore, molecular dynamics simulations were conducted to correlate these findings with the potential molecular mechanisms underlying the solubility enhancement. Results Solid-state characterization combined with molecular dynamics simulation revealed the presence of intermolecular hydrogen bonding interactions between baicalein and OMT/MT, and all co-amorphous systems exhibited a single glass transition temperature, indicating amorphous homogeneity. Solubility studies showed that the solubility of baicalein in BE-MT/OMT CM (at molar ratios of 1:1, 2:1, and 3:1) was higher than that of the raw drug and corresponding physical mixtures. In phosphate buffer (pH 7.4), all BE-OMT/MT CM exhibited significantly improved solubility. Specifically, the solubility of baicalein increased by 3.9—5.6 fold in BE-OMT CM and by 5.1—9.1 fold in BE-MT CM compared to pure baicalein. Furthermore, BE-OMT CM showed superior ability to maintain supersaturation and inhibit recrystallization across different pH media, along with lower hygroscopicity compared to BE-MT CM. The BE-OMT CM also demonstrated physical stability for up to nine months under storage conditions of 25  ℃ and 60% relative humidity. Conclusion BE-OMT/MT CM significantly enhanced the solubility, dissolution rate, and physical stability of baicalein. Among the two coformers, OMT is a more ideal coformer for CM, and the mechanism is related to the formation of intermolecular hydrogen bonds.

R283.6

湖北省自然科学基金中医药创新发展联合基金项目(2023AFD153); 湖北省科技厅自然科学基金面上项目(2023AFB964); 湖北省技术创新计划重大项目(2024BCA002)