有机药物共晶形成机理及其溶液微观结构的研究

Co-crystal is a homogeneous crystalline mixture of different drug ingredients, which can be obtained by crystallizing drug molecules with different reactivity. Recently, co-crystallization has been considered as a unique method for new drug development. Many properties of active pharmaceutical ingredients (APIs), such as bioavailability, solubility, thermal stability, et.al. can be improved by forming co-crystals. However, the mechanism of co-crystallization is still unclear and the thermodynamics of co-crystal system is lack of systematic studies. Thus the study on the process and structure analysis of co-crystals is the frontier in the field worldwide. In this work, urea/acetic acid and theophylline/gentisic acid will be chosen as the co-crystalline model system, molecular dynamics will be used to analyze the microstructure of the co-crystalline saturated solution; the relationship between the microscopic characteristics and the nucleation and growth mechanism of the co-crystalline solution will be explored. Based on the molecular recognition and supramolecular assembly technology, the microstructure of the co-crystalline solution will be designed by using membrane crystallization technology, which will induce nuclei and growth of co-crystals at the defined orientation. The mechanism of the nucleation and growth of crystalline introduced by the membrane crystallization technology will be observed by the atomic force microscopy, X-ray diffraction, photoelectron spectroscopy, and In –Situ Raman spectroscopy. This work will provide a novel method for the design and development of new active pharmaceutical ingredients and functional materials.

将具有不同活性的药物分子一起结晶，制备含有多种药物成分的晶态均匀混合物从而形成共晶，是新药开发的独特手段。共晶能够改善药物的诸多性能, 如生物利用度，溶解度, 热稳定性等。关于共晶的结晶机理尚不清楚，共结晶的热、动力学行为缺乏系统研究。对药物共结晶过程及共晶结构解析的深入研究是结晶领域的世界性前沿课题。本项目拟以尿素与乙二酸，茶碱与龙胆酸作为共结晶体系，首次利用分子动力学原理来分析共结晶体系饱和溶液的微观结构，探究溶液微观特征与共晶成核生长的关系，初步揭示溶液共结晶的机理。同时基于超分子组装和分子识别技术，利用膜结晶技术有目的地设计共结晶体系溶液微观结构，定向诱导共晶相的成核生长。应用原子力显微镜，X-射线衍射仪，光电子能谱和在线拉曼光谱等表征手段，从分子水平上分析膜结晶法制备共晶的成核及晶体生长机理，以期推动药物及功能新材料设计与开发。

将具有不同活性的药物分子一起结晶，制备含有多种药物成分的晶态均匀混合物从而形成共晶，是新药开发的独特手段。共晶能够改善药物的诸多性能，如生物利用度、溶解度、热稳定性等。关于共晶的结晶机理尚不清楚，共结晶的热、动力学行为缺乏系统研究。对药物共结晶过程及共晶结构解析的深入研究是结晶领域的世界性前沿课题。项目选取尿素-乙二酸共晶、茶碱-烟酰胺共晶、乙水杨胺-糖精共晶、呋塞米-4,4’-联吡啶共晶、丙磺舒-4,4’-偶氮吡啶共晶五种物系，研究其热力学、动力学及共结晶过程的生长机理、转晶行为、并对其进行分子模拟，首次利用分子动力学原理来分析共结晶体系饱和溶液的微观结构，探究溶液微观特征与共晶成核生长的关系，初步揭示溶液共结晶的机理。应用光学显微镜，X-射线衍射仪，在线傅里叶红外光谱仪和在线拉曼光谱仪等表征手段，并结合分子模拟加以辅助和佐证，从分子水平上分析制备共晶的成核及晶体生长机理，以期推动药物及功能新材料设计与开发。