酰胺类药物多晶型成核过程分子组装机理及调控规律研究

Due to different crystal structure, pharmaceutical polymorphs present different physicochemical properties, such as solubility, melting point, dissolution rate, crystal habit, density and hardness, which then affect stability and bioactivity of pharmaceuticals. Therefore, exploring the crystallization process of pharmaceutical polymorphs and controlling the ideal polymorph have become hot topics for researchers at home and abroad. Previous studies are mainly focused on polymorphs development and transformation process, few literatures about molecular assembly mechanism and control principle of pharmaceutical polymorphs are reported. In this project, amide class pharmaceuticals are selected as model objects, and the nucleation process of polymorphs will be investigated into molecular scale. First of all, the form and structure evolution of pharmaceuticals molecular aggregates in solution will be determined through study of intramolecular hydrogen bonds. Secondly, the theoretical relationship between solution chemistry and molecular assembly method will be analyzed by in-situ monitoring of the whole crystallization process of pharmaceutical polymorphs using process analytic tools (PAT), then the molecular assembly mechanism of polymorphs can be determined. Finally, the control principle of pharmaceutical polymorphs can be further investigated by exploring the interaction between additive molecules and pharmaceutical molecules, additive molecules and solvent molecules, pharmaceutical molecules and solvent molecules. Results of the project will be applied in the field of developing new pharmaceutical polymorphs, and it will provide theoretical guidance for new pharmaceutical research and innovation.

药物的不同晶型由于晶体结构的不同，会造成物化性质的差异，如：溶解度、熔点、溶出度、晶习、密度、硬度等，进而影响到药物的稳定性与生物活性等。因此，探索药物多晶型结晶过程并最终实现药物多晶型的调控已成为各国学者的研究热点问题。目前研究人员对药物多晶型的研究大多侧重于晶型开发与转化方面，而关于多晶型成核过程分子组装机理以及调控的研究却鲜有报导。本项目拟以酰胺类药物为研究对象，从分子尺度上深入研究成核过程。首先，通过分子间氢键作用的研究确定溶液中药物分子聚集体的存在形式及结构演变规律；其次，利用过程分析技术监测药物多晶型结晶整个过程，分析溶液化学性质与分子组装方式之间的理论关系，揭示不同晶型成核过程分子组装机理；最后，深入探讨添加剂分子与药物分子、添加剂分子与溶剂分子、药物分子与溶剂分子间的相互作用对药物多晶型的调控规律。本项目研究成果将应用于新晶型药物开发领域，为新型药物研究与开发提供理论指导。

多晶型会影响药物的物理化学性质，如：溶解度、熔点、溶出度、晶习、密度、硬度等，进而影响到药物的稳定性与生物活性等。因此，探索药物多晶型结晶过程并最终实现药物多晶型的调控对于医药工业具有重要意义。本项目以酰胺类模型药物（盐酸沃尼妙林、烟酰胺、苯甲酰胺等）为研究对象，基于结晶热力学数据测量，构建了不同晶型溶解度的预测模型，分析了溶剂-溶质分子间作用形式对溶解度数据的影响机理；在此基础上开展了药物多晶型结晶过程的系统研究工作，重点探讨了分子间氢键作用对酰胺类药物多晶型的稳定机制，并利用溶液光谱确定了不同晶型成核前的分子聚集体结构形式；联合过程分析技术，考察了不同因素包括温度、过饱和度、溶剂等对多晶型成核的影响，确定了不同晶型成核动力学区间，建立了多晶型成核动力学与转晶动力学模型；开展了功能化硅基纳米模板调控酰胺类药物多晶型成核研究，通过对硅基纳米模板表面进行功能化，实现了亚稳晶型在低过饱和度下的成功制备。本项目成果将为酰胺类药物多晶型的筛选制备提供实验方法和理论依据，对于最终实现酰胺类药物多晶型的调控和优化等方面具有重要的理论指导意义。