分子构象灵活性对药物多晶型成核与生长的影响规律及机理研究

The nucleation and growth processes of polymorphs are common technical and economic problems during product regulation, optimization and polymorph control. In this project, conformational polymorphs will be chosen as the model system to investigate the mechanism of conformational change and conformer self-association on the nucleation and growth processes of conformational flexible molecules. The conformational change kinetics will be established using molecular simulation software. The molecular conformation and conformer self-association during nucleation and growth will be quantitative analyzed with the assistance of NMR, ATR-FTIR, UV-vis and Raman spectroscope to study the effect of crystallization conditions on the polymorph formation. The “molecular conformational change–crystal nucleation-crystal growth” and “molecular conformational change-pharmaceutical polymorphic transformation” models will be established, which can provide experiment method and theory basis for the pharmaceutical production technology design， and will be of great theoretical significance for the control and optimization of pharmaceutical polymorphism.

多晶型的成核和生长过程是调控和优化药物产品质量、控制产品晶型所共有的技术经济问题。本项目拟以构象多晶型为研究体系，以具有构象灵活性的药物分子在结晶过程中分子构象转变、构象体聚集或自缔合形式对成核和生长的影响机理为研究目标，以分子模拟软件构建分子构象转变动力学；以核磁共振、红外光谱仪以及紫外可见吸收光谱仪、拉曼光谱仪为核心测试手段，对药物构象多晶型成核和生长过程中分子构象、构象体聚集或自缔合形式进行定量描述,考察各结晶条件对多晶型形成的影响规律；构建“分子构象转变—晶体成核—晶体生长”和“分子构象转变—药物晶型转变”模型，为制定多晶型的工艺条件提供实验方法和理论依据，对于最终实现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。

药物多晶型的分子组装过程是调控和优化药物产品质量和晶型可控制备的关键。本项目以呋塞米、氟芬那酸、螺内酯等构象多晶型为研究体系，重点研究了柔性药物分子在结晶过程中分子构象转变、构象体聚集或自缔合形式对结晶热力学和结晶动力学的影响机理，基于密度泛函理论，以Gussian09软件构建了分子构象势能面；以核磁共振、红外光谱仪、拉曼光谱仪为核心测试手段，对药物构象多晶型成核和生长过程中分子构象、构象体聚集或自缔合形式进行定量描述,考察了结晶方式（冷却结晶、溶析结晶、蒸发结晶）、温度、溶剂和过饱和度等条件对多晶型形成的影响规律；构建了“分子构象转变—晶体成核—晶体生长”和“分子构象转变—药物晶型转变”模型，为制定多晶型的工艺条件提供实验方法和理论依据，对于最终实现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。通过本项目的研究，在结晶类高水平期刊Crystal Growth and Design，Journal of Molecular Liquids, RSC Advances，International Journal of Thermodynamics等国内外知名期刊中累计发表和接收SCI论文4篇并依托本项目申请了国家发明专利3项。