基于热力学的多晶型药物成核调控机制与动力学

Polymorphism is an important factor for the clinic effect of drugs and nucleation is the decision step of the polymorphism. Therefore, the investigation on nucleation is of great significance. The microstructure of the supersaturation solution will be investigated, which can provide a guidance for the control of polymorphism and the developing of a nucleation kinetic model. In the two-step nucleation mechanisms, pre-nucleation clusters are considered to be exist in the supersaturation solution. However, it is not available in the thermodynamic models. In this project, it is proposed that the model of pre-nucleation clusters can be established with reference to solvation and molecular association effect on the basis of E-NRTL equation. At present, the application of thermodynamic approach on the investigation of crystallization is only limited to simple systems such as the crystal growth process of a single type of crystal. In this project, with the variation laws of activity in the supersaturation solution, the nucleation of polymorphism will be investigated. Both cooling crystallization and anti-solvent crystallization will be carried out in the induction time and metastable zone width (MZW) experiments. The main influence factors of polymorphism and kinetics will be investigated and expressed as thermodynamic parameters. Then a nucleation kinetic model will be developed on the basis of activity. With the model, the nucleation rate will be calculated more accurate and the polymorphism is expected to be predicted on the basis of calculation results.

晶型是影响药物临床疗效的重要因素，成核阶段决定了产生的晶型，因此对多晶型药物成核的研究有重要意义。想要深入理解多晶型成核规律，建立调控机制并实现模型化，就需要从热力学角度考察过饱和溶液微观结构的变化。两步成核机理认为成核过程存在溶质聚集体，而现有的热力学模型中不存在这种形态的粒子。申请人提出参照溶剂化和分子缔合作用建立溶质聚集体的物理模型和计算方法，基于电解质NRTL方程进行热力学模拟。热力学在结晶方面的应用目前还仅限于单晶型的晶体生长等影响因素较少的体系，而本项目将结合过饱和溶液活度变化从热力学角度解析多晶型成核规律。采用冷却和溶析结晶相结合的方式测定成核诱导期和介稳区（MZW），从热力学角度解析不同晶型的成核动力学影响因素，并深入考察晶型的热力学控制因素和规律，在此基础上建立以活度为基准的成核动力学模型。新模型有望能更准确预测成核速率并为晶型比例分析提供更坚实的理论依据。

多晶型药物普遍存在，而成核能够决定晶体的晶型，所以对多晶型药物成核的研究有重要意义。要深入理解多晶型成核规律，建立调控机制并实现模型化，就需要从热力学角度考察过饱和溶液微观结构的变化。热力学在结晶方面的应用目前还仅限于单晶型的晶体生长等影响因素较少的体系，而本项目结合过饱和溶液活度变化从热力学角度解析多晶型成核规律。本项目制备了不同晶型的L-组氨酸并测定了L-组氨酸体系溶解度并利用NRTL方程等进行了热力学模拟；采用冷却和溶析结晶相结合的方式测定成核诱导期和介稳区（MZW），从热力学角度解析了不同晶型的成核动力学影响因素，并深入考察晶型的热力学控制因素和规律。此外，还通过热力学与分子模拟相结合的方法对晶型的变化规律进行了研究。