基于水活度的药物热力学及转晶过程研究

The drug polymorphism has a profound effect on the quality, safety and efficiency of the drug product. The polymorphism of drug is associated with thermodynamics and kinetics, and how to manipulate the production of objective polymorph by studying the thermodynamics and kinetics was the focus and difficulties of current research. In this work, effect of water activity on phase equilibrium was studied, transformation water activity and transformation temperature were obtained by the analysis of data and meanwhile the relation between them was related so as to further predict transformation water activity or to predict phase equilibrium of metastable polymorph. FBRM and PVM were used to research the influence of water activity on transformation process. Combined with the microcalorimetry technique, the characteristics and regularity of thermodynamics and kinetics during crystal nucleation, transformation and morphology evolution were revealed. The combined online technology made the correlation and completely scientific expression of the transformation process of the objective system during the study come true. And meanwhile, influence of water activity on the rate of transformation was studied by on line Raman spectroscopy. Based on the result, water activity as a way to manipulate the production of objective polymorph was realized. The result of the study will supply theoretical basis and research method for the hydrate drug development and its further medical applications, for the prediction of the new polymorph and its property, and for the drug quality control.

药物晶型可显著影响药品质量、安全性和有效性。药物的晶型与其热力学、动力学密切相关，如何通过研究多晶型药物的热力学、动力学过程，实现目标晶型的有效生产，是现今多晶型研究的热点和难点。展开水活度对相平衡的影响研究，通过数据分析，获得转晶温度、转晶水活度等参数，同时应用相平衡理论建模将转晶水活度、水活度、相平衡数据相关联，实现对转晶水活度或者亚稳定晶型相平衡的预测。采用在线FBRM、PVM技术研究水活度对转晶过程的影响，结合微热量技术揭示晶体成核、晶型转化、形貌结构演变的热动力学特征和规律，实现水活度动力学研究目标体系晶型结构转化的关联及完整科学表达。采用在线拉曼技术研究水活度对晶型转化速率的影响，探索水活度对动力学的影响。结合热力学、动力学的研究结果，通过水活度实现目标晶型的调控。本研究成果可为对水合物药物研发应用、对物质的未知多晶型和性质进行预测及质量控制提供理论指导。

药物晶型可显著影响药品质量、安全性和有效性。药物的晶型与其热力学、动力学密切相关，如何通过研究多晶型药物的热力学、动力学过程，实现目标晶型的有效生产，是现今多晶型研究的热点和难点。本项目主要以L-苯丙氨酸作为模型药物，从水活度的角度出发，探讨了水活度与转晶的关系。主要研究结果如下：应用相平衡理论，建立了L-苯丙氨酸在甲醇水体系中的三元相图，获得了转晶水活度与温度的关系方程（y=0.00667×T−1.03424），建立了转晶水活度、水活度、相平衡数据的关联式，实现了对转晶水活度或者亚稳定晶型相平衡的预测。研究了水活度对转晶成核速率过程的影响，结果表明，提高水活度有利于加快成核。探讨了水活度对转晶过程的影响，结果表明提高水活度有利于晶型转化的进行。 并在此基础上 实现了水活度对目标晶型的调控。本研究成果可为对水合物药物研发应用、对物质的未知多晶型和性质进行预测及质量控制提供理论指导。