改善难溶性药物的溶解度、生物利用度并开展机制研究是药剂学发展和应用中极具挑战性的科学难题。药物共晶是解决上述问题的有效方法之一，但其合成仍严重依赖溶剂、污染环境且缺乏可靠的热力学理论模型进行相关性预测分析。申请人在前期工作中采用环境友好的机械化学方法发现了多个新共晶体系，并在此基础上开展了PEG诱导共晶合成实验，初步证实有效性，但其作用与机理有待进一步研究。本项目拟在前期工作基础上，选择水难溶性药物为模型：（1）建立辅料诱导的共晶合成方法并考察PEG分子量、含量、研磨条件等作用；（2）基于PC-SAFT状态方程计算活度系数（γ）并结合共晶溶度积Ks, cc、三元相图法阐明溶解机理；（3）探讨共晶形成后药剂学性质改变与生物利用度的相关性。研究所建立的具有预测功能的热力学模型可为阐明药用辅料对共晶形成的影响、溶解机理提供数据支持与理论依据，对难溶性药物生物利用度的提高及制剂学研究具有重要意义。

One of the challenging scientific problems in pharmaceutical development and application is to improve the solubility and bioavailability of poorly water-soluble drugs based on the kinetic mechanism. So far, pharmaceutical cocrystal is one of the effective methods to solve above problems, but its synthesis is heavily dependent on the solvent with environmental pollution and insufficient reliable theoretical thermal kinetic models to elucidate and predict the cocrystal formation. We have discovered several new cocrystal systems through environment-friendly mechanochemical method. On this basis, we developed a method to synthesis cocrystal induced by polyethylene glycol (PEG) and confirmed its effectiveness preliminarily. But, how PEG works and the mechanism needs further study. On the basis of our previous research foundation, this project intends to select poorly water-soluble marketed drugs as the model: (1) To establish cocrystal synthesis assisted with PEG and optimize the molecular weight, content and grinding condition which could affect on the formation of cocrystal; (2) To elucidate the solubility and dissolution mechanism of cocrystal through calculation of activity efficient (γ) and ternary phase diagram based on PC-SAFT status equation and cocrystal solubility product Ks, cc. (3) To discuss the cocrystal physicochemical and bioavailability alteration with the inter-correlation. A predictive thermal kinetic model will be developed in this study and it is expected that this model could be used to clarify the solubility mechanism and provide data support. Furthermore, it is of great significance to the development on bioavailability improvement and pharmaceutical research of poorly water-soluble drugs.