对乙酰氨基酚-茶碱药物共晶热力学稳定性机理研究

Pharmaceutical cocrystals are an emerging class of engineered solid forms to improve the physicochemical properties of drug substances without changing their chemical structures. Understanding the thermodynamic phase behavior and solubility is essential to cocrystal screening, synthesis, characterization, manufacture, and formulation, however, it is less studied compared to cocrystal synthesis..The proposal aims at the thermodynamic stability mechanism of the acetaminophen-theophylline cocrystals. Here the physical stability phase diagram is proposed to describe the cocrystal stability by extending the established hydrate stability phase diagram..In the study ,a mathematical model will be derived from solution chemistry to describe the solubility behavior of the cocrystal and the effect of cocrystal constitutes on the cocrystal solubility. Triangular Phase Diagram will be plotted to deonstrate the stable domain of each phase. The mathematical model and Triangular Phase Diagram will be used to better understand and prove the proposed stability phase diagram. The eutectic point,where theophylline and acetaminophen-theophylline are of the same solubility and in equilibrium, will be proposed to be a meaningful indicator for cocrystal thermodynamic stability. Then the effect of pH, solvent, cocrystal constitutes concentration on the cocrystal stability will be studied. The phase transformation between the cocrystal and solvate or hydrate will be investigated..The objectives of this project lie in: 1)understanding the mechanism of acetaminophen-theophylline cocrystal thermodynamic stability and phase transformation, 2)establishing a systematic protocol to study cocrystal thermodynamic stability, 3)developing a method to measure true cocrystal solubility since cocrystal can transform to the most stable drug in solution, 4)proposing a rule to describe thermodynamic stability of cocrystals and elucidating the critical point for cocrystals.

药物共晶（以下简称共晶）是晶体工程学的研究热点。针对在溶液中制备共晶重复性差、所得共晶不稳定且易发生相转变等问题，课题通过借鉴物质水化规律，提出共晶形成与热力学稳定性准则。构建对乙酰氨基酚-茶碱-溶剂三元相图，运用溶液化学理论建立共晶溶解度数学模型，以解决以下科学问题：①结合模型和相图来验证共晶形成与热力学稳定性准则的正确性，阐明准则中临界点的意义；②建立测定共晶溶解度的方法。课题通过研究pH值、溶剂、共晶组成成分的浓度、药物其他固体形态（多晶型、溶剂化物、水化物等）对共晶形成与稳定性的影响，揭示①对乙酰氨基酚-茶碱共晶在溶液中的溶解行为和热力学稳定性机理；②共晶与药物其他固体形态之间的相平衡及过饱和度差异导致的相转化机理。课题将建立共晶热力学研究方法，提出的共晶形成与热力学稳定性准则对共晶筛选、制备、生产具有指导意义，在制剂和保存中，应用该准则可避免共晶因相转变而导致药物失效的问题。

药物共晶（以下简称共晶）是晶体工程学的研究热点。针对在溶液中制备共晶重复性差、所得共晶不稳定且易发生相转变等问题，运用溶液化学理论和相平衡理论，课题①提出并验证了共晶形成与热力学稳定性准则以及构建APAP-THEO热力学稳定性相图，准则中的临界点和三元相图中的三相点具有相同的意义。②建立了测定共晶溶解度的方法。③揭示药物共晶在溶液中稳定存在的热力学条件。在非复杂体系中共晶形成和稳定存在的前提是共晶体形成物的活度高于临界值，不受温度限制。溶剂选取与任一单体均不生成溶剂化物的溶剂。④揭示了对乙酰氨基酚-茶碱共晶在溶液中的溶解行为以及共晶与单体之间的溶剂介导相转化机理。课题提出的共晶形成与热力学稳定性准则对共晶筛选、制备、生产具有指导意义，在制剂和保存中，应用该准则可避免共晶因相转变而导致药物失效的问题。