柚皮素-异烟酰胺共晶形成热力学的研究

Thermodynamic studies of naringenin-isonicotinamide cocrystals

以柚皮素(naringenin,NAR)为模型药物,异烟酰胺(isonicotinamide,INT)为共晶形成物(CCF),研究NAR-INT共晶在不同溶剂(甲醇、乙醇、异丙醇和乙酸乙酯)中的形成热力学。通过混悬液结晶法制备化学计量比为1∶2的NAR-INT共晶,考察了共晶在水中的溶出行为,测定其在不同溶剂和不同温度下的溶解度,采用络合模型计算共晶的溶度积(K_(sp))、络合常数(K_(12))及反应吉布斯自由能(ΔG)等热力学参数,同时绘制不同温度下的NAR-INT-溶剂三元相图。研究表明,NAR-INT共晶在乙醇、异丙醇和乙酸乙酯中符合1∶2溶液络合模型,而在甲醇中符合无溶液络合模型。NAR-INT共晶的生成是一个熵减放热的自发反应(ΔG<0、ΔH<0、ΔS<0),而共晶的溶解为吸热过程(Δ_(sol)H_m>0)。随着温度升高,K_(sp)逐渐增大,而K_(12)逐渐减小,共晶的溶解加快,不利于NAR和INT的络合,不易生成共晶。比较共晶在4种溶剂中的三元相图,发现在乙酸乙酯中的单相不饱和溶液区域最小,共晶在乙酸乙酯中最易形成。该热力学研究为NAR-INT共晶的制备条件优化奠定了理论和应用基础。

The purpose of this study was to investigate the thermodynamics of naringenin （NAR）-isonicotinamide （INT） cocrystal （stoichiometric ratio, 1 ： 2） formed in different solvents. The dissolution behavior of cocrystal was explored in the water. Solubility of NAR-INT cocrystals under various temperatures were measured, followed by fitting the complexation model to calculate the thermodynamic parameters solubility products （Ksp）, complexation constants （K12） and Gibbs energy change （AG） of cocrystal during formation progress. Ternary phase diagrams （TPDs） of the NAR-INT-solvent systems under various temperatures were plotted. Based on the non-linear simulation, 1 ： 2 complexation model was well fitted to the NAR-1NT cocrystal formation in ethanol, isopropanol and ethyl acetate, while no complexation model was more suitable for that in methanol. The cocrystallization reaction was exothermic and spontaneous （AG〈0, AH〈0, AS〈0）. Ksp increased while K12 decreased when increasing temperature, suggesting that the two components could cocrystallize more easily at the lower temperature. homogeneous liquid phase in ethyl acetate was the In comparison to TPDs in other solvents, the area of smallest, indicating the easiest formation of NAR-INT cocrystal in ethyl acetate. The current study provides a theoretical foundation for preparation and optimization of scale-up NAR-INT cocrystals.