黄芩素-烟酰胺共晶结晶过程的热力学研究
Thermodynamics of baicalein-nicotinamide co-crystallization process
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摘要: 以黄芩素-烟酰胺共晶为模型药物，研究共晶形成的热力学。通过测定不同温度下黄芩素在不同浓度烟酰胺溶液中的溶解度，探讨黄芩素-烟酰胺共晶的络合形式，计算相关热力学参数，并绘制不同温度下的黄芩素-烟酰胺-乙酸乙酯三元相图。结果表明，黄芩素-烟酰胺共晶在乙酸乙酯中符合物质的量比1∶1溶液络合模型，共晶形成反应为热力学自发反应(ΔG°<；0)，随着温度升高，Ksp逐渐增大，K11逐渐减小，反应自发程度减弱，三元相图中共晶区域减小，当温度达到T*=315 K后，ΔG°=0(ΔH°=-6.314×10-2 kJ/mol，ΔS°=-0.200 5 J/mol·K)，自发反应不再进行，证明低温有利于共晶的形成。根据三元相图的非对称特点，设计了3种不以物质的量比1∶1为出发点制备共晶的方法，DSC结果表明，3种方法制备得到的黄芩素-烟酰胺共晶均为熔点单一的纯共晶。Abstract: Baicalein-nicotinamide(BE-NCT)co-crystal was chosen as model drug to investigate the thermodynamic characteristics. Solubilities of BE in NCT solutions in ethyl acetate at different temperatures were determined in order to explain the complexation behavior of BE-NCT co-crystal. Thermodynamic parameters of co-crystal formation progress were calculated. Ternary phase diagrams(TPDs)of the BE-NCT-ethyl acetate systems at various temperatures were established. The non-linear fitting equation according to 1 ∶1 complexation mechanism of BE-NCT co-crystal demonstrated a good correlation between calculated and experimental data(R2> 0. 98). Co-crystal formation is a spontaneous process(ΔG°< 0). Increase in temperature resulted in the increase of Ksp, decrease of K11 and a narrowed co-crystal zone. The degree of spontaneous reaction also decreased with increased temperature. The spontaneous reaction no longer carried out if the temperature reached T*=315 K since ΔG°=0(ΔH°=-6. 314×10-2 kJ/mol, ΔS°=-0. 200 5 J/mol ·K). A drop in temperature favors the complexation between BE and NCT in ethyl acetate. Since NCT has higher solubility than BE in ethyl acetate, the TPDs of co-crystal was asymmetric. The DSC diagrams of products prepared via three presupposed methods confirmed that the BE-NCT co-crystal could be generated in solutions of nonstoichiometric compositions.
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Keywords:
- baicalein /
- nicotinamide /
- co-crystal /
- solvent complexation /
- thermodynamics /
- ternary phase diagram
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