聚合物对阿德福韦酯-糖精共晶形成过程中热力学行为的影响

Effect of polymers on the formation thermodynamics of adefovir dipifoxil-saccharin cocrystal

考察了聚合物对阿德福韦酯(AD)-糖精(SAC)共晶形成过程中热力学的影响。选择聚乙二醇、乙基纤维素、聚维酮和聚丙烯酸树脂作为代表性聚合物,通过HPLC法测定了不同温度下AD和SAC在不同聚合物乙醇溶液中的溶解度以及AD-SAC共晶在不同浓度SAC的聚合物乙醇溶液中的溶解度。通过建立数学模型,描述了聚合物及温度对AD-SAC共晶溶解度的影响;依据溶解度数据,构建了AD-SAC共晶的三元相图,预测了共晶溶解度以及共晶产率的变化。结果显示,聚合物的加入提高了共晶的溶解度,共晶的络合常数(K11)减小,溶度积(Ksp)有增大的趋势,共晶反应自由能(ΔG0)的绝对数值呈减小趋势,并且三元相图中不饱和溶液的单相区域以及共晶与其不饱和溶液的两相平衡区域明显增大。因此,聚合物会在不改变共晶生成反应自发性的前提下降低共晶形成速度,降低纯共晶的产率,同时拓宽了制备纯共晶所需AD与SAC溶液的浓度可选择范围。

The aim of this study was to investigate the effect of polymers on the formation thermodynamics of adefovir dipifoxil （AD） -saccharin （SAC） cocrystal. In the absence and presence of polymers such as polyethylene glycol, ethyl cellulose, polyvinylpyrrolidone and Eudragit El00, solubilities of AD and SAC in ethanol solution containing different concentrations of SAC at variable temperatures were determined by high-performance liquid chromatography （HPLC）. Appropriate mathematical model for the description of the influence of polymers and temperature on the solubility of AD-SAC coerystal was established. The ternary phase diagrams were set up using the assayed solubilities data, and they were used to predict changes of cocrystals solubility and product yield. Addition of polymers resulted in increased solubility of AD-SAC cocrystal, decreased complexation constants （Kll）, enhanced solubility products （Ksp）, but there was a gradually decreased free energy change （AGO）. The areas of homogeneous liquid phase and pure solid cocrystal in equilibrium with the liquid phase in ternary phase diagrams were also found to be larger. Therefore, although there was no change to the spontaneity of AD-SAC cocrystal formation, there existed retardation to cocrystal formation and reduction in product yield of pure cocrystal in the presence of polymers. Moreover, application of polymers could broaden the concentration range of AD and SAC solutions when solution crystallization was selected to prepare cocrystal.