Abstract Nifedipine is an oral calcium channel blocker in clinical practice, and widely used to prevent and treat heart diseases. In this work, the equilibrium solubility of nifedipine (NIF) in twelve pure solvents including alcohols and esters was determined by static method at temperatures ranging from 283.15 K to 323.15 K. In all studied solvent systems, the solubility increases monotonously with increasing temperature. Besides, the effect of solvent properties on solid–liquid phase equilibrium of NIF was investigated. The results show that the solubility of NIF correlates well with the solvent properties in alcohol solvents but no obvious correlation can be found in ester solvents. In addition, the solubility data was correlated with the modified Apelblat equation, λh equation, van't Hoff equation and NRTL model, and the overall fitting ARD% are 0.94%, 2.15%, 2.75% and 4.03% respectively. Therefore, the modified Apelblat equation achieves the best fitting performance. Furthermore, in order to quantitatively study how the solute–solvent interaction affects the solubility, the solvation free energy was calculated by the molecular dynamic (MD) simulation. The absolute values of solvation free energy of esters (−18.96 to −20.32 kJ·mol−1) are higher than those of alcohols (−15.21 to −17.54 kJ·mol−1), which is consistent with the order of solubility values. Moreover, COSMO-RS σ-profiles were employed to qualitatively describe the intermolecular interactions. Finally, the COSMO-RS model was employed to predict the solubility of NIF in the studied solvents. The results show a good performance on predicting the solubility of NIF though the deviations existed in some cases.

中文翻译：

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硝苯地平在十二种纯溶剂中固液相平衡的实验测定和计算分析

摘要 硝苯地平是临床上一种口服钙通道阻滞剂，广泛用于预防和治疗心脏病。在这项工作中，硝苯地平 (NIF) 在 12 种纯溶剂（包括醇和酯）中的平衡溶解度是通过静态方法在 283.15 K 到 323.15 K 的温度范围内测定的。在所有研究的溶剂系统中，溶解度随着温度的升高而单调增加。此外，还研究了溶剂性质对 NIF 固液相平衡的影响。结果表明，NIF的溶解度与醇类溶剂中的溶剂性质有很好的相关性，但在酯类溶剂中没有发现明显的相关性。此外，溶解度数据与修正的 Apelblat 方程、λh 方程、van't Hoff 方程和 NRTL 模型相关，总体拟合ARD%分别为0.94%、2.15%、2.75%和4.03%。因此，修改后的 Apelblat 方程达到了最佳拟合性能。此外，为了定量研究溶质 - 溶剂相互作用如何影响溶解度，通过分子动力学（MD）模拟计算溶剂化自由能。酯的溶剂化自由能绝对值（-18.96 至-20.32 kJ·mol-1）高于醇（-15.21 至-17.54 kJ·mol-1），这与溶解度值的顺序一致。此外，COSMO-RS σ-profiles 用于定性描述分子间相互作用。最后，采用 COSMO-RS 模型预测 NIF 在所研究溶剂中的溶解度。