Department of Physical Chemistry, Pharmacy Faculty, Collegium Medicum of Bydgoszcz, Nicolaus Copernicus University in Toruń, Kurpińskiego 5, 85-096 Bydgoszcz, Poland.
Molecules. 2023 Jan 7;28(2):629. doi: 10.3390/molecules28020629.
Edaravone, acting as a cerebral protective agent, is administered to treat acute brain infarction. Its poor solubility is addressed here by means of optimizing the composition of the aqueous choline chloride (ChCl)-based eutectic solvents prepared with ethylene glycol (EG) or glycerol (GL) in the three different designed solvents compositions. The slurry method was used for spectroscopic solubility determination in temperatures between 298.15 K and 313.15 K. Measurements confirmed that ethaline (ETA = ChCl:EG = 1:2) and glyceline (GLE = ChCl:GL = 1:2) are very effective solvents for edaravone. The solubility at 298.15 K in the optimal compositions was found to be equal x = 0.158 (c = 302.96 mg/mL) and x = 0.105 (c = 191.06 mg/mL) for glyceline and ethaline, respectively. In addition, it was documented that wetting of neat eutectic mixtures increases edaravone solubility which is a fortunate circumstance not only from the perspective of a solubility advantage but also addresses high hygroscopicity of eutectic mixtures. The aqueous mixture with 0.6 mole fraction of the optimal composition yielded solubility values at 298.15 K equal to x = 0.193 (c = 459.69 mg/mL) and x = 0.145 (c = 344.22 mg/mL) for glyceline and ethaline, respectively. Since GLE is a pharmaceutically acceptable solvent, it is possible to consider this as a potential new liquid form of this drug with a tunable dosage. In fact, the recommended amount of edaravone administered to patients can be easily achieved using the studied systems. The observed high solubility is interpreted in terms of intermolecular interactions computed using the Conductor-like Screening Model for Real Solvents (COSMO-RS) approach and corrected for accounting of electron correlation, zero-point vibrational energy and basis set superposition errors. Extensive conformational search allowed for identifying the most probable contacts, the thermodynamic and geometric features of which were collected and discussed. It was documented that edaravone can form stable dimers stabilized via stacking interactions between five-membered heterocyclic rings. In addition, edaravone can act as a hydrogen bond acceptor with all components of the studied systems with the highest affinities to ion pairs of ETA and GLE. Finally, the linear regression model was formulated, which can accurately estimate edaravone solubility utilizing molecular descriptors obtained from COSMO-RS computations. This enables the screening of new eutectic solvents for finding greener replacers of designed solvents. The theoretical analysis of tautomeric equilibria confirmed that keto-isomer edaravone is predominant in the bulk liquid phase of all considered deep eutectic solvents (DES).
依达拉奉作为一种脑保护剂，用于治疗急性脑梗死。本研究通过优化由乙二醇（EG）或甘油（GL）组成的三种不同设计溶剂组合物的水合氯化胆碱（ChCl）基共晶溶剂的组成，解决了其溶解度差的问题。在 298.15 K 至 313.15 K 的温度范围内，使用浆态法进行光谱溶解度测定。测量结果证实，乙二胺（ETA = ChCl：EG = 1：2）和甘油胺（GLE = ChCl：GL = 1：2）是依达拉奉的非常有效的溶剂。在最佳组成中的 298.15 K 下的溶解度分别为 x = 0.158（c = 302.96 mg/mL）和 x = 0.105（c = 191.06 mg/mL），分别用于甘油胺和乙二胺。此外，有文献记载，纯净共晶混合物的润湿会增加依达拉奉的溶解度，这不仅是从溶解度优势的角度来看是一个幸运的情况，而且还解决了共晶混合物的高吸湿性问题。含有 0.6 摩尔分数最佳组成的水混合物在 298.15 K 下的溶解度分别为 x = 0.193（c = 459.69 mg/mL）和 x = 0.145（c = 344.22 mg/mL），分别用于甘油胺和乙二胺。由于 GLE 是一种可接受的药物溶剂，因此可以将其视为该药物的潜在新液体形式，其剂量可调。实际上，可以使用研究的系统轻松实现推荐给患者的依达拉奉的剂量。观察到的高溶解度可以根据使用导体相似性屏蔽模型（COSMO-RS）方法计算的分子间相互作用来解释，并进行了校正，以考虑电子相关、零点振动能和基组叠加误差的影响。广泛的构象搜索允许确定最可能的接触，收集和讨论了其热力学和几何特征。有文献记载，依达拉奉可以通过五元杂环之间的堆积相互作用形成稳定的二聚体。此外，依达拉奉可以作为氢键受体与研究系统的所有成分相互作用，与 ETA 和 GLE 的离子对具有最高的亲和力。最后，提出了线性回归模型，可以利用从 COSMO-RS 计算中获得的分子描述符准确估计依达拉奉的溶解度。这使得可以筛选新的共晶溶剂以寻找设计溶剂的更环保替代品。互变异构平衡的理论分析证实，酮式依达拉奉在所有考虑的深共晶溶剂（DES）的主体液相中占优势。
