Intermolecular Interactions of Edaravone in Aqueous Solutions of Ethaline and Glyceline Inferred from Experiments and Quantum Chemistry Computations

Abstract

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 xE = 0.158 (cE = 302.96 mg/mL) and xE = 0.105 (cE = 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 xE = 0.193 (cE = 459.69 mg/mL) and xE = 0.145 (cE = 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).

Deep Eutectic Solvents as Agents for Improving the Solubility of Edaravone: Experimental and Theoretical Considerations

“…The current study is an extension of the previous investigations regarding the solubility of edaravone in organic solvents [ 72 ] and DES systems [ 71 ]. The main motivation is finding pharmaceutically acceptable systems with elevated solubility of this active pharmaceutical ingredient.…”

“…Despite these limitations, DESs are extensively utilized in many applications, including the pharmaceutical industry [ 68 , 69 , 70 ]. In fact, one of our previous studies was focused on the solubility of edaravone in DESs [ 71 ].…”

Experimental and Machine-Learning-Assisted Design of Pharmaceutically Acceptable Deep Eutectic Solvents for the Solubility Improvement of Non-Selective COX Inhibitors Ibuprofen and Ketoprofen

“…This approach, acronymed as COSMO-RS (COnductor-like Screening Model for Realistic Solvents) [120], is designed for bulk systems, in principle, of arbitrary compositions, concentrations, and temperature ranges. That is why this particular framework is selected as a default source of theoretically determined molecular characteristics, as it was already successfully documented in our previous projects [79,83,117,118,[121][122][123][124]. In particular, the COSMO-RS theory implemented in the COSMOtherm package (version 24.0.0) offers a very convenient way to saturate system characteristics and is used as the source of molecular descriptors also in this project.…”

Solubility and Stability of Carvedilol in Deep Eutectic Solvents: A Step Towards a Sustainable Pharmaceutical Formulation in the Liquid State

“…It has previously been shown that the amount of water in DESs can affect the solubility of the active ingredient. [57] On the other hand, it is well known that the high viscosity of DES may be a limitation for the development of new liquid formulations. For these reasons, different amounts of water have been explored for each of the DESs to reduce the viscosity of the preparations and increase their usability.…”

“…It has previously been shown that the amount of water in DESs can affect the solubility of the active ingredient [57] . On the other hand, it is well known that the high viscosity of DES may be a limitation for the development of new liquid formulations.…”