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

Abstract

In this study, both practical and theoretical aspects of the solubility of edaravone (EDA) in Deep Eutectic Solvents (DESs) were considered. The solubility of edaravone in some media, including water, can be limited, which creates the need for new efficient and environmentally safe solvents. The solubility of EDA was measured spectrophotometrically and the complex intermolecular interactions within the systems were studied with the COSMO-RS framework. Of the four studied DES systems, three outperformed the most efficient classical organic solvent, namely dichloromethane, with the DES comprising choline chloride and triethylene glycol, acting as hydrogen bond donor (HBD), in a 1:2 molar proportion yielding the highest solubility of EDA. Interestingly, the addition of a specific amount of water further increased EDA solubility. Theoretical analysis revealed that in pure water or solutions with high water content, EDA stacking is responsible for self-aggregation and lower solubility. On the other hand, the presence of HBDs leads to the formation of intermolecular clusters with EDA, reducing self-aggregation. However, in the presence of a stoichiometric amount of water, a three-molecular EDA–HBD–water complex is formed, which explains why water can also act as a co-solvent. The high probability of formation of this type of complexes is related to the high affinity of the components, which exceeds all other possible complexes.

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

“…Then, the most effective solvent systems were systematically studied at different temperatures and by dilution with water. This aspect of adding water to the DES often leads to a surprising structure [92,93] and solubilizing properties [79,83]. Water is considered an antisolvent because the aqueous solubility of various compounds is several orders of magnitude lower compared to DESs, and dilution with water in excess amounts significantly reduces the solubility of many solutes in such DES-water mixtures.…”

“…This method has been used numerous times by many researchers, including our research team [113][114][115][116], and has proven its reliability through the comparison of obtained solubility values with the literature data. The choice of the eutectic components was based on our previous experiences, which resulted in the elevated solubility of many APIs [79,83,115].…”

“…The training of nonlinear models was performed according to the scheme already applied to our previous projects [79,83,117,118]. Since details were already presented, here, only a brief synopsis is provided.…”

“…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.…”

“…DESs exhibit a unique combination of properties such as low toxicity, biodegradability, and importantly tunable physicochemical characteristics [71][72][73]. Despite the fact that the extent of their environmental friendliness has recently become a topic of debate [74][75][76][77], DESs showcase remarkable potential across various domains of pharmaceutical applications, including drug synthesis, formulation, and extraction processes [78][79][80][81][82][83][84][85][86][87][88]. Noteworthily, DESs have been shown to be effective solubilizers of ibuprofen [89,90] and ketoprofen [91].…”