Natural Deep Eutectic Solvents: Mechanistic Insights, Analytical Applications and Emerging Role of Drug Solubility Enhancement

Abstract

Natural Deep Eutectic Solvents (NADES), are an emerging class of green solvent system that has a great potential in analytical and pharmaceutical sciences. Strong intermolecular interactions (hydrogen bonding) between naturally occurring hydrogen bond donors (HBDs) and hydrogen bond acceptors (HBAs) including sugars, organic acids, amino acids and polyols form NADES. The interactions lead to the formation of eutectic mixtures that have distinct physicochemical characteristics including tunable polarity, high solubilization capacity, low volatility, and increased thermal stability rendering them desirable substitutes of traditional organic solvents that are characterized by toxicity and environmental challenges. Mechanistically, NADES increase the solubility of water-insoluble compounds via various mechanisms such as large hydrogen-bonding structures, interruption of crystalline drug frameworks, the modulation of polarity, and encapsulation into structured solvent networks at a molecular-scale level. Such properties help to enhance the solubility, stability, and bioavailability possibilities of the hydrophobic drugs and bioactive substances. Analytically, NADES have seen extensive use as green extraction agents to recover bioactive compounds phenolics, flavonoids, alkaloids and terpenoids as examples of complex biological matrices. The fact that they are compatible with various forms of analysis such as high-performance liquid chromatography (HPLC), gas chromatography (GC), capillary electrophoresis and spectroscopic methods further underscores the fact that they can be used as eco-friendly solvents. NADES have proven useful in pharmaceutical sciences to improve drug solubility, to stabilize labile compounds, and to develop more complex drug delivery systems such as oral and transdermal systems. Future directions involve using NADES with nanotechnology, computational modeling, and solvent design by artificial intelligence to incorporate the rational and application-specific development of formulations. It is hoped that these advances will result in more rapid translation of NADES into industrial and pharmaceutical applications. NADES are a fast-developing area that is consistent with the principles of green chemistry and provides new mechanisms on how to improve solubility and ensure sustainable processing.