Deep Eutectic Solvents: An Eco-friendly Design for Drug Engineering

Abstract

In the spirit of circular economy and sustainable chemistry, the use of environmentally friendly chemical products in pharmacy has become a hot topic. In recent years, organic solvents have been the subject of a great range of restriction policies due to their harmful effects on the environment and toxicity to human health. In parallel, deep eutectic solvents (DESs) have emerged as suitable greener solvents with beneficial environmental impacts and a rich palette of physicochemical advantages related to their low cost and biocompatibility. Additionally, DESs can enable remarkable solubilizing effect for several active pharmaceutical ingredients (APIs), thus forming therapeutic DESs (TheDESs). In this work, special attention is paid to DESs, presenting a precise definition, classification, methods of preparation, and characterization. A description of natural DESs (NaDESs), i. e., eutectic solvents present in natural sources, is also reported. Moreover, the present review article is the first one to detail the different approaches for judiciously selecting the constituents of DESs in order to minimize the number of experiments. The role of DESs in the biomedical and pharmaceutical sectors and their impact on the development of successful therapies are also discussed.

Introduction

Solvents are generally employed in about 85 % of pharmaceutical processes. In this domain, water is the most convenient solvent due to its safety and eco-friendliness. However, organic solvents are used the most for poorly water-soluble active pharmaceutical ingredients (APIs) employed in formulation development and manufacturing. Many conventional organic solvents are harmful to the environment or toxic to human health. Consequently, many regulations have limited their use, especially for the ones classified as carcinogenic or toxic for reproduction.1, 2

Two main categories of solvents can be considered of great interest as eco-friendly alternatives: Ionic liquids (ILs) and deep eutectic solvents (DESs). ILs emerged as outstanding green alternatives to conventional organic solvents due to their negligible vapor pressures and good chemical/thermal inertness.3, 4

However, some limitations are still encountered regarding their biotoxicity and biodegradability.5 On the other hand, Abbott et al. described in 2003 a fascinating class of nonaqueous solvents, which is called deep eutectic solvents, representing eutectic mixtures of ammonium salts (e. g., choline chloride, ChCl) and hydrogen bond donors (HBD) (e. g., urea and glycerol).6

This class of solvents has some IL-like solvent properties such as low melting point and volatility, high thermal stability and solubility, and finetuned physicochemical properties by choosing appropriate DES components.7-9 Interestingly, a great range of DESs components are present in nature and are easily prepared by several approaches.

DESs can be considered as a greener alternative compared to ILs, accompanied with interesting advantages: Low cost, higher purity and biodegradability, and potential low toxicity. Consequently, such DESs have been extensively employed in different pharmaceutical applications, including solubilization of poorly water-soluble drugs, permeability enhancement, stability improvement, and designing polymeric and self-assembled nanocarriers.10-12 Furthermore, they have attracted a great attention in many academic and industrial fields, such as inorganic synthesis, organic (bio)catalysis and synthesis, dissolution and extraction processes, material chemistry, bioengineering, and biotechnology.13-17 The evolution of the DESs and their involvement in various research areas during the last years are summarized in Figure1.

This review aims to clarify some misconceptions about DESs, unveiling the main difference between eutectic and deep eutectic mixtures, which has been misused in several published articles. Also, we highlight the importance of natural deep eutectic solvents (NaDES) to avoid the potential environmental hazards of traditional solvents. Moreover, the main criteria involved in the selection process of DESs components is illustrated in addition to the methods of preparation and characterization tools of these systems. Finally, we discuss the role and the potential activity of DESs in pharmaceutical applications, also providing a brief future perspective for using this eutectic system in drug discovery and formulation development.

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Table 1. Classification of deep eutectic solvents based on the nature of the constituents.

Feras Oyoun, Dr. Antoniya Toncheva, Luis Castillo Henríquez, Dr. Raphael Grougnet, Dr. Fouad Laoutid, Dr. Nathalie Mignet, Dr. Khair Alhareth, Prof. Yohann Corvis, Deep Eutectic Solvents: An Eco-friendly Design for Drug Engineering, First published: 18 July 2023 https://doi.org/10.1002/cssc.202300669

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