## 2 Applications Related to Peculiar Solubility Properties of DESs
\begin{table}
\begin{tabular}{c c c c} \hline \hline \multirow{2}{*}{**Eutectic Mixture**} & \multirow{2}{*}{**Drug**} & \begin{tabular}{c} **Increased Solubility** \\ **with Respect to** \\ **Water Solution** \\ **(T = 298.15 K)** \\ \end{tabular} & \multirow{2}{*}{**Reference**} \\ \cline{2-3}  & Benzoic acid & 80 times & [40] \\ \cline{2-3}  & AMG517 & 100 times & [40] \\ \hline \multirow{2}{*}{\begin{tabular}{c} Choline chloride and \\ malonic acid (1:1) \\ \end{tabular} } & Danazol & 320 times & [40] \\ \cline{2-3}  & AMG517 & 20,000 times & [40] \\ \hline \multirow{3}{*}{\begin{tabular}{c} Choline chloride and \\ glycolic acid (1:2) \\ \end{tabular} } & Itraconazole & 6700 times & [45] \\ \cline{2-3}  & Pirovicam & 430 times & [46] \\ \cline{2-3}  & Lidocaine & 2. times & [46] \\ \cline{2-3}  & Posaconazole & 6400 times & [46] \\ \hline \multirow{3}{*}{\
\begin{tabular}{c} Choline chloride, \\ glycolic acid, and \\ oxalic acid (1:1:7:0.3) \\ \end{tabular} } & Itraconazole & 50,000 times & [45] \\ \cline{2-3}  & Pirovicam & 135 times & [46] \\ \cline{2-3}  & Lidocaine & 81 times & [46] \\ \cline{2-3}  & Posaconazole & 7400 times & [46] \\ \hline \multirow{3}{*}{
\begin{tabular}{c} Menthol \\ \end{tabular} } & Ibuprofen & 2.5 times & [48] \\ \cline{2-3}  & Menthol:Poloxamer & 6 times & [48] \\ \cline{1-1} \cline{2-3}  & Choline chloride and \\ \cline{1-1} \cline{2-3}  & glycolic acid (1:2) & Cefixime trihydrate & 2418 times & [49] \\ \hline \hline \end{tabular}
\end{table} 
Table 1: List of drug solubility in DESs. In addition, other studies have focused on the application of DESs in terms of improving solubility, and more specifically for pharmaceutical applications. Thus, [PERSON] et al. improved the solubility of the drug lovastatin in three binary eutectic mixtures with three different carboxylic acids (benzoic, salicylic, and cinnamic carboxylic acids), being higher for the system formed with salicylic acid. Moreover, the systems showed stability since there was no dissociation and the results achieved indicated that binary eutectic mixtures can be excellent for the preparation of pharmaceutical formulations [44]. Accordingly, another report observed that the use of a DES, composed of betaine and urea, stabilized two therapeutic B-lactam molecules, clavulanic acid and impenem, with respect to the use of water and with no effect on their antimicrobial activity [52]. On the other hand, NADES can play an important role in small-molecule formulations such as hydrogels or as a vehicle of lipophilic bioactive ingredients [16]. Moreover, NADES also have an analogous structure to cyclodextrin, and thus can be used as an excipient in hydrophobic drug delivery systems [53]. Thereby, DESs could be interesting alternatives in pharmaceutical formulations, however, more knowledge is necessary at preclinical and clinical phases of implementation as well as their toxic effects in organisms. _Pharmaceutical Applications: Therapeutical Deep Eutectic Solvent-Thedes_  
The development of bioactive eutectic systems containing active principles increases the potential of these systems and opens a wide spectrum for future developments in pharmaceutical and biomedical applications. One of these techniques, which can be used to increase the solubility of drugs, is related to the use of THEDES. A THEDES (DES + active pharmaceutical ingredient (API)) and their transdermal drug delivery was first described in 1998 by [PERSON] et al. [54] who showed some mixtures of an API with different enhancers of skin permeation (terpenes). Additionally, two manuscripts reported an increase in the solubility of benzoic acid, danazol, and griseofulvin, an itraconazole using urea-choline chloride and malonic acid-choline chloride DES [9; 40]. At the topical level, it was in the 1980s when the first eutectic mixture formulation (EMLA) was marketed, containing an 80% eutectic mixture of lidocaine and prilicolaine [33; 55].