## 2 Applications Related to Peculiar Solubility Properties of DESs  
Considering the growing interest in the use of solvents which allow solubility to be improved in health application, DESs seem to be a good alternative [41]. Therefore, a solution for drugs with poor water solubility is necessary. Currently, to solve this problem, some mechanisms have been used such as new dosage forms, use of other chemical  
Figure 1: Properties and applications of the most important DESs. structures (salts, esters), prodrugs, active metabolites, different routes of administration, etc. [42]. In fact, the use of adequate media for dealing with active pharmaceutical ingredients (APIs) with a poor water solubility is one of the most important challenges for the pharmaceutical industry. It is well known that solubility has a direct relationship on a therapeutic effect of a drug [43]. In addition, in the last few years, several studies have focused on the use of eutectic mixtures in the pharmaceutical area with the aim of improving the solubility and bioavailability of drugs [40; 44]. In Figure 2, a scheme of the evolution of these new solvents is shown. Figure 2: Evolution of DESs over time and their relationship with pharmaceutical applications. Choline-based DESs are one of the most common eutectic mixtures found. The choline cation can be combined with different chemicals (alcohols, fatty acids, carboxylic acids,... ) due to their ability as hydrogen bond acceptors. These kinds of mixtures allow one to increase the solubility of diverse drugs [33]. As a matter of fact, a mixture of a choline chloride-based DES with urea (ChCl:U (1:2)) increased the solubility of benzoic acid and AMG517 by 80 and 100 times, respectively, and the mixture of the same cation with malonic acid (ChCl:MaLA (1:1)) reached a solubilization of 320 and 20,000 times higher than that for the solubilization of danazol and AMG517 with respect to pure water [40]. Similarly, several reports have indicated that binary and ternary eutectic mixtures have been used to dissolve itraconazole, pirovicam, lidocaine, and posaconazole and the solubilization ability was augmented in all situations in comparison to water [45; 46]. Other substances such as menthol, borneol, and camphor have been used as hydrogen bond acceptors to prepare eutectic mixtures and as vehicles for transdermal drug delivery, analgesic, antimicrobial, anti-inflammatory, and antitussive compounds [47] of testosterone, ibuprofen, lidocaine, ubiquitinationone, captopril, or Itkonazole have been used. For instance, [PERSON] et al. studied the in vitro dissolution of poorly water-soluble ibuprofen using polaxamer and menthol in an aqueous solution. It was observed that a relation 4 ibuprofen:6 menthol increased its solubility by 2.5, however, when the polaxamer was included, a 6-fold increase in the aqueous solubility of the drug was found [48]. [PERSON] and [PERSON] observed that the solubility of cefixime was increased when a mixture of cefixime and DES was prepared. In this case, DES was formed by choline chloride and glycolic acid in a 1:2 molar ratio [49]. The solubility of other active pharmaceutical ingredients with DES has also been analyzed. Another report has studied the solubility of nonsteroidal anti-inflammatory drugs (aspirin, acetaminophen, ibuprofen, ketoprofen, and naproxen) in the presence of deep eutectic solvents, observing that their solubilities increased by 100- to 5400-fold over water solution [50; 51]. In Table 1, a summary of the drug solubility comparison between water and DES is presented.