# Diversity of Potential (Bio)Technological Applications of Amino Acid-Based Ionic Liquids
## 2 Bioapplications of AA ILs: An Overview
### Drug Formulations and Delivery
demonstrated a shorter distribution phase and better gastrointestinal tolerability with orally administered [Lys][Ibu] compared to the same dose of the parent Ibu in its acidic form administered by injection [49]. Similarly, [Lys][Keto] exhibited improved water solubility, resulting in a 4-fold faster increase in plasma concentration compared to the parent molecule [50]. Moreover, [Lys][Keto] caused no gastric side effects and was able to repair ethanol-injured gastric mucosa in an animal model [50]. On the other hand, cationic lipidoamino acids such as decyl alanine and decyl phenylalanine are excellent counterions for tolfenamic acid, an NSAID used for the treatment of acute migraines, rheumatoid arthritis, osteoarthritis, and other inflammatory diseases [51]. In vivo oral bioavailability studies with this API-IL showed that the drug is delivered effectively, dispersed, and solubilized. Subsequently, the cationic lipidoamino acid ion is digested into non-toxic components. Another remarkable result was observed with the API-IL formulations of methotrexate containing ProOEt, PheOEt, and AspOEt cations, which demonstrated excellent solubility enhancement in simulated body fluids--500-1000 times higher than the pure drug [52]. However, their solubility levels remain below those achieved by ILs based on choline, tetraalkylammonium, or tetraalkylphosphonium salts, which exhibit over 5000-fold enhanced solubility. Some reports have shown that [Ch][AAs] have great potential as functional excipients capable of enhancing the solubility of poorly soluble drugs, nutraceutical, and active cosmetic ingredients. For example, the solubility of ferulic acid and rutin is increased up to 6- and 45-fold, respectively, when 1% of [Ch][Glu] or [Ch][Phe] is added to w/o emulsions [53]. The solubility of these compounds depends on the concentration of ILs and temperature, while their radical scavenging properties and cytotoxicity remain unaffected. In line with these findings, [PERSON] et al. demonstrated enhanced solubility and maintained antitumor activity of rutin when loaded into a [Ch][Phe]- or [Ch][Gly]-based water-in-oil nanoparticle hybrid system [54]. Furthermore, in vitro studies have shown that [Ch][AAs] facilitate the permeation of ferulic acid and Puerrin through an artificial model polyethersulfone membrane [55]. In addition, [PERSON] et al. reported that, compared to polymer capsules alone, hybrid polymer materials incorporating [Ch][Phe] or [Ch][Glu] exhibited a 35-50% enhanced capacity for loading rutin [56]. However, the two ILs have almost no effect on the solubility and permeation of caffeine and SA, two hydrophilic drugs [57]. Furthermore, another study showed that the solubility of biotin (vitamin B8) in water is increased in the presence of [Ch][Gly] or [Ch][Ala] due to strong polar-polar interactions and hydrogen bonding. These interactions are stronger for [Ch][Ala], which could be used as an excipient in biotin formulations [58]. Additionally, both ILs were shown to increase the solubility of ibuprofen in PBS buffer by fivefold at low concentrations (<1 wt%) and to almost double its permeability across artificial model membranes [59]. A twofold increase in the solubility of glibenclamide has been reported with the addition of 6% [Ch][Trp], which was attributed to strong \(\pi\)-\(\pi\) interactions between the AA anion and the drug molecule [60]. All tested AA ester NSAIDs, including Ibu, Keto, Nap, and SA, showed enhanced solubility in water and PBS compared to the acid form of the drug [61]. Notably, the increased solubility and storage stability of paclitaxel in media containing [Ch][AA] is worth highlighting [62]. This formulation offers a promising alternative to the widely used co-solvent Cremophor EL, which is known to cause precipitation in aqueous solutions and hypersensitivity side effects upon injection.