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Dai et al. studied the potential of a range of natural deep eutectic solvent compositions as “green” solvents for a number of natural products with pharmaceutical
activity: rutin, quercetin, cinnamic acid, carthamin, 1,8-dihydroxyl anthraquinone,
taxol, and ginkgolide B (Dai et al. 2013). A large array of combinations of compounds were screened using nuclear magnetic resonance (NMR) spectroscopy, thermogravimetric analysis, differential scanning calorimetry, and viscosity
measurements in order to characterize the mixtures. Four compositions were chosen
for solubility studies: 1,2-propanediol:choline chloride:water 1:1:1, glucose:choline
chloride:water 2:5:5, lactic acid:glucose:water 5:1:3, and xylitol:choline
chloride:water 1:2:3. For all the active compounds cited, at least one of the natural
deep eutectic solvents allowed a considerable increase in solubility compared with
pure water, the most spectacular being that of quercetin multiplied over 400,000
times in xylitol:choline chloride:water. They also observed that temperature had a
strong effect on solubility in natural deep eutectic solvents, with an increase of 1.6
to 2.3 times at 50 °C compared with 40 °C. In a follow-up study, in 2015, they investigated the effect of adding water to the natural deep eutectic solvents containing
quercetin and carthamin in an attempt to reduce the viscosity (Dai et al. 2015).
Although the presence of water reduced hydrogen bonding in the deep eutectic solvents, a small proportion was able to reduce the viscosity significantly without
much impact on the solubility of the active molecule.
Choi et al. reported that the solubility of the flavonoid rutin was 50–100 fold
higher in natural deep eutectic solvents than in water, the highest solubility being
attained in an aconitic acid:choline chloride mixture (Choi et al. 2011). They also
reported good solubility of paclitaxel and ginkgolide B in a deep eutectic solvent
composed of glucose and choline chloride. A naturally occurring alkaloid with
antiparasitic activity, berberine, was formulated in deep eutectic solvents passed on
proline and organic acids with the aim of improving its oral bioavailability (Sut
et al. 2017).
In a study published in 2016, Li and Lee coined the term “deep eutectic solvent
derivatives” for mixtures of choline chloride and carboxylic acids that, although not
precisely eutectics, were liquid at room temperature (Li and Lee 2016). They
determined the solubility of four model drugs (itraconazole, piroxicam, lidocaine,
and posaconazole) in a choline chloride:glycolic acid 1:2 mixture. Again, the solubility of itraconazole and that of another antifungal from the same class, posaconazole, was greatly increased in these solvents, with smaller effects seen on piroxicam
and lidocaine. The addition of a third component, oxalic acid, further increased the
solubility of the antifungals but also increased the viscosity of the formulations.
Lidocaine (a local anesthetic) was also used as a model compound for investigating the potential of deep eutectic solvents by Gutiérrez et al. (2018). In a first, theoretical, study, they examined the molecular interactions that could occur between
lidocaine and the selected deep eutectic solvent components: choline chloride,
β-alanine (hydrogen bond acceptors), and lactic acid (hydrogen bond donor)
(Gutiérrez et al. 2018). In the second study, they studied deep eutectic solvents composed of arginine combined in an equimolar ratio with tartaric acid, oxalic acid, and
2 Deep Eutectic Solvents for Innovative Pharmaceutical Formulations
Dai et al. studied the potential of a range of natural deep eutectic solvent compositions as “green” solvents for a number of natural products with pharmaceutical
activity: rutin, quercetin, cinnamic acid, carthamin, 1,8-dihydroxyl anthraquinone,
taxol, and ginkgolide B (Dai et al. 2013). A large array of combinations of compounds were screened using nuclear magnetic resonance (NMR) spectroscopy, thermogravimetric analysis, differential scanning calorimetry, and viscosity
measurements in order to characterize the mixtures. Four compositions were chosen
for solubility studies: 1,2-propanediol:choline chloride:water 1:1:1, glucose:choline
chloride:water 2:5:5, lactic acid:glucose:water 5:1:3, and xylitol:choline
chloride:water 1:2:3. For all the active compounds cited, at least one of the natural
deep eutectic solvents allowed a considerable increase in solubility compared with
pure water, the most spectacular being that of quercetin multiplied over 400,000
times in xylitol:choline chloride:water. They also observed that temperature had a
strong effect on solubility in natural deep eutectic solvents, with an increase of 1.6
to 2.3 times at 50 °C compared with 40 °C. In a follow-up study, in 2015, they investigated the effect of adding water to the natural deep eutectic solvents containing
quercetin and carthamin in an attempt to reduce the viscosity (Dai et al. 2015).
Although the presence of water reduced hydrogen bonding in the deep eutectic solvents, a small proportion was able to reduce the viscosity significantly without
much impact on the solubility of the active molecule.
Choi et al. reported that the solubility of the flavonoid rutin was 50–100 fold
higher in natural deep eutectic solvents than in water, the highest solubility being
attained in an aconitic acid:choline chloride mixture (Choi et al. 2011). They also
reported good solubility of paclitaxel and ginkgolide B in a deep eutectic solvent
composed of glucose and choline chloride. A naturally occurring alkaloid with
antiparasitic activity, berberine, was formulated in deep eutectic solvents passed on
proline and organic acids with the aim of improving its oral bioavailability (Sut
et al. 2017).
In a study published in 2016, Li and Lee coined the term “deep eutectic solvent
derivatives” for mixtures of choline chloride and carboxylic acids that, although not
precisely eutectics, were liquid at room temperature (Li and Lee 2016). They
determined the solubility of four model drugs (itraconazole, piroxicam, lidocaine,
and posaconazole) in a choline chloride:glycolic acid 1:2 mixture. Again, the solubility of itraconazole and that of another antifungal from the same class, posaconazole, was greatly increased in these solvents, with smaller effects seen on piroxicam
and lidocaine. The addition of a third component, oxalic acid, further increased the
solubility of the antifungals but also increased the viscosity of the formulations.
Lidocaine (a local anesthetic) was also used as a model compound for investigating the potential of deep eutectic solvents by Gutiérrez et al. (2018). In a first, theoretical, study, they examined the molecular interactions that could occur between
lidocaine and the selected deep eutectic solvent components: choline chloride,
β-alanine (hydrogen bond acceptors), and lactic acid (hydrogen bond donor)
(Gutiérrez et al. 2018). In the second study, they studied deep eutectic solvents composed of arginine combined in an equimolar ratio with tartaric acid, oxalic acid, and
2 Deep Eutectic Solvents for Innovative Pharmaceutical Formulations