66
number of compositions. This provided a nontoxic alternative to dimethyl sulfoxide
(DMSO) for studies of its physiological effects in brown adipose tissue cells
(Rozema et al. 2015).
The group of Shekaari have characterized the solubility of acetaminophen in
choline-based deep eutectic solvents in close detail. In a first work, they compared
urea, oxalic acid, and malonic acid as hydrogen bond donors (Shekaari et al. 2017).
The last named had the greatest impact on solubility. As might be expected, increasing concentrations of deep eutectic solvents in water and increased temperature
increased the solubility. They measured the volumetric and compressibility properties in the drug in the different solvents to gain an insight into the interactions
between the drug and the solvent, which were in fact found to be strong. In a followup study, they added some thermodynamic measurements and determined that the
main contribution to the energy of dissolution was enthalpic (Shekaari et al. 2018a).
In another work, they performed similar experiments using deep eutectic solvents
with the compositions choline chloride:glycerol 1:2 and choline chloride:ethylene
glycol 1:2. Choline chloride:ethylene glycol was the better solvent (Shekaari et al.
2018b). They also extended their observations to another active molecule, the antiepileptic drug lamotrigine, again finding that choline chloride:ethylene glycol was
the best solvent of three tested (Shekaari et al. 2019).
Phenols and Flavonoids
Salvianolic acid B is a natural product with applications for cardiovascular diseases.
Although it is water-soluble, it is easily hydrolyzed with subsequent loss of activity.
Chen et al. investigated the possible improvement in stability brought about by the
use of deep eutectic solvents, composed of choline chloride with ethylene glycol,
glycerol, 1,2-propanediol, and 1,4-butanediol (Chen et al. 2016). The degradation
of salvianolic acid B was reduced in all tested solvents compared with water, with
maximum stability observed in choline chloride:glycerol with an optimal molar
ratio of 1:2. Infrared spectroscopy showed interactions between the deep eutectic
solvents and the carbonyl group of this phenolic acid. The authors then determined
the pharmacokinetics and acute toxicity of salvianolic acid B after oral administration within this optimized deep eutectic solvent (see below).
As well as their use as solvents for phenolic compounds, deep eutectic solvents
have also been employed for the extraction of this type of molecule from plants.
Thus, Benlebna et al. used a natural deep eutectic solvent composed of betaine and
glycerol (1:2) to extract polyphenols from green coffee beans (Benlebna et al.
2018). However, some toxicity was observed when this extract was administered
orally to rats (see section on toxicity above). Radošević et al. also used natural deep
eutectic solvents to extract phenols and anthocyanins from grape skin (Radošević
et al. 2016). Formulations combining choline chloride with glucose, fructose,
xylose, glycerol, and malic acid, in mixtures containing 30% of water, were prepared. The best extraction efficiency was achieved with the deep eutectic solvent
containing malic acid, judged not only by assay of the different molecules extracted
C.-H. Nguyen et al.
number of compositions. This provided a nontoxic alternative to dimethyl sulfoxide
(DMSO) for studies of its physiological effects in brown adipose tissue cells
(Rozema et al. 2015).
The group of Shekaari have characterized the solubility of acetaminophen in
choline-based deep eutectic solvents in close detail. In a first work, they compared
urea, oxalic acid, and malonic acid as hydrogen bond donors (Shekaari et al. 2017).
The last named had the greatest impact on solubility. As might be expected, increasing concentrations of deep eutectic solvents in water and increased temperature
increased the solubility. They measured the volumetric and compressibility properties in the drug in the different solvents to gain an insight into the interactions
between the drug and the solvent, which were in fact found to be strong. In a followup study, they added some thermodynamic measurements and determined that the
main contribution to the energy of dissolution was enthalpic (Shekaari et al. 2018a).
In another work, they performed similar experiments using deep eutectic solvents
with the compositions choline chloride:glycerol 1:2 and choline chloride:ethylene
glycol 1:2. Choline chloride:ethylene glycol was the better solvent (Shekaari et al.
2018b). They also extended their observations to another active molecule, the antiepileptic drug lamotrigine, again finding that choline chloride:ethylene glycol was
the best solvent of three tested (Shekaari et al. 2019).
Phenols and Flavonoids
Salvianolic acid B is a natural product with applications for cardiovascular diseases.
Although it is water-soluble, it is easily hydrolyzed with subsequent loss of activity.
Chen et al. investigated the possible improvement in stability brought about by the
use of deep eutectic solvents, composed of choline chloride with ethylene glycol,
glycerol, 1,2-propanediol, and 1,4-butanediol (Chen et al. 2016). The degradation
of salvianolic acid B was reduced in all tested solvents compared with water, with
maximum stability observed in choline chloride:glycerol with an optimal molar
ratio of 1:2. Infrared spectroscopy showed interactions between the deep eutectic
solvents and the carbonyl group of this phenolic acid. The authors then determined
the pharmacokinetics and acute toxicity of salvianolic acid B after oral administration within this optimized deep eutectic solvent (see below).
As well as their use as solvents for phenolic compounds, deep eutectic solvents
have also been employed for the extraction of this type of molecule from plants.
Thus, Benlebna et al. used a natural deep eutectic solvent composed of betaine and
glycerol (1:2) to extract polyphenols from green coffee beans (Benlebna et al.
2018). However, some toxicity was observed when this extract was administered
orally to rats (see section on toxicity above). Radošević et al. also used natural deep
eutectic solvents to extract phenols and anthocyanins from grape skin (Radošević
et al. 2016). Formulations combining choline chloride with glucose, fructose,
xylose, glycerol, and malic acid, in mixtures containing 30% of water, were prepared. The best extraction efficiency was achieved with the deep eutectic solvent
containing malic acid, judged not only by assay of the different molecules extracted
C.-H. Nguyen et al.