58
A recent article by Halder et al. has brought together data from a number of the
studies reported above and subjected them to a multitasking-Quantitative Structure
Toxicity Relationships (mtk-QSTR) analysis (Halder et al. 2019). This revealed a
number of parameters that were important in determining toxicity: polarizability,
electronegativity, nature of the hydrogen bond donor, and topological features. They
were able to rank the main classes of hydrogen bond donor in terms of deep eutectic
solvent toxicity: sugar alcohols and straight-chain alcohols giving low toxicity, sugars and amides giving intermediate toxicity, and organic and inorganic acids giving
a high level of toxicity. More studies of this type, and more standardized protocols
for toxicity studies, should in the future guide the choice of deep eutectic solvent
compositions for pharmaceutical applications.
Table 1 summarizes the results that have been obtained to date about the toxicity
of deep eutectic solvents. It is clear that a wide range of different models and criteria
of toxicity have been used and that there is a need for more systematic
investigations.
2.3 Pharmaceutical Applications of Deep Eutectic Solvents
It will be evident from the above that the main application of deep eutectic solvents
in pharmaceutical science is as solvents for hydrophobic drugs. As well as a large
number of small molecules, deep eutectic solvents have also been found to have
advantages for solubilizing larger macromolecules such as proteins, nucleic acids,
and polysaccharides. Not only do they increase solubility per se compared with
aqueous media but may also increase the stability of the compound and favor
particular conformations. Deep eutectic solvents have also been discovered to have
intrinsic properties such as antimicrobial activity and as promoters of absorption.
2.3.1 Solubilization of Small Molecules in Deep
Eutectic Solvents
Early Work and Model Drugs
Some early work on deep eutectic solvents as vehicles for drug solubilization was
performed by Morrison et al. (Morrison et al. 2009). They studied the thermal properties of mixtures of choline chloride with urea or malonic acid using, among other
techniques, hot stage microscopy to allow them to define eutectic compositions of
urea:choline chloride 2:1 and malonic acid:choline chloride 1:1. The solubility of
five poorly water-soluble compounds (benzoic acid, danazol, griseofulvin,
AMG517, itraconazole) in these mixtures was tested, yielding improvements in all
cases, notably an increase in the solubility of the antifungal drug itraconazole by
22,000 times compared with water.
C.-H. Nguyen et al.
A recent article by Halder et al. has brought together data from a number of the
studies reported above and subjected them to a multitasking-Quantitative Structure
Toxicity Relationships (mtk-QSTR) analysis (Halder et al. 2019). This revealed a
number of parameters that were important in determining toxicity: polarizability,
electronegativity, nature of the hydrogen bond donor, and topological features. They
were able to rank the main classes of hydrogen bond donor in terms of deep eutectic
solvent toxicity: sugar alcohols and straight-chain alcohols giving low toxicity, sugars and amides giving intermediate toxicity, and organic and inorganic acids giving
a high level of toxicity. More studies of this type, and more standardized protocols
for toxicity studies, should in the future guide the choice of deep eutectic solvent
compositions for pharmaceutical applications.
Table 1 summarizes the results that have been obtained to date about the toxicity
of deep eutectic solvents. It is clear that a wide range of different models and criteria
of toxicity have been used and that there is a need for more systematic
investigations.
2.3 Pharmaceutical Applications of Deep Eutectic Solvents
It will be evident from the above that the main application of deep eutectic solvents
in pharmaceutical science is as solvents for hydrophobic drugs. As well as a large
number of small molecules, deep eutectic solvents have also been found to have
advantages for solubilizing larger macromolecules such as proteins, nucleic acids,
and polysaccharides. Not only do they increase solubility per se compared with
aqueous media but may also increase the stability of the compound and favor
particular conformations. Deep eutectic solvents have also been discovered to have
intrinsic properties such as antimicrobial activity and as promoters of absorption.
2.3.1 Solubilization of Small Molecules in Deep
Eutectic Solvents
Early Work and Model Drugs
Some early work on deep eutectic solvents as vehicles for drug solubilization was
performed by Morrison et al. (Morrison et al. 2009). They studied the thermal properties of mixtures of choline chloride with urea or malonic acid using, among other
techniques, hot stage microscopy to allow them to define eutectic compositions of
urea:choline chloride 2:1 and malonic acid:choline chloride 1:1. The solubility of
five poorly water-soluble compounds (benzoic acid, danazol, griseofulvin,
AMG517, itraconazole) in these mixtures was tested, yielding improvements in all
cases, notably an increase in the solubility of the antifungal drug itraconazole by
22,000 times compared with water.
C.-H. Nguyen et al.