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Aroso et al. were the first to refer to this sort of system as therapeutic deep eutectic solvents (THEDES). They performed a study in which they associated three
drugs that can act as hydrogen bond donors (acetylsalicylic acid, benzoic acid, and
phenylacetic acid) with choline chloride or menthol (Aroso et al. 2016). The antibacterial activity of benzoic and phenylacetic acids was maintained in the solvents.
They also showed increased permeability through an artificial membrane when the
drugs were formulated in this way (Duarte et al. 2017).
Wolbert et al. attempted to use thermodynamic modelling to predict the formation of therapeutic deep eutectic solvents (Wolbert et al. 2019). Lidocaine, ibuprofen, and phenylacetic acid were used as examples of drugs that could act as hydrogen
bond donors, while the potential hydrogen bond acceptors were thymol, vanillin,
lauric acid, para-toluic acid, benzoic acid, and cinnamic acid. Predictions were
made based on melting temperature and melting enthalpy, and differential scanning
calorimetry was used to confirm the formation of a deep eutectic solvent. In most
cases, the melting point of the mixture could be predicted to +/− 3 °C. They were
also able to model the behavior of a ternary system of lidocaine, thymol, and water.
This revealed that a small amount of water did not necessarily perturb the formation
of a therapeutic deep eutectic solvent. Other solvents formed from lidocaine and
prilocaine, and their hydrochloride salts were studied by Wojnarowska et al. both
experimentally by differential scanning calorimetry and crystallography as well as
in silico methods. Both the ionic (hydrochloride) and the nonionic combinations
were able to form eutectic mixtures. The importance of hydrogen bonding in the
nonionic deep eutectic solvents was highlighted (Wojnarowska et al. 2018).
Pereira et al. investigated the formation of therapeutic deep eutectic solvents
between a monoterpene with anticancer activity, limonene, and capric acid, malic
acid, ibuprofen, and menthol. In particular, the combination with ibuprofen increased
the solubility of the anti-inflammatory drug and reinforced its activity against reactive oxygen species while also possessing antiproliferative activity against HT29
cells (Pereira et al. 2019).
After using their own observations and data from the literature on choline
chloride- based deep eutectic solvents, Abranches et al. used the conductor-like
screening model for real solvents method to generate a model and attempt to predict
the formation of therapeutic deep eutectic solvents from acetylsalicylic acid, ibuprofen, paracetamol, and ketoprofen (Abranches et al. 2019). In general, they found
good agreement between the eutectic temperature calculated from the model and
that observed experimentally. The results of all these studies using in silico techniques to predict eutectic formation should allow a more rational approach to formulation compared with the empirical one that has been used up to now.
All these observations concerning the solubility of pharmaceutically active lowmolecular- weight compounds in deep eutectic solvents are summarized in Table 2.
C.-H. Nguyen et al.
Aroso et al. were the first to refer to this sort of system as therapeutic deep eutectic solvents (THEDES). They performed a study in which they associated three
drugs that can act as hydrogen bond donors (acetylsalicylic acid, benzoic acid, and
phenylacetic acid) with choline chloride or menthol (Aroso et al. 2016). The antibacterial activity of benzoic and phenylacetic acids was maintained in the solvents.
They also showed increased permeability through an artificial membrane when the
drugs were formulated in this way (Duarte et al. 2017).
Wolbert et al. attempted to use thermodynamic modelling to predict the formation of therapeutic deep eutectic solvents (Wolbert et al. 2019). Lidocaine, ibuprofen, and phenylacetic acid were used as examples of drugs that could act as hydrogen
bond donors, while the potential hydrogen bond acceptors were thymol, vanillin,
lauric acid, para-toluic acid, benzoic acid, and cinnamic acid. Predictions were
made based on melting temperature and melting enthalpy, and differential scanning
calorimetry was used to confirm the formation of a deep eutectic solvent. In most
cases, the melting point of the mixture could be predicted to +/− 3 °C. They were
also able to model the behavior of a ternary system of lidocaine, thymol, and water.
This revealed that a small amount of water did not necessarily perturb the formation
of a therapeutic deep eutectic solvent. Other solvents formed from lidocaine and
prilocaine, and their hydrochloride salts were studied by Wojnarowska et al. both
experimentally by differential scanning calorimetry and crystallography as well as
in silico methods. Both the ionic (hydrochloride) and the nonionic combinations
were able to form eutectic mixtures. The importance of hydrogen bonding in the
nonionic deep eutectic solvents was highlighted (Wojnarowska et al. 2018).
Pereira et al. investigated the formation of therapeutic deep eutectic solvents
between a monoterpene with anticancer activity, limonene, and capric acid, malic
acid, ibuprofen, and menthol. In particular, the combination with ibuprofen increased
the solubility of the anti-inflammatory drug and reinforced its activity against reactive oxygen species while also possessing antiproliferative activity against HT29
cells (Pereira et al. 2019).
After using their own observations and data from the literature on choline
chloride- based deep eutectic solvents, Abranches et al. used the conductor-like
screening model for real solvents method to generate a model and attempt to predict
the formation of therapeutic deep eutectic solvents from acetylsalicylic acid, ibuprofen, paracetamol, and ketoprofen (Abranches et al. 2019). In general, they found
good agreement between the eutectic temperature calculated from the model and
that observed experimentally. The results of all these studies using in silico techniques to predict eutectic formation should allow a more rational approach to formulation compared with the empirical one that has been used up to now.
All these observations concerning the solubility of pharmaceutically active lowmolecular- weight compounds in deep eutectic solvents are summarized in Table 2.
C.-H. Nguyen et al.