Chem. Pharm. Bull.(オピニオン)

Deep eutectic solvents (DESs) are an emerging class of mixtures characterized by significant depressions in melting points compared to those of the neat constituent components. These materials are promising for applications as inexpensive "designer" solvents exhibiting a host of tunable physicochemical properties. A detailed review of the current literature reveals the lack of predictive understanding of the microscopic mechanisms that govern the structure-property relationships in this class of solvents. Complex hydrogen bonding is postulated as the root cause of their melting point depressions and physicochemical properties; to understand these hydrogen bonded networks, it is imperative to study these systems as dynamic entities using both simulations and experiments. This review emphasizes recent research efforts in order to elucidate the next steps needed to develop a fundamental framework needed for a deeper understanding of DESs. It covers recent developments in DES research, frames outstanding scientific questions, and identifies promising research thrusts aligned with the advancement of the field toward predictive models and fundamental understanding of these solvents.

Deep Eutectic Solvents: A Review of Fundamentals and Applications.

Salts and cocrystals are multicomponent crystals that can be distinguished by the location of the proton between an acid and a base. At the salt end of the spectrum proton transfer is complete, and on the opposite end proton transfer is absent in cocrystals. However, for acid−base complexes with similar pKa values, the extent of proton transfer in the solid state is not predictable and a continuum exists between the two extremes. For these systems, both the ΔpKa value (pKa of base − pKa of acid) and the crystalline environment determine the extent of proton transfer. A total of 20 complexes containing theophylline and guest molecules with ΔpKa values less than 3 have been prepared, resulting in 13 cocrystals, five salts, and two complexes with mixed ionization states based on IR spectroscopy and single-crystal diffraction data. We propose modifications to the ΔpKa rule for selecting salt screen counterions that focus on the discovery of solid forms with useful physical properties rather than an arbitrary ...

http://pubs.acs.org/doi/pdf/10.1021/mp0601345

The Salt−Cocrystal Continuum: The Influence of Crystal Structure on Ionization State

Isokinetic relationship, isoequilibrium relationship, and enthalpy-entropy compensation.

Solubility parameters as predictors of miscibility in solid dispersions

Enthalpy–entropy compensation for the solubility of drugs in solvent mixtures: Paracetamol, acetanilide, and nalidixic acid in dioxane–water

The solubility of paracetamol was studied at 25°C in mixtures of amphiprotic and aprotic solvents of varying polarity (ethyl acetate-ethanol, ethanol-water, dioxane-water). A plot of the solubility mole fraction of the drug versus the solubility parameter of the solvent mixtures reached a peak in dioxane-water, and two solubility maxima within the polarity range provided by the ethanol-water and ethanol-ethyl acetate mixtures. This "chameleonic effect" can be quantitatively described in terms of cavity formation, nonspecific and specific interactions, represented by the Hildebrand solubility parameter and the acidic and basic solubility parameters of the solvent mixtures. The model predicts two solubility maxima, as found experimentally. The behavior of paracetamol in dioxane-water mixtures is similar to that of other drugs, showing a single maximum, although a small peak and a valley are also observed near the solubility parameter region where the maximum in ethanol-water appears. An increase in the temperature of fusion of the solid phase by about eight degrees was observed after equilibration of the powder with ethanol, ethyl acetate and dioxane. No changes in the solid phase were observed in water and aqueous mixtures below 50% water. The same change in the solid phase was also found in ethanol-ethyl acetate mixtures; it was independent of the nature and cosolvent ratio and had little effect on the relative variation of solubility with solvent composition. The solid phase contributes as a constant to the total solubility.

The Behavior of Paracetamol in Mixtures of Amphirotic and Amphiprotic-Aprotic Solvents. Relationship of Solubility Curves to Specific and Nonspecific Interactions

Solubility behavior of polymorphs I and II of mefenamic acid in solvent mixtures.

Thermodynamic analysis and enthalpy―entropy compensation for the solubility of indomethacin in aqueous and non-aqueous mixtures

A modification of the extended Hildebrand equation is proposed to estimate the solubility of an organic drug in solvent mixtures. The equation accurately reproduces the solubility of four sulphonamides in dioxane-water mixtures without requiring the heat of fusion of the solute. A single equation is obtained for predicting the solubility of related drugs using the solubilities of the drugs in the pure solvents, dioxane and water, and solute-solvent interaction terms consisting of the solubility parameter, delta 2, of the solute and the solubility parameter, delta 1, and basic partial solubility parameter, delta 1b, of the solvent mixture. By this procedure a single equation was obtained to estimate the solubilities of three xanthines in dioxane-water and another equation to obtain the solubilities of four sulphonamides. The equation obtained for sulphonamides is able to predict the experimental solubilities of two parent compounds, sulphasomidine and sulphathiazole, and the solubilities of a drug of different structure, p-hydroxybenzoic acid. This suggests that the intermolecular solute-solvent interaction of sulphonamides and p-hydroxybenzoic acid are similar. The results indicate that the solubility behaviour of drugs having different structures may be modelled using a common equation provided that they show similar solute-solvent interactions.

Pilar Bustamante

Papers

Enthalpy–entropy compensation for the solubility of drugs in solvent mixtures: Paracetamol, acetanilide, and nalidixic acid in dioxane–water

The Behavior of Paracetamol in Mixtures of Amphirotic and Amphiprotic-Aprotic Solvents. Relationship of Solubility Curves to Specific and Nonspecific Interactions

Solubility behavior of polymorphs I and II of mefenamic acid in solvent mixtures.

Thermodynamic analysis and enthalpy―entropy compensation for the solubility of indomethacin in aqueous and non-aqueous mixtures

A modification of the extended Hildebrand approach to predict the solubility of structurally related drugs in solvent mixtures.