Chemistry Research Unit of University of Porto

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Designing type V deep eutectic solvents with antimalarial pharmaceutical ingredients

Publication . Teixeira, Gabriel; Brandão, Paula; Ferreira, Ana I.M.C. Lobo; Abranches, Dinis O.; Santos, L.uís M.N.B.F.; Ferreira, Olga; Coutinho, João A.P.

This work studies the formation of deep eutectic solvents formed by one active pharmaceutical ingredient (quinine, pyrimethamine, or 2-phenylimidazopyridine) and a second component potentially acting as an excipient (betaine, choline chloride, tetramethylammonium chloride, thymol, menthol, gallic acid, vanillin, acetovanillone, 4-hydroxybenzaldehyde, syringaldehyde, propyl gallate, propylparaben, or butylated hydroxyanisole), aiming to address challenges regarding drug solubility, bioavailability, and permeability. A preliminary screening was carried out using the thermodynamic model COSMO-RS, narrowing down the search to three promising excipients (thymol, propyl gallate, and butylated hydroxyanisole). Nine solid–liquid equilibrium (SLE) phase diagrams were experimentally measured combining the three model drugs with the screened excipients, and using a combination of a visual melting method and differential scanning calorimetry. Negative deviations from thermodynamic ideality were observed in all nine systems. Furthermore, a total of four new cocrystals were found, with powder and single crystal X-ray diffraction techniques being employed to verify their unique diffraction patterns. In the thermodynamic modelling of the SLE diagrams, two COSMO-RS parametrizations (TZVP and TZVPD-FINE) were also applied, though neither consistently delivered a better description over the other.

2024Journal article

Restricted access

Extensive characterization of choline chloride and its solid–liquid equilibrium with water

Publication . Ferreira, Ana I.M.C. Lobo; Vilas-Boas, Sérgio M.; Silva, Rodrigo M.A.; Martins, Mónia A.R.; Abranches, Dinis O.; Paz, Filipe A. Almeida; Ferreira, Olga; Pinho, Simão; Santos, Luís M.N.B.F.; Coutinho, João A.P.

The importance of choline chloride (ChCl) is recognized due to its widespread use in the formulation of deep eutectic solvents. The controlled addition of water in deep eutectic solvents has been proposed to overcome some of the major drawbacks of these solvents, namely their high hygroscopicities and viscosities. Recently, aqueous solutions of ChCl at specific mole ratios have been presented as a novel, low viscous deep eutectic solvent. Nevertheless, these proposals are suggested without any information about the solid–liquid phase diagram of this system or the deviations from the thermodynamic ideality of its precursors. This work contributes significantly to this matter as the phase behavior of pure ChCl and (ChCl + H2 O) binary mixtures was investigated by calorimetric and analytical techniques. The thermal behavior and stability of ChCl were studied by polarized light optical microscopy and differential scanning calorimetry, confirming the existence of a solid–solid transition at 352.2 0.6 K. Additionally, heat capacity measurements of pure ChCl (covering both ChCl solid phases) and aqueous solutions of ChCl (xChCl o 0.4) were performed using a heat-flow differential scanning microcalorimeter or a high- precision heat capacity drop calorimeter, allowing the estimation of a heat capacity change of (ChCl) E 39.3 10 J K 1 mol 1 , between the hypothetical liquid and the observed crystalline phase at 298.15 K. The solid–liquid phase diagram of the ChCl + water mixture was investigated in the whole concentration range by differential scanning calorimetry and the analytical shake-flask method. The phase diagram obtained for the mixture shows an eutectic temperature of 204 K, at a mole fraction of choline chloride close to xChCl = 0.2, and a shift of the solid–solid transition of ChCl–water mixtures of 10 K below the value observed for pure choline chloride, suggesting the appearance of a new crystalline structure of ChCl in the presence of water, as confirmed by X-ray diffraction. The liquid phase presents significant negative deviations to ideality for water while COSMO-RS predicts a near ideal behaviour for ChCl.

2022Journal article

Open access

Liquefying flavonoids with terpenoids through deep eutectic solvent formation

Publication . Teixeira, Gabriel; Abranches, Dinis O.; Silva, Liliana P.; Vilas-Boas, Sérgio M.; Pinho, Simão; Ferreira, Ana I.M.C. Lobo; Santos, Luís M.N.B.F.; Ferreira, Olga; Coutinho, João A.P.

The formation of deep eutectic solvents (DES) is tied to negative deviations to ideality caused by the establishment of stronger interactions in the mixture than in the pure DES precursors. This work tested thymol and menthol as hydrogen bond donors when combined with different flavonoids. Negative deviations from ideality were observed upon mixing thymol with either flavone or flavanone, two parent flavonoids that only have hydrogen bond acceptor (HBA) groups, thus forming non-ionic DES (Type V). On the other hand, the menthol systems with the same compounds generally showed positive deviations from ideality. That was also the case with the mixtures containing the more complex hydroxylated flavonoid, hesperetin, which resulted in positive deviations when mixed with either thymol or menthol. COSMO-RS successfully predicted the behavior of the solid-liquid phase diagram of the studied systems, allowing for evaluation of the impact of the different contributions to the intermolecular interactions, and proving to be a good tool for the design of DES.

2022Journal article

Open access