CICECO-Aveiro Institute of Materials

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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

The role of ionic vs. non-ionic excipients in APIs-based eutectic systems

Publication . Martins, Mónia A.R.; Silva, Liliana P.; Jorge, Patrícia S.; Abranches, Dinis O.; Pinho, Simão; Coutinho, João A.P.

Aiming to contribute to drug pre-formulation, new eutectic mixtures were developed. Thymol, coumarin, or quaternary ammonium chlorides as excipients, were combined with the active pharmaceutical ingredients (APIs) acetylsalicylic acid, acetaminophen, ibuprofen, ketoprofen, or lidocaine. Their solid-liquid equilibrium (SLE) binary phase diagrams were measured to study eventual phase separation between the compounds, preventing manufacturing problems, and to study the molecular interactions between the APIs and ionic or non-ionic excipients. The Conductor-like Screening Model for Real Solvents (COSMO-RS) capability to predict the SLE of mixtures containing non-ionic excipients was further evaluated. COSMO-RS gives a good quantitative description of the experimental SLE being a tool with great potential in the screening of eutectic systems containing APIs and non-ionic excipients. While thymol presents strong interactions with the APIs, and consequently negative deviations to thermodynamic ideality, systems containing coumarin follow a quasi-ideal behavior. Regarding the ionic excipients, both choline chloride and the tetraalkylammonium chlorides are unable to establish relevant interactions with the APIs, and no significant negative deviations to ideality are observed. The liquefaction of the APIs here studied is favored by using non-ionic excipients, such as thymol, due to the strong interactions it can establish with the APIs.

2021Journal article

Open 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.; Soares-Santos, Paula C.

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

Estimating the melting temperatures of type V deep eutectic solvents

Publication . Teixeira, Gabriel; Abranches, Dinis O.; Ferreira, Olga; Coutinho, João A.P.

The recently proposed category of type V deep eutectic solvents (DESs), composed only of non-ionic species, has attracted great interest in the literature. However, despite their importance in solvent design, measuring the solid−liquid equilibrium (SLE) diagrams of all possible type V DES precursor combinations is unfeasible. Therefore, a reliable computational tool must be found to estimate SLE phase diagrams and, thus, the melting points of type V DESs. In this work, a total of 134 different binary eutectic systems (1744 datapoints) were gathered from the literature, and the calculation capabilities and accuracy of three different models COSMO-RS, UNIFAC of Dortmund, and Group and Group-Interaction Contribution method (GGIC) were evaluated. UNIFAC and COSMO-RS were, by far, the best performing models, with average absolute deviations (AADs) of, respectively, 6.9 K for 94 systems and 7.4 K for 133 systems. Due to a lack of group interaction parameters, UNIFAC could only describe 94 systems, a severe disadvantage over COSMO-RS. Moreover, despite being able to describe all 134 systems, the GGIC model resulted in an AAD of 37 K. Finally, the effect of using the different parametrizations or multiple conformers in COSMO-RS predictions was also evaluated, and the validity of neglecting heat capacity terms when performing SLE calculations was verified.

2023Journal article

Restricted access

Tetraalkylammonium Chlorides as Melting Point Depressants of Ionic Liquids

Publication . Martins, Mónia A. R.; Abranches, Dinis O.; Silva, Liliana P.; Pinho, Simão; Coutinho, João A.P.

With the (re)advent of eutectic mixtures within the field of deep eutectic solvents, special attention has been given to the measurement of solid–liquid equilibrium (SLE) phase diagrams, supported by the relevant information they can provide on the molecular interactions and melting temperature depression of any given system. As such, this work investigates the SLE phase diagrams of mixtures between ionic liquids and tetraalkylammonium chlorides (methyl, ethyl, and propyl), with the goal of decreasing the melting temperature of ionic liquids and ammonium salts, thus, expanding their application scope. Results show that tetraalkylammonium salts exhibit negative deviations from thermodynamic ideality when mixed with ionic liquids, which are increased by increasing their alkyl chain length and are interpreted in terms of anion exchange mechanisms. In turn, this nonideality contributes greatly to depression of the melting point of the ionic liquids examined. Overall, this work demonstrates that the correct combination of tetraalkylammonium/ILs anions and cations can lead to significant melting point depressions in both species, thus creating new ionic liquid mixtures using an approach akin to that used to form deep eutectic solvents.

2023Journal article

Open access