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When solids become liquids: natural deep eutectic solvents for chemical process engineering

Periodic Reporting for period 2 - Des.solve (When solids become liquids: natural deep eutectic solvents for chemical process engineering)

Reporting period: 2017-10-01 to 2019-03-31

Sugars, aminoacids or organic acids are typically solid at room temperature. Nonetheless when combined at a particular molar fraction they present a high melting point depression, becoming liquids at room temperature. These are called Natural Deep Eutectic Solvents – NADES. NADES are envisaged to play a major role on different chemical engineering processes in the future, playing a significant role towards the development of greener and sustainable processes. Nonetheless, there is a significant lack of knowledge on fundamental and basic research on NADES, which is hindering their industrial applications. For this reason it is important to extend the knowledge on these systems, boosting their application development. NADES applications go beyond chemical or materials engineering and cover a wide range of fields from biocatalysis, extraction, electrochemistry, carbon dioxide capture or biomedical applications. Des.solve encompasses four major themes of research: 1 – Development of NADES and therapeutic deep eutectic solvents – THEDES; 2 – Characterization of the obtained mixtures and computer simulation of NADES/THEDES properties; 3 – Phase behaviour of binary/ternary systems NADES/THEDES + carbon dioxide and thermodynamic modelling; 4 – Application development. Starting from the development of novel NADES/THEDES which, by different characterization techniques, will be deeply studied and characterized, the essential raw-materials will be produced for the subsequent research activities. The envisaged action involves modelling and molecular simulations. Des.solve will be deeply engaged in application development, particularly in extraction, biocatalysis and pharmaceutical/biomedical applications. The knowledge that will be created in this action is expected not only to have a major impact in the scientific community, but also in society, economy and industry.
Development of NADES and THEDES
Production and characterization of NADES and THEDES
The production of NADES and THEDES will be prepared either by mixing the two components until a clear viscous liquid is obtained or after the evaporation of water solutions of each component in a rotary evaporator. NADES were prepared from different combinations of raw materials which include amino-acids, organic acids, sugars and choline derivatives. The choice of the combination is not completely random, as in the past couple of years a lot of new systems have been described and it is of general knowledge that a hydrogen bond donor and a hydrogen bond acceptor molecule are required. In this action, some of the molecules that were studied include menthol, lauric acid, stearic acid, myristic acid, ascorbic acid, citric acid, tartaric acid, galic acid, l-proline, sucrose, glucose, mannose, and xylose. Regarding the formulation of therapeutic mixtures, anti-inflammatory agents such as ibuprofen, flurbiprofen, naproxen, acetylsalicylic acid, anti-oxidants such as mandelic acid or antibacterials such as fatty acids were tested.
The different systems prepared and fully characterized are presented bellow in each one of the categories for which it was studied. Additionally, the characterization of the systems was carried out according to the expected application of each system. The characterization of NADES/THEDES involves the application of several different techniques, such as the water content determination; density and viscosity assessment; polarity; thermal behavior and cytotoxicity evaluation.

Modelling thermophysical data
Deep eutectic solvents (DESs) mostly comply with the principles of green chemistry. Therefore, they are being widely investigated due to their great potential for a variety of applications in the industries. However, it is necessary to have accurate (thermo)-physical property information on any solvent before it can pave its way into the industries. Among such properties, density as a function of temperature is one of the most important. In this study, a simple, accurate and global correlation is proposed to estimate the densities of a large number of DESs of different nature. The proposed model is a function of the critical temperature, critical volume and acentric factor of the DES, as well as the temperature of the system. In this way, the model is capable of accurately predicting the density of DESs without the need for any reference-temperature density data, in contrast to most of the literature models that do require a reference data point. The average relative error for 149 DESs of different natures was estimated to be 3.12% by the proposed model, indicating its accuracy compared to previous models.

Phase behaviour and theoretical modelling of binary and ternary mixtures of NADES/THEDES and supercritical carbon dioxide
Phase behavior – vapour liquid equilibrium
The implementation of this task has started late 2018 and therefore no major scientific results were obtained up to date. However, the team has started to determine the vapor-liquid equilibrium (VLE) of the binary mixtures THEDES + CO2 as this is crucial for their formulation (task 4.3). To be able to design formulation processes, such as particles from gas saturated solutions (PGSS) it is important to determine the VLE of the pseudo-binary system DES + CO2. THEDES systems based on anti-tuberculosis drugs ethambutol and L-arginine were studied. These will allow the understanding of the impact of its thermodynamic state in the design of innovative systems, from the appropriate choice of starting materials, conditions and technique, to the required final product properties or application outcome. In this work, the VLE was studied by determining pressure bubble points of different THEDES:CO2 ratios, in isothermic conditions, using variable-volume view cell methodology. Results suggest that it is possible to formulate drug delivery systems using the THEDES here
Despite the knowledge that has been generated within Des Solve there are still many questions that remain unanswered. Until the end of the project efforts will be made to respond to the challenges proposed in Des Solve. Particularly, to enlighten the propensity of different pairs of compounds to form an eutectic system, to perceive the role of water on the properties of these new entities and develop molecular simulations and computational models which explain NADES formation. A theoretical approach based on molecular simulations to understand the mechanisms of formation of NADES will be put in place. Molecular simulations based on classical models play an important role on the understanding of how condensed phase properties are linked to chemical structure and composition. Molecular simulations of NADES and THEDES will be performed using a Monte Carlo simulation approach. This methodology is based on atomic charges, which are not always known. These can be predicted through charge derivation methods, such as the Restrained Electrostatic Potential (RESP) method. Molecular simulations will allow a better understanding of NADES/THEDES structure and the prediction of some relevant properties such as transport properties. Simulations will be complemented with experimental data from the characterization of the systems performed earlier, particularly the spectroscopic analysis (FTIR and NMR) of the interactions of the molecules which compose the NADES.
Under a different topic, not yet fully explored within Des Solve is the study of the phase behaviour of NADES in the presence of supercritical fluids and thermodynamic modeling of the binary and/or ternary mixtures. The prediction of the phase behavior will be performed using the Cubic Plus Association (CPA) Equation of State (EoS) and optimizations will be done using Genetic Algorithm.The design of separation processes requires the knowledge of the phase equilibrium. However, data regarding phase equilibra for systems involving NADES are almost inexistent in literature. For that purpose, binary phase equilibrium studies for the system NADES/scCO2 will be performed to determine the solubility of scCO2 in different NADES and the solubility of NADES in scCO2. The latter is essential to evaluate the feasibility of a two phase extraction system where virtually no NADES is lost in the gas phase. In line with this, modelling plays here an important role towards the design and scale-up of the processes envisaged (separation/extraction and formulation). Experimental equilibrium data of the binary and ternary systems, will be hence required to validate the models. The CPA EoS is among the best EoSs to study the phase behavior of associating mixtures. CPA actually adds to the physical interactions of a simple cubic EoS, a term that takes into account the contribution of the association interactions between molecules. Therefore, it has the potential to handle much more complex mixtures, as compared to the simple engineering EoSs. Because DESs are polar systems with different hydrogen bonding sites on their structure, the CPA EoS is among the best choices for modelling such mixtures, which can reliably handle the necessary phase equilibrium calculations. The optimizations will be done using Genetic Algorithm (GA), which is among the powerful and well known optimization algorithms. In order to have more comprehensive investigation, the simple conventional engineering equations of state, such as the Peng-Robinson (PR) and the Soave-Redlich-Kwong (SRK), the standard equations of commercial software, will also be investigated and their results compared to those of the CPA. This will provide valuable data on the binary/ternary systems NADES/THEDES + supercritical fluids, being not only relevant to the characterization of the systems, but it allows the unraveling of new processing methodologies, based on green technologies.
Other technological breakthroughs are expected on the application development