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Projeto de investigação
When solids become liquids: natural deep eutectic solvents for chemical process engineering
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Optimal design of thedes based on perillyl alcohol and ibuprofen
Publication . Silva, Eduardo; Oliveira, Filipe; Silva, Joana M.; Matias, Ana; Reis, Rui L.; Duarte, Ana Rita C.; DQ - Departamento de Química; LAQV@REQUIMTE; MDPI AG
Therapeutic deep eutectic systems (THEDES) have dramatically expanded their popularity in the pharmaceutical field due to their ability to increase active pharmaceutical ingredients (APIs) bioavailability. However, their biological performance has not yet been carefully scrutinized. Herein, THEDES based on the binary mixture of perillyl alcohol (POH) and ibuprofen (IBU) were prepared using different molar ratios. Our comprehensive strategy includes the characterization of their thermal and structural behavior to identify the molar ratios that successfully form deep eutectic systems. The in vitro solubility of the different systems prepared has demonstrated that, unlike other reported examples, the presence of the terpene did not affect the solubility of the anti-inflammatory agent in a physiological simulated media. The biological performance of the systems was studied in terms of their antimicrobial activity against a wide panel of microorganisms. The examined THEDES showed relevant antimicrobial activity against all tested microbial strains, with the exception of P. aeruginosa. A synergistic effect from the combination of POH and IBU as a eutectic system was verified. Furthermore, the cytotoxic profile of these eutectic systems towards colorectal cancer (CRC) in vitro cell models was also evaluated. The results provide the indication that the cell viability varies in a dose-dependent manner, with a selective THEDES action towards CRC cells. With tunable bioactivities in a ratio-dependent manner, THEDES enhanced the antimicrobial and anticancer properties, representing a possible alternative to conventional therapies. Therefore, this study provides foreseeable indications about the utility of THEDES based on POH and IBU as strong candidates for novel active pharmaceutical systems.
Organic salts based on isoniazid drug: Synthesis, bioavailability and cytotoxicity studies
Publication . Santos, Filipa; Branco, Luís C.; Duarte, Ana Rita C.; LAQV@REQUIMTE; DQ - Departamento de Química; MDPI AG
Tuberculosis is one of the ten causes of morbidity and mortality worldwide caused by Mycobacterium tuberculosis complex. Some of the anti-tuberculosis drugs used in clinic studies, despite being effective for the treatment of tuberculosis, present serious adverse effects as well as poor bioavailability, stability, and drug-resistance problems. Thus, it is important to develop approaches that could provide shorter drug regimens, preventing drug resistance, toxicity of the antibiotics, and improve their bioavailability. Herein, we reported the use of organic salts based on the isoniazid drug, which can act as an organic cation combined with suitable organic anions such as alkylsulfonate-based (mesylate, R or S-Camphorsulfonate), carboxylate-based (glycolate, vanylate) and sacharinate. The synthesis, characterization, and cytotoxicity studies comparing with the original isoniazid drug have been performed. The possibility to explore dicationic salts seems promising in order to improve original bioavailability, and promote the elimination of polymorphic forms as well as higher stability, which are relevant characteristics that the pharmaceutical industry pursues.
Exploring anti-tuberculosis drugs through green solvents for effective treatment of tuberculosis
Publication . Santos, Márcia Filipa Carvalho dos; Duarte, Ana; Branco, Luís
Tuberculosis is an airborne infectious disease caused by Mycobacterium tuberculosis that remains to be one of the deadliest infectious diseases worldwide. Despite being considered treatable, the treatment of this disease involves a combination of different antibacterial drugs administrated for several months. This may cause serious adverse effects and lead to low treatment compliance by the patient, contributing to the ineffectiveness of the therapy and the emergence of drug resistance. The approaches used for treating tuberculosis are the same since their development, around 50 years ago. Therefore, and given the emergence and persistence of drug resistance to the various antibiotics used, it is of the utmost importance to conduct a breakthrough investigation to find alternatives able to rapidly reduce the incidence of tuberculosis, mainly in low-income countries. Considering the drawbacks of tuberculosis therapy, it is proposed in this work to explore alternative strategies to address long term therapies and poor patient compliance, which include the use of alternative solvents, such as ionic systems, therapeutic liquid mixtures, and supercritical fluid technology. In a first step, the preparation of ionic systems (organic salts) and eutectic mixtures incorporating anti-tuberculosis drugs in their structure were explored. Then, all prepared compounds were fully characterized both in terms of their physicochemical properties and their in vitro biological performance through a myriad of different procedures and techniques, such as polarized optical microscopy, differential scanning calorimetry, nuclear magnetic resonance, infrared spectroscopy, solubility, permeability (using Franz cells and transwell inserts), cytotoxicity in different cell lines, antibacterial activity, among others. Additionally, eutectic mixtures were prepared by dissolving first-line treatment anti-tuberculosis drugs and an organic salt (isoniazid di-chloride, [INH][Cl]2) in the system composed by citric acid, ethambutol, and water in a ratio of 1:1:5. In order to obtain inhalable particles for targeted site-infection delivery of these formulations, supercritical fluid technology was used to encapsulate the eutectic mixtures and formulate biocompatible particles with a suitable size for pulmonary administration. In general, the main objectives of the work were achieved, being the alternative strategies explored (ionic systems, eutectic mixtures, and supercritical fluid technology) capable to improve some essential characteristics of anti-tuberculosis drugs, in particularly, its solubility and stability. Hereupon, their potential should be further explored with different and more complex biological models.
Review of deep eutectic systems from laboratory to industry, taking the application in the cosmetics industry as an example
Publication . Rente, Duarte; Cvjetko Bubalo, Marina; Panić, Manuela; Paiva, Alexandre; Caprin, Benoit; Radojčić Redovniković, Ivana; Duarte, Ana Rita C.; DQ - Departamento de Química; LAQV@REQUIMTE; Elsevier
Green and sustainable chemistry principles have been employed in different industries to create greener and safer chemicals and processes, by replacing hazardous solvents with safer and more efficient ones. A state-of-the-art analysis on deep eutectic systems (DES) shows their consistent growth in the fields of chemistry, particularly as extraction solvents, mainly of bioactive compounds from natural sources. In this sense, a patent review was carried out, to highlight the relevance of DES, formed by natural compounds, in the cosmetic industry and the commercial added value of this technology at the industrial scale. Despite their good extraction efficiency, DES physicochemical properties need to be considered, as they may present some limitations in the process scale-up. This implies the study of several parameters, such as the cost of raw materials, the investment necessary to adapt or implement new equipment, energy consumption (for instance for pumping, heating, and stirring), and treatment of any by-products and wastes, in both the upstream and the downstream operations. Due to their inherent properties, DES can also be used as stabilizing agents of the bioactive compounds extracted, allowing their direct use in final products, namely in cosmetics, which is translated into a reduction of the downstream costs. This work further reports a case study of the extraction of grape anthocyanins with DES, and the necessary steps required to take this process from a laboratory scale to an industrial scale, targeting the cosmetic industry.
Synthesis and Physical and Thermodynamic Properties of Lactic Acid and Malic Acid-Based Natural Deep Eutectic Solvents
Publication . Castro, Vânia I. B.; Mano, Francisca; Reis, Rui L.; Paiva, Alexandre; Duarte, Ana Rita C.; LAQV@REQUIMTE; DQ - Departamento de Química; ACS - American Chemical Society
In this paper, four natural deep eutectic solvents (NADES) systems were prepared at specific molar ratios, La:Bet (2:1) (lactic acid/betaine), La:Hist (9:1) (lactic acid/histidine), Ma:Bet:H2O (1:2:3) (malic acid/betaine/water) and Ma:Bet:Pro:H2O (1:1:1:2) (malic acid/betaine/proline/water). Their physical and thermodynamic properties were studied, namely viscosity, electrical conductivity, and heat capacity. The viscosity and electrical conductivity were determined as a function of temperature and the correlation for the temperature dependence was obtained and discussed based on Arrhenius theory. The heat capacity for all eutectic systems was measured by differential scanning calorimetry (DSC) over a temperature range of 293.15-363.15 K. The ability of these NADES to reduce cellulose crystallinity was evaluated. Cellulose crystallinity after suspension in these NADES was studied by X-ray diffraction. Cellulose suspended in Ma/Bet/H2O (1:2:3) suffer the highest crystallinity reduction among the systems studied and was about of 20%.
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Entidade financiadora
European Commission
Programa de financiamento
H2020
Número da atribuição
725034