Separação enentiosseletiva de compostos quirais usando sistemas aquosos bifásicos e sistemas de duas fases sólida-líquida

Mestrado em Biotecnologia - Industrial e AmbientalTipicamente, apenas um dos enantiómeros é responsável pelo efeito pretendido de um fármaco, sendo que o outro pode levar a respostas menos potentes ou até mesmo indesejadas. As entidades reguladoras praticam políticas restritas em relação à comercialização de fármacos como misturas racémicas. Assim, a indústria farmacêutica tem enfrentado desafios relacionados com o desenvolvimento de métodos para produção de fármacos oticamente puros. No entanto, e considerando a dificuldade acrescida na produção de enantiómeros puros por síntese direta, a síntese de misturas racémicas seguida da sua purificação surge como uma alternativa mais barata, simples e flexível. Os sistemas aquosos bifásicos (SABs) e os sistemas de duas fases sólida-líquida (SDFSL) são técnicas alternativas mais biocompatíveis que têm sido utilizados como técnicas de separação enantiosseletiva de fármacos e/ou aminoácidos com enantiosseletividades bastante promissoras. Para além disso, apresentam benefícios de custo, rapidez, simplicidade e versatilidade de operação e possibilidade de aumento de escala. Este trabalho foca-se no desenvolvimento de SABs e SDFSL constituídos por seletores quirais que possam atuar simultaneamente como solvente. Numa primeira abordagem o objetivo foi desenvolver novos SABs quirais, mais biocompatíveis, simples e eficientes. Para tal, SABs constituídos por açúcares, aminoácidos e líquidos iónicos quirais foram aplicados na resolução enantiomérica de ácido mandélico racémico. O sistema mais promissor, composto por [C1Qui][C1SO4] + K3PO4, obteve um excesso enantiomérico de -33.4%. Numa segunda abordagem, foi possível criar uma alternativa mais simples e mais eficiente recorrendo a SDFSL. Com estes sistemas, foi obtido o valor mais elevado de excesso enantiomérico deste trabalho, de 49.0%, através da precipitação enantiosseletiva do R-ácido mandélico por interação com [N4444][D-Phe].Conventionally, only one of the enantiomers is responsible for the intended effect of a drug, whilst the other may lead to a less potent or even undesired response. Regulation entities are very strict regarding the commercialization of racemic drugs. Thus, pharmaceutical industry has been facing challenges related to the creation of methods to produce optically active drugs. However, considering the increased difficulty in the production of pure enantiomers by direct synthesis, the synthesis of racemic mixtures followed by their purification appears as a cheaper, simpler and more flexible alternative. Aqueous biphasic systems (ABS) and solid-liquid biphasic system (SLBS) are more biocompatible alternatives that have been used to separate racemic drugs and amino acids with promising enantioselectivities. Furthermore, these are cost-effective, quick, simple and operationally flexible. This work intended to develop ABS and SLBS using chiral selectors that can simultaneously act as solvents. In a first attempt, chiral ABS of better biocompatibility, simplicity and efficiency were developed. For that purpose, ABS constituted by sugars, amino acids and chiral ionic liquids (CILs) were applied for chiral resolution of racemic mandelic acid (MA). The most promising ABS was a system composed of [C1Qui][C1SO4] + K3PO4 which yielded the maximum enantiomeric excess of -33.4%. In a second approach, it was possible to create a simpler and more efficient technique resorting to SLBS. The enantiomeric excess value of 49.0% was achieved, by the enantioselective precipitation of the R-MA caused by interactions with [N4444][D-Phe]

Hybrid ASP-based multi-objective scheduling of semiconductor manufacturing processes (Extended version)

Modern semiconductor manufacturing involves intricate production processes consisting of hundreds of operations, which can take several months from lot release to completion. The high-tech machines used in these processes are diverse, operate on individual wafers, lots, or batches in multiple stages, and necessitate product-specific setups and specialized maintenance procedures. This situation is different from traditional job-shop scheduling scenarios, which have less complex production processes and machines, and mainly focus on solving highly combinatorial but abstract scheduling problems. In this work, we address the scheduling of realistic semiconductor manufacturing processes by modeling their specific requirements using hybrid Answer Set Programming with difference logic, incorporating flexible machine processing, setup, batching and maintenance operations. Unlike existing methods that schedule semiconductor manufacturing processes locally with greedy heuristics or by independently optimizing specific machine group allocations, we examine the potentials of large-scale scheduling subject to multiple optimization objectives.Comment: 17 pages, 1 figure, 4 listings, 1 table; a short version of this paper is presented at the 18th European Conference on Logics in Artificial Intelligence (JELIA 2023

Carotenoid production from microalgae: the portuguese scenario

Microalgae have an outstanding capacity to efficiently produce value-added compounds. They have been inspiring researchers worldwide to develop a blue biorefinery, supporting the development of the bioeconomy, tackling the environmental crisis, and mitigating the depletion of natural resources. In this review, the characteristics of the carotenoids produced by microalgae are presented and the downstream processes developed to recover and purify them are analyzed, considering their main applications. The ongoing activities and initiatives taking place in Portugal regarding not only research, but also industrialization under the blue biorefinery concept are also discussed. The situation reported here shows that new techniques must be developed to make microalgae production more competitive. Downstream pigment purification technologies must be developed as they may have a considerable impact on the economic viability of the process. Government incentives are needed to encourage a constructive interaction between academics and businesses in order to develop a biorefinery that focuses on high-grade chemicals.publishe

Extraction and purification of phycobiliproteins from algae and their applications

Microalgae, macroalgae and cyanobacteria are photosynthetic microorganisms, prokaryotic or eukaryotic, living in saline or freshwater environments. These have been recognized as valuable carbon sources, able to be used for food, feed, chemicals, and biopharmaceuticals. From the range of valuable compounds produced by these cells, some of the most interesting are the pigments, including chlorophylls, carotenoids, and phycobiliproteins. Phycobiliproteins are photosynthetic light-harvesting and water-soluble proteins. In this work, the downstream processes being applied to recover fluorescent proteins from marine and freshwater biomass are reviewed. The various types of biomasses, namely macroalgae, microalgae, and cyanobacteria, are highlighted and the solvents and techniques applied in the extraction and purification of the fluorescent proteins, as well as their main applications while being fluorescent/luminescent are discussed. In the end, a critical perspective on how the phycobiliproteins business may benefit from the development of cost-effective downstream processes and their integration with the final application demands, namely regarding their stability, will be provided.publishe

Carotenoid Production from Microalgae: The Portuguese Scenario

Microalgae have an outstanding capacity to efficiently produce value-added compounds. They have been inspiring researchers worldwide to develop a blue biorefinery, supporting the development of the bioeconomy, tackling the environmental crisis, and mitigating the depletion of natural resources. In this review, the characteristics of the carotenoids produced by microalgae are presented and the downstream processes developed to recover and purify them are analyzed, considering their main applications. The ongoing activities and initiatives taking place in Portugal regarding not only research, but also industrialization under the blue biorefinery concept are also discussed. The situation reported here shows that new techniques must be developed to make microalgae production more competitive. Downstream pigment purification technologies must be developed as they may have a considerable impact on the economic viability of the process. Government incentives are needed to encourage a constructive interaction between academics and businesses in order to develop a biorefinery that focuses on high-grade chemicals

Problem Decomposition and Multi-shot ASP Solving for Job-shop Scheduling

The Job-shop Scheduling Problem (JSP) is a well-known and challenging combinatorial optimization problem in which tasks sharing a machine are to be arranged in a sequence such that encompassing jobs can be completed as early as possible. In this paper, we propose problem decomposition into time windows whose operations can be successively scheduled and optimized by means of multi-shot Answer Set Programming (ASP) solving. Decomposition aims to split highly complex scheduling tasks into better manageable sub-problems with a balanced number of operations so that good quality or even optimal partial solutions can be reliably found in a small fraction of runtime. Problem decomposition must respect the precedence of operations within their jobs and partial schedules optimized by time windows should yield better global solutions than obtainable in similar runtime on the entire instance. We devise and investigate a variety of decomposition strategies in terms of the number and size of time windows as well as heuristics for choosing their operations. Moreover, we incorporate time window overlapping and compression techniques into the iterative scheduling process to counteract window-wise optimization limitations restricted to partial schedules. Our experiments on JSP benchmark sets of several sizes show that successive optimization by multi-shot ASP solving leads to substantially better schedules within the runtime limit than global optimization on the full problem, where the gap increases with the number of operations to schedule. While the obtained solution quality still remains behind a state-of-the-art Constraint Programming system, our multi-shot solving approach comes closer the larger the instance size, demonstrating good scalability by problem decomposition.Comment: Paper presented at the 38th International Conference on Logic Programming (ICLP 2022), 16 page

Aqueous biphasic systems based on chiral ionic liquids as platforms for chiral resolution

The production of enantiopure drugs is a major challenge for the pharmaceutical industry [1]. Considering the increased difficulty in the production of pure enantiomers by direct synthesis, the synthesis of racemates followed by their chiral resolution is a simpler, more flexible and cheaper alternative. This approach is commonly achieved by chromatography and crystallization, yet other methods, such as enantioselective liquid-liquid extraction can provide a better balance between costs, operational versatility and scale-up opportunities. Aqueous biphasic systems (ABS) are good candidates to turn enantioseparations not only into more biocompatible but also more versatile approaches [2]. Ionic liquids are alternative solvents with an enormous degree of structural diversity, allowing the design of task-specific solvents and, by their introduction in ABS, of highly performant extraction/separation approaches. Being made up of ions, if one can select/develop chiral structures to function as cations, anions or both, the opportunity of creating chiral ionic liquids (CILs) emerges [3,4]. This work proposes the development of a versatile enantioseparation platform for the chiral resolution of racemic mandelic acid. ABS using CILs simultaneously as chiral selectors and phase forming agents is proposed. Five different ABS were studied to determine the CIL structure and salt role on the ABS aptitude to separate mandelic acid enantiomers. Optimization studies were further pursued, as representative CIL-based ABS were employed in optimization studies, where the mandelic acid content, temperature, tie-line length, salt and phases weight ratio were studied. The influence of these parameters is shown to be highly dependent on the CIL-based ABS, nevertheless the results attained suggest that the key driving the enantioseparation in these ABS is a combination of the enantiorecognition ability of a given CIL with the solubility of mandelic acid in the corresponding CIL-rich phase. By closely manipulating the two conditions of the purification process, good enantioselective separations can be achieved.publishe

Unveiling the use of hydrophobic eutectic solutions as task-specific solvents to recover bacterioruberin from Haloferax mediterranei

Haloarchaea make up a class of untapped marine microbial resources that constitute a promising source of valuable compounds with unique characteristics. Bacterioruberin is a C50 carotenoid produced by haloarchaea that possesses interesting antioxidant properties and bioactivities relevant to the food and cosmetic industries. As a substitute for the conventional organic solvents used in the extraction of nonpolar pigments, natural and biocompatible hydrophobic eutectic solvents (HES) based on the mixture of menthol with carboxylic acids were investigated for the extraction of bacterioruberin. Seven HES systems were screened both as neat solvents and in the presence of water. The menthol and levulinic acid mixture displayed a 4-fold improvement over both the ethanol control and the other HES, due to the dual action of its components. Additionally, the recovery of proteins could be achieved by the addition of water to the extract, resulting in a three-phase partition system and the formation of a protein-rich interfacial precipitate. The process intensification was assessed through the reuse of the eutectic phase over five successive extraction cycles, achieving a bacterioruberin-rich extract of 2.13 mgbacterioruberin mLHES–1. Finally, the carbon footprint of the process was determined. The results highlight the potential of HES as biocompatible solvents for the recovery of value-added compounds from marine biomass, while the use of three-phase partition allows the recovery of proteins producing a second product stream.publishe

Chiral ionic liquids in the development of enantioselective aqueous biphasic systems

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Investigation of Nonlinear Optical Processes in Mercury Sulfide Quantum Dots

European Regional Development Fund (1.1.1.5/19/A/003), State Assignment to Higher Educational Institutions of Russian Federation (FZGU-2020-0035), Russian Foundation for Basic Research (18-29-20062). Institute of Solid State Physics, University of Latvia as the Center of Excellence acknowledges funding from the European Union’s Horizon 2020 Framework Programme H2020-WIDESPREAD-01-2016-2017-TeamingPhase2 under grant agreement No. 739508, project CAMART2.The authors report the third-harmonic generation, nonlinear refraction, and nonlinear absorption in HgS quantum dot (QD) suspensions and films using the nanosecond and femtosecond pulses. High conversion efficiency (7 × 10−4) towards the third harmonic (TH) of the 900–1700 nm, 150 fs laser in the thin (70 nm) films containing HgS QDs deposited on the glass substrates is obtained. The authors analyze spectral dependencies of the TH, nonlinear refractive indices, and nonlinear absorption coefficients of QDs in the 500–1700 nm range and discuss the relation between the TH process and the low-order nonlinear optical properties of these quantum dots. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.ERDF (1.1.1.5/19/A/003); State Assignment to Higher Educational Institutions of Russian Federation (FZGU-2020-0035), Russian Foundation for Basic Research (18-29-20062). Institute of Solid State Physics, University of Latvia as the Center of Excellence acknowledges funding from the European Union’s Horizon 2020 Framework Programme H2020-WIDESPREAD-01-2016-2017-TeamingPhase2 under grant agreement No. 739508, project CAMART2