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]

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

Chiral ionic liquids in the development of enantioselective aqueous biphasic systems

publishe

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

Chiral ionic liquid-based aqueous biphasic systems for the separation of mandelic acid enantiomers

No abstract available.publishe

Enantioselective precipitation of racemic mandelic acid using chiral ionic liquids

publishe

Separation of racemic mandelic acid by enantioselective precipitation using chiral ionic liquids

In spite of sharing the same physical and chemical properties (excepting for their optical rotation), the two enantiomers of a drug can be discriminated by biological systems. While one of the enantiomers exerts the desired pharmacological effect, the other may be inert, less potent or even toxic. Under this scenario, pharma industry is constantly searching for efficient methods to obtain enantiopure drugs. The direct synthesis of the desired enantiomer represents the most widely used route; yet, its high cost and operational complexity are restricting substantial progress in the development of enantiopure drugs. As a simpler, cheaper and more flexible alternative, the chiral resolution of racemates emerged. In this work, the enantiomeric precipitation of racemic drugs is proposed as a simple and low-cost enantioseparation technique. To this aim, chiral ionic liquids (CILs) were applied as chiral selectors in the selective precipitation of mandelic acid (MA) enantiomers (here used as model drug). Aqueous solutions of CILs bearing chirality on the cation or the anion were evaluated regarding their capacity to selectively precipitate one enantiomer. The precipitation studies were performed using different CILs’ aqueous solutions, where the impact of the CIL structure and chirality was investigated. The influence of different operational conditions (e.g., time, agitation speed, CIL concentration and MA concentration) on the formed precipitate was additionally appraised. Remarkably, the developed CIL-based precipitation approach led to c.a. 49% of enantiomeric excess in a single-step and without further additives.publishe

Selective biphasic systems for the resolution of propranolol enantiomers, 6th International Conference on Ionic Liquid based Materials

Since enantiomers may have different biological properties, the use of racemates for the treatment of diseases can complicate the biological action of pharmaceuticals. For this reason, the commercialization of racemates should be increasingly prioritized. The synthesis of enantiopure molecules is difficult. Thus, the synthesis of racemates followed by their chiral resolution is often considered an easier and cost-effect alternative.[1] The resolution of pharmaceuticals can be accomplished by the employment of enantioselective liquid-liquid extraction (ELLE). ELLE is composed of two non-miscible phases that allow the optimization of enantioseparation through the addition of a chiral selector, such as chiral ionic liquids (CIL) or tartaric acid derivatives. The introduction of chiral selectors in ELLE may improve its selectivity, contributing to a high performant extraction/separation approach. In this work, CILs and tartaric acid derivatives were used in biphasic systems as chiral selectors, aiming to separate R/S-propranolol (R/S-PRP) enantiomers. The effect of the length of the alkyl chain of the tartaric acid derivatives was studied, being di-pentyl-L-tartrate the most effective tartaric acid derivative with a selective of 2.6. The most promising system was applied in centrifugal partition chromatography to further improve the enantiomeric purification rates.publishe