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Grudzien, Lukasz Andrzej. "Enantioseparation using a counter-current bioreactor." Thesis, Brunel University, 2011. http://bura.brunel.ac.uk/handle/2438/6496.
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The potential of countercurrent chromatography (CCC) as a small footprint bioreactor/separator for manufacture of enantiopure chiral molecules was explored, using as a model reaction the isolation of L-amino butyric acid (L-ABA) from a DL-ABA racemate and the enantioselectivity of D-amino acid oxidase (DAAO). Bioconversion of D-ABA to ketobutyric acid (KBA) by DAAO, immobilised by selective partitioning in the stationary phase of the CCC centrifuge, was accompanied by separation of unreacted L-ABA from KBA by the countercurrent action of the centrifuge. For effective bioreactor/separator action, a high partition of the biocatalyst to the stationary phase was required in order to retain the biocatalyst in the coil, with differing partitions of substrates and products between the stationary phase (SP) and mobile phase (MP) so that these could be separated. Aqueous two-phase systems (ATPS) were the major two-phase systems used to provide SP and MP, as these are well reported to be effective in preserving enzyme activity. The distribution ratios of DL-ABA, KBA and DAAO were measured in a range of phases with polyethylene glycols (PEGs) of different molecular weights, different salts, and different compositions of PEG and salt, using an automated robotic method, developed for the purpose. A system of 14% w/w PEG 1000/ 14% w/w potassium phosphate, pH 7.6, gave the best combination of distributions ratios (CPEG phase/Csalt phase = CSP/CMP) for ABA, KBA and biocatalyst (DAAO) of 0.6, 2.4 and 19.6 respectively. A limited number of aqueous-organic and ionic liquid two-phase systems were also reviewed, but found unsatisfactory. CCC operating conditions such as substrate concentration, biocatalyst concentration, the mobile phase flow rate (residence time in the CCC coil), temperature, rotational speed and operational modes (single flow and multiple-dual flow) and types of mixing (cascade and wave-like) were optimised to produce total conversion of D-ABA to KBA, which was then completely separated from unreacted, enantiomerically pure (>99% ee), LABA. Advantages of the CCC bioreactor over conventional technology include reduced equipment footprint, cheaper running costs, and faster purifications. However, in its current format the drawbacks, such as enzyme instability and excessive optimisation time, reduce its commercial appeal. Additional investigations into the use of whole cell preparations of biocatalyst in the CCC bioreactor showed potential to overcome the problem of enzyme instability and this may in the future give the CCC bioreactor a place in the enantioseparation field.
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Snyder, Chad. "Enantioseparation of Alkylaryl Sulfoxides Using Capillary Zone Electrophoresis." TopSCHOLAR®, 1999. https://digitalcommons.wku.edu/theses/3040.
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Alkylaryl sulfoxides possess a chiral sulfur atom easily identifiable by capillary zone electrophoresis (CZE). Separation of chiral alkylaryl sulfoxides has already been accomplished by modified method of CZE known as micellar electrokinetic chromatography (MEKC). However, no articles have been published on the enantioseparation of alkylaryl sulfoxides using capillary zone electrophoresis.
A series of sulfoxides were synthesized, purified and identified via NMR. Enantioseparation was performed using CZE employing a 10 mmol. Phosphate buffer (pH 4.0, 25% acetonitrile, 2% sulfated-β-cyclodextrin). Synthesis of these sulfoxides will be presented along with the results of the procedure’s optimization. Separation of the sulfoxide enanitomers relies on the partitioning between the chiral additive (sulfated-β-cyclodextrin) and buffer solution.
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Chen, Taiyi. "Chloroperoxidase Catalyzed Enantioselective Epoxidation of Selected Olefins and Regiospecific Degradation of Dimethylsulfoniopropionate." FIU Digital Commons, 2011. http://digitalcommons.fiu.edu/etd/514.
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Chloroperoxidase (CPO), secreted by marine fungus Caldariomyces fumago, is the most versatile catalyst among known heme enzymes. Chloroperoxidase can catalyze epoxidation reactions with high enantioselectivity and high yield, which makes CPO an attractive candidate for both industrial and medicinal chiral synthesis. Toward this end, we have constructed two CPO mutants, F103A and N74V. Chiral HPLC was used to evaluate the enantioselectivity and yield of CPO and the mutants toward the epoxidation of styrene and its derivatives. Both of the mutants show dramatically changed epoxidation profiles compared to the parent protein. This information provided fresh insight into the mechanism through which CPO achieves its enantioselectivity. Furthermore, effort was made to understand the biological function of CPO through characterization of CPO catalyzed oxidation of dimethylsulfoniopropionate (DMSP), a secondary metabolite of many marine algal species that plays a pivotal role in marine ecology and global climate.
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Wahl, Joachim [Verfasser], and Ulrike [Gutachter] Holzgrabe. "The Use of Ionic Liquids in Capillary Electrophoresis Enantioseparation / Joachim Wahl ; Gutachter: Ulrike Holzgrabe." Würzburg : Universität Würzburg, 2019. http://d-nb.info/117907968X/34.
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Didier, Delphine. "Functionalized analogues of Tröger's base: synthesis, enantioseparation, and application as a chiral scaffold in organocatalysis." Doctoral thesis, Universite Libre de Bruxelles, 2009. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210277.
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Jusqu’à très récemment, les catalyseurs pour la synthèse asymétrique étaient limités aux enzymes et aux complexes de coordination. Depuis les années 2000, une troisième approche a vu le jour: l’organocatalyse asymétrique. Il est assez surprenant de constater que parmi la multitude de catalyseurs organiques développés chaque année, une minorité d’entre eux seulement est basée sur de nouveaux squelettes chiraux. En effet, l’introduction d’une nouvelle entité chirale pourrait mener à la découverte de nouvelles combinaisons de substrats ainsi qu’à de nouvelles réactions catalytiques hautement stéréosélectives. C’est pourquoi, nous nous sommes proposé de préparer une série de nouveaux catalyseurs organiques bifonctionnels incluant des fonctions thiourées et basée sur le squelette chiral de la base de Tröger.L’accès aux dérivés énantiopures de la base de Tröger reste un défi majeur. C’est pourquoi, nous avons décidé de mettre au point une méthode efficace et prévisible, pour la résolution des analogues de la base de Tröger. Dans la mesure où l’élaboration d’une telle méthode nécessite un grand nombre de molécules, nous avons synthétisé une série de dérivés de la base de Tröger.
La condensation d’anilines variablement substituées avec du paraformaldehyde dans de l’acide trifluoroacétique a été étudiée, conduisant à la synthèse d’analogues symétriques de la base de Tröger. L’utilisation de paraformaldehyde n’étant pas compatible avec tous les groupements fonctionnels, d’autres voies de synthèse ont également été explorées. Ainsi, des dérivés amino et cyano ont été préparés par l’intermédiaire de réactions organométalliques. Ensuite, une voie de synthèse menant aux analogues non-symétriques de la base de Tröger a été mise au point. Finalement, une série de dérivés présentant un pont –NCH2CH2N- a été préparée.
La résolution de l’ensemble des composés a été systématiquement étudiée par chromatographie sur la phase stationnaire chirale commerciale Whelk O1. Des relations structure vs. énantioséléctivité ont pu être établies permettant de prédire la séparation par notre méthode. Une corrélation entre l’ordre d’élution et la configuration absolue a également pu être mise en évidence.
Enfin, l’activité catalytique des dérivés thiourées de la base de Tröger a été évaluée dans la réaction d’addition de Michael de différents dérivés de l’acide malonique au trans-nitrostyrene. Compte tenu de la faible basicité de la base de Tröger, il a été démontré que l’issue de la réaction est fortement dépendante du pKa du nucléophile. De plus, aucune stéréosélectivité n’a pu être mise en évidence dans cette réaction d’addition.
Doctorat en Sciences
info:eu-repo/semantics/nonPublished
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Levkin, Pavel. "Practice and theory of gas chromatographic enantioseparation on single- and binary-selector chiral stationary phases." [S.l. : s.n.], 2007.
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Bortoleto, Marcela Armelim. "Avaliação de fungos na obtenção do metabólito quiral e ativo O-desmetilvenlafaxina." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/59/59138/tde-08082014-122129/.
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A venlafaxina é um fármaco quiral utilizado no tratamento da depressão e da ansiedade associada à depressão. A ação farmacológica desse fármaco está associada principalmente ao enantiômero (+)-(S)-venlafaxina, que inibe a recaptação da serotonina enantiosseletivamente. Quando metabolizada pelas enzimas da citocromo P450 dois metabólitos são produzidos, também quirais, a O-desmetilvenlafaxina (ODV) e a N-desmetilvenlafaxina (NDV). O estudos mostram que o metabólito ODV é farmacologicamente ativo, apresentando ação farmacológica semelhante a venlafaxina. Fungos são micro-organismos capazes de mimetizar o metabolismo de mamíferos, produzindo, muitas vezes, os mesmos metabólitos. Além disso, esse processo pode ser enantiosseletivo. Dessa forma, o objetivo desse trabalho foi avaliar a capacidade de fungos em biotransformar a venlafaxina em seus metabólitos ODV e NDV de uma maneira enantiosseletiva. A separação quiral dos analitos foi realizada por cromatografia liquida de alta eficiência (CLAE) e eletroforese capilar (CE). Como técnica de preparação de amostra foi empregada a microextração liquido-liquido dispersiva (DLLME). Essa técnica recente de preparação de amostra possui alta eficiência na extração, permitindo a obtenção de altos valores de recuperação e um consumo mínimo de solvente orgânico. Anterior aos estudos de biotransformação, o método foi validado para análise por CLAE e CE, empregando, em ambos os casos, a DLLME como técnica de preparação de amostras. A validação foi realizada de acordo com as recomendações da ANVISA para análise de fármacos em material biológico. Todos os parâmetros avaliados (linearidade, precisão, exatidão, estabilidade, seletividade e limite de quantificação) apresentaram valores dentro das exigências da ANVISA. Os estudos de biotransformação foram realizados empregando os seguintes fungos: Mucor rouxii, Cunninghamella echinulata ATCC 8688A, Cunninghamella elegans 10028B, Beuveria bassiana ATCC 7159, Phomopsis sp (TD2), Chaetomiun globosun (VR10) e Glomerela cingulata (VA1). Entre esses, o fungo Cunninghamella elegans mostrou-se promissor na biotransformação da venlafaxina. Dessa forma, diversos fatores foram avaliados na tentativa de melhorar a biotransformação, sendo esses: troca de fonte de carbono do meio de cultura, alteração de meios de biotransformação e adição de cofatores ao meio de cultura. Os resultados mostraram fortes indícios de biotransformação enantiosseletiva da venlafaxina em seu metabólito (+)-(S)-N-desmetilvenlafaxina.Venlafaxine is a chiral drug used in the treatment of depression and anxiety associated with depression. The pharmacological activity of this drug is mainly associated to the enantiomer (+)-(S)-venlafaxine, which inhibits the reuptake of serotonin with enantioselectivity. When metabolized by the cytochrome P450 enzymes, two metabolites, also chiral, are produced, O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV). The studies have demonstrated that the ODV metabolite is pharmacologically active, with similar pharmacological activity of venlafaxine. Fungal are microorganisms capable of mimicking the mammalian metabolism, often producing the same metabolites. Moreover, this process can be enantioselective. Thus, the aim of this study was to evaluate the ability of fungi to biotransform, with enantioselectivity, the venlafaxine in its metabolites ODV and NDV. The chiral separation of the analytes was performed by high performance liquid chromatography (HPLC) and capillary electrophoresis (CE). As sample preparation was employed the dispersive liquid-liquid microextraction (DLLME). This recent technique of sample preparation has high extraction efficiency, allowing obtaining high values of recovery and minimal consumption of organic solvent. Before the biotransformation studies, the method was validated employing CE and HPLC with the DLLME technique as sample preparation. The validation was performed according to ANVISA recommendations. All parameters (linearity, precision, accuracy, stability, selectivity and limit of quantification) were acceptable as required by ANVISA. The biotransformation studies were conducted using the following fungal: Mucor rouxii, Cunninghamella echinulata ATCC 8688A, Cunninghamella elegans 10028B, Beuveria bassiana ATCC 7159, Phomopsis sp (TD2), Chaetomiun globosun (VR10) and Glomerela cingulata (VA1). Among these, the fungus Cunninghamella elegans was promising in the biotransformation of venlafaxine. Thus, several factors were evaluated in an attempt to improve the biotransformation: carbon source exchange in the liquid culture medium, changes of the biotransformation medium and addition of cofators in the culture medium. The results provides strong evidences of enantioselective biotransformation of venlafaxine in its metabolite (+)-(S)-N-desmethylvenlafaxine.
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Fortes, Simone Silveira. "Avaliação de fungos na biotransformação estereosseletiva da Hidroxizina e obtenção do metabólito quiral e ativo Cetirizina." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/59/59138/tde-11072013-103307/.
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Modelos microbiológicos tem sido usado na biotransformação de fármacos para a obtenção de metabólitos. Fungos de diversos gêneros têm sido amplamente utilizados para mimetizar o metabolismo hepático de mamíferos. O uso de fungos é vantajoso uma vez que apresentam um crescimento rápido e de fácil formação do sistema multienzimático. Além disso, hoje, a biotransformação é considerada como uma tecnologia econômica e competitiva, na busca de novas rotas de produção farmacêutica e de compostos agrotóxicos. Em muitos casos a transformação biológica é enantiosseletiva, permitindo a produção de enantiômeros puros a partir de misturas racêmicas. Devido à ausência de um método de extração com baixo consumo de solventes orgânicos para a determinação enantiosseletiva da hidroxizina (HZ) e cetirizina (CTZ), foi desenvolvido um método que combina a microextração liquido-liquido dispersiva (DLLME) e eletroforese capilar (CE) para estudar a biotransformação enantiosseletiva da HZ pelos fungos Penicillium crustosum, Mucor rouxii, Cunnonghamella echinulata var. elegans ATCC 8688, Cunnonghamella echinulata var. elegans ATCC 10028, Nigrospora sphaerica e Fusarium oxysporum. Um método por CE foi desenvolvido para a análise enanatiosseletiva da hidroxizina e cetirizina em meio de cultura Czapek. As análises por CE foram realizadas utilizando um capilar de sílica fundida não revestida, 50 mmol L-1 de borato de sódio como solução tampão de análise (pH 9,0) contendo 0,8% p/v de ciclodextrina--sulfatada como seletor quiral. A tensão aplicada e temperatura foram de +6 kV e 15 ºC, respectivamente. O detector UV foi ajustado no comprimento de onda 214 nm. As condições da DLLME envolvidas foram: clorofórmio (300 µL) como solvente extrator, etanol (400 µL) como solvente dispersante. Após a formação da solução turva, as amostras foram submetidas a agitação por vórtex durante 30 segundos a 2000 rpm e centrifugação durante 5 minutos a 3000 rpm. As recuperações foram na faixa de 87,4 91,7%. O método se mostrou linear na faixa de concentração 250 12500 ng mL-1 para cada enantiômero da HZ (r > 0.998) e de 125 6250 ng mL-1 para cada enantiômero da CTZ (r > 0.998). Os limites de quantificação foram 125 e 250 ng mL-1 para CTZ e HZ, respectivamente. Dentre os seis fungos estudados, três foram capazes de converter a HZ em CTZ enantiosseletivamente, especialmente o fungo Cunninghamella elegans ATCC 10028 que converteu 19% de (E1)-HZ em (S)-CTZ com excesso enantiomérico de 65%.Microbial models have been used in biotransformation studies of many drugs aiming their metabolite production. Fungi of various genera have been extensively used to mimic the mammals hepatic metabolism. The use of fungi is advantageous because they present fast growth and easy formation of the multienzymatic system. Moreover, the biotransformation is, nowadays, considered an economically and competitive technology, in the search of new production routes for fine chemical, pharmaceutical and agrochemical compounds. In many cases, the biological transformation is enantioselective, allowing the production of pure enantiomers from racemic mixtures. In light of the above considerations and due to the absence of a low consuming organic solvent extraction method for the enantioselective determination of hydroxyzine (HZ) and cetirizine (CTZ), it was developed a method combining dispersive liquid-liquid microextraction (DLLME) and capillary electrophoresis (CE) to study the enantioselective biotransformation of HZ through the fungi Penicillium crustosum, Mucor rouxii, Cunnonghamella echinulata var. elegans ATCC 8688, Cunnonghamella echinulata var. elegans ATCC 10028, Nigrospora sphaerica e Fusarium oxysporum. A CE method was developed for the enantioselective analysis of hydroxyzine (HZ) and cetirizine (CTZ) in Czapek liquid culture medium. The CE analyses were performed using an uncoated fused-silica capillary and 50 mmol/L sodium borate buffer (pH 9.0) containing 0.8% (w/v) sulfated--cyclodextrin. The applied voltage and temperature used were +6 kV and 15 °C, respectively. The UV detector was set at 214 nm. The DLLME conditions involved: chloroform (300 µL) as extraction solvent and ethanol (400 µL) as dispersive solvent. After the formation of the cloudy solution, the samples were subjected to vortex agitation during 30 s at 2000 rpm and centrifugation for 5 min at 3000 rpm. The recoveries were in the range of 87.4 91.7%. The method was linear over the concentration range of 250 12500 ng/mL for each enantiomer of HZ (r > 0.998) and of 125 6250 ng/mL for each enantiomer of CTZ (r > 0.998). The quantification limits were 125 and 250 ng/mL for CTZ and HZ, respectively. Among the six studied fungi three were able to convert HZ to CTZ enantioselectively, especially the fungus Cunninghamella elegans ATCC 10028B that converted 19% of (E1)-HZ to (S)-CTZ with an enantiomeric excess of 65%.
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Zanão, Lídia Renata. "Avaliação de fungos e complexos de salen na obtenção do metabólito quiral e ativo terbutalina." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/59/59138/tde-26112013-203126/.
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Enantiômeros podem interagir de maneira diferenciada no organismo, ocasionando efeitos farmacológicos variados. Dessa forma, metodologias para a obtenção de fármacos enantiomericamente puros são importantes para a indústria farmacêutica. Modelos sintéticos empregando reagentes quirais, como complexos de salen e modelos biológicos utilizando fungos estão sendo muito estudados neste contexto. O uso de fungos apresenta como principais vantagens o crescimento rápido, baixo custo e fácil operação, além da produção de metabólitos em grande quantidade. Complexos de salen são eficientes e estáveis, possuindo ampla aplicabilidade e possibilidade de produzir reações enantiosseletivas. O objetivo deste trabalho foi avaliar fungos e complexo de salen como alternativas na produção enantiosseletiva de terbutalina, o metabólito quiral e ativo de seu pró-fármaco, o bmbuterol. A separação enantiosseletiva dos analitos foi realizada empregando a cromatografia líquida de alta eficiência com detector UV-Vis (LC/UV). A validação da metodologia analítica e os estudos de biotransformação foram executados por cromatografia líquida de alta eficiência acoplada à espectrometria de massas (LC-MS). A resolução do bambuterol e da terbutalina por LC/UV foi realizada utilizando como fase estacionária a coluna Chirobiotic T e como fase móvel acetonitrila:metanol (80:20, v/v) + 0,3% de ácido fórmico e 0,1% de trietilamina, numa vazão de 1,5 mL min-1 e por LC-MS utilizando a mesma fase estacionária e a fase móvel composta por 96% de metanol em água + 0,2% de ácido acético e 0,1% de acetato de amônio na vazão de 1 mL min-1. A extração dos analitos em meio de cultura líquido (Czapek, 2 mL) foi feita empregando a microextração liquido-liquido dispersiva (DLLME), nas condições: solvente dispersor,isopropanol (600 µL); solvente extrator, diclorometano (50 µL); reagente par iônico, di(2-etil-hexil)fosfato (100µL); e solução tampão fosfato de sódio (2 mL, pH 7,6). A recuperação do bambuterol foi de 92% e a da terbutalina foi estimada em 55%. O método foi validado para a análise do bambuterol no meio de cultura e se mostrou linear na faixa de concentração 500 17500 ng mL-1 para cada enantiômero (r > 0.998).O limite de quantificação foi igual a 500 ng mL-1. Dentre os fungos avaliados neste trabalho, nenhum foi capaz de realizar a biotransformação do bambuterol em terbutalina nas condições empregadas. Nos estudos feitos utilizando catálise assimétrica também não foi possível observar esse metabólito. Dada a complexidade do metabolismo do bambuterol (reações de hidrólise e/ou oxidação) e da formação de vários intermediários anterior a etapa de formação da terbutalina, as condições avaliadas nesse estudo não foi capaz de produzir o metabólito ativo do bambuterol, terbutalina.Enantiomers may interact differently in the organism causing pharmacological sundry effects. For these reason, enantiomeric pure drugs are very important for the pharmaceutical industries. Synthetic models employing chiral reagents, like salen complexes, and biological models using fungi are been very studied in this context. Fungi present as main advantage the fast growing up, low costs and easily application, moreover, their metabolites are produced in huge quantities. Salen complexes are efficient and stable. They have a wide application and the possibility of production of high enantiomeric excess. The aim of this work was to evaluate fungi and salen complex as alternatives to the enantioselective production of terbutaline, the chiral and active metabolite of your prodrug, bambuterol. The analytes enantioselective separation was done employing high performance liquid chromatography with UV-Vis detector (LC/UV). The method validation and the studies of biotransformation were done using high performance liquid chromatography coupled with mass spectrometry (LC-MS). The resolution of bambuterol and terbutaline by LC/UV was accomplished using the Chirobiotic T column and acetonitrile: methanol (80:20, v/v) + 0.3% formic acid and 0.1% triethylamine as mobile phase at a flow rate of 1.5 mL min-1 and by LC-MS employing the same column and the mobile phase was composed by 96% of methanol in water + 0,2% acetic acid and 0,1% ammonium acetate at a flow rate of 0.1 mL min-1. The analytes extraction of the culture medium (Czapek, 2 mL) was done using the dispersive liquid liquid microextraction (DLLME), in the following conditions: dispersive solvent, isopropanol (600 µL); extractor solvent, dichloromethane (50 µL); ionic-pair reagent; di(2-ethylhexyl)phosphate (100 µL); and sodium phosphate buffer (2 mL, pH 7.6). The recoveries were 92% for the bambuterol and estimated in 55% for terbutaline. The method was validated for the analysis of bambuterol in the culture medium and was linear over the concentration range of 500 17500 ng mL-1 for each enantiomer (r > 0.998). The quantification limit was 500 ng mL-1. Among the evaluated fungi, none was able to do the biotransformation process of bambuterol at terbutaline in the employed conditions and so do the studies employing asymmetric catalyses. Because the complexity of bambuterols metabolism for producing terbutaline (hydrolysis and/or oxidation reactions) and the formation of several intermediates before the terbulalines formation step, the evaluated conditions in this study were not able to produce the chiral active metabolite, terbutaline.
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Wang, Bin. "Utility of Cationic and Anionic Chiral Surfactants in Capillary Electrophoresis (CE) and CE Coupled to Mass Spectrometry (CE-MS)." Digital Archive @ GSU, 2009. http://digitalarchive.gsu.edu/chemistry_theses/16.
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The research presented in this thesis involves the application of chiral cationic and anionic surfactants for simultaneous enantioseparation of structurally similar compounds in capillary electrophoresis (CE) and CE coupled to mass spectrometry (CE-MS). The first chapter briefly introduces the fundamentals of CE and CE-MS, emphasizing the micellar electrokinetic chromatography (MEKC) and MEKC-MS techniques, as well as ionic liquids (ILs) and affinity CE (ACE). In chapter 2, a mixture of five racemic profen (PROF) drugs are simultaneously separated with the combined use of 2,3,6-tri-O-methyl-β-cyclodextrin (TM-β-CD) and IL-type surfactant, N-undecenoxycarbonyl-L-leucinol bromide (L-UCLB). Enantioseparations of these PROFs are optimized using a standard recipe containing 35.00 mM TM-β-CD, 5.00 mM sodium acetate at pH 5.0, and varying the concentration as well as chain length of the IL surfactants. The batch-to-batch reproducibility of L-UCLB is found to be acceptable in terms of enantiomeric resolution, and migration time. A competitive inhibition mechanism is proposed to investigate the ternary interactions among TM-β-CD, ILs, and PROFs. The apparent binding constant of TM-β-CD to L-UCLB is estimated by nonlinear and linear plotting methods. The binding constants of one representative PROF (e.g., fenoprofen) to TM-β-CD and to L-UCLB are estimated by a secondary plotting approach. The R- and S-fenoprofen having different binding constant values, resulting in the enantioseparation due to the synergistic effect of TM-β-CD and L-UCLB. The R- and S-configurations of barbiturates display differences in potency and biological activity. In Chapter 3, a multivariate MEKC-ESI-MS approach for the simultaneous analysis of the racemic mixture of three barbiturates is presented. The chiral selector employed is the polymeric surfactant polysodium N-undecenoxycarbonyl-L-isoleucinate. The central composite design is used to optimize the chiral resolution, decrease the total analysis time, and improve the ESI-MS signal-to-noise ratio for these barbiturates. In preliminary experiments, the ranges of the factors investigated in the multivariate approaches are determined. Then the multivariate optimizations are conducted to determine the best overall chiral resolution with shortest possible run times for barbiturates. The limit of detection of ESI-MS is several folds higher compared to the UV detection. The predicted optimum results are in good agreement with the experimental data.
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Ouyang, Wuye. "Dispersed and deposited polyelectrolyte complexes and their interactions to chiral compounds and proteins." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2009. http://nbn-resolving.de/urn:nbn:de:bsz:14-ds-1233841492089-61523.
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Polyelectrolyte complexation is a rapidly growing field with applications in functional multilayer (PEM) and nanoparticle (PEC) generation, where PEM films are deposited using Layer-by-Layer technique initiated by Decher and PECs are prepared using mixing-centrifugation technique initiated by our group. Its advantages (e.g. easy preparation) result in various applications in aqueous solution, especially in pharmaceutical and biomedical fields. Therefore, the objectives in this study are to explore interesting applications of polyelectrolyte complexation in the field of low molecular chiral compound and high molecular protein binding. Due to the rapidly growing demands for preparing optically pure compounds in the pharmaceutical field, herein, enantiospecific PEM and PEC were prepared using chiral polyelectrolytes (e.g. homo-polypeptide) and their ability of chiral recognition was investigated by ATR-FTIR, UV/Vis etc.. Chiral PEM and PEC showed pronounced enantiospecificity for both small (amino acids, vitamin) and large (protein) chiral compounds. This chiral recognition is performed by a diffusion process of chiral compounds into PEM based on the structures of chiral selector (PEM, PEC) and chiral probes (chiral compounds). However, the influences, e.g. pH value, ionic strength, surface orientation etc., were found to affect significantly the enantiospecificity. Beside planar substrates, porous membranes (e.g. PTFE) were modified using chiral PEM and successfully applied in enantiospecific permeation. Additionally, protein binding properties of PEC particle dispersions or PEC particle films were also studied. Due to the properties of polyelectrolytes used for PEC (e.g. molecular weight, charge density) and proteins (e.g. isoelectric point, size, hydrophobicity), PEC showed different uptake characteristics towards different proteins. Electrostatic and hydrophobic interaction as well as counterion release force were considered as possible driving forces for protein binding.
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Ouyang, Wuye. "Dispersed and deposited polyelectrolyte complexes and their interactions to chiral compounds and proteins." Doctoral thesis, Technische Universität Dresden, 2008. https://tud.qucosa.de/id/qucosa%3A23825.
Full textAbstract:
Polyelectrolyte complexation is a rapidly growing field with applications in functional multilayer (PEM) and nanoparticle (PEC) generation, where PEM films are deposited using Layer-by-Layer technique initiated by Decher and PECs are prepared using mixing-centrifugation technique initiated by our group. Its advantages (e.g. easy preparation) result in various applications in aqueous solution, especially in pharmaceutical and biomedical fields. Therefore, the objectives in this study are to explore interesting applications of polyelectrolyte complexation in the field of low molecular chiral compound and high molecular protein binding. Due to the rapidly growing demands for preparing optically pure compounds in the pharmaceutical field, herein, enantiospecific PEM and PEC were prepared using chiral polyelectrolytes (e.g. homo-polypeptide) and their ability of chiral recognition was investigated by ATR-FTIR, UV/Vis etc.. Chiral PEM and PEC showed pronounced enantiospecificity for both small (amino acids, vitamin) and large (protein) chiral compounds. This chiral recognition is performed by a diffusion process of chiral compounds into PEM based on the structures of chiral selector (PEM, PEC) and chiral probes (chiral compounds). However, the influences, e.g. pH value, ionic strength, surface orientation etc., were found to affect significantly the enantiospecificity. Beside planar substrates, porous membranes (e.g. PTFE) were modified using chiral PEM and successfully applied in enantiospecific permeation. Additionally, protein binding properties of PEC particle dispersions or PEC particle films were also studied. Due to the properties of polyelectrolytes used for PEC (e.g. molecular weight, charge density) and proteins (e.g. isoelectric point, size, hydrophobicity), PEC showed different uptake characteristics towards different proteins. Electrostatic and hydrophobic interaction as well as counterion release force were considered as possible driving forces for protein binding.
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Fernandes, Andreia Patrícia Macedo. "Separation of mandelic acid enantiomers using aqueous biphasic systems containing chiral selectors." Master's thesis, Universidade de Aveiro, 2017. http://hdl.handle.net/10773/22869.
Full textAbstract:
Mestrado em Bioquímica - Métodos BiomolecularesA quiralidade é a uma propriedade importante na indústria farmacêutica, uma vez que um enantiómero de um fármaco pode exercer o efeito terapêutico desejado enquanto o outro pode ser inerte ou mesmo nefasto. Embora vários fármacos sejam comercializados na sua forma racémica, as entidades regulatórias aconselham o desenvolvimento de fármacos enantiomericamente puros e mais seguros. Neste contexto, a indústria farmacêutica procura formas baratas e eficientes de produzir fármacos enantiomericamente puros, sendo este o objetivo da presente tese. A separação enantiomérica do ácido mandélico (AM), aqui utilizado como um fármaco racémico modelo, será tentada recorrendo a sistemas aquosos bifásicos (SABs) constituídos por seletores quirais de origem natural (proteínas e açúcares). Serão usadas duas abordagens: (i) a introdução de proteínas como seletores quirais em diferentes tipos de SABs; e (ii) o uso de (D)-sacarose simultaneamente como seletor quiral e componente de fase em SABs. Na primeira abordagem, foram utilizados diferentes tipos de SABs (polímero+polímero, polímero+sal, sal+líquido iónico (LI), polímero+LI e polímero+açúcar) e duas proteínas (albumina de soro bovino – BSA – e citocromo C – Cit c). A escolha das proteínas assentou em resultados de molecular docking que indicaram interações distintas entre diferentes proteínas e os enantiómeros do AM. Nestas fases, os sistemas constituídos por PPG400+(D)-Sacarose+BSA (excesso enantiómerico de -5.9± 0.5%) e PPG400+dihidrogeno fosfato de colínio+Cit c (excesso enantiomérico de -9.0 ± 1.2%) revelaram-se os mais eficientes. As proteínas e os constituintes de fase dos SABs afetaram a separação enantiomérica de ácido mandélico. Uma vez que a docagem molecular não considera as interações com os componentes de fase, esta abordagem revelou ser incapaz de prever o desempenho das proteínas como seletores quirais em SABs. Com o objetivo de ultrapassar as limitações de seletividade enantiomérica e melhorar a simplicidade operacional da tecnologia proposta, a (D)-sacarose foi usada simultaneamente como formador de fase e seletor quiral em SABs. Depois de uma otimização cuidada, foi possível obter um excesso enantiomérico máximo de -12.3 ± 0.5% com um SAB constituído por polímero e (D)-sacarose.
Chirality is an important property for the pharmaceutical industry, since one enantiomer of a drug can exert a therapeutic action, while the other may be inert or even nefarious. While several drugs are commercialized as racemates, regulatory bodies strongly encourage the development of safer enantiopure drugs. In this context, pharmaceutical industry seeks for cheap and efficient ways of obtaining enantiopure pharmaceuticals and this is the main objective of this thesis. The enantiomeric separation of mandelic acid (MA), here used as a model racemic drug, using aqueous biphasic systems (ABS) composed of natural chiral selectors (proteins and sugars) will be proposed. Two different approaches were used: (i) the introduction of proteins as chiral selectors in several types of ABS; and (ii) ABS formed by D-Sucrose as both phase former and chiral selector. Within the first approach, different types of systems (polymer+polymer, polymer+salt, polymer+sugar, and ionic liquids (ILs)+salt, ILs+polymer) and of proteins (bovine serum albumin –BSA - and cytochrome C – Cyt C) were used. These two proteins were chosen based on molecular docking results that shown distinctive interactions with the two MA enantiomers among eleven screened proteins. PPG400+(D)-sucrose+BSA system (enantiomeric excess of -5.9 ± 0.5%) and PPG+cholinium dihydrogenphosphate+Cyt C (enantiomeric excess of -9.0 ± 1.2% were the most efficient ABS developed up to this stage. Both the protein and ABS phase formers affected the enantioseparation of MA. Since molecular docking does not encompass the interactions with the ABS phase formers, it was limited at predicting the proteins’ performance as chiral selectors in ABS. In order to surpass the limited enantioselectivity displayed and to improve the operational simplicity of the proposed technology, (D)-sucrose was employed as both chiral selector and phase former in ABS. After a proper optimization, it was possible to achieve a maximum enantiomeric excess of -12.3 ± 0.5% with an ABS composed of polymer and (D)-sucrose.
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Kholany, Mariam Achraf Mohamed Bahie El Din El. "Enantioselective separation of chiral compounds using aqueous biphasic systems and solid-liquid biphasic system." Master's thesis, Universidade de Aveiro, 2017. http://hdl.handle.net/10773/22708.
Full textAbstract:
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].
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Yeung, Kai Tai. "Molecular simulations of the enantioseparating mechanism of polysaccharide-based chiral stationary phase and enzymatic acylation of N-benzoyl-L-arginine ethyl ester in binary aquo-organic solvent mixtures." HKBU Institutional Repository, 2007. http://repository.hkbu.edu.hk/etd_ra/819.
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Chen, Yu Chen, and 陳宥辰. "Enantioseparation of phenylglycinol by distillative freezing." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/61367623570773172552.
Full textAbstract:
碩士長庚大學
化工與材料工程學系
99
Distillative freezing (DF) is a new separation technique which combines distillation and crystallization to produce pure crystals. In principle, DF is operated at a triple-point condition, in which the liquid mixture is simultaneously vaporized and crystallized due to the three-phase equilibrium. The process is continued until the liquid phase is completely eliminated and only the pure solid crystals remain in the feed. Thus, crystal washing is not required since no impurities are adhered on the crystal surfaces at the end of DF. This study is to apply DF for phenylglycinol enantiomers separation. A thermodynamic model is developed to simulate the three-phase equilibrium during the DF operation. Various operating pressure are also adopted during the temperature-decreasing to simulate the actual three-phase equilibrium conditions. The experiments show the R-phenylglycinol can be purified from 95% to 96% with the recovery 82%, or from 97% to 98% with the recovery rate 87% with magnetic stirring. The purity of final obtained R-phenylglycinol crystals decreases with increasing operating pressure while the recovery rate increases with increasing operating pressure.
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Chiu, Chien Ning, and 邱健寧. "Enantioseparation of phenylethanol by distillative freezing." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/75479369376582896562.
Full textAbstract:
碩士長庚大學
化工與材料工程學系
99
Distillative freezing (DF) is a new separation technique which combines distillation and crystallization to produce pure crystals. In principle, DF is operated at a triple-point condition, in which the liquid mixture is simultaneously vaporized and crystallized due to the three-phase equilibrium. The process is continued until the liquid phase is completely eliminated and only the pure solid crystals remain in the feed. Thus, crystal washing is not required since no impurities are adhered on the crystal surfaces at the end of DF. Due to the close-boiling points, it is very difficult to separate enantiomers by distillation. DF is applied in this study to separate the phenylethanol enantiomers. The experiments confirm that seeding with magnetic stirring can be efficiently employed to break subcooling. S-phenylethanol can be purified from 95% to 96% with the recovery rate 79.3%, or from 97% to 98.3% with the recovery rate 77% by seeding with magnetic stirring.
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Yang, Sheng Chin, and 楊勝欽. "Enantioseparation of menthol by stripping crystallization." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/75853125092001193123.
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Teng, Hou Guo, and 鄧厚國. "Enantioseparation by stripping crystallization and sweating process." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/57828254237728541509.
Full textAbstract:
碩士長庚大學
化工與材料工程學系
101
Stripping crystallization (SC) is introduced in this work for the purification of 2-Amino-1-phenylethanol (2-APE) enantiomers. In principle, SC is operated at a series of the three-phase equilibrium conditions, in which the liquid mixture is simultaneously vaporized and crystallized. Thus, SC combines distillation and crystallization to produce pure crystals. A thermodynamic model is developed to simulate the three-phase equilibrium during the SC operation and to direct the batch SC experiments. The experiments show that no crystallization occurs during SC without seeding due to subcooling of the liquid enantiomers. On the other hand, seeding can eliminate subcooling during SC, leading to the R-2-APE crystals gradually formed preferentially on the seeds. Thus, seeding with magnetic stirring can be successfully employed to purify R-2-APE from the 2-APE enantiomers. The experimental purity of the resulting R-2-APE product is higher than predicted by the model although the experimental recovery ratio is slightly lower than the simulated recovery ratio. It is found that sweating can be successfully employed to further purify R-2-APE for the resulting R-2-APE product obtained from SC.
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YU-YOU, HSIAO, and 蕭育祐. "Enantioseparation of Phenothiazines in Cyclodextrix-Modified Micellar Electrokinetic Chromatography." Thesis, 2002. http://ndltd.ncl.edu.tw/handle/75376156135019963967.
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Wahl, Joachim. "The Use of Ionic Liquids in Capillary Electrophoresis Enantioseparation." Doctoral thesis, 2019. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-176397.
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Two chiral chemical molecules being mirror images of each other, also referred to as enantiomers, may have different pharmacokinetic, pharmacodynamic, and toxicological effects. Thus, pharmaceutical manufacturers and authorities are increasingly interested in the approval of enantiopure drugs. However, the isomeric purity and the limits for isomeric impurities have to be specified applying enantioselective analytical methods, such as capillary electrophoresis. The separation of enantiomers in capillary electrophoresis may be improved by the addition of ionic liquids to the background electrolyte. The aim of this work was to investigate the influence of different separation conditions on the enantioseparation of phenethylamines in background electrolytes containing ionic liquids based on tetrabutylammonium cations. Best chiral separations were achieved at acidic pH values using phosphate buffers containing 125 mmol/L tetrabutylammonium based salts. Different reasons explaining enhanced enantioseparations in buffers containing ionic liquids were found. First, due to an improvement of the cyclodextrin solubility, the addition of ionic liquids to the background electrolyte enables the use of higher concentrations of these chiral selector. Furthermore, the adsorption of tetrabutylammonium cations to the negatively charged capillary surface results in a reduction of the electroosmotic flow. Hence, the resulting prolongation of migration times leads to a longer period of time for the separation of temporarily formed diastereomeric analyte cyclodextrin complexes, which yields improved enantioseparation. Additionally, due to a decrease of the adsorption of positively charged phenethylamine analyte molecules to capillary surface silanol groups, the adsorption of ionic liquid cations inhibits peak broadening. A further reason explaining an enhanced enantioseparation by the addition of ionic liquids to the background electrolyte is a competition between tetrabutylammonium cations and analyte enantiomers for the inclusion into cyclodextrin cavities. Furthermore, the influence of different chiral counterions, combined with tetrabutylammonium cations, on the enantioseparation of phenethylamines was investigated. Solely anions based on the basic proteinogenic amino acids L lysine and L arginine yielded chiral separation results superior to those achieved using achiral tetrabutylammonium chloride as background electrolyte additive. Especially the application of tetrabutylammonium L argininate gave very good enantioseparations of all investigated ephedrine derivatives, which might be explained by the ability of L arginine to affect the formation of complexes between analytes and cyclodextrins. Besides the investigation of the influence of ionic liquids on the enantioseparation, complexes between phenethylamine enantiomers and β cyclodextrin derivatives were characterized by affinity capillary electrophoresis. The binding constants between analyte enantiomers and cyclodextrins and the electrophoretic mobilities of the temporarily formed complexes were determined and compared to the observed chiral resolution values. While neither the calculated binding constants nor their differences correlated with the quality of the enantioseparation, a strong correlation between the differences of the electrophoretic mobilities of the complexes and the chiral resolution values was foundChemische Moleküle, die sich zueinander wie Bild und Spiegelbild verhalten, so genannte Enantiomere, können im menschlichen Organismus unterschiedliche pharmakodynamische und toxikologische Wirkungen zeigen. Aus diesem Grund legen pharmazeutische Unternehmen und Arzneimittelbehörden vermehrten Wert auf die Zulassung enantiomerenreiner Arzneistoffe. Da sowohl die Reinheit eines Enantiomers als auch der Gehalt an isomeren Verunreinigungen spezifiziert werden müssen, besteht ein zunehmender Bedarf an analytischen Methoden zur Enantiomerentrennung, wie zum Beispiel der Kapillarelektrophorese. Das Ziel dieser Arbeit war die Verbesserung der kapillarelektrophoretischen Enantiomerentrennung von Ephedrin Derivaten unter Zuhilfenahme von auf Tetrabutylammonium basierenden Ionische Flüssigkeiten. Der Einfluss diverser Parameter auf die Trennung von Phenethylamin-Enantiomeren in Puffern, die Ionische Flüssigkeiten enthalten, wurde systematisch untersucht. Dabei konnten die besten Trennergebnisse unter stark sauren Bedingungen in Phosphatpuffern, die 125 mmol/L Tetrabutylammonium Salze enthielten, erreicht werden. Verschiedene Faktoren, die zu einer Verbesserung der Enantiomerentrennung führten, konnten festgestellt werden. Erstens wurde eine Verbesserung der Cyclodextrin-Löslichkeit durch die Zugabe von Ionischen Flüssigkeiten zum Trennpuffer festgestellt. Dies ermöglicht eine Verwendung höherer Konzentrationen dieser chiralen Selektoren. Des Weiteren führt eine Anlagerung von Tetrabutylammonium-Kationen an die negativ geladene Oberfläche der Kapillare zu einer Reduktion des elektroosmotischen Flusses. Daraus resultiert einerseits eine Verlängerung der Migrationszeiten, die bewirkt, dass eine längere Zeit zur Trennung der temporär gebildeten diastereomeren Cyclodextrin-Einlagerungskomplexe zur Verfügung steht. Andererseits wird durch die Adsorption von Tetrabutylammonium-Kationen an die Kapillarwand die Anlagerung von positiv geladenen Phenethylamin-Analyten an die Silanoloberfläche verhindert. Dies führt durch eine Reduktion der Peakbreite zu einer Verbesserung der Trennergebnisse. Als dritter Grund für verbesserte Trennungen nach Zugabe von Ionischer Flüssigkeit zum Trennpuffer kann ein kompetitiver Mechanismus zwischen Analyt Enantiomeren und Tetrabutylammonium-Kationen um den Einschluss in Cyclodextrine aufgeführt werden. Zusätzlich wurde der Einfluss verschiedener chiraler Gegenionen, die mit Tetrabutylammonium-Kationen kombiniert wurden, auf die Trennung von Phenethylamin-Enantiomeren untersucht. Dabei konnte ausschließlich unter Verwendung von Anionen der basischen proteinogenen Aminosäuren L Lysin und L Arginin eine Verbesserung der Trennung beobachtet werden. Vor allem die Verwendung von L Arginin, für welches eine Beeinflussung der Komplexbildung zwischen Analyten und Cyclodextrin vermutet wird, ergab eine starke Verbesserung der Trennung aller Ephedrin Derivate. Neben der Untersuchung des Einflusses von Ionischen Flüssigkeiten auf die kapillarelektrophoretische Trennung wurde auch die Komplexbildung zwischen Phenethylamin-Enantiomeren und verschiedenen β Cyclodextrin Derivaten mittels Affinitätskapillarelektro-phorese untersucht. Die Bindungskonstanten zwischen Analyt-Enantiomeren und Cyclodextrinen und die elektrophoretische Mobilität der gebildeten Komplexe wurden bestimmt und mit den dabei beobachteten chiralen Trennungen verglichen. Dabei konnte eine starke Korrelation zwischen den Unterschieden in den elektrophoretischen Mobilitäten der Komplexe und der Güte der Enantiomerentrennung festgestellt werden, während kein Zusammenhang zwischen den Bindungskonstanten, beziehungsweise deren Differenzen, und der chiralen Auflösung zwischen Phenethylamin Enantiomeren zu beobachten war
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Lin, Sheng-li, and 林勝立. "Enantioseparation and Migration Behavior of Benzoins in Capillary Zone Electrophoresis." Thesis, 2003. http://ndltd.ncl.edu.tw/handle/18327122466645421247.
Full textAbstract:
碩士國立臺灣大學
化學研究所
91
In the first part, enantiosepartions of benzoins, including hydrobenzoin, benzoin and benzoin methyl ether in capillary zone electrophoresis using sulfated β-cyclodextrin (S-β-CD) as a chiral selector in the presence and absence of borate complexation were investigated. The influences of by separation parameters, such as S-β-CD concentration, borate concentration, the borate/phosphate ratio of phosphate-borate buffer and the pH of borate buffer on the separation and migration behavior of hydrobenzoin, in particular, in a borate buffer containing S-β-CD were examined. In a phosphate background electrolyte, the separation window was markedly enlarged and the enantioseparability of benzoins was remarkably enhanced as S-β-CD concentration increased. In a buffer system containing borate ion, due to the presence of strong borate complexation, enantioselectivity of hydrobenzoin is considerably reduced. Effective enantioseparations of benzoins were simultaneously achieved with addition of S-β-CD as a chiral selector at a concentration greater than 2.5 % (w/v) in a phosphate background electrolyte and at 3.0 % (w/v) in a borate buffer at pH 9.0. The mobility curves of benzoins were simulated and the bonding constants of benzoins, and hydrobenzoin-borate complex as well, to S-β-CD were evaluated. The results indicate that enantioseparation of benzoins in a phosphate background electrolyte was primarily determined by weak CD complexation, whereas enantioseparation of hydrobenzoin in the presence of borate complexation was governed by both CD complexation and CD-borate complexation. The results also demonstrate that the interaction between hydrobenzoin-borate complex and S-β-CD plays an important role in the prediction of the migration behavior of hydrobenzoin in CZE using a borate buffer at pH 9.0. In the second part, enantiosepartion of benzoins, including benzoin, methylether benzoin and hydrobenzoin, in capillary zone electrophoresis with sulfated β-cyclodextrin (S-β-CD) and dual cyclodextrin systems in the presence of borate complexation were investigated. Effective enantioseparation of benzoins could be simultaneously achieved with addition of either S-β-CD at a concentration greater than 3.0 % (w/v) or neutral CDs, including β-CD, hydroxypropyl-β-CD, and α-CD, at an appropriate concentration in the presence of S-β-CD (≥3.0 % (w/v)) using a borate buffer (50 mM) at pH 9.0. The enantioselectivity of benzoins increases with increasing S-β-CD concentration. However, the enantioselectivity of hydrobenzoin was greatly reduced due to the presence of strong borate complexation. With dual CD systems, phenomena of the enantiomer migration reversal could be observed for hydrobenzoin in a borate buffer at pH 9.0. The migration behavior of benzoins will be described and separation mechanism of dual CD systems will be discussed.
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Huang, Wen-Ping, and 黃玟萍. "Studies of Migration Behavior and Enantioseparation of Antihistamines in Capillary Zone Electrophoresis." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/44948680975911277080.
Full textAbstract:
碩士國立臺灣大學
化學研究所
92
Capillary zone electrophoresis has proven to be a powerful technique for enantioseparation. In this study, five chiral antihistamines were investigated using cyclodextrins as chiral selectors. The results of this thesis are presented in two parts: In the first part, we focus on the binding constants of antihistamines with addition of neutral cyclodextrins (HP-β-CD, β-CD, DM-β-CD). In this work, the interaction of chiral analytes with chiral selectors was studied through the variation of mobility as a function of neutral cyclodextrins concentration. Binding constants of antihistamines to HP-β-CD, β-CD and DM-β-CD were evaluated through curve-fitting. The results indicate that the interaction of antihistamines with neutral cyclodextrins, which are also affected by antihistamines structures, play a major role in the determination of enantioseparation. In the second part , we focus on the enantioseparation of antihistamines with addition of randomly sulfate-substituted β-CD (MI-S-β-CD) and single-isomer heptakis (2,3-dihydroxy-6-O-sulfo )-β-cyclodextrin (SI-S-β-CD) and the optimization of separation. Moreover, by mixing MI-S-β-CD with SI-S-β-CD, the enantioseparation efficiency is considerably enhanced. In comparison with the use of SI-S-β-CD alone, the enantiomers of three antihistamines could be baseline separated when mixed cyclodextrins were used.
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Liao, Wei-Ssu, and 廖尉斯. "Studies of Migration Behavior and Enantioseparation of Phenothiazines in Capillary Zone Electrophoresis." Thesis, 2002. http://ndltd.ncl.edu.tw/handle/54915058258265392293.
Full textAbstract:
碩士國立臺灣大學
化學研究所
90
Capillary zone electrophoresis has proven to be a powerful technique for enantioseparation. In this study, five chiral phenothiazines were investigated using cyclodextrins as chiral selectors. The results of this thesis are presented in two parts: In the first part, we focus on the reversal of migration order of the enantiomers of phenothiazines with addition of γ-cyclodextrin (γ-CD). As enantioseparation is an important issue in chemical and pharmaceutical research, the influence of migration reversal on the assignment of enantiomers has to pay a great concern. In this work, the interaction of chiral analytes with chiral selectors was studied through the variation of mobility as a function of γ-CD concentration. Binding constants of phenothiazines to γ-CD were evaluated through curve-fitting. The results indicate that the interaction of phenothiazines with γ-CD, which are also affected by citrate buffer, plays a major role in the determination of the migration reversal. In the second part, we focus on the enantioseparation of phenothiazines with addition of sulfated cyclodextrins and the optimization of separation. Moreover, by mixing neutral cyclodextrin with sulfated cyclodextrins, the enantioseparation efficiency is considerably enhanced. In comparison with the use of sulfated cyclodextrins alone, the enantiomers of four phenothiazines could be baseline separated when mixed cyclodextrins were used.
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Mitchell, Clifford Ross. "Study of the mechanism of enantioseparation of macrocyclic glycopeptide-based chiral stationary phases /." 2006.
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Fang, Wei-Ru, and 方巍儒. "Enantioseparation of Hydroxyflavanones inCyclodextrin-Modified Capillary Zone ElectrophoresisUsing Sulfated Cyclodextrins as Chiral Selectors." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/02734278252950864924.
Full textAbstract:
碩士國立臺灣大學
化學研究所
95
In this study, enantioseparations of three hydroxyflavanone aglycones, including 2’-，3’- and 4’-hydroxyflavanone, in cyclodextrin (CD)-modified capillary zone electrohphoresis using randomly sulfate-substituted b-CD (MI-S-b-CD) or dual CD systems consisting of MI-S-b-CD and neutral CDs such as b-CD or g-CD as chiral selectors were investigated with a phosphate buffer at low pH. Sodium dodecyl sulfate (SDS) monomers were used as complexing agents for manipulating the selectivity of hydroxyflavanones. The results indicate that MI-S-b-CD is an excellent chiral selector for enantioseparation of hydroxyflavanone aglycones, especially for 2’-hydroxyflavanone. The enantioselectivity of hydroxyflavanones can be greatly enhanced using dual CD systems. Effective enantioseparations of these three hydroxyflavanones can be simultaneously achieved within 20 minutes with 2.0 % (w/v) MI-S-b-CD or dual CD systems in combination with the addition of SDS monomers at a concentration less than 2 mM.
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Phyo, Ye Zaw. "Chiral stationary phases for liquid chromatography: development, enantioseparation and molecular recognition mechanism studies." Doctoral thesis, 2019. https://hdl.handle.net/10216/121244.
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Phyo, Ye Zaw. "Chiral stationary phases for liquid chromatography: development, enantioseparation and molecular recognition mechanism studies." Tese, 2019. https://hdl.handle.net/10216/121244.
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Hu, Jie-Bi, and 胡傑筆. "Application of ionic liquid-coating capillary electrophoresis on enantioseparation of flavanones and β2-agonists." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/99100444946981163697.
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Silva, Cátia Sofia Rodrigues. "HPLC enantioseparation of tramadol and its metabolites: method validation and application to environmental samples." Master's thesis, 2016. https://repositorio-aberto.up.pt/handle/10216/86860.
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Silva, Cátia Sofia Rodrigues. "HPLC enantioseparation of tramadol and its metabolites: method validation and application to environmental samples." Dissertação, 2016. https://repositorio-aberto.up.pt/handle/10216/86860.
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Cheng, Hsu-Tun, and 鄭旭敦. "Enantioseparation of Catecholamines and Structurally Related Compounds by Capillary Zone Electrophoresis Using Sulfated-β-Cyclodextrin as Chiral Selectors." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/89611257204424526558.
Full textAbstract:
碩士國立臺灣大學
化學研究所
92
In this study, we focus on the enantioseparation of three catecholamines and three structurally related compounds with addition of sulfated cyclodextrins and the optimization of separation. The influences of buffer concentration and temperature on the migration behavior and enantioseparation of these cationic solutes with addition of sulfated cyclodextrins were investigated. The results indicate that, buffer concentration and temperature play important roles in the enantioseparation of these cationic solutes. In order to understand enantoseparation mechanisms of these cationic solutes also used three kind of neutral cyclodextrins as chiral selectors. Moreover, by mixing two kind of cyclodextrins, we found the reversal of migration order of norephedrine、synephrine and octopamine. The interaction of chiral analytes with chiral selectors was studied through the variation of mobility of norephedrine、synephrine and octopamine.
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Shie, Ying-ying, and 謝瑩瑩. "Enantioseparation of Acids by Partial Filling Technique of Capillary Electrophoretic Chromatography with π-Acid Derived Quinidine as Chiral Ion-Pair Reagent." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/01261368607598987489.
Full textAbstract:
碩士朝陽科技大學
應用化學系碩士班
92
The potential of 3,5-dinitrobenzoyl quinidine as chiral selector added to a non-aqueous background buffer for the capillary electrophoretic separation of the enantiomers of N-derivatized amino acids and non-steroidal anti-inflammatory drugs are evaluated. Separation is based on chiral analytes of R or S of negatively charged and positively charged quinidine-derived chiral selector to form temporary ion-pair, because of different molecular interactions and mobiling. As a result, the differences in the overall migration of analytes can be achievd. To suppress one problems associated with the high UV absorption of the chiral selector and thus the high detecting background in the ‘total filling technique’, the ‘partial filling technique’ has been adopted. Several parameters including selector filling time and length of selector zone, selector concentration, type of non-aqueous background electrolyte and length of column have been evaluated. Optimun experimental conditions were found with a electrolyte made of 80 mM acetic acid, 20 mM triethylamine and 150 mM 3,5-dinitrobenzoyl quinidine in an EtOH-MeOH (60:40, v/v), and at voltage of –30kV. Under these conditions, (R) and (S) enantiomers of 3,5-dinitrobenzoyl leucine could be separated with α=1.10, Rs=5.16. (R) and (S) enantiomers of ketoprofen could be separated with α=1.06, Rs=1.13. Similar resolution, and efficiencies were observed for other analytes. 3,5-dinitrobenzoyl quinidine as chiral selector can be utilized to separate several kinds of compound induding aromatic π acid, aromatic π base and ascorbic acid.
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Lin, Ce-Hsuan, and 林世軒. "Enantioseparation of N-protected amino acids and carboxylic acids by high-performance liquid chromatography with π-acid derived quinidine as chiral stationary phase." Thesis, 2003. http://ndltd.ncl.edu.tw/handle/22960169773696111614.
Full textAbstract:
碩士朝陽科技大學
應用化學系碩士班
91
Abstract Due to dissimilarity of steric structure, the optically active medicines often result in the significant difference of pharmacology. This situation is gradually changing as number of companies have now stared to move towards producing enatiomerically pure forms. This proposal plans to develop one type of quinidine-derived chiral stationary phases (3,5-dinitrobenzoyl quinidine thiopropylsilanized silica ) which simultaneously possess the functions of aromatic π acid, aromatic π base and anion-exchanger. With this type of CSP, we plan to do enantioseparations of non-steroidal anti-inflammatory drugs and N-derivatized amino acids by high performance liquid chromatography. This CSP is used in HPLC with normal-phase mode and reversed-phase mode. In normal-phase mode, DNB-, DNP-derivatized amino acids and ascorbic acid are well separated. An example of 3,5-dintrobenzoyl leucine, the mobile phase was 100% methanol at a flow-rate of 1 ml/min and 240 nm wavelength of detection. The resolution(Rs) is 1.3. In reversed-phase mode, DNB-, DNP-derivatized amino acids and non-steroidal anti- inflammatory drugs are well separated. An example of 3,5-dintrobenzoyl leucine, the mobile phase is consisted of 2% 10 mM ammonium acetate (the mixture is adjusted with trifluoracetic acid to the pH = 4.5) and 98% methanol at a flow-rate of 1 ml/min and 240 nm wavelength of detection. This resolution is 2.5. This chiral column can enantioseparate several kinds of compound induding aromatic π acid, aromatic π base and ascorbic acid.
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Geryk, Radim. "Optimalizace a validace analytické metody na stanovení výbraných léčiv." Master's thesis, 2012. http://www.nusl.cz/ntk/nusl-309699.
Full textAbstract:
The aim of this work was finding suitable conditions for separation of enantiomers of citalopram and citadiol, optimization of chromatographic system and validation of the analytical method for determination of selected enantiomers in drugs. Drugs are often chiral compounds. In many cases, only enantiomer has required pharmacological effects. Advanced chemical technologies associated with the synthesis, separation and analysis of the individual enantiomers caused an increase of the number of new chiral drugs in the form of single pure enantiomers, the chiral switch. Citalopram is one of the widely used antidepressants of selective serotonin reuptake inhibitors (SSRI). Citalopram is used for treatment of depression, panic anxienty or obsessive compulsive disorder of pathological laughing and crying. The pharmacological activity is associated with the S-citalopram, while R-enantiomer is essentially inactive and even counteracts the activity of escitalopram. Citadiol is a chiral syntetic precursor of citalopram. This thesis was focused on monitoring enantioseparation "behaviour" of selected enantiomers. HPLC method with chiral stationary phases based on macrocyclic antibiotics, cyclofructans and cellulose was applied for enantioseparation of the above-mentioned compounds. The optimized chromatographic...
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Kanizsová, Lívia. "Komplexační rovnováhy beta-blokátorů v CZE." Master's thesis, 2016. http://www.nusl.cz/ntk/nusl-347961.
Full textAbstract:
Drugs used in the pharmaceutical industry often occur as a mixture of several isomers with a different biological activity. In a case that some isomer provides an undesirable side effect, it is important to separate it from the mixture and check the chiral purity of a drug. Capillary zone electrophoresis plays a significant role in chiral separations. A different affinity of isomers to complexation reagent is used for their separation from each other. The extent of their interaction is characterized by the complexation constant. Most commonly the cyclodextrins are used for the chiral separations of β-blockers and they could be in neutral or charged form. They probably interact with them through the creation of inclusion complexes. A successful baseline enantioseparation of all the β-blockers that have been studied, labetalol, pindolol, alprenolol and atenolol, was provided by using the background electrolyte containing charged cyclodextrins. The highest resolution of peaks was observed using sulfated cyclodextrins.
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Silva, Ana Francisca Osório de Almeida Coelho e. "Extraction and separation of drugs using alternative solvents." Doctoral thesis, 2018. http://hdl.handle.net/10773/25788.
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The processes of production in chemical-related industries often rely on the use of volatile organic solvents, normally generating large amounts of hazardous wastes. During the past decades, major efforts have been done to transform chemical processes included in the principles of Green Chemistry, Sustainability and, more recently, Circular Economy. This thesis intends to work on two important challenges of pharmaceutical industry, namely the valorization of pharmaceutical wastes and the separation of enantiomers resorting on the application of alternative solvents, in particular, ionic liquids (ILs) and deep eutectic solvents (DES).
Motivated by circular economy and searching for a new strategy to the currently proposed (i.e., incineration), novel aproaches to valorize wastes of domestic origin (unspent and/or outdated medicines) are proposed. Since circa 90 % of the active ingredients in an outdated medicine are still in their active form, in this work, the recovery of valuable active drugs from pharmaceutical wastes using IL-mediated extraction processes is proposed. The processes of extraction and separation of drugs from pharmaceutical wastes require an initial step of solid-liquid extraction, which was designed in this work by the use of different ILs, well-recognized by their solvency power of ILs for a large plethora of compounds/biomolecules. The separation stage of the extracted active ingredients was also investigated by the application of IL-based aqueous biphasic systems (ABS) or IL-based three-phase partitioning (TPP). In the end, the isolation of the active ingredients was accomplished by the addition of anti-solvents properly selected. The wide applicability of the proposed ABS-based technology was evidenced by the recovery of several model active pharmaceutical ingredients (three non-steroidal anti-inflammatory drugs and one antidepressant).
The challenge of dealing with racemic mixtures and the differentiated biological activities that enantiomers generally present is investigated in this thesis. The most common two approaches to obtain pure enantiomers are the asymmetric synthesis and the separation of racemates. Although being considered the most powerful approach, the asymmetric synthesis is limited by the high costs and complexity of the processes. In turn, the separation of racemates is more flexible, cheaper and simpler. Under this scenario, it is here proposed the use of ABS composed of chiral ILs (CILs) as an alternative to enantioseparation. Two groups of CILs, i.e., those bearing chiral cations and those containing chiral anions were synthesized and applied to enantioseparation. After the characterization of the ABS phase diagrams (CIL + salt, CIL + polymer) it was possible to evaluate their enantioselectivity on the separation of racemic mandelic acid, here used as model racemic compound. In a second approach, deep eutectic solvents (DES) were envisaged as potential chiral solvents by the study of chirality impact on the solid-liquid equilibrium diagram.Os processos de produção da indústria química e relacionadas baseiam-se no uso de solventes orgânicos voláteis, gerando quantidades elevadas de resíduos perigosos. Durante as últimas décadas, têm sido realizados inúmeros esforços para modificar os processos químicos tendo em conta os princípios da Química Verde, Sustentabilidade e, mais recentemente, da Economia Circular. Esta tese pretende solucionar dois importantes desafios da indústria farmacêutica, a valorização de resíduos farmacêuticos e a separação de enantiómeros, utilizando duas classes de solventes alternativos, em particular, os Líquidos Iónicos (LIs) e os Solventes Eutéticos Profundos. No âmbito do conceito da Economia Circular e na procura de uma alternativa à estratégia atualmente utilizada (i.e., incineração), novas estratégias para a valorização de resíduos farmacêuticos domésticos (medicamentos não usados e/ou fora da validade) são apresentadas. Dado que cerca de 90 % dos princípios ativos num medicamento fora do prazo permanecem no seu estado ativo, é aqui sugerida a recuperação de fármacos a partir de resíduos farmacêuticos utilizando processos de extração com LIs. Os processos de separação dos princípios ativos de fármacos a partir destes resíduos requerem uma etapa inicial de extração sólido-líquido, desenvolvida neste trabalho pelo uso de diferentes LIs, reconhecidos pelo seu elevado poder solvente para uma larga gama de compostos/biomoléculas. A etapa de separação dos princípios ativos após a sua recuperação dos resíduos foi estudada pela aplicação de sistemas aquosos bifásicos (SABs) e sistemas de partição de três fases aquosas igualmente constituídos por LIs. Por sua vez, a etapa de isolamento dos princípios ativos após a sua separação foi desenvolvida pela adição de anti-solventes devidamente selecionados. O desafio de lidar com misturas racémicas e com as atividades biológicas diferenciadas que os enantiómeros geralmente apresentam foi investigado nesta tese. As duas práticas mais comuns na obtenção de enantiómeros puros são a síntese assimétrica e a separação de racematos. Apesar da síntese assimétrica ser considerada a abordagem mais poderosa, esta é limitada pelos elevados custos e complexidade tecnológica. A separação de racematos, por sua vez, representa uma alternativa mais flexível e simples do ponto de vista operacional e de custos. Neste contexto, o uso de SABs formados por LIs quirais foi considerado neste trabalho como uma alternativa na separação de misturas recémicas. Dois conjuntos distintos de LIs quirais, um com quiralidade no catião e o segundo com quiralidade no anião foram sintetizados e aplicados na separação de enantiómeros. Assim, e após caracterização dos diagramas de fase para os diferentes SABs (LI quiral + sal, LI quiral + polímero), foi possível avaliar a sua enantioseletividade na separação dos enantiómeros do ácido mandélico, aplicado neste trabalho como mistura racémica modelo. Numa segunda abordagem, a possibilidade de implementação de solventes eutécticos profundos como solventes quirais foi investigada pelo estudo do impacto da quiralidade no diagrama de equilíbrio sólido-líquido.
Programa Doutoral em Engenharia Química
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Levkin, Pavel [Verfasser]. "Praxis und Theorie der gaschromatographischen Enantiomerentrennung an chiralen Stationärphasen mit einfachen und binären Selektoren = Practice and theory of gas chromatographic enantioseparation on single- and binary-selector chiral stationary phases / vorgelegt von Pavel Levkin." 2007. http://d-nb.info/984085467/34.
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Araújo, João Miguel Mendes de. "Optimal design and operation of compact simulated moving bed processes for enantioseparations." Doctoral thesis, 2009. http://hdl.handle.net/10362/15752.
Full textAbstract:
Simulated moving bed (SMB) chromatography is attracting more and more attention
since it is a powerful technique for complex separation tasks. Nowadays, more than
60% of preparative SMB units are installed in the pharmaceutical and in the food in-
dustry [SDI, Preparative and Process Liquid Chromatography: The Future of Process
Separations, International Strategic Directions, Los Angeles, USA, 2002. http://www.
strategicdirections.com]. Chromatography is the method of choice in these ¯elds, be-
cause often pharmaceuticals and ¯ne-chemicals have physico-chemical properties which
di®er little from those of the by-products, and they may be thermally instable. In these
cases, standard separation techniques as distillation and extraction are not applicable.
The noteworthiness of preparative chromatography, particulary SMB process, as a sep-
aration and puri¯cation process in the above mentioned industries has been increasing,
due to its °exibility, energy e±ciency and higher product purity performance.
Consequently, a new SMB paradigm is requested by the large number of potential small-
scale applications of the SMB technology, which exploits the °exibility and versatility of
the technology. In this new SMB paradigm, a number of possibilities for improving SMB
performance through variation of parameters during a switching interval, are pushing the
trend toward the use of units with smaller number of columns because less stationary
phase is used and the setup is more economical. This is especially important for the phar-
maceutical industry, where SMBs are seen as multipurpose units that can be applied to
di®erent separations in all stages of the drug-development cycle.
In order to reduce the experimental e®ort and accordingly the coast associated with the
development of separation processes, simulation models are intensively used. One impor-
tant aspect in this context refers to the determination of the adsorption isotherms in
SMB chromatography, where separations are usually carried out under strongly nonlinear
conditions in order to achieve higher productivities. The accurate determination of the
competitive adsorption equilibrium of the enantiomeric species is thus of fundamental
importance to allow computer-assisted optimization or process scale-up.
Two major SMB operating problems are apparent at production scale: the assessment
of product quality and the maintenance of long-term stable and controlled operation.
Constraints regarding product purity, dictated by pharmaceutical and food regulatory
organizations, have drastically increased the demand for product quality control. The
strict imposed regulations are increasing the need for developing optically pure drugs.(...)