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Separation of nadolol stereoisomers by liquid chromatography using Chiralpak IA chiral stationary phase

2015DissertaĆ§Ć£o de mestrado Acesso aberto
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dc.contributor.advisorPais, LuĆ­s S.
dc.contributor.advisorRibeiro, AntĆ³nio E.
dc.contributor.authorArafah, Rami
dc.date.accessioned2016-03-22T16:46:49Z
dc.date.available2016-03-22T16:46:49Z
dc.date.issued2015
dc.description.abstractThe main objective of this work is to study the chiral separation of stereoisomers of nadolol by preparative liquid chromatography. In this report it is presented the state of the art and experimental results obtained for optimizing the methodology for preparative scale separation of nadolol stereoisomers using an immobilized chiral stationary phase (ChiralpakĀ® IA). The screening of the solvent composition is based on the best solvent or solvents mixture to perform the pseudo-binary separation (1+2+3/4) of the more retained stereoisomer using the simulated moving bed technology. The three least retained components (1, 2 and 3) co-elute in the raffinate outlet stream and the more retained component (4) will elute in the extract outlet stream. After the solvent composition optimization, 100%methanol:0.1%diethylamine solvent composition was selected to perform the experimental SMB separation. Experimental results also include adsorption equilibrium isotherm and breakthroughs measurements followed by SMB experimental operation. Using a 2 g/L total feed concentration, the more retained stereoisomer was totally recovered at the extract outlet stream with 100% purity, obtaining a system productivity of 0.31 gtarget product/(Lbed.hr) and requiring a solvent consumption of 27.71 Lsolvent/gtarget product. Another SMB run was performed using a considerable higher feed concentration of 10 g/L and an improvement in the performance parameters were observed. For the more retained stereoisomer in the extract outlet stream, a purity of 99.5%, and a recovery of 97.6% was obtained, with a productivity of 1.98 gtarget product/(Lbed.hr) and a solvent consumption of 3.13 Lsolvent/gtarget product. The extract and raffinate SMB outlet streams were collected and used to perform additional adsorption equilibrium isotherm and breakthroughs experiments. These results were used to evaluate the differences in the adsorption equilibrium dynamics for pure and racemic nadolol feed mixtures. This work introduced new alternative results for the separation of nadolol stereoisomers and contributed for a future objective of the complete separation of the four nadolol stereoisomers by SMB technology using different modes of SMB operation, adsorbents and solvent compositions.pt_PT
dc.description.abstractO principal objetivo deste trabalho consiste no estudo da separaĆ§Ć£o quiral dos estereoisĆ³meros do nadolol por cromatografia lĆ­quida preparativa. Neste relatĆ³rio apresenta-se o estado da arte assim como alguns resultados obtidos da otimizaĆ§Ć£o da composiĆ§Ć£o do solvente para a separaĆ§Ć£o Ć  escala preparativa utilizando uma fase estacionĆ”ria quiral (ChiralpakĀ® IA). O estudo da composiĆ§Ć£o do solvente Ć© baseado na seleĆ§Ć£o do solvente ou mistura de solventes mais apropriada para realizar a separaĆ§Ć£o pseudo-binĆ”ria (1+2+3/4) dos estereoisĆ³meros do nadolol utilizando a tecnologia de leito mĆ³vel simulado. Os trĆŖs componentes menos retidos (1, 2 e 3) co-eluem na corrente de refinado e o componente mais retido Ć© recuperado na corrente de extrato. Na fase inicial, realiza-se uma comparaĆ§Ć£o dos resultados experimentais obtidos com a fase estacionĆ”ria ChiralpakĀ® IA com os resultados obtidos com a fase estacionĆ”ria ChiralpakĀ® AD. Para este estudo, empacotaram-se duas colunas com dimensƵes preparativas, com estas fases estacionĆ”rias e repetiram-se algumas anĆ”lises cromatogrĆ”ficas com a fase estacionĆ”ria ChiralpakĀ®AD. ApĆ³s a otimizaĆ§Ć£o da composiĆ§Ć£o do solvente, foi selecionada a mistura 100%methanol:0.1%diethylamine para realizar a separaĆ§Ć£o preparativa utilizando a tecnologia de leito mĆ³vel simulado. Os resultados experimentais incluem a determinaĆ§Ć£o experimental de dados de equilĆ­brio atravĆ©s da mediĆ§Ć£o e modelizaĆ§Ć£o de isotĆ©rmicas de equilĆ­brio de adsorĆ§Ć£o assim como mediƧƵes experimentais e a modelizaĆ§Ć£o de experiĆŖncias de cromatografia frontal (breakthroughs). Finalmente, apersentam.se os resultados experimentais obtidos das experiĆŖncias de separaĆ§Ć£o pseudo-binĆ”ria dos estereoisĆ³meros de nadolol utilizando um sistema de leito mĆ³vel simulado (SMB). Utilizando uma concentraĆ§Ć£o da soluĆ§Ć£o de alimentaĆ§Ć£o de 2 g/L, o estereoisĆ³mero mais retido foi totalmente recuperado na corrente de extrato com uma pureza de 100%, obtendo-se uma produtividade de 0.31 gtarget product/(Lbed.hr) sendo necessĆ”rio um consumo de solvente de 27.71 Lsolvent/gtarget product. Uma outra experiĆŖncia de SMB foi realizada utilizando uma concentraĆ§Ć£o da corrente de alimentaĆ§Ć£o de 10 g/L, tendo-se obtido um aumento da produtividade e uma diminuiĆ§Ć£o do consumo de solvente. Para o estereoisĆ³mero mais retido, obteve-se na corrente de extrato, uma pureza de 99.5% e uma recuperaĆ§Ć£o de 97.6%, uma produtividade de 1.98 gtarget product/(Lbed.hr) e um consumo de solvente de 3.13 Lsolvent/gtarget product. As correntes de extrato e de refinado das operaƧƵes de SMB foram recolhidas e utilizadas para realizar experiĆŖncias adicionais de medidas de isotĆ©rmicas de equilĆ­brio de adsorĆ§Ć£o e experiĆŖncias de breakthrough de forma a avaliar a diferenƧa do comportamento de adsorĆ§Ć£o dos estereoisĆ³meros quando presentes na mistura ou na forma ā€œpuraā€ (1+2+3 e 4). Este trabalho introduz novas alternativas para a separaĆ§Ć£o dos estereoisĆ³meros do nadolol, contribuindo para o objetivo futuro que serĆ” a separaĆ§Ć£o completa dos quatro estereoisĆ³meros do nadolol, utilizando diferentes modos de operaĆ§Ć£o SMB, adsorventes e composiƧƵes de solvente.pt_PT
dc.description.abstractŲ„Ł† Ų§Ł„Ł‡ŲÆŁ Ų§Ł„Ų±Ų¦ŁŠŲ³ŁŠ Ł…Ł† Ł‡Ų°Ų§ Ų§Ł„Ų¹Ł…Ł„ Ł‡Łˆ ŲÆŲ±Ų§Ų³Ų© Ų¹Ł…Ł„ŁŠŲ© Ų§Ł„ŁŲµŁ„ Ų§Ł„ŁƒŁŠŲ±Ų§Ł„ŁŠ Ł„Ł„Ł†ŲøŲ§Ų¦Ų± Ų§Ł„ŁŲ±Ų§ŲŗŁŠŲ© Ł„Ł…Ų±ŁƒŲØ Ų§Ł„Ł†Ų§ŲÆŁˆŁ„ŁˆŁ„ ŲØŁˆŲ§Ų³Ų·Ų© Ų§Ł„ŁƒŲ±ŁˆŁ…ŲŖŲŗŲ±Ų§ŁŁŠŲ§ Ų§Ł„Ų³Ų§Ų¦Ł„Ų© Ų§Ł„ŲŖŲ­Ų¶ŁŠŲ±ŁŠŲ©. Ł†ŲŖŲ·Ų±Ł‚ ŁŁŠ Ł‡Ų°Ų§ Ų§Ł„ŲŖŁ‚Ų±ŁŠŲ± Ų„Ł„Ł‰ ŲØŲ¹Ų¶ Ų§Ł„ŲÆŲ±Ų§Ų³Ų§ŲŖ Ų§Ł„Ų³Ų§ŲØŁ‚Ų© Ų„Ų¶Ų§ŁŲ© Ł„Ų¹Ų±Ų¶ Ų§Ł„Ł†ŲŖŲ§Ų¦Ų¬ Ų§Ł„ Ł… Ų­ Ųµ Ł„Ų© ŲØŁ‡ŲÆŁ Ų§Ł„ŲŖŁˆŲµŁ„ Ų„Ł„Ł‰ Ų§ŁŲ¶Ł„ Ł…Ł†Ł‡Ų¬ŁŠŲ© Ł„ŁŲµŁ„ Ų§Ł„Ł†ŲøŲ§Ų¦Ų± Ų§Ł„ŁŲ±Ų§ŲŗŁŠŲ© Ł„Ł„Ł†Ų§ŲÆŁˆŁ„ŁˆŁ„ Ų¶Ł…Ł† Ų§Ł„Ł†Ų·Ų§Ł‚ Ų§Ł„ŲŖŲ­Ų¶ŁŠŲ±ŁŠ ŲØŲ„Ų³ŲŖŲ®ŲÆŲ§Ł… Ų§Ł„Ų·ŁˆŲ± Ų§Ł„ŁƒŁŠŲ±Ų§Ł„ŁŠ Ų§Ł„Ų«Ų§ŲØŲŖ ) IA Ā®Chiralpak ) . ŁŠŲ³ŲŖŁ†ŲÆ ŁŲ­Ųµ ŲŖŲ±ŁƒŁŠŲØ Ų§Ł„Ł…Ų°ŁŠŲØ Ų¹Ł„Ł‰ Ų£ŁŲ¶Ł„ Ł…Ų°ŁŠŲØ Ų£Łˆ Ų®Ł„ŁŠŲ· Ł…Ł† Ų§Ł„Ł…Ų°ŁŠŲØŲ§ŲŖ Ų§Ł„ŲŖŁŠ ŲŖŲ³Ł…Ų­ ŲØŲ„Ų¬Ų±Ų§Ų” Ų¹Ł…Ł„ŁŠŲ© Ų§Ł„ŁŲµŁ„ Ų§Ł„Ų«Ł†Ų§Ų¦ŁŠŲ© ( 1 + 2 + 3 / 4 ( Ł„Ł„Ł†ŲøŁŠŲ± Ų§Ł„Ų°ŁŠ ŁŠŁ…ŲŖŁ„Łƒ Ų²Ł…Ł† Ų§Ł„ŲØŁ‚Ų§Ų” Ų§Ł„Ų£ŁƒŲØŲ± ŁˆŲ°Ł„Łƒ ŲØŲ„Ų³ŲŖŲ®ŲÆŲ§Ł… ŲŖŁ‚Ł†ŁŠŲ© Ł…Ų­Ų§ŁƒŲ§Ų© Ų§Ł„Ų³Ų±ŁŠŲ± Ų§Ł„Ł…ŲŖŲ­Ų±Łƒ ( SMB (. Ų§Ł„Ł…Ų±ŁƒŲØŲ§ŲŖ Ų§Ł„Ų«Ł„Ų§Ų«Ų© Ų§Ł„ŲŖŁŠ ŲŖŁ…ŲŖŁ„Łƒ Ų²Ł…Ł† ŲØŁ‚Ų§Ų” Ų£Ł‚Ł„ ) 1 , 2 Łˆ 3 ( ŲŖŁ…ŲŖŲ²Ų¬ Ł…Ų¹ Ų§Ł„Ł…Ų°ŁŠŲØ Ł„ŲŖŲ®Ų±Ų¬ Ł…Ų¹ Ų§Ł„ŲŖŁŠŲ§Ų± Ų§Ł„Ų«Ų§Ł†ŁˆŁŠ, Ų£Ł…Ų§ Ų§Ł„Ł…Ų±ŁƒŲØ Ų§Ł„Ų£ŁƒŲ«Ų± ŲØŁ‚Ų§ Ų” ) 4( ŁŠŲ®Ų±Ų¬ Ł…Ų¹ ŲŖŁŠŲ§Ų± Ų§Ł„Ų„Ų³ŲŖŲ®Ł„Ų§Ųµ. ŲØŲ¹ŲÆ Ų§Ł„Ų„Ł†ŲŖŁ‡Ų§Ų” Ł…Ų¹ Ų¹Ł…Ł„ŁŠŲ© ŲŖŲ­Ų³ŁŠŁ† ŲŖŲ±ŁƒŁŠŲØ Ų§Ł„Ł…Ų°ŁŠŲØ, 100% Ł…ŁŠŲ«Ų§Ł†ŁˆŁ„: % 0.1 ŲÆŲ§ŁŠ Ų„ŁŠŲ«ŁŠŁ„ Ų£Ł…ŁŠŁ† Ł‡Łˆ Ų§Ł„Ł…Ų°ŁŠŲØ Ų§Ł„Ų°ŁŠ ŲŖŁ… Ų„Ų®ŲŖŁŠŲ§Ų±Ł‡ Ł„Ų„Ų¬Ų±Ų§Ų” Ų¹Ł…Ł„ŁŠŲ© Ų§Ł„ŁŲµŁ„ ŲØŲŖŁ‚Ł†ŁŠŲ© SMB . Ų§Ł„Ł†ŲŖŲ§Ų¦Ų¬ Ų§Ł„ŲŖŲ¬Ų±ŁŠŲØŁŠŲ© ŲŖŲŖŲ¶Ł…Ł† Ų§Ł„Ų„Ł…ŲŖŲ²Ų§Ų² Ų§Ł„ŲŖŁˆŲ§Ų²Ł†ŁŠ Ų¹Ł†ŲÆ ŲÆŲ±Ų¬Ų© Ų­Ų±Ų§Ų±Ų© Ų«Ų§ŲØŲŖŲ© Ų„Ų¶Ų§ŁŲ© Ų„Ł„Ł‰ ŲŖŲ¬Ų§Ų±ŲØ Ų§Ł„Ų„Ų®ŲŖŲ±Ų§Ł‚Ų§ŲŖ Ų£Łˆ Ł…Ų§ ŁŠŲ¹Ų±Ł ŲØŲ§Ł„ŁƒŲ±ŁˆŁ…ŁˆŲŖŲŗŲ±Ų§ŁŁŠŲ© Ų§Ł„Ų£Ł…Ų§Ł…ŁŠŲ© (breakthrough) , ŁŁŠ Ų§Ł„Ł†Ł‡Ų§ŁŠŲ© Ł†Ų¹Ų±Ų¶ Ų§Ł„Ł†ŲŖŲ§Ų¦Ų¬ Ų§Ł„ŲŖŲ¬Ų±ŁŠŲØŁŠŲ© Ł„Ł…Ų­Ų§ŁƒŁŠ Ų§Ł„Ų³Ų±ŁŠŲ± Ų§Ł„Ł…ŲŖŲ­Ų±Łƒ SMB . ŲØŲ„Ų³ŲŖŲ®ŲÆŲ§Ł… 2 g/L ŁƒŲŖŲ±ŁƒŁŠŲ² ŁƒŁ„ŁŠ Ł„Ł„Ł…Ų­Ł„ŁˆŁ„ Ų§Ł„Ł…ŲŗŲ°ŁŠ, ŲŖŁ… Ų§Ł„Ų„Ų³ŲŖŲ±Ų¬Ų§Ų¹ ŁˆŲØŲ“ŁƒŁ„ ŁƒŲ§Ł…Ł„ Ł„Ł„Ł†ŲøŁŠŲ± Ų§Ł„ŁŲ±Ų§ŲŗŁŠ Ų§Ł„Ų£ŁƒŲ«Ų± Ų„Ų­ŲŖŁŲ§ŲøŲ§ Ł…Ł† ŲŖŁŠŲ§Ų± Ų§Ł„Ų„Ų³ŲŖŲ®Ł„Ų§Ųµ ŁˆŲØŁ†ŁŲ§ŁˆŲ© ŁˆŲµŁ„ŲŖ Ų„Ł„Ł‰ % 100 , ŲØŲ„Ł†ŲŖŲ§Ų¬ŁŠŲ© ŲØŁ„ŲŗŲŖ .hr)bed/(Ltarget productg 0.31 Ų„Ų¶Ų§ŁŲ© Ų„Ł„Ł‰ Ų„Ų³ŲŖŁ‡Ł„Ų§ŁƒŁŠŲ© Ų§Ł„Ł…Ų°ŁŠŲØ target product/gsolventL.27.71 ŲØŲ„Ų³ŲŖŲ®ŲÆŲ§Ł… ŲŖŲ±ŁƒŁŠŲ² Ų£Ų¹Ł„Ł‰ Ł„Ł„Ł…Ų­Ł„ŁˆŁ„ Ų§Ł„Ł…ŲŗŲ°ŁŠ 10 g/L , ŲŖŁ…ŲŖ Ų¹Ł…Ł„ŁŠŲ© Ų§Ł„ŁŲµŁ„ Ł…Ų±Ų© Ų¢Ų®Ų±Ł‰ ŲØŁˆŲ§Ų³Ų·Ų© ŲŖŁ‚Ł†ŁŠŲ© SMB Ų­ŁŠŲ« Ł„ŁˆŲ­Ųø ŲŖŲ­Ų³Ł† ŁŁŠ Ł…Ų¹Ų§ŁŠŁŠŲ± Ų§Ł„Ų£ŲÆŲ§Ų”. Ł†Ł‚Ų§ŁˆŲ© Ų§Ł„Ł†ŲøŁŠŲ± Ų§Ł„Ų£ŁƒŲ«Ų± ŲØŁ‚Ų§ Ų” Ų§Ł„Ų®Ų§Ų±Ų¬ Ł…Ų¹ ŲŖŁŠŲ§Ų± Ų§Ł„Ų„Ų³ŲŖŲ®Ł„Ų§Ųµ ŁˆŲµŁ„ŲŖ Ų„Ł„Ł‰ 99.5% , ŁˆŲ„Ų³ŲŖŲ±Ų¬Ų¹ ŲØŁ†Ų³ŲØŲ© 97.6% , Ų§Ł„Ų„Ł†ŲŖŲ§Ų¬ŁŠŲ© ŁˆŲµŁ„ŲŖ Ų„Ł„Ł‰ .hr)bed/(Ltarget productg1.98 Ų„Ų¶Ų§ŁŲ© Ų„Ł„Ł‰ Ų„Ų³ŲŖŁ‡Ł„Ų§ŁƒŁŠŲ© Ų§Ł„Ł…Ų°ŁŠŲØ target product/gsolventL3.13 . ŲŖ Ł… Ų¬Ł…Ų¹ Ų¹ŁŠŁ†Ų§ŲŖ Ł…Ł† ŲŖŁŠŲ§Ų±Ų§ŲŖ Ų§Ł„Ų„Ų³ŲŖŲ®Ł„Ų§Ųµ ŁˆŲ§Ł„Ų±Ų“Ų§Ų­Ų© Ų§Ł„Ų®Ų§Ų±Ų¬Ų© Ł…Ł† SMB Ł„ŲŗŲ±Ų¶ Ų§Ł„Ł‚ŁŠŲ§Ł… ŲØŲÆŲ±Ų§Ų³Ų§ŲŖ Ų„Ų¶Ų§ŁŁŠŲ© Ų­ŁˆŁ„ Ų§Ł„Ų„Ł…ŲŖŲ²Ų§Ų² Ų¹Ł†ŲÆ ŲÆŲ±Ų¬Ų© Ų­Ų±Ų§Ų±Ų© Ų«Ų§ŲØŲŖŲ© ŁˆŁƒŲ°Ł„Łƒ ŲŖŲ¬Ų§Ų±ŲØ Ų§Ł„ŲŗŲ±ŁˆŁ…Ų§ŲŖŁˆŲŗŲ±Ų§ŁŁŠŲ§ Ų§Ł„Ų£Ł…Ų§Ł…ŁŠŲ©. Ł„ŲŖŁ‚ŁŠŁŠŁ… Ų§Ł„ŁŲ±ŁˆŁ‚Ų§ŲŖ ŁŁŠ ŲÆŁŠŁ†Ų§Ł…ŁŠŁƒŁŠŲ© Ų§Ł„Ų„Ł…ŲŖŲ²Ų§Ų² Ų§Ł„ŲŖŁˆŲ§Ų²Ł†ŁŠ Ł„ŁƒŁ„Ų§ Ų§Ł„Ų­Ų§Ł„ŲŖŁŠŁ† Ł„Ł„Ł†Ų§ŲÆŁˆŁ„ŁˆŁ„ Ų³ŁˆŲ§Ų” Ų„Ł† ŁƒŲ§Ł† Ł†ŁŁŠŲ§ Ų£Łˆ Ų„Ł† ŁƒŲ§Ł† ŁƒŁ…Ų±ŁƒŲØ Ų¹Ł†Ł‚ŁˆŲÆŁŠ. Ł‡Ų°Ų§ Ų§Ł„Ų¹Ł…Ł„ Ł‚ŲÆŁ… Ł†ŲŖŲ§Ų¦Ų¬ Ų„Ų¶Ų§ŁŁŠŲ© Ł„ŁŲµŁ„ Ų§Ł„Ł†ŲøŲ§Ų¦Ų± Ų§Ł„ŁŲ±Ų§ŲŗŁŠŲ© Ł„Ł…Ų±ŁƒŲØ Ų§Ł„Ł†Ų§ŲÆŁˆŁ„ŁˆŁ„ ŁˆŲ³Ų§Ł‡Ł…ŲŖ Ł‡Ų°Ł‡ Ų§Ł„Ł†ŲŖŲ§Ų¦Ų¬ ŁŁŠ ŁˆŲ¶Ų¹ Ų§Ł„Ų®Ų·Ų© Ų§Ł„Ł…Ų³ŲŖŁ‚ŲØŁ„ŁŠŲ© Ł„ŁŲµŁ„ Ł†ŲøŲ§Ų¦Ų± Ų§Ł„Ł†Ų§ŲÆŁˆŁ„ŁˆŁ„ ŲØŲ“ŁƒŁ„ ŁƒŲ§Ł…Ł„ ŲØŲ„Ų³ŲŖŲ®ŲÆŲ§Ł… ŲŖŁ‚Ł†ŁŠŲ© SMB ŲØŁ…ŲŖŁˆŲ§Ł„ŁŠŲ§ŲŖ Ł…Ų®ŲŖŁ„ŁŲ© Ł…Ł† Ų·Ų±Ł‚ Ų§Ł„ŲŖŲ“ŲŗŁŠŁ„, ŁƒŲ°Ł„Łƒ Ų§Ł„Ł…Ł…ŲŖŲ²Ų§ŲŖ ŁˆŲ£Ų®ŁŠŲ±Ų§ ŲŖŲ±Ų§ŁƒŁŠŲØ Ų§Ł„Ł…Ų°ŁŠŲØ.pt_PT
dc.identifier.tid201456460
dc.identifier.urihttp://hdl.handle.net/10198/12816
dc.language.isoengpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectNadololpt_PT
dc.subjectChiralpakĀ® IApt_PT
dc.subjectPreparative liquid chromatographypt_PT
dc.subjectSimulated moving bed (SMB)pt_PT
dc.titleSeparation of nadolol stereoisomers by liquid chromatography using Chiralpak IA chiral stationary phasept_PT
dc.typemaster thesis
dspace.entity.typePublication
person.familyNameArafah
person.givenNameRami
person.identifier.ciencia-idAB16-ECBF-B886
person.identifier.orcid0000-0002-7743-4988
person.identifier.scopus-author-id57151342900
rcaap.rightsopenAccesspt_PT
rcaap.typemasterThesispt_PT
relation.isAuthorOfPublication3cd4864a-8aa6-46a2-9415-767a7551ee62
relation.isAuthorOfPublication.latestForDiscovery3cd4864a-8aa6-46a2-9415-767a7551ee62
thesis.degree.nameMestrado em Engenharia QuĆ­micapt_PT

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