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Chiral separation of Ketoprofen enantiomers by preparative and simulated moving bed chromatography

Publication . Ribeiro, António E.; Gomes, Pedro Sá; Pais, Luís S.; Rodrigues, Alírio

The pharmaceutical industry is now directed to the market of more safety and efficient drugs, based on single enantiomers. Ketoprofen, still used as a racemic pharmaceutical drug, belongs to the profens class, one of the most representative of the non-steroidal anti-inflammatory drugs. This work presents the chiral separation of ketoprofen enantiomers by simulated moving bed technology, using a laboratory scale unit (the FlexSMB-LSRE1) with six columns, packed with the Chiralpak AD1 stationary phase (20 lm). A comparative study between a mobile phase composed of a traditional high hydrocarbon content (10%ethanol=90%n-hexane=0- .01%TFA) and a strong polar organic composition (100%ethanol= 0.01%TFA) is presented. The study includes the measurement of the adsorption isotherms, elution, and frontal chromatography experiments, carried out on a SMB column for both compositions. The results obtained allowed the prediction and optimization of the SMB operation. Using pure ethanol as solvent and a racemic feed concentration of 40 g=L, purities above 98.6% on both outlet streams were obtained, with a productivity of 3.84 gfeed=(Lbed.hr) and a solvent consumption of 0.78Lsolvent=gfeed. The results obtained in the experimental separation of ketoprofen enantiomers by SMB chromatography indicates that pure ethanol presents better performances than the classic high hydrocarbon content composition.

2011Journal article

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Optimization of the mobile phase composition for preparative chiral separation of flurbiprofen enantiomers

Publication . Ribeiro, António E.; Graça, Nuno S.; Pais, Luís S.; Rodrigues, Alírio

This work presents the experimental and simulation results obtained for the optimization of the mobile phase composition for the preparative separation of flurbiprofen enantiomers by liquid chromatography using an amylose-based chiral stationary phase (Chiralpak AD). The experimental work carried out includes solubility and adsorption isotherm measurements and pulse and breakthrough experiments under preparative conditions. The simulation work predicts the operation of a simulated moving bed (SMB) system for the separation of flurbiprofen enantiomers to compare the productivity and solvent consumption performances, for the different mobile phase compositions and using the experimental data obtained. This paper presents a new and different case study (flurbiprofen) of the one recently reported by the authors (ketoprofen enantiomers [A. Ribeiro, N. Grac¸ a, L. Pais, A. Rodrigues, Preparative separation of ketoprofen enantiomers: choice of mobile phase composition and measurement of competitive adsorption isotherms, Sep. Purif. Technol. 61 (2008) 375–383]), to clearly show that the optimization of the mobile phase composition for preparative chiral separation requires an individualized study, since different results are obtained even for enantiomers systems of the same family.

2009Journal article

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Chiral separation of flurbiprofen enantiomers by preparative and simulated moving bed chromatography

Publication . Ribeiro, António E.; Gomes, Pedro Sá; Pais, Luís S.; Rodrigues, Alírio

This study presents the chiral resolution of flurbiprofen enantiomers by preparative liquid chromatography using the simulated moving bed (SMB) technology. Flurbiprofen enantiomers are widely used as nonsteroidal anti-inflammatory drugs, and although demonstrate different therapeutic actions, they are still marketed as a racemic mixture. The results presented here clearly show the importance of the selection of the proper solvent composition for the preparative separation of flurbiprofen enantiomers. Chiral SMB separation is carried out using a laboratory-scale unit (the FlexSMB-LSRE1) with six columns, packed with the Chiralpak AD1 stationary phase (20 lm). Results presented include the experimental measurement of equilibrium and kinetic data for two very different solvent compositions, a traditional high hydrocarbon content [10%ethanol/90%n-hexane/0.01% trifluoroacetic acid (TFA)] and a strong polar organic composition (100%ethanol/0.01%TFA). Experimental data, obtained using the two mobile phase compositions, are used to predict and optimize the SMB operation. After selecting 10%ethanol/90%n-hexane/0.01%TFA as the most appropriate solvent composition, three feed concentrations of racemic flurbiprofen were considered. Using 40 g/l of racemic flurbiprofen feed solution, the purities for both outlet streams were above 99.4%, the productivity was 13.1 gfeed/(Lbed h), and a solvent consumption of 0.41 Lsolvent/gfeed was achieved.

2011Journal article

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Preparative separation of ketoprofen enantiomers: choice of mobile phase composition and measurement of competitive adsorption isotherms

Publication . Ribeiro, António E.; Graça, Nuno S.; Pais, Luís S.; Rodrigues, Alírio

The present work intends to investigate how mobile phase composition influences the adsorption behavior of ketoprofen enantiomers (a nonsteroidal anti-inflammatory drug) on an amylose-based chiral stationary phase (Chiralpak AD). Three mobile phase compositions were studied: the usual 20% ethanol/80% n-hexane mixture and two pure mobile phases; methanol and ethanol. Pulse and breakthrough experiments under preparative conditions were carried out in order to measure and test adsorption isotherms. The results obtained show that, for preparative separations, pure ethanol is a better mobile phase than the usual 20% ethanol/80% n-hexane mixture: it allows higher solubility of the racemate, lower retention times, and also a higher selectivity at high enantiomer concentrations. These are aspects of crucial importance when the final goal is to achieve high productivity preparative separations, as it is shown for the simulated moving bed (SMB) operation.

2008Journal article

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