L.S. Pais

Separation of 1,1'-bi-2-naphthol enantiomers by continuous chromatography in simulated moving bed

Abstract The chromatographic separation of 1,1′-bi-2-naphthol enantiomers with 3,5-dinitrobenzoyl phenylglycine bonded to silica gel stationary phases is studied. Continuous chromatography in simulated moving bed (SMB) is analyzed by modeling, simulation and operation of a SMB pilot unit Licosep 12–26 from Separex (France). A model for the prediction of the cyclic steady-state performance of the SMB is developed based on the analogy with the true moving bed (TMB). The model assumes axial dispersion flow for the liquid phase, linear driving force (LDF) approximation for intraparticle mass transfer rate and takes into account multicomponent adsorption equilibria. The SMB package allows the simulation of the pilot unit. The effect of operating variables (switching time, extract and feed flow rates, section length) and number of mass transfer units on the SMB performance is analyzed. The SMB performance is characterized by purity, recovery, solvent consumption and adsorbent productivity. The package also allows the simulation of the dynamic evolution of internal profiles for the transient operation of a TMB. The operation of the SMB pilot unit was carried out for the separation of racemic mixtures of bi-naphthol enantiomers. Using a 8-column configuration purities as high as 94.5% of the more retained species in the extract and 98.9% of the less retained species in the raffinate were obtained.

Modeling, simulation and operation of a simulated moving bed for continuous chromatographic separation of 1,1′-bi-2-naphthol enantiomers

Abstract The objective of this paper is to study the separation of enantiomers of 1,1′-bi-2-naphthol in 3,5-dinitrobenzoyl phenylglycine bonded to silica gel, using heptane–isopropanol (72:28) as eluent by simulated moving bed chromatography (SMB). A model for the prediction of the cyclic steady state performance of the SMB, based on the analogy with the true moving bed, is developed assuming axial dispersion flow, linear driving force approximation for intraparticle mass transfer and multicomponent adsorption equilibria. The SMB package allows the simulation of the pilot unit. The effect of several operating parameters on the SMB performance is analyzed. The performance is characterized by purity, recovery, solvent consumption and adsorbent productivity. The package is an important tool for learning and training operators, allowing the choice of best operating conditions. The operation of the SMB pilot unit was carried out for the separation of racemic mixtures using a 8-column configuration. Purities and recoveries higher than 95% in the extract and raffinate were obtained. Model and experimental results are compared and the package is also used to predict the steady state internal profiles for the SMB operation in good agreement with experimental results.

Separation of enantiomers of a chiral epoxide by simulated moving bed chromatography

Abstract The paper deals with chiral separation by simulated moving bed (SMB) chromatography. The separation of chiral epoxide enantiomers in microcrystalline cellulose triacetate using methanol as eluent is considered as illustrative example. The use of microcrystalline cellulose triacetate for the chromatographic separation of enantiomers is first reviewed and a methodology for obtaining basic data (adsorption equilibrium isotherms, axial dispersion and mass transfer coefficient) is discussed. A model for the prediction of the cyclic steady-state performance of the SMB, based on the analogy with the true moving bed, is developed assuming multicomponent adsorption equilibria, axial dispersion flow and linear driving force approximation to describe the intraparticle mass transfer rate. The simulation package is used to predict the effect of operating variables on the process performance and to define the regions for enantiomer separation. A simple optimization procedure is proposed for choosing the best SMB operating conditions. This procedure is extensively tested for the separation of chiral epoxide enantiomers. The experimental operation of a SMB pilot unit was carried out for this system. Purities and recoveries higher than 90% were obtained for both extract and raffinate, using a 420 ml inventory of stationary phase. The SMB pilot allows the continuous resolution of 52 g of racemic mixture per day and per liter of bed, with a solvent consumption of 0.4 l of mobile phase per gram of racemic mixture processed. The simulation package is also used to predict the steady-state internal concentration profiles for the SMB operation with reasonable agreement with experimental results.

Design of simulated moving bed and Varicol processes for preparative separations with a low number of columns

Simulated moving bed (SMB) chromatography has received significant attention in the last decade, particularly as regards the production of very valuable products, such as enantiomerically pure pharmaceutical compounds. Recent applications in the pharmaceutical industry use SMB systems containing a low total number chromatographic columns, usually four to eight. This paper deals with the modeling and simulation of SMB systems with only four, five and six columns. In particular, two modeling strategies, the equivalent true moving bed and the real SMB models, are compared for these units in terms of separation regions and system productivity. Also, the recently proposed Varicol process is analyzed and compared with the classical SMB operation, and the advantages of this new operation mode are shown for systems using a low number of columns.

Design of SMB chiral separations using the concept of separation volume

Abstract The article deals with chiral separation by simulated moving bed (SMB) chromatography. When mass transfer resistances are negligible, equilibrium theory provides explicit criteria for the choice of the SMB operating conditions. However, in the presence of mass transfer resistances, the SMB operating conditions should be evaluated through simulation. Using a package based on the analogy with the true moving bed operation, this work shows how mass transfer resistance can affect the conditions for enantiomers separation, as well as the critical values stated by equilibrium theory. The concept of separation volume is applied to show how the flow‐rate constraints, in presence of mass transfer resistances, have to be modified for chiral separations in which the adsorption equilibrium isotherms of both enantiomers are of linear + Langmuir type.

Chiral separation by SMB chromatography

The paper deals with chiral separation by simulated moving bed (SMB) chromatography. A model for the prediction of the cyclic steady-state performance of the SMB, based on the analogy with the true moving bed (TMB), is developed assuming multicomponent adsorption equilibria, axial dispersion flow and the linear driving force approximation to describe the intraparticle mass transfer rate. The simulation package is used to predict the effect of operating variables on the process performance and to define the regions for enantiomers separation. The influence of mass transfer resistance in the separation region is analyzed. A practical tool for choosing the better SMB operating conditions as a function of the feed flow-rate is proposed. The experimental operation of a pilot unit of SMB, Licosep 12-26 (Novasep, France), is carried out for the separation of enantiomers and illustrated with two systems: the bi-naphthol and the chiral epoxide enantiomers. Experimental results and model predictions are compared in terms of process performance and internal concentration profiles.

Cyclic steady state of simulated moving bed processes for enantiomers separation

Abstract Simulated moving bed (SMB) technology developed by UOP in early 1960s has expanded greatly in the last decade, finding new applications in the area of natural products, fine chemistry and pharmaceutical industry. SMB processes are periodic processes designed to operate in cyclic steady state (CSS) and, therefore, the correct determination of CSS is needed for the assessment of the SMB performance. Two approaches can be used for determination of CSS: the dynamic simulation until CSS is reached and direct prediction of CSS. The direct prediction of CSS could be obtained in two ways: (i) considering that at CSS the spatially distributed SMB unit state at the end of the cycle is identical to that at its beginning (Method 1); or (ii) considering that at CSS the spatially distributed SMB unit state at the end of a switching time interval is identical to the state at the beginning of the interval, apart from a shift of exactly one column length (Method 2). The mathematical models assume axial dispersion flow and linear driving force (LDF) approximation for intraparticle mass transfer. Mathematical models were solved using the g proms (general Process Modelling System) software package. Both approaches (dynamic simulation and direct CSS prediction) were applied to the prediction of cyclic steady state of SMB unit for 1,1′-bi-2-naphthol enantiomers separation. The direct CSS predictions were compared with the standard dynamic simulation CSS prediction in terms of accuracy of SMB performance and computing time requirements; the Method 2 for CSS prediction is more efficient than the standard dynamic simulation.

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

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-LSRE®) with six columns, packed with the Chiralpak AD® stationary phase (20 μm). 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 0.78 Lsolvent/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.

Separation of enantiomers of 1a,2,7,7a-tetrahydro-3-methoxynaphtha-(2,3b)-oxirane by liquid chromatography: laboratory-scale elution chromatography and modelling of simulated moving bed

Abstract The separation of enantiomers of 1 a ,2,7,7 a -tetrahydro-3-methoxynaphtha-(2,3 b )-oxirane (Sandoz epoxide) on cellulose triacetate HPLC columns was investigated on the laboratory scale. The performance of the columns was calculated by HEPT measurements and the slopes of the adsorption equilibrium isotherms and effective diffusivities were calculated from elution chromatographic experiments. Multi-component adsorption equilibrium isotherms were calculated from single isotherms by using the ideal adsorbed solution (IAS) model. Simulation of continuous chromatographic separation of the racemic mixture of Sandoz epoxide in a simulated moving bed was carried out and the effect of mass transfer coefficient on process performance was analysed.

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

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-LSRE®) with six columns, packed with the Chiralpak AD® stationary phase (20 μm). 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 g(feed) /(L(bed) h), and a solvent consumption of 0.41 L(solvent) /g(feed) was achieved.