Relay simulated moving bed chromatography: concept and design criteria.

We present a new class of multicolumn chromatographic processes that change the classical way of handling the product outlets of simulated moving-bed (SMB) chromatography to avoid the use of flow controllers or an extra pump-the objective is to have just two- or three-way valves at a column outlet-while maintaining the analogy with the SMB in terms of displaced volumes of fluid per switch interval. In this class of processes the flow through a zone (or column) is always in one of the three states: (i) frozen, (ii) completely directed to the next zone (or column), or (iii) entirely diverted to a product line. We use the term relayed stream to refer to this particular type of manipulation of the outflow from a column. For this class of processes we derive a SMB analog-the R-SMB process-and demonstrate, under the framework of the equilibrium theory, that this process has the same separation region as the classical SMB for linear adsorption systems. In addition, the results from the equilibrium theory show that the R-SMB process consists of two distinct cycles that differ only in their intermediate sub-step: one cycle for selectivities α smaller than (3+√5)/2 and another cycle for larger values of α; in the former case no product stream is collected during the intermediate sub-step, whereas in the latter case both product streams are collected. We also examine the R-SMB process under conditions of finite column efficiency and compare its performance against those of the classical open- and closed-loop SMBs. Our simulation results show that the R-SMB process requires less desorbent and is more productive than the standard SMB processes under conditions of finite column efficiency and that the comparison increasingly favors the R-SMB as the column efficiency decreases.

A new multicolumn, open-loop process for center-cut separation by solvent-gradient chromatography.

A comprehensive description of a new process--the GSSR (Gradient with Steady State Recycle) process--for center-cut separation by solvent-gradient chromatography is provided, highlighting its versatility, flexibility, and ease of operation. The GSSR process is particularly suited for ternary separation of bioproducts: it provides three main fractions or cuts, with a target product contained in the intermediate fraction. The process comprises a multicolumn, open-loop system, with cyclic steady state operation, that simulates a solvent gradient moving countercurrently with respect to the solid phase. However, the feed is always injected into the same column and the product always collected from the same column as in a batch process; moreover, both steps occur only once per cycle. The GSSR process was experimentally validated in a pilot unit, using the purification of a crude peptide mixture by reversed phase as a proof of concept; the crude mixture is roughly 50% pure and some of its impurities have isocratic retention times very close to that of the target peptide. Experimental results are reported in terms of cyclic steady-state profiles and process performance indicators, which include product purity and yield. A simplified model-based approach, which uses only a few key components of the crude mixture, is employed to assist in the explanation of the process operation. By dynamically adjusting the switching interval while the process is running, to correctly position the composition profile with respect to the outlet ports, pure product satisfying the target specifications--98% purity and 95% recovery--was obtained under stable operation in the pilot unit.

Chiral separation by two-column, semi-continuous, open-loop simulated moving-bed chromatography.

A two-column version of a multicolumn, semi-continuous, open-loop chromatograph for chiral separation is presented and validated experimentally. The heart of the process is a flexible node design and cyclic flow-rate modulation that succeed at keeping the mass-transfer zone inside the system without resorting to any recycling technique. One advantage of this streamlined design is the simplicity of its physical realization: regardless of the number of columns, it only requires two pumps to supply feed and desorbent into the system, while the flow rates of liquid withdrawn from the system are controlled by material balance using simple two-way valves. A rigorous model-based optimization approach is employed in the optimal cycle design to generate a solution that is physically realizable in the experimental apparatus. The optimized scheme for two-column operation supplies fresh feed into the system where the composition of the circulating fluid is closest to that of the feedstock fluid, and recovers the purified products, extract and raffinate, alternately at the downstream end of the unit while desorbent is supplied into the upstream end of the system. The feasibility and effectiveness of the two-column process are verified experimentally on the separation of reboxetine racemate, a norepinephrine re-uptake inhibitor, under overloaded conditions. Our set-up employs an automated on-line enantiomeric analysis system, comprising an analytical HPLC set-up with two UV detectors to monitor the composition profile at the downstream end of one of the columns; this monitoring system does not use a polarimeter.

Streamlined, two-column, simulated countercurrent chromatography for binary separation.

We report on a numerical and experimental study of two-column versions of streamlined, multicolumn, semi-continuous chromatography for binary separation. The systems combine a flexible node design, cyclic flow-rate modulation, and relayed operation of the inlet/outlet ports to extend the mass-transfer zone over the largest possible length, while keeping it inside the system at all times. One advantage of these streamlined designs is the simplicity of their physical realization: regardless of the number of columns, they only require two pumps to supply feed and desorbent into the system, while the flow rates of liquid withdrawn from the system are controlled by material balance using simple two-way valves. In one case, an extra pump is needed to recirculate the fluid in closed-loop. A rigorous model-based optimization approach is employed in the optimal design of the cycles to generate solutions that are physically realizable in the experimental set-ups. The optimized schemes for two-column operation supply fresh feed into the middle of the system where the composition of the circulating fluid is closest to that of the feedstock fluid, and recover the purified products, extract and raffinate, alternately at the downstream end of the unit, while desorbent is continuously supplied into the upstream end of the system. By internally recycling part of the non-pure cut fraction, the scheme with a step of closed-loop recycling significantly reduces its solvent consumption. The feasibility and effectiveness of the reported two-column processes have been verified experimentally on the linear separation of nucleosides by reversed phase subject to 99% purity constraints on both products. It is shown that our processes compare favorably against single-column batch chromatography, steady-state recycling, and four-column, open-loop SMB, for the same amount of adsorbent; they are also better than the four-column, closed-loop SMB at high feed throughputs.

Determination of competitive isotherms of enantiomers by a hybrid inverse method using overloaded band profiles and the periodic state of the simulated moving-bed process.

A procedure for determination of adsorption isotherms in simulated moving-bed (SMB) chromatography is presented. The parameters of a prescribed adsorption isotherm model and rate constants are derived using a hybrid inverse method, which incorporates overloaded band profiles of the racemic mixture and breakthrough data from a single frontal experiment. The latter are included to reduce the uncertainty on the estimated saturation capacity, due to the dilution of the chromatograms with respect to the injected concentrations. The adsorption isotherm model is coupled with an axially dispersed flow model with finite mass-transfer rate to describe the experimental band profiles. The numerical constants of the isotherm model are tuned so that the calculated and measured band profiles match as much as possible. The accuracy of the isotherm model is then checked against the cyclic steady state (CSS) of the target SMB process, which is readily and cheaply obtained experimentally on a single-column set-up. This experiment is as expensive and time consuming as just a few breakthrough experiments. If necessary, the isotherm parameters are adjusted by applying the inverse method to the experimental CSS concentration profile. The method is successfully applied to determine the adsorption isotherms of Trögers base enantiomers on Chiralpak AD/methanol system. The results indicate that the proposed inverse method offers a reliable and quick approach to determine the competitive adsorption isotherms for a specific SMB separation.

Two-column simulated moving-bed process for binary separation.

A two-column simulated moving-bed system has been developed for binary separation. The system combines a flexible node design, robust pump configuration, and cyclic flow-rate modulation to exploit the benefits of simulated counter-current operation. The feasibility of the proposed two-column system is demonstrated on the linear separation of two nucleosides by reversed phase. Emphasis is given to the potentialities of the process compared to single-column batch chromatography with recycling for the same amount of stationary phase. The performance of the proposed two-column process is verified with laboratory-scale experiments and detailed simulations for different difficulties in separation and desorbent-to-feed ratios.

On-line enantiomeric analysis using high-performance liquid chromatography in chiral separation by simulated moving bed.

An automated on-line enantiomeric analysis system comprising an analytical HPLC set-up with two UV detectors sharing the same light source has been employed to monitor the internal composition profile in chiral simulated moving bed chromatography. This monitoring scheme does not use a polarimeter. Using a sampling interface placed between two SMB columns, effluent samples are directed onto a high-efficiency analytical column at a sampling rate faster than the overall dynamics of the preparative unit to achieve on-line enantiomeric analysis of the composition profile. The other UV detector is placed in the SMB loop before the fraction collector to provide instantaneous measurement of the total enantiomeric concentration. The feasibility and effectiveness of the on-line enantiomeric monitoring scheme were assessed experimentally on the separation of Tröger's base racemate, using Chiralpak AD as stationary phase and methanol as eluent. It was found that robust monitoring of the concentration profiles of the individual enantiomers is best achieved when the enantiomeric purity obtained from the peak areas of the on-line enantiomer analysis chromatograms is combined with the on-line UV measurement of total enantiomeric concentration. The accuracy and robustness of the proposed on-line enantiomeric monitoring system open up promising perspectives for process control and dynamic optimization of the SMB.

Optimal design and experimental validation of synchronous, asynchronous and flow-modulated, simulated moving-bed processes using a single-column setup.

The performance of asynchronous (Varicol) and flow-modulated (PowerFeed) simulated moving-bed processes, as well as their combination into a single hybrid scheme, are studied both experimentally and by numerical simulation. A recently developed single-column experimental setup is employed to demonstrate the feasibility of the various schemes, explore the effect of their major operating parameters, and illustrate the performance enhancements that are obtained when these schemes are properly optimized. The experimental feasibility and effectiveness of the various schemes are assessed by running and comparing optimized configurations for the linear separation of two nucleosides on a high-performance reversed-phase stationary phase.

Experimental assessment of simulated moving bed and varicol processes using a single-column setup.

A novel single-column setup for experimentally reproducing the steady periodic behavior of simulated countercurrent multicolumn chromatography is presented. The system relies on accurate online monitoring of the outlet effluent composition, processing the measured data through a node balance, and feeding it back into the column with an appropriate time delay using a multi-pump configuration to reproduce the desired inlet stream. The feasibility of the proposed system is demonstrated on the linear separation of two nucleosides using three different column configurations, which include both synchronous and asynchronous port switchings. By judiciously selecting the switching interval for process startup and applying a model-based startup procedure, the periodic state can be attained in just one or two cycles. Therefore, mobile phase and solute consumptions required to experimentally reproduce the periodic state of the equivalent multicolumn process are reduced to a minimum. This may be an economic, optimal manner of experimentally testing a set of operating conditions or cycle policy to achieve a given separation performance for a new multicolumn chromatographic separation.

Optimal design and operation of a certain class of asynchronous simulated moving bed processes.

A compact representation of the cyclic operation of simulated moving-bed chromatography is established from the governing equations for the analogous single-column model that reproduces the cyclic steady-state (CSS) behavior of the multi-column process. A broad class of physically realizable asynchronous processes is then derived by dropping the integrality condition on the number of columns per zone, which now represents the average over a cycle. The steady periodic solution of the multi-column unit is computed by solving the analogous single-column model using a full-discretization method. The nonlinear algebraic system resulting from the simultaneous discretization of both spatial and temporal coordinates is solved using the gPROMS software. This solution strategy leads to shorter computational times than those previously reported in the literature. Process optimization is handled using single objective functions, to avoid competing effects, which are explicitly constrained by product quality and maximum allowable internal flow rates. The process is optimized for maximum feed throughput, with a possible upper bound on eluent consumption or flow rate, or minimum eluent consumption for a given feed flow rate. The nonlinear programming problem is solved by an external solver while still carrying out the CSS calculations in gPROMS. The feasibility of the approach is demonstrated on the chromatographic separation of an enantiomeric mixture with nonlinear competitive isotherm. Emphasis is given to the benefits that can be gained by upgrading an existing system to asynchronous operation. It is shown that eluent consumption for optimized asynchronous configurations in the higher feed-throughput region can be significantly reduced by modulation of eluent flow rate and selective product withdrawal.