Optimal operation of simulated moving bed chromatographic processes by means of simple feedback control

In this contribution, simple methods are presented for controlling a simulated moving bed (SMB) chromatographic process with standard PI (proportional integral) controllers. The first method represents a simple and model-free inferential control scheme which was motivated from common distillation column control. The SMB unit is equipped with UV detectors. The UV signals in the four separation zones of the unit are fixed by four corresponding PI controllers calculating the ratio of liquid and solid flow in the respective separation zone. In order to be able to adjust the product purity a second, model-based control scheme is proposed. It makes use of the nonlinear wave propagation phenomena in the apparatus. The controlled chromatographic unit is automatically working with minimum solvent consumption and maximum feed throughput--without any numerical optimization calculations. This control algorithm can therefore also be applied for fast optimization of SMB processes.     

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.     

Optimization of startup and shutdown operation of simulated moving bed chromatographic processes

This paper presents new multistage optimal startup and shutdown strategies for simulated moving bed (SMB) chromatographic processes. The proposed concept allows to adjust transient operating conditions stage-wise, and provides capability to improve transient performance and to fulfill product quality specifications simultaneously. A specially tailored decomposition algorithm is developed to ensure computational tractability of the resulting dynamic optimization problems. By examining the transient operation of a literature separation example characterized by nonlinear competitive isotherm, the feasibility of the solution approach is demonstrated, and the performance of the conventional and multistage optimal transient regimes is evaluated systematically. The quantitative results clearly show that the optimal operating policies not only allow to significantly reduce both duration of the transient phase and desorbent consumption, but also enable on-spec production even during startup and shutdown periods. With the aid of the developed transient procedures, short-term separation campaigns with small batch sizes can be performed more flexibly and efficiently by SMB chromatography.     

Continuous chromatographic separation process: simulated moving bed allowing simultaneous withdrawal of three fractions

Continuous counter-current chromatographic separation has been carried out in a simulated moving bed system (SMB). We have worked with a SMB pilot plant (8 columns, 4.4 litres of resin each) which allows the continuous withdrawal of two different fractions. A mixture of glucose-fructose has been separated. To calculate the concentration profile within the separator an axial dispersed plug flow model and an equilibrium stage model have been employed; software has been created to simulate the behaviour of the separator. The necessary parameters of the mode: the adsorption equilibrium constant, the height equivalent to a theoretical plate and the bed voidage, have been acquired experimentally from elution chromatography measurements. The results calculated by simulation give a good representation of the experimental concentration profiles; other separations like xylitol-arabitol have been simulated. The influence of some factors like desorbent flow-rate, feed flow-rate and the bed voidage have been studied using the software. Once the system has worked in a two withdrawal way, an extension of the pilot plant has been constructed so as to obtain a third one. The necessary parameters of the three withdrawal model will be studied.     

Development of an high-performance liquid chromatographic simulated moving bed separation from an industrial perspective

A binary test mixture consisting of cyclopentanone and cycloheptanone is used for the performance evaluation of a pilot-scale simulated moving bed unit. The involved adsorption equilibria and the kinetic behavior are discussed in detail. The results of the test runs are evaluated using the recently introduced "triangle theory" which allows to account for the overload conditions prevailing under preparative chromatographic conditions and to select optimal operating conditions. Under optimized conditions the separation of 735 g test mixture/kg stationary phase per day with purities >99.9% for extract and raffinate stream has been achieved.     

Optimization of simulated moving bed and Varicol processes

A new continuous chromatographic process (Varicol) has been presented recently. Its basic principle consists, in contrast to the traditional simulated moving bed (SMB) technology, of an asynchronous shift of the inlet/outlet lines in a multi-column system with a recycle loop. Due to the stronger influence of the discrete dynamics on the plant behavior, the design of a Varicol process requires the use of model-based optimization to take advantage of the very high flexibility of this process. The equilibrium theory which has been successfully applied to SMB by many practitioners fails to predict the region of complete separation accurately. In this paper, we present a rigorous model-based optimization framework, which can handle the SMB and the novel Varicol process in a systematic manner. The feasibility of the approach is demonstrated by the separation of a mixture of propranolol isomers which exhibits a highly non-linear multi-component adsorption behavior. Experimental results are presented and discussed.     

Two-fraction and three-fraction continuous simulated moving bed separation of nucleosides

A new experimental set-up and a new simulated moving bed (SMB) operation are presented in this work. A desktop SMB unit developed as a modification of the commercial AKTA explorer working platform has been utilized for the separation of different mixtures of nucleosides. Both two fraction and three fraction SMB separations have been carried out, the latter made possible by the adoption of a new SMB configuration and operating mode (three fraction SMB, 3F-SMB, operation). Experiments demonstrate the feasibility of the 3F-SMB operation, and confirm the trends predicted based on considerations about retention of the components to be separated along the unit.     

Batch and simulated moving bed chromatographic resolution of a pharmaceutical racemate

The preparative chromatographic resolution of racemates has become over the past few years a standard approach for the generation of enantiomers in pharmaceutical research and development. This paper will discuss the chromatographic resolution of a racemic pharmaceutical intermediate. Initial analytical method development to determine the best preparative conditions will be presented. Batch resolution of kg quantities of racemate followed by the simulated moving bed resolution of tens and hundreds of kg of racemate will also be discussed. Finally the different approaches used for the separation will be compared.     

Parametric uncertainties and influence of the dead volume representation in modelling simulated moving bed separation processes

In this study, a systematic numerical procedure for identifying the model parameters of simulated moving bed (SMB) separation processes is developed. The parameters are first estimated by minimizing a weighted least-squares criterion using experimental data from batch experiments, e.g. the time evolution of the concentration of elution peaks. Then, a cross-validation is achieved using data from experiments in SMB operation. At this stage, the importance of a careful modelling of the dead volumes within the SMB process is highlighted. In addition, confidence intervals on the estimated parameters and on the predicted concentration profiles are evaluated.     

Equilibrium theory based design of simulated moving bed processes for a generalized Langmuir isotherm

In the frame of the local equilibrium theory of chromatography, design criteria for complete separation of binary mixtures in simulated moving bed (SMB) separations are developed, presented and discussed. These apply to systems, whose retention behavior is characterized by a generalized Langmuir isotherm. By allowing for negative terms in the denominator of the classical Langmuir isotherm, this newly introduced adsorption model captures a broad class of competitive or synergistic adsorption, including anti-Langmuir behavior for both adsorbates, and mixed cases where one species behaves in a Lagmuirian and the other in an anti-Langmuirian manner. By extending classical equilibrium theory results for the binary Langmuir isotherm, and by generalizing the approach followed earlier to derive SMB design criteria for the binary and multi-component Langmuir isotherm, exact algebraic equations for the boundary of the complete separation region in the operating parameter space are derived for all possible generalized Langmuir isotherm. The effect of changing feed composition on the shape of the complete separation region and on the position of the optimal operating point is analyzed and discussed.     

Equilibrium theory-based design of simulated moving bed processes under reduced purity requirements linear isotherms

The design of simulated moving bed processes under reduced purity requirements for systems whose isotherm is linear is considered. Based on the equilibrium theory of chromatography, explicit equations to uniquely identify the separation region that will ensure specified extract and raffinate purities are derived. The identification of the region requires only the knowledge of Henry constants of the solutes, the concentration of the solutes in the feed and the purity specifications. These results are validated using numerical simulations.     

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.     

Multiobjective optimization of simulated moving bed and Varicol processes using a genetic algorithm

The size of the packing material, the total number of columns and the total feed concentration have significant impacts on the economics of a preparative chromatographic separation, through their effects on column pressure drop, column efficiency and thermodynamics. In this work, the role of these parameters on the performances of a simulated moving bed and a Varicol process is investigated on a chiral separation system from literature, using an equilibrium stage model. A multiple objective optimization technique based on a genetic algorithm is adopted, which allows to maximize simultaneously the purity of the extract and productivity of the unit. In this way, it is possible to optimize and compare the performances of both processes in a wide range of parameter values, so as to assess their relative potential under equally optimized conditions. The optimization results, i.e. the so-called Pareto sets, have been discussed in the frame of equilibrium theory and the roles of these three parameters have been clarified.     

Chiral separation and modeling of the three-chiral-center beta-blocker drug nadolol by simulated moving bed chromatography

Nadolol, a beta-blocker used in the management of hypertension and angina pectoris, has three chiral centers and is currently marketed as an equal mixture of its four stereoisomers. Resolution of three of the four stereoisomers of nadolol was obtained previously by HPLC, with a complete separation of the most active enantiomer (RSR)-nadolol, on a column packed with perphenyl carbamoylated beta-cyclodextrin (beta-CD) immobilized onto silica gel. In this study, continuous separation of the target enantiomer of (RSR)-nadolol from its racemic mixture (which is a ternary mixture in the chromatographic system) was studied by non-linear SMB chromatography. Different regions of (2, 3) and (1, 2) complete separation regime were determined in the (m2, m3) region and the effect of non-linearity such as overall feed concentration and component composition on the separation performances was investigated. A direct simulation approach has been proposed to simulate the SMB separation performance for the pseudo-binary mixture of nadolol. The simulation was conducted on the basis of a shortcut method constituted only of the weak-key and strong-key components. The performance of the cyclic steady-state behavior of the SMB unit was predicted reasonably well. It was also discussed quantitatively that the complete separation region obtained from the shortcut method is a subset of the true complete separation region and the optimal separation conditions obtained differed slightly from the "true" separation.     

模拟移动床色谱分离制备手性农药甲霜灵的研究

利用自行组建的模拟移动床色谱(SMBC),在正相条件下,在自制的涂敷型纤维素-三(3,5-二甲基苯基氨基甲酸酯)手性固定相上成功制备出甲霜灵对映体,所制备的对映体纯度达到99%以上,与高效液相色谱法制备相比较,模拟移动床技术制备甲霜灵对映体的效率以及流动相的利用率均明显高于高效液相色谱法.     

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 Tr?ger'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.     

Enantiomers separation by simulated moving bed chromatography. Non-instantaneous equilibrium at the solid-fluid interface

The simulated moving bed (SMB) technology, first conceived for large bulk-scale separations in the petrochemical industry, has found increasingly new applications in the pharmaceutical industry. Among these, the separation of fine chemicals has been the subject of considerable study and research. This work presents the modeling, simulation and design of the operation of a SMB plant in order to separate a binary chiral mixture. The usual assumption of instantaneous equilibrium at the solid-fluid interface is questioned and a first-order kinetics of adsorption is taken into account. The cases of linear, Langmuir and modified Langmuir equilibria are studied. The equivalent true moving bed (TMB) model was used assuming axial dispersion for the fluid flow and plug flow for the solid-phase flow. Intraparticle diffusion was described by a linear driving force (LDF) approximation. Simulation results indicate that, under certain conditions, equilibrium is not actually reached at the adsorbent surface. This leads to different unit performances, in terms of product purities and recoveries, as compared to those predicted assuming instantaneous equilibrium. Moreover, SMB units may be improperly designed by the usual methods (flow-rate ratio separation regions) if non-equilibrium effects are overlooked.     

Experimental implementation of automatic 'cycle to cycle' control of a chiral simulated moving bed separation

In the absence of a suitable controller, currently simulated moving beds (SMBs) are operated suboptimally to cope with system uncertainties and to guarantee robustness of operation. Recently, we have developed a 'cycle to cycle' optimizing controller that not only makes use of minimal system information, i.e. only the Henry constants and average bed voidage, but also optimizes the process performance and taps the full economic potential of the SMB technology. The experimental implementation of the 'cycle to cycle' optimizing controller had been carried out for achiral separation. For chiral separation however, application of any online controller has not been possible because an appropriate online monitoring system has not been available. This work reports and discusses the first experimental implementation of the 'cycle to cycle' optimizing control for chiral separations. A mixture of guaifenesin enantiomers is separated on Chiralcel OD columns with ethanol as mobile phase in a eight-column four sections laboratory SMB unit. The results show that the controller, although using minimal information about the retention of the two enantiomers, is able to meet product and process specifications, can optimize the process performance, and is capable of rejecting disturbances that may occur during the operation of the SMB plant.     

Monolithic silica sorbents for the separation of diastereomers by means of simulated moving bed chromatography

Monolithic silica sorbents with a dual pore system can be used in preparative chromatography for the separation of diastereomers. They exhibit some special features, which allows them to be operated at high linear velocities due to their reduced pressure drop and fast diffusion kinetics. Especially in the continuous set-up of simulated moving bed chromatography monolithic sorbents show high productivities, which make them well suited in pharmaceutical drug development for the production of pure isomers.     

Optimization strategy for simulated moving bed systems

Simulated moving bed (SMB) systems are of rising interest in the purification of pharmaceuticals or specialty chemicals (racemic mixtures, proteins, organic acids, etc.). This is particularly due to their advantage in solvent reduction, obtained productivity and purities as well as investment costs in comparison to eluent chromatography. This paper evolved from the need for a readily available algorithm in order to find optimal operating conditions for SMB chromatography systems with nonlinear or coupled adsorption isotherms. The herein developed algorithm is based on a semi-deterministic two-step approach. First, optimal operating conditions with regard to an objective function are found by knowing adsorption measurements only. In a second step actual SMB results are used to adapt the initial isotherm measurements and match the simulation with the experiment. The algorithm is verified on a bench-scale SMB unit applied for the separation of a racemic epoxide with Chiralcel-OD as stationary phase. The developed algorithm improved the productivity of the investigated experimental design by 24%.