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%.     

Optimizing control of simulated moving bed separations of mixtures subject to the generalized Langmuir isotherm

Simulated moving bed (SMB) is a cost-efficient separation technique that offers high productivity and low solvent consumption. SMB has gained importance in the pharmaceutical and fine chemical industry to perform complex separation tasks. However, an open and challenging problem is the optimal, robust operation of the SMB process. We have developed a control scheme that integrates the optimization and control of the SMB unit. A significant feature of the controller is that only minimal information of the system has to be provided, i.e. the linear adsorption behavior of the mixture to be separated and the average void fraction of the columns. Therefore, a full characterization of the adsorption behavior of the mixture and the columns is no longer required. In this ‘cycle to cycle’ control scheme, the measurements, optimization and control actions are performed once in every cycle. This paper presents simulation results of the control scheme applied to the separation of binary mixtures characterized by generalized Langmuir isotherms. The results are presented and analyzed in the frame of the triangle theory that has been recently extended to encompass these types of isotherms. Besides, online optimum performance of the SMB unit is compared with off-line optimization carried out using genetic algorithm. The results show that the controller fulfills the product and process specifications while operating the SMB unit optimally, regardless of the different types of Langmuir isotherms that the systems exhibit.     

Variable desorbent strength: influence on SMB operating conditions and performance

The aim of this work was to evaluate the role of desorbent selectivity variation on the tuning and the performance of a SMB process. For this purpose a separation regions study in the case of a four-zones non-linear transfer limited SMB was carried out. The SMB unit was modelled considering the equivalent True Moving Bed (TMB). A set of 11 desorbents with different strength was considered: 3 desorbents with constant strength and 8 desorbents with variable strength. For each system, the optimal operating conditions are determined using the separation regions approach, with plots in both (Q₂, Q_F) and (Q₄, Q_D) planes. Depending on the separation considered, a variable selectivity desorbent can lead to an improvement or can be detrimental to process performances. A careful choice of desorbent selectivity (either constant or variable) is then crucial to achieve maximal process performance.     

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.     

Optimization of a hybrid chromatography-crystallization process for the separation of Tröger's base enantiomers

This paper presents an analysis of a hybrid process consisting of simulated moving bed (SMB) chromatography and crystallization and studies its performance for the separation of the Tr?ger's base enantiomers. The SMB is simulated using a detailed model including column efficiency, thus, implying a proper evaluation of the effect of column size on column efficiency and separation performance. The crystallization operations are accounted for through material balances, assuming equilibrium between enantiopure crystals and mother liquor. A genetic algorithm is used to optimize the combined process, using proper definitions of objective functions. Multi-objective optimization of this hybrid process for productivity and evaporation cost in terms of operating parameters, column length, and SMB feed concentration shows an optimum SMB purity value as a trade off between increased SMB performance and recycle of the mother liquor.     

Solvent gradient operation of simulated moving beds. 2. Langmuir isotherms

Simulated Moving Bed separations of enantiomers or fine chemicals are usually carried out in the isocratic mode, i.e. by applying the same operating conditions (temperature, pressure, mobile phase composition, pH) in the whole SMB unit. However, it has been recently recognized that by properly modulating operating conditions in the SMB sections. i.e. Sections 1-4 normally, separation performance in terms of productivity and solvent consumption can be significantly improved. In this work, we study solvent gradient SMB (SG-SMB) operation, where the concentration of a modifier in the main solvent constituting the mobile phase is adjusted along the SMB unit, so as to have weaker retention of the species to be separated in the first two sections, and stronger retention in Sections 3 and 4. Overload chromatographic conditions are considered, where the adsorption behavior is characterized by a nonlinear competitive adsorption isotherm, e.g. a binary Langmuir isotherm. Design criteria to achieve complete separation are developed in the frame of the equilibrium theory of chromatography. The theoretical findings are discussed in view of typical effects of the modifier concentration on retention times and solubility of the species to be separated, and an overall assessment of the SG-SMB technology is attempted.     

Separation of stereoisomers in a simulated moving bed-supercritical fluid chromatography plant

The combination of two techniques, simulated moving bed (SMB) and supercritical fluid chromatography (SFC), leads to an apparatus with unique features. Besides the known advantages of the SMB process, like reduced solvent consumption and its continuity, the use of supercritical carbon dioxide as the mobile phase offers an easy product recovery by depressurizing the supercritical fluid. Details of a SMB-SFC plant are presented for the first time. Due to the large number of process parameters a simulation of the SMB process is necessary to achieve optimal operating conditions. The most important thermodynamic information for a SMB process is the adsorption isotherms. Therefore, isotherms for two phytol isomers are measured and correlated. A fast dynamic model for the simulation of SMB is used to calculate the region of complete separation taking different column configurations and the compressibility of the mobile phase into account.     

Optimization of simulated moving bed chromatography with fractionation and feedback: Part II. Fractionation of both outlets

A new improvement based on outlet fractionation and feedback has been developed for simulated moving bed (SMB) chromatography. In this contribution, this fractionation and feedback SMB (FF-SMB) concept is extended to the general scenario which integrates a simultaneous fractionation of both outlet streams. A model-based optimization approach, previously adopted to investigate single fractionation, is extended to consider this flexible fractionation policy. Quantitative optimization studies based on a specific separation problem reveal that the double fractionation is the most efficient operating scheme in terms of maximum feed throughput, while the two existing single fractionation modes discussed in our previous study are also significantly superior to the conventional SMB operation. The advantages of the double fractionation extension are further demonstrated in terms of several more detailed performance criteria. In order to evaluate the applicability of the fractionation and feedback modification, the effect of product purity, adsorption selectivity, column efficiency and column number on the relative potential of FF-SMB over SMB is examined.     

Optimal design of batch and simulated moving bed chromatographic separation processes

Preparative chromatography, especially simulated moving bed (SMB) chromatography, is a key technology for the separation of fine chemicals on a production scale. Most of the design methods for batch and SMB processes proposed in the open literature deal with the optimisation of the operating conditions for a given chromatographic unit only. Therefore, a comparison of the process economy may lead to incorrect results. In this contribution, an effective strategy for the optimal choice of all process parameters (operation and design parameters) is proposed. The main idea of this strategy is to apply a detailed and experimentally validated process model and to reduce the number of influencing parameters by introducing and optimising dimensionless process parameters. It is shown that there is an infinite choice of design and operating parameters to achieve maximum productivity or minimum separation costs and not at the maximum pressure drop only. The detailed design of the chromatographic unit and the selection of the operating conditions can be adjusted by considering the availability of columns and packing materials. As the model system, the separation of a racemic mixture (EMD53986) on Chiralpak AD was investigated. After complete optimisation of a batch and a SMB unit, a real comparison of the process economy can be achieved. Finally, the influences of two different objective functions, productivity and specific separation cost, are analysed.     

Effect of the homogeneity of the column set on the performance of a simulated moving bed unit. I. Theory

Although it is impossible to manufacture identical columns for use in a simulated moving bed (SMB) process, theoretical studies assume that all the columns in an SMB unit have identical characteristics. In practice, calculations in modeling and optimization studies are made with the average values of each column parameter set. In this report, the effects on SMB process performance caused by column-to-column fluctuations of the parameters are discussed. As a first step, we show how the differences in porosity of the columns may be taken into account with a revised set of separation conditions. Reductions in the purity of the extract and the raffinate streams are quantitatively related to the column-to-column fluctuations of the retention times of the two components arising from these porosity differences. For the sake of simplicity, the discussion first addresses the case of a four-column SMB operating under linear conditions. Then, the scope is extended to the cases of SMB units incorporating several columns in each section and to SMB units operating under nonlinear conditions.     

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.     

Optimizing control of simulated moving beds--experimental implementation

The operation of simulated moving beds (SMBs) at their optimal operating conditions is difficult and not robust. Therefore, it is common practice to operate SMB units far from their economic optimum in order to tolerate uncertainties in the system and minimize the effect of disturbances. Recently, we have proposed an on-line optimization based SMB control scheme that allows to exploit the full economic potential of SMB technology. The goal of this work is two-fold. Firstly, to experimentally evaluate and demonstrate the capability of the controller to optimize and operate the SMB units, thus delivering the products with maximum productivity and minimum solvent consumption. Secondly, to show the suitability of the controller even using a minimum of system information, thus making the detailed isotherm measurements redundant and saving time in the separation design phase. This paper reports and discusses the first experimental implementation of the control concept on a high purity separation of nucleosides (uridine, guanosine) with an eight-column four-section SMB where the species to be separated are retained on the source 30RPC stationary phase according to a linear isotherm.     

Solvent gradient operation of simulated moving beds. I. Linear isotherms

The simulated moving bed (SMB) is a multi-column chromatographic separation process, which--with respect to the single-column preparative batch process--allows for a continuous separation with larger productivity and smaller solvent consumption at the same time. The benefits of this process have been shown for several different applications in fine chemistry, particularly for the separation of enantiomers. In general, SMBs are operated under isocratic conditions. However, separation performance can be further improved by applying some sort of gradient mode operation, in order to optimize the operating conditions of each individual section of the unit. This can be achieved by tuning the retention behavior of the solutes to be separated along the unit, namely by enforcing weak adsorption conditions in sections 1 and 2, and strong adsorption conditions in sections 3 and 4. This can be achieved by applying a temperature gradient (high temperature in section 1, and low temperature in section 4), a pressure gradient (e.g. in the supercritical SMB, when pressure is high in section 1, and low in section 4), or a solvent gradient, which is the aim of this work. In the solvent gradient mode the mobile phase consists of a mixture of two or more solvents. To different mobile phase compositions corresponds a different retention behavior of the solutes, i.e. different adsorption isotherms. In this work we study a closed loop SMB unit with solvent mixtures of two different compositions entering the unit at the feed and desorbent inlet ports, respectively. Thereby two different mobile phase compositions are established in sections 1 and 2, and sections 3 and 4, respectively. To optimize this process the equilibrium theory design criteria for non-linear SMBs are extended to describe this operation mode. It is shown how the region of separation is derived and how the optimal operating conditions can be found. Finally the solvent gradient mode is compared with the isocratic mode in terms of productivity and solvent consumption.     

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.     

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.     

Optimization of simulated moving bed chromatography with fractionation and feedback: Part I. Fractionation of one outlet

A novel modification of simulated moving bed (SMB) technology, referred to as fractionation and feedback SMB (FF-SMB), has been introduced recently. This concept is based on fractionating one or both outlet streams and feeding the off-spec fractions back into the unit alternatingly with the original feed mixture. In this paper, the optimization problem of FF-SMB realizing one outlet fractionation is considered. A mathematical optimization framework based on a detailed process model is presented which allows to evaluate quantitatively the potential of this operating scheme. Detailed optimization studies have been carried out for a difficult separation characterized by small selectivity and low column efficiency. The results reveal that the proposed fractionation and feedback regime can be significantly superior to the classical SMB chromatography, in terms of both feed throughput and desorbent consumption. The effect of the feeding sequence on the performance of FF-SMB is also examined.     

Partial port-closing strategy for obtaining high throughput or high purities in a four-zone simulated moving bed chromatography for binary separation

The “partial port-closing” operation strategy for a four-zone simulated moving bed (SMB) chromatographic process for binary separation was developed to improve the SMB performance. This strategy included the partial extract-closing (PEC) and the partial raffinate-closing (PRC) operations. In case of the PEC operation, the extract port is made to be closed during the first-half stage of a switching period. During the latter-half stage, the extract port is made to be open. In case of the PRC operation, the raffinate port is made to be open during the first-half stage of a switching period. During the latter-half stage, the raffinate port is made to be closed. If the operating conditions are chosen properly in each operation using a highly efficient optimization tool, the product stream can be collected during only the period that the product is almost separated from impurity. During the other period that the product is contaminated with impurity, the collection of the product stream can be stopped by closing the product port. The uncollected product stream is then allowed to keep migrating through the adjacent zone within the SMB process. Such a partial port-closing operation including PEC and PRC was found to surpass a conventional SMB operation remarkably in throughput and product purity.     

Optimization of azeotropic protein separations in gradient and isocratic ion-exchange simulated moving bed chromatography

The separation of dilute binary mixtures of proteins by salt aided ion-exchange simulated moving bed (SMB) chromatography is optimized with respect to throughput, desorbent consumption and salt consumption. The optimal flow-rate ratios are analytically determined via an adopted "triangle theory". Azeotropic phenomena are included in this procedure. The salt concentrations in the feed and recycled liquid are subsequently determined by numerical optimization. The azeotropic separation of bovine serum albumin and a yeast protein is used to illustrate the procedure. Gradient operation of the SMB is generally preferred over isocratic operation. A feed of azeotropic salt concentration can only be separated in a gradient SMB. Desorbent and salt consumption are always lower in gradient than in isocratic SMB chromatography.     

Extra-column dead volume in simulated moving bed separations: Theory and experiments

In small-scale SMB units typically set up by a number of HPLC columns connected in series, the volume of the connecting tubing parts and valves may become comparable to the column volume. Therefore, to guarantee proper and satisfying separation results, the introduced extra-column dead volume needs to be considered in the calculations of the operating parameters. In this work, the impact of extra-column dead volume on the separation performance is studied, with the objective to introduce guidelines and rather simple rules to account for it. It is shown, how these results can be used in the frame of the triangle theory to determine operating conditions that allow to achieve the desired separation performance. For the experiments the separation of a racemic mixture of (±$\pm$)-3,5-bis[1-(4-methoxyphenyl)-1-methyl]hepta-3,4-diene-1,6-diyne was carried out. The numerical model used for the simulation describes explicitly the geometric configuration of the HPLC–SMB laboratory unit to take into account the effect of extra-column dead volume.     

Experimental implementation of identification-based optimizing control of a simulated moving bed process

Experimental implementation of an optimizing controller based on identified model for the separation of nucleosides in a laboratory scale simulated moving bed (SMB) unit is reported in this study. The manipulative variables are the three external and one internal flow rates while the outputs are productivity, solvent consumption, and purities of extract and raffinate streams averaged over a switching period. The feedback information is the concentration profile of extract and raffinate measured online using two ultraviolet (UV) detectors. Experimental results show that the designed controller is able to operate the SMB units under optimal condition fulfilling the purity requirements. Besides, the controller demonstrated excellent performance in terms of rejecting disturbances that may occur during SMB operations.