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.     

Intermittent simulated moving bed chromatography: 3. Separation of Tröger's base enantiomers under nonlinear conditions

One of the modified simulated moving bed (SMB) processes, the intermittent SMB (I-SMB) process, has been recently analyzed theoretically [1] and its superior performance compared to the conventional SMB process has been demonstrated at a rather low total feed concentration through experiments and simulations [2]. This work shows that the I-SMB process outperforms the conventional SMB process also at high feed concentration where the species are clearly subject to a nonlinear adsorption isotherm. In the case of the separation of the Tröger's base's enantiomers in ethanol on ChiralPak AD, the two processes operated in a six-column 1-2-2-1 configuration (one column in sections 1 and 4 and two columns in sections 2 and 3) and in a four-column 1-1-1-1 configuration (one column in each section) are compared at high feed concentration through both experiments and simulations. Even under nonlinear conditions the four column I-SMB process can successfully separate the two enantiomers achieving purity levels as high as the two six column processes and exhibiting better productivity.     

Intermittent simulated moving bed chromatography: 1. Design criteria and cyclic steady-state

The intermittent SMB (I-SMB) process is a multi-column chromatographic process, which is a modification of the conventional SMB process, has been applied so far only in the sugar industry and is claimed to achieve higher productivity. In the I-SMB process the time interval between two port switches is divided in two sub-intervals, and only during the first the product streams are collected. The potential of the I-SMB technology is demonstrated in the case of the separation of a binary mixture subject to the linear isotherm by using both the equilibrium theory of chromatography and detailed simulations. It is shown that a I-SMB with only four columns can achieve much higher separation performance than a SMB unit with four columns.     

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.     

Model-based design of a pilot-scale simulated moving bed for purification of citric acid from fermentation broth

One of the conventional processes used for the recovery of citric acid from its fermentation broth is environmentally harmful and cost intensive. In this work an innovative benign process, which comprises simulated moving bed (SMB) technology and use of a tailor-made tertiary poly(4-vinylpyridine) (PVP) resin as a stationary phase is proposed. This paper focuses on a model-based design of the operation conditions for an existing pilot-scale SMB plant. The SMB unit is modeled on the basis of experimentally determined hydrodynamics, thermodynamics and mass transfer characteristics in a single chromatographic column. Three mathematical models are applied and validated for the prediction of the experimentally attained breakthrough and elution profiles of citric acid and the main impurity component (glucose). The transport dispersive model was selected for the SMB simulation and design studies, since it gives a satisfactory prediction of the elution profiles within acceptable computational time. The equivalent true moving bed (TMB) and SMB models give a good prediction of the experimentally attained SMB separation performances, obtained with a real clarified and concentrated fermentation broth as a feed mixture. The SMB separation requirements are set to at least 99.8% citric acid purity and 90% citric acid recovery in the extract stream. The complete regeneration in sections 1 and 4 is unnecessary. Therefore the net flow rates in all four SMB sections have been considered in the unit design. The influences of the operating conditions (the flow rate in each section, switching time and unit configuration) on the SMB performances were investigated systematically. The resulting SMB design provides 99.8% citric acid purity and 97.2% citric acid recovery in the extract. In addition the citric acid concentration in the extract is a half of its concentration in the pretreated fermentation broth (feed).     

Effect of mobile phase composition on the SMB processes efficiency. Stochastic optimization of isocratic and gradient operation

The solvent composition was adjusted in a theoretical study in order to maximize the efficiency of a simulated moving bed (SMB) process. The isocratic realization of the process as well as the solvent gradient mode were considered. The solvent composition and the flow rates were used as decision variables in a random search optimization algorithm known to be a reliable tool for nonlinear programming problems. The results of the optimization indicate that the optimal composition of the mobile phase depends strongly on the feed concentration. The asymmetry of the internal concentration profiles, which has a negative effect on the separation efficiency, can be partly damped by an increase of the solvent strength. In the cases studied the optimal solvent strength determined for concentrated feed streams is higher than that for diluted ones. Moreover, the optimum is strongly influenced by the value of the selectivity factor and its dependency on the mobile phase composition. Different results were obtained for cases, in which the separation factor increases with increasing the modifier concentration, than for cases, in which the separation factor decreases with increasing the modifier concentration. A similar analysis was performed for a solvent gradient SMB process, in which different solvents are used at the two inlet ports: a weak solvent in the feed stream and a strong solvent in the desorbent stream. Again the optimal mobile phase composition was strongly affected by the type of the isotherms and their non-linearity. The potential of a gradient SMB process in terms of increasing the productivity and reducing the eluent consumption is exemplified.     

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.     

模拟移动床色谱法拆分甲霜灵对映体

模拟移动床(SMB)色谱作为一种精确、高效的制备色谱技术引起研究者的极大关注。本文以EnantioPak OD填料为手性固定相,正己烷-乙醇(70 : 30, v/v)为流动相,在四区模拟移动床上手性拆分甲霜灵外消旋体。采用旋光检测器研究甲霜灵异构体在手性柱上的洗脱顺序;探讨进样浓度、进样流速、各区流速和切换时间等条件对手性分离甲霜灵外消旋体的影响,并与制备色谱进行比较。结果表明:S-(+)-甲霜灵先于R-(-)-甲霜灵被流动相洗脱,R-(-)-甲霜灵在色谱柱上的保留强于S-(+)-甲霜灵;在线性和非线性条件下,模拟移动床都能很好地拆分甲霜灵外消旋体,在优化SMB工艺条件下,S-(+)-甲霜灵和R-(-)-甲霜灵的光学纯度都大于99%;在样品质量浓度为15 mg/mL的条件下,模拟移动床色谱分离的样品量显著高于制备色谱,而流动相消耗仅为后者的1/9。这对于发展大规模色谱拆分甲霜灵工艺具有良好的指导意义。     

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.     

Recombinant protein purification using gradient assisted simulated moving bed hydrophobic interaction chromatography. Part II: process design and experimental validation

In the first part of this work adsorption isotherm parameters were acquired to describe the migration of recombinant streptokinase in Butyl Sepharose columns at different salt concentrations. Based on these results, a simulated moving bed (SMB) chromatographic process was designed and realised, which exploits a two-step salt gradient and allows the continuous separation of streptokinase from contaminants present in a clarified Escherichia coli cell lysate solution. This second part describes the design of the three-zone open-loop gradient SMB process applying both equilibrium theory and an equilibrium stage model and presents results of a series of experiments aiming to obtain pure streptokinase. Moreover, the potential of the SMB process and the design approach are evaluated.     

Characterization of some physical and chromatographic properties of monolithic poly(styrene-co-divinylbenzene) columns

Monolithic capillary columns were prepared by copolymerization of styrene and divinylbenzene inside a 200 microm i.d. fused silica capillary using a mixture of tetrahydrofuran and decanol as porogen. Important chromatographic features of the synthesized columns were characterized and critically compared to the properties of columns packed with micropellicular, octadecylated poly(styrene-co-divinylbenzene) (PS-DVB-C18) particles. The permeability of a 60 mm long monolithic column was slightly higher than that of an equally dimensioned column packed with PS-DVB-C18 beads and was invariant up to at least 250 bar column inlet pressure, indicating the high-pressure stability of the monolithic columns. Interestingly, monolithic columns showed a 3.6 times better separation efficiency for oligonucleotides than granular columns. To study differences of the molecular diffusion processes between granular and monolithic columns, Van Deemter plots were measured. Due to the favorable pore structure of monolithic columns all kind of diffusional band broadening was reduced two to five times. Using inverse size-exclusion chromatography a total porosity of 70% was determined, which consisted of internodule porosity (20%) and internal porosity (50%). The observed fast mass transfer and the resulting high separation efficiency suggested that the surface of the monolithic stationary phase is rather rough and does not feature real pores accessible to macromolecular analytes such as polypeptides or oligonucleotides. The maximum analytical loading capacity of monolithic columns for oligonucleotides was found to be in the region of 500 fmol, which compared well to the loading capacity of the granular columns. Batch-to-batch reproducibility proved to be better with granular stationary phases compared to monolithic stationary phase, in which each column bed is the result of a unique column preparation process.     

Implementation of an automated on-line high-performance liquid chromatography monitoring system for ‘cycle to cycle’ control of simulated moving beds

In continuous chromatography simulated moving bed (SMB) is a firmly established powerful technique for the separation of fine chemicals and enantiomers. The use of a controller could improve the operation conditions and increase the productivity of an SMB unit. However, the performance of any controller is greatly affected by the reliability and the quality of the feedback information from the plant. Therefore, to overcome the limitations of optical detectors, such as UV and polarimeter, an automated on-line HPLC monitoring system was developed and installed to monitor the product streams. The performance of the system is tested experimentally separating a mixture of guaifenesin enantiomers on Chiralcel OD columns with ethanol as mobile phase in our laboratory SMB unit under both linear and nonlinear chromatographic conditions. The results show that the new monitoring system provides precise and accurate data about the concentration of the components in the two product streams. Moreover, they prove that despite disturbances a combination of the controller and the new on-line monitoring system allows to fulfill the product specifications and to improve the performance of the process in terms of feed throughput and solvent consumption.     

Two-step solvent gradients in simulated moving bed chromatography. Numerical study for linear equilibria

The application of gradients in simulated moving bed (SMB) chromatography has recently attracted interest as a method for further improving the performance of this continuous separation process. One possible implementation of gradients consists in setting the solvent strength in the desorbent stream higher than that in the feed stream. As a result, the components to be separated are more retained in the zones upstream of the feed position and more easily eluted in the zones downstream of the feed position. If a liquid mobile phase is used, gradients can be created by dosing different solvents into the feed and desorbent ports. In a closed-loop gradient SMB arrangement the solvent strength within the unit will depend on the two feed compositions and on the characteristic flow-rates of the process. In this work an equilibrium stage model describing a true moving bed process is used to analyze numerically the main features of a two-step gradient SMB process. The adsorption isotherms are assumed to be always linear under isocratic conditions. The relevant Henry constants depend in a nonlinear manner on the composition of the solvent. Based on numerical simulations the impact of the two inlet solvent compositions is demonstrated in terms of the size and shape of regions of applicable flow-rates. Different strategies of designing the process are discussed and compared with respect to maximizing productivities and minimizing desorbent requirements.     

Selectivity differences for C18 and C8 reversed-phase columns as a function of temperature and gradient steepness. II. Minimizing column reproducibility problems

The choice of T and tG as variables for controlling selectivity and resolution during reversed-phase liquid chromatography (RPLC) method development can be used to minimize problems caused by column batch-to-batch irreproducibility. When a new column fails to provide adequate separation of the sample, altered values of T and tG can be predicted that will restore the separation obtained with the previous column. Alternatively, columns from different manufacturers can be tested during method development, in order to find a common set of conditions (T and tG) that provide acceptable separation with two or more of these columns. In this way, any of several columns from different sources become usable for the method. Examples are shown of these different computer-assisted procedures for minimizing problems due to column variability.     

Twin column chromatography for industrial-scale decontamination processes

A frontal chromatographic unit was devised consisting of a column-detector-column array. The unit is either equipped with identical columns (identical twins) or with columns of varying length (fraternal twins). Due to the finite nature of the columns, a prerun is formed at the column walls following the same regularities as the main stream. These regularities are used for the identification of the process termination below the detection limits of the monitor. For the implementation, a clear preference is given to the employment of fraternal twins, as the feed assay can be integrated into the separation process.     

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.     

Optimization of simulated moving bed and column chromatography for a plasmid DNA purification step and for a chiral separation

This work analyzes the performance of the SMB and the column chromatography processes for two different case studies: the first stage of the plasmid DNA (pDNA) polishing, and the Tr?ger's base enantiomer separation, in which the adsorption isotherms are linear and non-linear, respectively. Simulation tools are used together with an optimization routine (Non-Sorting Genetic Algorithm (NSGA)) in order to find the optimum operating conditions leading to maximum productivity and minimum solvent consumption; the optimum solution for each of the processes is a curve on the productivity-solvent consumption plane, the so-called Pareto set. The comparison between the column and the SMB processes is based on the relative position of the two Pareto sets calculated at equal conditions and for the same final purity and recovery of the target species. The results show that SMB is superior to column chromatography in the two case studies investigated, i.e. in the case of the linear isotherm (pDNA), the productivity gain is up to a factor two for a given value of the solvent consumption. Furthermore, the flexibility of the SMB operation is larger, since the Pareto sets are flatter and they prolong into regions of the productivity-solvent consumption plane that are not accessible with the column chromatography process.     

Intermittent simulated moving bed chromatography: 2. Separation of Tröger’s base enantiomers

The intermittent simulated moving bed (I-SMB) process is a modification of the conventional SMB process that has been recently analyzed theoretically [1]. Here, we present a comparative analysis of the two processes, each operated in a six column 1-2-2-1 configuration (one column in sections 1 and 4 and two columns in sections 2 and 3) and in a four-column 1-1-1-1 configuration. Experiments are carried out on a properly modified laboratory unit to separate racemic mixtures of the enantiomers of Tröger’s base in ethanol on ChiralPak AD at a total feed concentration of 1 g/L. Simulations are carried out for the same system using the equilibrium dispersive model and a bi-Langmuir isotherm, whose parameters have been preliminarily estimated from pulse and breakthrough experiments. Experiments and simulations are fully consistent and demonstrate that the four-column I-SMB process (but not the four-column SMB process) can separate the two enantiomers at very high purity and achieve a productivity twice as large as that of the six-column I-SMB and conventional SMB processes with the same solvent consumption.     

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.