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.     

Step gradients in 3-zone simulated moving bed chromatography. Application to the purification of antibodies and bone morphogenetic protein-2

The simulated moving bed (SMB) technology is a proven tool for efficient separation of binary mixtures. However, relying on isocratic conditions limits the applicability of the classical SMB approach when considering the field of bioseparations. Here, the use of gradients opens up new possibilities. A gradient in a SMB process can be established by using different solvent strengths in the incoming feed and desorbent streams, resulting in two internal plateaus of elution strength. Thus, compared to the conventional process, the overall amount of solvent needed can be reduced, productivity can be increased and more concentrated product streams can be obtained. In this contribution, two case studies will be presented. At first, the separation of bovine IgG from lysozyme will be analyzed as a model system. Antibodies are a common target substance in bio-chromatography, as therapeutic monoclonal antibodies are among the most promising biopharmaceuticals. Using adsorption data obtained from single-column experiments, an appropriate SMB process was designed and implemented. The second target component is the active dimeric form of the bone morphogenetic protein-2 (BMP-2). This protein was isolated from a renaturation solution, which also contained its inactive monomeric form as well as other undefined proteins from the bacterial production strain. A 3-zone open-loop gradient-SMB approach was used successfully for both separations.     

Linear two-step gradient counter-current chromatography analysis based on a recursive solution of an equilibrium stage model

The implementation of gradients in continuously operated chromatographic counter-current processes has recently attracted considerable interest as a method to improve the performance of this effective separation method. If liquid mobile phases are applied it is advantageous to set the solvent strength in the desorbent stream higher than that in the feed stream. As a consequence. the components to be separated are more retained in the adsorption zones and more easily eluted in the desorption zones. Due to the additional degrees of freedom the design and the optimization of such a two-step gradient counter-current process is difficult. In this paper a steady state equilibrium stage model is used to simulate the process under linear conditions. A simple solution of the underlying model equations is presented capable to describe efficiently the unit for large stage numbers typically encountered in chromatographic columns. Due to the rapidity of the algorithm developed a broad range of operating conditions can be evaluated systematically for different types of gradients. The impact of (a) the functional dependence of the adsorption equilibrium constants on the solvent composition, (b) the number of equilibrium stages and (c) the specification of purity requirements is illustrated and discussed based on results of parametric calculations. The results achieved emphasize the potential of two-step gradient counter-current chromatography.     

Simulated moving bed process with cyclic modulation of the feed concentration

The improvement of the simulated moving bed (SMB) process based on the introduction of a cyclic modulation of the feed concentration is described. It is demonstrated that such a feed concentration gradient during the shifting cycle can improve the performance significantly. The productivity and the product concentrations can be increased while simultaneously the solvent consumption can be decreased compared to the conventional SMB process with constant feed parameters.     

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.     

Optimized design of recycle chromatography to isolate intermediate retained solutes in ternary mixtures: Langmuir isotherm systems

Batch chromatography with a recycle stream is a popular and simple technique to separate a single target component in a complex mixture with moderate operating conditions. Design of recycle chromatography depends on the retention behaviors of the mixture components. In this work, four nucleosides were considered as solutes. Feed concentration and recycle methods were optimized to isolate only the intermediate retained solute in ternary and pseudo-ternary mixtures. Two recycle methods introduced in our previous work for linear isotherms, the desorbent and feed recycle methods, were compared in terms of productivity and desorbent to feed ratio, D/F, with various feed concentrations for competitive Langmuir isotherm systems. The simulation results show that the target (intermediate retained solute) was separated with over 99.76% purity and 99.88% yield. Productivity of the feed recycle method was increased by up to 162% and D/F was decreased by up to 59% compared to the desorbent recycle method. For the separation of nucleosides, recycle chromatography was compared to eight column simulated moving bed (SMB) cascades with a recycle stream and D/F of the SMB cascades was 58% lower than D/F of recycle chromatography at the same productivity. However, recycle chromatography is much simpler.     

Optimization of throughput and desorbent consumption in simulated moving-bed chromatography for paclitaxel purification.

In simulated moving-bed (SMB) applications, throughput and desorbent consumption are two key factors that control process cost. For a given adsorbent volume and product purity requirements, throughput and desorbent consumption depend on desorbent composition, column configuration, column length to diameter ratio, and adsorbent particle size. In this study, these design parameters are systematically examined for paclitaxel purification. The results show that if adsorbent particle size, column dimensions and column configuration are fixed, the higher the product purity required, the lower the throughput. If product purity and yield are fixed, the larger the solute migration speed ratio, the higher the throughput, and the lower the desorbent consumption. If total bed volume and product purities are fixed, the longer the separation zones, the higher the throughput, but the higher the desorbent flow-rate. An intermediate configuration gives the minimum desorbent consumption. If there are no limits on pressure drop or zone flow-rate, the larger the column length to diameter ratio, the smaller the adsorbent particle size, the higher the throughput, and the lower the desorbent consumption. If the maximum zone flow-rate is controlled by the pressure drop limit and not by the standing waves requirement, the longer the columns, the lower the zone flow-rates and the lower the throughput. For 150 microns adsorbent particles and a maximum zone flow-rate of 300 ml/min, a design with optimal throughput and desorbent consumption is found for paclitaxel purification.     

Effect of salt gradients on the separation of dilute mixtures of proteins by ion-exchange in simulated moving beds

Salt gradients can improve the efficiency during fractionation of proteins by ion-exchange in simulated moving beds (SMBs). The gradients are formed using feed and desorbent solutions of different salt concentrations. The thus introduced regions of high and low affinity may reduce eluent consumption and resin inventory compared to isocratic SMB systems. This paper describes a procedure for the selection of the flow-rate ratios that enables successful fractionation of a dilute binary mixture of proteins in a salt gradient. The procedure is based on the so-called "triangle theory" and can be used both for upward gradients (where salt is predominantly transported by the liquid) and downward gradients (where salt is predominantly transported by the sorbent). The procedure is verified by experiments.     

Novel simulated moving-bed method for reduced solvent consumption

Simulated moving-bed (SMB) chromatography is attractive for reducing sorbent and solvent consumption relative to fixed-bed systems. In this contribution, we describe a novel and versatile method for further reducing solvent consumption in the case of reversed-phase chromatography. The method is based on the variation of the distribution coefficients of solutes to be separated upon varying the composition of a multi-component mobile phase. If the solvent strength of the desorbent is set higher than the solvent strength of the feed, the components will have smaller distribution coefficients in the extraction section of the SMB and hence will be more easily eluted. This will result in a lower desorbent flow and possibly also in a shorter desorbent zone, and, ultimately, in more concentrated products. The so-called "Triangle-method" by Storti et al. [AIChE J., 39 (1993) 471] to obtain the region of complete separation, is extended for this novel SMB method. Theoretical evaluation of the proposed methodology supports the anticipated solvent reduction relative to fixed-bed RP-HPLC for the cases of the purification of the polyketide antibiotic nystatin and the separation of bovine insulin from porcine insulin.     

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.     

Optimization of simulated moving bed plants with low efficient stationary phases: separation of fructose and glucose

An optimization procedure for simulated moving bed (SMB) plants with low efficient stationary phases is presented. The new aspect is that the desorbent consumption can be cut by 70% by running the plant with lower internal liquid flows and a corresponding larger switch time while the productivity is kept constant. This concept was validated by the separation of fructose and glucose in water on a calcium resin with an eight-column SMB plant. The separation can be predicted well by a true moving bed (TMB) and a simulated moving bed simulation. Adsorption isotherms were determined up to 300 kg/m3 for glucose and 500 kg/m3 for fructose from 25 to 80 degrees C. Experimental SMB runs were performed over a wide range of feed concentrations (10-350 kg/m3) and temperatures (25-80 degrees C). The strong influence of the delay volume is pointed out. For an experimental run with high feed concentration a complete set of data is presented. To reduce biological growth separation at 80 degrees C is recommended.     

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.     

Bi-level optimizing control of a simulated moving bed process with nonlinear adsorption isotherms

A bi-level optimizing control scheme originally proposed for a simulated moving bed (SMB) with linear isotherms has been extended to an SMB with nonlinear isotherms. Cyclic steady state optimization is performed in the upper level to determine the optimum switching period and time-varying feed/desorbent flow rates, and repetitive model predictive control is run in the lower level for purity regulation, taking the decision variables from the upper level as feed-forward information. Experimental as well as numerical study for an SMB process separating a high-concentration mixture of aqueous L-ribose and L-arabinose solutions showed that the proposed scheme performs satisfactorily against various disturbances. In contrast, an alternative scheme based on an SMB model with linear isotherms showed a limitation in the control performance; this scheme was apt to fail in purity regulation.     

Continuous voltage gradients and their application to true moving bed electrophoresis

Gradient elution has been practiced in chromatographic separations for many years. The application of discontinuous "step" gradients in simulated moving bed (SMB) chromatography has been very successful in increasing both processing rates and column productivity, resulting in a reduction in the number of SMB columns required. With the advent of the field gradient focusing techniques, electrophoresis has gained the ability to apply a continuous electric field gradient to a true moving bed (TMB) electrophoretic separation. Application of a spatial gradient allows a large degree of control of the product concentrations inside the separation unit as well as a large increase in product throughput. A model of moving bed electrophoretic separations has been developed that demonstrates the potential advantages of applying a continuous gradient to the moving bed process. These advantages include the reduction of detrimental peak tailing and the ability to decrease the concentrations of the compounds being separated in comparison with commonly used step gradient elution.     

Optimizing the separation of gaseous enantiomers by simulated moving bed and pressure swing adsorption

The resolution of racemic gas mixtures by simulated moving bed (SMB) and pressure swing adsorption (PSA) is investigated by dynamic simulation and optimization. Enantiomer separation of inhalation anesthetics is important because there is evidence that the purified enantiomers may have different pharmacological properties than the racemate. The model parameters reported in an experimental investigation performed elsewhere are used to study the feasibility of this separation using SMB and PSA configurations. Both processes were modeled in gPROMS^® as systems of differential algebraic equations. Operating conditions are optimized such that the feed throughput and product recovery for each process were maximized subject to equal constraints on the pressures and superficial gas velocities. SMB was found to be capable of resolving racemic feed mixtures with purity and recovery exceeding 99%. On the other hand, PSA was also able to provide a single purified enantiomer with low recovery of about 30% which may limit its application to enantiomer separation. Nevertheless, PSA consumes less desorbent, and achieves higher throughput at the sacrifice of lower recovery.     

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.     

Application of equilibrium theory to ternary moving bed configurations (four+four, five+four, eight and nine zones) I. Linear case

In this article, different ternary moving bed configurations are studied by determining the working flow-rates of the equivalent true moving bed at the low solvent consumption point using equilibrium theory. This method has been applied for linear adsorption isotherms. The simulated moving bed flow-rates can then be calculated and a final comparison between the performances of each process is given based upon two different objective functions.     

Theoretical study of multicomponent continuous countercurrent chromatography based on connected 4-zone units

Continuous countercurrent or simulated moving bed (SMB) chromatography is a well-established separation technology. Conventional processes are based on four zones which fulfil distinct functions in order to split a feed into two fractions. Frequently there is an interest in isolating a target component out of a feed mixture containing more than two components. Modifications of the classical SMB process are required to solve this task. In the last years several concepts exploiting more than four zones have been suggested. To analyse these concepts the equilibrium theory has been frequently applied, neglecting all kinetic effects. It is the purpose of this paper to apply an equilibrium stage model in order to describe the performance of a combination of two or three 4-zone true moving bed units which are connected in series or integrated into 8- or 12-zone true moving bed units. The performance of such units is evaluated with respect to their potential to continuously separate ternary or quaternary mixtures. The analysis is based on the assumption of linear adsorption isotherms. An important aspect is the introduction of additional purge streams required for a successful operation of integrated 8- and 12-zone units.     

Gas phase SMB for propane/propylene separation using enhanced 13X zeolite beads

A gas phase simulated moving bed technology using improved 13X zeolite beads and isobutane as desorbent is assessed for the separation of propane/propylene. Adsorption equilibrium (via gravimetric method) and dynamics (via breakthrough curves) were determined in order to validate the mathematical model used to describe the adsorption process. Simulation results have shown that it is possible to separate propylene from a mixture with propane using gas phase SMB technology. The results indicate that high purity propylene (99.99 % desorbent free basis) can be recovered up to 99.96 % with a productivity of 17.6 mol kg^?1 h^?1, with propane being also recovered at high levels (99.98 %) and high purity (99.89 % desorbent free basis). Comparing the SMB simulation results obtained for this new 13X zeolite beads with those obtained with a commercial 13X zeolite characterized elsewhere, it was found that the productivity of the process was raised by 25 %, with half desorbent consumption.     

A novel pseudo simulated moving bed with solvent gradient for ternary separations

A novel pseudo simulated moving bed was suggested to separate a ternary mixture. A solvent gradient was created to make the solvent strength decreasing from zone II to zone III. Under suitable conditions, the least retained solute A moved forward and the most retained solute C moved backward in zones II and III whereas the medium retained solute B moved forward in zone II but backward in zone III to be trapped in the two zones consequently. Once the columns in zones II and III were saturated with solute B, the solvent dissolving the feed was introduced at the feed port to remove solute A from the raffinate-port and solute C from the extract-port. Finally, solute B was recovered from the extract port by stopping the liquid flow in zone II. This scheme was validated by the successful separation of dihydrocapsaicin from capsaicinoids.