Henner Schmidt-Traub

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.

Parameter estimation for the simulation of liquid chromatography

The simulation of preparative or production scale chromatographic processes becomes necessary, as far as not only separation but optimal operation is required. The proposed strategy for modelling and parameter estimation provides a straightforward method for successful imaging of chromatographic processes in computer mathematics as an axial dispersed tubular reactor model with linear diffusion between solid and mobile phase and arbitrary isotherms. Consistent data for parameter estimation are collected from a simple single-column setup. All calculations (parameter estimations and simulations) were performed using the dynamic simulation tool SPEEDUP (Aspen, Cambridge, MA, USA).

Dynamic simulation of simulated moving-bed chromatographic processes for the optimization of chiral separations

Mass separation by simulated moving-bed (SMB) chromatographic processes is influenced by a number of different parameters. Therefore planning and realization of pilot experiments as well as process design and optimization are complicated tasks. Todays new applications of SMB processes in the pharmaceutical, agrochemical and biochemical production have to deal with concentration-dependent capacity and separation factors near unity and have to be operated at high resolution, yield and purity. Therefore rigorous dynamic process modelling combined with a few characteristic experiments to determine the model parameters which describe axial dispersion, multi-component equilibrium with interference of the components and mass transfer resistances has proved necessary. The detailed dynamic model which has been developed is a crucial aid in understanding malfunctions of pilot plants, optimizing process conditions and specifying start-up procedures for SMB processes. This paper presents a first study to verify the rigorous dynamic SMB process model by experimental data of a SMB process. The proposed modelling approach, method of model parameter estimation and process optimization are verified by experimental data of an enantioseparation. The model parameters are estimated by experiments at an analytical HPLC single column and a pilot pulse through the SMB columns. Experimental process data are used to compare the results of process simulations with measured axial concentration profiles.

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.

Dynamic simulation of simulated-moving-bed chromatographic processes

Abstract The Simulated Moving Bed process is a powerful tool for continuous separation of multicomponent mixtures in which the components have different adsorption affinities. It is suitable for a broad range of preparative or production scale applications and allows the separation of components with separation factors near unity with high resolution, yield and purity. Furthermore, the desorbent rates and the amount of adsorbent required by Simulated Moving Bed processes are much lower than those for corresponding batch pocesses. The SMB-process is subject to different parameters specifying plant size, operating conditions and process variables. Precise simulations are therefore necessary for process design and evaluation of experimental results. Different rigorous models which describe the chromatographic process in terms of either moving beds with steady state countercurrent flow or simulated moving beds with periodic fluid port switching have been evaluated. The results demonstrate that because of the real periodic flow SMB-processes must be described by rigorous dynamic models with tubular reactor units and fluid port switching. Axial dispersion and mass transfer resistance have to be taken into account in order to obtain a good agreement with experimental results. The detailed dynamic model which has been developed makes it possible to understand malfunctions of pilot plants, to optimise process conditions and to specify startup procedures for SMB-processes.

DESIGN, OPTIMIZATION, AND OPERATION OF SMB CHROMATOGRAPHY IN THE PRODUCTION OF ENANTIOMERICALLY PURE PHARMACEUTICALS

The utility of simulated moving bed (SMB) chromatography for the preparative chromatographic enantioseparation on chiral stationary phases (CSP) is shown. A design and optimization methodology is proposed and verified with production scale enantioseparations. The study combines two modelling approaches. The equilibrium theory for true countercurrent (TCC) liquid chromatography is used to generate a first set of operating parameters. Afterwards, detailed process optimization is done by systematic simulation studies with the rigorous dynamic SMB process model. Using the preparative enantioseparations of two new drug candidates, EMD 53986 a precursor of a cardiovascular drug and a chroman ester derivative which is a precursor of EMD 128130, the model approaches are verified and compared. The necessity and benefit of careful system design and optimization by detailed process simulation is demonstrated. Chirality 11:440–450, 1999.

Effect of the homogeneity of the column set on the performance of a simulated moving bed unit. II. Experimental study.

Previous studies of the simulated moving bed (SMB) process assume identical characteristics of all the columns incorporated in a given unit. Due to the practical impossibility to manufacture identical columns, numerical applications of the theory to modeling and optimization use for each of the needed column parameter the average value for the entire column set. In this study, the effects of these simplifications on the actual productivity of the SMB process are evaluated by making exact calculations, i.e., by taking the differences in the porosity values into account. We apply a revised set of separation conditions previously introduced and derived from the equilibrium theory. Earlier theoretical results are compared to experimental results obtained in the study of the enantiomeric separation of Trögers base on Chiralpak AD. Due to the nonLangmuirian character of the adsorption isotherms of these two compounds on the packing material used, the separation area cannot be determined analytically. As an alternative, a reliable numerical algorithm was used to scan a wider region and to define the separation area. The form of this area depends on the applied porosity values. A UV detector and a laser polarimeter located at one node of the SMB monitor on-line the internal concentration profiles. Excellent agreement between the calculated and the experimentally determined concentration profiles was obtained under nonlinear conditions. The influence of column-to-column variations on the performance of the SMB process was found to be more significant under nonlinear than under linear conditions.

Dynamic simulation of simulated moving bed chromatographic reactors

The combination of a chemical reaction and a chromatographic separation process in a single unit-operation may improve the course of reaction as well as the separation efficiency. Higher conversions and better yields can be achieved by separating educts and products of an equilibrium reaction from each other. Other fields of application exist for the removal of inhibitors, poisons, or acceptor products to enhance reaction yields. Especially for a continuous process, based on a chromatographic simulated-moving-bed (SMB) unit, reactor design and layout is complicated by the integrated process. Dynamic simulation, however, is a powerful tool to assist reactor layout and optimization. This paper presents different types of chromatographic reactors and a simulation based strategy for the design and optimization of SMB chromatographic reactors. Also, dynamic simulation studies using a rigorous model of the SMB process illustrate the advantages of chromatographic reactors in comparison to conventional processes.

CAPD: computer-aided plant design

Abstract This paper describes the prototype of a concept modelling software. It is used to figure out a good layout of chemical plants and estimates the amount of piping material (material take off, MTO) to be used. The conceived layout is a result of the extended basic engineering and is used as a basis for further detail engineering. The described software creates extended equipment models including equipment related piping and areas for maintenance. It creates simple steel structures with a mouse click or helps to customise more complicated ones. Next, layout modelling by rule based algorithms and force directed placement is employed to receive optimal equipment positions. A routing algorithm connects the equipment according to the “from-to-list” and a MTO can be generated. Finally, some evaluation criteria analyse the results and may show flaws in the layout that shall be solved by the engineer. Since only a minimum effort has to be invested, the software is also suitable to estimate a bid price for an advertised project.

Modelling gradient elution of bioactive multicomponent systems in non-linear ion-exchange chromatography.

A theoretical framework for the ion-exchange behaviour of bioactive substances in non-linear ion-exchange chromatogaphy is described. The aim of the study was the creation of a model basis to support a process design for production-scale ion-exchange chromatography. The theory can be applied to a whole variety of biological substances, such as amino acids, polysaccharides, peptides and proteins and either isocratic or gradient elution can be carried out. The influence of the eluent concentration on the ion-exchange as well as on the characteristic charge was considered. Experimental measurements showed a strong non-linear ion-exchange equilibrium with a transition from a Langmuir-type to a sigmoidal isotherm at higher eluent concentrations. Hereby, the compound binds to the surface though it is not ionic. Therefore, the model considered the possibility of ion-exchange as well as adsorption. A simplified distribution of the counter-ions based on the Gouy-Chapman theory with a discrete distribution of the counter-ions was used. The theory was extended by a selectivity in the double layer to allow specific adsorption. Calculations of adsorption-elution cycles showed, in agreement with the experimental observations, the development of non-linear elution profiles with a desorption fronting. As a result, the column loading and the eluent concentration were varied. The effect of contaminants, in this case sodium ions, was investigated and included in the model. Finally, the model was extended to multicomponent systems to investigate the effect of side components on the retention behaviour. The development of the characteristic elution profiles and the effect of the column loading on the separation are discussed. Calculated concentration profiles along the column at discrete time steps were used to reveal the influence of side components and the underlying separation mechanism. The simulations provided a new insight into the phenomena involved in biochromatography and make convenient design concepts at least doubtful as the separation is in this case mainly determined by the loading step and not by the choice of the elution gradient.