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Simulated Moving Bed Chromatography- An advanced chromatography technique

Chromatography Technology


Chromatographic processes play an important role in the production of bio-pharmaceuticals. Polypeptides, proteins, enzymes and antibodies are captured, purified and polished by ion exchange, size exclusion, reverse phase, hydrophobic interaction or affinity chromatographic processes. Their scales range from a few kilograms a year of very potent compounds to large bulk productions of several tons. Only recently research groups primarily from academics have started to investigate continuous operating technologies such as simulated moving bed chromatography (SMB) to increase productivity of purification processes for bio-pharmaceuticals which is based on counter-current moving bed chromatography. This technology has been used in large scale operations in the petrochemical and sugar industries for almost half a century. This article will addresses the fundamentals of simulated moving bed chromatography technology and its applications. 


In the last decade the concept of simulated moving bed (SMB) chromatography has been successfully applied in several fields, e.g. for the separation of enantiomers and purification of pharmaceutical proteins. In order to further increase potential of SMB chromatography, several increasingly sophisticated modes of operation have been developed based on applying gradients and on dynamically varying certain parameters during the separation. Examples include new process variants VariCol, PowerFeed and ModiCon. Another alternative capable to enhance the process performance is based on the introduction of an enrichment step between zones I and II.

The process was developed in the 1960s for the purification of sugars from molasses. It was used to pharmaceutical industry for the purification of enantiomers from racemic mixtures. Its applications have expanded beyond the sugar and racemic separations to more complex separations.

SMB chromatography has received attention for chiral separations since early 1990s and is today, considered as a cost-effective preparative scale purification technology and common to tool for separating isomers at production scale, and several active pharmaceutical ingredient (API) and intermediate producers. The design method was verified with rate model simulations and then tested for enantioseparation of phenylpropanolamine. Both high purity (>99 per cent) and high yield (>99 per cent) were achieved experimentally using an SMB with a pressure limit of 2.4 MPa. It enables substance mixtures to be continuously separated and extracted in two fractions. By repeated use of the SMB process each partial fraction can be separated into a further fraction-up to binary substance mixtures. Typically, the SMB process is set up in advance for a two component mixture. Following this, both substances can be immediately extracted in pure form-up to 1000 kg per year.

It is a continuous multi-column chromatographic process has become one of the preferred techniques for the separation of the enantiomers of a chiral compound. Several active pharmaceutical ingredients, including blockbuster drugs, are manufactured using the SMB technology. Compared to single column preparative chromatography, SMB separations achieve higher productivity and purity, while reducing the solvent consumption. In the last few years, rapid developments have been made in the areas of design, improved process schemes, optimization and robust control.


Fig. 1) General setup of the SMB unit

Simulated Moving Bed Chromatography is a continuous purification technique that has higher throughput and requires less solvent than regular batch chromatography. It is used to separate particles and/or chemical compounds that would be difficult separation problems in petrochemical, fine chemical and pharmaceutical industries. The SMB process employs a series connection of several chromatographic columns.

It permits large amounts of mobile phase to be saved and productivity increased, thus reducing production costs. Its advantages such as reduction of solvent consumption, high productivity and final purities as well as low investment costs in comparison to eluent chromatography. Simulated Moving Bed Chromatography units can operate under high productivity overloaded conditions.

Application Areas

Range of Application Separation & Extraction of
Pharmaceutical Chemistry Chiral compounds [Ex: Cis-Trans Phytol, Steroids, Peptides, and Antibiotics]
Food Chemistry  Fatty acids; Carbohydrate mixture (Ex: Sucrose/Molasses or Fructose/Glucose]
Biochemistry Citric acid; Phenylalanine
Petro chemistry C8-Hydrocarbon [Ex: Xylene; Toluene]

Principle and Method

1. Determine the phase volume ratio or porosity between the stationary and mobile phase.

2. Determine the adsorption isotherms for each component based on the overload chromatogram from each component of the mixture.

3. Determine the isotherm parameters using the isothermFit software.

4. Arrange the hardware.

5. Simulation of the process and optimization of the interpretation using the SMB_Guide simulation    software.

6. Carry out a continuous SMB separation.

7. Optimize the productivity.

Fig. 2) Basic schematic diagram of SMB

Simulated Moving Bed Chromatography is a chromatographic technique based on a flow of liquid (mobile phase) moving countercurrent to a constant flow of solid (stationary phase). Countercurrent flow enhances the potential for the separation and, hence, makes the process more efficient. It also allows a continuous flow of feed material to be separated, which improves the throughput of the equipment compared to traditional batch chromatography.

Providing a constant flow of solid is impractical in a production process. Therefore, the solid instead is packed into high pressure columns. These columns are arranged in a ring formation made up of four sections with one or more columns per section. Two inlet streams (feed and eluent) and two outlets streams (extract and raffinate) are directed in alternating order to and from the column ring. The inlet and outlet position is switched at regular time intervals in the direction of the liquid flow, thus simulating countercurrent movement of columns.

Fig. 3) Columns arrangement

The flow rates in Sections II and III are important because this is where the separation occurs. Sections I and IV handle cleaning. Mobile phase exiting Section IV is directly recycled to section I. The solid is regenerated there by desorbing the more retained compound with a high flow rate so the complete column can be moved into section IV.


  • The entire stationary phase is continuously covered with the mixture to be separated which produces a much higher productivity.

  • A 90 per cent reduction in the demand for solvent due to solvent recycling

  • High plate counts or particle sizes are no longer required, reducing packing material costs by 80 per cent.
  • Extract and raffinate are extracted in high concentration which makes it easier to remove solvent.
  • The patented multi-function valve enables and extremely small dead volume.


 Simulated Moving Bed Chromatography is ideal for the separation of

  • Enantiomers,
  • Diastereoismers,
  • Purification of proteins, pharmaceuticals, fine chemicals and
  • It can provide high purity and high recovery in a very short time.
  • Drugs like Prozac; Citalopram etc., can be purified.


The major challenges of the SMB process principle are:

  • Higher investment cost compared to single column operations
  • A higher complexity
  • As well as higher maintenance costs.



Since last 40 years, SMB chromatography has been used successfully on a large scale in the petrochemical industry. More recently, the high potential of SMB-approach has also been recognized by the fine chemistry and pharmaceutical industries. Applications in the biotechnology field are increasing, where an SMB can be used for many different products and applications such as: proteins, isomers, chiral compounds or in desalting/polishing steps.

Previously designed for large scale production processes (100,000 tonne/year), nowadays, SMB is also operated on a comparatively small scale for production processes involving less than 1 kg/run. Presently, some of the technology advancements in chromatography, which are in the R&D phase, can help improve performance of SMB. In the future, these technology developments will overcome some of the challenges of the SMB approach making it more efficient and effective, for various industries

Fig. 4) SMB application industries


[1] Dr. Kathleen Mihlbachler, Ph.D., Eli Lilly and Company, Advances in Large-Scale Biopharmaceutical Manufacturing and Scale-Up Production, Available from -

[2] Arvind Rajendranb, Galatea Paredesa, Marco Mazzotti, Simulated moving bed chromatography for the separation of enantiomers, Volume 1216, Issue 4, 23 January 2009, Pages 709-738, Available from

[3 Separations Analytical Instruments bv website,

Image Reference

Fig. 1): M. A. G. Santos; V. Veredas; I. J. Silva Jr.; C. R. D. Correia; L. T. Furlan; C. C. Santana, Simulated moving-bed adsorption for separation of racemic mixtures, Available from-

Fig. 2): Malte Kaspereit, Achim Kienle, Design of Simulated Moving Bed Chromatography, Available from-

Fig. 3): Kathleen Mihlbachler, Eli Lilly and Company, and Olivier Dapremont, Aerojet Fine Chemicals, Simulated Moving Bed Chromatography Offers Real Attractions, Available from

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