1. Simulated Moving Bed Chromatography Chemistry 230 Chemical Separations Presented by Brenden Jiang and Leonard Bellini

2. Overview  Introduction  Theory  Background  Advantages  Disadvantages  Applications  Conclusion  Questions

3. Introduction  Simulated Moving Bed Chromatography is a variant of Liquid Chromatography and based on a True Moving Bed model.  Initially developed to separate petrochemicals when conventional methods failed (e.g. distillation)  In the 1990’s SMB used for enantiomer and chiral separations.  Now often used for separating chiral compounds in pharmaceutical manufacturing. 1,2

4. Theory  True Moving Bed Chromatography  Chromatographic resin circulating in one direction.  Continuous flow of eluent in opposite direction inside the loop Chromatographic resin Mobile Phase 1,2

5. Theory Binary mixture added continuously. Raffinate: Poorly absorbed compounds move with mobile phase. Can be removed down stream. Eluent is fed continuously. Extractant: More absorbed compounds move with “stationary phase”. Can be removed up stream. 1,2

6. Theory  Techniques that employ moving the stationary phase in the column are known as True Moving Bed (TBM) Chromatography.  TMB methods has been used for over 50 years. First suggested by Oil Product Company in 1960’s.  Some methods developed using GC.  Difficulty in moving stationary phase of HPLC columns, which as giving rise to the use of simulated moving bed (SMB) chromatography. 1,2,5

7. Background: Simulated Moving Bed Infeed A+B Extract ARaffinate B Solvent Feed  SMB have conventional fixed bed chromatographic columns  Inlet and outlet ports are switched periodically in the direction of the fluid flow  This simulates the countercurrent movement of the solid phase in the TMB process  Pure components can be obtained at the exit ports. Direction of Flow and Port Switching 1,2

8. Background: Simulated Moving Bed Infeed A+BExtract A Raffinate B Solvent Feed  SMB have conventional fixed bed chromatographic columns  Inlet and outlet ports are switched periodically in the direction of the fluid flow  This simulates the countercurrent movement of the solid phase in the TMB process  Pure components can be obtained at the exit ports. Direction of Flow and Port Switching 1,2

9. Background: Simulated Moving Bed Infeed A+B Extract A Raffinate B Solvent Feed  SMB have conventional fixed bed chromatographic columns  Inlet and outlet ports are switched periodically in the direction of the fluid flow  This simulates the countercurrent movement of the solid phase in the TMB process  Pure components can be obtained at the exit ports. Direction of Flow and Port Switching 1,2

10. Background: Simulated Moving Bed Infeed A+B Extract A Raffinate B Solvent Feed  SMB have conventional fixed bed chromatographic columns  Inlet and outlet ports are switched periodically in the direction of the fluid flow  This simulates the countercurrent movement of the solid phase in the TMB process  Pure components can be obtained at the exit ports. Direction of Flow and Port Switching 1,2

11. Background: Simulated Moving Bed Infeed A+B Extract ARaffinate B Solvent Feed  SMB have conventional fixed bed chromatographic columns  Inlet and outlet ports are switched periodically in the direction of the fluid flow  This simulates the countercurrent movement of the solid phase in the TMB process  Pure components can be obtained at the exit ports. Direction of Flow and Port Switching 1,2

12. Background: Simulated Moving Bed Solvent Feed Extract A Raffinate B Infeed A+B  SMB have conventional fixed bed chromatographic columns  Inlet and outlet ports are switched periodically in the direction of the fluid flow  This simulates the countercurrent movement of the solid phase in the TMB process  Pure components can be obtained at the exit ports. Direction of Flow and Port Switching 1,2

13. Background: Simulated Moving Bed Infeed A+B Extract A Raffinate B Solvent Feed  SMB have conventional fixed bed chromatographic columns  Inlet and outlet ports are switched periodically in the direction of the fluid flow  This simulates the countercurrent movement of the solid phase in the TMB process  Pure components can be obtained at the exit ports. Direction of Flow and Port Switching 1,2

14. Advantages  No need for a complete resolution to obtain pure products.  Resolution of compounds that have similar retention with columns with low efficiency.  Allows for continuous feed increasing processing abilities.  Solvent can be recycled.  Cost Effective in comparison to alternatives such as batch extractions, or some chiral specific synthesis.  Addresses government regulations, FDA encourages Quality by Design principles.  Cleaner, Safer, more efficient compared to Batch processing.  Scalable process. 1,2,3

15. Advantages Simulated moving-bed chromatographic process for a chiral separation with eluent recycling and unwanted enantiomer revalorization. (Figure is courtesy of PharmTech.com and Olivier Dapremont) 3

16. Disadvantages  Method works best for binary mixtures.  Equipment more complex than traditional column chromatography.  Flow and pressure constraints necessitates zone manipulation.  Sampling needed during performance to ensure parameters.  Collection and injection shifts must be at fixed times  Chiral specific synthesis

17. Recent Applications  Chiral separations. Many companies, such as AMPC, use SMB to separate chiral compounds for pharmaceutical use. Recently a Graduate student form Ontario chirally separated Nadolol, a drug used to treat blood pressure, by SMB.  Simplification of complex samples into binary separation. In the purification of paclitaxel, a cancer drug, crystaliztion failed where SMB was able to reach 95% purity.  Food industry. Beet molasses from beet sugar had yield increase from 85% to over 95% using SMB. Others, crystalline fructose and oligosaccharides. This year cyclic peptides separated that occur in flaxseed oil. 1,2,3,6

18. Conclusion  For the separation of enantiomers of chiral compounds Simulated Moving Bed chromatography has become a popular technique. While there are many pharmaceuticals that are being manufactured using SMB, the interest is growing for its use in other industries and research.  Higher purity, lower cost, and production edge can make SMB more attractive than single column chromatography.  Most new developments being made in SMB focus on optimizing the technique through sensors and valve switching. These advancements are often safeguarded trade secrets. 1,2,3,6

19. References (1)Rajendranb, A; Paredesa,G; Mazzotti,M; Journal of Chromatography A, 2009, 709-38 (2)Nishizawa, H; Tahara, K; Miyamori, S; Motegi, Y; Shoji, T; Abe, Y; Journal ofChromatography A, 1998, 849, 61-69 (3)Dapremont, O; Pharmaceutical Technology, PharmTech.com, 2001, s22-s27 (4)Juzaa,M; Mazzottib,M; Morbidellia,M; Trends in Biotechnology, 2000, 18, 108- 118 (5)Baker, P.E., Ganestos, G, Sep. Sci Technol, 22, 1987, 2011 (6)Hashem, N, Western University, 2012 http://ir.lib.uwo.cahttp://ir.lib.uwo.ca (7)P. Metz et al., Pharm. Manuf. 3 (9), 27–29 (2004)