Simulated Moving Bed SMB

Since the first separation of enantiomers by SMB chromatography, described in 1992 [95], the technique has been shown to be a perfect alternative for preparative chiral resolutions [10, 21, 96, 97]. Although the initial investment in the instrumentation is quite high - and often prohibitive for small companies - the savings in solvent consumption and human power, as well as the increase in productivity, result in reduced production costs [21, 94, 98]. Therefore, the technique would be specially suitable when large-scale productions ( 100 g) of pure enantiomers are needed. Despite the fact that SMB can produce enantiomers at very high enantiomeric excesses, it is sometimes convenient to couple it with another separation 

The type of CSPs used have to fulfil the same requirements (resistance, loadabil-ity) as do classical chiral HPLC separations at preparative level [99], although different particle size silica supports are sometimes needed [10]. Again, to date the polysaccharide-derived CSPs have been the most studied in SMB systems, and a large number of racemic compounds have been successfully resolved in this way [95-98, 100-108]. Nevertheless, some applications can also be found with CSPs derived from polyacrylamides [11], Pirkle-type chiral selectors [10] and cyclodextrin derivatives [109]. A system to evaporate the collected fractions and to recover and recycle solvent is sometimes coupled to the SMB. In this context the application of the technique to gas can be advantageous in some cases because this part of the process can be omitted [109]. 

Enantiomeric drugs or intermediates in their synthesis are the compounds most often purified with this technology and reported in the literature, although many resolutions performed in the industry have not been published for reasons of confidentiality. Some of the most recent examples in the field are summarized in Fig. 1-1. 

4 Closed-loop Recycling with Periodic Iiitra-proflle Injection (CLRPIPI) 

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Since the 1960s the commercial development of continuous countercurrent processes has been almost entirely accompHshed by using a flow scheme that simulates the continuous countercurrent flow of adsorbent and process Hquid without the actual movement of the adsorbent. The idea of a simulated moving bed (SMB) can be traced back to the Shanks system for leaching soda ash (58). 

On that basis, crystallization is often used in combination with other enantiose-lective techniques, such as enantioselective synthesis, enzymatic kinetic resolution or simulated moving bed (SMB) chromatography [10, 11]. In general, when referring to crystallization techniques, the aim is to obtain an enantiomeric enrichment in the crystallized solid. However, the possibility of producing an enrichment in the mother liquors [12, 13], even if this is not a general phenomenon [14], must be taken into account. 

These policy decisions by the FDA were the driving force for chiral switches and the commercial development of chromatographic processes such as simulated moving bed (SMB) technology. Due to technological advances such as SMB and the commercial availability of CSPs in bulk quantities for process-scale purification of enantiopure drugs, the production of many single enantiomers now exists on a commercial scale. 

Figure 10.2. Principle of the simulated moving bed (SMB), left inlet and outlet lines are shifted discontinuously right inlet and outlet lines are shifted simultaneously.

FIG. 16-48 General scheme of a simulated moving bed (SMB) adsorption system. Bed rotation is simulated by periodic switching of ports in the direction of fluid flow. A is less strongly retained than B. 

At present, the purification by chromatographic processes is the most powerful high-resolution bioseparation technique for many different products from the laboratory to the industrial scale. In this context, continuous simulated moving bed (SMB) systems are of increasing interest for the purification of pharmaceuticals or specialty chemicals (racemic mixtures, proteins, organic acids, etc.).This is particularly due to the typical advantages of SMB-systems, such as reduction of solvent consumption, increase in productivity and purity obtained as well as in investment costs in comparison to conventional batch elution chromatography [1]. 

Nicoud RM (1998) Simulated Moving Bed (SMB) Some Possible Applications for Biotechnology. In Subramanian G (ed) Bioseparation and Bioprocessing, Wiley-VCH, Wein-heim-New York... 

The performance of HPLC separations can be increased not only by the application of two- or multidimensional techniques but also by the use of simulated moving bed (SMB) [100-102] or true moving bed (TMB) techniques [103,104], SMB is a multicolumn separation technique allowing the continuous separation of analyses with higher productivity and smaller eluent consumption than the traditional single-column procedures. TMB... 

The productivity of the plant was assessed to amount to about 5 kg DNB-D-Leu and DNB-L-Leu per mol of carrier with a purity of 99% (i.e., 98% ee). If a similar amount of selector is immobilized on silica gel and the CSP operated in a simulated moving bed (SMB) process, it was assumed to achieve roughly productivities between 1 and 7 kg pure enantiomer per day. Hence, it was concluded that a SLM process could be quite competitive to a SMB process in the production of pure enantiomers. 

Simulated moving-bed (SMB) pilot plant Saltigo (Lanxess), Leverkusen, Germany... 

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