Simulated Moving Bed Chromatography Offers Real Attractions

A continuous purification technique, simulated moving bed chromatography combines high yields and purities with easy scale up and reasonable throughputs.

By Kathleen Mihlbachler, Eli Lilly and Company, and Olivier Dapremont, Aerojet Fine Chemicals

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Simulated Moving Bed (SMB) chromatography is a continuous purification technique that has higher throughput and requires less solvent than regular batch chromatography. Even for difficult separations, it can achieve high yield and high purity at a reasonable production rate.

The process was developed in the 1960s for the purification of sugars from molasses. Since then it has won a role in the pharmaceutical industry for the purification of enantiomers from racemic mixtures [1]. In recent years, interest in the technology by both industry and academia has grown.  As a result, SMB applications have expanded beyond the sugar and racemic separations to more complex separations.
Today, a few active pharmaceutical ingredients (APIs) are produced using SMB. However, some obstacles prevent the broader application of the technology. This article will present these obstacles and how to overcome them to perform successful separations.

Process principle
SMB 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 (see Figure 1). Two inlet streams (feed and eluent) and two outlets streams (extract and raffinate) are directed in alternating order to and from the column ring. Because the columns cannot be moved, the inlet and outlet position is switched at regular time intervals in the direction of the liquid flow, thus simulating countercurrent movement of columns.

 

Figure 1
SMB Figure 1



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 SMB process can be modeled with the appropriate mass-balance equations for each column and the adsorption isotherms for each compound.  Experimental data are used to verify and adjust the model. Simulations are then conducted to design the equipment to satisfy the required production.

How the technique compares
A single enantiomer can be manufactured by either an asymmetric route, such as biocatalysis or asymmetric synthesis, or by purification of a racemic mixture via crystallization, chemical resolution, chiral membranes or chromatography.

The first option requires the discovery of the right enzyme or catalyst. Enantiomeric ratios are not always good and asymmetric techniques require long and expensive process development. However, the theoretical yield is 100% because only the desired enantiomer is prepared.

Racemic purification is usually a simpler route because the synthesis of the racemic is less complex. Crystallization processes require enrichment of the desired enantiomer in the mixture and often result in low yields. Chemical resolution involves three steps: making a salt, performing the separation and then recovering the product from the salt. Even if the yields are good, each step introduces a cost to the final API. Chiral membranes are still in their early stages and are limited to certain solvents and small molecules. In contrast, method development for chromatography is very fast (a couple of weeks) and scale up is straightforward, making it attractive. The theoretical yield for these methods is 50% because both enantiomers are present; however, if racemization is possible the yield can be increased, thereby improving the process economics. It is not uncommon to find that SMB processes are more economical at commercial scale than any other option.

One of the great advantages of chromatography compared to other processes is the capacity to scale up linearly. A process demonstrated at pilot scale can be reproduced very quickly at production scale without sacrificing purity and production rate.

Developing a process
Actual process development is fairly straightforward and involves the usual steps of data generation and modeling.

Chromatographic conditions. Several combinations of stationary phases and eluent mixtures must be tested to identify suitable separation conditions.  SMB can work with small selectivity (less than 1.2); however, it is better to have both large selectivity and small retention factor k'. Having small k' reduces the amount of solvent required for the process. A large selectivity is most likely to provide higher throughput — however, too large selectivity (>6) necessitates handling high volumes of solvent and thus limits the production rate.

For an API, the stationary phase must be available in large quantities and manufactured under cGMP to ensure lot-to-lot reproducibility of the packing.

Single solvent systems are always preferable for practical reasons (recycling, composition); unfortunately, they are not always possible. When considering binary systems, the effect of small variations in the composition should be evaluated carefully because they can affect the process robustness.

Additionally, product solubility must be assessed. Low solubility (<20 g/l) will impact the production rate. Higher solubility is preferable because it facilitates the preparation of the feed solution and also reduces potential crystallization in the lines.

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