7


Chiral Technologies we screen both HPLC and SFC screens are conducted, choosing the technique which gives the most economical solution, although HPLC becomes the preferred methodology for projects in excess of around 1 kg. As the simpler process, HPLC retains several advantages over SFC, in that sample cannot be lost during fraction collection, safety precautions are less stringent as the mobile phase is an incompressible liquid and as there are no phase changes, heating and cooling services are not necessary.


Separations in HPLC are usually scaled to “touching band” level, where the sample load is increased to the point where the front of the second band starts where the tail of the first eluted component reaches the baseline. Displacement effects are not as strong in chiral separations as in many achiral situations for a number of reasons and recovery of valuable material is often a priority so heavier loading is rarely used.


Simulated Moving Bed


Chromatography (SMB). SMB as a process for the pharmaceutical industry was implemented in the mid 1990s as an adaptation of the large scale processes for p-xylene and high fructose corn syrup. SMB is a multi-column, countercurrent continuous binary separation process and is preferred on the basis of process economics as the scale of the separation increases toward production . There are currently several enantiomerically pure pharmaceutical products that are produced at a manufacturing scale (ie multi-MTA) using this technique.


Although at first sight it appears to be complex, it is based on simple chromatographic concepts. As bands separate in a column they move at differing speeds. If we could move the stationary phase as well as the mobile phase, then moving it in the opposite direction at a speed intermediate between the two band speeds would result in the slower moving band being transported with the stationary phase while the faster one would move with the mobile phase. If nothing else happens, the two bands would move further apart with time, leaving an unused space in the centre of the column. This means that one can introduce the feed continuously into the centre of the column and the two components would continue to separate. The products are removed by bleeding off material from the pure zones at the outer ends of the band. As the stationary phase cannot be moved while maintaining a well- packed bed, the entire column must move. This is accomplished by using multiple columns in series, with movement affected not by moving the columns but by moving the inlet and outlet positions instead.


Unlike the situation in HPLC, where it is straightforward to design the preparative separation from a series of mass-overloaded injections, SMB requires a more complex procedure; usually computer simulations are used to develop operating conditions suitable for the separation followed by experiment to “fine-tune” the conditions thus developed. The data from the HPLC loading study is used to determine the parameters for the adsorption isotherms of the components which are then used in the computer simulations. Empirical determination of the operating conditions, although it is somewhat slower, is fortunately not too exacting a task and is normally used for the situations where the adsorption isotherms are not well described by a theoretical model.


An excellent account of the development of a large scale manufacturing process by SMB has been written and although it is not the purpose here to go deeply into a description of such a procedure, there are some basic principles that can be noted. At the laboratory scale, the most precious resources are time and manpower. Thus, separations are generally designed to take the shortest possible time in the equipment available and the emphasis is on the rate of production of the desired enantiomer. In a manufacturing process, the emphasis is on cost of the product (in $ per kg, etc) and this may change the way in which the process is run. Where the final product is valuable, the rate of production remains critical but cost considerations can result in a non-optimum process (from the chromatographic viewpoint) being preferred. For a production process it is worth spending the time to optimize the separation using all possible stationary phase and mobile phase combinations – and also to calculate the economic consequences of several options to determine the best. It is essential to test intermediates at all points in the synthetic process downstream of the introduction of the chiral centre where there is no possibility of racemisation in processes still further downstream to find the best point at which to run the chromatographic resolution. This may be self-selecting in some cases where the chiral centre is introduced late in the synthesis, while in others there can be a genuine best point at which to introduce the resolution. Although at the production scale the recovery of solvent can reach over 99.9%, the cost of some solvents (such as acetonitrile under the present economic climate) may influence the choice of one separation option over another.


At present, manufacturing scale SMB processes are generally outsourced to a CMO with this capability. There are several companies in the world with such equipment (eg Ampac, Daicel, Johnson Matthey,


Novasep and SAFC) where large scale separations may be carried out. This is because one of the greater costs of SMB processing is the investment in equipment and infrastructure. If a new crystallization process is envisioned for a pharmaceutical product, there are usually sufficient tanks in a manufacturing plant to accommodate it. Most companies do not have SMB equipment in place and this extra investment can militate against implementation of a process even where it has longer term economic advantage. Another advantage of outsourcing such processes is that the CMOs have good experience in design, running and maintaining them which is not generally available.


Conclusion Preparative enantioselective chromatography is a fast and efficient way to produce highly pure enantiomers from racemic (or enriched) mixtures. Where there is a critical need to prepare pure enantiomers in the shortest possible time (for example in the pharmaceutical industry from early discovery to the point where the product is moving through Phase 1 and perhaps Phase IIa clinical trials) the most effective route is generally through chromatographic resolution of the racemate. It is easy to develop a small scale separation of a few hundred milligrams of racemate and to progress to having operating conditions for isolation of kilogram quantities and even a production scale process within a few weeks. Once the first few kg of enantiomer have been prepared, the pressure to have material quickly is reduced so there is time, perhaps, to compare the chromatographic route with alternatives. This does not imply that enantioselective chromatographic processing is not used at the manufacturing scale; the imperative is to find the most cost- effective process. It should, of course, be remembered that the cost of chromatography for the first few grams of material is very different from that for the first 10 metric tons; the costs decrease quickly with scale and with further optimization of the separation process. Chromatographic processing should always be considered as one of the options for the manufacture of pure enantiomers.


Reference


L R Snyder, J W Dolan and G B Cox, J Chromatogr., 1989, 483, 63. J W Priegnitz and B McCulloch, US Patent 5518625. P Franco and T Zhang, J Chromatogr., B, 2008, 875, 48. J Dingenen, Analusis, 1998, 26, M18. R M Nicoud, Pharma. Technol. Eur.,1999, March/April.


M. Hamende, “Case Study in Production-Scale Multicolumn Continuous Chromatography” in Preparative Enantioselective Chromatography, Ed G B Cox, Blackwell, Oxford, 2005.


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