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November/December 2009
Preparative Chiral Separations – from Laboratory Scale to Production
Geoffrey B Cox, Chiral Technologies, Inc., 800 N Five Points Rd., West Chester, PA 19380 USA •
gcox@chiraltech.com
Over the past few years, preparative chromatographic separation of racemic mixtures into their individual enantiomers has become an integral part of the development process for new drug entities. This is because the number of chiral drug candidates has been increasing, a not surprising development, given the asymmetric nature of the drug receptor sites. At an early stage in development it is essential to know the differences in activity and toxicity between the two enantiomers in order to maximize the effectiveness of the product while minimizing the possible negative side effects of the new drug. At this stage of the process there is practically nothing known about the chemistry and physical properties of the molecule and the fastest and most convenient way to the pure enantiomers is usually chromatographic purification. In contrast to other possible procedures, only a few mg of product and a few hours are needed to develop a chromatographic separation method – important for these new candidates where there may be only a few hundred mg of the product in the world.
Once developed, the chromatographic procedure can be used both to analyse the optical purity of the product and to isolate the enantiomers. In the drug development process, speed to market is vital and rapidly reaching a go / no-go decision point for the development is critical in resource allocation. Thus, as the new drug moves through the early stages of development and increasing amounts of material are needed, the initial chromatographic method can grow in scale with the needs of the project, often reaching the isolation (under cGMP) of kilogram quantities for Phase 1 clinical trials. At this point the immediate pressure of development eases, allowing a more leisurely investigation of the possible processes to make the desired enantiomer. The focus at this point is to find the most economical procedure for the production of the material in time for Phase III, where the manufacturing process is typically locked in and all alternative processes from crystallization through asymmetric synthesis are investigated. In some cases, chromatography remains the option of choice while in others the alternative procedures are chosen. While the aim is generally to use the process that results in the lowest cost per kg of the final product, the choice may also be influenced by capital expenditure requirements or by concerns about the scalability of the process. While the latter concerns should by now be alleviated by the success of the current production scale chromatographic enantiomer separations, the capital expense of installing a large scale chromatographic system as opposed to utilization of existing tankage (for a
crystallization, for example) could result in a decision to use a more expensive but less capital intensive process.
Considerations of scale. In the progression from the small scale chromatographic purification to production scale operations there are many changes made in both the chromatographic methodology and its philosophy. At the smallest scale, cost is not important and the need is to find an adequate separation method in the shortest possible time which can produce the few tens to hundreds of mg. At this scale the separation time for the isolation is short; there is little purpose in spending several days to develop an optimised separation. As the scale increases, there is increasing emphasis on the economics of the separation. Despite the high overall costs of bringing a new pharmaceutical product to market, the costs of individual steps remain under strict scrutiny and the chromatographic method frequently is optimized and in some cases may be redeveloped in order to meet the cost requirements. Much more care is taken to find a high selectivity and to optimize the separation when the scale increases to the few hundred grams needed for toxicology or the kg quantities for Phase 1 trials. The transition to large scale processing beyond Phase 1 is usually accompanied by a transition from conventional batch chromatographic separation techniques to the production-scale oriented simulated moving bed technology. This continuous chromatographic process is generally more cost effective than conventional single column chromatography,
combining use of significantly less solvent and stationary phase with higher productivity, but it requires more optimization and development time than the simpler batch process.
Early Stages.
Separation method development time has to be short in the early stages of the development of the new product to meet the stringent time constraints. Methods are typically developed by screening a small set of enantioselective columns with the aim of finding a baseline separation quickly. Increasingly (in the USA at least) this is done using supercritical fluid chromatography; replacement of organic solvents with a mobile phase predominantly consisting of supercritical carbon dioxide results in approximately a fourfold reduction in solvent viscosity. This allows the columns to be operated at four times the flow velocity used in corresponding HPLC methods, dramatically reducing the screening and separation time. SFC methods also result in the use of smaller volumes of organic solvent during the separation process. While efficient solvent recycling procedures minimize the environmental impact of this reduction in solvent use relative to HPLC, the products are isolated in smaller volumes (often 5 to 10 times less) than in HPLC. This reduces the evaporation time and results in a little less energy use in the process (though it should be noted that operation in SFC involves several phase transitions which consume more energy than simply pumping solvent as in an HPLC system). Although SFC is widely used at this stage of development, this does not mean that HPLC processing should be avoided or
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