Enantiomers purification

From the pioneering studies of Ito et al. [117], CCC has been mainly used for the separation and purification of natural products, where it has found a large number of applications [114, 116, 118, 119]. Moreover, the potential of this technique for preparative purposes can be also applied to chiral separations. The resolution of enantiomers can be simply envisaged by addition of a chiral selector to the stationary liquid phase. The mixture of enantiomers would come into contact with this liquid CSP, and enantiodiscrimination might be achieved. However, as yet few examples have been described in the literature. 

Although very efficient, the broad application of the direct preparation is restricted due to the limited number of pure starting enantiomers. The design of a multistep process that includes asymmetric synthesis is cumbersome and the development costs may be quite high. This approach is likely best suited for the multi-ton scale production of commodity enantiomers such as the drugs ibuprofen, naproxen, atenolol, and albuterol. However, even the best asymmetric syntheses do not lead to products in an enantiomerically pure state (100 % enantiomeric excess). Typically, the product is enriched to a certain degree with one enantiomer. Therefore, an additional purification step may be needed to achieve the required enantiopurity. 

Finally, the data in Table 8-6 show the elution of the lead column. The eluent is H,0. The driving force for the elution in this case is the lack of C10 present to act as an anion in the binding of the ammonium perchlorate salt pair. The D-enantiomer versus L-enantiomer ratio in the elution is slightly greater than 6 1, as expected by the inherent selectivity of the ligand. For this separation system, LiClO is then added back to the eluent and the eluent is sent on as load to the next purification stage. 

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. 

Process validation should be extended to those steps determined to be critical to the quality and purity of the enantiopure drug. Establishing impurity profiles is an important aspect of process validation. One should consider chemical purity, enantiomeric excess by quantitative assays for impurity profiles, physical characteristics such as particle size, polymorphic forms, moisture and solvent content, and homogeneity. In principle, the SMB process validation should provide conclusive evidence that the levels of contaminants (chemical impurities, enantioenrichment of unwanted enantiomer) is reduced as processing proceeds during the purification process. 

SMB is now accepted as a real production tool. For instance, the Belgium pharmaceutical company U.C.B. Pharma announced recently the use of SMB for performing multi-ton scale purification of an enantiopure drug substance. The concept of large-scale purification of enantiomers using chromatographic techniques has moved from a dream to a reality within the last few years. 

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