Figure 4: Separation of impurity(ies) during a chiral resolution by chromatography shown with simulated chromatograms. The
red graphs represents an overall chromatogram, and the blue graph denotes the impurity(ies). Figure 4(a) is an impurity eluting
with one of the enantiomers. Figure 4(b) is an impurity eluting between the two enantiomers. Figure 4(c) shows impurities
eluting much earlier or later than the enantiomer. (FIGURE IS COURTESY OF THE AUTHOR)
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Five major cases can be identified, and Figure 4 shows some examples of the removal of an impurity with a chiral separation.
The first case is when the impurity elutes with the desired compound (see Figure 4a). The only way to address this case is
to change the separation conditions. The second case is when the impurity elutes with the unwanted enantiomer. This is a good
case because the impurity will be completely removed (see Figure 4a). If the second enantiomer is to be recycled by racemization,
one must ensure that the impurity is addressed in the recycle step to avoid accumulation over time. For the third case, the
impurity is eluted between the two enantiomers (see Figure 4b). This case is more difficult but can usually be solved with
the existing separation method. The fourth and fifth cases are when the impurity is eluted much later or earlier than the
enantiomers (see Figure 4c). Under these conditions, the impurity is usually distributed evenly in both the extract and the
raffinate streams. By adjusting certain flow rates, it is possible to control the ratio of the impurity in the outlet streams.
Removal of a suspected toxic impurity
. During the past few years, there has been a lot of interest in the identification and removal of genotoxic or carcinogenic
impurities to very low levels in APIs. This removal is usually difficult to do by traditional crystallization techniques without
losing significant amounts of product in the mother liquor. Chromatography is one technique that can achieve very high purity
while maintaining a high recovery of product (i.e., greater than 95%). The removal of a toxic impurity is a binary separation
and can be done by SMB. These separations can normally be developed on normal-phase packing materials (i.e., bare silica or
silica functionalized with a cyano or amino group, for example). These phases are not as expensive as chiral phases and provide
larger loading capacity, thereby resulting in high throughput.
AFC recently developed an SMB process to solve an impurity problem that was originally performed using crystallization to
remove an impurity from about 1% to 10 ppm. The purification was performed using crystallization and required two to three
crystallizations with an 85% yield for each step, thereby bringing the overall yield to 61–72%. As an example, the processing
of 50 metric tons of this intermediate using crystallization would result in only 30.7 metric tons of pure product after three
crystallizations. Assuming that each crystallization adds a cost of $30/kg to the product and that the crude feed costs $1000/kg,
the crystallization process increased the pure-product cost to $53.3 million or $1736/kg. Despite a relatively cheap crystallization
process, the overall cost of the product is drastically increased because a significant amount of product is lost to the mother
liquors. Alternatively, if the purification is done by SMB and the estimated cost for the SMB separation is $50/kg, then the
associated manufacturing cost for the pure product is only $52.4 million or $1104/kg with a total of 47.5 metric tons of pure
product recovered. The lower cost of the SMB process is mostly due to the high recovery of product because it is not lost
in the mother liquors as in the crystallization process. In this example, a 95% recovery was estimated; however, at commercial
scale, typical yields of > 98% are realized. This difference in cost between the two methods can significantly increase when
the price of the material to purify increases.
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