A scalable process
Figure 1: A simulated moving-bed chromatography unit (5 x 1000 mm) at AMPAC Fine Chemicals' Rancho Cordova, California, facility.
(FIGURE IS COURTESY OF THE AUTHOR)
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The scale-up of chromatographic processes follows a simple linear rule based on the square diameter of the columns. All the
parameters gathered at small scale are sufficient to calculate the process throughput and quality at any other scale. As a
result, the development time for an SMB process is short. In a matter of weeks, one can have an idea of the performance of
the process. Scale-up to commercial scale is straightforward and usually limited only by the availability of the feed material
to be separated or by the availability of the equipment. Because of the cost of the CSP as well as the quantity of solvent
involved, small-scale separations can be relatively expensive even though they may not be the most efficient. These considerations
are normally balanced by the short period of time needed for development compared with other methods. Once the process reaches
commercial scale, the CSP is usually amortized over a large amount of product, so the contribution of the CSP to the final
product is small. AMPAC Fine Chemicals (AFC, Rancho Cordova, CA) has operated two large-scale SMB units for the same product
using the same packing material for more than 10 years in one unit and for five years for the second unit (see Figure 1).
During that time, the amount of product processed was more than 2500 metric tons of racemic feed using only about 400 kg of
CSP. Additionally, the solvent used for the process can be integrally recycled. SMB is an isocratic process that operates
under mild conditions. Unless volatile impurities in the product build up in the solvent and eventually affect the process,
typically more than 99% of the solvent is recycled without difficulties. In the first stage, 65–85% of the solvent is stripped
from the product in falling-film evaporators. This solvent is directly recycled to the eluent tank. The remaining solvent
is recovered from the drying process (see Figure 2). This solvent is returned after appropriate quality controls to the eluent
tank or to a make-up tank. As a result, the solvent consumption at commercial scale is low. The 5 X 1000 mm SMB unit uses
about 38,000 gallons of solvent per day, but only three to six 55-gallon drums of solvent per month are used to make up the
inevitable losses from the process. In 2007, AFC received the Pollution Prevention Recognition Award from the Chemical Industry
Council of California and the Department of Toxic Substance of California for implementing recycling in its commercial-scale
SMB units.
Figure 2: Simulated moving-bed (SMB) chromatographic process for a chiral separation with eluent recycling and unwanted enantiomer
revalorization. (FIGURE IS COURTESY OF THE AUTHOR)
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The fate of the unwanted enantiomer is an important factor. Because 50% of the manufactured product is to be discarded, it
is important to try to conduct the separation as early as possible in the synthetic scheme to avoid carrying the dead weight
throughout the process. It may be more economical, however, to conduct the chiral separation at a further downstream intermediate
stage where the unwanted enantiomer can be recycled (i.e., racemized or sold as a side product). Under these conditions, the
economics of the process drastically improve.
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