Evolution of Continuous Chromatography: Moving Beyond Chiral Separations - Pharmaceutical Technology

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Evolution of Continuous Chromatography: Moving Beyond Chiral Separations
The author presents recent developments in simulated moving-bed chromatography in production of active pharmaceutical ingredients and intermediates. This article is part of a special issue on APIs.

Pharmaceutical Technology
pp. s22-s27

Reclaiming product from mother liquor . It is not unusual for a chemical synthesis to require more than five steps of chemistry, and every manufacturer is looking to improve the overall yield as much as possible by fine-tuning every unit operation involved in the process. Once the chemistry has been optimized to provide the best possible conversion and the best yield, a major loss of product can happen during the final crystallization and subsequent product washes. Ideally, these steps (i.e., crystallization and washes ) are conducted with a solvent that can solubilize the impurities but not the product. Unfortunately, the product is always slightly soluble in the crystallization solvent and the wash solvent. As a result, 5-20% of the valuable product can be lost to the mother liquor and the cake washes. It is very difficult to recover the product from these effluents because of the level of impurities is significantly higher. Additional crystallization will only result in marginal product recovery and is usually not economical.

AFC recently developed a process to reclaim the product from these effluents by using continuous chromatography. In one specific case, the mother liquor contained about 30% of the desired product and two major impurities that prevented further product recovery by classical crystallization. AFC developed a chromatographic separation process that allows the product to elute away from the main impurities. This separation becomes a binary-like separation that can be processed on an SMB unit. Once the purified product is recovered from the SMB, it can be crystallized using the normal crystallization method. Because the crystallization process has an 87% recovery, the 13% product loss was reclaimed in the SMB with a 95% recovery. This material is crystallized with an 85% yield, corresponding to a recovery of 10.5% of the original quantity. By adding these two steps, the total yield of the process increases from 87% to 97.5%. The additional SMB and crystallizations steps, however, add cost to the final product. In this example, however, the savings in the raw material were significant.


Continuous chromatography can provide a step-change in process economics. SMB technology was developed more than 50 years ago and is intensively used in the food and petroleum industry to achieve low manufacturing costs. This technology also has been implemented successfully in highly regulated environments for the manufacturing of pure chiral APIs. The justified interest in continuous processes and the push by regulatory agencies for more efficient, controlled, and robust processes are major reasons to implement continuous chromatography in manufacturing operations. High purity with high yield at a low cost is achievable. The technology, the experience, and the know-how are available to perform these operations at all scales.

Olivier Dapremont, PhD, is director of process technologies, AMPAC Fine Chemicals, PO Box 1718, Rancho Cordova, CA 95741, tel. 916.357.6242,


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