Complexation-Assisted Continuous Crystallization of Isomeric Systems with Nanofiltration Recycle

Abstract

In API-impurity systems consisting of structural isomers, the impurity has a strong affinity to incorporate into the host crystal owing to their identical molecular weight and similar structure. Conventional successive recrystallization turns out to be an unattractive purification strategy in such cases, since it can improve crystal purity only at the cost of yield. As an alternative, selective complexation of the impurity can sterically prevent its incorporation into the host lattice by increasing the apparent molecular weight and dimensions of the impurity. The increase in size of the impurity post complexation can be further exploited using a nanofiltration membrane to preferentially reject the complex in solution, while allowing the smaller molecules of uncrystallized API to permeate through. The crystallization yield can be enhanced by concentrating the permeate stream and recycling it back to the crystallizer. Thus, complexation-assisted nanofiltration recycle presents a strategy to improve both yield and crystal purity simultaneously in a continuous mode. In the present work, the application of this strategy is described for the continuous cooling crystallization of two isomeric systems in a mixed-suspension mixed-product removal (MSMPR) crystallizer. The first system consists of 4-nitrophenol with 3-nitrophenol as an added impurity in an aqueous solvent, while the second one consists of the active pharmaceutical ingredient (API) acetaminophen with its isomer 3-acetamidophenol added as an impurity in a mixed solvent of 50:50 ethanol and water by volume. A working strategy for selecting the complexing agent and nanofiltration membrane is discussed. For both systems, the complexation-assisted continuous mode with nanofiltration recycle performed better than both the batch process as well as the unrecycled MSMPR process in terms of higher crystallization yield and lower impurity incorporation in crystals.

Impurity incorporation in solution crystallization: diagnosis, prevention, and control

“…In 2017, this technology was also applied in continuous crystallization by Vartak and Myerson. 118,119 To mitigate the common trade-off between crystallization yield and purity, their focus was to allow for solution recycling in systems with impurity complexation. Crystallization of the target molecule, filtration of the pure crystals, and nanofiltration for the removal of impurity complexes were all carried out in a continuous loop (Fig.…”

Mechanisms and Control of Impurities in Continuous Crystallization: A Review

“…The integrated membrane module helps to reduce accumulation of impurities over time . Furthermore, the crystal purity can be enhanced by incorporating the complexing agent where this process is utilized when the host and impurity compounds have a similar structure or size . The complexing agents have a larger molecular weight and will adsorb the impurity to form the impurity complexation.…”

“…93 Furthermore, the crystal purity can be enhanced by incorporating the complexing agent where this process is utilized when the host and impurity compounds have a similar structure or size. 94 The complexing agents have a larger molecular weight and will adsorb the impurity to form the impurity complexation. The impurity complexation which has a larger molecular weight and dimensions will be filtered in the nanofiltration membrane during recycling the mother liquor to enhance the yield.…”