No abstract

For crystal-impurity systems with similar structures and molecular weights, the impurity has a strong tendency to incorporate into the crystal lattice, making it difficult to obtain high purity with a single crystallization or even multiple crystallizations. In such cases, complexation of the impurity with an additive can be used to sterically prevent impurity incorporation in the host lattice. A nanofiltration membrane can be used to preferentially reject the higher molecular weight impurity complex in solution, while allowing the lower molecular weight API to permeate through. This permeate stream can be concentrated and recycled to operate the crystallization in a continuous mode with the aim of enhancing both yield and crystal purity simultaneously. In the present work, this strategy was applied to the continuous cooling crystallization of two systems in a mixed-suspension mixed-product removal (MSMPR) crystallizer from their solutions in 50:50 (by volume) water–ethanol mixed solvent. The first system consists of benzamide with 3-nitrobenzoic acid added as an impurity, while the second one is the active pharmaceutical ingredient (API) ketoprofen containing two impurities, ibuprofen and α,4-dimethyl­phenylacetic acid. A working strategy for selecting the complexing agent and nanofiltration membrane was established. For both systems, the membrane-coupled continuous mode with recycle and complexation was found to have a better performance in terms of higher crystallization yield and lower impurity incorporation in crystals compared to both the batch process as well as the continuous process without recycle.

Functionalized nanoporous silica can induce crystallization from undersaturated solutions due to the combined effects of antisolvent functionalization and confinement.

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.