Solubility-Limited Impurity Purge in Crystallization

Crystallization from solution is a key unit operation utilized across the synthetic scheme to remove impurities. However, little is still known of the underlying impurity purge mechanisms that are responsible for controlling the final purity of the product. Reported herein is the solubility-limited impurity purge (SLIP) mechanism in which the impurity exists as a separate solid phase with its own solubility. A mathematical framework is presented that describes the separation of the impurity in the solid and liquid phases based on the relative solubilities of the product and impurity, and initial impurity level. Three theoretical solubility-limited impurity purge mechanisms are derived that are confirmed experimentally using salicylic acid, ibuprofen and acetaminophen as model compounds. A practical experimental test is introduced that is used to identify if the impurity is rejected by solubility-limitation and its corresponding type. Finally, development strategies are presented to remove impurities that ...