(421c) Solubility-Limited Impurity Purge in Crystallization – Theory, Applications and Development Strategies

Impurity control in pharmaceutical industry is imperative in ensuring the quality of the drug substance. Crystallization is a key unit operation in removing impurities and is relied upon across the synthetic scheme. Different mechanisms for rejecting impurities in the crystallization have been proposed, including surface adsorption, solid solutions, inclusions and solubility. Presented in this contribution is the mechanism of solubility-limited impurity purge in which the purge ability of the impurities is dependent on the respective solubilities in the crystallization solvent relative to the product. A theoretical framework is presented that is confirmed experimentally for three different types of solubility-limited impurity rejection mechanisms. A practical experimental test, the so-called SLIP test, is described that is able to identify the corresponding type of impurity purge mechanism. The novel approach to control purity in the crystallization is showcased using pharmaceutical compounds. Development strategies are presented that are based on the corresponding type of solubility-limited impurity purge mechanism.