(174bn) Preventing “Crusty” Phase Impurities during Crystallization Scale-up

During process development of a traditional seeded, cooling, antisolvent crystallization, an unexpected phase impurity was detected at low levels in the isolated product. This impurity was discovered to be a kinetically-favored form that was generated in a “crust” that formed on the crystallizer wall at the interface with the slurry. Upon antisolvent addition, the undesired form was then incorporated into the slurry. Traditional approaches were unsuccessful in eliminating or minimizing the formation of this phase impurity. Instead, due to an understanding of the mechanism of the phase impurity formation, the crystallization was run at elevated pressure to significantly reduce the rate of “crust” formation. This approach was successfully scaled up, and used to deliver API. This talk will discuss the mechanism of crust formation and how this was exploited to develop a scaleable process.