(223b) Optimization of a Reactive Crystallization Using a Pharmaceutical Engineering Approach

Reactive crystallizations are complex and difficult to control due to the number of competing parameters influencing the chemical transformation and particle growth. Here we will discuss a salt-to-salt transformation in the presence of multiple reactive chemical species. The crystallization is further burdened by the potential to create a poorly soluble free form that poses a risk to both product quality and yield. The presentation will highlight the use of FBRM in combination with other analytical techniques to identify and elucidate the side reactions responsible for observed variability in product potency. Detailed understanding of the upstream composition and the seed point proved vital to delivering a robust process. To offer reasonably broad parameter ranges to manufacturing and further mitigate risk, the refined process incorporates a crude crystallization focused upon yield and a re-crystallization that assures high quality. A fundamental understanding of the interactions of the chemical species and the root causes of variability were needed to deliver a suitable process for commercial manufacturing.