(83b) Effects of an Impurity On the Morphology of an API: Using ATR-FTIR, FBRM and PVM to Confirm a Hypothesis

During the crystallization of multiple 1-2 kg batches of API, a substantial change in morphology from needles (aspect ratio 10-20) to plates (aspect ratio 1-2) was observed in some of the lots.  An unknown impurity found at trace levels was found to correlate with the change in morphology.  This impurity was isolated chromatographically and identified as a dimeric species of the parent compound.  Several milligrams of the impurity were isolated and used to spike into subsequent crystallizations in order to confirm the hypothesis that the impurity alone was responsible for the morphology change.  These crystallizations were characterized by using ATR-FTIR to monitor solute concentration changes with time, FBRM to monitor particle chord length (along with aspect ratio) changes with time, and PVM was used as visual confirmation of the aspect ratio changes.  Crystallizations (over a range of impurity levels) show an evolution from expected needle morphology to plate morphology. The results find that the aspect ratio is altered by slowing the growth of the expected axial face.