(646e) In Situ Polymorph Transformation of a Pharmaceutical Intermediate

We discovered that the polymorph of a pharmaceutical intermediate transformed in situ during crystallization from solution. Initially, we noted an anomaly in the signal recorded during a crystallization experiment using a Mettler-Toledo Particle Track G400 instrument, an unexplained decrease followed by an increase in the average chord length of the particles. At roughly the same time, we discovered that there is a clear change in the rheology of the suspension. Rapid crystallization early in the process produces a suspension with a yield-stress that flows and mixes poorly. This gradually transforms during subsequent antisolvent addition to a free-flowing suspension without yield stress. We determined that the phenomenon causing both the observed change in particle size and rheology is crystal polymorph transformation accompanied by a dramatic change in habit. Our first indication of the transformation was obtained observing suspension sampled early in the crystallization under an optical microscope. We observed a clear habit change with time. We then further explored this transformation using simultaneous in situ Raman spectroscopy (Kaiser RXN1-785) and microscopy (Mettler-Toledo PVM and EasyViewer). We verified that a polymorph transformation occurs during the antisolvent addition phase of crystallization, accompanied by a change in crystal habit. The initial form grows rapidly as acicular crystals, followed by a gradual transformation to a second, more stable form characterized by roughly equant crystal aggregates. This transformation is responsible for the change in suspension rheology and the observed change in particle size. The dependence of the transformation on process conditions and seeding, as well as the kinetics of the transformation, have been determined. Knowledge of this transformation allowed us to understand the experimental observations and enabled confident scale-up.