In some cases, new polymorphic forms can appear during development and fast identification is critical. In other cases, the presence of more than one polymorph is known, and an in-process transition is required to produce the desired polymorph. For both cases, it is useful to apply PAT methodology to ensure that the transition from the less stable to more stable polymorph occurs consistently across all scales and operating conditions.
In this example, a polymorphic transformation is studied. Both the RBI and real-time microscopy images provide detailed and unambiguous process understanding. When the initiator is added, nucleation occurs immediately, as indicated by the rapid increase in the RBI signal, corresponding to the formation of crystals. While the temperature remains constant at 50 °C, the RBI reaches a steady state, but soon increases again rapidly – indicating a second nucleation event has occurred. Checking the real-time microscopy images confirms the presence of a second crystal morphology that has nucleated, which can be verified as a different polymorphic form using offline XRD analysis.
Over time, the transition from the less stable for the more stable form occurs, until the RBI trend again reaches a steady state, and the real-time microscopy images show that only needle shape crystals persist.
This case study demonstrates the ease with which scientists can obtained extremely useful process understanding using a PAT, which is simple to implement and requires very limited data analysis expertise.