Polymorph Form Control: Why Care About Seeding and Cooling Rates?

In Situ Monitoring of Supersaturation and Polymorphic Form of Piracetam during Batch Cooling Crystallization

Mark Barrett and others at the University College Dublin (UCD) recently published a paper (Org. Process Res. Dev., 2011, 15 (3), pp 681–687) which outlines the reasoning (and provides convincing empirical data) showing how cooling rates and seeding may affect the polymorphic form.  Further, the UCD engineers show that it only takes one single experiment to understand the form, supersaturation, metastable zone width, and particle size distribution for each processing condition.  By applying in situ FTIR infrared spectroscopy (ReactIR™), Focused Beam Reflectance Measurement (FBRM®), and Raman they identify the ideal seeding and cooling conditions to optimize nucleation and growth the desired polymorph form.

University College Dublin (UCD), pioneer of the calibration-free method for in situ supersaturation monitoring, used ReactIR™ to track the supersaturation trajectory during slow, fast, and crash cooling profiles.  Raman was used to identify the form, and FBRM® was used to measure the nucleation and growth, and track changes between the endpoint particle size distributions.   In a few experiments, they determined the cooling conditions necessary to isolate the thermodynamically stable form and particle size distribution.

UCD engineers then applied seeding to force nucleation of the stable polymorph form and control consistency for all experiments regardless of the cooling rate or seed loading.  What made this paper novel was that the information used to optimize the crystallization process was not done in a large Design of Experiment (DOE) but rather, a set of six well designed experiments.  How was this possible?  UCD concludes:

in situ tools offer valuable insight into crystallization mechanisms and maximize the information which can be obtained from a single experiment.

Learn more about polymorph control using in situ monitoring.