(467a) Insights Gained Using Latest PAT Tool Eliminate Production Failure of a Metastable Form Crystallization

Polymorphism presents multidimensional challenges in the pharmaceutical industry. Aside from the consequential impacts on bioavailability and performance of a drug product, different physicochemical properties of polymorphs can impact significantly processibility of a drug substance in production. This presentation will discuss a challenging production case where the metastable form is preferred (targeted) over the thermodynamic stable form for its desired performance in the subsequent processing step. As an enantiotropic pair with very similar solubility of desired and undesired forms, isolation of the metastable form was very difficult to achieve consistently in production.

We conducted an in-depth investigation of this crystallization system applying the latest PAT tool (BlazeMetrics particle analyzer with Raman), and gained a solid understanding of the thermodynamics and kinetics of polymorphic interconversions under relevant production conditions. Initial process optimization increased production success rate from about 70% to 92%. Further investigation employing the PAT tool helped to identify a critical root cause of the batch failure. The insights gained from this study allow design of a better control strategy in production for achieving 100% success rate (zero failure) and over 6-fold cycle time reduction.