(69c) Control of Polymorphism and Crystal Size Distribution and in Pharmaceutical Crystallization

An overview is provided on the design and operation of pharmaceutical crystallizations to control polymorphism and crystal size distribution. A semi-automated methodology is described for the selective crystallization of metastable and stable polymorphic and solvatamorphic forms based on Attenuated Total Reflection-Fourier Transform Infrared (ATR-FTIR) spectroscopy, laser backscattering, and process data analytics. The methodology enables the design and operation of seeded batch crystallizers to manufacture large crystals of uniform size by suppressing secondary nucleation. A modification of the methodology achieves a target size distribution in a semi-batch crystallization configuration by employing continuously generated seeding. Theoretical, simulation, and experimental results are reported for a variety of pharmaceutical compounds. The presentation ends with a discussion of directions towards control of multiple properties of the crystal product.