Quantitative Link between Secondary Nucleation and Mixing Hydrodynamics in Batch Cooling Crystallization: A New Approach in Process Development

Precise control of a crystallization process requires a clear understanding of nucleation kinetics. Interpreting secondary nucleation threshold (SNT) of a given crystallization process under optimized hydrodynamic conditions can highlight the impact of critical process variables on product particle size distribution (PSD). In this work, a new approach is proposed in industrial crystallization process development in which a quantitative link was developed between batch cooling crystallization and fluid turbulent shear stress (TSS). The experiments involve solution crystallization of paracetamol in isopropanol. A novel method was adopted in which a large single seed crystal of paracetamol was held stationary in an agitating reactor. Using particle imaging velocimetry, a constant TSS was obtained across different scales which resulted in a constant SNT because of crystal nuclei breeding. This led to better control over the crystallization process which eventually resulted in a consistent PSD, independent of the scale. A uniform PSD was observed at each scale which was evident through scanning electron microscopy. The investigation explicates that it is feasible to control PSD across different scales by controlling the SNT through hydrodynamics. This is proposed to be a robust approach in the crystallization process via crystal nuclei breeding, hence, providing a potential opportunity to improve the manufacturing process.