Solvent Effects on Crystallization Kinetics: Investigating Trends across Scales, Methods, and Process Analytical Technologies

High Resolution Image Download MS PowerPoint Slide Characterizing the crystallization kinetics is essential for robust process design and successful scale-up execution. The accuracy of this step is dependent on key considerations, such as crystallization methods, process monitoring tools, data processing techniques, and kinetic modeling approaches. These factors often limit the effective comparison and synergistic application of findings from multiple sources, particularly in the academic domain. In this work, we seek to examine how scale, operation mode, and particle size measurement techniques influence the trends in kinetic constants for secondary nucleation and crystal growth. This study builds on prior efforts toward extracting kinetic trends using small-scale crystallization experiments to support early characterization and prediction. The focus here is to investigate the behavior of the kinetic parameters in response to changes in solvent composition. Our central hypothesis is that, while absolute values of kinetic parameters will change between scales and methodologies, the general trend (e.g., which solvents promote a given rate) will be comparable. We thus investigate two strategies for estimating kinetics in academic literature: batch desupersaturation experiments at a 5 mL suspension volume and continuous antisolvent mixed suspension mixed product removal (MSMPR) crystallization experiments at the 300 mL scale. Our results indicate that the general shape of kinetic trends (i.e., solvent comparison) translates across scales and between methods, but with significant differences in the magnitude of the estimated kinetic parameters. These results highlight the significance of standardized scale-down, material-sparing experiments for the early identification of optimal operating regions and narrowing of the design space to be investigated at larger scales.