(478b) Data-Driven Process Development and Scale-up of an Acetal Protection Reaction and Crystallization

Integrated process design provides many benefits such as supplying fundamental process knowledge, identifying important scaling parameters to ensure quality performance upon scale-up, and detecting safety and quality risks within the process. Herein, the principles of integrated process design were employed in the development and scale-up of an acetal protection reaction and subsequent crystallization.

The challenges associated with the acetal protection reaction were instability of the product at end-of-reaction, solvent related impurity formation, and side reaction between reagents. Kinetic, thermodynamic, and multivariate statistical models, constructed through data-rich experimentation using parallelized reactors equipped with automated sampling, elucidated key sensitivities controlling reaction rates and selectivity. This enabled optimization of the reagent loadings and conditions to achieve reasonable reaction rates and stability at the end of reaction. In the subsequent crystallization, particle agglomeration and attrition caused slow filtration. Process analytical technology in scale-down studies of shear rates revealed shear sensitivity and particle attrition of agglomerates as well as the effect of the particle size distribution on filtration rate. Mixing models guided manufacturing operating conditions to minimize particle nucleation and attrition to achieve fast filtration. These process conditions were successfully scaled-up.