Digital Design of an Integrated Continuous Crystallization, Wet Milling and Classification System with Recycle for Purity and Crystal Size Distribution Control

In recent years, continuous crystallization has gained interest in the pharmaceutical sector due to its lower manufacturing costs and maintenance. However, controlling multiple critical quality attributes (CQAs) simultaneously is challenging due to trade-offs between various mechanisms influenced by limited operating conditions. To enhance the controllability, crystallization is often integrated with other unit operations, requiring an overall process designed as an integrated system. This paper focuses on a continuous 3-stage crystallization, wet milling, and classification system within a quality-by-digital design (QbDD) framework. Emphasizing process intensification and sustainability, the system incorporates recycling to increase robustness. The attainable region of the crystal size and impurity is broadened through recirculation and the integration of downstream units. The effects of design variables on start-up behavior are also analyzed, and kinetic parameter uncertainties are studied for robustness. Validation experiments confirm that the digital design successfully predicts the system behavior for CQAs of crystal size and impurity.