Automatic Design of Wet-Milling-Integrated Batch Crystallization Processes by Process Analytical Technology-Based Split-Range Direct Nucleation Control

Wet milling is increasingly employed as a process-intensification tool in pharmaceutical batch crystallization, not only as a terminal particle-size reduction step but also as an integrated unit operation synchronized with the crystallizer to enhance process robustness and expand the attainable range of particle-size and shape distributions. Designing a high-performance batch crystallization process is challenging because of the large number of design variables that often require repeated crystallization and dissolution cycles. Synchronizing the crystallizer and wet-milling operations adds further complexity. Direct nucleation control (DNC) is widely used to automatically design cycles of crystal growth and dissolution for single-input, single-output systems─for example, adjusting the temperature to maintain the relative number density within a predefined range. This study extends the DNC principle to handle an integrated system. We propose a sequential split-range controller that regulates the relative number density by employing cooling and heating as the primary manipulated variables. When the target particle count cannot be achieved by cooling alone, a wet-milling cycle is automatically initiated to increase the count through high shear, thereby enhancing the nucleation, attrition, and breakage. Experimental results indicate that this control strategy can drive the process beyond the limits of conventional DNC, producing repeated cycles of growth and nucleation (by cooling or sequential cooling and milling) and dissolution (by heating). In addition to generating larger crystals, the automatic milling cycles also reduced the aspect ratio of rod-like particles, demonstrating the potential for simultaneous crystal-shape control. Repeated implementation of the integrated operation discovered by split-range DNC exhibited high reproducibility, underscoring the potential of the method not only as a control strategy but also as a rapid process-design tool.