(328a) Continuous Plug-Flow Crystallization with Anti-Fouling Control

While plug-flow crystallization (PFC) has been touted as a promising continuous pharmaceutical unit operation, it is prone to fouling or "encrustation", a phenomena by which uncontrolled crystallization occurs on the crystallizer's surface. This results in operational issues such as flow blockage, increased thermal resistance, and reduced supersaturation, which in turn lead to limited continuous operation and reduced crystal quality and yield. Here, we introduce a model-based and model-free anti-fouling control (AFC) via spatial and temporal heating and cooling cycle. The two methods are compared with optimized PFC operation without AFC under two conditions: (1) maximization of crystal growth in the presence of encrustation and (2) minimization of encrustation while maintaining sufficient crystal growth. Specifically, the study contrasts an open-loop control approach, analogous to quality-by-design (QbD), with a feedback control approach, referred to herein as quality-by-control (QbC) concept. The computational and experimental results highlight the pros and cons of the different AFC designs as well as demonstrates the effect of PFC designs in terms of number of temperature segmentations, the segment length and the cycling frequency between the heating and cooling cycles, to the control performance.