The integration of rotor-stator wet mill and continuous mixed suspension mixed product removal crystallizer (MSMPRC) is studied in this work. The wet mill is applied in two different configurations: (1) downstream in a recycle loop to continuously reduce particle size via controlled secondary nucleation and breakage; and (2) upstream as a high shear nucleator to continuously generate seed crystals in situ. These two novel approaches are compared to continuous MSMPRC without wet mill. In addition, the influences of wet mill operating conditions (i.e., tip speed, number of turnover per residence time) on five important product and process qualities, including average particle size, particle number, width of size distribution, yield, and startup duration are identified for both configurations. The paper demonstrates that desired average crystal size, narrow size distribution, high yield, and very short startup duration can be achieved at the same time by applying the rotor-stator wet mill upstream as a continuous in situ high shear seed generator followed by continuous MSMPRC.

Automated direct nucleation control (ADNC) is a focused beam reflectance measurement-based feedback control approach that is used to produce large and uniform crystals in batch cooling crystallization. In this work, this feedback control approach is modified to work for continuous cooling crystallization processes, including single-stage and multistage mixed suspension mixed product removal crystallizers. The proposed continuous ADNC approach is observed to provide quick startup, high quality control of crystal size distribution, as well as automated and effective disturbance suppression.

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A continuous multistage mixed suspension, mixed product removal (MSMPR) cascade crystallization system has been modeled and optimized for both the steady-state and the startup behaviors when both cooling and antisolvent addition are applied as the crystallization driving forces. The optimal steady-state operating profiles of MSMPR cascade crystallizers have been obtained and found to be similar to the optimal batch trajectory. In addition, the minimum startup duration time is used as the objective function to optimize the startup behavior. Methods, including changing the initial solution compositions, applying dynamic antisolvent profiles, applying dynamic temperature profiles, and applying dynamic combined antisolvent and temperature profiles, are discussed and used to formulate the optimization problems. The optimal results indicate that for a cascade of two MSMPR crystallizers, it is possible to achieve a reduction of approximately 50% of the startup duration time and amount of waste. A model-free or direct design approach via closed-loop control to improve the startup performance is also proposed.

As the pharmaceutical industry evolves and goes through the paradigm shift from batch to continuous manufacturing, innovative processes need to be developed to replace unit operations that have historically been batch operations. This requires innovation in the continuous crystallization field of study as well as innovation in downstream processes (e.g. filtration, drying, milling, and granulation). Herein a novel and commercially available continuous filter carousel (CFC) system was assessed for its feasibility of continuous filtration while coupled with a continuous mixed suspension mixed product removal (MSMPR) crystallizer. The filtration system was assessed using two different crystallization systems (i.e. cooling and antisolvent) with significantly different kinetics and morphologies to assess the robustness of the integrated platform. With proper optimization of the various filtration parameters for the different crystallization systems a controlled state of operation was achieved in each case. The crystal product from the CFC system shows good consistency with the crystals in the slurry in the MSMPR. Moisture content and productivity of the filtration system were reported and show dependency on crystal properties. The CFC system was equipped with solvent vessels that aided the continuous filtration by acting as a wash or a clean-in-place solvent, preventing or removing filter clogging, respectively.