GOALI: Novel Plug flow Continuous Crystallizer with Diaphragm-Driven Suspension Transfer

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Continuous, end-to-end, and modular pharmaceutical manufacturing can increase resilience to supply chain disruption and better meet fluctuating market needs. Crystallization, a key unit operation in this value chain, is a robust and cost-effective purification and separation technique. Unlike the large-scale, high-volume productions of bulk chemicals, continuous crystallizers with well-characterized, predictable performance in the small pharmaceutical manufacturing scales and production volumes are still challenging to develop and implement. Specifically, miniaturized crystallizers ( 100 mL) are needed to accommodate the typically smaller production rates of potent and precious pharmaceuticals that can also reduce their consumption during early research and process development (R&D). This Grant Opportunities for Academic Liaison with Industry (GOALI) funded project impacts the pharmaceutical industry by addressing these needs. In addition, the project contributes to a thrust towards re-shoring pharmaceutical manufacturing to the US, initiated in 2020. Simultaneously this project offers a rich environment for undergraduate and graduate student training and exposure in interdisciplinary engineering research via strong partnerships between the University of Puerto Rico (98% Hispanic Americans, 65% women), the Massachusetts Institute of Technology, and one industrial partner.The objective of this project is to study an innovative continuous crystallizer concept that addresses the needs of pharmaceutical manufacturing for robust, scalable, and miniaturized equipment (100 mL). Ths project's novel crystallizer with a diaphragm-driven slurry transfer is expected to outperform the two common continuous crystallizers (i) mixed suspension, mixed product removal crystallizer and (ii) plug flow crystallizer by addressing all outstanding challenges of solid motion. It includes e.g., eliminating interstage slurry transfer lines, pumps/vacuum, enabling plug flow characteristics even at small flow rates, allowing more uniform spatial distribution, permitting distributed antisolvent addition, improving scalability, and offering a modular design. The project focuses on three research tasks; (1) experimentally characterize the unexplored continuous crystallizer, (2) study the hydrodynamic environment within the novel crystallizer, and (3) mathematically model and compare the novel crystallizer with common continuous crystallizers. Understanding the role of critical process parameters (e.g., supersaturation, residence time, antisolvent addition, agitation speed) and their impact on critical quality attributes (e.g., crystal size and distribution, yield) lead to mapping out the design space for the innovative crystallizer. Though focused on pharmaceutical manufacturing, the advanced science applies to all industries where process intensification for continuous crystallization is vital (e.g., fine chemicals).This project is jointly funded by the Advanced Manufacturing program, the Established Program to Stimulate Competitive Research (EPSCoR), and the Process Systems, Reaction Engineering, and Molecular Thermodynamics program.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.