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

连续、端到端和模块化的制药制造可以提高供应链中断的弹性，更好地满足波动的市场需求。结晶是该价值链中的关键单元操作，是一种稳健且具有成本效益的纯化和分离技术。与大宗化学品的大规模、高产量生产不同，在小型制药生产规模和生产量中具有良好特征和可预测性能的连续结晶器的开发和实施仍然具有挑战性。具体而言，需要小型化结晶器（100 mL）来适应强效和贵重药物通常较小的生产率，这也可以减少早期研究和工艺开发（R D）期间的消耗。这个赠款机会学术联络与行业（GOALI）资助的项目通过解决这些需求影响制药行业。此外，该项目还有助于推动2020年启动的将制药制造业转移到美国的计划。同时，该项目通过波多黎各大学之间的强有力的合作伙伴关系，为本科生和研究生的培训和跨学科工程研究提供了丰富的环境。（98%的西班牙裔美国人，65%的女性），马萨诸塞州理工学院，该项目的目标是研究一种创新的连续结晶器概念，以满足制药行业的需求。用于制造耐用、可扩展和小型化设备（100 mL）。该项目的新型结晶器采用了螺杆驱动的浆料传输，预计将优于两种常见的连续结晶器（i）混合悬浮液、混合产物去除结晶器和（ii）活塞流结晶器，解决固体运动的所有突出挑战。它包括，例如，消除了级间淤浆输送管线、泵/真空，即使在小流速下也能实现活塞流特性，允许更均匀的空间分布，允许分散的抗溶剂添加，提高可扩展性，并提供模块化设计。该项目的重点是三个研究任务：（1）实验表征未开发的连续结晶器，（2）研究新型结晶器内的流体动力学环境，（3）数学模型，并将新型结晶器与普通连续结晶器进行比较。了解关键工艺参数的作用（例如，过饱和度、停留时间、反溶剂添加、搅拌速度）及其对关键质量属性的影响（例如，晶体尺寸和分布、产率）导致绘制出创新结晶器的设计空间。虽然专注于制药，先进的科学适用于所有行业的过程强化连续结晶是至关重要的（例如，该项目由先进制造计划、刺激竞争研究的既定计划（EPSCoR）以及过程系统、反应工程和分子热力学计划共同资助。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.