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

连续、端到端和模块化的制药生产可以提高对供应链中断的弹性，并更好地满足不断变化的市场需求。结晶是这一价值链中的关键单元操作，是一种稳健且具有成本效益的提纯和分离技术。与大规模、大批量生产散装化学品不同，连续结晶器在小规模和生产量的制药生产中具有良好的特性和可预测的性能，在开发和实施方面仍然具有挑战性。具体地说，需要微型结晶器(100毫升)，以适应通常较小的强效和贵重药物的生产速度，这也可以减少它们在早期研究和工艺开发(R&A；D)期间的消耗。这项由GOALI资助的学术联系机会项目通过满足这些需求影响了制药业。此外，该项目有助于推动2020年启动的将制药制造业务迁往美国的努力。同时，该项目通过波多黎各大学(98%的拉美裔美国人，65%的女性)、麻省理工学院和一个工业合作伙伴之间的紧密合作，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。该项目的目标是研究一种创新的连续结晶器概念，以满足制药制造对坚固、可扩展和小型化设备(100毫升)的需求。该项目的新型结晶器采用隔膜驱动的浆料输送，预计其性能将超过两种常见的连续结晶器(I)混合悬浮结晶器、混合产品去除结晶器和(Ii)推流结晶器，因为它解决了固体运动的所有突出挑战。它包括，例如，取消级间浆料输送管道、泵/真空、即使在小流量下也能实现推流特性、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，以及提供模块化设计。本项目主要集中在三个方面的研究工作：(1)对尚未开发的连续结晶器进行实验表征；(2)研究新型结晶器内的流体力学环境；(3)对新型结晶器与普通连续结晶器进行数学建模和比较。了解关键工艺参数(例如过饱和度、停留时间、抗溶剂添加、搅拌速度)的作用及其对关键质量属性(例如晶体大小和分布、产率)的影响，有助于规划创新结晶器的设计空间。虽然专注于制药制造，但先进科学适用于所有持续结晶的过程强化至关重要的行业(例如精细化学品)。该项目由先进制造计划、既定的激励竞争研究计划(EPSCoR)以及过程系统、反应工程和分子热力学计划联合资助。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.