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

GOALI：带有隔膜驱动悬浮液传输的新型活塞流连续结晶器

• 批准号: 2242255
• 负责人: Torsten Stelzer
• 金额: $ 64.72万
• 依托单位: University of Puerto Rico Medical Sciences Campus
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2242255&HistoricalAwards=false
• 关键词: GOALI; Novel; Plug; flow; Continuous

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.

连续、端到端和模块化的药品生产可以增加对供应链中断的弹性，并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，是一种强大且具有成本效益的纯化和分离技术。与大规模、大批量生产散装化学品不同，在小型制药生产规模和产量中，具有良好特征、可预测性能的连续结晶器的开发和实施仍然具有挑战性。具体来说，需要小型化结晶器（100 mL）来适应强效和珍贵药物的通常较小的生产率，这些药物在早期研究和工艺开发期间也可以减少其消耗。这个与行业学术联络的资助机会（GOALI）资助的项目通过解决这些需求来影响制药行业。此外，该项目还有助于推动2020年启动的将制药生产转移到美国。同时，该项目通过波多黎各大学（98%为西班牙裔美国人，65%为女性）、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，以满足制药制造对强大，可扩展和小型化设备（100 mL）的需求。该项目的新型结晶器采用隔膜驱动的浆液输送，通过解决固体运动的所有突出挑战，其性能有望超过两种常见的连续结晶器(1)混合悬浮结晶器、混合产物去除结晶器和(2)塞流结晶器。它包括消除级间泥浆输送管线、泵/真空、即使在小流速下也能实现塞流特性、允许更均匀的空间分布、允许分布式抗溶剂添加、提高可扩展性以及提供模块化设计。该项目主要有三个研究任务；(1)对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动力环境；(3)对新型结晶器进行数学建模并与普通连续结晶器进行比较。了解关键工艺参数（如过饱和、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（如晶体尺寸和分布、产量）的影响，可以为创新结晶器规划设计空间。虽然专注于制药制造，但先进的科学适用于所有对连续结晶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、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。该奖项反映了美国国家科学基金会的法定使命，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。