(267d) Robust Parallelization of Triphasic Micro/Millireactors for Sustainable Pharmaceutical Manufacturing
AIChE Annual Meeting
2015 AIChE Annual Meeting Proceedings
Pharmaceutical Discovery, Development and Manufacturing Forum
Applications of Continuous Processing in the Manufacture of Pharmaceuticals: Drug Substance I
Tuesday, November 10, 2015 - 9:45am to 10:10am
Robust Parallelization of Triphasic Micro/Millireactors for Sustainable Pharmaceutical Manufacturing
Swee Kun Yap, Wai Kuan Wong, Nicholas Xiang Yang Ng, Ning Yan, and Saif A. Khan
Department of Chemical and Biomolecular Engineering
National University of Singapore, SINGAPORE
Metal-catalyzed gas-liquid reactions, such as hydrogenation, carbonylation and halogenations are ubiquitous in pharmaceutical and fine chemical manufacturing. Such reactions are typically carried out in stirred batch reactors, and face several challenges in the form of mass and heat transport limitations, which often require energy intensive solutions such as high stirring rates and pressurization. There is considerable interest in continuous-flow micro/millireactor technology for gas-liquid reactions due to the tremendous acceleration in heat and mass transport possible in such systems, in addition to the prospect of facile phase separation. We have previously demonstrated the design and application of a triphasic segmented flow millireactor for rapid nanoparticle-catalyzed reactions with facile catalyst recovery.[2,3] Here, we present the first demonstration of robust eight-fold parallelization of triphasic millireactors for sustainable pharmaceutical manufacturing. Specifically we demonstrate a novel parallelized reactor system for rapid hydrogenation reactions with facile catalyst recovery and recycle. Parallel operation of multiphase microfluidic circuits presents several unique challenges over their single-phase counterparts; in particular, nonlinear pressure-flow characteristics lead to severe problems with robust and equal routing of the same multiphase flow in the various arms of a parallelized flow network. Biphasic circuits have been studied extensively in recent years, and parallelized biphasic circuits have been demonstrated recently. The dynamics of triphasic circuits, comprising a gas and two liquid phases, are considerably more complex. In our demonstration of numbering-up to eight parallel triphasic flow millireactors, the segmented flow in each millireactor consists of aqueous NPs, organic substrate and hydrogen gas at near atmospheric pressure. Feed solutions (aqueous NPs and organic substrate) are drawn from their respective reservoirs by means of peristaltic pumps, the latter being preferred over syringe pumps due to limited syringe capacities. However, flow rate fluctuations are typical of peristaltic pumps, and these fluctuations dramatically influence the stability of the three-phase flows in the parallelized reactor system. We also demonstrate the design of inline hydraulic damper systems for fluid delivery, which are able to damp out pressure fluctuations from the pumps, thereby allowing for the formation of a smooth triphasic flow in all the eight millireactors. We model, from the principles of fluid mechanics, the flow profile of fluid in the hydraulic dampers to better understand the influence of tube material in regulating pressure fluctuations in a parallelized multiphase flow system. Our system is then applied in the hydrogenation of nitrobenzene, a model pharmaceutical substrate. The parallelized system yields a consistent conversion of (80 ± 4)% across all eight reactors over the course of several hours, with a throughput of ~10 mL/h. Finally, we demonstrate continuous catalyst recovery and recycle, where the aqueous PtNPs are subsequently continuously recycled. In summary, we present a robust and general scheme for parallelization of triphasic flows, and demonstrate an industrially relevant application in sustainable pharmaceutical manufacturing.
 E.R. Murphy, J.R. Martinelli, N. Zaborenko, S.L. Buchwald, K.F. Jensen, Angew. Chem. Int. Ed. 46, pp. 1734- 1737, 2007.
 S.K. Yap, Y. Yuan, L. Zheng, W.K. Wong, J. Zhang, N. Yan, S.A. Khan, Green Chem. 16, pp. 4654-4658, 2014.
 S.K. Yap, Y. Yuan, L. Zheng, W.K. Wong, N. Yan, S.A. Khan, J. Flow Chem. 4, pp. 200-205, 2014.
 M. Al-Rawashdeh, L.J.M. Fluitsma, T.A. Nijhuis, E.V. Rebrov, V. Hessel and J.C. Schouten, Chem. Eng J., 181-182, 549 (2012).
 "The Physics of Pulsatile Flow," M. Zamir, Biological physics series, Springer, 2000