(328c) Advancing Flow Chemistry Portability: Approach to Crossing the Chasm

Authors: 
Naber, J. R. - Presenter, Merck & Co. Inc.
Levesque, F., Merck & Co. Inc.
Rogus, N., Merck and Co. Inc.
Spencer, G., Merck and Co. Inc.
Grigorov, P., Merck & Co. Inc.
McMullen, J. P., Merck & Co. Inc.
Thaisrivongs, D. A., Merck and Co. Inc.
Davies, I. W., Princeton University
Advancing Flow Chemistry Portability: Approach to Crossing the Chasm

François Lévesque, Nicholas J. Rogus, Glenn Spencer, Plamen Grigorov, Jonathan P. McMullen, David A. Thaisrivongs, Ian W. Davies, John R. Naber

The manufacturers of active pharmaceutical ingredients and their intermediates have recently rediscovered flow chemistry and continuous processing.[i] This renewed interest in these technologies[ii] has arisen from the anticipated benefit in supply chain economics and regulatory pressure in addition to the obvious opportunity for improved control including heat and mass transfer,[iii] process safety, access to high pressure and high temperature conditions,[iv] and use of supported catalysts[v] and biocatalysts[vi].

In some parts of the community there has been an assumption of ease and straightforward scalability for flow chemistry. However, when a flow step is embedded between two batch operations the flow step would ideally be completed within the same amount of time as a typical batch operation, which in our experience is usually 8 - 24 hours. To achieve this requirement, productivity obtained in a laboratory scale reactor would need to be increased by several orders of magnitude, precluding the simple scale out or numbering-up approaches. In the case of reactions that require optimal mixing for selectivity and yield, the need to preserve the same characteristics at production scale is essential. Achieving this goal would depend on our capacity to characterize mixers and define the minimum requirements to maintain the same mixing intensity.

We report mixing characterization of five lab scale and eight production scale static mixers using a modified 4th Bourne reaction. An efficient inline method relying on UV-visible spectroscopy was developed to streamline analysis of product distribution. As a result of these studies we have designed, 3D-printed and characterized a stainless steel static mixer across four orders of magnitude. This approach allowed evaluation of different configurations and ensures efficient scale-up across development and commercial facilities that should allow for enhanced portability of mixing sensitive processes.

[i] Cole, K. P.; McClary Groh, J.; Johnson, M. D.; Burcham, C. L.; Campbell, B. M.; Diseroad, W. D.; Heller, M. R.; Howell, J. R.; Kallman, N. J.; Koenig, T. M.; May, S. A.; Miller, R. D.; Mitchell, D.; Myers, D. P.; Myers, S. S.; Phillips, j. L.; Polster, C. S.; White, T. D.; Cashman, J.; Hurley, D.; Moylan, R.; Sheehan, P.; Spencer, R. D.; Desmond, K.; Desmond, Gowran, O. Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions, Science, 2017, 356, 1144-1150.

[ii] Plutschack, M. B.; Pieber, B.; Gilmore, K.; Seeberger, P. H. The Hitchhiker’s Guide to Flow Chemistry, Chem. Rev. 2017, 117, 11796-11893.

[iii] Yoshida, J.-I.; Takahashi, Y.; Nagaki, A. Flash chemistry: flow chemistry that cannot be done in batch, Chem. Comm. 2013, 49, 9896-9904.

[iv] Gutmann, B.; Cantillo, D.; Kappe, C. O. Continuous-flow technology—a tool for the safe manufacturing of active pharmaceutical ingredients, Angew. Chem. Int. Ed. 2015, 54, 6688-6728.

[v] Kirschning, A.; Solodenko, W.; Mennecke, K. Combining Enabling Techniques in Organic Synthesis: Continuous Flow Processes with Heterogenized Catalysts, Chem. Eur. J. 2006, 12, 5972-5990.

[vi] Sheldon, R. A.; Woodley, J. M. Role of Biocatalysis in Sustainable Chemistry, Chem. Rev. 2017, asap. DOI: 10.1021/acs.chemrev.7b00203