Abstract
A variety of high-pressure and low-pressure plug flow reactors (PFRs) are described in this chapter with manufacturing examples for each. Coiled tube PFRs and vertical pipes-in-series PFRs were used for two-phase gas–liquid reactions. A pulsating flow coiled tube PFR was used for gas–liquid reaction with solids precipitate. Superheated PFRs were used for reactions involving homogeneous solutions, heated above the boiling point of the solvent. Disposable coiled tube PFRs were used with highly potent compounds. Continuous stirred tank reactors (CSTRs) were needed for heterogeneous continuous processes. CSTRs, CSTRs-in-series, and intermittent flow CSTRs were used for reactions with long reaction times, positive order kinetics, and multiple reaction phases, either solid/liquid or liquid/liquid. This chapter also explains how to calculate the actual internal temperature profile along the length of a PFR, which is often not practical to measure.
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- A/V :
-
Surface area to volume ratio
- API:
-
Active pharmaceutical ingredient
- CSTR:
-
Continuous stirred tank reactor
- dtbpf:
-
1,1′-Bis(di-tert-butylphosphino)ferrocene
- EE:
-
Ethoxy ethyl
- i.d. :
-
Inside diameter
- PFR:
-
Plug flow reactor
- RTD:
-
Residence time distribution
- S/C:
-
Substrate to catalyst ratio
- τ :
-
Mean residence time
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Acknowledgments
Doug Kjell and Chris Doecke developed the process for continuous hydroformylation. Brian Haeberle, Philip Hoffman, Randy Lambertus, and Tim White developed the Ir-catalyzed homogeneous reductive amination process, and Declan Hurley, Niall G. Kerrigan, and Richard Spencer scaled it up to manufacturing. Brandon Reizman and Richard Cope were engineers for the thermal EE deprotection in superheated PFR, and Mike Frederick and Joel Calvin developed the chemistry. Brandon Reizman led the thermal EE deprotection scale up to GMP manufacturing at a CMO. Ed Deweese, Paul Milenbaugh, and Rick Spears of D and M Continuous Solutions constructed and operated most of the continuous reactor systems. Matt Yates was the lead chemist for development of the continuous Schotten-Baumann reaction. Brandon Reizman and Chris Polster were engineers for the intermittent flow stirred tank reactor for 2-phase Suzuki cross-coupling. Rick Spencer, Jeff Lewis, and Mike Heller scaled up the CSTRs in series for Barbier Grignard, quench, and neutralization. Wei-Ming Sun was the deltaV automation engineer for most of these projects. We thank Bret Huff for initiating, leading, and sponsoring the continuous reaction design and development work at Eli Lilly and Company.
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© 2020 American Association of Pharmaceutical Scientists
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Johnson, M.D. et al. (2020). Continuous Reactors for Pharmaceutical Manufacturing. In: Nagy, Z., El Hagrasy, A., Litster, J. (eds) Continuous Pharmaceutical Processing. AAPS Advances in the Pharmaceutical Sciences Series, vol 42. Springer, Cham. https://doi.org/10.1007/978-3-030-41524-2_2
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DOI: https://doi.org/10.1007/978-3-030-41524-2_2
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