[en] Pharmaceutical manufacturing typically uses batch processing at multiple locations. Disadvantages of this approach include long production times and the potential for supply chain disruptions. As a preliminary demonstration of an alternative approach, we report here the continuous-flow synthesis and formulation of active pharmaceutical ingredients in a compact, reconfigurable manufacturing platform. Continuous end-to-end synthesis in the refrigerator-sized [1.0 meter (width) × 0.7 meter (length) × 1.8 meter (height)] system produces sufficient quantities per day to supply hundreds to thousands of oral or topical liquid doses of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride that meet U.S. Pharmacopeia standards. Underlying this flexible plug-and-play approach are substantial enabling advances in continuous-flow synthesis, complex multistep sequence telescoping, reaction engineering equipment, and real-time formulation.
Research Center/Unit :
MIT
Disciplines :
Chemistry
Author, co-author :
Adamo, Andrea; Massachusetts Institute of Technology - MIT > Chemical Engineering
Beingessner, Rachel L.; Massachusetts Institute of Technology - MIT > Chemistry
Behnam, Mohsen; Massachusetts Institute of Technology - MIT > Chemical Engineering
Chen, Jie; Massachusetts Institute of Technology - MIT > Chemical Engineering
Jamison, Timothy F.; Massachusetts Institute of Technology - MIT > Chemistry
Jensen, Klavs F.; Massachusetts Institute of Technology - MIT > Chemical Engineering
Monbaliu, Jean-Christophe ; Université de Liège > Département de chimie (sciences) > Center for Integrated Technology and Organic Synthesis - CiTOS
Myerson, Allan S.; Massachusetts Institute of Technology - MIT > Chemical Engineering
Revalor, Eve M.; Massachusetts Institute of Technology - MIT > Chemical Engineering
Snead, David R.; Massachusetts Institute of Technology - MIT > Chemistry
Stelzer, Torsten; Massachusetts Institute of Technology - MIT > Chemical Engineering
Weeranoppanant, Nopphon; Massachusetts Institute of Technology - MIT > Chemical Engineering
Wong, Shin Yee; Massachusetts Institute of Technology - MIT > Chemical Engineering
Zhang, Ping; Massachusetts Institute of Technology - MIT > Chemistry
scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.
Bibliography
C. Badman, B. L. Trout, J. Pharm. Sci. 104, 779-780 (2015).
I. R. Baxendale et al., J. Pharm. Sci. 104, 781-791 (2015).
S. Byrn et al., J. Pharm. Sci. 104, 792-802 (2015).
R. F. Service, Science 347, 1190-1193 (2015).
S. Mascia et al., Angew. Chem. Int. Ed. 52, 12359-12363 (2013).
Food and Drug Administration, Strategic Plan for Preventing and Mitigating Drug Shortages (October 2013; www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM372566.pdf).
L. Malet-Sanz, F. Susanne, J. Med. Chem. 55, 4062-4098 (2012).
D. Webb, T. F. Jamison, Chem. Sci. 1, 675-680 (2010).
R. L. Hartman, J. P. McMullen, K. F. Jensen, Angew. Chem. Int. Ed. 50, 7502-7519 (2011).
V. Hessel, Chem. Eng. Technol. 32, 1655-1681 (2009).
R. J. Ingham et al., Angew. Chem. Int. Ed. 54, 144-148 (2015).
B. Gutmann, D. Cantillo, C. O. Kappe, Angew. Chem. Int. Ed. 54, 6688-6728 (2015).
M. Baumann, I. R. Baxendale, Beilstein J. Org. Chem. 11, 1194-1219 (2015).
F. Lévesque, P. H. Seeberger, Angew. Chem. Int. Ed. 51, 1706-1709 (2012).
M. D. Hopkin, I. R. Baxendale, S. V. Ley, Org. Biomol. Chem. 11, 1822-1839 (2013).
C. A. Correia, K. Gilmore, D. T. McQuade, P. H. Seeberger, Angew. Chem. Int. Ed. 54, 4945-4948 (2015).
M. Viviano, T. N. Glasnov, B. Reichart, G. Tekautz, C. O. Kappe, Org. Process Res. Dev. 15, 858-870 (2011).
P. Zhang, M. G. Russell, T. F. Jamison, Org. Process Res. Dev. 18, 1567-1570 (2014).
D. Ghislieri, K. Gilmore, P. H. Seeberger, Angew. Chem. Int. Ed. 54, 678-682 (2015).
P. R. D. Murray et al., Org. Process Res. Dev. 17, 1192-1208 (2013).
P. L. Heider et al., Org. Process Res. Dev. 18, 402-409 (2014).
D. J. Am Ende, in Chemical Engineering in the Pharmaceutical Industry, D. J. am Ende, Ed. (Wiley, NJ, 2011), chap. 1.
A. Adamo, P. L. Heider, N. Weeranoppanant, K. F. Jensen, Ind. Eng. Chem. Res. 52, 10802-10808 (2013).
C. F. Carter et al., Org. Process Res. Dev. 14, 393-404 (2010).
G. Rieveschl, Dialkylaminoalkyl benzhydryl ethers and salts thereof, U.S. Patent 2,421,714A, 3 June 1947.
S. Y. Wong, J. Chen, L. E. Forte, A. S. Myerson, Org. Process Res. Dev. 17, 684-692 (2013).
Food and Drug Administration, FDA Perspective on Continuous Manufacturing, (February 2013; www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM341197.pdf).
S. L. Lee et al., J. Pharm. Innov. 10, 191-199 (2015).
S. D. Schaber et al., Ind. Eng. Chem. Res. 50, 10083-10092 (2011).
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