\\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Title-R1d.png Petr Beňovský CONTINUOUS PROCESSES, FLOW CHEMISTRY \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CONTINUOUS PROCESSES BATCH PRODUCTION CONTINUOUS PRODUCTION 2 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png Typical Signals of Potential Problems on Scale-up • •Change of mixing speed changes product yield; •Different mode of addition changes product yield; •The position of a feed stream changes product yield; •Scale up to a vessel with different geometry; •Different holding time before work up; •Poor heat transfer; •Stability of intermediates; •Different stirring • • • • CONTINUOUS PROCESSES 3 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CONTINUOUS PROCESSES 4 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CONTINUOUS PROCESSES Typical Elements of a Continuous process: •Efficient mixing enables fine control of reaction temperature within the whole reactor Static mixers High Surface area / Volume Ratio 5 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CONTINUOUS PROCESSES Typical Elements of a Continuous process: •Continuous operations can be applied for both cryogenic and high temperature processes; •Much broader range of temperatures; •Effective with respect to energy; 6 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CONTINUOUS PROCESSES Typical Elements of a Continuous process: •Reactive species can be separated thus minimizing side products (and raising yields); • 7 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CONTINUOUS PROCESSES Typical Elements of a Continuous process: •Utilization of nontraditional techniques (photochemistry, sonochemical reactions, passing through a bed of a catalyst or immobilized enzyme) • 8 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CONTINUOUS PROCESSES Typical Elements of a Continuous process: •Enables much safer processes; •Only tiny portion of the reaction mixture is exposed to high temperature or exothermic reaction occurs only with very small amount of reactants; •Advantage working with highly toxic compounds (cyanides, phosgene, diazomethane, ozone) • 9 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CONTINUOUS PROCESSES Typical Elements of a Continuous process: •Opportunity in the field of intellectual property; •Relatively easy monitoring in real time (PAT); •Variability according to a purpose; •Supported by authorities; •Fitting well into Quality by Design concept; •Sometimes untypically milder reaction conditions; •Increasing of productivity (scaling out, numbering up); • 10 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CONTINUOUS PROCESSES Typical Elements of a Continuous process: •Need for efficient and robust pumps, inert tubings, vessels to collect products and store starting components, fittings, pressure gauges, pressure relief valves, static mixers, heat exchangers, separators •Residence time (average time needed for a molecule to pass through a reactor); •Flow rate (ml per min.); • 11 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png FLOW CHEMISTRY Artemisinin continuous production Used in the treatment of malaria 2015 – Nobel prize for its discovery (1972) Extracted from plant Artemisia annua (sweet wormwood) 12 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png FLOW CHEMISTRY Artemisinin continuous production Lévesque, F.; Seeberger, P.H. Angew.Chem. Int. Ed. 51, 1706 (2012) 13 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png FLOW CHEMISTRY Artemisinin continuous production Lévesque, F.; Seeberger, P.H. Angew.Chem. Int. Ed. 51, 1706 (2012) 14 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png FLOW CHEMISTRY Artemisinin continuous production Lévesque, F.; Seeberger, P.H. Angew.Chem. Int. Ed. 51, 1706 (2012) 1500 simple photoreactors (each 200 g of artemisinin a day) would be sufficient to cover demand for roughly 225 million doses necessary for the malaria treatment (2009 WHO estimate) 15 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png FLOW CHEMISTRY Microreactors Chemtrix company microreactor 16 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png FLOW CHEMISTRY Microreactors DSM company, control of the exothermic Ritter reaction on very large scale (40 tons a day); Decreased decomposition Yield was increased by 15% Waste was decreased by 15% Ondrey, G. Chem. Eng. 118, 17 (2011) 17 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png FLOW CHEMISTRY DSM company The microstructured flow reactor for throughput at 1700 kg per hour 18 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png FLOW CHEMISTRY Microreactors ThalesNano company Spadoni, C. et al Chim. Oggi 38 (2006) 19 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png FLOW CHEMISTRY Microreactors Uniqsys (GB) 20 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png FLOW CHEMISTRY Microreactors Chemtrix 21 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png FLOW CHEMISTRY Microreactors ThalesNano 1.Q 2020 MicroCubeTM 22 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png FLOW CHEMISTRY Microreactors ThalesNano product brochure 23 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CONTINUOUS PROCESSING Halford, B. C&EN Global Enterprise 95, 23 (2017) Eli Lilly, new production unit utilizing continuous processes in Kinsale, Ireland; Prexasertib monolactate monohydrate 8 continuous process step, including using hydrazine; Designated production unit, the product is cytotoxic ® extensive cleaning measures, only 24 kg needed; Small flow set up could be after each lot discarded; 24 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CONTINUOUS PROCESSING Continuous Operations Using Larger Reactors Spinning Disk Reactor •Thin films of reactant solution permitting rapid heat exchange; •Solutions applied to the center of a spinning disk are driven to the edges by centrifugal forces; •The contact time with the disk is inversly proportional to the angular velocity; •Preferred for fast reactions; • Org. Process Res. Dev. 15, 997 (2011) https://www.youtube.com/watch?v=6HRed3JPXTk 25 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CONTINUOUS PROCESSING Continuous Operations Using Larger Reactors Spinning Disk Reactor 26 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CONTINUOUS PROCESSING Continuous Operations Using Larger Reactors Spinning Tube-in-Tube Reactor •Reactor of this type increases reaction rates by improving mixing through high shear rate, which is independent of the residence time and dependent upon the angular velocity and the gap between the spinning internal tube and the stationary external tube • •Gonzales, M.A. et al Org. Process Res. Dev. 13, 64 (2009) • •Hampton, P.D. et al Org. Process Res. Dev. 12, 946 (2008) 27 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CONTINUOUS PROCESSING Continuous Operations Using Larger Reactors Spinning Tube-in-Tube Reactor 28 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CONTINUOUS PROCESSING Continuous Operations Using Larger Reactors Plug Flow Reactors •Reactants mix in thin discs (plugs) moving away from the entry point (theoretical assumption); •Mixing in radial direction, no mixing in axial direction; •The composition changes until a plug of product emerges from the reactor; •Turbulence can be amplified by the presence of static mixers 29 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CONTINUOUS PROCESSING Continuous Operations Using Larger Reactors Plug Flow Reactors 30 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CONTINUOUS PROCESSING Kitson, P.J. et al Science 359, 314 (2018) 31 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CONTINUOUS PROCESSING AND FLOW CHEMISTRY Summary •Used for decades in petrochemical and food industry; •Start to attract attention even in conservative pharmaceutical industry; •Going commercial – new already established companies offering service, expertise, solutions and products; •Boom of new materials – microreactors (glass, ceramic, metal), pumps, tubings, mixers, fittings, valves, prepacked columns); •Disadvantage – clogging, corrosion, •Lack of common experience and expertise; •Continuous processes are not suitable for all reactions 32