(250c) Continuous Processing at Kilo Scale with Solids in Flow

Continuous processing is currently used for speed to early phase material delivery of pharmaceutical intermediates at Eli Lilly. Typical campaign size in the laboratory is 20 to 100 kg compound, and production rates are about 5-15 kg/day. Most continuous processes that we run at research and kilo scale in the development laboratory have solids in flow. Patented methods and devices for slurry mass transport are described. No mechanical pumps are used for slurry flow. Instead, automated sequenced block valves and pressure differentials are used for generating and controlling overall volumetric throughput. Pressure swing fluid transfer chambers are used for pumping and flow metering of slurries. Expansion chambers-in-series are used for depressurization of flowing slurry, and flow metering of gas. Slurry does not flow through a restricting orifice for depressurization, only sequenced block valves and finite volume pressure swing chambers. A pulsed flow generator on the outlet side of the reactor or crystallizer is used for forward and reverse direction flow pulses to minimize solids fouling and plugging. The main reasons for application of flow chemistry in our development laboratories are extreme temperatures and pressure outside the normal operating range for standard batch equipment, and hazardous chemistries. Examples presented include a thermal epimerization reaction which required superheating, and a carbonylation reaction which required high pressure. Both processes had solids in flow, and in both examples reaction, workup, and isolation were all done continuously.