Continuous flow reactor for pharmaceutical synthesis

01

Set residence time, pressure and temperature

The University of Liège's FloW4All facility describes its Corning Advanced-Flow Reactor G1 in glass as a pilot-scale continuous flow reactor with 9 mL internal volume per fluidic module, flow rates of 30–200 mL/min, operating conditions from –60 °C to 200 °C up to 18 bar, and wetted parts of glass, perfluorinated polymers and PEEK, designed for simplified scale-up to production with Corning technology. [2]

ICH Q13 notes that plug-flow reactor design — dimension and configuration — allows control of temperature, heat and mass-transfer rates and reaction time, and that in its worked example these parameters were shown to drive the drug substance impurity profile; stoichiometry was controlled by feed concentrations and flow rates, and conversion by reaction temperature and flow rate. [1]

Editorial calculation: mean residence time is internal volume divided by total flow. One 9 mL module gives 9 / 200 ≈ 2.7 s at 200 mL/min and 9 / 30 = 18 s at 30 mL/min; ten modules in series (90 mL) at 30 mL/min give 3 min. Running at 200 mL/min for 24 h passes about 288 L. The module count is an assumed example. [2]

Give the supplier the chemistry (phases, solids, gases, exotherm, corrosives), required residence time and temperature, maximum pressure, total flow and annual output, wetted-material compatibility, mixing and heat-transfer needs, PAT and sampling points, diversion valves, automation and data integrity, and cleaning approach.

02

Build the ICH Q13 control strategy around the reactor

ICH Q13 (Continuous Manufacturing of Drug Substances and Drug Products, adopted November 2022) says process dynamics should be characterised, for example by residence time distribution (RTD), which is specific to the process, material and equipment design, and which supports material tracking, sampling and diversion strategies; changes in RTD can affect conversion, yield and impurity formation. RTD may be studied with tracers that behave like the stream they replace, or by step changes in composition. [1]

The guideline allows batch size to be defined by output quantity, input quantity, or run time at a defined mass flow rate, or as a range of run times. In its drug-substance example, diversion points after each plug-flow reactor remove non-conforming material when conditions fall outside acceptance criteria, online PAT at the second reactor exit feeds back to the addition rate of a reagent, timing and duration of diversion are set from the modelled and tracer-confirmed RTD, and surge tanks decouple upstream and downstream flow rates. [1]

Editorial note: ask the reactor supplier to provide the RTD of the delivered equipment at your planned flow rates, the hold-up volume between each sensor and diversion valve, and how alarms trigger diversion — these define how much material is lost on a disturbance.

03

Read a telescoped three-step API synthesis in tubing reactors

US patent 8,426,630 B2, assigned to the Florida State University Research Foundation (priority 2009), describes a three-step continuous synthesis of ibuprofen in PFA tubing with no intermediate purification. Step one, a Friedel-Crafts acylation of isobutylbenzene with propionic acid in triflic acid (TfOH), runs through a 50 cm PFA segment in an oil bath at about 150 °C; the stream is cooled to about 0 °C at a tee, joined by a PhI(OAc)2/TMOF stream at 131.5 µL/min, and passed through 80 cm of PFA at about 50 °C; a base stream at about 260.0 µL/min then enters 300 cm of PFA at about 65 °C for hydrolysis. The patent states that unions, junctions and tubes must resist TfOH, naming Teflon PFA or metal. [4]

The patent reports about 68% crude yield (average of three trials) at about 96% purity by GC and GC/MS, and states that with under 500 cm of tubing and five syringe pumps the system generates about 9 mg/min of crude ibuprofen, with parallel reactors or longer channels proposed for higher throughput. It notes that at 50 °C with a 5 minute residence time, reagent immiscibility and plug flow gave poor mixing and low conversion in step one, so it raises that temperature to 150 °C. [4]

Editorial calculation: the first-step feeds of 15.1 µL/min and 28.7 µL/min total 43.8 µL/min; after the two later additions, total flow reaches about 435 µL/min, ten times the first-step flow, so later reactors need longer tubing for comparable residence time. About 9 mg/min is 0.54 g/h, about 13 g per 24 h day. [4]

04

Multiphase, microchannel and photochemical modules on offer

The listing reviewed offers multiphase, microchannel, hydrogenation, Grignard, loop and photochemical continuous flow reactors as skid-mounted modules [3]; ask for internal volume, flow, pressure and temperature ratings and wetted materials for each.

05

Pumps, reactor modules, back-pressure and diversion on a flow skid

Diversion valves and surge tanks come from the ICH Q13 example rather than a reactor maker's list; ask whether they sit inside the supplier's scope. [1]

06

Residence time is volume over flow: give the supplier both

Residence time follows from module volume and flow, so give both; the example ratings come from the Liège Corning G1 module. [2]

07

Send the chemistry, flow and GMP data together

Paste it into your enquiry below or into an email to a maker, then replace every bracket.

Chemistry: [phases; solids; gases; exotherm; corrosives]
Conditions: [temperature; pressure; residence time]
Output: [flow; kg per day]
Materials: [wetted parts]
Monitoring: [PAT; sampling]
Control: [diversion valves; surge; automation]
GMP: [RTD data; batch definition; data integrity]
Cleaning: [method; changeover]

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