Chemical reactions in flow reactors

1. Mahendra.G.S.
M.Pharm 1st year
Pharmaceutical
Chemistry
JSS College of Pharmacy,
Mysore

2. Introduction
 The concept of "flow chemistry" defines a very general
range of chemical processes that occur in a continuous
flowing stream, conventionally taking place in a
reactor zone.
 The application of flow chemistry relies on the concept
of pumping reagents using many reactors types to
perform specific reactions.
(piston pump, syringe pump etc., )

3.  Organic synthesis has traditionally been performed in
batch process..(RBF, Test tubes, clossed vessels..)
 Recently continues flow methodologies have gained
much attention from synthetic organic chemistry.
 Until a few year ago, continuous flow process were
majorly used by petrochemical & bulk chemical
industries and they proved as most economical
method.

4.  It can also be easily combined with other enabling
techenique such as: microwave irradiation, supported
reagent or catalyst, photochemistry, elecrtochemistry
etc.,
 This combination could allow the development of fully
automated process with an increased efficiency.
 Some synthetic steps that were not permitted for safety
reason can also be obtained under continuous flow ,
with minimum risk.

5. Instrumentation
a) Pumps: used to deliver reproducible quantities of solvents and reagents; the usual types are
piston, peristaltic, syringe or gear centrifugal pumps
b) Reaction loops: used to introduce small volumes of reagents
c) T-piece: primary mixing point, where reagents streams are combined
d) Coil reactor: provides residence time for the reaction
e) Column reactor: packed with solid reagents, catalysts or scavengers
f) Back pressure regulator: controls the pressure of the system
g) Downstream unit: in-line analytics, work-up operations, etc

6. Why flow chemistry…?
 Researchers from the Novartis-MIT Center for
Continuous Manufacturing in Cambridge reported in
a spectacular work the end-to-end continuous
manufacturing of an API, aliskiren hemifumarate.
 Process starts from a chemical intermediate and
perform the reaction & the required additional
operations in a continuous flow,
(quench, crystallization, isolation, purification).

7. Volume 136L
1hr
Solvent free
48hr & 13units
Flow
reactor Volume 1500L
48 hr
Solvent used
300 hr 21 units
batch
Continuous reactor volume - 0.7L 0.8 tons/ year
Commercial scale= 188 tons API / year

8. Scaling-up..
 Scaling up a chemical reaction is a challenging
process, since many problems may arise like,.
by product formation
inefficient mixing
runaway reaction
 But reaction scale-up in micro-reactor is easy when
compare to batch and there are 3 approaches.

9. 1. Scaling-out:
Run the process longer, easiest method
2. Numbering-up:
Multi-reactors in parallel are used
3. Scaling-up:
Use of larger continuous reactor
Flow chemistry can be seen as a Novel technology

10. Batch Vs Flow ChemistryBatchChemistry
• Stoichiometry is set by the
molar ratio of the reagents
used
• The reaction time is
determined by the time a
vessel is stirred under
fixed conditions
FlowChemistry
• Stoichiometry is set by
ratio of flow rate and
molarity.
• The reaction time is
expressed by the residence
time, i.e., the time
reagents spend in the
reactor zone. Residence
time is given by
• τ = V/q
where V is the volume of
the system, and q is the
flow rate for the system.

11. BatchChemistry
• The reaction kinetics are
controlled essentially by
the reagent exposure time
under the specified
reactions conditions
• Flexibility is more &
hence it is preferred in
initial production of new
compounds
• Great for the production
of small qty,
FlowChemistry
• reactions kinetics are
controlled by the flow
rates of the reagents
streams.
• Flexibility is less since it is
continuous reaction.,
modification of the
process is difficult
• Great for the commercial
production.

12. BatchChemistry
• The reagent and product
concentrations vary over
the time, and mixing
becomes very important
aspect in order to reduce
concentration gradients
that affect the kinetics of a
reaction.
• Mixing and mass transfer
is less efficient
FlowChemistry
• Each portion of the reactor
is defined by specific
concentrations of the
starting material(s) and
product(s)
• Mixing and mass transfer
is very effective and
efficient.
• The control of
temperature in flow
processes can be achieved
very accurately, due to the
high surface area-to-
volume ratio.

13. Advantages of flow chemistry
There are well-defined key advantages using flow
technologies as compared to standard batch chemistry
methods:
 Scale-up
 Extreme reaction conditions (high/low temperature, high
pressure)
 In-line downstream processing
 Automation
 Improved Safety (managing hazardous reagents and
intermediates)
 Solvent efficiency
 Improved heat transfer
 Improved mass transfer/mixing
 Reproducibility

14. Types of Flow Reactors

15. Types of Flow Reactors
 Plug flow reactors
 Column reactors
 Gas reactors
 Reactors for slurries
 Photochemical flow reactors
 Trickle bed reactors

16. Commercially available reactors
http://www.organicchemistry.org/topics/flowchemistry.shtm

17. Applications
Continuous flow synthesis of Telemisartan
Yield = 81% (97% HPLC purity)
Production rate = 1mg/min

18. Continuous flow synthesis of Ibuprofen
Yield = 83%
Production rate = 8.1g/hr
3 min synthesis

19. Continuous flow synthesis of Diphenhydramine HCl
Yield =90%
Production rate = 2.4g/hr

20. limitations
 In the synthesis of API ; clogging of the reactor
happens due to the precipitation of solids.
this is why sophisticated technologies are developed
for the handling of solids.
 Catalytic deactivation
 Future challenge is to accomplish efficient synthesis of
enantiomericaly pure product under continous flow
conditions.

21. REFERENCES
 Review article on- flow chemistry: Recent
Developments in the synthesis of pharmaceutical
product;;, Riccardo Porta, Maurizio Benaglia, and
Alessandra Puglisi
 http://www.flowchemistrysociety.com/
 http://www.flowchemistrysociety.com/journal_of_fc.p
hp
 https://en.wikipedia.org/wiki/Flow_chemistry