This document discusses flow chemistry and its advantages over traditional batch chemistry. Flow chemistry involves pumping reagents continuously through reactors to perform reactions. It offers benefits like improved safety, reproducibility, mixing, heat/mass transfer. Several types of flow reactors and applications in drug synthesis are described. Advantages include ease of scale-up, ability to achieve extreme reaction conditions, integration with downstream processing, and automation. Limitations include potential for clogging and catalytic deactivation over time.

1. Mahendra.G.S.
M.Pharm
Pharmaceutical Chemistry
JSSCP,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