Flow Chemistry:

Dr John TsanaktsidisSenior Principal Research ScientistCSIRO Materials Science and Engineering

What Is It and What Can It Do?

Agenda

•Conventional Batch Manufacture

•Flow Chemistry

•Case Studies

•Summary & Conclusions

The Business of Chemistry

“The Australian chemical industry currently generates in excess of $30 billion per annum, directly employs more than 60,000 people and provides the products and 

services that underpin a modern economy”

Victorian Centre for Sustainable Chemical Manufacturing Business Plan June 2012

“The chemical sector has long been viewed by wider society as being ‘dirty’; ....”

Green Chem., 2012, 14, 38

However, .....

Conventional Chemical Manufacture

•mainstay of the fine chemical & pharmaceutical industries

Batch processing

Discovery  Development Pilot scale  Batch manufacturing scale 

Conventional Chemical Manufacture

•Capital & labour intensive– high plant, operation & maintenance costs

•Waste intensive– 5‐100+ kg of chemical wastes per kilogram of fine chemicals & 

pharmaceuticals produced

•Safety issues– high risk of exposure, runaway reactions, catastrophic events....

However.....

175 Times, and then.......

• Production of fuel additive • methylcyclopentadienyl manganese tricarbonyl

• Plant destruction due to catastrophic thermal runaway

T2 Laboratories, Florida

So how do we do it better?

•Better yields

•Less waste

•Shorter processing times

•Smaller footprint

•Lower cost ‐ plant & operating costs

What does better mean?

Chemical & Process Intensification

•Deep understanding of underlying process chemistry

•Better use of intensive reactor technologies

•Transition from batch to continuous processing 

•Modular plug & play approach; mix of process technologies

Hessel, et al, ChemSusChem, 2013, 6, 746–789

What is Flow Chemistry?

Continuous performance of chemical reactions

A

B

Reactant feed tanks

Pump

Pump Flowreactor

C

Producttank

Backpressureregulator

Mixingdevice

Pump

Additional reagents

Purificationmodule

In‐line monitoring

Pumps

Mixing Devices

Passive mixing(laminar flow)

Turbulent  mixing

Flow Reactors

A flow reactor is tubular or channelled device

Surface Area to Volume Ratio

SAV =

2rhr2h =

2r

m2/m3=4d

d

microfluidicsd (mm)

SAV

m2/m3

1 100 5000 10,000 50,0002000

4000 40 0.8 0.4 0.082

Batch mesofluidics(1‐6mm ID)

Surface Area to Volume Ratio

SAV =

2rhr2h =

2r

m2/m3=4d

d

microfluidicsd (mm)

SAV

m2/m3

1 100 5000 10,000 50,0002000

4000 40 0.8 0.4 0.082

Batch mesofluidics(1‐6mm ID)

Increasing rate of heat transfer

Flow Chemistry

•Temperature

•Residence Time  = 

•Pressure  =

•Stoichiometry

Novel process windows

Reaction (process) Parameters

Reactor VolumeTotal Flow Rate

ForceArea

Hessel, et al, ChemSusChem, 2013, 6, 746–789

Flow Chemistry – Key attributes & benefits

•Better process control• higher product yields & purities • shorter processing times 

• less waste generation

•Easily (infinitely) scalability• Scale  = Total Flow Rate x Time

•Smaller physical footprint• reduced capital, operating & maintenance costs 

• reduced energy usage

•Inherently safer• lower risk of catastrophic events & exposure

Flow Chemistry Laboratory

Vapourtec© R2/R4 Uniqsis Flowsyn

Flow Chemistry Laboratory

Chemtrix MR260 plate reactor

CRD Shell and Tube Reactor (100mL)

Flow Chemistry Laboratory

Case Study 1: Pharmaceutical Production

Reaction time:  2 min in flow vs 2days in batchYield:  ~100% increase over batch processPurity:  cleaner crude product  simpler purificationThroughput:  flexiblePlant costs: ~$0.5M vs $4‐5M for new batch plant

Pilot‐scale API manufacture

Case Study 2: Fine Chemical Manufacture

Synthesis of a photochromic dye

Case Study 2: Fine Chemical Manufacture

Synthesis of a photochromic dye (1kg scale)• 8 of the 9 steps found to be “flowable”

Dr Mark York, CMSE

Case Study 3: Fine Chemical Manufacture

Fine chemicals from refined sugars

Carbohydrateg/10 mL(conc.) Solvent T (ºC) Flow Rate

(mL/min)RT

(min)Yield(%)

Sucrose (10g) 1.0 (0.29 m) DCE 130 5 + 5 1 61

D-glucose 0.2 (0.11 m) DCE 120 1 + 1 5 58

D-fructose (10g)

1.0 (0.56 m) CH2Cl2 100 5 + 5 1 79

M. Brasholz, K. von Kaenel, C. H. Hornung, S. Saubern, J. Tsanaktsidis, Green Chemistry, 2011, 13, 1114

Summary & Conclusions

Key benefits• Better process control• Infinite scalability• Small physical footprint• Better safety

Take home• High‐value fine chemicals can be manufactured at scale, with better quality outcomes (yield, purity), at lower cost, & with better safety.

Flow Chemistry provides new paradigm for fine chemical manufacture

Questions