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Flow Chemistry:
Dr John TsanaktsidisSenior Principal Research ScientistCSIRO Materials Science and Engineering
What Is It and What Can It Do?
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
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
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 (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