Week 3: Green Chemistry and Continuous-Flow Processing

Week 3: Green Chemistry and
Continuous-Flow Processing
 Green chemistry and sustainable engineering
 Process intensification and its reactors
 Flow chemistry
 Modularised flexible container production
 Life-cycle assessment for sustainability assessment
Understand modern processing concepts that are game-

changing for pharma – flow chemistry, green chemistry, …
Week 3 School of Chemical Engineering Life Impact The University of Adelaide

LECTURER
Prof. Volker Hessel
Room: N210, Engineering North
Email: volker.hessel@adelaide.edu.au
Student Consulting Period: Friday 09:30 - 11:30 am
Literature
1) Green Chemistry: (a) P. T. Anastas Tetrahedron 66 (2010) 1026–1027
2) Process Intensification: A. I. Stankiewicz, J. A. Moulijn, Chem. Eng. Progress 1, (2000)
22-34. b) J. R. Burns, J. N. Jamil, C. Ramshaw, Chem. Eng. Sci. 2000, 55, 2401-2415
3) Microreactors: P. L.Suryawanshi, S. P. Gumfekar, B. A. Bhanvase, S. H. Sonawane, M.
S. Pimplapure Chem. Eng. Sci. 189 (2018) 431-448; Y. Yan, Y. Zhang, L. Du, J. Liu, J.
Yao Renewable and Sustainable Energy Reviews 47 (2015) 519-539
4) Flow Chemistry: M. B. Plutschack, B. Pieber, K. Gilmore , P. H. Seeberger Chem. Rev.
117, 18 (2017) 11796–11893; V. Hessel, N. Kockmann, D. Kralisch, T. Noel, Q. Wang
ChemSusChem. 65 (2013) 746-789
5) Green engineering: P. T. Anastas, J. B. Zimmerman Environ. Sci. Technol. 37, 5 (2003)
94A–101A; M. J. Mulvihill, E. S. Beach, J. B. Zimmerman, P. T. Anastas Annu. Rev.
Environ. Resour. 36 (2011) 271–293
Week 3 School of Chemical Engineering Life Impact The University of Adelaide Slide 2
LEARNING OUTCOMES
 Motivation
Pharma industry / FDA decided for change – holistic approach needed
 Green Chemistry
Definition, essence, metrics, solvents, agents, examples
 Process Intensification (PI)

Definition, methodology, reactor types, hybrid processing, benefits
 PI Reactors, Microreactors, & Flow Chemistry

Examples, principles, potential, integration, automation, big vision
 Green Engineering & Future Factories

Green Engineering, 50% idea, process equipment container, process
development container, cash-flow opportunities via distributed production
 Life Cycle Assessment

Definition, methodology, impact categories, examples
 Motivation
Pharma industry / FDA decided for change
– holistic approach needed

2026: YEAR OF ACCOMPLISHED SWITCH OF BATCH TO CONTINUOUS

CHEMISTRY EQUIPMENT OVER CENTURIES
18-19th century ~1900
Batch
procedure
Today

LENGTH AND TIME SCALE OF
TRANSPORT PHENOMENA
Green
Engineering
Future
Factories
Conventionally
Flow
Chemistry
Micro-flow
Microreactors
V. Hessel, D. Kralisch, N.
Kockmann Novel Process
Windows, Wiley-VCH,
Green Weinheim, 2014.
Chemistry

 Green Chemistry
Definition, essence, solvents, agents, examples

GREEN CHEMISTRY - CHANGE OF VIEW WITH TIME
25 years ago: Socially & disaster-ban motivated

Banning some chemistries & resource efficiency
Green
Chemistry
Enabling new products & business

Today: Industrially motivated
TWELVE PRINCIPLES OF GREEN CHEMISTRY
• Prevention “Green chemistry is the utilization

• Atom Economy of a set of principles that reduces or
eliminates the use or generation of
• Less Hazardous Chemical Syntheses
hazardous substances in the design,
• Designing Safer Chemicals manufacture, and application of
• Safer Solvents and Auxiliaries chemical products.”
• Design for Energy Efficiency
• Use of Renewable Feedstocks
• Reduce Derivatives
• Catalysis Examples
• Design for Degradation
• Real-time Analysis for Pollution Prevention Redefinition
• Inherently Safer Chemistry for Accident Prevention

For Dummies
P.T. Anastas, J.C. Warner, Green Chemistry: Theory and Practice,
Oxford University Press: New York, 1998, p.30.
www.epa.gov/greenchemistry/pubs/principles

GROUPING THE TWELVE
PRINCIPLES OF GREEN CHEMISTRY
1. Feedstock & Use of Life Cycle Thinking

shift to renewable (non-petroleum) feedstocks
2. Efficiency & Environmental

a) make maximal use of starting materials (reactants) and minimize waste;
b) minimize solvent load; c) energy efficiency
3. Safety
have maximal process safety and minimize toxicity (to human)

SWITCH TO GREEN SOLVENTS
IN CHEMICAL INDUSTRY
Composition by mass of the type of

materials used to manufacture API
Solvents, water, reactants, …
C. Jimenez-Gonzalez, C.S. Ponder, Q.B. Broxterman, J.B. Manley Org. Process Res. Dev. 15 (2011) 912–917.

Vol. 2,
10, 283
GREEN CHEMISTRY METRICS
molecular weight of desired product

R E A C T I O N
Atom Economy  100%

molecular weight of all products
amount of carbon in product (kg )

% Carbon Efficiency  100
total carbon present in reactants (kg )
total mass of waste (kg )

E factor 
mass of product (kg )
total mass used in process or process step - mass of product (kg )

mass of product (kg )
C. Jimenez-Gonzalez,
C.S. Ponder, Q.B.
mass of solvent(kg ) Broxterman, J.B. Manley
P R O C E S S
Solvent Rate  Org. Process Res. Dev.

mass of product (kg ) 15 (2011) 912–917.
mass of all materials used excluding water (kg)

Mass Intensity 
mass of product (kg)
total mass in a process or process step (kg)

Process Mass Intensity 
mass of product (kg)
SWITCH TO GREEN SOLVENTS
IN CHEMICAL INDUSTRY
Comparison of solvent use in GlaxoSmithKline Pharmaceuticals
D.J.C. Constable, C. Jimenez-Gonzalez, R.K. Henderson, Org. Process Res. Dev. 11 (2007) 133-137

 Process
Intensification (PI)
Definition, methodology, reactor types,
hybrid processing, benefits

Vol. 1,
2, 55 PROCESS INTENSIFICATION
Process optimization Process intensification
Performance improvement Development of new concepts

Aim of existing concepts of process steps & equipment
Focus Model, numerical method Experiment, phenomenon,

interphase
Interdisci- Weak Strong

plinarity Applied mathematics Chemistry & catalysis, applied
physics, mechanical engineering,
materials science, electronics, etc.
European Roadmap on Process Intensification,

Creative Energies, Energy Transition, 2008

TWO BRANCHES OF PROCESS INTENSIFICATION
Microreactors
Hybrid Reactions
& Separations
A. Stankiewicz Chem. Eng. Process. 42 (2003) 137-144.

PROJECTED IMPACT OF INTENSIFICATION
AND MODULARIZATION
The Industrial Case Studies Delivered
Successful demonstration in an industrial environment
Quantified potential of intensification + modularization for the chemical industry
up to up to
Time-to-market -50 % CAPEX -40 %
OPEX -20 % Design effort -25 %
Solvent use -100 % Processing

steps -30 %
Energy Space time

-30 % 102-fold
consumption yield
Logistics -30 % Footprint -50 %
F3 Factory Dissemination and Closing

F3 Factory = x % conventional = 100 % Event, Leverkusen, 2013-051-15
 PI Reactors,
Microreactors, &
Flow Chemistry
Examples, principles, potential, integration,
automation, big vision

HIGH-G REACTORS
Spinning disk reactors Rotating packed-bed reactors

Liquid
Feed
Seal
Outlet gas
Inlet gas
Seal
Rotating
Bed Liquid
Discharge

REVERSE FLOW REACTOR

PI REACTORS WITH NON-
THERMAL ACTIVATION
Electro Extreme pressure
Photo
Microwave
Sono
Behr/Neubert: 39 Electrocatalysis/Sonocatalysis/Photocatalysis/ Microwave/Extreme

Pressure: Alternative Methods of Activation
MICRO(STRUCURED)REACTORS
– LAB TO PRODUCTION
Microstructure: single channel Microfabricated, lab, glass 3D-printed, bench, steel
Millifabricated,
Microfabricated, pilot, steel production, steel
PACKED-BED ENZYMATIC
MICRO-FLOW REACTORS
Packed bed microreactor… Vl = 0.5 mL

dr = 4.5 mL
mcat = 650 mg
for a lipase based… Novozym 435,

500 – 710 μm
… biocatalytic flow process

WHAT IS IDEAL CHEMICAL PROCESSING?
• Transport intensification * ‘be at the right place; move fast’
• Chemical Intensification **,*** ‘have the right energy, collision angle’
• Process-design intensification **** ‘keep your advance & maximize’
* Microreaction technology
** Flow chemistry
*** Novel process windows
“Snooker with Molecules” **** Continuous processing
A. Stankiewicz, TU Delft
ERC Advanced Grant 2010
I. Vural - Gursel, Q. Wang, V. Hessel, T. Noel, J. Lang, Chem. Eng. Technol. 25 (2012) 1184-1204

TRANSFER INTENSIFICATION IS
(SIMPLY) SCALING DOWN
 Decrease of diffusion paths, e.g. for mixing and heat

exchange
 Increase of specific interfaces, e.g. for films, catalysts or for

emulsions / droplets (phase transfer catalysis) / dispersions
 Increase of respective gradients, e.g. for concentration and

temperature
 Decrease of active volume in chemical reaction chambers
 Small residence time distribution

INTENSIFICATION OF MASS TRANSPORT
s2
Time constant of diffusion: tD 
D
Reduction of the channel Channel Time constant of Time constant of

width s by a factor of 10 width s diffusion tD diffusion tD
for gas (N2) for liquids (H2O)
[mm] [ms] [min]
1000 100.00 16.7
Intensification of mass 500 25.00 4.2
transport by a factor of 100 100 1.00 0.16 (10 s)
Application: -) Micromixers
-) Microstructured reactors
E. Klemm Grundlagen der Reaktionsführung in Mikroreaktoren Course MMV 024/08, GdCh, 2008

INTENSIFICATION OF SURFACE PHENOMENA

HEAT EXCHANGER PERFORMANCES

MIXING RELEVANCE
Vol. 1: 2, 9 - CONSECUTIVE REACTIONS
+ 3, 59
A+B=R rate k1 Reaction B B A A

Slow
to R A B B A
R+B=S rate k2 preferred B A reaction
B A
R is target product, subject to further reaction with B

Problem, if mixing time > reaction time (for stoich. case)
Uneven c profile comprises regions of enlarged B
concentration (local overstoich. profiles)
Problem increases with increasing rate k1/k2
Product ratio R/S, i.e. selectivity, is dependent on mixing !

INTENSIFICATION ENABLES TO
HANDLE LARGER HEAT FLOWS

TEMPERATURE DISTRIBUTION AND
POTENTIAL ENERGY PROFILES
Side reactions with different reaction enthalpies
Schwalbe, T., Autze, V., Hohmann, M., Stirner, W.

Org. Proc. Res. Dev. 8, 3 (2004) 440-454

PARALLEL REACTIONS WITH DIFFERENT
Vol. 1: 2, 9
+ 3, 59
POTENTIAL ENERGY PROFILES
Example (non-microreactor) to illustrate the effect:

Ortho- and meta-adducts are formed with different reaction enthalpies
B
B/C
A
C
Best temperature control

can set B/C ratio to optimal
value; hot spots will make it
lower than desirable

BOOST THROUGH PHOTO-ACTIVATION
Batch reactor Tube Flow reactor
Metal-free photo-
catalytic aerobic
disulfide formation
Talla, Driessen, Straathof, Milroy,

Brunsveld, Hessel, Noel, Adv. Synth.
Catal. 357 (2015) 2180-2186

PHOTO-EFFICIENCY
rate of the reaction


photon flux
Photonic efficiency:
ξ = 0.0086-0.0042 for batch reactors
ξ = 0.0262 for microreactors with CFL irradiation
ξ = 0.66 for our design using LED irradiation
Conclusion: the better the match between light source Metal-free photo-
and reactor, the higher the photonic efficiency (ξ) catalytic aerobic
disulfide formation
Su, Talla, Hessel, Noel, Chem. Eng. Technol. 38, 10 (2015) 1733-1742

SEGMENTED FLOW
- RESIDENCE TIME DISTRIBUTION

QUENCHING OF EXPLOSIONS
Inherent safety
Quenching of Quenching of chain

heat explosions explosions
Semenov diagram
Number of wand collisions
qR qab (quenching by radical
combination)
1
ZW k BT 1
Heat transfer line    aV
(Microreactor)
1
Z AA 2 2 p
Number of dual collisions

qR  k(T )  c  HR
n
(chain propagation)
qab  k W  a V  Tm
E. Klemm Grundlagen der Reaktionsführung in Mikroreaktoren Course MMV 024/08, GdCh, 2008.
AVALANCHE: RADICAL CHAINS

SHIFT OF EXPLOSION
REGIMES WITH DIMENSIONS

TEMPERATURE WINDOWS
Microreactors expand the p, T

process window and more (e.g.,
concerning c). Microwave did
similar, but is difficult to scale-up
NOVEL PROCESS WINDOWS

V. Hessel, N. Kockmann, D. Kralisch, T.
Noel, Q. Wang, ChemSusChem.
65 (2013) 746-789
T. Razzaq, C. O. Kappe, Chem.

Asian J. 5, 6, 1274-128
M. Damm, T. N. Glasnov, C. O. Kappe, Org.
Process Res. Dev. 14 (2010) 215-224
T. Razzaq, T. N. Glasnov, C. O. Kappe,
European J. Org. Chem. (2010) 1321-1325
T. Razzaq, T. N. Glasnov, C. O. Kappe,
Chem. Eng. Technol. 32, 11 (2009) 1-16

THREE STEPS AT ONCE
- UNINTERRUPTED CONTINUOUS SYNTHESIS
20% water savings
30% water savings
S. Borukhova, T. Noel, V. Hessel Green Chem. 18 (2016) 4947-4953

PROCESS ANALYTICAL TECHNOLOGY: UHPLC
M. Escriba, E. Shahbazali, M. Honing,

V. Hessel et al. Tetrahedron Lett. 74, 25
(2018) 74, 25 3143-3151

HUMAN-MACHINE INTERFACE:
PROCESS AUTOMATION
M. B. Plutschack, B. Pieber, K. Gilmore , P. H. Seeberger, Chem.

Rev. 117, 18 (2017) 11796–11893

THE BIG VISION FOR THE NEXT 20 YEARS
“MARCH OF THE MACHINES” “THE ROBO CHEMIST”
Special Issue:
150 Years of BASF
Ley et al. Angew.
Chem. Int. Ed. 2015 Peplow, Nature News 2014
“CHEMICAL NESPRESSO MACHINE” “ALL-AROUND-THE-WORLD-SYNTHESIS”
Ley, FROST
Cronin et al. Beilstein 2017
J. Org. Chem. 2017
THE BIG VISION: CONTINUOUS PILL
PRODUCTION “END-TO-END”
Jensen, Trout, et al. Angew. Chem. Int. Ed.

52 (2013) 12359-12363.
Adamo, Jamison, Jensen et al.,

Science 352, 6281 (2016) 61-67.

COMPACT, RECONFIGURABLE FLOW
SYSTEM FOR MULTI-STEP SYNTHESIS
A. Adamo, T. F. Jamison, K. F. Jensen et al. Science 352, 6281 (2016) 61-67

 Green Engineering
& Future Factories
Green Engineering, 50% idea, process equipment
container, process development container, cash-
flow opportunities via distributed production.

TEN KEY GREEN ENGINEERING
RESEARCH AREAS
ACS GCI Pharmaceutical Roundtable
American Chemical Society (ACS) Green Chemistry Institute (GCI) and global pharmaceutical
companies - Integration of green chemistry and engineering into the pharmaceutical industry.
Boehringer Ingelheim Pharmaceuticals, Pfizer, Eli Lilly, GlaxoSmithKline, DSM, Johnson &
Johnson, AstraZeneca, Merck (US).
D. J. C. Constable, C.
Jimenez-Gonzalez, R.
K. Henderson, Org.
Process Res. Dev. 11
(2007) 133-137

AGE OF MODULAR PRODUCTION

TWO TYPES OF CONTAINER PLANTS
• Container platform for modular, preassembled process equipment

in a central docking hub
= multi-purpose plant (possibly with process-group dedication)
Process Equipment Container
• Container platform with standardized process control, IT, wiring,

tubing, utilities etc. - yet specialized reaction & separation equipment
= dedicated mobile plant; suited for distributed manufacture (‘Plant
on Wheels’); suited for whole process development in one unit (lab
– pilot – production)
Process Development Container
Both have also common grounds = 50% idea for time-to-market

ASSEMBLING PEA’s INTO CONTAINER
& WHOLE FACTORY CONCEPT
Container within factory building Process Equipment Container
“Container” Docking Feed Process Control

station & Operator
“Container” = factory housing Process Development Container

HIERARCHICAL DESIGN OF PROCESS
EQUIPMENT CONTAINER PLANT
Backbone infrastructure
Process
equipment
container
Process equip-
ment assembly
Components
N. Krasberg, L. Hohmann, T. Bieringer, C. Bramsiepe, N. Kockmann Processes 2 (2014) 265-292

MODULAR HIERARCHY OF
PROCESS EQUIPMENT CONTAINER
Process Equipment Process Equipment

Assembly (PEA) Container (PEC)

Lab – Pilot – Production = “In One Box”
= Same Professional Environment
4 cabinets
‘Chemistry
Feed on Wheels’
Process
control Safety pans
Reaction &
Separation Climate control
Wiring, tubing
Gate
Operator & IT
Specially welded walls

fulfilling ex-standards
Entrance & gate

CONTAINER PLANTS
– POTENTIALS FOR COST REDUCTION
risk [%] > risk [%] Legislation: GMP …
Workflow Based on Modular Components
Process Selection Risk depends on capacity
cash
Modular Assembly Planning PDSA, KAIZEN, LEAN, LPS,
Optimal Configuration Selection
Six Sigma, ToC, QbD, PAT
Preassembling Modules  time NPV
risk [%] ECV
Short Field Installation
PhD thesis A. Mitic, DTU
(K. Gernaey; H. Lundbeck A/S)
Start-up
Faster time to market

(“50% idea”) Standardized compact modules &
infrastructure: fixed, small CAPEX
costs through serial manufacturing
Lower interest rates

 Life Cycle
Assessment
Definition, methodology, impact categories,
examples

LIFE CYCLE ASSESSMENT, LCA
• LCA: methodological framework for assessing the environmental impact

• Time span attributed: the life cycle of a product or process
• Support tool for decision making

STEPS OF LCA – INVENTORY ANALYSIS
ISO 14040 and 14044

INVENTORY ANALYSIS IN REAL
Feed Decomposition
reaction
Oxidation reaction Distillation
Feed
Bleacher
Absorber Nitration Oxidation

reaction
Concentration Crude
and distillation crystallizer
Software: Umberto
Refined crystallizer

IMPACT CATEGORIES
– Global warming (GWP)
– (Stratospheric) ozone depletion (ODP)
– (Tropospheric) photochemical ozone creation (POCP)
– Acidification (AP)
– Eutrophication (NP)
– Human toxicity (HTP)

n
– Ecotoxicity (ETP) IP   mi  WF
WP IFii
i 1
– Land use
m = mass
– Cumulative Energy Demand (CED) IF = impact factor

IMPACT CATEGORIES,
- GROUPED ON LOCATION OF IMPACT
– (Tropospheric) photochemical ozone creation (POCP)

ECOLOGICAL BACKPACK
IN MULTI-STEP SYNTHESIS
Sankey diagram – share of GWP
Line width is scale for effect
D. Ott,S. Borukhova, V. Hessel Green Chem. 18, 4 (2016) 1096-1116

Week 3: Green Chemistry and Continuous-Flow Processing

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Week 3: Green Chemistry and

 Green chemistry and sustainable engineering

 Process intensification and its reactors

 Modularised flexible container production

 Life-cycle assessment for sustainability assessment

Understand modern processing concepts that are game-

Week 3 School of Chemical Engineering Life Impact The University of Adelaide

 Process Intensification (PI)

 PI Reactors, Microreactors, & Flow Chemistry

 Green Engineering & Future Factories

 Life Cycle Assessment

Week 3 School of Chemical Engineering Life Impact The University of Adelaide

Week 3 School of Chemical Engineering Life Impact The University of Adelaide

18-19th century ~1900

Week 3 School of Chemical Engineering Life Impact The University of Adelaide

Week 3 School of Chemical Engineering Life Impact The University of Adelaide

Week 3 School of Chemical Engineering Life Impact The University of Adelaide

25 years ago: Socially & disaster-ban motivated

Enabling new products & business

• Prevention “Green chemistry is the utilization

• Inherently Safer Chemistry for Accident Prevention

Week 3 School of Chemical Engineering Life Impact The University of Adelaide

1. Feedstock & Use of Life Cycle Thinking

2. Efficiency & Environmental

Week 3 School of Chemical Engineering Life Impact The University of Adelaide

Composition by mass of the type of

Week 3 School of Chemical Engineering Life Impact The University of Adelaide

molecular weight of desired product

Atom Economy  100%

amount of carbon in product (kg )

total mass of waste (kg )

Solvent Rate  Org. Process Res. Dev.

mass of all materials used excluding water (kg)

total mass in a process or process step (kg)

Comparison of solvent use in GlaxoSmithKline Pharmaceuticals

Week 3 School of Chemical Engineering Life Impact The University of Adelaide

Week 3 School of Chemical Engineering Life Impact The University of Adelaide

Process optimization Process intensification

Performance improvement Development of new concepts

Focus Model, numerical method Experiment, phenomenon,

Interdisci- Weak Strong

European Roadmap on Process Intensification,

Week 3 School of Chemical Engineering Life Impact The University of Adelaide

A. Stankiewicz Chem. Eng. Process. 42 (2003) 137-144.

Week 3 School of Chemical Engineering Life Impact The University of Adelaide

OPEX -20 % Design effort -25 %

Solvent use -100 % Processing

Energy Space time

Logistics -30 % Footprint -50 %

F3 Factory Dissemination and Closing

Week 3 School of Chemical Engineering Life Impact The University of Adelaide

Spinning disk reactors Rotating packed-bed reactors

Week 3 School of Chemical Engineering Life Impact The University of Adelaide

Week 3 School of Chemical Engineering Life Impact The University of Adelaide

Electro Extreme pressure

Behr/Neubert: 39 Electrocatalysis/Sonocatalysis/Photocatalysis/ Microwave/Extreme

Microstructure: single channel Microfabricated, lab, glass 3D-printed, bench, steel

Packed bed microreactor… Vl = 0.5 mL

for a lipase based… Novozym 435,

… biocatalytic flow process

Week 3 School of Chemical Engineering Life Impact The University of Adelaide

• Transport intensification * ‘be at the right place; move fast’

• Chemical Intensification ,* ‘have the right energy, collision angle’