Microreactor Technology at Lonza
Location, 14 June 2009
Name / Lonza / Date
slide 2 28-Oct-11
Agenda
Reaction classes and chemical examples
Lonza Universal Reactor Technology
Scale-up strategy and production units
Lonza proposal
Joe Pont, Chemistry Today, June 2009
Adapt as a function of your needs
slide 3 28-Oct-11
Lonza has been working closely with
microreactor technology for some time
1992: “Microreactors” for cryogenic organometallic reaction
Microreactor Team Formed in 2003
Two dedicated laboratories
Connected with the kg-lab to produce kg-quantities
Two Integrated production units (Launch Plant, Visp)
Own reactor development and collaborations with others
Seven chemical patent applications (wide-ranging)
process, nitration, and organometallic reactions
Three technical patent applications
Two microreactors, one lab system
Several publications (CET, Angewandte Chemie, OrgProcR&D)
Citations in Nature, Chemical & Engineering News, etc.
slide 4 28-Oct-11
Microreactor Technology
It enables Continuous Processes based on plug flow reactors with
minimal volume of reagents, rapid dynamic responses and
robustness, good temperature control,
efficient mixing, etc.
inlet cooling
outlet cooling
inlet fluid 1
inlet fluid 2
outlet product
inlet cooling
outlet cooling delay
loop
slide 5 28-Oct-11
Batch
Process
Synthesis Design
Continuous
Batch
Protection Li exchange Coupling Hydrolysis Extraction Distillation
DryerCentrifuge
Protection Hydrolysis Extraction Distillation
DryerCentrifugeCoupling
Microreactor
Li exchange
Microreactor
Value-added
in terms of Yield
Extraction Distillation
dryerCentrifugeCoupling
Microreactor
Li exchange
Microreactor
Value-added
in terms of Yield
Protection
Microreactor
Hydrolysis
Microreactor
Conventional
Current
Future
The Toolbox Approach:
Integration into Production
slide 6 28-Oct-11
Reaction Classification & Advantages
Type A reactions
very fast (< 1s)
controlled by the mixing process
Increase Yield through better mixing/heat exchange
Type B reactions
rapid reaction (10 s to 20 min)
predominantly kinetically controlled
Avoid overcooking and increase Yield
Type C reactions
slow reaction (> 10 min)
Batch processes with thermal hazard
Enhance safety
Need intensification
slide 7 28-Oct-11
Reactions at Lonza
D.M. Roberge et al., CE&T 2005 (28) 318
Big circle based on kinetics only
Inner circle based on kinetics and phases
81%
21%
23%
6%
50%
8%9%
2%
Type A reactions
Type B reactions
Type C reactions
Remaining
Organometallic reactions
Diketene reactions
Autocatalytic nitrations
slide 8 28-Oct-11
Shifting reactions to suit Microreactors
Reactions can be designed to suit
microreactor technology:
Increased concentration
harsher reaction conditions
fast reactions
Increased temperature
Adjusted residence time RT
Hazardous reagents and intermediates
Expensive, but more effective solvent and catalysts
Controlled educt quality, filtering,
avoid impurities and particles
Type A
Type C
Type B
slide 9 28-Oct-11
Chemical examples
Organolithium exchange, Dibal-H, and Grignard reactions [Type A]
Organolithium coupling reaction [Type B]
Nitration as hazardous reactions [Type C]
Ar H Ar NO2HNO3+ Ducry & Roberge Angew. Chem. IE 2005 (44) 7972
Ducry & Roberge OrgProc R&D 2008 (12) 163
Roberge et al. PharmaChem 2006 (June) 14
Roberge et al. CE&T 2008 (31) 1155
Roberge et al. OrgProc R&D 2008 (12) 905 R X Li Ar Li+
R1 X
O
R2 Mg X
O
R1 R2+
R O
O
R
ODibal-H
LiR1
R3
O
R2
R1 R3
OH
R2
+
slide 10 28-Oct-11
Industrial Reactors
Module A Multi-injection reactor to avoid hot spot formation
Module B
Module C
Multi-scale reactor design
Gain volume and limit pressure drop
Conventional technology
Static mixer / mini-heat exchanger
costs efficient
Corning S.A.S. Fontainebleau Research Center
Lonza design
For example Exergy
slide 11 28-Oct-11
Lonza Microreactor as Universal Modules
Modular, robust, pressure over 100 bar
Hastelloy plates: process fluid
Aluminum plates: thermal fluid
Compactness, ease of adaptation
Each plate = one specific design
1 Plate for Gas-liquid reactions
2 Plate for multi-injection
2 2
slide 12 28-Oct-11
All Lonza Microreactors
Lonza development reactor
A6 A5
View the chemistry
Reaction at tiny flow rates
Test different mixing structures
Lonza production reactor
Design as key ingredient to scale-up
Avoids totally parallelization
Multi-purpose
Lab-Plate
channel structure
slide 13 28-Oct-11
Basic Flow Rates
For Type A reactions (Multi-injection)
Ensure sufficient cooling between the plates or mixing points
Provide maximum mixing capacity → large ΔP
For Type B reactions (Multi-scale design)
Scale-up issues are avoided if the same area to volume ratio is
maintained
Optimize mixing quality → ΔP as low as possible
Isolated product
per campaign
Lab Plate = 1-10 mL/min development tool, few grams
A6 = (10) 50-150 mL/min 0.1 - 300 kg
A5 = 100-300 mL/min 300 - 900 kg
A4 = 200-600 mL/min 900 - 2500 kg
slide 14 28-Oct-11
Lonza has an extensive track record
with continuous flow processes
Type A
reactions
Type B
reactions
Type C
reactions
Continuous flow
benefits
Grignard
reaction
Simmons-Smith
reaction
Nitrations (many
examples)
saponification
organolithium
reaction
Wittig reaction amination hydrogenation
alkylation Diketene reactions methylation dehydrogenation
bromination Coupling of unstable
intermediates
oxonolysis
chlorination oxidation Emulsion reaction
nitrosation BOC-protection
Reduction
(DIBAL)
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Straightforward Scale-up Approach
Simple numbering-up / device parallelization is limited
Control issue
Chemical systems are in general meta-stable
Not acceptable cleaning capacity
How can I insure all channels are cleaned
No pressure driven system
Always ensure stoichiometry
Operation time
Reactor design
High pressure pump
Cross section
More reactors
campaign size
lab scale small scale production large scale production
100x
2-6x
4x
4-6x
10 1 kg 100 1 t 10 100 t 10 g 100
slide 16 28-Oct-11
Scale-up concept with MR in Plant - MiP
laboratory system
Microreactors & conventional technology
30-200 g/min 2-10 kg campaigns
1-50 g/min sample production
Pre-clinical phase, Process research, Process development
MiP-SSP
Microreactors & conventional technology, cGMP, EX environment
200-1000 g/min 0.1-2 t campaigns
Clinical phase I, II, III
MiP-LSP
Microreactors & conventional technology, cGMP, EX environment
10 times
1- 5 kg/min 50 t + campaigns
Commercial Products
10 times
Under
Development
Lab-Plate A6 A5 A4
slide 17 28-Oct-11
Case Study Scale-up
2-step Serial Reaction
Various reactors are studied
Feed-1: Substrate (15 wt%)
Feed-2: Reagent 1 (30 wt%)
Feed-3: Reagent 2 (17 wt%)
Stoichiometric reaction, two temperature levels
First reaction is of Type A highly exothermic (ΔTad > 75°C)
Various reactors are studied
Second reaction is of Type B and exothermic (ΔTad < 25°C)
Use of a static mixer under adiabatic conditions
H (acidic)R1 Li LiR1+ +
LiR1
R2
O
R3 R2R1
O
LiR3+ +
slide 18 28-Oct-11
Flow Diagram
Feed-1
Feed-2
Feed-3
Pump-1
Pump-2
Pump-3
Reactor XX
Quench tank
T
P
F MR
F Total
Static mixer
Thermal fluid
large excess
cryogenic
Outlet
adiabatic
slide 19 28-Oct-11
Scale-Up Results
Reactor F Total
[g/min]
F MR
[g/min]
T
[°C]
P
[bar]
Yield
Glass MR 100 33 -14 0.4 86
Glass MR 440 148 15 3.2 88
Static mixer 100 33 9 0.3 88
Static mixer 440 148 41 1.6 84
Lonza MR-A6 100 33 -22 0.9 89
Lonza MR-A6 420 140 -16 8.8 90
Lonza MR-A5 450 150 -21 2.0 88
Lonza MR-A5 562 187 -19 3.0 89
Lonza MR-A5 614 204 -18 3.4 88
Lonza MR-A5 711 237 -16 4.5 87
slide 20 28-Oct-11
Chemical project
Multiple-tons of isolated material have been produced
All product within specifications
More than 20 m3 of processed reaction volume
Lonza Universal Reactor Technology
Clear path from laboratory chemistries to large-scale
manufacturing processes
Completely avoids the parallelization / numbering-up strategies
Microreactor platform that supports rapid process development;
It is also robust, multi-purpose and scalable
Was tested for several customer products
Conclusions for Scale-up
slide 21 28-Oct-11
Pilot Plant Microreactor Technology
Key Features
Multi-purpose system
Modular
Hastelloy
T = -80 to +180°C
ATEX standards
Qualifiable for cGMP
production
Track record
organolithium exchange
organolithium coupling
nitration reaction
3 dosage lines
1 - 6 bar
5 - 300 g/min (per line)
slide 22 28-Oct-11
Continuous Production in Launch Plant
Key Features
Multi-purpose system
Capacity in the range of
150 kg/h
Campaigns were performed
with in-between cleaning
Track record
Simmons-Smith reaction
organolithium coupling
Based on conventional technology
Static mixers
Mini-heat exchangers
slide 23 28-Oct-11
Continuous Ozonolysis (Gas-liquid)
Key Features
Only for gasses with low
solubility and large volume
fraction such as ozonolysis
Gas-liquid mass transfer
intensification
Scale-up: predictable mass
and heat transfer (Kla)
Fully automated system
Track record
Several ozonolysis projects Kg-scale lab system with Sulzer
SMV mixing elements
Ton-scale system with Sulzer SMV
mixing elements in the launch
plant for industrial production
slide 24 28-Oct-11
Continuous work-up steps
Key Features
2-step bi-phasic reaction and
quench with following phase
separation
complete continuous flow
miniplant
Scale-up: adjust residence time
and temperature
Fully automated system
Track record
nitration
saponification phase separation
solvent distillation in falling film
solvent extraction in Karr column
slide 25 28-Oct-11
Conclusions
Lonza is a leading player in microreactor technology
The lab development is solely made in the microreactor
Lonza has developed own microreactor concept
Different sizes of microreactors are in operation
Microreactor setup and chemical production
Reaction classification based on reaction kinetics
Scale-up to large scale and microreactor applications
Manufacture under cGMP conditions
slide 26 28-Oct-11
Back-up
slide 27 28-Oct-11
Lonza’s Proprietary Microreactor Technology
WO2007/045509: Mass flow rate control system
WO2007/087816: Nitration of activated aromatics in MRs
WO2007/112945: Micro-reactor system
WO2008/006420: Swern oxidation
WO2008/009378: Method for Grignard Type Reactions in MRs
WO2008/095646: Method for Lithium Exchange Reactions
WO2009/003661: Process for the preparation of Aldehydes
WO2009/046992: Method for the preparation of organic nitrates
EP1500649A1: In-situ quench method
Others pending
slide 28 28-Oct-11
Lonza Proposal
Phase 1: Proof of Concept (2 weeks)
Phase 2: Optimization Study (2-4 weeks)
Design of experiments (DOE) or complete kinetic analysis
Phase 3: Long Run Study (3 weeks)
kg-Lab production from 1–20 kg
Phase 4: Pilot Production & Commercial Manufacturing
From 20 kg to 2.5 tons of product for pilot production
Ton quantities for commercial manufacturing
CAPEX assessment
time &
co
mp
lexity
slide 29 28-Oct-11
Phase 1: Proof of Concept
Activities
Safety assessment (if
required)
Determine maximum feed
solubility at different
temperatures
Solvent screening
Determine reaction class
(Type A, B, and C)
Flow rate versus residence
time
Ascertain optimal reactor
Requirements
Lab batch protocol, RC-1 data
Supply of raw materials
Analytical method with product
sample for calibration
Deliverables
Statement on process
compatibility with MRT for
operability and plugging
Solution yield, including
impurity profiling
Basic PowerPoint report for
go/no-go decision
slide 30 28-Oct-11
Phase 2: Optimization Study
Activities
Factors analysis using DOE
→ Type A Reactions
Temperature, stoichiometry,
concentration,
additives/stabilizers, multi-
injection..
Kinetic analysis including
activation energy → Type B
Reactions
Obtain highest Yield and
optimal operability
Requirements
See Proof of Concept &
detailed product
specifications
Deliverables
Isolated product, including
yield and purity
Firmed process description
for application in
Microreactor Technology
PowerPoint report on most
optimal process conditions
with MRT
slide 31 28-Oct-11
Phase 3: Long Run Study (1/2)
Activities
Process Synthesis Design (if required)
Scalability
Perform a long run with the smallest MRT structure
Use various proprietary de-plugging methods
Perform reaction at high flow rate for a short period
xx g for yield assessment and impurity profiling
Kg-lab production campaign
Preparation (short risk assessment), production, cleaning
GMP: Qualify start-up and termination phases
slide 32 28-Oct-11
Phase 3: Long Run Study (2/2)
Requirements
See Proof of Concept & Optimization Study
Deliverables
Statement on readiness of process for Pilot Production or Commercial Manufacturing
Requested kg-quantity of materials
slide 33 28-Oct-11
Phase 4: Pilot Production &
Commercial Manufacturing
Activities
20 kg to 2.5 tons of product
for Pilot Production
Tons quantities for on a case
by case analysis for
Commercial Manufacturing
Including CAPEX
assessment
GMP manufacturing
On going optimization
Requirements
Supply agreement
Deliverables
Product
Documentation
Final evaluation of the project and production report
slide 34 28-Oct-11
We have observed a wide range of
applications for microreactor technology
Fast Kinetics
Less than 10 min
Mixing Sensitivity
Long dosing time
High stirrer speed, selectivity depends on stirrer speed
Temperature Sensitive
Selectivity is lower in larger vessels/beakers (heat transfer)
Strong exothermic reaction
Autocatalytic, reaction rate depends on product
High Activity
Reagent, catalyst, or solvent
Undesired By-product Formation
slide 35 28-Oct-11
Reactions Can be Designed for Microreactor Technology
Increased concentration
harsher reaction conditions
fast reactions
Increased temperature
Hazardous reagents and intermediates
Expensive, but more effective solvent and catalysts
Controlled educt quality, filtering,
avoid impurities and particles
We are able to shift reactions to suit
microreactor technology
slide 36 28-Oct-11
Microreactors have a wide range of
benefits over conventional reactors
Mixing Controlled Reactions
Mixing time shorter than
reaction time
Energy dissipation
determines mixing time
Temperature-Sensitive
Reactions
Avoid hot spots by high
heat transfer and multi-
injection
Higher process
temperatures are possible
Volume Minimization
Autocatalytic reactions are
controllable
Unstable intermediates can
be intercepted
New Process Windows
Higher educt concentrations
or temperatures
Highly efficient solvents and
catalysts
But, Limitations Exist
Slow reactions, solid forming,
polymerization, etc.
slide 37 28-Oct-11 D.M. Roberge et al, WO2007112945, to Lonza AG
Types of Microreactors:
Lonza
Key Features
Design by Lonza
Aimed at maximizing heat
transfer and mixing but
allowing a residence unit
Material: Hastelloy C, SiC
Minimize pressure drop
Modular, ease of adaptation
Excellent mixing performance, can
also be used for Type A
Modular residence time up to 1 min.
Pressure up to 100 bar
Various partners for the reaction plates
slide 38 28-Oct-11
© hiTran CalGavin
Types of Microreactors:
Static Mixer Technology Modules
Key Features
Conventional modules based
on standard heat exchangers
and static mixers with high
flexibility example are from
BHR (Flex reactor), Sulzer
(SMR reactor), or Fluitec.
Engineer and construct
appropriate residence time
modules (RT-module)
© Exergy © Sulzer
© Fluitec