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Expanding the Commercial Manufacturing Envelope
High Performance Fixed Bed Flow
Hydrogenation
Chemspec Europe 2017
Oliver Tames
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Summary
1) Current Hydrogenation technology review
• Trickle bed
• Batch
• CSTR
2) Fixed bed flow hydrogenation
• Approach
• Basic principles
• Safety and Risk
• advantages
3) The path to plant
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Background
Increased interest in continuous flow approach
• Increased yields
• Reduced impurities
• Reduced footprint
• Automated efficient manufacturing
Hydrogenation technology drivers:
• Economical use of PGM catalysts
• Exploration of new synthetic methodology
• Supporting continuous manufacturing strategies
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Heterogeneous Hydrogenation
Gas Liquid Solid
Phase Interfaces
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Hydrogenation Technology Review
• Batch
• CSTR
• Fixed bed
• Loop
• Trickle Bed
Trickle bed reactor: Daniele Pugliesi Creative Commons Attribution-ShareAlike 4.0 License
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Trickle Bed – Extruded Catalyst
• Catalyst presented in pellet form
• Catalyst pellet has small surface area
• Catalyst can come in a number of different
extruded cross sections
• Material can flow over
• Material can flow through
• Reaction path difference
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Extruded catalyst - Cont
• Gas is at surface of pellet
• Long gas diffusion path
• Surface high gas concentration
• Inside particle – low concentration
• Different reaction conditions
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Trickle Bed - Thermal Control
• Liquid phase passes down through bed under gravity
• Catalyst pellets connected by liquid film
• Heat generation results in vaporisation of solvent
• ‘Hot Spots’ can form as areas loose more liquid
• Poor control of reaction temperature
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Trickle Bed - Summary
• Poor control of reaction
• Poor control of gas concentration
• Poor thermal control
• Sensitive compounds can suffer thermal
degradation and impurity formation from over
reduction.
• May be possible, but control remains a
significant challenge
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Batch - General
• The batch reactor is the tool of choice for
current fine chemical and pharmaceutical
manufacturing
• Excellent thermal control
• While hydrogen is easily controlled in a semi-
batch protocol, it is mass transfer limited.
• Extensive catalyst screening is normally
performed during development – an essential
optimisation tool.
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Batch - Safety
• Batch reactors are large, and filled with
explosive gas
• Expensive protocols are required to ensure
safety – blast walls, bunkers, up not out
• Explosion risks are low – but essential to
reduce to an absolute minimum due to severity
of potential incident
• Essentially safe – at a cost
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Batch limitations
• Reaction time limited by mass transfer
• Batch optimisation precludes fast reactions –
can take hours just to reach temperature
• Normally low pressure (~10 bar) for
heterogeneous catalysis – large high pressure
vessels are extremely expensive
• Does not interface well with other continuous
processes
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CSTR
• Continuous
• Batch conditions
• Catalyst
management
• Good slurry option
• Slightly more
enabling than batch
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Hydrogenation Overview
Rea
ctio
n
Tim
e C
on
tro
l
Gas
Mas
s Tr
ansf
er
Rea
ctio
n
Spee
d
Safe
ty R
isk
Co
nti
nu
ou
s
Slu
rry
Ph
ase
Rea
ctio
ns
Batch Excellent Poor hours High No Yes
Trickle bad Good minutes High Yes No
CSTR good Poor hours Medium Yes Yes
Loop bad Good hours High No Yes
HPFB? Excellent Excellent seconds Low Yes No!
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High Performance Fixed Bed -
Trickle Bed Without the Trickle
• Fixed bed with catalyst particles typically less
than 100um
• Use of high pressure pumps – not gravity
• Control of hydrogen injection rate
• Tight residence time distribution
• Suitable for complex pharmaceutical products
• However - Traditionally challenging scale up.
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Simple Flow Diagram
Liquid Reservoir
Pump
Mixer
Reactor
Back Pressure regulator
Hydrogen Source
Mass Flow Controller
Product Reservoir
The Devil is in the Detail!
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Reaction Time Distribution
and Path Length
Reaction Time
Wide
Tight
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The effect of bed particle size on
gas surface area
0
200
400
600
800
1000
1200
0 500 1000 1500 2000 2500
Gas
Su
rfac
e A
rea
Particle Size (um)
Hydrogen surface area (cm2/ml)
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Gas Solubility vs Temperature
0
1000
2000
3000
4000
5000
6000
7000
0 50 100 150 200 250
Co
nce
ntr
atio
n (m
ol/
m3
)
Temperature (°C)
Concentration of Hydrogen in Methanol @100bar
Calculated By Dynochem
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Pressure
• High performance fixed bed hydrogenation
can easily be configured for high pressure
• Using off the shelf components, IntensiChem
is assembling a 700bar (10,000psi) system
• Hydrogen concentration is proportional to
pressure
• Processes sensitive to hydrogen concentration
can be optimised by using higher pressures
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Heterogeneous Hydrogenation
Gas Liquid Solid
Phase Interfaces
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Summary of driving principles
• High pressure – gas concentration
proportional to pressure
• Small particles – High gas surface area
• High temperature – Gas concentration
increases with temperature
• Effective control of mass transfer
• Enabling commercial scalability
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Note on Case Studies
• All current project work is commercially sensitive.
• The only limitation is solids. Solids cannot be present in
the feed and solids cannot be formed during the reaction.
• As long as this criterion is met, we can adapt the
approach to any commercial hydrogenation challenge.
• We have achieved good conversion on every project
attempted – unless solids present.
• All existing chemistry is in scope – google for flow
examples.
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Safety and Risk
Very small reactors
• 250ml – 1tonne per month
• Can be enclosed in economical explosion proof container
Steady state quality
• Only waste small amount of material when reaching steady state
• Parameter failure would cease flow – limiting losses
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Process Advantages
• Optimisation of the process chemistry without
limitation
• Fast reactions, but also high yielding with
reduced impurity formation
• Can carry out processes that are not
commercial in batch
• Can easily interface with other continuous
manufacturing systems
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The Path to Plant
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Lab Development Tool
• Manual parameter setup
• Maximum pressure – 100bar
• 250°C Maximum temperature
• Maximum flow rate –
15ml/min
• Automated sampling
• Focus on flexibility and
reaction understanding
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Scale up basis
• Scale up is proportional to cross sectional area
and bed length – due to effective elimination of
mass transfer at scale
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Scale Up System
• Maximum pressure 200bar
(120bar current)
• Maximum flow rate –
200ml/min
• Maximum temperature –
200°C+ (engineered for
production chemistry)
• Re-configured to the
specifics of the clients
chemistry
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Delivering the Solution
• IntensiChem is working with Manrochem to
deliver manufacturing plant
• First plant has just completed commissioning
• Pharmaceutical ‘GMP’ grade
• Delivers better yields than batch technology
• Laboratory scale up system was shown to be
an excellent process model!
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The Plant Solution
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Summary
• Optimisation of temperature, pressure and
surface area using a fixed bed has delivered
seamless scale up to plant manufacturing
• Cheaper, safer, more efficient and cleaner than
other current manufacturing technologies
• Efficient integration with other continuous
manufacturing technology
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Questions?