Stirred Tank Scale-Up

Stirred Tank Scale-Up
An (ex-) Practitioner’s View
MemTide Process Development Course
London, 23-24 February 2012
Dr. Clemens Brechtelsbauer
Principal Teaching Fellow
Department of Chemical Engineering
Imperial College London
c.brechtelsbauer@imperial.ac.uk
Contents
 Further Reading
 The Design Environment
 Manufacturing steps
 Unit operations
 The design base
 Mixing
 Vessels, impellers and baffles
 Flow regimes
 Power draw
 Scale-Up
 Similarity concept
 Scale-up rules
 Multiphase systems
Dr. Clemens Brechtelsbauer
Slide 2
Stirred Tank Scale-Up
Further Reading
 Edward L. Paul, Victor A. Atiemo-Obeng, Suzanne M. Kresta (Eds.)
Handbook of Industrial Mixing
John Wiley & Sons, 2004
 Ekato Ruehr- und Mischtechnik GmbH
Ekato Handbook of Mixing Technology
Ekato GmbH, 2000
 John H. Atherton, Keith J. Carpenter
Process Development: Physicochemical Concepts
Oxford University Press, 1999
Dr. Clemens Brechtelsbauer
Slide 3
Stirred Tank Scale-Up
Steps in API/Fine Chem Manufacture
Risk
Scale
Dr. Clemens Brechtelsbauer
Slide 4
Stirred Tank Scale-Up
Unit Operations
Particle Forming Unit Operations
Chemistry: Reactions and Separations
Reactions
• Kinetics
• Multiphase
Separations
• Distillation
• Extraction
Environmental
• Mass Balance
• Recovery
Crystallisation
• Scale-up
Isolation
• Filtration
• Centrifuges
Drying
• FilterDryers
Reaction
Extraction
Distillation
Crystallisation
Filtration
Drying
Dr. Clemens Brechtelsbauer
Slide 5
Stirred Tank Scale-Up
The Nature of the Beast
Process
=
Chemistry
+
Physics
Equipment
Or
“chemical rate constants are scale independent,
whereas physical parameters are not”
John H. Atherton
Author of
“Process Development: Physicochemical Concepts”
Simply put:
“Ye cannae change the
laws of physics, Jim!”
Dr. Clemens Brechtelsbauer
Slide 6
Stirred Tank Scale-Up
Standard Vessel Geometry
B
=
T/10
H=T
D
C=T/3
T
Dr. Clemens Brechtelsbauer
Slide 7
Stirred Tank Scale-Up
Ship’s Wheel vs. Cartwheel
 High shear
 Good for dispersions
 Low shear
 Good for solid suspension
Dr. Clemens Brechtelsbauer
Slide 8
Stirred Tank Scale-Up
Beware of the Dork Side
Minimum Stir and Mixing Volumes
D
V(stir, min) / V(mix, min) [L]
1200
1000
800
600
V stir min [L]
400
V mix min [L]
200
0
0
500
1000
1500
2000
2500
3000
Nominal vessel volume [L]
D
1%
V nominal
V stir, min  5 %
V nominal
7%
V nominal
V static
V dish
V mix, min  30-40 % V nominal
Dr. Clemens Brechtelsbauer
“Minimum stirred volume”
does not mean
“Minimum mixed volume”
Slide 9
Stirred Tank Scale-Up
Impeller Types
 Radial flow impeller
 Discharges liquid radially outwards
towards vessel walls
• Transitional & turbulent regime
• Good for dispersing
 Axial flow impeller
 Discharges liquid axially towards base
or liquid surface depending on
rotation direction
• Transitional & turbulent regime
• Good for blending & suspending
 Mixed flow impeller
 Flow predominantly in axial direction
with also a radial component
• Transitional & turbulent regime
• Good for blending, suspending &
dispersing
 Close clearance impeller
 Ensures good motion near vessel walls
• Laminar regime
• Good for blending
Dr. Clemens Brechtelsbauer
Slide 10
Stirred Tank Scale-Up
Understanding the Force
In a stirred vessel, the presence of baffles is essential to convert the vortexing motion of
the impeller into top to bottom mixing.
No baffles is worst.
Partial baffling is better.
Full baffling is best.
 Baffles are needed to promote the flow pattern
characteristic of the impeller type
 4 Baffles, typical width T/12 (US) or T/10 (EU)
with wall gap to prevent solids build-up
 Beavertail and finger baffles are often used in
glass-lined vessels
Dr. Clemens Brechtelsbauer
Slide 11
Stirred Tank Scale-Up
Power Draw
 The power drawn by an
impeller is expressed through a
power number equation:
P = Po ρ N3 D5
 Power number
 Po, or Newton number, Ne
 Depends on
• Impeller type
• Impeller and vessel
DE/V
dimensions
• Properties of the phases
present
 Must be measured!
Dr. Clemens Brechtelsbauer
Slide 12
E1/V
A1, v1, h1, p1
A2, v2, h2, p2
E2/V
Stirred Tank Scale-Up
Flow Regimes
 Different parts of a vessel can
experience different flow conditions
 Assess by Reynolds number
 N D2
Inertial Force
Re 


Frictional Force
 The “power curve” Po vs Re can be used
to evaluate the flow regime for the
whole process
 Laminar: Re < 10
• Po  Re-1
 Transitional:
10 < Re < 103
• Po = f(Re)
 Turbulent:
Re >
103
Ekato Handbook of Mixing
Technology, p. 15
• Po = constant
Dr. Clemens Brechtelsbauer
Slide 13
Stirred Tank Scale-Up
Geometric Similarity
 A single scale ratio, s, defines the relative magnitude of all
linear dimensions between the large and small scale:
H1
D1
C1
D2 T2 H 2 C2
s
 

D1 T1 H1 C1
H2
D2
T1
T2
Dr. Clemens Brechtelsbauer
Slide 14
Stirred Tank Scale-Up
C2
Kinematic & Dynamic Similarity
 Kinematic Similarity
 Dynamic Similarity
 Velocities at
geometrically similar
positions remain
constant
• Constant tip speed
• Constant superficial
gas velocity
• Constant maximum
liquid velocity in
impeller discharge
Dr. Clemens Brechtelsbauer
Slide 15
 Ratio of forces
(dimensionless groups)
remain constant at
different scales
• Beware:
– The relationship
between process
performance and the
dimensionless group
may not be linear!
Stirred Tank Scale-Up
Process Requirements
 A process may be controlled by one or more of:
 Liquid blending
• reaction
• homogenisation
 Solid-liquid mixing
• solid catalysed reaction
• dispersion
 Gas-liquid mixing
• fermentation
• hydrogenation
 Dispersing immiscible liquid
• reaction
• emulsions
 Heat transfer
 Defining controlling duty is key to successful scale-up!
Dr. Clemens Brechtelsbauer
Slide 16
Stirred Tank Scale-Up
Scale-Up Rules
 Geometrically similar vessels
 Turbulent regime
Process
Rule
Constant Parameter
Liquid blending
Equal tip speed
ND
Solid suspension
Zwietering
Njs  D0.85
Solid distribution
Equal energy input
P/V
Gas-liquid
Equal mass transfer
P / V (= kLa)
Heat transfer
Equal Re
N  D2
Fast reactions
Equal mixing time
N
Dr. Clemens Brechtelsbauer
Slide 17
Stirred Tank Scale-Up
Scale-Up Decisions
(1) Constant Mixing Time
(2) Constant P/V
(3) Just suspension
(4) Tip speed
(5) Reynolds number
Note:
• Criteria are mutually exclusive
• On scale-up, impeller speed
goes down
Scale-up experiments and modelling essential!
Dr. Clemens Brechtelsbauer
Slide 18
Stirred Tank Scale-Up
Future Multi-Purpose Plants
 Mixing design by function
 Principles
 Focused diversity by unit
operation
 Multi-flight agitation
 Vessel types
 A: Reactor with work-up
 B: Reactor / crystalliser
 C: Crystalliser
 D: Reactor / hydrogenator
 E: Hydrogenator
 Physical properties determine
process design envelope
 Implemented at GSK
Dr. Clemens Brechtelsbauer
A
B
C
D
E
Slide 19
Stirred Tank Scale-Up
Multiphase Systems Scale-Up
Scale-down Study
Process Assessment
Continuous
Improvement
Scale-up Projection
Plant Supplies Campaign
Dr. Clemens Brechtelsbauer
Slide 20
Stirred Tank Scale-Up
Process Assessment
 Respiratory portfolio, final stage re-crystallisation
 Important for process success:
 Minimisation of variability on scale-up of “particle forming step”
 Reproducible, narrow particle size distribution
• Homogeneous growth conditions to promote particle uniformity
• Low shear to prevent attrition
 Initial hydro-dynamic simulation of flow profile by CFD for pilot and plant vessels
1500 L Pilot Plant
Dr. Clemens Brechtelsbauer
4000 L Manufacturing
Slide 21
Stirred Tank Scale-Up
Scale-Down Study
 To determine the effect of
shear & suspension on
particle size & distribution,
which cannot be predicted
through CFD
 2 L conical base lab reactor
set up to scale-down
manufacturing reactor
 Effect of improved suspension:
 No effect on particle size
 Effect of shear:
 No effect on particle size or
distribution (PSD)
Dr. Clemens Brechtelsbauer
Slide 22
Stirred Tank Scale-Up
Scale-Up Projection
 Just suspension speed determined experimentally for 2L lab reactor
 CFD multi-phase
Lab, 2 L, 400 RPM
Pilot Plant, 1500 L, 60-70 RPM
simulation based on
experimental stirrer
speed:
 Plant operating impeller speeds recommended to maintain
homogeneous suspension

Stevenage pilot plant (1500 L): 60-70 RPM



prevent risk of settling
provide homogeneous growth conditions
verify negligible shear effect
Dr. Clemens Brechtelsbauer
Slide 23
Stirred Tank Scale-Up
Plant Supplies Campaign
 Analysis of lab and pilot plant
results by different scale-up
parameters
 solid suspension
 shear
 overall energy input
 Shear and energy input have
 no effect on particle size
 Increased suspension on scale-up:
 no effect on particle size
 slightly narrower PSD
Penney Diagram
1000
Scale-up by constant
mixing time
[microns]
100
(P/V) l arge / (P/V) l ab
energy input
solid suspension
10
shear
heat transfer
1
0.1
0.01
1.00E+00
1.00E+01
1.00E+02
1.00E+03
1.00E+04
Vplant / Vlab
Dr. Clemens Brechtelsbauer
Slide 24
Stirred Tank Scale-Up
Process Assessment
Jurong V460 (4000 L), 48 RPM
 Extrapolation to Manufacturing:
Dr. Clemens Brechtelsbauer
Slide 25
Stirred Tank Scale-Up
The Voice of Scale-Up Experience
Do
Don’t
Add solids to a reaction
Evaporate to dryness
Use “all in & heat”
Rely on critical timing
Do hot filtrations
Risk all in one batch
Collaborate
Log
Sample
Safety test & review
Use test
Keep it simple
McConville, F. X., CEP 103 (2007) 18-19
Dr. Clemens Brechtelsbauer
Slide 26
Stirred Tank Scale-Up
As Clear as Mud?
"No one will believe you solved this problem in one day!
We've been working on it for months.
Now, go act busy for a few weeks and I'll let you know
when it's time to tell them."
(R&D supervisor, Minnesota Mining and Manufacturing/3M Corp.)
Dr. Clemens Brechtelsbauer
Slide 27
Stirred Tank Scale-Up