Stirred Tank Scale-Up

An (ex-) Practitioners 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

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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

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Stirred Tank Scale-Up

Steps in API/Fine Chem Manufacture

Risk

Scale

Dr. Clemens Brechtelsbauer

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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

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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

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Stirred Tank Scale-Up

Standard Vessel Geometry

B
=
T/10

H=T

C=T/3

Dr. Clemens Brechtelsbauer

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Stirred Tank Scale-Up

Ships Wheel vs. Cartwheel

High shear
Good for dispersions

Low shear
Good for solid suspension
Dr. Clemens Brechtelsbauer

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Stirred Tank Scale-Up

Beware of the Dork Side

Minimum Stir and Mixing Volumes

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
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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

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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

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Stirred Tank Scale-Up

Power Draw
The power drawn by an
impeller is expressed through a
power number equation:
P = Po 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

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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

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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

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Stirred Tank Scale-Up

Scale-Up Rules
Geometrically similar vessels
Turbulent regime
Process

Rule

Constant Parameter

Liquid blending

Equal tip speed

ND

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

Dr. Clemens Brechtelsbauer

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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

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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

D
E
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Multiphase Systems Scale-Up

Scale-down Study

Process Assessment

Continuous
Improvement

Scale-up Projection

Plant Supplies Campaign

Dr. Clemens Brechtelsbauer

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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
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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

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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

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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

0.1

0.01
1.00E+00

1.00E+01

1.00E+02

1.00E+03

1.00E+04

Vplant / Vlab

Dr. Clemens Brechtelsbauer

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Stirred Tank Scale-Up

Process Assessment
Jurong V460 (4000 L), 48 RPM

Extrapolation to Manufacturing:

Dr. Clemens Brechtelsbauer

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Stirred Tank Scale-Up

The Voice of Scale-Up Experience

Do

Dont
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

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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

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Stirred Tank Scale-Up