Brechtelsbauer - Workspace - Imperial College London

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 


Steps in API/Fine Chem Manufacture 

Risk 

Scale 


Reactions 

• Kinetics 

• Multi- 

phase 

Reaction 

Extraction 

Unit Operations 

Chemistry: Reactions and Separations Particle Forming Unit Operations 

Separations 

• Distillation 

• Extraction 

Environmental 

• Mass Balance 

• Recovery 

Distillation 

Crystallisation 

• Scale-up 

Crystallisation 

Isolation 

• Filtration 

• Centri- 

fuges 

Filtration 

Drying 

• Filter- 

Dryers 

Drying 


The Nature of the Beast 

Process = Chemistry + Equipment Physics 

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!” 


H=T 

Standard Vessel Geometry 

D 

T 

B 

= 

T/10 

C=T/3 


Ship’s Wheel vs. Cartwheel 

� Low shear 

� Good for solid suspension 

� High shear 

� Good for dispersions 


D 

D 

V static � 1 % V nominal 

V stir, min � 5 % V nominal 

V dish � 7 % V nominal 

V mix, min � 30-40 % V nominal 

Beware of the Dork Side 

V(stir, min) / V(mix, min) [L] 

1200 

1000 

800 

600 

400 

200 

0 

Minimum Stir and Mixing Volumes 

0 500 1000 1500 2000 2500 3000 

Nominal vessel volume [L] 

“Minimum stirred volume” 

d o e s n o t m e a n 

“Minimum mixed volume” 

V stir min [L] 

V mix min [L] 


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 


• Good for blending & suspending 

� Mixed flow impeller 

� Flow predominantly in axial direction 

with also a radial component 


• Good for blending, suspending & 

dispersing 

� Close clearance impeller 

� Ensures good motion near vessel walls 

• Laminar regime 

• Good for blending 


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 


Power Draw 

� The power drawn by an 

impeller is expressed through a 

power number equation: 

P = Po ρ N 3 D 5 

� Power number 

� Po, or Newton number, Ne 

� Depends on 

• Impeller type 

• Impeller and vessel 

dimensions 

• Properties of the phases 

present 

� Must be measured! 

DE/V 

E 1/V 

E 2/V 

A 1, v 1, h 1, p 1 

A 2, v 2, h 2, p 2 


Flow Regimes 

� Different parts of a vessel can 

experience different flow conditions 

� Assess by Reynolds number 

2 

� N D 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 < 10 3 

• Po = f(Re) 

� Turbulent: Re > 10 3 

• Po = constant 

Ekato Handbook of Mixing 

Technology, p. 15 


Geometric Similarity 

� A single scale ratio, s, defines the relative magnitude of all 

linear dimensions between the large and small scale: 

H 1 

D 1 

T 1 

C 1 

D 

D 

2 2 2 

s � � � � 

1 

T 

T 

1 

Dr. Clemens Brechtelsbauer Slide 14 Stirred Tank Scale-Up 

H 

H 

1 

C 

C 

2 

1 

H 2 

D 2 

T 2 

C 2

Kinematic & Dynamic Similarity 

� Kinematic Similarity 

� Velocities at 

geometrically similar 

positions remain 

constant 

• Constant tip speed 

• Constant superficial 

gas velocity 

• Constant maximum 

liquid velocity in 

impeller discharge 

� Dynamic Similarity 

� Ratio of forces 

(dimensionless groups) 

remain constant at 

different scales 

• Beware: 

– The relationship 

between process 

performance and the 

dimensionless group 

may not be linear! 


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! 


Scale-Up Rules 

� Geometrically similar vessels 

� Turbulent regime 

Process Rule Constant Parameter 

Liquid blending Equal tip speed N � D 

Solid suspension Zwietering N js � D 0.85 

Solid distribution Equal energy input P / V 

Gas-liquid Equal mass transfer P / V (= k La) 

Heat transfer Equal Re N � D 2 

Fast reactions Equal mixing time N 


Scale-Up Decisions 

Scale-up experiments and modelling essential! 

(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 


� Mixing design by function 

� Principles 

Future Multi-Purpose Plants 

� 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 

A 

B C 

E 


D

Multiphase Systems Scale-Up 

Process Assessment 

Scale-down Study 

Continuous 

Improvement 

Plant Supplies Campaign 

Scale-up Projection 



� 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 4000 L Manufacturing 


� 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 

Scale-Down Study 

� Effect of improved suspension: 

� No effect on particle size 

� Effect of shear: 

� No effect on particle size or 

distribution (PSD) 


Scale-Up Projection 

� Just suspension speed determined experimentally for 2L lab reactor 

� CFD multi-phase 

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 

Lab, 2 L, 400 RPM Pilot Plant, 1500 L, 60-70 RPM 


(P/V)large / (P/V)lab 

Plant Supplies Campaign 

� Analysis of lab and pilot plant 

results by different scale-up 

parameters 

� solid suspension 

� shear 

� overall energy input 

1000 

100 

10 

1 

0.1 

0.01 

Scale-up by constant 

mixing time 

energy input 

solid suspension 

shear 

heat transfer 

Penney Diagram 

1.00E+00 1.00E+01 1.00E+02 1.00E+03 1.00E+04 

Vplant / Vlab 

� Shear and energy input have 

� no effect on particle size 

� Increased suspension on scale-up: 

� no effect on particle size 

� slightly narrower PSD 


[microns]

� Extrapolation to Manufacturing: 


Jurong V460 (4000 L), 48 RPM 


The Voice of Scale-Up Experience 

Do Don’t 

Collaborate Add solids to a reaction 

Log Evaporate to dryness 

Sample Use “all in & heat” 

Safety test & review Rely on critical timing 

Use test Do hot filtrations 

Keep it simple Risk all in one batch 

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.)

Brechtelsbauer - Workspace - Imperial College London

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