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 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
Chemistry: Reactions and Separations
Reactions Kinetics Multiphase Separations Distillation Extraction Environmental Mass Balance Recovery Particle Forming Unit Operations 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
Or

Physics Equipment

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

H=T

B = T/10

C=T/3

Dr. Clemens Brechtelsbauer

Slide 7

Stirred Tank Scale-Up

Ships Wheel vs. Cartwheel

Low shear Good for solid suspension

Dr. Clemens Brechtelsbauer Slide 8

High shear Good for dispersions

Stirred Tank Scale-Up

Beware of the Dork Side

Minimum Stir and Mixing Volumes
1200

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

1000 800 600 400 200 0 0 500 1000 1500 2000 2500 3000 Nominal vessel volume [L] V stir min [L] V mix min [L]

V static V dish

1% 7%

V stir, min 5 %

V mix, min 30-40 % V nominal

Dr. Clemens Brechtelsbauer

D D V nominal V nominal

V nominal

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

Laminar regime Good for blending

Ensures good motion near vessel walls

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 N3 D5 Power number Po, or Newton number, Ne Depends on
Impeller type Impeller and vessel DE/V dimensions Properties of the phases present

E1/V A1, v1, h1, p1

A2, v2, h2, p2 E2/V

Must be measured!

Dr. Clemens Brechtelsbauer

Slide 12

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:
Po = f(Re)

10 < Re < 103

Turbulent:
Po = constant
Dr. Clemens Brechtelsbauer

Re >

103

Ekato Handbook of Mixing Technology, p. 15

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 T1 C1

D2 T2 H 2 C2 s D1 T1 H1 C1

H2

D2

C2

T2

Dr. Clemens Brechtelsbauer

Slide 14

Stirred Tank Scale-Up

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!

Dr. Clemens Brechtelsbauer

Slide 15

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 Liquid blending Solid suspension Solid distribution Gas-liquid Heat transfer Fast reactions Rule Equal tip speed Zwietering Equal energy input Equal mass transfer Equal Re Equal mixing time Constant Parameter ND Njs D0.85 P/V P / V (= kLa) N D2 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

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 Slide 21

4000 L Manufacturing
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
Slide 23 Stirred Tank Scale-Up

Dr. Clemens Brechtelsbauer

Plant Supplies Campaign

Analysis of lab and pilot plant results by different scale-up parameters
solid suspension shear overall energy input
Penney Diagram
1000
Scale-up by constant

Shear and energy input have no effect on particle size Increased suspension on scale-up: no effect on particle size slightly narrower PSD

energy input

(P/V) l arge / (P/V) l ab

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

Slide 24

[microns]

100

mixing time

Stirred Tank Scale-Up

Process Assessment
Extrapolation to Manufacturing:
Jurong V460 (4000 L), 48 RPM

Dr. Clemens Brechtelsbauer

Slide 25

Stirred Tank Scale-Up

The Voice of Scale-Up Experience

Do
Collaborate Log Sample Safety test & review Use test Keep it simple

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

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