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`TEVA EXHIBIT 1016
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`
`Mixing in the Process Industries
`
`Second edition
`
`Editors: N Harnby, M F Edwards, A W Nienow
`
`TEVA EXHIBIT 1016
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`TEVA EXHIBIT 1016
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`

`
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`
`Butterworth—Heinemann
`Linacre House, Jordan Hill, Oxford OX2 8DP
`225 Wildwood Avenue, Woburn, MA 01801~204l
`A division of Reed Educational and Professional Publishing Ltd
`& A member of the ReedElsevier plc group
`OXFORD AUCKLAND BOSTON
`JOHANNESBURG MELBOURNE NEW DELHI
`
`First published 1985
`Reprinted 1987, 1989, 1990
`Second edition 1992
`Paperback edition 1997
`Reprinted 2000
`
`© Reed Educational and Professional Publishing Ltd 1985, 1992
`
`All rights reserved. No part of this publication
`may be reproduced in any material form (including
`photocopying or storing in any medium by electronic
`means and whether or not transiently or incidentally
`to some other use of this publication) without the
`written permission of the copyright holder except in
`accordance with the provisions_of the Copyright,
`Designs and Patents Act 1988 or under the terms of a
`licence issued by the Copyright Licensing Agency Ltd,
`90 Tottenham Court Road, London, England WIP OLP.
`Applications for the copyright holder’s written permission
`to reproduce any part of this publication should be addressed
`to the publishers
`
`British Library Cataloguing in Publication Data
`A catalogue record for this book is available from the British Library
`
`Library of Congress Cataloguing in Publication Data
`A catalogue record for this book is available from the Library of Congress
`
`ISBN 0 7506 3760 9
`
`Printed and bound in Great Britain by
`Antony Rowe Ltd, Chippenham, Wiltshire
`
`TEVA EXHIBIT 1016
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`TEVA EXHIBIT 1016
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`

`
`Contents
`
`Preface xi
`Listof contributors
`
`xii
`
`1.
`
`1
`Introduction to mixing problems
`A. W. Nienow, N. Harnby and M. F. Edwards
`1.1
`Range of problems
`2
`1.1.1
`Problem identification and philosophy 2
`1.1.2
`Single phase liquid mixing
`2
`1.1.3
`Solid——liquid mixing
`3
`3
`1.1.4
`Gas—liquid mixing
`1.1.5
`Liquid-liquid (immiscible) mixing 4
`1.1.6
`Three-phase contacting 4
`1.1.7
`Solids mixing 4
`1.1.8
`Heat transfer
`5
`
`1.2
`
`Overmixing 5
`1.1.9
`Mixing mechanisms
`5
`5
`1.2.1
`Liquid mixing
`10
`1.2.2
`Solids mixing
`Assessment of mixture quality
`1.3
`Rheology
`18
`1.4
`Notation 22
`References
`
`23
`
`16
`
`25
`
`Characterization of powder mixtures
`N. Harnby
`2.1
`A qualitative approach 25
`2.2
`A quantitative approach 26
`27
`2.2.1
`Powder sampling
`2.2.2
`Limiting variance values
`2.2.3
`Statistical inference
`30
`
`28
`
`A typical mixture analysis
`2.3
`Non-ideal mixtures
`40 A
`2.4
`References
`41
`
`33
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`
`3. The selection of powder mixers
`N. Harnby
`3.1
`The range of mixers available
`3.1.1
`Tumbler mixers
`42
`3.1.2
`Convective mixers
`
`42
`
`42
`
`42
`
`3.1.3
`3.1.4
`
`High shear mixers
`Fluidized mixers
`
`47
`48
`
`51
`Hopper mixers
`3.1.5
`52
`Multi—purpose mixers
`3.1.6
`Selection based on process requirements
`3.2
`Selection based on mixture quality
`54
`3.3
`Selection based on mixing costs
`59
`3.4
`Selection decision chart
`61
`3.5
`References
`61
`
`52
`
`Mixing in fluidized beds
`D. Geldart
`
`62
`
`4.1
`4.2
`
`‘
`
`Introduction 62
`Fundamentals of fluidization
`4.2.1
`Minimum fluidization
`
`63
`
`63
`
`4.2.2
`4.2.3
`
`Types of fluidization
`The role of bubbles
`
`64
`67
`
`68
`Types of mixing problems
`Mixing in non-segregating systems
`4.4.1
`Background theory 69
`4.4.2
`Turnover times
`71
`4.4.3
`Residence time distributions
`
`69
`
`71
`
`Mixing in segregating systems
`4.5.1
`Mixing criteria
`73
`4.5.2
`Powders containing particles of equal density but
`variable size
`74
`
`73
`
`4.5.3
`
`Powders containing species of differing densities and
`sizes
`75
`
`Concluding remarks
`4.6
`Notation 77
`References
`
`78
`
`76
`
`The mixing of cohesive powders
`N. Harnby
`5.1
`Introduction 79
`
`79
`
`I
`
`5.2
`
`5.3
`
`82
`Interparticulate forces
`5.2.1
`Bonding due to moisture
`5.2.2 .
`Electrostatic bonding 88
`5.2.3
`Van der Waals’ force bonding 89
`5.2.4
`Interaction of the bonding forces
`Selection of mixer
`94
`
`82
`
`91
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`Mixture quality for cohesive systems
`5.4
`References
`98
`
`~
`
`95
`
`6. The dispersion of fine particles in liquid media
`G. D. Parfitt and H. A. Barnes
`6.1
`.
`Introduction
`99
`
`99
`
`6.2
`
`M
`
`Stages in the dispersion process
`6.2.1
`Incorporation
`100
`6.2.2 Wetting
`102
`6.2.3
`Breakdown of agglomerates and aggregates
`6.2.4
`Stability to flocculation or colloidal stability
`Other considerations
`115
`6.3
`References
`116
`
`100
`
`106
`107
`
`A review of liquid mixing equipment
`M. F. Edwards and M. R. Baker
`7.1
`Introduction
`118
`
`118
`
`7.2
`
`7.3
`
`7.4
`
`7.5
`7.6
`
`7.7
`7.8
`7.9
`7.10
`
`Mechanically—agitated vessels
`7.2.1 _ Vessels
`119
`7.2.2
`Baffles
`120
`
`119
`
`Impellers 120
`7.2.3
`-Jet mixers
`125
`
`In~line static mixers
`
`126
`
`In-line dynamic mixers
`Mills
`128
`
`127
`
`High~speed dispersing units
`Valve homogenizers
`130
`Ultrasonic homogenizers . 130
`Extruders
`132
`
`128
`
`Equipment selection
`7.11
`References
`136
`
`136
`
`137
`Mixing of liquids in stirred tanks
`M. F. Edwards, M. R. Baker and J. C. Godfrey
`8.1
`Introduction
`137
`
`8.2
`
`8.3
`8.4
`8.5
`
`137
`Power input
`137
`8.2.1
`Newtonian liquids
`8.2.2
`Non-Newtonianliquids
`Flow patterns
`145
`Flow rate—head concepts
`Turbulence measurements
`
`147
`148
`
`8.6
`
`149
`Mixingtime
`151
`8.6.1
`Newtonianliquids
`8.6.2
`Non-Newtonianliquids
`Mixingefficiency
`155
`8.7
`Notation
`156
`References
`157
`
`140-
`
`154
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`
`9.
`
`Jet mixing
`B. K. Revill
`
`159
`
`9.1
`9.2
`9.3
`
`161
`
`Introduction
`159
`Fluid dynamics of turbulent jets
`Jet mixing in tanks
`163
`163
`9.3.1
`Measurement of mixing time
`164
`9.3.2
`Fluid dynamics of jet mixed tanks
`9.3.3
`Theoretical prediction of batch mixing time
`9.3.4
`Experimental correlations for jetmixing time
`9.3.5
`Recommended jet/tank geometry
`170
`9.3.6
`Stratification
`172
`
`165
`166
`
`9.4
`
`174
`Liquid level variation
`9.3.7
`174
`Continuous‘ mixing
`9.3.8
`174
`Design procedure
`9.3.9
`9.3.10 When to usejet mixed tanks
`Jet mixing in tubes
`177
`177
`9.4.1
`Design basis
`9.4.2
`Coaxial jet mixer design
`9.4.3
`Side entry jet mixer design
`9.4.4
`Use of tubular jet mixers
`Notation
`181
`References
`182
`
`175
`
`178
`180
`180
`
`10. Mixing in single-phase chemical reactors
`J. R. Baurne
`10.1
`Introduction
`
`184
`
`184
`
`184
`10.2 Mechanisms ofmixing
`10.2.1
`Convective, distributive mixing of a single—feed
`stream 185
`
`188
`10.2.2 Diffusivemixing
`10.2.3 Approximate method
`10.2.4 More accurate methods
`Notation 196
`References
`198
`
`189
`190
`
`Laminar flow and distributive mixing
`M. F. Edwards
`11.1
`Introduction 200
`11.2
`Laminar shear
`202
`
`200
`
`Elongational (or extensional) laminar flow 210
`11.3
`11.4 Distributive mixing 214
`216
`11.5
`Dispersive mixing in laminar flows
`11.6 Applications to blending and dispersing equipment
`11.7
`Assessment of mixture quality
`222
`Notation 223
`References
`224
`
`217
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`
`12. Static mixers
`
`225
`
`J. C. Godfrey
`12.1
`Introduction 225
`
`226
`
`12.2
`
`12.1.1 Mixertypes
`Laminarmixing 227
`232
`12.2.1 Mixingindices
`12.2.2 Mixingrate
`234
`12.2.3
`Energy and efficiency
`Turbulentmixing 242
`243
`12.3.1 Mixingrate
`12.3.2
`Energyrequirements
`12.3.3
`Applications
`245
`Conclusions
`246
`12.4
`Notation 247
`References
`248
`
`238
`
`245
`
`13. Mechanical aspects of mixing
`R. King
`13.1
`Introduction 250
`
`250
`
`'
`
`13.2
`
`The production of ‘steady’ forces on an agitator and transmission
`of power
`251
`251
`13.2.1
`‘Steady’ forces on an agitator
`13.2.2
`Transmission of power by an agitator shaft
`The EEUA method of shaft sizing
`254
`13.3.1
`Introduction 254
`13.3.2
`Combined torsion and bending 256
`13.3.3
`Stress analysis
`258
`Fluctuating forces and vibrations
`13.4.1
`Resonance
`259
`
`254
`
`259
`
`Vibrations ,
`’ 259
`13.4.2
`Response to forcing I 261
`13.4.3
`Fluctuating loads on an agitator shaft
`13.4.4
`13.4.5 Whirling of the agitator shaft
`264
`Shaft design to accommodate fluctuating loads — the FMP
`approach 265
`13.5.1
`Introduction 265
`
`262
`
`Sizing the shaft
`13.5.2
`Stress analysis
`13.5.3
`Fatigue analysis
`268
`13.6.1
`Introduction 268
`
`266
`267
`
`13.6.2
`13.6.3
`13.6.4
`13.6.5
`
`268
`Bending only
`Combined bending and torsion 269
`Checking the safety of the design for fatigue
`The importance of a fatigue check 272
`
`271
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`
`Seals, gearboxes and impellers
`13.7.1
`Seals
`272
`13.7.2
`Gearboxes
`
`275
`
`272
`
`278
`Impellers
`13.7.3
`279
`Economic considerations
`13.8.1
`Introduction 279
`13.8.2
`Remediallosses
`
`279
`
`13.8.3 Marketing losses
`13.8.4
`Examples
`280
`Overall conclusions
`283
`13.9
`Notation 283
`References
`285
`
`280
`
`Appendix 13.1 Worked examples
`
`286
`
`14. Dynamics of emulsification 294
`D. C. Peters
`L
`14.1
`Introduction
`294
`
`295
`
`Rheology and stability
`14.2
`14.3 Dropletformation 300
`14.3.1
`Deformation and breakup in steady flows
`14.3.2
`Dynamic effects
`306
`14.3.3
`Turbulence
`306
`
`301
`
`14.4
`
`309
`Implications for process design
`14.4.1
`Batch processing 309 5
`14.4.2
`Continuous processing 311
`Notation 311
`References
`313
`315
`Appendix 14.1: Numerical example of process design
`Appendix 14.2: A procedure for scaling up or down non—Newtonian
`processes
`318
`
`Gas—-liquid dispersion and mixing
`J. C. Middleton
`15.1
`Introduction — classification of gas-liquid mixing problems
`15.2
`Types and configurations of turbulent gas—1iquid stirred ‘
`vessels
`326
`
`322
`
`322
`
`15.3
`15.4
`15.5
`
`A design basis for gas—liquid agitated vessels
`Power consumption 331
`Bubble size and coalescence
`
`341
`
`330
`
`15.6
`15.7
`
`Gas hold~up fraction 342
`Concentration driving force
`15.7.1
`Liquid mixing 343
`15.7.2
`Gas mixing
`343
`Gas—liquid mass transfer
`15.8
`15.9 Heat transfer
`349
`
`343
`
`346
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`15.10
`
`349
`Gas—liquid mixers as reactors
`15. 10.1 Theory of mass transfer with reaction 350
`15. 10.2 Locale of diffusion limitation 351
`
`15 . 10.3 Mixing mode and reaction 352
`15. 10.4 Scale of mixing
`353
`15. 10.5 Experimental work for classification of reaction
`regimes
`354
`15.10.6 Gas—liquid reactor modelling
`15.11
`Example of scale-up
`357
`Notation 360
`References
`361
`
`355
`
`16. The suspension of solid particles
`A. W. Nienow
`16.1
`Introduction 364
`16.2
`
`364
`
`Definitions of states of suspension and distribution
`16.2.1
`Just complete suspension
`364
`16.2.2
`Homogeneous suspension
`365
`Bottom or corner fillets
`365
`16.2.3
`16.2.4
`
`364
`
`365
`Dispersion of floating solids
`Power consumption in systems with suspended particles
`Mechanisms and models of particle suspension and
`distribution
`366
`16.4.1
`16.4.2
`
`366
`Particle suspension
`Solids distribution 368
`
`365
`
`Experimental measurement of particle suspension and
`distribution
`369
`
`16.5.1
`
`_Particle distribution 369‘
`
`Just complete suspension speed, N15
`16.5.2
`Experimental results and correlations for NJS
`16.6.1
`Introduction 370
`
`369
`370
`
`16.6.2
`16.6.3
`16.6.4
`
`372
`Correlations for N15
`Particle and fluid properties
`Solid concentration 373
`
`373
`
`Standard geometry 374
`16.6.5
`Other geometries
`379
`16.6.6
`Scale-up
`380
`16.6.7
`Selection of geometry and the scale-up rule for (é-T)_[S
`Solids distribution and withdrawal
`382
`
`381
`
`16.7
`16.8
`
`16.8.1
`16.8.2
`
`Assessment of solids distribution and scale-up
`Solid withdrawal
`384
`
`382
`
`16.9
`
`386
`Three phase systems
`16.10 The ingestion and dispersion of floating solids
`16.11 Conclusions
`390
`Notation 390
`References
`392
`
`388
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`
`17. The mixer as a reactor: liquid/solid systems
`A. W. Nienow
`,
`
`394
`
`17.3.3
`17.3.4
`
`394
`Reactor types
`17.1
`395
`Reaction rates
`17.2
`398
`17.3 Mass transfer
`398
`17.3.1 Measurement of mass transfer coefficient, k
`17.3.2
`The relationship between k and impeller speed
`N 399
`.
`400
`kjs at NJS and as a function of (ET)_[S
`Prediction of the bulk diffusion mass transfer
`coefficient, k
`402
`The dissolution time when Sh = 2
`17.3.5
`The use of the slip velocity equation 406
`17.4
`Particle impacts and abrasion
`407
`17.5
`Conclusions
`409
`17.6
`Notation 409 .
`References
`410
`
`406
`
`Index 412
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`
`Range of problems
`
`When chemical reactions occur between miscible liquids it is necessary to
`bring together the reactants at the molecular level by mixing before the
`reaction can occur. The important interaction between mixing and reaction is
`developed in detail in Chapter 10.
`I
`
`1.1.3
`Solid—liquid mixing
`In operations such as crystallization or solid-catalysed liquid reactions, it is
`necessary to suspend solid particles in a relatively low viscosity liquid. This can
`be achieved in mechanically agitated vessels where the mixer is used to prevent
`sedimentation ofthe solids and to provide conditions suitable for good liquid-
`solid mass transfer and/or chemical reaction. If agitation is stopped the solids
`will settle out or float to the surface, depending upon the relative densities of
`the solid and liquid phases. The suspension of solids in mixing vessels and the
`design ofmixing vessels for solid-liquid reactions are treated in Chapters 16
`and 17 respectively.
`At the opposite extreme, it may be required to disperse very fine particles
`into a highly viscous liquid. For example, the incorporation of carbon black
`into rubber is such an operation. Here, as with emulsilication in1iquid—1iquid
`mixing, the product is stable, highly viscous and may well exhibit complex
`rheology. Such processes often involve surface phenomena and physical
`contacting only,
`in contrast to the mass transfer and chemical reactions
`described in the previous paragraph. The dispersion of fine particles in liquids
`is considered in detail in Chapter 6.
`
`1.1.4 Gas—liquid mixing
`Several major industrial operations, e.g. oxidation, hydrogenation, and biolo-
`gical fermentations, involve the contacting of gases and liquids. Often the latter I
`are rheologically complex. It is the objective in such processes to agitate the
`gas—liquid mixture in order to generate a dispersion of gas bubbles in a
`continuous liquid phase. Mass transfer then takes place across the gas—-
`liquid interface which is created. .In some instances, chemical reactions
`may also accompany the mass transfer in the liquid phase. These gas dis~
`persing duties are similar to the crystallization processes described in solid-
`liquid contacting, that is, the term ‘mixing’ covers a mass-transfer process.
`Furthermore, all the mixtures are unstable and separate if agitation is stopped.
`Gas—liquid contacting involving mass transfer and chemical reaction in
`mixing vessels is considered in Chapter 15.
`In some instances, gases and liquids are mixed to provide a stable batter or
`foam. This contacting is of a physical nature and the resulting product will
`often exhibit non~Newtonian flow characteristics.
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`Other considerations
`
`115
`
`and operates at short distances. Hence the flocculation behaviour depends on
`the structure of the adsorbed layer (solvency, molecular weight, thickness,
`segment distribution), and the magnitude of the repulsive and/or attractive
`interactions arising from adsorbed layer overlap.
`Significant advances have been made over the last three decades in our
`understanding of steric stabilization, and recently measurements have
`been reported on the force between two surfaces containing adsorbed
`po1ymer*““. Data on the measurement of the force due to the electrostatic
`interaction of surfaces have also been presented, as well as those arising from
`non-DLVO interactions.
`
`An interesting example of the application of the concept of steric stabiliza-
`tion is the interpretation ofthe optical performance of alkyd paints pigmented
`with TiO3 by Franklin et al.33. Having established from electrophoresis and
`opacity measurements that the electric charge on the particles is not the
`controlling factor in flocculation, a study was made of the adsorption
`characteristics ofthe resin using pigments coated with different levels of silica/
`alumina such that the surfaces created varied from predominantly silica to
`mostly alumina.
`Interpretation ofthe adsorption isotherms indicated that for the acidic silica
`surface the basic resin molecules interactedstrongly with the surface and
`adopted a parallel orientation, thus making little contribution to preventing
`flocculation; On the other hand, for the predominantly alumina~coated
`surface, the resin only made contact with the surface with its limited number of
`acid groups, the rest of the molecule being extended into the medium and
`providing a steric barrier to flocculation.
`When the surface coverage of polymer is low then ‘bridging’ flocculation is
`possible. This is brought out by the polymer becoming simultaneously
`adsorbed on two or more particles—a ‘bridging’ mechanism leading to a
`rather open structure in the llocculates. The mechanism has been summarized
`by Kitchener”. Since polymer adsorption is usually irreversible, the method
`of mixing of the components can have a profound effect on the flocculation
`process. Tadros has reported5" a good demonstration of the effect, using silica
`and aqueous solutions of polyvinyl alcohol. The effect depends on the
`pretreatment ofsilica, hence the surface hydroxyl population, and on the pH of
`the solution which determines the particle charge, both factors influencing the
`adsorption sites for PVA adsorption. _
`
`6.3 Other considerations
`
`Once dispersion has been achieved, the deflocculated particles can be kept in
`suspension by agitation in the mixing vessel. However, once agitation ceases
`sedimentation begins and sediment begins to accumulate. In many cases this is
`unimportant because other components are added either to finish formulating
`the product as for instance in paints, and these give physical stability.
`
`TEVA EXHIBIT 1016
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05022437
`
`TEVA EXHIBIT 1016
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC