Pharmaceutical Blending and Mixing

511 Pages·2015·11.86 MB·English

by  P. J. Cullen

Pharmaceutical Blending and Mixing

Pharmaceutical Blending
and Mixing
Edited by
P.J. CullEn
School of Chemical Engineering,
University of New South Wales,
Australia
Rodolfo J. RomañaCh
Department of Chemistry,
University of Puerto Rico – Mayagüez,
Puerto Rico
niColas abatzoglou
Chemical Engineering and Biotechnological Engineering,
Université de Sherbrooke, Canada
ChRis d. RiElly
Department of Chemical Engineering,
Loughborough University, UK
this edition first published 2015
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Cover credit: Photograph kindly provided by gebruder lodige
set in 10/12pt times by sPi global, Pondicherry, india
1 2015
Contents
Contributor List xv
Preface xvii
Part I Fundamentals of Mixing 1
1 Mixing Theory 3
Chris D. Rielly
1.1 Introduction 3
1.2 Describing Mixtures 5
1.3 Scale of Scrutiny 6
1.4 Quantifying Mixedness for Coarse and Fine‐Grained Mixtures 8
1.4.1 Coarse and Fine‐Grained Mixtures 8
1.4.2 Scale and Intensity of Segregation 9
1.5 Determining the End‐Point of Mixing: Comparison of Mixing Indices 15
1.6 Continuous Flow Mixers 19
1.6.1 Idealized Mixing Patterns 19
1.6.2 Residence Time Distributions 21
1.6.3 Back‐Mixing and Filtering of Disturbances Using a CSTR 23
References 24
2 Turbulent Mixing Fundamentals 27
Suzanne M. Kresta
2.1 Introduction 27
2.2 The Velocity Field and Turbulence 28
2.3 Circulation and Macro‐Mixing 29
2.4 Fully Turbulent Limits and the Scaling of Turbulence 32
2.5 The Spectrum of Turbulent Length Scales, Injection of a Scalar
(Either Reagent or Additive) and the Macro‐, Meso‐ and
Micro‐Scales of Mixing 34
2.6 Turbulence and Mixing of Solids, Liquids, and Gases 37
2.7 Specifying Mixing Requirements for a Process 38
2.8 Conclusions 39
Notation 39
Roman Characters 39
Greek Characters 40
References 40
vi Contents
3 Laminar Mixing Fundamentals 43
P.J. Cullen and N.N. Misra
3.1 Laminar Flows 43
3.2 Mixing in Laminar Flows 44
3.2.1 Chaos and Laminar Chaotic Mixing 45
3.2.2 Granular Chaotic Mixing 50
3.3 Recent Advances 53
References 54
4 Sampling and Determination of Adequacy of Mixing 57
Rodolfo J. Romañach
4.1 Introduction, Process Understanding, and Regulations 57
4.2 Theory of Sampling 59
4.3 Sampling of Pharmaceutical Powder Blends 63
4.4 Stratified Sampling Approach 65
4.5 Testing 67
4.6 Process Knowledge/Process Analytical Technology 68
4.7 Real Time Spectroscopic Monitoring of Powder Blending 70
4.8 Looking Forward, Recommendations 73
4.9 Conclusion 74
4.10 Acknowledgments 75
References 75
Part II Applications 79
5 Particles and Blending 81
Reuben D. Domike and Charles L. Cooney
5.1 Introduction 81
5.2 Particle Geometry 82
5.2.1 Particle Size and Size Distribution 82
5.2.2 Particle Shape and Shape Distribution 83
5.3 Particle Interactions 84
5.3.1 van der Waals Forces 84
5.3.2 Electrostatic Forces 85
5.3.3 Adsorbed Liquid Layers and Liquid Bridges 85
5.3.4 Solid Bridges 86
5.3.5 Use of AFM to Measure Interparticle Forces 87
5.3.6 Interparticle Friction 89
5.4 Empirical Investigations of Particles and Blending 90
5.4.1 Blending of Powders 90
5.4.2 Impact of Particle Geometry on Blending 92
5.4.3 Impact of Interparticle Forces on Blending 93
5.4.4 Impact of Blender Conditions on Blending 95
Contents vii
5.5 Simulation Techniques 95
5.5.1 Full Physics Models Using Discrete Element Modeling 96
5.5.2 Continuum Models 97
5.5.3 Cellular Automata 98
References 98
6 Continuous Powder Mixing 101
Juan G. Osorio, Aditya U. Vanarase, Rodolfo J. Romañach, and
Fernando J. Muzzio
6.1 Introduction 101
6.2 Overview 102
6.3 Theoretical Characterization 107
6.3.1 Residence Time Distribution (RTD) Modeling 107
6.3.2 Variance Reduction Ratio 108
6.4 Experimental Characterization 108
6.4.1 Hold‐Up 109
6.4.2 Residence Time Distribution (RTD) Measurements 109
6.4.3 Mean Strain 110
6.5 Continuous Mixing Efficiency 110
6.5.1 Variance Reduction Ratio 110
6.5.2 Blend Homogeneity 111
6.6 Effects of Process Parameters on Mixing Behavior
and Performance 112
6.6.1 Hold‐Up 113
6.6.2 RTD Measurements 113
6.7 Mixing Performance 118
6.7.1 Modeling 120
6.7.2 PAT, QbD, and Control 122
6.8 Conclusions and Continuing Efforts 124
References 125
7 Dispersion of Fine Powders in Liquids: Particle Incorporation
and Size Reduction 129
Gül N. Özcan-Taşkın
7.1 Particle Incorporation into Liquids 129
7.1.1 Wetting 130
7.1.2 Stirred Tanks for Particle Incorporation 132
7.1.3 In‐Line Devices Used for Particle Incorporation 140
7.2 Break Up of Fine Powder Clusters in Liquids 143
7.2.1 Mechanisms of Break Up 146
7.2.2 Process Devices for Deagglomeration\Size Reduction
of Agglomerates 147
References 150
viii Contents
8 Wet Granulation and Mixing 153
Karen P. Hapgood and Rachel M. Smith
8.1 Introduction 153
8.2 Nucleation 154
8.2.1 Drop Penetration Time 156
8.2.2 Dimensionless Spray Flux 158
8.2.3 Nucleation Regime Map 160
8.3 Consolidation and Growth 162
8.3.1 Granule Consolidation 162
8.3.2 Granule Growth Behaviour 164
8.3.3 Granule Growth Regime Map 165
8.4 Breakage 167
8.4.1 Single Granule Strength and Deformation 167
8.4.2 In‐Granulator Breakage Studies 170
8.4.3 Aiding Controlled Granulation via Breakage 172
8.5 Endpoint Control 174
8.5.1 Granulation Time 175
8.5.2 Impeller Power Consumption 176
8.5.3 Online Measurement of Granule Size 176
8.5.4 NIR and Other Spectral Methods 177
References 178
9 Emulsions 183
Andrzej W. Pacek
9.1 Introduction 183
9.2 Properties of Emulsions 185
9.2.1 Morphology 185
9.2.2 Volumetric Composition 185
9.2.3 Drop Size Distributions and Average Drop Sizes 186
9.2.4 Rheology 191
9.3 Emulsion Stability and Surface Forces 195
9.3.1 Surface Forces 195
9.3.2 Emulsion Stability 199
9.4 Principles of Emulsion Formation 203
9.4.1 Low Energy Emulsification 204
9.4.2 High Energy Emulsification 205
9.5 Emulsification Equipment 216
9.5.1 Stirred Vessels 216
9.5.2 Static Mixers 218
9.5.3 High Shear Mixers 219
9.5.4 High‐Pressure Homogenizers 223
9.5.5 Ultrasonic Homogenizers 225
9.6 Concluding Remarks 226