Pharmaceutical Blending and Mixing

Dr PJ Cullen is a lecturer in?the Faculty of Engineering at the University of New South Wales. His current research interests include rheology, mixing, chemical imaging and non-thermal plasmas for biological applications in food. He has published over 35 journal papers, 15 book chapters and edited 1 book on food mixing. Professor Rodolfo J. Romañach is Professor of Chemistry at the University of Puerto Rico. He has over 20 years of experience in vibrational spectroscopy, and worked in Puerto Rico's pharmaceutical industry for 12 years prior to joining the UPR-Mayagüez faculty. In the pharmaceutical industry he worked extensively in assay and cleaning validation, and in providing analytical support for API and pharmaceutical process related problems. Professor Nicolas Abatzaglou is Director of the?Chemical Engineering and Biotechnological Engineering Department and Holder of the Pfizer Chair: PAT in Pharmaceutical Engineering at the Universite de Sherbrooke, Canada. He is the current recipient of Quebec's Minister of Education (MELS Chantier II) Fellowship award for his excellence in research and teaching. Professor Chris Rielly is Head of the Department of Chemical Engineering at Loughborough University. He has taught chemical engineering for over 20 years at Cambridge and Loughborough Universities and is a Fellow of the Institution of Chemical Engineers with more than 20 years of experience working in experimental and computational fluid mechanics. His interests include multi-phase flow, mass transfer and turbulent mixing in chemical processing equipment. He has served on the Scientific Committees of the European Conference on Mixing, the International Conference on Gas-Liquid-Solid Reaction Engineering and the Process Innovation and Intensification Conference. He is an academic consultant to BHR Group's Fluid Mixing Processes Industrial Consortium and Chairman of the IChemE's Fluid Mixing Subject Group. He has previously edited books.

• Contributor List xv Preface xviiPart I Fundamentals of Mixing 11 Mixing Theory 3Chris D. Rielly1.1 Introduction 31.2 Describing Mixtures 51.3 Scale of Scrutiny 61.4 Quantifying Mixedness for Coarse and Fine‐Grained Mixtures 81.4.1 Coarse and Fine‐Grained Mixtures 81.4.2 Scale and Intensity of Segregation 91.5 Determining the End‐Point of Mixing: Comparison of Mixing Indices 151.6 Continuous Flow Mixers 191.6.1 Idealized Mixing Patterns 191.6.2 Residence Time Distributions 211.6.3 Back‐Mixing and Filtering of Disturbances Using a CSTR 23References 242 Turbulent Mixing Fundamentals 27Suzanne M. Kresta2.1 Introduction 272.2 The Velocity Field and Turbulence 282.3 Circulation and Macro‐Mixing 292.4 Fully Turbulent Limits and the Scaling of Turbulence 322.5 The Spectrum of Turbulent Length Scales, Injection of a Scalar (Either Reagent or Additive) and the Macro‐, Meso‐ and Micro‐Scales of Mixing 342.6 Turbulence and Mixing of Solids, Liquids, and Gases 372.7 Specifying Mixing Requirements for a Process 382.8 Conclusions 39Notation 39Roman Characters 39Greek Characters 40References 403 Laminar Mixing Fundamentals 43P.J. Cullen and N.N. Misra3.1 Laminar Flows 433.2 Mixing in Laminar Flows 443.2.1 Chaos and Laminar Chaotic Mixing 453.2.2 Granular Chaotic Mixing 503.3 Recent Advances 53References 544 Sampling and Determination of Adequacy of Mixing 57Rodolfo J. Romañach4.1 Introduction, Process Understanding, and Regulations 574.2 Theory of Sampling 594.3 Sampling of Pharmaceutical Powder Blends 634.4 Stratified Sampling Approach 654.5 Testing 674.6 Process Knowledge/Process Analytical Technology 684.7 Real Time Spectroscopic Monitoring of Powder Blending 704.8 Looking Forward, Recommendations 734.9 Conclusion 744.10 Acknowledgments 75References 75Part II Applications 795 Particles and Blending 81Reuben D. Domike and Charles L. Cooney5.1 Introduction 815.2 Particle Geometry 825.2.1 Particle Size and Size Distribution 825.2.2 Particle Shape and Shape Distribution 835.3 Particle Interactions 845.3.1 van der Waals Forces 845.3.2 Electrostatic Forces 855.3.3 Adsorbed Liquid Layers and Liquid Bridges 855.3.4 Solid Bridges 865.3.5 Use of AFM to Measure Interparticle Forces 875.3.6 Interparticle Friction 895.4 Empirical Investigations of Particles and Blending 905.4.1 Blending of Powders 905.4.2 Impact of Particle Geometry on Blending 925.4.3 Impact of Interparticle Forces on Blending 935.4.4 Impact of Blender Conditions on Blending 955.5 Simulation Techniques 955.5.1 Full Physics Models Using Discrete Element Modeling 965.5.2 Continuum Models 975.5.3 Cellular Automata 98References 986 Continuous Powder Mixing 101Juan G. Osorio, Aditya U. Vanarase, Rodolfo J. Romañach, and Fernando J. Muzzio6.1 Introduction 1016.2 Overview 1026.3 Theoretical Characterization 1076.3.1 Residence Time Distribution (RTD) Modeling 1076.3.2 Variance Reduction Ratio 1086.4 Experimental Characterization 1086.4.1 Hold‐Up 1096.4.2 Residence Time Distribution (RTD) Measurements 1096.4.3 Mean Strain 1106.5 Continuous Mixing Efficiency 1106.5.1 Variance Reduction Ratio 1106.5.2 Blend Homogeneity 1116.6 Effects of Process Parameters on Mixing Behavior and Performance 1126.6.1 Hold‐Up 1136.6.2 RTD Measurements 1136.7 Mixing Performance 1186.7.1 Modeling 1206.7.2 PAT, QbD, and Control 1226.8 Conclusions and Continuing Efforts 124References 1257 Dispersion of Fine Powders in Liquids: Particle Incorporation and Size Reduction 129Gül N. Özcan-Taşkın7.1 Particle Incorporation into Liquids 1297.1.1 Wetting 1307.1.2 Stirred Tanks for Particle Incorporation 1327.1.3 In‐Line Devices Used for Particle Incorporation 1407.2 Break Up of Fine Powder Clusters in Liquids 1437.2.1 Mechanisms of Break Up 1467.2.2 Process Devices for Deagglomeration\Size Reduction of Agglomerates 147References 1508 Wet Granulation and Mixing 153Karen P. Hapgood and Rachel M. Smith8.1 Introduction 1538.2 Nucleation 1548.2.1 Drop Penetration Time 1568.2.2 Dimensionless Spray Flux 1588.2.3 Nucleation Regime Map 1608.3 Consolidation and Growth 1628.3.1 Granule Consolidation 1628.3.2 Granule Growth Behaviour 1648.3.3 Granule Growth Regime Map 1658.4 Breakage 1678.4.1 Single Granule Strength and Deformation 1678.4.2 In‐Granulator Breakage Studies 1708.4.3 Aiding Controlled Granulation via Breakage 1728.5 Endpoint Control 1748.5.1 Granulation Time 1758.5.2 Impeller Power Consumption 1768.5.3 Online Measurement of Granule Size 1768.5.4 NIR and Other Spectral Methods 177References 1789 Emulsions 183Andrzej W. Pacek9.1 Introduction 1839.2 Properties of Emulsions 1859.2.1 Morphology 1859.2.2 Volumetric Composition 1859.2.3 Drop Size Distributions and Average Drop Sizes 1869.2.4 Rheology 1919.3 Emulsion Stability and Surface Forces 1959.3.1 Surface Forces 1959.3.2 Emulsion Stability 1999.4 Principles of Emulsion Formation 2039.4.1 Low Energy Emulsification 2049.4.2 High Energy Emulsification 2059.5 Emulsification Equipment 2169.5.1 Stirred Vessels 2169.5.2 Static Mixers 2189.5.3 High Shear Mixers 2199.5.4 High‐Pressure Homogenizers 2239.5.5 Ultrasonic Homogenizers 2259.6 Concluding Remarks 226Nomenclature 226Greek symbols 228References 22810 Mixing of Pharmaceutical Solid‐Liquid Suspensions 233Mostafa Barigou and Frans L. Muller10.1 Introduction 23310.1.1 Linking Solid‐Liquid Processing to Critical Quality Attributes 23310.1.2 Material Properties and Composition 23410.1.3 Impact of Blending and Homogenization 23410.1.4 Impact of Turbulence 23710.1.5 Impact of Heat Transfer 23710.2 Scale‐Up of Operations Involving Solid Suspensions 23710.2.1 The Nature of Suspensions 23710.2.2 Scale‐Up and Scale‐Down Rules 23910.2.3 Identification of Agitator Duties 24010.2.4 Solid‐Liquid Unit Operations 24210.3 General Principles of Solid‐Liquid Suspensions 24310.3.1 Rheological Behaviour of the Continuous Phase 24310.3.2 Rheology of Suspensions 24610.3.3 Terminal Velocity of Particles 24910.3.4 Turbulence 25410.4 Solids Charging 25710.4.1 Charging to Batch Vessels 25710.4.2 Charging Difficult Powders 26110.5 Solid Suspension 26110.5.1 States of Solid Suspension 26110.5.2 Prediction of Minimum Speed for Complete Suspension 26210.6 Solid Distribution 26910.6.1 Agitator Speed 26910.6.2 Homogeneity 27010.6.3 Geometry 27110.6.4 Practical Guidelines 27210.7 Blending in Solid‐Liquid Systems 27210.7.1 Mixing Time 27210.7.2 Viscoplastic Slurries Yield Stress and Cavern Formation 27210.8 Mass Transfer 27510.9 Size Reduction, Deagglomeration and Attrition 27710.9.1 Breaking Particles through Turbulent Forces 27710.9.2 Breaking Particles through Impact 278Nomenclature 281Greek symbols 281Abbreviations 282References 282Part III Equipment 28711 Powder Blending Equipment 289David S. Dickey11.1 Introduction 28911.2 Blending Mechanisms 29011.3 Blend Time 29011.4 Fill Level 29111.5 Segregation 29111.6 Powder Processing Difficulties 29211.7 Blender Classification 29211.7.1 Tumble Blenders 29311.7.2 Rotating Element Blenders 29811.7.3 Granulators 30311.7.4 Other Blenders – Mullers and Custom Blenders 30411.8 Continuous Blenders 30511.9 Blender Selection 30611.10 Equipment Specifications 30711.10.1 Materials of Construction 30911.10.2 Electrical Classification 30911.10.3 Drives and Seals 309References 31012 Fluid Mixing Equipment Design 311David S. Dickey12.1 Introduction 31112.2 Equipment Description 31212.2.1 Laboratory Mixers 31212.2.2 Development Mixers 31312.2.3 Portable Mixers 31312.2.4 Top-Entering Mixers 31512.2.5 High-Shear Dispersers 31812.2.6 High Viscosity Mixers 31912.2.7 Multi-Shaft Mixers 31912.2.8 Bottom-Entering Mixers 32012.2.9 Glass-Lined Mixers and Vessels 32112.2.10 Side-Entering Mixers 32212.2.11 Vessel Geometry 32212.2.12 Baffles 32312.3 Measurements 32312.3.1 Power 32412.3.2 Torque 32612.3.3 Tip Speed 32712.3.4 Blend Time 32712.4 Mixing Classifications 32812.4.1 Liquid Mixing 32812.4.2 Solids Suspension 33012.4.3 Gas Dispersion 33212.4.4 Viscous Mixing 33312.5 Mechanical Design 33412.5.1 Shaft Design 33412.5.2 Shaft Seals 33512.5.3 Materials of Construction 33612.5.4 Surface Finish 33712.5.5 Motors 33812.5.6 Drives 33912.6 Static Mixers 33912.6.1 Twisted Element 33912.6.2 Structured Element 33912.6.3 Basic Design 34012.7 Challenges and Troubleshooting 34112.7.1 Careful Observations 34112.7.2 Process Problems 341Nomenclature 342Greek 343References 34313 Scale‐Up 345David S. Dickey13.1 Introduction 34513.2 Similarity and Scale‐Up Concepts 34613.2.1 Dimensional Analysis 34613.2.2 Similarity 34713.2.3 Applied Scale‐Up 34913.3 Testing Methods 35013.4 Observation and Measurement 35213.5 Scale‐Up Methods 35413.5.1 Scale‐Up with Geometric Similarity 35413.5.2 Example of Geometric Similarity Scale‐Up 35813.5.3 Scale‐Up Without Geometric Similarity 35913.5.4 Example of Non‐Geometric Scale‐Up 36113.5.5 Scale‐Up for Powder Mixing 36413.6 Summary 367Nomenclature 367Greek 368References 36814 Equipment Qualification, Process and Cleaning Validation 369Ian Jones and Chris Smalley14.1 Introduction 36914.2 Blending Equipment Commissioning and Qualification 37014.2.1 Outline of the Verification Approach 37014.2.2 Requirements Phase 37114.2.3 Specifications and Design Review Phase 37314.2.4 Verification Phase 37514.3 Blending and Mixing Validation 38014.3.1 Why do You Need to Validate Pharmaceutical Blends/Mixes? 38214.3.2 When do You Need to Validate Blending/Mixing? 38414.3.3 Components of Blending/Mixing Validation 38514.3.4 What to Validate 38614.4 Blending Cleaning Validation 38914.4.1 Cleaning Development Studies 38914.4.2 Cleaning Validation 39514.5 Conclusion 39814.6 Acknowledgements 399References 399Part IV Optimization and Control 40115 Process Analytical Technology for Blending 403Nicolas Abatzoglou15.1 Introduction 40315.1.1 The Role of PAT in Pharmaceutical Manufacturing: Is PAT Really New? 40415.1.2 Why PAT is Feasible 40515.1.3 Where PAT can be Applied in Pharmaceutical Manufacturing 40615.1.4 The Regulatory Framework 40615.2 Chemometrics and Data Management 40815.2.1 PAT Data Management and Interpretation 40915.3 Near‐Infrared Spectroscopy (NIRS) 41215.4 Raman Spectroscopy (RS) 41915.5 Image Analysis 42215.6 LIF Spectroscopy 42415.7 Effusivity 42615.8 Other Potential Sensor Technologies 42615.9 Comments on PAT in Liquid Formulation Mixing 427References 42716 Imaging Fluid Mixing 431Mi Wang16.1 Introduction 43116.2 Point Measurement Techniques 43316.3 Photographic Imaging 43516.4 Digital Particle Image Velocimetry 43916.5 Magnetic Resonance Imaging 44316.6 Positron Emission Particle Tracking Imaging 44416.7 Electrical Process Tomography 446References 45217 Discrete Element Method (DEM) Simulation of Powder Mixing Process 459Ali Hassanpour and Mojtaba Ghadiri17.1 Introduction to DEM and its Application in Pharmaceutical Powder Processing 45917.2 DEM Simulation of Powder Mixing 46117.3 Validation and Comparison with the Experiments 46817.4 Concluding Remarks 474References 475Index 479