دانلود کتاب Handbook of Pharmaceutical Granulation Technology

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Cover Half Title Series Page Title Page Copyright Page Dedication Contents Preface Editor Contributors 1. Introduction 1.1. Introduction 1.2. Need for Granulating Powders 1.3. Granulation Options 1.4. Developments in Processing Solid Dosage Forms 1.5. Scope of This Book References 2. Theory of Granulation: An Engineering Perspective 2.1. Introduction 2.1.1. Overview 2.1.2. Granulation Mechanisms 2.1.3. Compaction Mechanisms 2.1.4. Formulation Versus Process Design 2.1.5. Key Historical Investigations 2.2. Wetting 2.2.1. Overview 2.2.2. Mechanics of the Wetting Rate Process 2.2.3. Methods of Measurement 2.2.4. Granulation Examples of Wetting 2.2.5. Regimes of Nucleation and Wetting 2.2.6. Example of Wetting Regime Calculation 2.3. Granule Growth and Consolidation 2.3.1. Mechanics of Growth and Consolidation 2.3.2. Interparticle Forces 2.3.3. Dynamic Wet Mass Rheology and Granule Deformability 2.3.4. Low-Shear, Low-Deformability Growth a) Noninertial Regime b) Inertial Regime c) Coating Regime 2.3.5. High-Shear, Deformable Growth 2.3.6. Example: High-Shear Mixer Growth 2.3.7. Power, Deformability, and Scale-Up of Growth 2.3.8. Determination of Stokes number, (St*) 2.3.9. Summary of Growth Patterns 2.3.10. Granule Consolidation 2.4. Granule Strength and Breakage 2.4.1. Overview 2.4.2. Mechanics of the Breakage 2.4.3. Fracture Measurements 2.4.4. Mechanisms of Breakage 2.5. Controlling Granulation Processes 2.5.1. An Engineering Approach to Granulation Processes 2.5.2. Scale of a Granule Size and Primary Feed Particles 2.5.3. Scale of a Granule Volume Element 2.5.4. Scale of the Granulator Vessel 2.5.5. Controlling Processing in Practice 2.5.6. Controlling Wetting in Practice 2.5.7. Controlling Growth and Consolidation in Practice 2.5.8. Controlling Breakage in Practice Acknowledgments Notes References Section I: Particle Formation 3. Drug Substance and Excipient Characterization 3.1. Introduction 3.2. Particle Size, Shape, and Surface Area 3.2.1. Particle Size 3.2.1.1. Microscopy 3.2.1.2. Sieving 3.2.1.3. Sedimentation 3.2.1.4. Electrical Sensing 3.2.1.5. Laser Scattering, Light Obscuration, and Photon Correlation Spectroscopy 3.2.1.6. Time of Flight 3.2.1.7. Focused Beam Reflectance Measurement 3.2.1.8. Spatial Filtering Velocimetry 3.2.1.9. 3D Imaging Using Photometric Stereo Imaging 3.2.1.9.1. 3D surface imaging 3.2.1.9.2. 3D particle characterizer 3.2.1.10. Laser Scanning Microscopy 3.2.1.11. Continuous Manufacturing and Material Sampling 3.2.2. Particle Shape 3.2.3. Particle Surface Area 3.2.3.1. Gas Adsorption 3.2.3.2. Gas Permeability 3.3. Density 3.3.1. Bulk Density 3.3.2. Conditioned Bulk Density 3.3.3. Tap Density 3.3.4. True Density 3.4. Solubility 3.5. Crystallinity and Polymorphism 3.5.1. Dissolution Study 3.5.2. X-Ray Diffractometry 3.5.3. Thermal Analysis 3.5.4. Vibrational Spectroscopy 3.5.4.1. Infrared Spectroscopy 3.5.4.2. Raman Spectroscopy 3.5.5. Solid-State Nuclear Magnetic Resonance 3.5.6. Moisture Sorption 3.5.7. Hot Stage Microscopy 3.5.8. Detection Limits of Different Methods 3.6. Other Physical Properties 3.6.1. Flow Properties 3.6.1.1. Hausner Ratio and Carr Index 3.6.1.2. Angle of Repose 3.6.1.3. Angle of Slide 3.6.1.4. Flowability Determined by Shear Tests 3.6.1.5. Dynamic Flow Analysis 3.6.1.6. Avalanche Behavior [56] 3.6.2. Segregation 3.6.3. Tableting Properties 3.6.4. Sticking 3.6.5. Compatibility 3.6.5.1. Stability Study 3.6.5.2. Chromatography 3.6.5.3. Thermal Methods 3.6.5.4. Other Methods 3.6.6. Internal Structure Analysis 3.7. Conclusion Abbreviations Symbols References 4. Binders in Pharmaceutical Granulation 4.1. Introduction 4.2. Commonly Used Binders in Current Pharmaceutical Practice 4.2.1. Hydroxypropylcellulose (HPC) 4.2.2. Methylcellulose (MC) 4.2.3. Hypromellose (HPMC) 4.2.4. Sodium Carboxymethyl Cellulose (NaCMC) 4.2.5. Povidone (PVP) 4.2.6. Copovidone (PVP-PVA) 4.2.7. Polyethylene Glycol (PEG) 4.2.8. Polyvinyl Alcohol (PVA) 4.2.9. Polymethacrylates 4.2.10. Starch and Modified Starches 4.2.10.1. Starch 4.2.11. Pregelatinized Starch (PGS) 4.2.12. Gum Acacia 4.3. Practical Considerations in Binder Selection and Use 4.3.1. Use Levels and Binder Efficiency 4.3.2. Stability and Compatibility 4.3.2.1. Aldehydes and Carboxylic Acids 4.3.2.2. Peroxides 4.3.3. Binder Hygroscopicity and Water Content 4.3.4. Wettability and Surface Energetics 4.3.5. Wetting Studies as Formulation Tools 4.4. The Role of Solvent 4.5. Thermal and Mechanical Properties 4.6. Regulatory Acceptance and Supplier Reliability References 5. Excipients and Their Attributes in Granulation 5.1. Introduction 5.2. Why Granulate? 5.3. Processing Options 5.3.1. From API to Processable Blend to Finished Product 5.4. Excipient Selection 5.4.1. Excipients in Wet Granulation, by Functionality 5.4.1.1 Inorganic, Insoluble Excipients 5.4.1.2 Organic, Insoluble Excipients 5.4.1.3 Organic Soluble Excipients 5.4.1.4 Sugar Alcohols 5.4.1.5 Starches and Sugar 5.4.1.6 Synthetic and Naturally Derived Binders 5.4.1.7 Excipients for Nutraceuticals 5.5. High Functionality Co-Processed Excipients 5.6. Excipient Variability 5.7. Conclusions Note References Additional Reading 6. Spray Drying and Pharmaceutical Applications 6.1. Introduction 6.1.1. Advantages and Limitation 6.2. Spray Drying Process Stages 6.2.1. Atomization 6.2.1.1. Atomizer Types and Designs 6.2.1.2. Droplet Formation Using Rotary Atomizer 6.2.1.3. Droplet Formation Using a Pneumatic Nozzle 6.2.2. Electrohydrodynamic Atomizers 6.2.2.1. Atomizer Selection 6.2.3. Spray Air Contact and Evaporation 6.2.3.1. Spray Air Contact 6.2.3.2. Drying 6.2.3.3. Drying Gas 6.2.4. Dried Powder Separation 6.3. Process Layouts 6.4. Theory of Spray Drying Fundamentals 6.4.1. Droplet Drying Mechanisms 6.4.2. Effect of Formulation on Droplet Drying Mechanisms 6.4.2.1. Pure Liquid Sprays 6.4.2.2. Feeds Containing Insoluble Solids 6.4.2.3. Feeds Containing Dissolved Solids 6.4.2.4. Spray Drying Parameters 6.5. Spray Drying Applications 6.5.1. Feasibility Assessments 6.5.2. Spray Drying to Produce a Specific Type of Particle 6.5.2.1. Granulation 6.5.2.2. Modification of Solid-State Properties 6.5.2.3. Microencapsulation 6.5.2.4. Inhalation and Nasal Dosage Forms 6.5.2.5. Liposomes 6.5.2.6. Peptides, Proteins, and Vaccines 6.5.2.7. Microparticles and Nanoparticles 6.5.2.8. Dry Elixirs and Emulsions 6.5.2.9. Effervescent Products 6.5.2.10. Other Process Variations 6.6. Advances in Spray Drying Technology 6.6.1. Electrostatic Spray Dryer 6.6.2. Aseptic Spray Dryer 6.6.3. Nanoscale Spray Dryers 6.7. Application of QbD/PAT to Spray Drying Process Conclusion Acknowledgment References 7. Emerging Technologies for Particle Engineering 7.1. Introduction 7.2 Nanotechnology 7.2.1. Introduction 7.2.2. Manufacture of Nanoparticles 7.2.3. Nanosuspensions 7.2.4. Nanoparticulate Drug Delivery Systems for Proteins and Peptides 7.2.5. Pulmonary Drug Delivery 7.2.6. Drug Delivery 7.2.7. Adverse effects of Nanoparticles 7.2.8. Summary: Nanotechnology 7.3. Super Critical Fluid Technologies 7.3.1. Super Critical Fluid (SCF) 7.3.2. Rapid Expansion of Supercritical Solutions (RESS) 7.3.3. Direct Particle Production: Antisolvent Techniques 7.3.4. Supercritical Anti-Solvent (SAS) 7.3.5. Fluid-Assisted Microencapsulation 7.4. Three Dimensional Printing (3DP) or Additive Manufacturing (AM) 7.5. Artificial Intelligence (AI) 7.6. Other Approaches 7.6.1. Spray Drying Particle Engineering for Inhalation 7.6.2. Particle Replication in Non-Wetting Templates (PRINT) 7.6.3. Co-Crystallization 7.6.4. Liqui-Pellet 7.6.5. Microencapsulation Using Polylactic-co-Glycolic Acid (PLGA) [115] 7.6.6. Electrospinning 7.6.7. Microbiome-Based Therapeutics 7.7. Summary References Section II: Granulation Processes 8. Roller Compaction Technology 8.1. Introduction 8.2. Active Pharmaceutical Ingredient Powders 8.3. Granulation Technologies 8.3.1. Summary 8.4. Compaction Theory 8.5. Design Features of Roller Compactors 8.5.1. Deaeration Theory 8.6. Formulation Considerations 8.6.1. Compaction Formulation Technology Needs 8.7. Instrumented Roller Compactor Technology for Product Development, Design of Experiments, and Scale-Up 8.7.1. Technology and Physics Understanding 8.7.2. Instrumented Roll Technology for Roller Compaction Process Development and Scale-Up 8.7.3. Placebo Model 8.7.4. Application of Placebo Model to Predict Ribbon Densities of Active Blends 8.7.5. Effect of Deaeration on Normal Stress (P2) Measurements and Gap 8.7.6. Use of Instrumented Roll Technology for Scale-Up Using Modified Johanson Model Note References 9. Advances in Wet Granulation of Modern Drugs 9.1. Introduction 9.2. Small Molecule Drug Granulation 9.2.1. Low-Shear Granulators a) Mechanical Agitator Granulators b) Rotating-Shape Granulators 9.2.2. High-Shear granulators a) Horizontal High-Shear Granulator b) Vertical High-Shear Granulator c) Single-Pot Granulators 9.2.3. Advanced Applications of Low- and High-Shear Wet Granulation a) Moisture Activated Dry Granulation b) Steam Granulation c) Effervescent Granulation d) Foam Granulation e) Melt Granulation f) Continuous Granulation 9.3. Granulation of Therapeutic Proteins 9.3.1. Protein Stability and Formulation Strategies 9.3.2. Slugging and Compaction of Freeze-Dried Powder 9.3.3. Spray Drying 9.3.4. Electrospray 9.3.5. Extrusion-Spheronization 9.4. Artificial Intelligence in Granulation 9.4.1. Application of AI in Twin-Screw Granulation 9.4.2. Application of AI in the Batch High-Shear Granulation Process 9.5. Conclusions References 10. Fluid Bed Processing 10.1. Introduction 10.2. Fluidization Theory 10.2.1. Understanding the Particles 10.3. System Description 10.3.1. Air Handling Unit 10.3.2. Product Container and Air Distributor 10.3.3. Spray Nozzle 10.3.4. Disengagement Area and Process Filters 10.3.5. Exhaust Blower or Fan 10.3.6. Control System 10.3.7. Solution Delivery System 10.4. Cleaning Fluid Bed Processor 10.5. Particle Agglomeration and Granule Growth 10.6. Fluid Bed Drying 10.7. Granulation Process 10.8. Variables in Granulation 10.8.1. Formulation-Related Variables 10.8.1.1. Low-Dose Drug Content 10.8.1.2. Binder 10.8.1.3. Binder Solvent 10.8.2. Equipment-Related Variables 10.8.2.1. Equipment Design 10.8.2.2. Air-Distributor Plate 10.8.2.3. Fan (Blower) and Pressure Drop (ΔP) 10.8.2.4. Filters and Shaker/Blowback Cycle Mechanism 10.8.2.5. Other Miscellaneous Equipment Factors 10.8.3. Process-Related Variables 10.9. Fluidized Hot Melt Granulation (FHMG) 10.10. Process Controls and Automation 10.10.1. Advances in Process Control and Automation 10.10.1.1. Near-Infrared (NIR) 10.10.1.2. Other Approaches for Process Control 10.11. Process Scale-Up 10.11.1. Scale-Up and Equipment Design 10.11.2. Scale-Up and Process Factors 10.12. Process Troubleshooting 10.12.1. Metrics: Granule Properties and Tableting 10.12.2. Proactive Troubleshooting - Design of Experiments 10.12.3. Reactive Trouble Shooting: Acquired Data as a Process Troubleshooting Tool 10.12.4. Process Trouble Shooting Summary 10.13. Safety in Fluid Bed 10.14. Material Handling Options 10.14.1. Loading 10.14.2. Unloading 10.15. Optimization of Fluid Bed Granulation Process 10.16. Fluid Bed Technology Developments 10.17. Bottom Spray 10.18. Rotary Inserts 10.19. Integrated Systems 10.20. Continuous Granulation Systems 10.21. Conclusion References 11. Single-Pot Processing 11.1. Introduction 11.2. Typical Single-Pot Process 11.2.1. Dry Mixing 11.2.2. Addition of Binder Solution 11.2.3. Wet Massing 11.2.4. Drying 11.2.5. Sizing and Lubrication 11.3. Drying Methods for Single-Pot Processors 11.3.1. Conductive Drying 11.3.2. Vacuum Drying 11.3.3. Gas-Assisted Vacuum Drying 11.3.4. Microwave Vacuum Drying 11.3.5. Fluid-Bed Drying 11.4. Applications 11.4.1. Main Applications 11.4.1.1. Expensive Products 11.4.1.2. Short Campaigns/Multiple Products 11.4.1.3. Highly Potent (Toxic) Products 11.4.1.4. Organic Solvent Processing 11.4.1.5. Effervescent Production 11.4.2. Other Applications 11.4.2.1. Melt Granulation 11.4.2.2. Pellet Production 11.4.2.3. Crystallization 11.5. Scale-Up of Drying Processes 11.6. Regulatory Considerations 11.7. Validation of Single-Pot Processors 11.8. Process Analytical Technology 11.9. Control Systems and Data Acquisition Systems 11.10. Conclusion References 12. Extrusion/Spheronization as a Granulation Technique 12.1. Introduction 12.2. Applications 12.3. General Process Description 12.4. Equipment Description and Process Parameters 12.4.1. Dry Mixing 12.4.2. Granulation 12.4.3. Extrusion 12.4.4. Spheronization 12.4.5. Drying 12.5. Formulation Variables 12.6. Compression of Spherical Granules or Pellets 12.7. Summary References 13. Continuous Granulation 13.1. Introduction: Continuous Processing of Solid Dosage Forms 13.2. Continuous Granulation 13.3. Continuous Fluid-Bed Granulators 13.4. Twin-Screw Granulation 13.4.1. Critical Process Parameters 13.4.2. Screw Configuration 13.4.3. Granulation Mechanism 13.4.4. Heat-Assisted Twin-Screw Granulation 13.5. Ring Layer Granulation 13.6. Downstream Processing and Integrated Manufacturing Lines References Section III: Product-Oriented Granulations 14. Effervescent Granulation 14.1. Introduction 14.2. The Effervescent Reaction 14.3. Formulation 14.4. Raw Materials 14.4.1. Acid Materials 14.4.1.1. Citric Acid 14.4.1.2. Tartaric Acid 14.4.1.3. Ascorbic Acid 14.4.1.4. Acid Anhydrides 14.4.1.5. Acid Salts 14.4.1.6. Other Less Frequent Sources of Acid 14.4.2. Sources of Carbon Dioxide 14.4.2.1. Sodium Bicarbonate 14.4.2.2. Sodium Carbonate 14.4.2.3. Potassium Bicarbonate and Potassium Carbonate 14.4.2.4. Calcium Carbonate 14.4.2.5. Sodium Glycine Carbonate 14.4.3. Binders 14.4.4. Lubricants 14.4.5. Additives 14.5. Manufacturing of Effervescent Forms 14.6. Granulation Methods 14.6.1. Granulation Technologies 14.6.1.1. Dry Blending of Powders 14.6.1.2. Dry Granulation 14.6.1.3. Wet Granulation 14.6.1.4. Wet Granulation According to Single-Step Method 14.6.1.4.1. Case Study 14.6.1.5. Hot-Melt Process 14.7. Conclusion References 15. Granulation of Plant Products and Nutraceuticals 15.1. Introduction 15.2. Nutraceutical Market 15.3. Regulatory Landscape Around the World 15.4. Manufacture of Nutraceuticals 15.4.1. Preparation of Extract 15.4.2. Dosage Form Manufacturing Challenges 15.4.2.1. Sourcing and Standardization 15.4.2.2. Physicochemical Properties of Powdered Plants and Herbal Parts 15.4.2.3. Microbiological Issues 15.4.2.4. Quality Challenges 15.5. Formulation and Processing 15.5.1. Direct Compression 15.5.2. Spray Drying 15.5.3. Fluid-Bed Granulation 15.5.4. Roller Compaction 15.5.5. Wet Granulation 15.5.6. Nanotechnology 15.5.7. Cannabis and Cannabidiol (CBD) Processing 15.6. Storage and Stability 15.7. GMP and Nutraceuticals 15.7.1. Key Requirements of the Final Rule 15.8. Conclusion References 16. Granulation Approaches for Modified-Release Products 16.1. Introduction 16.2. Scope 16.2.1. Establishment of a Target Product Profile (TPP) 16.3. Material Considerations 16.3.1. Drug Molecule or Active Pharmaceutical Ingredient (API) 16.3.2. Release-Modifying Ingredient(s) 16.3.2.1 Polymers 16.3.2.2 Long-Chain Hydrocarbons 16.3.3. Additional Formulation Ingredients 16.3.4. Compatibility of All Dosage Form Ingredients 16.4. Dosage Form Performance Considerations 16.4.1. Drug Release Mechanism 16.4.2. Drug Release Pattern and Predictability 16.4.3. Reproducibility of Drug Release Pattern 16.5. Types of MR Granulations and Case Studies 16.5.1. Case Study 1 16.5.2. Case Study 2 16.5.3. Case Study 3 16.4.4. Case Study 4 16.4.5. Case Study 5 16.5. Conclusions Acknowledgments References 17. Granulation of Poorly Water-Soluble Drugs 17.1. Introduction 17.2. Particle Reduction and Nanoparticles 17.3. Nanoparticles for Poorly Water-Soluble Drugs 17.4. Complexation 17.4.1. Background 17.4.2. Selection of Suitable Cyclodextrin and Determination of Stoichiometry 17.4.3. Complex Preparation Methods 17.4.3.1. Spray-Drying and Fluid-Bed Granulation 17.4.3.2. Kneading Process in High-Shear Mixer 17.4.3.3. Twin-Screw Kneading and Extrusion 17.4.3.4. Cogrinding 17.5. Solid Dispersions 17.5.1. Structures of Solid Dispersion 17.5.2 . Methods for Preparation of Amorphous Solid Dispersions 17.5.2.1. Hot-Melt Method 17.5.2.2. Solvent Evaporation Method 17.5.3. Carriers 17.5.3.1. Polyethylene Glycol 17.5.3.2. Polyvinylpyrrolidone and Polyvinylpyrrolidone-Polyvinyl Acetate Copolymer 17.5.3.3. Soluplus® 17.5.3.4. Cellulose Derivatives 17.5.3.5. Polyacrylates and Polymethacrylates 17.5.3.6. Surfactants References 18. Granulation and Production Approaches of Orally Disintegrating Tablets 18.1. Descriptions of Orally Disintegrating Dosage Forms 18.2. Desired Properties of ODTs 18.3. The Need for the Development of Orally Disintegrating Tablets (ODTs) and Their Desired Properties 18.3.1. Patient Factors 18.3.2. Effectiveness Factor 18.3.3. Manufacturing Factors 18.4. Technologies Used in the Production of ODTs 18.4.1. Compaction Methods 18.4.1.1. Direct Compression Method 18.4.1.2. Wet Granulation 18.4.1.3. Dry Granulation 18.4.2. Phase Transition Method (Crystalline Transition Process) 18.4.3. Sublimation 18.4.4. Lyophilization (Freeze Drying) 18.4.5. Molding 18.4.6. Cotton Candy Process 18.4.7. Melt Granulation (Nanocrystal Technology/Nanomelt) 18.5. Challenges in Preparation of ODTs 18.5.1. Disintegration Period and Fragility 18.5.2. Masking the Drug's Taste 18.5.3. Formation of Eutectic Mixtures 18.5.4. Size of Tablet and Amount of Drug 18.5.5. Safe Packing 18.6. Formulation Approaches to Induce Fast Disintegration in ODTs Using Granulation Methods 18.6.1. Disintegrants and Binders 18.6.2. Superdisintegrants 18.6.3. Taste Masking Using Dry Granulation in ODT Development 18.6.4. Challenges in Selection of ODT Drug Candidates 18.7. Characterization of ODTs Prepared by Granulation Technology 18.7.1. Wetting Time 18.7.2. Disintegration Test 18.7.3. Dissolution Test 18.7.4. Moisture Uptake Studies 18.8. Future Prospects References 19. Melt Granulation 19.1. Introduction 19.2. Batch Melt Granulation 19.2.1. High-Shear Granulation 19.2.2. Fluidized Bed Granulation 19.2.3. Melt Pelletization 19.2.4. Tumbling Melt Granulation 19.3. Continuous Melt Granulation 19.3.1. Spray Congealing 19.3.2. Prilling 19.3.3. Melt Extrusion 19.3.4. Twin-Screw Melt Granulation 19.4. Formulation and Process Selection for Melt Granulation References Section IV: Characterization and Scale-UP 20. Sizing of Granulation 20.1. Introduction 20.2. Theory of Comminution or Size Reduction 20.3. Properties of Feed Materials Affecting the Sizing Process 20.4. Criteria for Selection of a Mill 20.5. Classification of Mills 20.5.1. Low-Energy Mills 20.5.1.1 Hand Screen 20.5.1.2 Oscillating or Rotary Granulator Mills 20.5.1.3 Low-Pressure Extruders 20.5.2. High-Energy Mills 20.5.2.1. Hammer Mill 20.5.2.2. Conical-Screening Mill 20.5.2.3. Centrifugal-Sifter Mills 20.6. Wet Milling 20.7. Variables Affecting the Sizing Process 20.7.1. Process Variables 20.7.2. Equipment Variables (Type of Mill) 20.7.2.1 Hammer Mill 20.7.2.2 Conical-Screening Mill 20.7.2.3 Hybrid Designs 20.7.3. Other Variables 20.8. Scale-Up 20.8.1. Hammer Mill 20.8.2. Conical-Screening Mill 20.9. Case Studies 20.9.1. Comparison of Fitzmill Variables 20.9.2. Comparison of Fitzmill vs. Comil 20.9.3. Comparison of Hand Screen vs. Comil 20.9.4. Modeling 20.9.5. Scale-Up and Post -Approval Changes (SUPAC: Manufacturing Equipment Addendum) Acknowledgments References List of Equipment Suppliers 21. Granulation Characterization 21.1. Introduction 21.2. Definitions 21.3. Granulation Structural Characterization 21.3.1. Molecular Level 21.3.1.1. Amorphous Transitions 21.3.1.2. Fusion Form Transitions 21.3.1.3. Polymer Transitions 21.3.1.4. Moisture Level and Location 21.3.2. Surface 21.3.3. Granular Level Characterization 21.3.3.1. Granule Physical Structure 21.3.3.2. Granule Density and Porosity 21.3.4. Granulation Level Characterization 21.4. Granulation Performance 21.4.1. Granulation Flowability 21.4.2. Granulation Deformation Strength 21.4.3. High-Pressure Characterization 21.4.3.1. Plastic Deformation 21.4.3.2. Repack and Deformation 21.4.3.3. Focus on Granulation Surface 21.4.4. Granulation Surface Area 21.4.4.1. Granule Size and Size Distribution 21.4.5. Equivalent Diameters 21.4.5.1. Sieve Analysis 21.4.6. Granulation Shape 21.5. Active Principle Characterization 21.5.1. Crystallinity and Polymorphism 21.5.2. Hydrates 21.5.3. API Uniformity References 22. Bioavailability and Granule Properties 22.1. Introduction 22.2. Drug Dissolution 22.3. Bioavailability Parameters 22.3.1. Peak Time (tmax) 22.3.2. Peak Plasma Concentration (Cp)max 22.3.3. Area Under the Plasma Concentration-Time Curve (AUC)0∞ 22.4. Factors Affecting the Bioavailability 22.5. Dissolution and Granule Properties 22.6. In Vitro-In Vivo Correlation 22.6.1. Definitions United States Pharmacopoeia (USP) definition Food and Drug Administration (FDA) definition 22.6.2. Correlation Levels 22.6.3. Level A Correlation 22.6.4. Level B Correlation 22.6.5. Level C Correlation 22.6.5.1. Multiple Level C Correlation 22.6.6. Level D Correlation 22.6.7. Systematic Development of a Correlation 22.6.7.1. Important Considerations in Developing a Correlation 22.7. Biopharmaceutics Classification System (BCS) 22.7.1. Absorption Number (An) 22.7.2. Dissolution Number (Dn) 22.7.3. Dose Number (Do) 22.8. Summary References RECOMMENDED READING 23. Granulation Process Modeling 23.1. Modeling of Granulation Systems 23.1.1. Motivation for Modeling 23.1.1.1. Benefits 23.1.1.2. Costs 23.1.2. Process Modeling Fundamentals 23.1.2.1. A Systems Perspective 23.1.2.2. Modeling Methodology and Workflow 23.1.2.3. The Modeling Goal 23.1.2.4. System Optimization 23.1.2.5. Process Control 23.1.3. Approaches to Modeling 23.1.3.1. Empirical or Black Box Methods 23.1.3.2. Mechanistic and Gray Box Models 23.1.4. Quality-by-Design Approach 23.2. Key Factors in Granulation Modeling 23.2.1. Conservation Principles 23.2.2. The Principal Constitutive Mechanisms 23.2.2.1. Nucleation 23.2.2.2. Growth 23.2.2.3. Breakage 23.3. Representing Granulation Processes Through Population Balances 23.3.1. General Population Balance Equations 23.3.2. One-Dimensional Population Balance Models 23.3.2.1. Batch Systems 23.3.2.2. Continuous Systems 23.3.2.3. Coalescence Kernels 23.3.3. Multidimensional Population Balance Models 23.3.3.1. Two-Dimensional Population Balance Models 23.3.3.2. Higher-Dimensional Population Balance Models 23.3.4. Reduced-Order Models 23.3.4.1. Reduced-Order Models Using the Concept of Lumped Regions in Series 23.3.4.2. Model Order Reduction for Multidimensional Population Balances 23.3.4.3. Reduced-Order Models Using the Method of Moments 23.3.4.4. Multi Timescale Analysis 23.3.4.5. Regime Separated Approach 23.3.5. A Multiform Modeling Approach 23.3.6. Hybrid Models 23.3.6.1. Population Balance Model (PBM) Coupled with Discrete Element Method (DEM) 23.3.6.2. Population Balance Model (PBM) Coupled with Computational Fluid Dynamics (CFD) 23.4. Solving Population Balances 23.4.1. Conventional Discretization Methods 23.4.2. Wavelet-Based Methods 23.4.3. Hierarchical Two-Tier Technique 23.4.4. Solving Differential-Algebraic Equation Systems 23.4.5. Monte Carlo Methods 23.4.5.1. Classification of Monte Carlo Methods 23.4.5.2. Key Equations for Constant Number Monte Carlo Simulation 23.4.5.3. Simulation Procedure 23.5. Application of Population Balance Modeling 23.5.1. Modeling for Closed-Loop Control Purposes 23.5.1.1. Development of Control Relevant, Linear Models 23.5.1.2. ARX and ARMAX Models for Linear Model Predictive Control 23.5.1.3. Linear Model Predictive Control 23.5.1.4. Nonlinear Model Predictive Control Structure 23.5.1.5. Online Measurement-Based Control Schemes 23.5.2. Modeling for Optimal Design, Operation, and Open-Loop Optimal Control 23.5.2.1. Statement of Optimization and Open-Loop Optimal Control Problems 23.5.2.2. Optimization and Open-Loop Optimal Control Equations 23.5.2.3. Dynamic Optimization Algorithm 23.5.2.4. Selected Simulation Results and Discussion 23.5.3. Sensitivity and Reliability Analysis 23.5.3.1. Sensitivity Analysis for Application of Multidimensional Models 23.5.3.2. Reliability Analysis for Model Failure Diagnosis 23.6. Summary References 24. Scale-Up Considerations in Granulation 24.1. Introduction 24.2. General Considerations in Process Scale-Up: Dimensional Analysis and the Principle of Similarity 24.3. Analysis of Granulation Rate Processes 24.3.1. Wetting and Nucleation 24.3.2. Growth and Consolidation 24.3.3. Breakage and Attrition 24.4. Implications for Scale-Up 24.5. Scale-Down, Formulation Characterization, and Formulation Design in Pharmaceutical Granulation 24.6. Scale-Up of Fluidized-Bed Granulators 24.6.1. Bed Hydrodynamics and Scale-Up 24.6.2. Granulation Rate Processes in Fluidized Beds 24.6.3. Suggested Scaling Rules for Fluid-Bed Granulators 24.7. Scale-Up of High-Mixer Granulators 24.7.1. Geometric Scaling Issues 24.7.2. Powder Flow Patterns and Scaling Issues 24.7.3. Granulation Rate Processes and Related Scaling Issues 24.7.4. Recommended Scaling Rules for High-Shear Mixer Granulators and Case Study Examples 24.8. Scale-Up of Twin-Screw Granulators 24.8.1. Characteristics of TSG Processes 24.8.2. Granulation Rate Processes and the Scaling Issues of TSGs 24.8.3. Suggested Scaling Rules for TSGs 24.9. Concluding Remarks Nomenclature References 25. Advances in Process Controls and End-Point Determination 25.1. Introduction 25.2. Roller Compaction 25.3. Fluid-Bed Granulation 25.4. Dense-Phase Wet Granulation 25.5. Twin-Screw Wet Granulation 25.6. Emerging Approaches 25.6.1. Surface Chemistry and Energetics in Granulation 25.6.2. Measurements and Controls References Section V: Optimization Strategies,Tools, and Regulatory Considerations 26. Use of Artificial Intelligence and Expert Systems in Pharmaceutical Applications 26.1. Introduction 26.2. Building an Expert System 26.2.1. Who Is a Domain Expert? 26.2.2. Who Is a Knowledge Engineer? 26.2.3. Who Is the End-User? 26.2.3.1. Why Build an Expert System? 26.2.3.2. Phases of an Expert System Development Process 26.2.4. Feasibility Study 26.2.5. Conceptualization and Acquisition of the Knowledge 26.2.6. Design of the Expert System 26.2.7. Implementation, Testing the Modules and Development of the Prototype, and Troubleshooting of the Final Program 26.2.8. Verification and Validation (V&V) of an Expert System 26.2.9. Training of Users 26.2.10. Maintenance and Upgrade of the Program 26.2.11. Manage Expectations 26.2.11.1. Expert System Components 26.2.12. Knowledge Base 26.2.13. Working Memory 26.2.14. Inference Engine 26.2.15. Explanation Facility 26.2.16. User interface 26.2.16.1. Knowledge Representation 26.2.17. Object-Attribute-Value Triplets 26.2.18. Semantic Networks 26.2.19. Frames 26.2.20. Fuzzy Logic 26.2.21. Rule-Based Systems 26.2.22. Artificial Neural Networks 26.2.23. Genetic Algorithms (GA) 26.2.24. Other Methods of Knowledge Representation 26.2.25. Hybrid Systems 26.3. An Example to Expert Systems: SPRAYex, a Spray-Drying Expert System 26.3.1. Spray-Drying Feasibility Decision Trees 26.3.2. Prediction of Optimum Spray-Drying Conditions 26.3.3. Mathematical Modeling and Database 26.4. Pharmaceutical Applications of Expert Systems 26.5. Conclusion Acknowledgment Note References 27. Regulatory Issues in Granulation: Leading Next-Generation Manufacturing 27.1. Introduction 27.2. Pharmaceutical Quality Management 27.2.1. Current Good Manufacturing Practices 27.2.2. International Council for Harmonization 27.2.3. ISO 9000 Standards 27.3. Manufacturing Science 27.3.1. Regulatory Outlook 27.4. Process Analytical Technology 27.5. Quality Risk Management 27.6. Continuous Manufacturing 27.7. Data Integrity 27.8. Postapproval Change Considerations 27.8.1. Component and Composition Changes 27.8.1.1. Level 1 Changes 27.8.1.2. Level 2 Changes 27.8.1.3. Level 3 Changes 27.8.2. Site Changes 27.8.3. Changes in Batch Size 27.8.4. Manufacturing Equipment/Process Changes 27.8.5. Modified-Release Solid Dosage Forms 27.8.6. Changes to Granulation Equipment 27.9. International Change Notification 27.10. Life Cycle Management 27.11. Validation of Granulation Processes 27.11.1. Equipment/Utilities Qualification 27.11.2. Performance Qualification 27.11.3. Computer Validation 27.11.4. Current Guidance for Process Validation References 28. QbD and PAT in Granulation 28.1. Introduction 28.2. Definition and Objectives of Quality by Design 28.3. Phases and Elements of Quality by Design (QbD) 28.3.1. Definition of Quality Target Product Profile (QTPP) 28.3.2. Determination of Critical Quality Attributes (CQAs) 28.3.3. Risk Assessment of Material Attributes (MAs) and Process Parameters (PPs) 28.3.3.1. Risk Assessment of Dry Mixing-Blending Process 28.3.3.2. Risk Assessment of Dry Granulation-Roller Compaction Process 28.3.3.3. Risk Assessment of High-Shear Wet Granulation Process 28.3.3.4. Risk Assessment of Fluid Bed Granulation Process 28.3.3.5. Risk Assessment of Extrusion-Spheronization Process 28.3.4. Designing of Experiments (DoE) and Development of Design Space 28.3.4.1. Definition of Objective and Selection of Designs 28.3.4.2. Types of Regression Models for Analysis of Responses 28.3.4.3. Analysis of Regression Model with Numerical and Graphical Indicators 28.3.4.4. Numerical and Graphical Optimization for Development of Design Space 28.3.4.5. Verification of Design Space concerning Prediction Intervals (PI) and Confidence Interval (CI) 28.3.5. Implementation of Control Strategy 28.3.6. Continuous Improvement and Process Capability 28.4. PAT Definition and Goals 28.5. PAT Phases and Tools 28.5.1. Designing Phase with Multivariate Tools for Design, Data Acquisition, and Analysis 28.5.2. Analysis Phase with Process Analyzers 28.5.3. Controlling Phase and Process Control Tools 28.6. Applications of QbD and PAT 28.7. Summary and Conclusion References Abbreviations Used in the Chapter Index