Handbook of Pharmaceutical Granulation Technology

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