Advances in Pharmaceutical Product Development

Cover
Half Title
Advances in Pharmaceutical Product Development
Copyright
Preface
Contents
Editors and Contributors
1. Advances in Development of Pharmaceutical Products
	1.1	 Introduction
	1.2	 Preformulation Studies
		1.2.1	 Solubility
		1.2.2	 Partition Coefficient
		1.2.3	 Polymorphism and Crystallinity
		1.2.4	 Bulk Properties
	1.3	 Prototype Development
		1.3.1	 Experimental Design and Optimisation of Product
		1.3.2	 Parenteral Dosage Forms
		1.3.3	 Oral Dosage Form
		1.3.4	 Transdermal Dosage Form
		1.3.5	 Inhalational Formulation
		1.3.6	 Nasal Formulations
		1.3.7	 Ophthalmic Dosage Form
		1.3.8	 Stability Analysis of Pharmaceutical Products
	1.4	 Scale-Up Studies
		1.4.1	 Pilot Plant
			1.4.1.1	 Requirements for a Pilot Plant Scale-Up
		1.4.2	 Current Good Manufacturing Practices (cGMP)
		1.4.3	 Regulatory Approval
	1.5	 Commercialisation
		1.5.1	 Life Cycle Management of Pharmaceutical Product
			1.5.1.1	 Product Development and Launch
			1.5.1.2	 Increase Market Access and Product Reach
			1.5.1.3	 Product Optimisation and Enhancement
			1.5.1.4	 Regulatory Compliance and Post-marketing Surveillance
			1.5.1.5	 Life Cycle Extension Strategies
	1.6	 Role of SUPAC Guidelines (Scale-Up and Post Approval Changes)
	1.7	 Role of Pharmacovigilance
	1.8	 Conclusion
	References
2. Design of Materials and Product Specifications for Pharmaceutical Dosage Forms
	2.1	 Introduction
		2.1.1	 The Objective of Design of Materials and Product Specifications
		2.1.2	 Product Specification
		2.1.3	 Types of Product Specification
			2.1.3.1	 In-Process Specification
			2.1.3.2	 Release Specification
			2.1.3.3	 Shelf Life Specification
		2.1.4	 Specification Design
		2.1.5	 Specification Justification
		2.1.6	 Revision of Specification
	2.2	 ICH Guidelines for the Product Specifications
		2.2.1	 The Mission of ICH
		2.2.2	 Aims of the ICH
		2.2.3	 ICH Q6A Guideline
			2.2.3.1	 Objective
			2.2.3.2	 New Drug Product
			2.2.3.3	 New Drug Substance
			2.2.3.4	 Universal Tests
			2.2.3.5	 Specific Tests
		2.2.4	 ICH Q6B Guideline
			2.2.4.1	 Scope
			2.2.4.2	 Specifications
				2.2.4.2.1 Specifications for Drug Substance
				2.2.4.2.2 Specifications for Drug Products
		2.2.5	 ICH Q8R2 Guidelines for the Product Specification
			2.2.5.1	 Q8(R2): Structure—Parent Guideline (Knight 2014)
				2.2.5.1.1 Pharmaceutical Development: Introduction
				2.2.5.1.2 Components of Drug Product
					Drug Substances
					Excipients
				2.2.5.1.3 Drug Product
					Formulation Development
					Overages
					Physicochemical and Biological Properties
				2.2.5.1.4 Manufacturing Process Development
				2.2.5.1.5 Container Closure System
				2.2.5.1.6 Microbiological Attributes
				2.2.5.1.7 Compatibility
			2.2.5.2	 Q8(R2): Structure—Annex
				2.2.5.2.1 Introduction
				2.2.5.2.2 The Elements of Pharmaceutical Development
					Quality Target Product Profile
					Critical Quality Attributes (CQA)
					Risk Assessment: Linking Material Attributes and Process Parameters to Drug Product CQAs
					Design Space
					Control Strategy
					Product Life Cycle Management and Continual Improvement
				2.2.5.2.3 Submission of Pharmaceutical Development and Related Information in Common Technical Documents (CTD) Format
					Quality Risk Management and Product and Process Development
					Design Space
					Control Strategy
					Drug Substance-Related Information
	2.3	 Conclusion
	References
3. Optimization Techniques for the Development of Pharmaceutical Products
	3.1	 Introduction
	3.2	 Role of QbD and FbD in the Development of Pharmaceutical Products
	3.3	 Key Experimental Designs Employed for Optimization of Drug Delivery Systems
		3.3.1	 Factorial Designs (FD)
		3.3.2	 Fractional Factorial Designs (FFDs)
		3.3.3	 Plackett–Burman Designs (PBDs)
		3.3.4	 Central Composite Designs (CCD)
		3.3.5	 Box–Behnken Designs (BBD)
		3.3.6	 Equiradial Designs
		3.3.7	 Mixture Designs
		3.3.8	 Taguchi Designs
		3.3.9	 Optimal Designs
	3.4	 Elements of QbD
		3.4.1	 Quality Target Product Profile (QTPP)
		3.4.2	 Critical Quality Attributes (CQAs)
		3.4.3	 Risk Management
		3.4.4	 Design Space
		3.4.5	 Control Strategy
		3.4.6	 Product Life Cycle Management and Continual Improvement
	3.5	 Various Approaches Employed in QbD Optimization
	3.6	 Various Approaches Employed in FbD Optimization
		3.6.1	 Design of Experiments (DoE)
		3.6.2	 Constraint-Based Optimization
		3.6.3	 Multi-objective Optimization
		3.6.4	 Expert Systems
		3.6.5	 Evolutionary Algorithms
	3.7	 Tools Used in Formulation-Based Design (FbD) Optimization
	3.8	 FbD Opti-tactics for Drug Delivery Systems
	3.9	 Available Software Employed for QbD Optimization
		3.9.1	 Design-Expert
		3.9.2	 SIMCA
		3.9.3	 Minitab
		3.9.4	 JMP
		3.9.5	 MATLAB
		3.9.6	 Aspen Plus
		3.9.7	 AutoCAD
	3.10	 Applications of QbD and FbD in Different Fields
		3.10.1	 Pharmaceutical Industry
		3.10.2	 Food Industry
		3.10.3	 Chemical Industry
		3.10.4	 Biotechnology Industry
		3.10.5	 QbD in Analytical Method Development
	3.11	 Conclusion
	References
4. Pharmaceutical Product Development: Formulation Additives
	4.1	 Introduction to Formulation Additives
	4.2	 Importance of Additives in Development of Pharmaceutical Dosage Form
	4.3	 Types of Formulation Additives
		4.3.1	 Additives for Oral Solid Dosage Forms
			4.3.1.1	 Fillers/Diluents
			4.3.1.2	 Binders
			4.3.1.3	 Disintegrants
			4.3.1.4	 Glidants and Lubricants
			4.3.1.5	 Coating Agents
			4.3.1.6	 Sweeteners, Flavourings and Colouring Agents
			4.3.1.7	 Preservatives and Antioxidants
			4.3.1.8	 Solubilisers
		4.3.2	 Additives for Oral Liquid Dosage Forms
			4.3.2.1	 Vehicles
			4.3.2.2	 Solubilisers
			4.3.2.3	 Sweeteners
			4.3.2.4	 pH Adjusters
			4.3.2.5	 Preservatives
			4.3.2.6	 Surfactant
			4.3.2.7	 Suspending Agent
			4.3.2.8	 Emulsifying Agent
			4.3.2.9	 Colorants
			4.3.2.10	 Viscosity Modifiers
		4.3.3	 Additives for Transdermal Dosage Forms
			4.3.3.1	 Penetration Enhancers
			4.3.3.2	 Solvents/Solubilisers
			4.3.3.3	 Adhesives
			4.3.3.4	 Backings and Release Liners
			4.3.3.5	 Plasticisers
			4.3.3.6	 Stabilisers and Antioxidants
		4.3.4	 Additives for Parenteral Dosage Forms
			4.3.4.1	 Additive Used in Lyophilisation
				4.3.4.1.1 Bulking Agents
				4.3.4.1.2 Lyoprotectants
				4.3.4.1.3 Antioxidants
				4.3.4.1.4 Buffering Agents
			4.3.4.2	 Additives Used in Liquid Injection
				4.3.4.2.1 Buffers
				4.3.4.2.2 Preservatives
				4.3.4.2.3 Tonicity Adjusters
				4.3.4.2.4 Solvent System
				4.3.4.2.5 Solubilisers
				4.3.4.2.6 Complexing and Dispersing Agents
				4.3.4.2.7 Flocculating/Suspending Agents (For Pharmaceutical Injectable Suspension)
	4.4	 Drug-Additive Interaction Studies in Development of Pharmaceutical Formulations
		4.4.1	 Physical Incompatibilities
		4.4.2	 Chemical Incompatibilities
		4.4.3	 Therapeutic or Physiological Incompatibilities
		4.4.4	 Analytical Techniques to Characterise Drug-Additive Incompatibility
	4.5	 Recent Advances in Additive Science
		4.5.1	 Functional and Co-processed Additives
		4.5.2	 Novel Materials and Multi-Materials
	4.6	 Related Regulatory Perspectives
		4.6.1	 GRAS
		4.6.2	 IIG
		4.6.3	 IPEC
	4.7	 Conclusion
	References
5. Advances in Pharmaceutical Oral Solid Dosage Forms
	5.1	 Introduction
	5.2	 Novel Excipients Involved in Manufacturing of Oral Solid Dosage Form
		5.2.1	 Binders
			5.2.1.1	 Hydroxy Propyl Methyl Cellulose (HPMC)
			5.2.1.2	 LYCATAB
			5.2.1.3	 GalenIQ (Isomalt)
		5.2.2	 Disintegrants
		5.2.3	 Lubricants
		5.2.4	 Co-processed Excipients
			5.2.4.1	 Kollitab™ DC 87 L
			5.2.4.2	 COMBILOSE
			5.2.4.3	 PEARLITOL CR-H
			5.2.4.4	 PROSOLV EASYtab SP (Silicified Microcrystalline Cellulose)
	5.3	 New-Age Material Handling Techniques Developed
		5.3.1	 Automated Dispensing System
			5.3.1.1	 Unit Dose Dispensing Systems
			5.3.1.2	 Centralised Dispensing Systems
			5.3.1.3	 Robotic Dispensing Systems
		5.3.2	 Vacuum Conveying Systems
		5.3.3	 Flexible Screw Conveyors
	5.4	 Advantages of New-Age Material Handling Techniques
		5.4.1	 Automation
		5.4.2	 Enhanced Safety
		5.4.3	 Higher Productivity
		5.4.4	 Enhanced Accuracy
		5.4.5	 Reduced Costs
	5.5	 Limitations of New-Age Material Handling
	5.6	 Utilisation of Artificial Intelligence in Solid Oral Dosage Forms
		5.6.1	 Widely Used Databases
		5.6.2	 Methods for Processing Data
		5.6.3	 Development of Solid Dosage Forms Using AI Algorithms
		5.6.4	 Evaluation and Explainability of Model Predictive Performance
		5.6.5	 Applications of Artificial Intelligence (AI) in Solid Dosage Forms
			5.6.5.1	 Tablets
			5.6.5.2	 Predicting Drug Release
			5.6.5.3	 Developing 3D-Printed Tablets Using Artificial Intelligence (AI)
			5.6.5.4	 Detecting Tablet Defects
			5.6.5.5	 Granules
	5.7	 Continuous Manufacturing Technology
		5.7.1	 Overcoming Obstacles to Continuous Manufacturing
			5.7.1.1	 Regulatory Uncertainties
			5.7.1.2	 Process Automation Technologies (PAT)
			5.7.1.3	 Equipment
			5.7.1.4	 Growth in Knowledge
			5.7.1.5	 Modern Process Control Techniques
			5.7.1.6	 Levels of Control
	5.8	 3D Printing Implementation in Oral Solid Dosage Form
		5.8.1	 Selective Laser Sintering (SLS)
			5.8.1.1	 Process Variables
			5.8.1.2	 Characteristics of Sintered Printlets
		5.8.2	 Applications
			5.8.2.1	 Stereolithography (SLA)
			5.8.2.2	 Printing Dosage Forms
		5.8.3	 Drawbacks and Challenges
			5.8.3.1	 Fused Deposition Modelling (FDM)
			5.8.3.2	 Polymer Filaments for Fused Deposition Modelling
			5.8.3.3	 Drawbacks
		5.8.4	 Advantages of 3D Printing Solid Dosage Forms
			5.8.4.1	 On-Demand Manufacturing
			5.8.4.2	 Improved Quality Dosage Forms
	5.9	 Summary
	References
6. Advances in Tablet Production and Tablet Coating
	6.1	 Introduction
	6.2	 Excipients
		6.2.1	 Superdisintegrants
		6.2.2	 Fillers and Binders
		6.2.3	 Lubricants/Anti-adherents
		6.2.4	 Solubility/Dissolution Enhancers
		6.2.5	 Drug Release Rate Modifiers
		6.2.6	 Co-processed Excipients
	6.3	 Advances in Tablet Manufacturing Processes
		6.3.1	 Advanced Granulation Approaches
	6.4	 Process Automation
		6.4.1	 Automation in Tablet Manufacturing
		6.4.2	 Fundamental Process Control Instruments
			6.4.2.1	 Automation in Direct Compaction Continuous Pharmaceutical Manufacturing Process
			6.4.2.2	 Rotary Tablet Press
	6.5	 Issues Concerning the Process of Tablet Manufacturing
		6.5.1	 Capping
			6.5.1.1	 The Causes and Remedies of Capping Related to Formulation (Granulation)
			6.5.1.2	 The Causes and Remedies of Capping Related to Machine (Dies, Punches, and Tablet Press)
		6.5.2	 Lamination
			6.5.2.1	 The Causes and Remedies of Lamination Related to Formulation (Granulation)
			6.5.2.2	 The Causes and Remedies of Lamination Related to Machine (Dies, Punches, and Tablet Press)
		6.5.3	 Chipping
			6.5.3.1	 The Causes and Remedies of Chipping Related to Formulation (Granulation)
			6.5.3.2	 The Causes and Remedies of Chipping Related to Machine (Dies, Punches, and Tablet Press)
		6.5.4	 The Defect Related to the Machine
			6.5.4.1	 Double Impression
	6.6	 Tablet Coating
		6.6.1	 Sugar Coating
		6.6.2	 Film Coating
	6.7	 Recent Advancements in Tablet Coating Technology
		6.7.1	 Electrostatic Coating
			6.7.1.1	 Mechanism of Corona Charging
			6.7.1.2	 Mechanism of Tribo Charging
		6.7.2	 Aqueous Film Coating Technology
		6.7.3	 Supercell Coating Technology (SCT)
		6.7.4	 Magnetically Assisted Impaction Coating (MAIC)
			6.7.4.1	 Mechanism of Coating in the MAIC Process
		6.7.5	 Dip Coating
		6.7.6	 Vacuum Film Coating
		6.7.7	 One-Step Dry-Coating (OSDrC®)
	6.8	 Defects of Tablet Coating
	6.9	 Conclusion
	References
7. Formulation Evaluation and Development of Specialized Tablets
	7.1	 Tablet Dosage Form
	7.2	 History of Tablet
	7.3	 Global Market Analysis
	7.4	 Types of Tablets
		7.4.1	 Organ-Targeted Tablets
		7.4.2	 Modified Release Tablets
		7.4.3	 Miscellaneous
			7.4.3.1	 Chewable Tablets
			7.4.3.2	 Effervescent Tablets
			7.4.3.3	 Orodispersible Tablets
	7.5	 Future Prospective and Conclusion
	References
8. Suspensions: Theory, Formulation Considerations, Flocculated and Deflocculated Suspensions, and Evaluation of Suspension Stability
	8.1	 Introduction
	8.2	 Theoretical Considerations
		8.2.1	 Interfacial Properties
		8.2.1.1	 Surface Free Energy
		8.2.1.2	 Surface Potential
		8.2.2	 Electric Double Layer (EDL)
		8.2.3	 Zeta and Nernst Potential
		8.2.4	 Wetting
		8.2.5	 Electrokinetic Phenomena
		8.2.6	 DLVO Theory
		8.2.7	 Theory of Sedimentation
		8.2.7.1	 Limitation of Stoke’s Equation
		8.2.8	 Important Considerations for Suspension
		8.3	 Classification of Suspensions
		8.3.1	 Flocculated Suspension
		8.3.2	 Deflocculated Suspension
	8.4	 Pharmaceutical Suspension Stability Study
		8.4.1	 Particle Settling
		8.4.2	 Particle Aggregation
		8.4.3	 Particle Growth (Ostwald Ripening)
	8.5	 Evaluation parameters of Suspension
		8.5.1	 Determination of the pH of the Suspension
		8.5.2	 Amount of Sedimentation
		8.5.3	 Redispersibility
		8.5.4	 Flow Rate (F)
		8.5.5	 Viscosity Determination
		8.5.6	 Degree of Flocculation (β)
		8.5.7	 Sedimentation Volume and Rate
		8.5.8	 Temperature Effect
		8.5.9	 Drug Content
		8.5.10	 In Vitro Dissolution Studies
		8.5.11	 Zeta Potential
		8.5.12	 Particle Size and Shape
		8.5.13	 Odor and Taste
		8.5.14	 Density
		8.5.15	 Freezing and Thawing
	8.6	 Conclusion
	References
9. Liquid and Polydisperse Systems: Emulsions
	9.1	 Introduction
	9.2	 Classification of Emulsions
		9.2.1	 Macroemulsion
		9.2.2	 Microemulsion
		9.2.3	 Nanoemulsion
		9.2.4	 Pickering Emulsion
	9.3	 Theories of Emulsions
		9.3.1	 Fischer’s Theory of Hydrates and Solvates
		9.3.2	 Surface Tension Theory
		9.3.3	 Molecular Adsorption Theory
		9.3.4	 Oriented Wedge Theory
	9.4	 Formulation
		9.4.1	 Method of Preparation
			9.4.1.1	 Dry Gum Method
			9.4.1.2	 Wet Gum Method
			9.4.1.3	 Bottle Method
			9.4.1.4	 In Situ Soap Method
			9.4.1.5	 Phase Titration Method
			9.4.1.6	 Phase Inversion Temperature Method
			9.4.1.7	 Spontaneous Emulsification
	9.5	 Stability
		9.5.1	 Gravitational Separation
			9.5.1.1	 Creaming
			9.5.1.2	 Sedimentation
			9.5.1.3	 Flocculation
		9.5.2	 Non-gravitational Separation
			9.5.2.1	 Coalescence
			9.5.2.2	 Droplet Aggregation
			9.5.2.3	 Ostwald Ripening
			9.5.2.4	 Phase Inversion
	9.6	 Evaluation
		9.6.1	 Macroscopic Evaluation
		9.6.2	 Microscopic Evaluation
		9.6.3	 Droplet Size Analysis
		9.6.4	 Rheology and Flow Behaviour
		9.6.5	 Determination of Emulsion Optical Properties
		9.6.6	 Determination of Zeta Potential
		9.6.7	 Determination of Electrical Conductivity
	9.7	 Conclusion
	References
10. Sterile Products and Admixtures
	10.1	 Introduction
		10.1.1	 Additives in Parenteral Products
		10.1.2	 Admixture in Parenteral: A Stability Monitor
		10.1.3	 Rates and Intensity of Severity of Intravenous Admixture in Healthcare
	10.2	 Additives in Large Volume Parenteral
		10.2.1	 Antimicrobial Preservatives
		10.2.2	 Antioxidants
		10.2.3	 Buffers
		10.2.4	 Vitamins
			10.2.4.1	 Vitamin B Complex
			10.2.4.2	 Vitamin C
			10.2.4.3	 Vitamin D
		10.2.5	 Electrolytes
		10.2.6	 Sodium
		10.2.7	 Potassium
		10.2.8	 Calcium
		10.2.9	 Magnesium
		10.2.10	 Chloride
		10.2.11	 Copper, Iron, and Zinc
		10.2.12	 Manganese
		10.2.13	 Selenium
		10.2.14	 Amino Acids
		10.2.15	 Carbohydrates
		10.2.16	 Dextrose
		10.2.17	 Lipids
	10.3	 Role and Benefits of Additives in LVPs
		10.3.1	 Nutritional Support
		10.3.2	 Role of Parentral Admixture in Nutritional Deficiencies
		10.3.3	 Therapeutic Benefits
		10.3.4	 Stabilization of the Solution
	10.4	 Preparation and Administration of Additives in LVPs
		10.4.1	 Guidelines for Adding Additives to LVPs
			10.4.1.1	 Compatibility and Stability
			10.4.1.2	 Aseptic Techniques
			10.4.1.3	 Dosing Considerations
			10.4.1.4	 Monitoring and Documentation
	10.5	 Regulatory Considerations in LVP Preparation
		10.5.1	 Guidelines and Standards by Regulatory Authorities
			10.5.1.1	 FDA Guidelines
			10.5.1.2	 EMA Standards
			10.5.1.3	 Quality Control and Assurance
			10.5.1.4	 Labeling and Documentation Requirements
	10.6	 Conclusion
	References
11. Challenges and Advances in Pharmaceutical Development of Topical and Transdermal Dosage Forms
	11.1	 Introduction
	11.2	 Formulation Challenges of Topical and Transdermal Products
		11.2.1	 Drug Solubility
		11.2.2	 Drug Stability
		11.2.3	 Skin Irritation
		11.2.4	 Bioequivalence Assessment and Regulatory Requirements
		11.2.5	 Challenges in Development of Standardized Bioequivalence Studies
		11.2.6	 Regulatory Approval Process for Topical and Transdermal Dosage Forms
		11.2.7	 Challenges in Meeting Regulatory Guidelines
	11.3	 Manufacturing Challenges
		11.3.1	 Ensuring Consistency and Reproductivity in the Manufacturing Process
	11.4	 Advances in Pharmaceutical Development
		11.4.1	 Nanotechnology-Based Drug Delivery System in Topical and Transdermal Formulations
		11.4.2	 Personalized Medicine Tailoring Topical and Transdermal Dosage Forms to Individual Patient Needs
		11.4.3	 Benefits and Challenges of Developing Combination Therapies in Topical and Transdermal Formulations
			11.4.3.1	 Case Studies and Examples of Combination Therapies of Transdermal Patches and Topical Drug
		11.4.4	 Continuous Monitoring and Controlled Release in Transdermal Drug Delivery System
			11.4.4.1	 Real-Time Monitoring and Control of Drug Release
	11.5	 Conclusion and Future Perspectives
	References
12. Advances in Ophthalmic Formulation Development
	12.1	 Introduction
	12.2	 Ideal Properties and Types of Ophthalmic Preparation
		12.2.1	 Ideal Properties for Ophthalmic Preparation
			12.2.1.1	 Sterility (Absence of Pyrogen)
			12.2.1.2	 Absence of Foreign Particle
			12.2.1.3	 Corneal Tissue Compatibility
			12.2.1.4	 Isotonicity
			12.2.1.5	 Optimum pH of the Solution
			12.2.1.6	 Viscosity (Appropriate Rheological Properties)
		12.2.2	 Types of Ophthalmic Preparations
	12.3	 Novel Drug Delivery Systems (NDDS) for Ophthalmic Formulations
		12.3.1	 In Situ Gelling System
		12.3.2	 Mucoadhesives
		12.3.3	 Ophthalmic Micro- and Nano-Emulsions
		12.3.4	 Ophthalmic Nano-Suspensions
		12.3.5	 Nanotechnologies Enabled Drug Delivery System in Ophthalmic Formulation Development
		12.3.6	 Therapeutic Contact Lenses
		12.3.7	 Ocular Inserts
	12.4	 Implementations of 3DP (Three-Dimensional Printing) in Ophthalmology and Its Regulatory Consideration
		12.4.1	 Corneal Tissue Bioprinting
		12.4.2	 Contact Lens
		12.4.3	 Drug Delivery
		12.4.4	 Regulatory Considerations of 3DP in Ophthalmology
	12.5	 Challenges in the Development of Ophthalmic Formulation
	12.6	 Evaluations Parameters/Test of the Ophthalmic Formulations
		12.6.1	 Physical Appearance
		12.6.2	 Identification
		12.6.3	 Assay
		12.6.4	 Impurities
		12.6.5	 Particulate and Foreign Matter
		12.6.6	 Antimicrobial Preservatives
		12.6.7	 Bacterial Endotoxins
		12.6.8	 Uniformity of Dosage Units
		12.6.9	 Sterility Test
		12.6.10	 Osmolarity
		12.6.11	 Ocular Irritation
		12.6.12	 Isotonicity Evaluation
		12.6.13	 Stability Study
		12.6.14	 pH
		12.6.15	 Viscosity
	12.7	 Regulatory and Future Consideration
	12.8	 Conclusion
	References
13. Advances and Developments in Formulation of Drug Nanocrystals
	13.1	 Introduction
		13.1.1	 Properties of Nanocrystals
		13.1.2	 Advantages of Nanocrystals
		13.1.3	 Disadvantages of Nanocrytals (Jahangir et al. 2022; Moroz et al. 2018)
	13.2	 Performance Attributes of Nanocrystals
		13.2.1	 Improved Dissolution Rate by Surface Area Enlargement
		13.2.2	 Increase in Saturation Solubility
		13.2.3	 Increase in Adhesiveness
		13.2.4	 Increase in Permeability
	13.3	 Preparation Techniques of Nanocrystals
		13.3.1	 Top-Down Approaches
			13.3.1.1	 Wet Bead Milling
			13.3.1.2	 Evaporation/Condensation
			13.3.1.3	 High-Pressure Homogenization
			13.3.1.4	 Laser Ablation
			13.3.1.5	 Ultrasound
		13.3.2	 Bottom-Up Approaches
			13.3.2.1	 Precipitation
			13.3.2.2	 Sol-Gel
			13.3.2.3	 Nanoprecipitation in Microfluidic Reactors
			13.3.2.4	 Liquid Antisolvent Precipitation
			13.3.2.5	 Precipitation Assisted by Acid-Base Method
			13.3.2.6	 High Gravity-Controlled Precipitation
			13.3.2.7	 Supercritical Fluid (SCF) Method
			13.3.2.8	 Emulsion Polymerization Method
		13.3.3	 Combinative Technology
			13.3.3.1	 Nano Edge Technology
			13.3.3.2	 Smart Crystal Technology
	13.4	 Characterization of Nanocrystals
		13.4.1	 Particle Size and Size Distribution
		13.4.2	 SEM
		13.4.3	 TEM
		13.4.4	 AFM
		13.4.5	 Surface Area and Pore Size Analysis
		13.4.6	 Zeta Potential
		13.4.7	 DSC
		13.4.8	 XRD
		13.4.9	 FTIR
		13.4.10	 Raman Spectroscopy
		13.4.11	 TGA
		13.4.12	 Permeation Study
	13.5	 Applications of Nanocrystals
		13.5.1	 Oral Delivery
		13.5.2	 Parenteral Administration
		13.5.3	 Pulmonary Drug Delivery
		13.5.4	 Ocular Drug Delivery
		13.5.5	 Topical Drug Delivery
		13.5.6	 Targeted Drug Delivery
	13.6	 Marketed Products of Nanocrystals
	13.7	 Conclusion
	References
14. A Technological Update on Inhalation Drug Delivery Devices
	14.1	 Introduction
	14.2	 Challenges and Their Probable Solutions
		14.2.1	 Device-Related Challenges
		14.2.2	 Biological Barriers
	14.3	 Inhalation Drug Delivery and Devices
		14.3.1	 Nebulizers
			14.3.1.1	 Conventional Nebulizers
				14.3.1.1.1 Jet Nebulizers
				14.3.1.1.2 Ultrasonic Nebulizer
			14.3.1.2	 Advances in Nebulizers
				14.3.1.2.1 Mesh Nebulizer
				14.3.1.2.2 Vibrating Mesh Nebulizer (VMN)
		14.3.2	 Dry Powder Inhalers
			14.3.2.1	 Challenges of Conventional Dry Powder Inhalers (Need for Advancement)
			14.3.2.2	 Advancements in DPI Devices
				14.3.2.2.1 Active Devices
				14.3.2.2.2 Digital/Smart Devices
		14.3.3	 Metered Dose Inhaler (MDI)
			14.3.3.1	 Recent Advances in MDI Devices
				14.3.3.1.1 Modified Design Based on Nozzle Geometry
				14.3.3.1.2 Extra-Fine Particle Atomization
				14.3.3.1.3 Addition of “Spacers”
			14.3.3.2	 Advancement in MDI Formulations
				14.3.3.2.1 Nano- and Microformulations
	14.4	 Applications of Inhalational Drug Delivery
	14.5	 Evaluation of Inhalation Drug Delivery Devices
		14.5.1	 In Vitro Evaluation of Inhalation Devices
		14.5.2	 Ex Vivo Evaluation of Inhalation Devices
		14.5.3	 In Vivo Evaluation of Inhalation Devices
	14.6	 Conclusion and Future Perspective
	References
15. Herbal Formulations: Development, Challenges, Testing, Stability, and Regulatory Guidelines
	15.1	 Introduction
	15.2	 Nanoformulations of Herbal Medicines
		15.2.1	 Herbal Nanoemulsion
		15.2.2	 Herbal Nanoparticles
		15.2.3	 Herbal Hydrogels
	15.3	 Challenges in the Development of Herbal Formulations
		15.3.1	 Extraction of Desired Herbal Compound
		15.3.2	 Difficulties in Crossing Biological Barriers
		15.3.3	 Higher Cost of Preparation
		15.3.4	 Physical Stability of Herbal Formulations
		15.3.5	 Toxicity of Herbal Medicine
	15.4	 Testing of Herbs and Herbal Formulations
		15.4.1	 Thermal Analysis
		15.4.2	 High-Performance Thin-Layer Chromatography (HPTLC)
		15.4.3	 High-Performance Liquid Chromatography (HPLC)
		15.4.4	 Liquid Chromatography Mass Spectrometry (LCMS)
		15.4.5	 Supercritical Fluid Chromatography
		15.4.6	 Gas Chromatography-Mass Spectrometry (GCMS)
		15.4.7	 Inductively Coupled Plasma-Mass Spectroscopy
	15.5	 Stability Requirement in Herbal Formulations
		15.5.1	 Physical Instability
		15.5.2	 Environmental Conditions
		15.5.3	 Chemical Instability
		15.5.4	 Complex Mixtures
		15.5.5	 Lack of Good Manufacturing Practices
	15.6	 Regulatory Guidelines in Approval of Herbal Formulations
	15.7	 Conclusion
	References
16. Drug Repurposing and Virtual Screening
	16.1	 Introduction
	16.2	 A Prime Candidate for Repurposing
	16.3	 Approaches
		16.3.1	 Phenotypic Screening
		16.3.2	 Target-Based Methods
		16.3.3	 Knowledge-Based Methods
		16.3.4	 Signature-Based Methods
		16.3.5	 Pathway or Network-Based Methods
		16.3.6	 Targeted Mechanism-Based Methods
		16.3.7	 Pharmacovigilance-Based Drug Repurposing
	16.4	 Virtual Screening (VS)
		16.4.1	 Molecular Docking
		16.4.2	 Ligand-Based Virtual Screening (LBVS)
		16.4.3	 Pharmacophore Modelling
		16.4.4	 Similarity Searching
		16.4.5	 Machine Learning (ML)
		16.4.6	 Structure Based
		16.4.7	 Molecular Dynamics Studies
		16.4.8	 Quantitative Structure-Activity Relationship (QSAR)
		16.4.9	 Commonly Used Databases/Software in Virtual Screening
			16.4.9.1	 Available Software for Docking Studies
				16.4.9.1.1 AutoDock
				16.4.9.1.2 Chimera
				16.4.9.1.3 Discovery Studio
				16.4.9.1.4 Dock
				16.4.9.1.5 MolDock
				16.4.9.1.6 Argus Lab
			16.4.9.2	 Available Software for Molecular Dynamics Studies
			16.4.9.3	 Databases/Software for Network
	16.5	 Conclusion
	References
17. Pre-clinical and Clinical Studies, Pharmacovigilance, Pharmacogenomics, and Commercialization of Pharmaceutical Products
	17.1	 Introduction
	17.2	 Pre-clinical Evaluations
		17.2.1	 In Vitro Pharmacological Studies
		17.2.2	 In Vivo Toxicity Studies
		17.2.3	 In Vivo Efficacy Studies
	17.3	 Clinical Evaluations
		17.3.1	 Clinical Trial Phases
			17.3.1.1	 Phase 0
			17.3.1.2	 Phase I
			17.3.1.3	 Phase II
			17.3.1.4	 Phase III
	17.4	 Pharmacovigilance
		17.4.1	 Role of PV in the Drug Development Process
		17.4.2	 Clinical Trial Designs
		17.4.3	 Randomized Controlled Trials
			17.4.3.1	 Parallel Arm Design
			17.4.3.2	 Cross-Over Design
			17.4.3.3	 Randomized Withdrawal Design
			17.4.3.4	 Factorial Design
		17.4.4	 Types of Randomization in RCTs
			17.4.4.1	 Stratified Randomization
			17.4.4.2	 Block Randomization
			17.4.4.3	 Cluster Randomization
	17.5	 Pharmacogenomics
		17.5.1	 Pharmacokinetic Gene Variation
		17.5.2	 Pharmacodynamics Gene Variation
		17.5.3	 Pharmacogenomics and Diagnosis
		17.5.4	 Implementation in a Clinical Setup
	17.6	 Commercialization of Pharmaceutical Products
	17.7	 Conclusions
	References