Solid State Development and Processing of Pharmaceutical Molecules: Salts, Cocrystals, and Polymorphism

Cover
Title Page
Copyright
Contents
Series Editors Preface
Preface
Chapter 1 Aspects for Developing and Processing Solid Forms
	1.1 Aspects for Developing and Processing Solid Forms
		1.1.1 Introduction
		1.1.2 Education and Personal Background
		1.1.3 Societal Impact – Fishing in Foreign Waters
			1.1.3.1 Motivation
			1.1.3.2 The Personal Dimension
			1.1.3.3 Beyond the Impact on Individuals
			1.1.3.4 Understanding the Market – Not an Easy Task
			1.1.3.5 Benefits of an Interdisciplinary Mindset
		1.1.4 The Basis for Mutual Understanding
		1.1.5 Crystallization is a Separation, Not a Separated Process
		1.1.6 Some Early Information About Solid‐state Properties
		1.1.7 Digitalization (Not Only) in the Laboratory
			1.1.7.1 Prerequisites – Technology and People
			1.1.7.2 Connect Data and the Right Information from Synthesis and Analysis
			1.1.7.3 Contributions and Choices
			1.1.7.4 Application of Digitalization
			1.1.7.5 Fully Digitalized Infrastructure
		1.1.8 Basic Terms and Concepts in the World of Solid State
			1.1.8.1 Crystalline and Amorphous
			1.1.8.2 Crystallization and Precipitation
			1.1.8.3 Understanding the Phase Diagram – Analytical Characterization of the Solid–Liquid and Solid–Solid Systems
			1.1.8.4 Polymorphism
			1.1.8.5 Multi‐component Compounds – Salt, Cocrystal, Solvate, and Hydrate
			1.1.8.6 Solvates, Hydrates, Non‐solvated Forms, or Ansolvates
			1.1.8.7 Dispersed Primary Particles, Aggregates, and Agglomerates
			1.1.8.8 Particle Size and Particle Size Distribution (PSD)
		1.1.9 Investigating and Understanding the Polymorphic Landscape
		1.1.10 Performing the Crystallization
		1.1.11 Objectives for the Optimization of Crystallization Processes and Solid‐State Properties
		1.1.12 Implementation of In Silico and Simulation Techniques
		1.1.13 Saving the Investment – Addressing Intellectual Property Rights
		1.1.14 Concluding Remarks
	List of Abbreviations
	References
Chapter 2 Determination of Current Knowledge
	2.1 Why Is it Important to Search for Relevant Information Before Starting a Solid‐State Project?
	2.2 Where to Begin a Literature Search for a Solid‐State Project?
		2.2.1 Literature Search
			2.2.1.1 Focusing Your Literature Search
		2.2.2 Staying on Top of the Latest Publications
	2.3 Patent Search
		2.3.1 Types of Patent Reports
		2.3.2 Understanding the Elements of Patents
		2.3.3 Patent Classification
		2.3.4 Patent Databases
			2.3.4.1 Free Patent Databases
	2.4 Other Useful Resources for Solid‐State Projects
		2.4.1 Cambridge Structural Database
		2.4.2 Crystallography Open Database
	List of Abbreviations
	References
Chapter 3 Systematic Screening and Investigation of Solid‐State Landscapes
	3.1 Introduction
	3.2 General Aspects of Solid‐State Investigations in Early Drug Discovery Phase
	3.3 Transition Phase from Late Stage Research to Early Stage Development
	3.4 Solid‐State Characteristics in Preclinical Formulations
	3.5 API‐crystallization Strategy in Candidate Profiling Phase
	3.6 Selection Criteria of a Suitable Solid Form
	3.7 Knowledge Management
	3.8 Control of Solid Form Properties in Development
	3.9 Exploratory Crystallization Experiments
	List of Abbreviations
	References
Chapter 4.1 Solid‐State Characterization Techniques: Microscopy
	4.1.1 Microscopy
		4.1.1.1 Optical Microscopy
			4.1.1.1.1 Bright‐Field Microscopy
			4.1.1.1.2 Dark‐Field Microscopy
			4.1.1.1.3 Polarized Light Microscopy
			4.1.1.1.4 Other Optical Microscopy Variants
		4.1.1.2 Electron Microscopy
			4.1.1.2.1 Scanning Electron Microscopy
			4.1.1.2.2 Transmission Electron Microscopy
		4.1.1.3 Atomic Force Microscopy
		4.1.1.4 Microscopy in Regulatory Documents
	List of Abbreviations
	References
Chapter 4.2 Standards and Trends in Analytical Characterization – X‐ray Diffraction (XRD)
	4.2.1 X‐ray Diffraction
		4.2.1.1 Introduction
		4.2.1.2 Measurement Principles
			4.2.1.2.1 The Crystal Lattice
			4.2.1.2.2 The Space Group Symmetry
			4.2.1.2.3 What Determines a Diffraction Peak
			4.2.1.2.4 X‐ray Scattering Technics
	4.2.2 Technics
		4.2.2.1 Single Crystal X‐ray Diffraction
		4.2.2.2 Powder X‐ray Diffraction
			4.2.2.2.1 Alternative Methods for Structure Determination
	4.2.3 Instrumentation
		4.2.3.1 X‐ray Sources
		4.2.3.2 Diffractometer Geometries
			4.2.3.2.1 Reflection Geometry
			4.2.3.2.2 Transmission Geometry
			4.2.3.2.3 Benchtop Diffractometers
		4.2.3.3 Detectors
		4.2.3.4 Peak Asymmetry
		4.2.3.5 Reproducibility of Diffraction Patterns: The Texture Effect (Preferred Orientation)
		4.2.3.6 Databases of Known Diffraction Patterns
	4.2.4 Measurement
		4.2.4.1 Instrument Calibration
		4.2.4.2 Sample Preparation
	4.2.5 Data Evaluation
		4.2.5.1 Qualitative Phase Analysis
			4.2.5.1.1 Phase Identification or Identity Check
			4.2.5.1.2 Amorphous Content
		4.2.5.2 Quantification
			4.2.5.2.1 Based on Calibration Curve
			4.2.5.2.2 Based on Internal Standard Addition
			4.2.5.2.3 Based on Rietveld Refinement
		4.2.5.3 Advanced Phase Analysis
	List of Abbreviations
	References
	Further Reading
Chapter 4.3 Standards and Trends in Solid‐State Characterization Techniques – Thermal Analysis
	4.3.1 Introduction
	4.3.2 Thermal Analysis in Drug Development
		4.3.2.1 Solid form Landscape
		4.3.2.2 Compatibility Studies
		4.3.2.3 Other Applications
	4.3.3 Methods
		4.3.3.1 Differential Scanning Calorimetry
			4.3.3.1.1 Techniques
			4.3.3.1.2 Sample Preparation and Measuring Parameters
			4.3.3.1.3 Evaluation
			4.3.3.1.4 Special Applications
			4.3.3.1.5 Detection Limits
		4.3.3.2 Thermogravimetric Analysis
			4.3.3.2.1 Technique
			4.3.3.2.2 Sample Preparation and Measuring Parameters
			4.3.3.2.3 Evaluation
			4.3.3.2.4 Special Applications
	4.3.4 Case Studies
		4.3.4.1 Understanding Polymorphic Transitions
		4.3.4.2 The Power of Ultra‐fast Heating Rates
		4.3.4.3 Understanding Amorphous Phases
		4.3.4.4 Identification of Solvate Structures
	4.3.5 Quality and Regulatory Aspects
	4.3.6 Outlook
	Acknowledgments
	List of Abbreviations
	Notes
	References
Chapter 4.4 Standards and Trends in Solid‐State Characterization Techniques: Infrared (IR) Spectroscopy
	4.4.1 Infrared (IR) Spectroscopy
		4.4.1.1 Introduction
		4.4.1.2 IR Spectroscopy as Identity Method for Drug Substances
			4.4.1.2.1 Transmission Mode
			4.4.1.2.2 Attenuated Total Reflectance (ATR)
			4.4.1.2.3 Sample preparation
			4.4.1.2.4 Analysis and Reporting
			4.4.1.2.5 Examples and Limitations
			4.4.1.2.6 Method Validation of IR Spectroscopy Identification and Quantification Methods
		4.4.1.3 Application of IR Microscopy‐Imaging Methods in Drug Development
			4.4.1.3.1 Spatial Resolution
			4.4.1.3.2 Measurement Setups
			4.4.1.3.3 Case Studies
		4.4.1.4 Conclusion
	List of Abbreviations
	References
Chapter 4.5 Transmission Raman Spectroscopy – Implementation in Pharmaceutical Quality Control
	4.5.1 Raman Spectroscopy – From Research to Broad Applications in Industry
		4.5.1.1 Objective
			4.5.1.1.1 History
			4.5.1.1.2 Introduction
			4.5.1.1.3 The Raman Effect
	4.5.2 Analytical use of Raman Spectroscopy for Pharmaceutical Purposes
		4.5.2.1 Transmission Raman Spectroscopy (TRS)
			4.5.2.1.1 Principles of Transmission Raman Spectroscopy
			4.5.2.1.2 A Practical Guide to a Successful Business Case
	4.5.3 Transmission Raman Spectroscopy – Another Practical Guide
		4.5.3.1 Evaluation Phase
			4.5.3.1.1 Prefeasibility Evaluation
			4.5.3.1.2 Feasibility of a Product
		4.5.3.2 Transmission Raman Method Development
			4.5.3.2.1 Transmission Raman Spectroscopic Method Development
			4.5.3.2.2 Risk Analysis
			4.5.3.2.3 Transmission Raman Model Development, Calibration, and Validation
	4.5.4 Regulatory Assessment and Guidelines
	List of Abbreviations
	References
Chapter 4.6 Solid‐state Characterization Techniques: Particle Size
	4.6.1 Introduction
	4.6.2 Analytical Methodologies Used to Measure Particle Size
		4.6.2.1 Sedimentation
		4.6.2.2 Electrozone Sensing
		4.6.2.3 Sieving
		4.6.2.4 Microscopy
		4.6.2.5 Dynamic Light Scattering
		4.6.2.6 Laser Diffraction
	4.6.3 Method Development for Precise Particle‐size Measurements by Laser Diffraction
		4.6.3.1 Instrumentation and Measurement
		4.6.3.2 Selection of an Appropriate Optical Model
		4.6.3.3 Sample Dispersion
			4.6.3.3.1 Wet Dispersion
			4.6.3.3.2 Dry Dispersion
		4.6.3.4 Sample Representativeness and Obscuration
		4.6.3.5 Readiness for Method Validation
	4.6.4 Unexpected Results and Troubleshooting in Laser Diffraction Measurement
		4.6.4.1 Inconsistent Disconnected Peaks
		4.6.4.2 Repeatable Artifact Peaks
	List of Abbreviations
	References
Chapter 4.7 Micro Computational Tomography
	4.7.1 Tomography Imaging Techniques
	4.7.2 Micro X‐ray Computed Tomography Scan
		4.7.2.1 The Use of CT in the Pharmaceutical Industry
			4.7.2.1.1 μCT Applied to Density Distribution and Porous Characterization
			4.7.2.1.2 μCT Applied for Characterization of Structural Features: Size, Shape, and Dimensions and Interfaces
			4.7.2.1.3 μCT Applied to Coating Characterization
			4.7.2.1.4 μCT Applied to Performance Evaluation
			4.7.2.1.5 Foreign Matter Detection by μCT
	List of Abbreviations
	Notes
	References
Chapter 4.8 In Situ Methods for Monitoring Solid‐State Processes in Molecular Materials
	4.8.1 In Situ Methods for Monitoring Solid‐State Processes in Molecular Materials
		4.8.1.1 The Complexity of Solid Materials
		4.8.1.2 Methods to Consider
		4.8.1.3 Methods to Monitor Crystallization Kinetics from Solution
			4.8.1.3.1 UV–Vis Spectroscopy
			4.8.1.3.2 Infrared Spectroscopy
		4.8.1.4 Monitoring Crystallization from Solution: Following Solid Product Formation
			4.8.1.4.1 Light Scattering
		4.8.1.5 Methods to Monitor Extrinsic Solid Properties
			4.8.1.5.1 Acoustic Emission
			4.8.1.5.2 Thermography
		4.8.1.6 Methods to Monitor Intrinsic Solid Properties
			4.8.1.6.1 X‐ray Diffraction
			4.8.1.6.2 Raman Spectroscopy
		4.8.1.7 Benefits of Combining Methods for In Situ Monitoring
		4.8.1.8 Summary
	List of Abbreviations
	References
Chapter 4.9 Application of Process Monitoring and Modeling
	4.9.1 In‐process Solid Form Monitoring Techniques
		4.9.1.1 Direct Characterization Techniques
			4.9.1.1.1 Raman Spectroscopy
			4.9.1.1.2 Near Infrared Spectroscopy
		4.9.1.2 Indirect Monitoring Tools
			4.9.1.2.1 Focused Beam Reflectance Measurement (FBRM)
			4.9.1.2.2 Monitoring Particle Shape Using In‐process Microscopy
			4.9.1.2.3 Monitoring Solute Concentration
		4.9.1.3 Advantages and Challenges of In Situ Solid Form Monitoring Techniques
	4.9.2 Quantification Methods and Application to Solid Form Transformation Modeling
		4.9.2.1 Multivariate Data Analysis
		4.9.2.2 Data‐driven Model for CLD–PSD Prediction
		4.9.2.3 Process Modeling of Polymorph Transformation Processes
	List of Abbreviations
	References
Chapter 4.10 Photon Density Wave (PDW) Spectroscopy for Nano‐ and Microparticle Sizing
	4.10.1 Classification of Particle Sizing Technologies
	4.10.2 Particle Size and Solid Fraction Ranges
	4.10.3 Photon Density Wave (PDW) Spectroscopy – Theory, Instrumentation, and Application Examples
	4.10.4 Particle Sizing by PDW Spectroscopy
	4.10.5 Sample Versus Process Measurements
	4.10.6 Technical Implementation and Data Access
	4.10.7 Examples for Process Analysis with PDW Spectroscopy
		4.10.7.1 Crystallization of Lactose
		4.10.7.2 Precipitation of Barium Sulfate
	4.10.8 Summary
	List of Abbreviations
	References
Chapter 5 Impact of Solid Forms on API Scale‐Up
	5.1 Introduction
	5.2 Background
	5.3 Small‐Scale Crystallization Development
		5.3.1 Form Selection
		5.3.2 Solvent Selection
			5.3.2.1 Solvent Screening
			5.3.2.2 Solubility Diagram
			5.3.2.3 Solubility Measurement
		5.3.3 Crystallization Process Selection
			5.3.3.1 Process Outline Selection
			5.3.3.2 Process Outline Evaluation
			5.3.3.3 Process Exploration
		5.3.4 Process Development Conclusions
	5.4 Crystallization Scale‐Up
		5.4.1 Crystallization Process Accommodation
			5.4.1.1 Vessel Size and MoC
			5.4.1.2 Agitation
			5.4.1.3 Heat Transfer
			5.4.1.4 Solution Addition
			5.4.1.5 Solid Addition
			5.4.1.6 Alternative Technologies
		5.4.2 Risks and Common Problems
			5.4.2.1 Metastable Forms
			5.4.2.2 Amorphous
			5.4.2.3 Salt Stoichiometry
			5.4.2.4 Oiling and Phase Separations
		5.4.3 Isolation and Drying
			5.4.3.1 Isolation
			5.4.3.2 Drying
		5.4.4 Agglomeration
		5.4.5 Particle Size Reduction
			5.4.5.1 Delumping
			5.4.5.2 Milling and Micronization
			5.4.5.3 Storage and Packing
		5.4.6 Scale‐up Conclusions
	5.5 People and Skill Requirements
	5.6 Regulatory Requirements
		5.6.1 Process Documentation
		5.6.2 Safety
		5.6.3 Quality and Manufacturability
	5.7 Closing Remarks
	List of Abbreviations
	References
Chapter 6 Impact on Drug Development and Drug Product Processing
	6.1 Introduction
	6.2 Pharmaceutical Profiling
	6.3 Formulation Development
		6.3.1 Liquid Formulations: Solutions and Suspensions
		6.3.2 Solid Dosage Forms
		6.3.3 Solubility Enhanced Formulations
			6.3.3.1 Lipid‐Based Formulations and Drug Delivery Systems
			6.3.3.2 Solid Solutions and Amorphous Solid Dispersions
	6.4 Process Development and Transfer to Commercial Manufacturing
		6.4.1 Particle Size Reduction
		6.4.2 Blending
		6.4.3 Granulation
			6.4.3.1 Wet Granulation and Drying
			6.4.3.2 Dry Granulation/Roller Compaction
		6.4.4 Tablet Compression
		6.4.5 Film Coating
	6.5 Control Strategy
	6.6 Regulatory Submissions
	List of Abbreviations
	References
Chapter 7 Workflow Management
	7.1 Motivation
	7.2 Workflow Management
	7.3 Organization of Solid‐State Development by Project Management
		7.3.1 Stakeholders
		7.3.2 CMC Project Management
		7.3.3 Substance Requirement Plan
		7.3.4 Pre‐CMC Data
	7.4 Workflows in the Environment of the Crystallization Laboratory
		7.4.1 Micro‐Project Management
		7.4.2 Dependencies
		7.4.3 Material Flow
		7.4.4 Designations and Code Assignment
		7.4.5 Analytic Database System
		7.4.6 Physical Sample Transfer
		7.4.7 Analytic Transfer Tool
		7.4.8 Analytical Processes – Timely Measurement
		7.4.9 Sample Storage Processes
		7.4.10 Documentation
		7.4.11 Review Process for ELN Documents
			7.4.11.1 Document Status
			7.4.11.2 Manual ELN Review Process
			7.4.11.3 Archive Process
		7.4.12 Communication with CROs
		7.4.13 Fundamental Lab Processes
	7.5 Processes in the Solid‐State Lab
		7.5.1 Initial Testing
		7.5.2 Solubility Estimation
		7.5.3 Manual Screening
		7.5.4 High‐Throughput Screening
		7.5.5 Processes for Replica Experiments and Scale‐Up of Solid Forms
	7.6 Development of Crystallization Processes
	7.7 Support Processes
		7.7.1 Route Scouting Process
		7.7.2 Crystallization of Impurities and Intermediates
		7.7.3 Downstream Processes
		7.7.4 Scale‐Up and Technology Transfer Process
		7.7.5 Analytical Development
		7.7.6 Preformulation
		7.7.7 Formulation
	7.8 Conclusion
	List of Abbreviations
	References
Chapter 8 Digitalization in Laboratories of the Pharmaceutical Industry
	8.1 Introduction
	8.2 Motivation of Digitalization in the Laboratory
		8.2.1 Expectations of the Staff
		8.2.2 Increasing Throughput
		8.2.3 Repeatability
		8.2.4 Enhanced Requirements on Data Integrity
		8.2.5 Centralized Archiving
		8.2.6 Ad Hoc Analysis
		8.2.7 The Value of Data
	8.3 Categories of Laboratory IT Systems
		8.3.1 Devices
		8.3.2 Lab Execution Systems (LES) and Scientific Data Management Systems (SDMS)
		8.3.3 Lab Data Systems
		8.3.4 Enterprise Resource Planning (ERP)
		8.3.5 Further Use of Data
			8.3.5.1 Data Analysis and Reporting
			8.3.5.2 Big Data Analytics and Artificial Intelligence
	8.4 System Interfaces for Data Exchange
		8.4.1 Adapters
			8.4.1.1 Serial Port (RS232)
			8.4.1.2 Universal Series Bus (USB)
			8.4.1.3 Ethernet
			8.4.1.4 Cable Less Connections
		8.4.2 Communication Medium and Protocols
			8.4.2.1 File‐Based Communication
			8.4.2.2 ANSI/ISA‐88 Batch Control (S‐88)
			8.4.2.3 Open Platform Communications Unified Architecture (OPC UA)
			8.4.2.4 Standards in Lab Automation (SiLA)
		8.4.3 Data Formats
			8.4.3.1 Common Data Formats (e.g. TXT, XML, JSON)
			8.4.3.2 Analytical Information Markup Language (AnIML)
			8.4.3.3 Allotrope Data Format (ADF)
	8.5 Implementation of IT Solutions
		8.5.1 Identification of Digital Gaps in the Lab Processes
			8.5.1.1 Contextual Inquiry
			8.5.1.2 Interaction Room
		8.5.2 Implementation Approach
			8.5.2.1 Design
			8.5.2.2 Realization
			8.5.2.3 Verification
			8.5.2.4 Rollout
	8.6 Conclusion
	List of Abbreviations
	References
Chapter 9.1 Polymorphs and Patents – the US Perspective
	9.1.1 Introduction
	9.1.2 What Is a Patent?
	9.1.3 How Are Patents Obtained?
	9.1.4 United States Patent Law
		9.1.4.1 Tapentadol Hydrochloride
			9.1.4.1.1 Tapentadol Hydrochloride Form A Held Not Obvious
			9.1.4.1.2 Tapentadol Hydrochloride Form A Was Found to Have Utility
		9.1.4.2 Paroxetine Hydrochloride Hemihydrate
			9.1.4.2.1 PHC Hemihydrate History
			9.1.4.2.2 Meaning of “Crystalline Paroxetine Hydrochloride Hemihydrate”
			9.1.4.2.3 PHC Hemihydrate: Infringed, But Invalid for Anticipation
		9.1.4.3 Ranitidine Hydrochloride
			9.1.4.3.1 History of RHCl Form 2
			9.1.4.3.2 RHCl Form 2 Not Anticipated by Example 32
		9.1.4.4 Cefdinir
		9.1.4.5 Amlodipine Besylate
			9.1.4.5.1 History of Amlodipine Besylate
			9.1.4.5.2 Amlodipine Besylate Found Obvious
		9.1.4.6 Concluding Remarks
	Notes
	References
Chapter 9.2 Polymorphs and Patents – The EU Perspective
	9.2.1 European Patent Applications and European Patents
		9.2.1.1 Introduction
		9.2.1.2 Summary of the Processing of Applications and Patents Before the European Patent Office (EPO)
		9.2.1.3 Economic Factors
		9.2.1.4 Unitary Patents
		9.2.1.5 Protection of Polymorphs and Solid Forms in General
		9.2.1.6 Polymorph Screening
	9.2.2 Decisions of Technical Boards of Appeal of the EPO
		9.2.2.1 Decision T 777/08 of 24 May 2011
		9.2.2.2 Decision T 1555/12 Dated 29 April 2015
		9.2.2.3 Decision T 2114/13 Dated 12 October 2016
		9.2.2.4 Decision T 2397/12 Dated 12 March 2018
		9.2.2.5 Decision T 246/15 Dated 13 November 2018
	9.2.3 Jurisdiction of the Federal Patent Court and the German Federal Supreme Court
		9.2.3.1 Decision “Kristallformen” German Federal Court
		9.2.3.2 Decision X ZR 58/08 Dated 15 March 15 2011
		9.2.3.3 Decision X ZR 98/09 Dated 15 May 2012
		9.2.3.4 Decision X ZR 110/16 Dated 7 August 2018
	9.2.4 Assessing Validity of a Patent or the Chances of Success
	9.2.5 Interaction with Patent Professionals
	List of Abbreviations
	References
Chapter 10 Regulatory Frameworks Affecting Solid‐State Development
	10.1 Introduction – The Need for Regulation in Pharmaceutical Industry
	10.2 Solid‐State Forms to Be Used for Drugs
	10.3 General Regulatory Considerations for Pharmaceutical Solid‐State Forms
	10.4 Regulatory Framework for Pharmaceutical Salts
		10.4.1 Pharmaceutical Equivalence and Pharmaceutical Alternatives
		10.4.2 Bioequivalence
		10.4.3 Therapeutic Equivalence
		10.4.4 Biowaivers
		10.4.5 Regulatory Approval for Pharmaceutical Salts
			10.4.5.1 Regulatory Approval Pathways in the United States
			10.4.5.2 Regulatory Approval Pathways in the European Union
		10.4.6 Regulatory Approval for Polymorphs
		10.4.7 Polymorphism in Pharmacopoeias
	10.5 Regulatory Framework for Co‐crystals
	10.6 Summary
	List of Abbreviations
	References
Chapter 11 Opportunities and Challenges for Generic Development from a Solid‐state Perspective
	11.1 The Birth of a New Drug and the Generic Siblings that Will Follow – Two Different Mindsets
		11.1.1 Generics
		11.1.2 Proprietary Products
		11.1.3 API and Solid State
			11.1.3.1 Generics
			11.1.3.2 Proprietary
	11.2 Portfolio Management – How Is a Portfolio Constructed and Maintained?
		11.2.1 Activities and Timelines
			11.2.1.1 Strategy
			11.2.1.2 Value
			11.2.1.3 Factors Impacting on Timing – When and How Does a Product Show Up on a Generic Company's Radar Screen?
		11.2.2 Timing
			11.2.2.1 When Is “On‐time?”
		11.2.3 Market‐specific Considerations Based on Local Legislation and Administration (OB, PIV, Various Exclusivities – US, EU, JP, etc.)
			11.2.3.1 Patents Through the Eyes of the Regulatory Authorities
			11.2.3.2 Data Exclusivity (Data Protection)
			11.2.3.3 Salts and Esters
			11.2.3.4 Think Global, Act Local
		11.2.4 Sources to Evaluate a Project
			11.2.4.1 Government and Regulatory Agencies
			11.2.4.2 Analyst Reports and Company Financial Reports
			11.2.4.3 Pay Data Sources
		11.2.5 Evaluation Tools
			11.2.5.1 Business Case
			11.2.5.2 Quality Target Project Profile (QTPP)
		11.2.6 Criteria for Identifying Promising Projects
		11.2.7 Criteria for Building a Robust Portfolio
	11.3 Challenges in Developing a Generic Product from the Solid‐state Perspective
		11.3.1 Implications in Developing Formulation with a Metastable API
		11.3.2 The Stability Question
			11.3.2.1 Polymorphic Stability in Dry Conditions
			11.3.2.2 Polymorphic Stability in Wet Conditions (Slurry)
	11.4 Generic Solid‐state Development
		11.4.1 General
		11.4.2 Predevelopment Phase: Solid‐state Strategy
			11.4.2.1 Review of the Solid State, Especially the Polymorph Patent Landscape
			11.4.2.2 Design‐around Considerations
		11.4.3 Crystal Forms Discovery
			11.4.3.1 Importance of the Crystal Forms Discovery Stage
			11.4.3.2 New Crystal Forms Unpredictability
			11.4.3.3 Pragmatic Questions About Crystal Forms Search
			11.4.3.4 Late‐appearing Polymorphs
			11.4.3.5 Irreproducibility of Procedures
			11.4.3.6 Analytical Focus
		11.4.4 Target Selection
			11.4.4.1 Solubility
			11.4.4.2 Morphology
			11.4.4.3 Solid‐state Stability
			11.4.4.4 Additional Factors
		11.4.5 Process Development in the Laboratory Scale
			11.4.5.1 Process Development
			11.4.5.2 Thermodynamic Stability Relationships
			11.4.5.3 Solubility Curves
			11.4.5.4 API Target
			11.4.5.5 Analytical Methods for Polymorphic Purity
		11.4.6 Scale‐up Challenges
			11.4.6.1 Control of Crystal Form
			11.4.6.2 Control of Particle Size and Morphology
			11.4.6.3 Lot‐to‐Lot Variability
			11.4.6.4 Analytical Focus
		11.4.7 Pharma Development
			11.4.7.1 The Tetrahedron Principle and Consistency Among Lots
			11.4.7.2 The Effect of Micronization on Amorphous Content in Crystalline APIs
			11.4.7.3 Solid‐state Stability upon Storage
		11.4.8 Impact on Formulation
		11.4.9 Summary of Timelines for Solid‐state Activity
		11.4.10 Intellectual Property (IP) Strategies and Activities
	11.5 Success Factors
		11.5.1 Successful Biostudy
		11.5.2 Successful Launch
		11.5.3 Generic Commercial Success
	List of Abbreviations
	References
Index
EULA