Solid State Development and Processing of Pharmaceutical Molecules

Michael Gruss, PhD, is owner and founder of Solid State Concepts. He works as an independent scientific consultant for the pharmaceutical, chemical and nutrition industry. Gruss is author or co-author of more than 15 patent applications in the field of salts, cocrystals and polymorphs.

• Series Editors Preface xxiPreface xxiii1 Aspects for Developing and Processing Solid Forms 1Michael Gruss1.1 Aspects for Developing and Processing Solid Forms 11.1.1 Introduction 11.1.2 Education and Personal Background 11.1.3 Societal Impact – Fishing in ForeignWaters 41.1.3.1 Motivation 41.1.3.2 The Personal Dimension 51.1.3.3 Beyond the Impact on Individuals 61.1.3.4 Understanding the Market – Not an Easy Task 71.1.3.5 Benefits of an Interdisciplinary Mindset 91.1.4 The Basis for Mutual Understanding 91.1.5 Crystallization is a Separation, Not a Separated Process 111.1.6 Some Early Information About Solid-state Properties 131.1.7 Digitalization (Not Only) in the Laboratory 131.1.7.1 Prerequisites – Technology and People 131.1.7.2 Connect Data and the Right Information from Synthesis and Analysis 151.1.7.3 Contributions and Choices 171.1.7.4 Application of Digitalization 181.1.7.5 Fully Digitalized Infrastructure 201.1.8 Basic Terms and Concepts in theWorld of Solid State 211.1.8.1 Crystalline and Amorphous 211.1.8.2 Crystallization and Precipitation 231.1.8.3 Understanding the Phase Diagram – Analytical Characterization of the Solid–Liquid and Solid–Solid Systems 231.1.8.4 Polymorphism 241.1.8.5 Multi-component Compounds – Salt, Cocrystal, Solvate, and Hydrate 251.1.8.6 Solvates, Hydrates, Non-solvated Forms, or Ansolvates 261.1.8.7 Dispersed Primary Particles, Aggregates, and Agglomerates 291.1.8.8 Particle Size and Particle Size Distribution (PSD) 291.1.9 Investigating and Understanding the Polymorphic Landscape 291.1.10 Performing the Crystallization 311.1.11 Objectives for the Optimization of Crystallization Processes and Solid-State Properties 321.1.12 Implementation of In Silico and Simulation Techniques 321.1.13 Saving the Investment – Addressing Intellectual Property Rights 351.1.14 Concluding Remarks 36List of Abbreviations 37References 382 Determination of Current Knowledge 45Andriy Kuzmov and Ronak Savla2.1 Why is it Important to Search for Relevant Information Before Starting a Solid-State Project? 452.2 Where to Begin a Literature Search for a Solid-State Project? 472.2.1 Literature Search 482.2.1.1 Focusing Your Literature Search 492.2.2 Staying on Top of the Latest Publications 512.3 Patent Search 512.3.1 Types of Patent Reports 522.3.2 Understanding the Elements of Patents 532.3.3 Patent Classification 542.3.4 Patent Databases 562.3.4.1 Free Patent Databases 572.4 Other Useful Resources for Solid-State Projects 612.4.1 Cambridge Structural Database 612.4.2 Crystallography Open Database 62List of Abbreviations 62References 633 Systematic Screening and Investigation of Solid-State Landscapes 67Ulrike Werthmann3.1 Introduction 673.2 General Aspects of Solid-State Investigations in Early Drug Discovery Phase 683.3 Transition Phase from Late Stage Research to Early Stage Development 693.4 Solid-State Characteristics in Preclinical Formulations 703.5 API-crystallization Strategy in Candidate Profiling Phase 733.6 Selection Criteria of a Suitable Solid Form 773.7 Knowledge Management 793.8 Control of Solid Form Properties in Development 793.9 Exploratory Crystallization Experiments 80List of Abbreviations 87References 884.1 Solid-State Characterization Techniques: Microscopy 91Luis Almeida e Sousa and Constança Cacela4.1.1 Microscopy 914.1.1.1 Optical Microscopy 914.1.1.1.1 Bright-Field Microscopy 924.1.1.1.2 Dark-Field Microscopy 934.1.1.1.3 Polarized Light Microscopy 934.1.1.1.4 Other Optical Microscopy Variants 954.1.1.2 Electron Microscopy 964.1.1.2.1 Scanning Electron Microscopy 964.1.1.2.2 Transmission Electron Microscopy 1004.1.1.3 Atomic Force Microscopy 1014.1.1.4 Microscopy in Regulatory Documents 103List of Abbreviations 103References 1044.2 Standards and Trends in Analytical Characterization – X-ray Diffraction (XRD) 107Clemens Kühn4.2.1 X-ray Diffraction 1074.2.1.1 Introduction 1074.2.1.2 Measurement Principles 1084.2.1.2.1 The Crystal Lattice 1084.2.1.2.2 The Space Group Symmetry 1084.2.1.2.3 What Determines a Diffraction Peak 1094.2.1.2.4 X-ray Scattering Technics 1104.2.2 Technics 1104.2.2.1 Single Crystal X-ray Diffraction 1104.2.2.2 Powder X-ray Diffraction 1114.2.2.2.1 Alternative Methods for Structure Determination 1114.2.3 Instrumentation 1124.2.3.1 X-ray Sources 1124.2.3.2 Diffractometer Geometries 1134.2.3.2.1 Reflection Geometry 1134.2.3.2.2 Transmission Geometry 1144.2.3.2.3 Benchtop Diffractometers 1154.2.3.3 Detectors 1154.2.3.4 Peak Asymmetry 1154.2.3.5 Reproducibility of Diffraction Patterns: The Texture Effect (Preferred Orientation) 1164.2.3.6 Databases of Known Diffraction Patterns 1184.2.4 Measurement 1184.2.4.1 Instrument Calibration 1184.2.4.2 Sample Preparation 1194.2.5 Data Evaluation 1194.2.5.1 Qualitative Phase Analysis 1194.2.5.1.1 Phase Identification or Identity Check 1204.2.5.1.2 Amorphous Content 1214.2.5.2 Quantification 1224.2.5.2.1 Based on Calibration Curve 1234.2.5.2.2 Based on Internal Standard Addition 1234.2.5.2.3 Based on Rietveld Refinement 1234.2.5.3 Advanced Phase Analysis 124List of Abbreviations 125References 125Further Reading 1274.3 Standards and Trends in Solid-State Characterization Techniques – Thermal Analysis 129Juergen Thun and Nikolaus Martin4.3.1 Introduction 1294.3.2 Thermal Analysis in Drug Development 1304.3.2.1 Solid form Landscape 1304.3.2.2 Compatibility Studies 1304.3.2.3 Other Applications 1304.3.3 Methods 1314.3.3.1 Differential Scanning Calorimetry 1314.3.3.1.1 Techniques 1314.3.3.1.2 Sample Preparation and Measuring Parameters 1314.3.3.1.3 Evaluation 1324.3.3.1.4 Special Applications 1344.3.3.1.5 Detection Limits 1344.3.3.2 Thermogravimetric Analysis 1344.3.3.2.1 Technique 1344.3.3.2.2 Sample Preparation and Measuring Parameters 1354.3.3.2.3 Evaluation 1354.3.3.2.4 Special Applications 1364.3.4 Case Studies 1364.3.4.1 Understanding Polymorphic Transitions 1364.3.4.2 The Power of Ultra-fast Heating Rates 1394.3.4.3 Understanding Amorphous Phases 1414.3.4.4 Identification of Solvate Structures 1424.3.5 Quality and Regulatory Aspects 1444.3.6 Outlook 145Acknowledgments 146List of Abbreviations 146Notes 146References 1464.4 Standards and Trends in Solid-State Characterization Techniques: Infrared (IR) Spectroscopy 151Dagmar Lischke4.4.1 Infrared (IR) Spectroscopy 1514.4.1.1 Introduction 1514.4.1.2 IR Spectroscopy as Identity Method for Drug Substances 1524.4.1.2.1 Transmission Mode 1524.4.1.2.2 Attenuated Total Reflectance (ATR) 1524.4.1.2.3 Sample preparation 1534.4.1.2.4 Analysis and Reporting 1534.4.1.2.5 Examples and Limitations 1544.4.1.2.6 Method Validation of IR Spectroscopy Identification and Quantification Methods 1554.4.1.3 Application of IR Microscopy-Imaging Methods in Drug Development 1564.4.1.3.1 Spatial Resolution 1564.4.1.3.2 Measurement Setups 1574.4.1.3.3 Case Studies 1584.4.1.4 Conclusion 162List of Abbreviations 162References 1634.5 Transmission Raman Spectroscopy – Implementation in Pharmaceutical Quality Control 165Meike Römer4.5.1 Raman Spectroscopy – From Research to Broad Applications in Industry 1654.5.1.1 Objective 1654.5.1.1.1 History 1654.5.1.1.2 Introduction 1654.5.1.1.3 The Raman Effect 1664.5.2 Analytical use of Raman Spectroscopy for Pharmaceutical Purposes 1674.5.2.1 Transmission Raman Spectroscopy (TRS) 1674.5.2.1.1 Principles of Transmission Raman Spectroscopy 1684.5.2.1.2 A Practical Guide to a Successful Business Case 1714.5.3 Transmission Raman Spectroscopy – Another Practical Guide 1734.5.3.1 Evaluation Phase 1744.5.3.1.1 Prefeasibility Evaluation 1744.5.3.1.2 Feasibility of a Product 1764.5.3.2 Transmission Raman Method Development 1774.5.3.2.1 Transmission Raman Spectroscopic Method Development 1774.5.3.2.2 Risk Analysis 1794.5.3.2.3 Transmission Raman Model Development, Calibration, and Validation 1804.5.4 Regulatory Assessment and Guidelines 180List of Abbreviations 181References 1824.6 Solid-state Characterization Techniques: Particle Size 185Maria Paisana and Constança Cacela4.6.1 Introduction 1854.6.2 Analytical Methodologies Used to Measure Particle Size 1874.6.2.1 Sedimentation 1874.6.2.2 Electrozone Sensing 1874.6.2.3 Sieving 1884.6.2.4 Microscopy 1884.6.2.5 Dynamic Light Scattering 1884.6.2.6 Laser Diffraction 1894.6.3 Method Development for Precise Particle-size Measurements by Laser Diffraction 1894.6.3.1 Instrumentation and Measurement 1894.6.3.2 Selection of an Appropriate Optical Model 1904.6.3.3 Sample Dispersion 1914.6.3.3.1 Wet Dispersion 1924.6.3.3.2 Dry Dispersion 1944.6.3.4 Sample Representativeness and Obscuration 1954.6.3.5 Readiness for Method Validation 1964.6.4 Unexpected Results and Troubleshooting in Laser Diffraction Measurement 1974.6.4.1 Inconsistent Disconnected Peaks 1974.6.4.2 Repeatable Artifact Peaks 199List of Abbreviations 199References 2004.7 Micro Computational Tomography 203Susana Campos and Constança Cacela4.7.1 Tomography Imaging Techniques 2034.7.2 Micro X-ray Computed Tomography Scan 2034.7.2.1 The Use of CT in the Pharmaceutical Industry 2044.7.2.1.1 μCT Applied to Density Distribution and Porous Characterization 2054.7.2.1.2 μCT Applied for Characterization of Structural Features: Size, Shape, and Dimensions and Interfaces 2074.7.2.1.3 μCT Applied to Coating Characterization 2074.7.2.1.4 μCT Applied to Performance Evaluation 2094.7.2.1.5 Foreign Matter Detection by μCT 210List of Abbreviations 211Notes 211References 2114.8 In Situ Methods for Monitoring Solid-State Processes in Molecular Materials 215Adam A. L. Michalchuk, Anke Kabelitz, and Franziska Emmerling4.8.1 In Situ Methods for Monitoring Solid-State Processes in Molecular Materials 2154.8.1.1 The Complexity of Solid Materials 2154.8.1.2 Methods to Consider 2164.8.1.3 Methods to Monitor Crystallization Kinetics from Solution 2184.8.1.3.1 UV–Vis Spectroscopy 2184.8.1.3.2 Infrared Spectroscopy 2194.8.1.4 Monitoring Crystallization from Solution: Following Solid Product Formation 2214.8.1.4.1 Light Scattering 2214.8.1.5 Methods to Monitor Extrinsic Solid Properties 2244.8.1.5.1 Acoustic Emission 2244.8.1.5.2 Thermography 2264.8.1.6 Methods to Monitor Intrinsic Solid Properties 2284.8.1.6.1 X-ray Diffraction 2284.8.1.6.2 Raman Spectroscopy 2324.8.1.7 Benefits of Combining Methods for In Situ Monitoring 2364.8.1.8 Summary 240List of Abbreviations 242References 2434.9 Application of Process Monitoring and Modeling 249Jochen Schoell and Roberto Irizarry4.9.1 In-process Solid Form Monitoring Techniques 2494.9.1.1 Direct Characterization Techniques 2504.9.1.1.1 Raman Spectroscopy 2504.9.1.1.2 Near Infrared Spectroscopy 2524.9.1.2 Indirect Monitoring Tools 2544.9.1.2.1 Focused Beam Reflectance Measurement (FBRM) 2544.9.1.2.2 Monitoring Particle Shape Using In-process Microscopy 2564.9.1.2.3 Monitoring Solute Concentration 2564.9.1.3 Advantages and Challenges of In Situ Solid Form Monitoring Techniques 2574.9.2 Quantification Methods and Application to Solid Form Transformation Modeling 2584.9.2.1 Multivariate Data Analysis 2594.9.2.2 Data-driven Model for CLD–PSD Prediction 2604.9.2.3 Process Modeling of Polymorph Transformation Processes 262List of Abbreviations 265References 2664.10 Photon Density Wave (PDW) Spectroscopy for Nano- and Microparticle Sizing 271Lena Bressel and Roland Hass4.10.1 Classification of Particle Sizing Technologies 2714.10.2 Particle Size and Solid Fraction Ranges 2724.10.3 Photon DensityWave (PDW) Spectroscopy – Theory, Instrumentation, and Application Examples 2754.10.4 Particle Sizing by PDWSpectroscopy 2774.10.5 Sample Versus Process Measurements 2804.10.6 Technical Implementation and Data Access 2814.10.7 Examples for Process Analysis with PDWSpectroscopy 2824.10.7.1 Crystallization of Lactose 2834.10.7.2 Precipitation of Barium Sulfate 2844.10.8 Summary 285List of Abbreviations 286References 2875 Impact of Solid Forms on API Scale-Up 289Sophie Janbon, Clare Mayes, and Amy L. Robertson5.1 Introduction 2895.2 Background 2905.3 Small-Scale Crystallization Development 2915.3.1 Form Selection 2915.3.2 Solvent Selection 2935.3.2.1 Solvent Screening 2935.3.2.2 Solubility Diagram 2945.3.2.3 Solubility Measurement 2955.3.3 Crystallization Process Selection 2985.3.3.1 Process Outline Selection 2985.3.3.2 Process Outline Evaluation 2995.3.3.3 Process Exploration 3005.3.4 Process Development Conclusions 3025.4 Crystallization Scale-Up 3025.4.1 Crystallization Process Accommodation 3035.4.1.1 Vessel Size and MoC 3045.4.1.2 Agitation 3045.4.1.3 Heat Transfer 3055.4.1.4 Solution Addition 3055.4.1.5 Solid Addition 3055.4.1.6 Alternative Technologies 3065.4.2 Risks and Common Problems 3075.4.2.1 Metastable Forms 3075.4.2.2 Amorphous 3075.4.2.3 Salt Stoichiometry 3085.4.2.4 Oiling and Phase Separations 3085.4.3 Isolation and Drying 3085.4.3.1 Isolation 3095.4.3.2 Drying 3115.4.4 Agglomeration 3145.4.5 Particle Size Reduction 3145.4.5.1 Delumping 3145.4.5.2 Milling and Micronization 3145.4.5.3 Storage and Packing 3155.4.6 Scale-up Conclusions 3155.5 People and Skill Requirements 3155.6 Regulatory Requirements 3155.6.1 Process Documentation 3165.6.2 Safety 3165.6.3 Quality and Manufacturability 3165.7 Closing Remarks 317List of Abbreviations 318References 3186 Impact on Drug Development and Drug Product Processing 325Susanne Page and Anikó Szepes6.1 Introduction 3256.2 Pharmaceutical Profiling 3276.3 Formulation Development 3306.3.1 Liquid Formulations: Solutions and Suspensions 3326.3.2 Solid Dosage Forms 3356.3.3 Solubility Enhanced Formulations 3396.3.3.1 Lipid-Based Formulations and Drug Delivery Systems 3396.3.3.2 Solid Solutions and Amorphous Solid Dispersions 3436.4 Process Development and Transfer to Commercial Manufacturing 3446.4.1 Particle Size Reduction 3456.4.2 Blending 3456.4.3 Granulation 3456.4.3.1 Wet Granulation and Drying 3466.4.3.2 Dry Granulation/Roller Compaction 3476.4.4 Tablet Compression 3476.4.5 Film Coating 3486.5 Control Strategy 3486.6 Regulatory Submissions 349List of Abbreviations 352References 3537 Workflow Management 365Christian Große7.1 Motivation 3657.2 Workflow Management 3657.3 Organization of Solid-State Development by Project Management 3667.3.1 Stakeholders 3667.3.2 CMC Project Management 3677.3.3 Substance Requirement Plan 3687.3.4 Pre-CMC Data 3697.4 Workflows in the Environment of the Crystallization Laboratory 3697.4.1 Micro-Project Management 3697.4.2 Dependencies 3707.4.3 Material Flow 3717.4.4 Designations and Code Assignment 3717.4.5 Analytic Database System 3737.4.6 Physical Sample Transfer 3757.4.7 Analytic Transfer Tool 3757.4.8 Analytical Processes – Timely Measurement 3767.4.9 Sample Storage Processes 3777.4.10 Documentation 3787.4.11 Review Process for ELN Documents 3797.4.11.1 Document Status 3797.4.11.2 Manual ELN Review Process 3807.4.11.3 Archive Process 3817.4.12 Communication with CROs 3817.4.13 Fundamental Lab Processes 3827.5 Processes in the Solid-State Lab 3827.5.1 Initial Testing 3827.5.2 Solubility Estimation 3847.5.3 Manual Screening 3847.5.4 High-Throughput Screening 3857.5.5 Processes for Replica Experiments and Scale-Up of Solid Forms 3877.6 Development of Crystallization Processes 3877.7 Support Processes 3887.7.1 Route Scouting Process 3897.7.2 Crystallization of Impurities and Intermediates 3897.7.3 Downstream Processes 3897.7.4 Scale-Up and Technology Transfer Process 3907.7.5 Analytical Development 3907.7.6 Preformulation 3917.7.7 Formulation 3917.8 Conclusion 392List of Abbreviations 393References 3938 Digitalization in Laboratories of the Pharmaceutical Industry 397Tanja S. Picker8.1 Introduction 3978.2 Motivation of Digitalization in the Laboratory 3988.2.1 Expectations of the Staff 3988.2.2 Increasing Throughput 4008.2.3 Repeatability 4008.2.4 Enhanced Requirements on Data Integrity 4008.2.5 Centralized Archiving 4018.2.6 Ad Hoc Analysis 4018.2.7 The Value of Data 4028.3 Categories of Laboratory IT Systems 4038.3.1 Devices 4038.3.2 Lab Execution Systems (LES) and Scientific Data Management Systems (SDMS) 4048.3.3 Lab Data Systems 4048.3.4 Enterprise Resource Planning (ERP) 4058.3.5 Further Use of Data 4058.3.5.1 Data Analysis and Reporting 4058.3.5.2 Big Data Analytics and Artificial Intelligence 4068.4 System Interfaces for Data Exchange 4068.4.1 Adapters 4078.4.1.1 Serial Port (RS232) 4078.4.1.2 Universal Series Bus (USB) 4078.4.1.3 Ethernet 4078.4.1.4 Cable Less Connections 4078.4.2 Communication Medium and Protocols 4088.4.2.1 File-Based Communication 4088.4.2.2 ANSI/ISA-88 Batch Control (S-88) 4088.4.2.3 Open Platform Communications Unified Architecture (OPC UA) 4088.4.2.4 Standards in Lab Automation (SiLA) 4088.4.3 Data Formats 4098.4.3.1 Common Data Formats (e.g. TXT, XML, JSON) 4098.4.3.2 Analytical Information Markup Language (AnIML) 4098.4.3.3 Allotrope Data Format (ADF) 4108.5 Implementation of IT Solutions 4118.5.1 Identification of Digital Gaps in the Lab Processes 4118.5.1.1 Contextual Inquiry 4118.5.1.2 Interaction Room 4118.5.2 Implementation Approach 4128.5.2.1 Design 4138.5.2.2 Realization 4158.5.2.3 Verification 4158.5.2.4 Rollout 4168.6 Conclusion 416List of Abbreviations 416References 4179.1 Polymorphs and Patents – the US Perspective 421Kristi McIntyre9.1.1 Introduction 4219.1.2 What is a Patent? 4219.1.3 How Are Patents Obtained? 4229.1.4 United States Patent Law 4229.1.4.1 Tapentadol Hydrochloride 4239.1.4.1.1 Tapentadol Hydrochloride Form A Held Not Obvious 4239.1.4.1.2 Tapentadol Hydrochloride Form AWas Found to Have Utility 4249.1.4.2 Paroxetine Hydrochloride Hemihydrate 4249.1.4.2.1 PHC Hemihydrate History 4259.1.4.2.2 Meaning of “Crystalline Paroxetine Hydrochloride Hemihydrate” 4259.1.4.2.3 PHC Hemihydrate: Infringed, But Invalid for Anticipation 4269.1.4.3 Ranitidine Hydrochloride 4269.1.4.3.1 History of RHCl Form 2 4269.1.4.3.2 RHCl Form 2 Not Anticipated by Example 32 4279.1.4.4 Cefdinir 4279.1.4.5 Amlodipine Besylate 4289.1.4.5.1 History of Amlodipine Besylate 4289.1.4.5.2 Amlodipine Besylate Found Obvious 4289.1.4.6 Concluding Remarks 429Notes 429References 4309.2 Polymorphs and Patents – The EU Perspective 431Oliver Brosch9.2.1 European Patent Applications and European Patents 4319.2.1.1 Introduction 4319.2.1.2 Summary of the Processing of Applications and Patents Before the European Patent Office (EPO) 4319.2.1.3 Economic Factors 4329.2.1.4 Unitary Patents 4339.2.1.5 Protection of Polymorphs and Solid Forms in General 4339.2.1.6 Polymorph Screening 4349.2.2 Decisions of Technical Boards of Appeal of the EPO 4359.2.2.1 Decision T 777/08 of 24 May 2011 4359.2.2.2 Decision T 1555/12 Dated 29 April 2015 4359.2.2.3 Decision T 2114/13 Dated 12 October 2016 4429.2.2.4 Decision T 2397/12 Dated 12 March 2018 4429.2.2.5 Decision T 246/15 Dated 13 November 2018 4429.2.3 Jurisdiction of the Federal Patent Court and the German Federal Supreme Court 4439.2.3.1 Decision “Kristallformen” German Federal Court 4439.2.3.2 Decision X ZR 58/08 Dated 15 March 15 2011 4439.2.3.3 Decision X ZR 98/09 Dated 15 May 2012 4449.2.3.4 Decision X ZR 110/16 Dated 7 August 2018 4449.2.4 Assessing Validity of a Patent or the Chances of Success 4459.2.5 Interaction with Patent Professionals 446List of Abbreviations 447References 44710 Regulatory Frameworks Affecting Solid-State Development 449Christoph Saal10.1 Introduction – The Need for Regulation in Pharmaceutical Industry 44910.2 Solid-State Forms to Be Used for Drugs 45110.3 General Regulatory Considerations for Pharmaceutical Solid-State Forms 45310.4 Regulatory Framework for Pharmaceutical Salts 45410.4.1 Pharmaceutical Equivalence and Pharmaceutical Alternatives 45410.4.2 Bioequivalence 45610.4.3 Therapeutic Equivalence 45810.4.4 Biowaivers 45810.4.5 Regulatory Approval for Pharmaceutical Salts 46010.4.5.1 Regulatory Approval Pathways in the United States 46010.4.5.2 Regulatory Approval Pathways in the European Union 46110.4.6 Regulatory Approval for Polymorphs 46310.4.7 Polymorphism in Pharmacopoeias 46910.5 Regulatory Framework for Co-crystals 47110.6 Summary 476List of Abbreviations 476References 47711 Opportunities and Challenges for Generic Development from a Solid-state Perspective 481Judith Aronhime and Mike Teiler11.1 The Birth of a New Drug and the Generic Siblings that Will Follow – Two Different Mindsets 48111.1.1 Generics 48111.1.2 Proprietary Products 48211.1.3 API and Solid State 48311.1.3.1 Generics 48311.1.3.2 Proprietary 48311.2 Portfolio Management – How is a Portfolio Constructed and Maintained? 48411.2.1 Activities and Timelines 48411.2.1.1 Strategy 48411.2.1.2 Value 48411.2.1.3 Factors Impacting on Timing – When and How Does a Product Show Up on a Generic Company’s Radar Screen? 48511.2.2 Timing 48711.2.2.1 When is “On-time?” 48711.2.3 Market-specific Considerations Based on Local Legislation and Administration (OB, PIV, Various Exclusivities – US, EU, JP, etc.) 48911.2.3.1 Patents Through the Eyes of the Regulatory Authorities 48911.2.3.2 Data Exclusivity (Data Protection) 48911.2.3.3 Salts and Esters 49011.2.3.4 Think Global, Act Local 49011.2.4 Sources to Evaluate a Project 49111.2.4.1 Government and Regulatory Agencies 49111.2.4.2 Analyst Reports and Company Financial Reports 49211.2.4.3 Pay Data Sources 49211.2.5 Evaluation Tools 49311.2.5.1 Business Case 49311.2.5.2 Quality Target Project Profile (QTPP) 49311.2.6 Criteria for Identifying Promising Projects 49311.2.7 Criteria for Building a Robust Portfolio 49411.3 Challenges in Developing a Generic Product from the Solid-state Perspective 49511.3.1 Implications in Developing Formulation with a Metastable API 49611.3.2 The Stability Question 49711.3.2.1 Polymorphic Stability in Dry Conditions 49711.3.2.2 Polymorphic Stability inWet Conditions (Slurry) 49811.4 Generic Solid-state Development 49811.4.1 General 49811.4.2 Predevelopment Phase: Solid-state Strategy 49911.4.2.1 Review of the Solid State, Especially the Polymorph Patent Landscape 49911.4.2.2 Design-around Considerations 50011.4.3 Crystal Forms Discovery 50311.4.3.1 Importance of the Crystal Forms Discovery Stage 50311.4.3.2 New Crystal Forms Unpredictability 50311.4.3.3 Pragmatic Questions About Crystal Forms Search 50411.4.3.4 Late-appearing Polymorphs 50511.4.3.5 Irreproducibility of Procedures 50611.4.3.6 Analytical Focus 50711.4.4 Target Selection 50711.4.4.1 Solubility 50811.4.4.2 Morphology 50911.4.4.3 Solid-state Stability 50911.4.4.4 Additional Factors 50911.4.5 Process Development in the Laboratory Scale 51011.4.5.1 Process Development 51011.4.5.2 Thermodynamic Stability Relationships 51011.4.5.3 Solubility Curves 51011.4.5.4 API Target 51111.4.5.5 Analytical Methods for Polymorphic Purity 51211.4.6 Scale-up Challenges 51211.4.6.1 Control of Crystal Form 51211.4.6.2 Control of Particle Size and Morphology 51311.4.6.3 Lot-to-Lot Variability 51311.4.6.4 Analytical Focus 51411.4.7 Pharma Development 51511.4.7.1 The Tetrahedron Principle and Consistency Among Lots 51611.4.7.2 The Effect of Micronization on Amorphous Content in Crystalline APIs 51611.4.7.3 Solid-state Stability upon Storage 51711.4.8 Impact on Formulation 51711.4.9 Summary of Timelines for Solid-state Activity 51811.4.10 Intellectual Property (IP) Strategies and Activities 51911.5 Success Factors 52011.5.1 Successful Biostudy 52011.5.2 Successful Launch 52111.5.3 Generic Commercial Success 522List of Abbreviations 523References 524Index 531