Solid-State Materials in Pharmaceutical Chemistry

Updated and expanded information on the properties of pharmaceutical solids and their impact on drug product performance, quality, and stability

Solid-State Materials in Pharmaceutical Chemistry provides readers with a comprehensive and up-to-date resource for understanding and controlling the solid-state properties of pharmaceutical materials, enabling the development of safe and effective medicines including small molecule compounds, peptides, proteins, and nucleotides. This new edition covers the significant transformations in the landscape of pharmaceutical research, development, and manufacturing since the previous edition was published, presenting both novel challenges and unprecedented opportunities.

New chapters in this edition cover physical and chemical properties of RNA therapeutics, a frontier to many life-saving medicines and vaccines including Covid vaccines, and final stage drug substance manufacturing and control, addressing challenges in API process development including impurity purging, chiral separation, final form preparation, particle size reduction, and nitrosamine control. Readers will also find other updated topics including bulk and surface properties of solids, lipid nanoparticles, applications of pharmaceutical solvates in impurity purging and final form preparation, pharmaceutical cocrystal engineering to enable chiral separation, the emerging technique of microcrystal electron diffraction in solid form characterization, poor wettability of APIs, oral delivery of peptides such as semaglutide, injectable drug-device combination products, and N-nitrosamine control in drug product.

This updated and revised Second Edition still features:

• Physical and chemical properties of solid-state pharmaceuticals such as amorphous forms, mesophases, polymorphs, hydrates/solvates, salts, co-crystals, nano-particles, and solid dispersions
• Characterization techniques for solid form identification and physical attribute analysis such as X-Ray powder diffraction, thermal analysis, microscopy, spectroscopy, solid state NMR, particle analysis, water sorption, mechanical property testing, solubility, and dissolution
• Applications of pharmaceutical chemistry and physical characterization techniques in developing and testing drug substances and drug products for small molecules and biopharmaceuticals

This book is an essential resource on the subject for formulation scientists, process chemists, medicinal chemists, and analytical chemists. The book will also appeal to quality control, quality assurance, and regulatory affair specialists and advanced undergraduate and graduate students in pharmaceutical chemistry, drug delivery, material science, crystal engineering, pharmaceutics, and biopharmaceutics.

Biography of Authors xv

Preface xvii

Preface to the First Edition xvii

Acknowledgment xix

1 Solid-State Properties and Pharmaceutical Development 1

2 Polymorphs 27

3 Pseudopolymorphs: Hydrates and Solvates 49

4 Pharmaceutical Salts 65

5 Pharmaceutical Cocrystals 81

6 Amorphous Solids 97

7 Crystal Mesophases and Nanocrystals 121

8 X-Ray Crystallography and Crystal-Packing Analysis 131

9 X-Ray Powder Diffraction 139

10 Differential Scanning Calorimetry and Thermogravimetric Analysis 159

11 Microscopy 181

12 Vibrational Spectroscopy 203

13 Solid-State NMR Spectroscopy 227

14 Particle and Powder Analysis 247

15 Hygroscopic Properties of Solids 267

16 Mechanical Properties of Pharmaceutical Materials 287

17 Solubility and Dissolution 307

18 Physical Stability of Solids 329

19 Chemical Stability of Solids 349

20 Solid-State Properties of Proteins 375

21 Physical and Chemical Properties of RNA Therapeutics 389

22 Solid Form Selection of Active Pharmaceutical Ingredients 411

23 Final Stage Drug Substance Manufacturing and Control 431

24 Solid-State Mixture Analysis 455

25 Drug Product Development 479

26 Quality by Design 511

Index 527

Stephen R. Byrn, PhD, Charles B. Jordan Professor of Medicinal Chemistry in the Department of Industrial and Molecular Pharmaceutics, Purdue University.

George Zografi, PhD, Edward Kremers Professor Emeritus of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison.

Xiaoming (Sean) Chen, PhD, works in the field of pharmaceutical product development and held various positions at Schering-Plough, OSI Pharmaceuticals, Astellas Pharma, Shionogi Inc, Antares Pharma, Arvinas, and Improved Pharma.

Updated and expanded information on the properties of pharmaceutical solids and their impact on drug product performance, quality, and stability

Solid-State Materials in Pharmaceutical Chemistry provides readers with a comprehensive and up-to-date resource for understanding and controlling the solid-state properties of pharmaceutical materials, enabling the development of safe and effective medicines including small molecule compounds, peptides, proteins, and nucleotides. This new edition covers the significant transformations in the landscape of pharmaceutical research, development, and manufacturing since the previous edition was published, presenting both novel challenges and unprecedented opportunities.

New chapters in this edition cover physical and chemical properties of RNA therapeutics, a frontier to many life-saving medicines and vaccines including Covid vaccines, and final stage drug substance manufacturing and control, addressing challenges in API process development including impurity purging, chiral separation, final form preparation, particle size reduction, and nitrosamine control. Readers will also find other updated topics including bulk and surface properties of solids, lipid nanoparticles, applications of pharmaceutical solvates in impurity purging and final form preparation, pharmaceutical cocrystal engineering to enable chiral separation, the emerging technique of microcrystal electron diffraction in solid form characterization, poor wettability of APIs, oral delivery of peptides such as semaglutide, injectable drug-device combination products, and N-nitrosamine control in drug product.

This updated and revised Second Edition still features:

• Physical and chemical properties of solid-state pharmaceuticals such as amorphous forms, mesophases, polymorphs, hydrates/solvates, salts, co-crystals, nano-particles, and solid dispersions
• Characterization techniques for solid form identification and physical attribute analysis such as X-Ray powder diffraction, thermal analysis, microscopy, spectroscopy, solid state NMR, particle analysis, water sorption, mechanical property testing, solubility, and dissolution
• Applications of pharmaceutical chemistry and physical characterization techniques in developing and testing drug substances and drug products for small molecules and biopharmaceuticals

This book is an essential resource on the subject for formulation scientists, process chemists, medicinal chemists, and analytical chemists. The book will also appeal to quality control, quality assurance, and regulatory affair specialists and advanced undergraduate and graduate students in pharmaceutical chemistry, drug delivery, material science, crystal engineering, pharmaceutics, and biopharmaceutics.