Formulation and Analytical Development for Low-Dose Oral Drug Products

There are unique challenges in the formulation, manufacture, analytical chemistry, and regulatory requirements of low-dose drugs. This book provides an overview of this specialized field and combines formulation, analytical, and regulatory aspects of low-dose development into a single reference book. It describes analytical methodologies like dissolution testing, solid state NMR, Raman microscopy, and LC-MS and presents manufacturing techniques such as granulation, compaction, and compression. Complete with case studies and a discussion of regulatory requirements, this is a core reference for pharmaceutical scientists, regulators, and graduate students.

Autorentext
Jack Zheng, PhD, is Research Advisor and Team Leader in the Pharmaceutical Sciences R&D Division of Eli Lilly and Company and Adjunct Professor at Beijing University. Dr. Zheng is the author of more than thirty articles and several book chapters. He has been invited to present his work at numerous national and international scientific meetings. He was involved in more than ten new drug product development and regulatory filing with the Food and Drug Administration.

Klappentext
Tested-and-proven strategies for developing and manufacturing low-dose oral drug products Developing and commercializing a low-dose oral drug product presents a number of hurdles that can quickly offset the drug's benefits. Written by a team of leading scientists in drug development, this book collects and synthesizes the knowledge, techniques, and strategies needed for developing low-dose drugs successfully. With this book's practical support, readers can overcome the hurdles at all stages in drug development, from formulation to manufacturing and control to regulatory compliance.

Following an overview of the drug discovery and development process, the book is divided into four parts:

• Part One examines formulation and process development of low-dose drugs, including theoretical considerations concerning the particle size of the drug substance and content uniformity, micronization of the drug substance, and manufacturing platform technologies.

• Part Two focuses on challenges in analytical method development, including analytical control strategy, physical characterization of the micronized powder and the solid state of the active pharmaceutical ingredient in dosage forms, and cleaning verification of manufacturing equipment.

• Part Three investigates containment technologies used in analytical laboratories and manufacturing plants.

• Part Four deals with important regulatory considerations.

Readers learn how a variety of analytical methodologies are used in low-dose drug development, including dissolution testing, NMR, HPLC, and X-ray diffraction. Moreover, the book explains several possible manufacturing techniques, such as wet granulation, roller compaction, and direct compression alongside containment technologies for highly potent drugs. Case studies throughout the book demonstrate how particular strategies and techniques are applied in practice.

Pharmaceutical scientists as well as students will find overcoming the obstacles in developing low-dose drug products much easier when they have this book on hand to consult at all stages in the drug development and manufacturing process.

Inhalt

Preface xv

Foreword xix

Contributors xxi

**1 An Overview 1
**Jack Y. Zheng

1.1 The Drug Discovery and Development Process 2

1.2 Challenges and Strategies in Development of Low-Dose Drug Products 10

1.3 Summary 20

Acknowledgments 20

References 20

I Challenges and Strategies In Formulation Development of Oral Low-Dose Drug Products 23

**2 Challenges and Strategies In Formulation Development of Oral Solid Low-Dose Drug Products 25
**Jack Y. Zheng

2.1 Introduction 25

2.2 Current Regulatory Environment and its Impact on New Drug Product Development 28

2.3 Challenges in Developing Low-Dose Formulations 31

2.4 Manufacturing Platforms for Low-Dose Drug Products 38

2.5 Use of Experimental Design in Formulation and Process Development 42

2.6 Containments 44

2.7 Summary 45

Acknowledgments 46

References 46

**3 Particle Size of Drug Substance and Product Content UniformityTheoretical Considerations 49
**Kevin C. Johnson

3.1 Introduction 49

3.2 Concept of Ideal Mixing 50

3.3 Ideal Mixing Model Comparison with the Yalkowsky and Bolton Approach 56

3.4 Experimental Support of Model Assumptions 59

3.5 Analytical and Practical Considerations 61

References 62

**4 Development of Low-Dose Formulations Using Fluidized Bed Granulation 63
**J. Joe Zhou and Ralph Lipp

4.1 Introduction 63

4.2 Granulation Fundamentals 66

4.3 Theory of Fluidization 68

4.4 Formulation Development 72

4.5 Process Development 77

4.6 Summary 86

References 86

**5 Development of Low-Dose Solid Oral Formulations Using Wet Granulation 89
**Ahmad Almaya

5.1 Introduction 89

5.2 Granulation Mechanisms 91

5.3 General Considerations on Wet Granulation 93

5.4 Advantages and Disadvantages of Wet Granulation 100

5.5 Use of Wet Granulation for Low-Dose Formulations 101

5.6 Process-Induced Form Changes in Wet Granulation 109

5.7 Concluding Remarks 111

References 112

**6 Challenges In Development and Scale-Up of Low-Dose Drug Products By Dry Granulation: A Case Study 117
**Mary T. Am Ende, Daniel O. Blackwood, Daniel S. Gierer, and Christopher P. Neu

6.1 Introduction 117

6.2 Dry Granulation ProcessPros and Cons 118

6.3 Overview of Dry Granulation Processes and Equipment Design 119

6.4 Challenges for Low-Dose Product Development and their Assessment Methods 125

6.5 Case Study: Formulation Challenges for Low-Dose Products 128

6.6 Process Challenges During Dry Granulation Optimization for Low-Dose Products 140

6.7 Conclusions 154

Acknowledgments 155

References 155

**7 Development of Low-Dose Solid Oral Tablets Using Direct Compression 159
**Jack Y. Zheng and Robert L. Ternik

7.1 Introduction 159

7.2 Advantages of Direct Compression 160

7.3 Challenges in Low-Dose Tablet Development Using Direct Compression 162

7.4 Formulation Development for Low-Dose Drug Products Using Direct Compression 169

7.5 Manufacturing Process Development for Low-Dose Drug Products 187

7.6 Scale-Up for Blending Operation 196

7.7 Formulation Examples for Direct Compression 197

7.8 Conclusions 199

Acknowledgments 199

References 200

**8 Reduction of Particle Size of Drug Substance For Low-Dose Drug Products 205
**Christopher L. Burcham, Paul C. Collins, Daniel J. Jarmer, and Kevin D. Seibert

8.1 Introduction 205

8.2 Reduction of Particle Size of Drug Substance by Milling Technologies 207 8.3 Reduction of Particle Size of Drug Substance Using Crystalliz...