Integrated pharmaceutics : applied preformulation, product design, and regulatory science /
Antoine Al-Achi, Mali Ram Gupta, William C. Stagner.
- Second edition.
- 1 online resource.
Includes bibliographical references and index.
Table of Contents Foreword to Second Edition xv
Foreword to First Edition xvi
Preface to Second Edition xvii
Preface to First Edition xviii
About the Companion Website xx
Part I Applied Preformulation 1
1 Mathematical Concepts 3
1.1 Introduction 3
1.2 Significant Figures and Rounding off Numbers 3
1.3 The Simple Linear Relationship 4
1.4 Exponential Rules 6
1.5 Logarithmic Rules 6
1.6 Differential Equations 7
1.7 Expanding and Reducing Formulas 9
1.8 Weights and Measures 9
References 10
Glossary 10
2 Thermodynamics 11
2.1 Introduction 11
2.2 The Zeroth Law of Thermodynamics 11
2.3 The First Law of Thermodynamics 11
2.4 The Second Law of Thermodynamics 12
2.5 The Third Law of Thermodynamics 13
2.6 Polymorphism 13
2.7 Physical Stability of Crystal Forms 14
2.8 Solubility 14
References 15
Glossary 16
3 Solubility and Dissolution 18
3.1 Introduction 18
3.2 Methods of API Solubility Enhancement 19
3.3 Nonionic, Ionic, and Acid–Base Concepts Related to Solubility and Dissolution 29
3.4 The Solubility of Gas in Liquid 29
3.5 The Solubility of Liquid in Liquid 30
3.6 The Solubility of Solid in Liquid 30
3.7 Disintegration and Dissolution 31
3.8 Concentration Units 34
3.9 The Partition Coefficient 39
3.10 Concluding Remarks 41
References 41
Glossary 44
Appendix 45
4 Biological Aspects of Formulations 46
4.1 Introduction 46
4.2 Bioavailability and Bioequivalence 46
4.3 Protocols for Determining Bioequivalence 48
4.4 Bioequivalence Procedure 49
4.5 FDA-Approved Methods for Bioequivalence Studies 49
4.6 Approaches to Improving Bioavailability 50
References 52
Glossary 53
5 Interfacial Properties 54
5.1 Introduction 54
5.2 Liquid–Solid Interface 54
5.3 Liquid–Liquid Interface 55
5.4 Dosage-Form Applications 55
5.5 Case Study: HLB Determination 58
5.6 Case Study: Determination of Required HLB (rHLB) 58
References 58
Glossary 59
6 Adsorption Phenomenon 60
6.1 Introduction 60
6.2 Adsorption on Filters 66
6.3 Adsorption of Proteins 66
References 66
Glossary 68
7 Rheological Principles 69
7.1 Introduction 69
7.2 Newtonian Systems 69
7.3 Non-Newtonian Systems 70
7.4 Viscoelasticity 72
7.5 Reynolds Number 74
7.6 Concluding Remarks 76
References 76
Glossary 77
8 Chemical Stability and Shelf-Life Determination 78
8.1 Introduction 78
8.2 Shelf-Life Determination 79
8.3 Stability of Biotechnology Products 84
8.4 Compounded Products and Their Beyond-Use Dates 86
References 102
Glossary 107
9 Particle Science 108
9.1 Introduction 108
9.2 Miromeritics 108
9.3 Micronization 113
9.4 Particle Size Preparation and Reduction for Pulmonary Delivery 114
9.5 Polymeric Particulate Matter 115
9.6 Nanoparticles 116
9.7 Segregation of Particles 121
9.8 Case Studies: Microscopic Particle Size Analysis, Determining Statistically Valid Sample Size, and Comparison of Sieve and Focused Beam Reflectance Measurement Chord Length Particle Size Distributions 122
References 126
Glossary 129
10 Basic Statistics and Design of Experimental Concepts 130
10.1 Descriptive Statistics 130
10.2 Inferential Statistics 131
10.3 Statistical Applications in Quality Control Testing 135
10.4 Design of Experiment 136
10.5 Multivariate Analysis (MVA) 140
10.6 Reliability and Validity Assessment 152
References 155
Glossary 155
11 Formulation Development Concepts 157
11.1 Preformulation 157
11.2 Scale-up Considerations 164
11.3 Combination Products 168
11.4 Rate-Controlled Drug Delivery 170
11.5 Drug Delivery Technologies for Improving Oral Delivery 172
11.6 Drug Delivery Technologies for Improving Transmucosal Delivery 173
11.7 Drug Delivery Technologies for Transdermal Delivery 173
11.8 Special Considerations for Biotechnology and Protein Delivery Systems 174
11.9 Drug–Excipient and Excipient–Excipient Interactions 177
11.10 The Presence of Contaminants in a Formulation 178
11.11 Other Considerations 179
References 179
Glossary 184
Part II Product Design 187
12 The Product Design Process 189
12.1 Introduction 189
12.2 Formulation Design 191
12.3 Process Design 194
12.4 Container Closure System Design 195
References 196
Glossary 198
12.A Appendix 199
13 Tablet Product Design 214
13.1 Introduction 214
13.2 Formulation Design 220
13.3 Process Design 225
13.4 Container Closure System Design 249
13.5 Risk Management 255
13.6 Attribute Tests 256
13.7 New Drug Application Stability Assessment 257
References 259
Glossary 264
13.A Appendix 265
14 Capsule Product Design 274
14.1 Introduction 274
14.2 Hard-Shell Capsules 274
14.3 Soft-Shell Capsules 288
14.4 Formulation and Process Optimization 291
14.5 Container Closure System Design 292
14.6 Risk Management 292
14.7 Attribute Tests 292
14.8 New Drug Application Stability Assessment 293
References 293
Glossary 295
14.A Appendix 296
15 Dispersed System Product Design 298
15.1 Introduction 298
15.2 Formulation Design 298
15.3 Process Design 322
15.4 Container Closure System Design 325
15.5 Risk Management 325
15.6 Attribute Tests 326
15.7 New Drug Application Stability Assessment 327
References 328
Glossary 330
Appendices 331
16 Aerosol Product Design 336
16.1 Introduction 336
16.2 Inhalation Formulation Design 338
16.3 Nasal, Buccal, Lingual, and Sublingual Aerosol Formulation Design 351
16.4 Container Closure System Design 354
16.5 Risk Management 356
16.6 Attribute Tests 356
16.7 New Drug Application Stability Assessment 359
References 363
Glossary 366
16.A Appendix 367
17 Sterile Injectable Product Design 369
17.1 Introduction 369
17.2 Formulation Design 370
17.3 Process Design 393
17.4 Container Closure System Design 404
17.5 Risk Management 407
17.6 Attribute Tests 407
17.7 New Drug Application Stability Assessment 408
References 409
Glossary 415
17.A Appendix 416
18 Ophthalmic Product Design 426
18.1 Introduction – Eye Anatomy and Physiology 426
18.2 Formulation Design 429
18.3 Process Design 436
18.4 Container Closure System Design 436
18.5 Attribute Tests 436
18.6 New Drug Application Stability Assessment 436
References 436
Glossary 438
18.A Appendix 438
19 Transdermal Product Design 442
19.1 Introduction – Skin Anatomy and Physiology 442
19.2 Formulation Design 444
19.3 Conclusions 457
References 457
Glossary 459
19.A Appendix 459
20 Oral Modified-Release Product Design 462
20.1 Introduction 462
20.2 FDA and U.S.P. Nomenclature 462
20.3 Modified-Release Mechanisms 464
20.4 In Vitro–In Vivo Correlations (IVIVC) 465
20.5 Coatings 466
20.6 Matrix Systems 467
20.7 Gastroretentive Devices 470
20.8 Osmotic-Controlled Release Systems 470
20.9 Conclusions 471
References 471
Glossary 472
20.A Appendix 473
Part III Regulatory Science 475
21 Regulatory Practices and Guidelines 477
21.1 Worldwide Regulatory Agencies 477
21.2 Good Manufacturing Practice (GMP) 484
21.3 FDA Inspection and Regulatory Actions (FDA 2020b, 2020d) 503
References 510
Glossary 511
21.A Appendix 519
22 Regulations for Compounding Pharmacies 525
22.1 Introduction 525
22.2 Sections 503A and 503B and Their Differences (FDA 2018a) 526
22.3 Compounding Guidelines 526
22.4 Good Compounding Practices (FDA 2007; Skoloff 2009; U.S.P <795> 2020: U.S.P <797> 2020); U.S.P. <1191> 2018; USP29 2006; USP29NF24 2006; OSBP 2017; NDBOPH 2020; NV 2020a; OR 2020; CPE 2017; OK 2020; KY 2016a; WA 2020a; FDA 2020a, 2020b) 527
22.5 Compounding Sterile Preparations (U.S.P. <797> 2020; WA 2020b; CT 2020; OR 2020; NV 2020b; OK 2020; KY 2016b; NYBOP (n.d.); ASPH 2003, 2020; TU n.d.) 532
22.6 Stability Criteria and Beyond-Use Dating of Compounded Non-Sterile Preparations (U.S.P. <797> 2020; WA 2020b; CT 2020; OR 2020; NV 2020b; OK 2020; KY 2016b; NYBOP (n.d.); ASPH 2003, 2020; TU n.d.) 536
34.5 Current Good Manufacturing Practice in Manufacturing, Packaging, Lableing, or Holding Operations for Dietary Supplements (21 CFR Part 111) (FDA 2019f) 741
34.6 FDA Inspection and Regulatory Actions (see – 21.3 FDA Inspection and Regulatory Actions – see Chapter 21 for details) 745
References 745
Glossary 745
34.A Appendix 746
35 Animal Drugs and Devices 751
35.1 FDA Center For Veterinary Medicine (CVM) (FDA 2019a) 751
35.2 Animal Drug Availability Act of 1996 (FDA 2019b) 751
35.3 Development and Approval Process (FDA 2017, 2020a) 752
35.4 CGMP and Others Compliance Requirements 756
35.5 Animal Drug Manufacturing Inspection – Pre-Approval (FDA 2006) 756
"This book provides a comprehensive introduction to the creation and manufacture of effective dosage forms for drug delivery. It presents its subject following the principles of physical pharmacy, product design, and drug regulations. This tripartite structure allows readers to move from theory to practice, beginning from a firm foundation of physical pharmacy principles, including drug solubility and stability estimation, rheology, and interfacial properties. From there, it proceeds to discussions of drug product design and of harmonizing pharmaceutical design with the regulatory regimens and technological standards of the United States, European Union, and Japan"--
About the Author Antoine Al-Achi, PhD, is a Professor of Pharmaceutical Sciences at the College of Pharmacy & Health Sciences at Campbell University in North Carolina. He is also a former track head of the Industrial Pharmacy graduate major and former Head of the Formulation Development Division of Campbell’s Pharmaceutical Sciences Institute.
Mali Ram Gupta, PhD, is an Associate Professor Emeritus of Pharmaceutical Sciences and Director of Pharmaceutical Education & Research (PERC) in the College of Pharmacy & Health Sciences Campbell University. Prior to joining Campbell in 2005, he spent over 25 years managing QA/QC departments of various pharma, cosmetic, and diagnostic companies.
William Craig Stagner, PhD, is a Professor Emeritus of Pharmaceutical Sciences at the College of Pharmacy & Health Sciences Campbell University. In his time at Glaxo Research Institute (1987-95), he established the Pharmaceutics Department.