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Pharmaceutical Dosage Forms and Drug Delivery
Pharmaceutical Dosage Forms and Drug DeliveryThird Edition: Revised and Expanded
byRam I. Mahato, PhD
Department of Pharmaceutical Sciences, University of Nebraska Medical Center
Omaha, NE
Ajit S. Narang, PhDSmall Molecule Pharmaceutical Sciences, Genentech, Inc.
One DNA Drive, South San Francisco, CA
CRC PressTaylor & Francis Group6000 Broken Sound Parkway NW, Suite 300Boca Raton, FL 33487-2742
© 2018 by Taylor & Francis Group, LLCCRC Press is an imprint of Taylor & Francis Group, an Informa business
No claim to original U.S. Government works
Printed on acid-free paper
International Standard Book Number-13: 978-1-4822-5362-7 (Hardback)
This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint.
Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers.
For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged.
Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe.
Library of Congress Cataloging‑in‑Publication Data
Names: Mahato, Ram I., author. | Narang, Ajit S., author.Title: Pharmaceutical dosage forms and drug delivery : third edition, revised and expanded / Ram I. Mahato and Ajit S. Narang.Description: Third edition. | Boca Raton : CRC Press, [2017] | Includes bibliographical references and index.Identifiers: LCCN 2017017702| ISBN 9781482253627 (hardback : alk. paper) | ISBN 9781315156941 (ebook)Subjects: LCSH: Drugs--Dosage forms. | Drug delivery systems.Classification: LCC RS200 .M34 2017 | DDC 615.1/9--dc23LC record available at https://lccn.loc.gov/2017017702
Visit the Taylor & Francis Web site athttp://www.taylorandfrancis.com
and the CRC Press Web site athttp://www.crcpress.com
CRC PressTaylor & Francis Group6000 Broken Sound Parkway NW, Suite 300Boca Raton, FL 33487-2742
© 2018 by Taylor & Francis Group, LLCCRC Press is an imprint of Taylor & Francis Group, an Informa business
No claim to original U.S. Government works
Printed on acid-free paper
International Standard Book Number-13: 978-1-4822-5362-7 (Hardback)
This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint.
Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers.
For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged.
Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe.
Library of Congress Cataloging‑in‑Publication Data
Names: Mahato, Ram I., author. | Narang, Ajit S., author.Title: Pharmaceutical dosage forms and drug delivery : third edition, revised and expanded / Ram I. Mahato and Ajit S. Narang.Description: Third edition. | Boca Raton : CRC Press, [2017] | Includes bibliographical references and index.Identifiers: LCCN 2017017702| ISBN 9781482253627 (hardback : alk. paper) | ISBN 9781315156941 (ebook)Subjects: LCSH: Drugs--Dosage forms. | Drug delivery systems.Classification: LCC RS200 .M34 2017 | DDC 615.1/9--dc23LC record available at https://lccn.loc.gov/2017017702
Visit the Taylor & Francis Web site athttp://www.taylorandfrancis.com
and the CRC Press Web site athttp://www.crcpress.com
I dedicate this book to my wife Subhashini, my children Kalika and Vivek for their love and support; my late mother Sarswati for believing in me; and to my students and mentors who have always helped me in my quest for learning and in achieving higher goals.
Ram I. Mahato
To Tirath Singh and Gurdip Kaur, my parents, who taught me simplicity, sincerity, and hard work.
Ajit S. Narang
vii
Contents
Foreword xxxiPreface xxxiiiAcknowledgments xxxvAbout the authors xxxvii
Part I Introductory chapters 1
1 Drug discovery 3
1.1 Introduction 31.1.1 Elements of drug discovery 41.1.2 Sources of drugs 6
1.1.2.1 Plant sources 61.1.2.2 Organic synthesis 71.1.2.3 Use of animals 71.1.2.4 Genetic engineering 71.1.2.5 Gene therapy 8
1.2 Collaborating disciplines 81.2.1 Biology 91.2.2 Chemistry 101.2.3 Pharmaceutics 111.2.4 Animal toxicology 111.2.5 Clinical pharmacology 121.2.6 Analytical and bioanalytical sciences 121.2.7 Regulatory sciences 13
1.3 Small- versus large-molecule paradigms 141.3.1 Preclinical discovery and toxicology assessment 171.3.2 Pharmaceutical development 181.3.3 Clinical development 18
viii Contents
1.4 Contemporary drug discovery case studies 181.4.1 Statins 181.4.2 Immuno-oncology 19
1.5 Summary and outlook to the future 21Review questions 21References 22Further reading 23
2 Drug development 25
2.1 Introduction 252.2 Stage-gate process of new drug discovery and development 29
2.2.1 Preclinical development 302.2.1.1 Physicochemical characterization 302.2.1.2 Efficacy studies 302.2.1.3 Toxicology studies 31
2.2.2 Clinical development 312.2.2.1 Phase I clinical trials 332.2.2.2 Phase II clinical trials 332.2.2.3 Phase III clinical trials 342.2.2.4 Evolving clinical development paradigms 34
2.3 Pharmaceutical development 352.3.1 Preformulation and formulation studies 362.3.2 Stage-appropriate drug product design 362.3.3 Stability 362.3.4 Bioavailability 372.3.5 Manufacturability 38
2.4 Regulatory approval 382.4.1 Investigational new drug application 392.4.2 New drug application 40
2.4.2.1 Basis of approval 402.4.2.2 Role of advisory committees 40
2.4.3 Biologics license application 412.4.4 Abbreviated new drug application 412.4.5 Biosimilars 422.4.6 Approval and postmarketing surveillance 422.4.7 Accelerated development/review 42
2.5 Postcommercialization activities 432.5.1 Manufacturing support 432.5.2 Intellectual property 432.5.3 Life cycle management 44
Contents ix
Review questions 45Further reading 47
3 Pharmaceutical considerations 49
3.1 Introduction 493.2 Advantages of pharmaceutical dosage forms 503.3 Influential factors in dosage form design 51
3.3.1 Molecular size and volume 513.3.2 Drug solubility and pH 533.3.3 Lipophilicity and partition coefficient 553.3.4 Polymorphism 583.3.5 Stability 593.3.6 pKa/Dissociation constants 603.3.7 Degree of ionization and pH-partition theory 63
3.3.7.1 Limitations of pH-partition theory 64Review questions 65Further reading 66
4 Biopharmaceutical considerations 69
4.1 Introduction 694.2 Diffusion 70
4.2.1 Drug transport across a polymeric barrier 704.2.1.1 Molecular diffusion 704.2.1.2 Pore diffusion 714.2.1.3 Matrix erosion 71
4.2.2 Principles of diffusion 724.2.2.1 Fick’s first law 724.2.2.2 Fick’s second law 73
4.2.3 Diffusion rate 734.2.3.1 Diffusion cell 744.2.3.2 Spherical membrane-controlled
drug delivery system 754.2.3.3 Pore diffusion 764.2.3.4 Determining permeability coefficient 764.2.3.5 Lag time in non-steady state diffusion 774.2.3.6 Matrix (monolithic)-type
non-degradable system 774.2.3.7 Calculation examples 78
x Contents
4.3 Dissolution 794.3.1 Noyes–Whitney equation 794.3.2 Calculation example 804.3.3 Factors influencing dissolution rate 81
4.4 Absorption 834.4.1 Passive transport 85
4.4.1.1 Simple diffusion 854.4.1.2 Carrier-mediated transport 854.4.1.3 Channel-mediated transport 864.4.1.4 Fick’s laws of diffusion
in drug absorption 864.4.2 Active transport 87
Review questions 87Further reading 89
5 Pharmacy math and statistics 91
5.1 Introduction 915.2 Systems of measure 92
5.2.1 Volume and weight interconversions 935.2.2 Temperature interconversions 935.2.3 Accuracy, precision, and significant figures 94
5.3 Ratio and proportion 945.4 Concentration calculations 95
5.4.1 Percentage solutions 955.4.2 Concentrations based on moles and equivalents 965.4.3 Parts per unit concentrations 975.4.4 Dilution of stock solutions 985.4.5 Mixing solutions of different concentrations 99
5.4.5.1 Alligation medial 995.4.5.2 Alligation alternate 100
5.4.6 Tonicity, osmolarity, and preparation of isotonic solutions 102
5.5 Clinical dose calculations 1065.5.1 Dosage adjustment based on body
weight or surface area 1065.5.2 Calculation of children’s dose 1075.5.3 Dose adjustment for toxic compounds 1105.5.4 Dose adjustment based on creatinine clearance 111
Contents xi
5.6 Statistical measures 1125.6.1 Measures of central tendency 1135.6.2 Measures of dispersion 1145.6.3 Sample probability distributions 115
5.6.3.1 Normal distribution 1165.6.3.2 Log-normal distribution 1165.6.3.3 Binomial distribution 1165.6.3.4 Poisson distribution 1165.6.3.5 Student’s t-distribution 1165.6.3.6 Chi-square distribution 118
5.7 Tests of statistical significance 1195.7.1 Parametric and nonparametric tests 1205.7.2 Null and alternate hypothesis 1205.7.3 Steps of hypothesis testing 1215.7.4 One-tailed and two-tailed hypothesis tests 1215.7.5 Regions of acceptance and rejection 1225.7.6 Probability value and power of a test 1235.7.7 Types of error 1245.7.8 Questions addressed by tests of significance 1245.7.9 Analysis of variance 128
5.7.9.1 One-way ANOVA 1285.7.9.2 Two-way ANOVA: Design
of experiments 135Review questions 140References 143
Part IIPhysicochemical principles 145
6 Complexation and protein binding 147
6.1 Introduction 1476.2 Types of complexes 150
6.2.1 Coordination complexes 1516.2.2 Molecular complexes 152
6.2.2.1 Small molecule–small molecule complexes 152
6.2.2.2 Small molecule–large molecule complexes 153
6.2.2.3 Large molecule–large molecule complexes 155
xii Contents
6.3 Protein binding 1566.3.1 Kinetics of ligand–protein binding 156
6.3.1.1 Parameters of interest 1576.3.1.2 Experimental setup 1576.3.1.3 Determining ka and ymax 157
6.3.2 Thermodynamics of ligand–protein binding 1606.3.3 Factors influencing protein binding 162
6.3.3.1 Physicochemical characteristics and concentration of the drug 162
6.3.3.2 Physicochemical characteristics and concentration of the protein 163
6.3.3.3 Physicochemical characteristics of the medium 163
6.3.4 Plasma protein binding 1636.3.4.1 Plasma proteins involved in binding 1646.3.4.2 Factors affecting plasma–protein
binding 1646.3.4.3 Consequences of plasma–protein
binding 1646.3.5 Drug receptor binding 1666.3.6 Substrate enzyme binding 166
Review questions 167Further reading 168
7 Chemical kinetics and stability 169
7.1 Introduction 1697.2 Reaction rate and order 170
7.2.1 Pseudo-nth order reactions 1727.2.2 Determining the order of a reaction 1727.2.3 Zero-order reactions 173
7.2.3.1 Rate equation 1737.2.3.2 Half-life 174
7.2.4 First-order reactions 1757.2.4.1 Rate equation 1757.2.4.2 Half-life 177
7.2.5 Second-order reactions 1777.2.5.1 Rate equation 1787.2.5.2 Half-life 179
Contents xiii
7.2.6 Complex reactions 1807.2.6.1 Reversible reactions 1807.2.6.2 Parallel reactions 1807.2.6.3 Consecutive reactions 181
7.3 Factors affecting reaction kinetics 1827.3.1 Temperature 182
7.3.1.1 Arrhenius equation 1827.3.1.2 Shelf life 1837.3.1.3 Thermodynamics of reactions 184
7.3.2 Humidity 1857.3.2.1 Water as a reactant 1857.3.2.2 Water as a plasticizer 1857.3.2.3 Water as a solvent 1867.3.2.4 Determination and modeling
the effect of water/humidity 1867.3.3 pH 187
7.3.3.1 Disproportionation effect 1877.3.3.2 Acid–base catalysis 1877.3.3.3 pH–rate profile 188
7.3.4 Cosolvent and additives 1897.3.4.1 Drug–excipient interactions 1897.3.4.2 Catalysis 190
7.4 Drug degradation pathways 1917.4.1 Hydrolysis 191
7.4.1.1 Ester hydrolysis 1927.4.1.2 Amide hydrolysis 1937.4.1.3 Control of drug hydrolysis 194
7.4.2 Oxidation 1947.4.2.1 Control of drug oxidation 196
7.4.3 Photolysis 1977.4.3.1 Control of photodegradation of drugs 198
7.5 Stabilization strategies 199Review questions 199Further reading 201
8 Interfacial phenomena 203
8.1 Introduction 2038.2 Liquid–liquid and liquid–gas interfaces 204
8.2.1 Surface tension 2058.2.2 Interfacial tension 206
xiv Contents
8.2.3 Factors affecting surface tension 2068.2.4 Surface free energy 207
8.3 Solid–gas interface 2078.3.1 Adsorption 2078.3.2 Factors affecting adsorption 2088.3.3 Types of adsorption 208
8.3.3.1 Physical adsorption 2088.3.3.2 Chemical adsorption (chemisorption) 209
8.3.4 Adsorption isotherms 2108.3.4.1 Type of isotherms 2108.3.4.2 Modeling isothermal adsorption 211
8.4 Solid–Liquid interface 2148.4.1 Modeling solute adsorption 2148.4.2 Factors affecting adsorption from solution 2158.4.3 Wettability and wetting agents 216
8.5 Biological and pharmaceutical applications 217Review questions 218Reference 218Further reading 219
9 Colloidal dispersions 221
9.1 Introduction 2219.2 Types of colloidal systems 222
9.2.1 Lyophilic colloids 2239.2.2 Lyophobic colloids 2239.2.3 Association colloids 223
9.3 Preparation of colloidal solutions 2249.4 Properties of colloidal solutions 225
9.4.1 Kinetic properties 2259.4.1.1 Brownian movement 2259.4.1.2 Diffusion 2259.4.1.3 Sedimentation 227
9.4.2 Electrical properties 2289.4.2.1 Surface charge 2289.4.2.2 Electrical double layer 2319.4.2.3 Electrophoresis 233
9.4.3 Colligative properties 2339.4.3.1 Lowering of vapor pressure 2339.4.3.2 Elevation of boiling point 234
Contents xv
9.4.3.3 Depression of freezing point 2349.4.3.4 Osmotic pressure 235
9.4.4 Optical properties 2359.5 Physical stability of colloids 236
9.5.1 Stabilization of hydrophilic colloids 2369.5.2 Stabilization of hydrophobic colloids 237
Review questions 237Further reading 239
10 Surfactants and micelles 241
10.1 Introduction 24110.2 Surfactants 242
10.2.1 Types of surfactants 24310.2.1.1 Anionic surfactants 24410.2.1.2 Cationic surfactants 24410.2.1.3 Nonionic surfactants 24510.2.1.4 Ampholytic surfactants 246
10.2.2 Hydrophile–lipophile balance system 24610.2.2.1 Type of emulsion formed 24710.2.2.2 Required HLB of a lipid 24810.2.2.3 Required HLB of a formulation 24910.2.2.4 Assigning a hydrophile–lipophile
balance value to a surfactant 24910.2.2.5 Selection of surfactant combination
for a target hydrophile–lipophile balance value 250
10.3 Micelles 25010.3.1 Types of micelles 25110.3.2 Micelles versus liposomes 25110.3.3 Colloidal properties of micellar solutions 25210.3.4 Factors affecting critical micelle
concentration and micellar size 25410.3.5 Krafft point 25510.3.6 Cloud point 25510.3.7 Micellar solubilization 256
10.3.7.1 Factors affecting the extent of solubilization 256
10.3.7.2 Pharmaceutical applications 25810.3.7.3 Thermodynamics/spontaneity 259
Review questions 260Further reading 261
xvi Contents
11 Pharmaceutical polymers 263
11.1 Introduction 26311.2 Definitions and architectures of polymers 26411.3 Polymer molecular weight and weight distribution 26811.4 Biodegradablity and biocompatibility 26911.5 Physicochemical properties and solubility 27011.6 Block copolymers 27111.7 Intelligent or stimuli-sensitive polymers 272
11.7.1 pH-Responsive polymers 27411.7.2 Thermosensitive polymers 27611.7.3 Other stimuli-responsive polymers 276
11.8 Water-soluble polymers 27711.8.1 Carboxypolymethylene (carbomer, carbopol) 27811.8.2 Cellulose derivatives 27811.8.3 Natural gum (acacia) 27811.8.4 Alginates 27811.8.5 Dextran 27911.8.6 Polyvinylpyrrolidone 27911.8.7 Polyethylene glycol 279
11.9 Bioadhesive/mucoadhesive polymers 27911.9.1 Advantages of mucoadhesive
drug delivery systems 28111.9.2 Mechanism of mucoadhesion 28111.9.3 Quantitation of mucoadhesion 28111.9.4 Sites of application 28211.9.5 Dosage forms 28211.9.6 Transdermal patches 283
Review questions 283References 284Further reading 284
12 Rheology 287
12.1 Introduction 28712.2 Newtonian flow 288
12.2.1 Temperature dependence and viscosity of liquids 289
12.3 Non-Newtonian flow 29012.3.1 Plastic flow 29012.3.2 Pseudoplastic (shear-thinning) flow 29112.3.3 Dilatant (shear-thickening) flow 291
Contents xvii
12.4 Thixotropy 29212.4.1 Hysteresis loop 293
12.5 Pharmaceutical applications of rheology 295Review questions 296Further reading 297
13 Radiopharmaceuticals 299
13.1 Introduction 29913.1.1 Types of radiation 30013.1.2 Units of radioactivity 30113.1.3 Radiation safety 302
13.2 Biomedical applications of radiopharmaceuticals 30313.2.1 Radioactive tracers and diagnosis 30313.2.2 Radiotherapy 304
13.3 Radiation detection equipment 30513.4 Formulation of radiopharmaceuticals 30713.5 Calculations 308Review questions 309
14 Drug delivery systems 313
14.1 Introduction 31314.2 Targeted drug delivery 31414.3 Prodrugs 31614.4 Soluble macromolecular carriers 31714.5 Particulate carrier systems 319
14.5.1 Liposomes 31914.5.1.1 Types of liposomes 32014.5.1.2 Fabrication of liposomes 321
14.5.2 Microparticles and nanoparticles 32314.5.2.1 Fabrication of microparticulates 323
14.5.3 Nanoparticles 32814.6 Oral drug delivery 32914.7 Alternative routes of delivery 330
14.7.1 Buccal and sublingual drug delivery 33014.7.2 Nasal drug delivery 33114.7.3 Pulmonary drug delivery 33214.7.4 Ocular drug delivery 33214.7.5 Rectal drug delivery 33314.7.6 Vaginal drug delivery 333
xviii Contents
Review questions 334References 335Further reading 335
15 Organ-specific drug delivery 337
15.1 Introduction 33715.2 Need for alternate, nonoral routes
to the systemic circulation 33815.2.1 Rectal drug delivery 33915.2.2 Vaginal drug delivery 34015.2.3 Transdermal drug delivery 34015.2.4 Buccal and sublingual drug delivery 34115.2.5 Nasal drug delivery 341
15.2.5.1 Barriers to transnasal drug delivery 34215.2.5.2 Drug delivery to the brain
through the nasal route 34215.2.5.3 Formulation factors affecting
transnasal drug delivery 34315.3 Need for organ specific and targeted drug delivery 343
15.3.1 Advantages of targeted drug delivery 34415.3.2 Examples of established drug
targeting strategies 34415.3.2.1 Pulmonary drug delivery 345
15.4 Local drug delivery to the lung 34615.5 Systemic drug delivery through the lung 34615.6 Devices for pulmonary drug delivery 347
15.6.1 Ocular drug delivery 34915.6.1.1 Structure of the eye 34915.6.1.2 Routes of drug administration
into the eye 35015.6.1.3 Challenges to ocular drug delivery 35115.6.1.4 Physicochemical characteristics
of the drug for ocular absorption 35215.6.1.5 Approaches for enhancing
drug delivery to the eye 35215.6.2 Brain targeted drug delivery 354
15.6.2.1 Blood–brain barrier 35415.6.2.2 Drug delivery strategies to the brain 355
15.6.3 Liver-targeted drug delivery 35615.6.3.1 Cellular components of the liver 35615.6.3.2 Common diseases of the liver 357
Contents xix
15.6.3.3 Natural mechanisms of hepatic drug uptake 358
15.6.3.4 Cellular targets for disease therapy 35915.6.4 Colon-targeted drug delivery 360
15.6.4.1 Utilization of the unique colonic microflora 361
15.6.4.2 pH-dependent dosage forms 36315.6.4.3 Time-dependent drug release 36415.6.4.4 Osmotically controlled
drug delivery systems 36515.7 Combination and other strategies for colon targeting 367
15.7.1 Kidney-targeted drug delivery 36915.7.1.1 Cellular drug targets 36915.7.1.2 Particulate systems 37015.7.1.3 The prodrug approach 37215.7.1.4 Bioconjugation approaches 373
Review questions 376References 378
Part III Dosage forms 385
16 Suspensions 387
16.1 Introduction 38716.2 Types of suspensions 38816.3 Powder for suspension 38916.4 Quality attributes 39016.5 Formulation considerations 393
16.5.1 Flocculation 39616.5.2 Quantitating the degree of flocculation 40016.5.3 Physics of particle sedimentation: Stokes’ law 401
16.6 Manufacturing process 402Review questions 403Further reading 404
17 Emulsions 407
17.1 Introduction 40717.2 Types of emulsions 408
17.2.1 Oil-in-water emulsion 40817.2.2 Water-in-oil emulsion 409
xx Contents
17.2.3 Multiple emulsions 40917.2.4 Microemulsions 410
17.2.4.1 Self-emulsifying drug delivery systems and self-microemulsifying drug delivery systems 410
17.3 Quality attributes 41117.4 Formulation considerations 413
17.4.1 Minimization of interfacial free energy 41317.4.2 Optimum-phase ratio 41417.4.3 Size, viscosity, and density: Stoke’s law 41417.4.4 Zeta potential 415
17.5 Emulsification 41617.5.1 Mechanisms of emulsification 41617.5.2 Surfactants 416
17.5.2.1 Ionic and nonionic surfactants 41717.5.2.2 Hydrophile-lipophile balance value 417
17.5.3 Hydrophilic colloids 41817.5.4 Finely divided solid particles 418
17.6 Manufacturing process 41817.7 Stability 419
17.7.1 Physical instability 41917.7.1.1 Creaming and sedimentation 42017.7.1.2 Aggregation, coalescence,
creaming, and breaking 42017.7.1.3 Phase inversion 421
17.7.2 Chemical instability 42117.7.3 Microbial growth 421
Review questions 421Further reading 423
18 Pharmaceutical solutions 425
18.1 Introduction 42518.2 Types of solutions 426
18.2.1 Syrup 42618.2.2 Elixir 42718.2.3 Tincture 42718.2.4 Oil-based solutions 42818.2.5 Miscellaneous solutions 42818.2.6 Dry or lyophilized mixtures for solution 428
18.3 Quality attributes 42818.4 Formulation components and manufacturing process 429
Contents xxi
18.5 Solubility 43018.5.1 pH and buffer capacity 430
18.5.1.1 pH and buffering capacity 43118.5.2 Surfactants and cosolvents 433
18.6 Stability 43318.6.1 Physical stability 43318.6.2 Chemical stability 43418.6.3 Microbial stability 435
Review questions 435Further reading 436
19 Powders and granules 437
19.1 Introduction 43719.2 Production of powders and granules 438
19.2.1 Origin of powdered excipients 43819.2.2 Origin of powdered active
pharmaceutical ingredients 44019.2.3 Amorphous and crystalline powders 44019.2.4 Production of crystalline powders 440
19.2.4.1 Crystallization versus dissolution 44119.2.4.2 Polymorphism 441
19.2.5 Production of amorphous powders 44319.3 Analyses of powders 443
19.3.1 Particle shape and size 44419.3.1.1 Defining particle shape and size 44419.3.1.2 Defining particle size distribution 44519.3.1.3 Desired particle shape and size 44819.3.1.4 Factors determining particle shape 44819.3.1.5 Techniques for quantifying
particle shape and size 44919.3.1.6 Changing particle shape and size 450
19.3.2 Surface area 45319.3.2.1 Significance of surface area 45319.3.2.2 Defining surface area 45319.3.2.3 Quantitation of surface
area by gas adsorption 45419.3.2.4 Altering powder surface area 455
19.3.3 Density and porosity 45619.3.3.1 Significance of density
determination 45619.3.3.2 Defining powder density 456
xxii Contents
19.3.3.3 Methods for quantifying powder density and porosity 457
19.3.3.4 Changing powder density and porosity 459
19.3.4 Flow 45919.3.4.1 Importance of flowability
of powders 45919.3.4.2 Factors influencing flow of powders 46019.3.4.3 Quantitation of powder flow 46019.3.4.4 Manipulation of flow
properties of powders 46119.3.5 Compactibility 461
19.3.5.1 Compressibility, compactibility, and tabletability 461
19.3.5.2 Importance of compactibility 46219.3.5.3 Determination of compaction
characteristics 46219.3.5.4 Factors affecting compactibility 463
19.3.6 Content uniformity 46319.3.6.1 Importance of uniform mixing 46319.3.6.2 Factors affecting mixing uniformity 46319.3.6.3 Assessment of content uniformity 46419.3.6.4 Addressing content
nonuniformity issues 46519.4 Powder processing 465
19.4.1 Increasing particle size: Granulation 46519.4.1.1 Dry granulation 46619.4.1.2 Wet granulation 467
19.4.2 Decreasing particle size: Comminution or milling 47019.4.2.1 Techniques for particle
size reduction 47119.4.2.2 Selection of size reduction technique 471
19.5 Powders as dosage forms 47219.5.1 Types of powder dosage forms 472
19.5.1.1 Oral powders in unit dose sachets 47219.5.1.2 Powders for oral solution
or suspension 47319.5.1.3 Bulk powders for oral
administration 47319.5.1.4 Effervescent granules 473
Contents xxiii
19.5.1.5 Dusting powders 47319.5.1.6 Dry powder inhalers 474
19.5.2 Advantages of extemporaneous compounding of powders 474
19.5.3 Extemporaneous compounding techniques 474Review questions 475References 477Further reading 477
20 Tablets 479
20.1 Introduction 47920.2 Types of tablets 480
20.2.1 Swallowable tablets 48020.2.2 Effervescent tablets 48020.2.3 Chewable tablets 48020.2.4 Buccal and sublingual tablets 48820.2.5 Lozenges 48820.2.6 Coated tablets 48820.2.7 Enteric-coated tablets 49020.2.8 Immediate release tablets 49120.2.9 Controlled release tablets 491
20.3 Tablet formulation 49220.3.1 Diluents 49220.3.2 Adsorbents 49520.3.3 Granulating fluid 49520.3.4 Binders 49520.3.5 Glidants 49620.3.6 Lubricants 49620.3.7 Disintegrants 49620.3.8 Miscellaneous 497
20.4 Manufacturing of tablets 49720.4.1 Requirements for tableting 49720.4.2 Powder flow and compressibility 49820.4.3 Types of manufacturing processes 49920.4.4 Packaging and handling considerations 502
20.5 Evaluation of tablets 50220.5.1 Appearance 50220.5.2 Uniformity of content 50320.5.3 Hardness 50320.5.4 Friability 503
xxiv Contents
20.5.5 Weight uniformity 50320.5.6 Disintegration 50320.5.7 Dissolution 504
20.6 Relationship among disintegration, dissolution, and absorption 504
Review questions 506Further reading 507
21 Capsules 509
21.1 Introduction 50921.2 Hard gelatin capsules 511
21.2.1 Advantages and disadvantages of hard gelatin capsules 51221.2.1.1 Comparison with tablets 51221.2.1.2 Comparison with soft
gelatin capsules 51321.2.2 Solid-filled hard gelatin capsules 513
21.2.2.1 Main applications 51321.2.2.2 Formulation considerations 51421.2.2.3 Formulation components 51521.2.2.4 Manufacturing process 516
21.2.3 Liquid- and semisolid-filled hard gelatin capsules 51821.2.3.1 Main applications 51821.2.3.2 Formulation considerations 52021.2.3.3 Formulation components 52021.2.3.4 Manufacturing process 520
21.3 Soft gelatin capsules 52121.3.1 Advantages and disadvantages
of soft gelatin capsules 52121.3.2 Drivers for development of soft gelatin capsules 52221.3.3 Formulation of soft gelatin capsule shell 52221.3.4 Drug formulation for encapsulation
in soft gelatin capsules 52421.3.5 Manufacturing process 52521.3.6 Nongelatin soft capsules 526
21.4 Evaluation of capsule drug products 52721.4.1 In-process tests 52721.4.2 Finished product quality control tests 527
21.4.2.1 Permeability and sealing 52721.4.2.2 Potency and impurity content 527
Contents xxv
21.4.2.3 Average weight and weight variation 528
21.4.2.4 Uniformity of content 52821.4.2.5 Disintegration 52821.4.2.6 Dissolution 52821.4.2.7 Moisture content 52921.4.2.8 Microbial content 529
21.5 Shelf-life tests 529Review questions 530Further reading 530
22 Parenteral drug products 533
22.1 Introduction 53322.2 Parenteral routes of administration 534
22.2.1 Intravenous route 53422.2.2 Intramuscular route 53522.2.3 Subcutaneous route 53522.2.4 Other routes 53522.2.5 Rate and extent of absorption 53622.2.6 Factors affecting selection of route 536
22.3 Types of parenteral dosage forms 53722.3.1 Small-volume parenterals versus
large-volume parenterals 53722.3.2 Injections versus infusions 53722.3.3 Types of formulations 537
22.3.3.1 Solutions 53822.3.3.2 Suspensions 53822.3.3.3 Emulsions 539
22.4 Quality attributes and evaluation 53922.4.1 Sterility 53922.4.2 Pyrogens 540
22.4.2.1 Endotoxins, exotoxins, and pyrogens 540
22.4.2.2 Endotoxin components and tolerance limits 540
22.4.2.3 Sources 54022.4.2.4 Depyrogenation 54022.4.2.5 Detection 541
22.4.3 Particulate matters 54122.5 Formulation components 541
xxvi Contents
22.6 Sterilization 54222.6.1 Filtration 54322.6.2 Dry heat sterilization 54322.6.3 Steam sterilization (autoclaving) 54322.6.4 Radiation sterilization 543
Review questions 544Further reading 544
23 Semisolid dosage forms 547
23.1 Introduction 54723.2 Ointments 548
23.2.1 Types of ointment bases 54823.2.1.1 Hydrocarbon bases 54823.2.1.2 Absorption bases 55023.2.1.3 Emulsion or water-removable
bases and creams 55123.2.1.4 Water-soluble bases 552
23.2.2 Selection of ointment bases 55323.2.3 Methods of incorporation
of drugs into ointment bases 55423.3 Creams 55423.4 Gels and jellies 555
23.4.1 Gels 55523.4.2 Jellies 556
23.5 Lotions 55723.6 Pastes 55723.7 Foams 55823.8 Manufacturing processes 558
23.8.1 Laboratory scale 55823.8.2 Industrial scale 559
23.9 Analysis of semisolid dosage forms 560Review questions 560Further reading 561
24 Inserts, implants, and devices 563
24.1 Introduction 56324.2 Inserts 564
24.2.1 Ocular inserts 56424.2.2 Suppositories 565
24.2.2.1 Types of suppositories 566
Contents xxvii
24.2.2.2 Suppository bases 56624.2.2.3 Manufacturing process and
formulation considerations 56724.2.3 Vaginal rings 568
24.3 Implants 56824.3.1 Types of implants based on
drug release mechanism 56824.3.1.1 Diffusion-controlled implants 56924.3.1.2 Osmotic minipumps 569
24.3.2 Types of implants based on clinical use 57124.3.2.1 Cardiac implants 57224.3.2.2 Dental implants 57224.3.2.3 Urological and penal implants 57224.3.2.4 Breast implants 57324.3.2.5 Ophthalmic implants 57324.3.2.6 Dermal or tissue implants 573
24.4 Devices 57424.4.1 Inhaler devices for pulmonary drug delivery 574
24.4.1.1 Nebulizers 57624.4.1.2 Metered-dose inhalers 57724.4.1.3 Dry powder inhalers 577
24.4.2 Intrauterine devices 57824.4.3 Subcutaneous devices 579
Review questions 580Further reading 581
25 Protein and peptide drug delivery 583
25.1 Introduction 58325.2 Structure 586
25.2.1 Amino acids 58725.2.2 Primary structure 59125.2.3 Secondary structure 59125.2.4 Tertiary structure 59225.2.5 Quaternary structure 592
25.3 Types of protein and peptide therapeutics 59225.3.1 Antibodies 59225.3.2 Hormones and physiological proteins 59525.3.3 Chemically modified proteins and peptides 595
25.3.3.1 Conjugation with sugars 59625.3.3.2 PEGylation 596
xxviii Contents
25.3.3.3 Other protein conjugation approaches 598
25.3.3.4 Antibody drug conjugates 59825.4 Protein characterization 598
25.4.1 Biophysical characterization 59825.4.2 Physicochemical characterization 599
25.4.2.1 Solubility 59925.4.2.2 Hydrophobicity 600
25.5 Instability 60125.5.1 Physical instability 601
25.5.1.1 Denaturation 60125.5.1.2 Aggregation and precipitation 60225.5.1.3 Surface adsorption 603
25.5.2 Chemical instability 60325.5.2.1 Hydrolysis 60425.5.2.2 Deamidation 60425.5.2.3 Oxidation 60525.5.2.4 Racemization 60625.5.2.5 Disulfide exchange 60625.5.2.6 Maillard reaction 606
25.6 Antigenicity and immunogenicity 60725.7 Drug product formulation and process 608
25.7.1 Route of administration 60825.7.2 Type of formulation 60925.7.3 Formulation components 61025.7.4 Manufacturing processes 611
25.7.4.1 Protein solution 61125.7.4.2 Lyophilization 612
Review questions 613Further reading 615
26 Biotechnology-based drugs 617
26.1 Introduction 61726.2 Gene and gene expression 61826.3 Gene silencing 61826.4 Gene silencing technologies 619
26.4.1 Antisense oligonucleotides 61926.4.2 Triplex-forming oligonucleotides 62026.4.3 Peptide nucleic acids 62126.4.4 Antisense RNA 62126.4.5 MicroRNA 622
Contents xxix
26.4.6 Aptamers 62226.4.7 Ribozymes 62226.4.8 RNA interference 622
26.5 Gene therapy 62426.5.1 Retroviral vector 624
26.5.1.1 MuLV 62526.5.1.2 Lentiviruses 625
26.5.2 Adenoviral vectors 62626.5.3 Adeno-associated virus vectors 62626.5.4 Herpes simplex virus vectors 62626.5.5 Nonviral gene expression system:
Plasmid vectors 62726.5.6 Gene delivery systems 628
26.5.6.1 Lipid-based gene delivery 62926.5.6.2 Peptide-based gene delivery 63026.5.6.3 Polymer-based gene delivery 631
Review questions 631Further reading 632
Answers to review questions 633Index 665
xxxi
Foreword
Education and practice of the pharmaceutical sciences are rapidly evolving in the modern times, not only with the new ways of doing things enabled by technological advancements of the twenty-first century—but also by the advent of new medicines and modalities of drug therapy. As much as the basic sciences and the fundamental principles of pharmaceutical sciences remain sound, there is an increasing need to integrate the education of dosage forms and drug delivery with the current research and contempo-rary practices in the current biopharmaceutical industry. It is here that this book—coauthored by leading scientists in both academia and industry—makes a strong impact by presenting the basic principles in a succinct man-ner that affords a deeper understanding of their reduction to practice.
The revised and expanded third edition of Pharmaceutical Dosage Forms and Drug Delivery provides greater emphasis to the multidisciplinary nature of drug discovery and development. The third edition has a new chapter on “Drug Discovery” and the authors have significantly updated and modi-fied the chapter on “Drug Development and Regulatory Processes.” These revised chapters provide not only an industry perspective of current prac-tices in pharmaceutical sciences, they also share interdisciplinary nature of what it takes to discover and bring a new drug to the market by equally emphasizing the role of regulatory authorities and decision-making criteria in a stage-gate process of drug development.
Modern drug discovery is facing increasing challenges of identifying new drug targets and accessing the difficult-to-reach targets. Although early years of drug discovery focused predominantly on extracellular and cell-surface targets, recent efforts have refocused on new mechanisms of disease progression and targets that are intracellular and often also intraorganelle. These new frontiers are exemplified by the treatment of hepatitis C infection and the emergence of immuno-oncology and antibody–drug conjugates. Pharmaceutical scientists are increasingly using targeted drug-delivery strategies to address challenges inherent with evolving targets and increas-ingly complex nature of the therapeutic moieties. This edition includes a new chapter on “Targeted Drug Delivery” that provides a concise and in-depth overview of different strategies as applied in current practice.
xxxii Foreword
A new chapter has been added on “Radiopharmaceuticals” to familiarize the students with the basic principles; their utilization is currently embed-ded in the current practice of diagnostic and therapeutic medicine, and the emerging paradigms of their use in new drug development. This revised edition has many more changes to improve and update several other chapters of this book.
The recent years have seen an explosive increase in the information and progress in various subdisciplines of pharmaceutical sciences as well as the basic sciences, which forms the foundation of this applied science. This up-to-date book incorporates both the basics of the underlying sciences and the changes currently underway in a balanced fashion to enable a holistic development of the next generation of students.
I am confident that this book will enable a deeper understanding of fundamental principles and a wider perspective of their practice to our next generation of students.
Happy reading!
Courtney FletcherUniversity of Nebraska Medical Center
xxxiii
Preface
This book is designed as a textbook for teaching basic principles of pharmaceutics, dosage form design, and drug delivery to the Doctor of Pharmacy (Pharm. D.) students in the United States and Bachelor of Pharmacy (B. Pharm.) students in other countries. Although there are numerous books on the science of pharmaceutics and dosage form design, including Martin’s Physical Pharmacy and Pharmaceutical Sciences by Sinko, Physicochemical Principles of Pharmacy by Florence and Attwood, Pharmaceutics: The Science of Dosage form Design by Aulton, Theory and Practice of Contemporary Pharmaceutics by Ghosh and Jasti, and Pharmaceutical Sciences by Remington, these books cover different areas of the discipline in varying depths and provide limited insight into con-temporary practices and practical applications. Each of these textbooks, by themselves, does not provide an integrated approach to the students. This leads to the students as well as the teachers to refer many textbooks to develop an overall understanding of the basic physicochemical principles and their applications to the design and development of different pharma-ceutical dosage forms. In an attempt to overcome these challenges, this book provides a unified perspective of the overall field to the students as well as instructors.
The students need to know the basic physicochemical principles, application of these principles to the design of dosage forms, and the rele-vance of these principles to the biopharmaceutical aspects of drugs. Another important aspect of teaching that is urgently needed in our Pharm. D. cur-ricula is to expose students to the latest developments in the application of biomaterials as well as protein and nucleic acid-based pharmaceutical dosage forms and therapeutics, and various biotechnology-based develop-ments. Various books that are currently taught to students miss these latest developments in the field of pharmaceutics and drug delivery. Exposure of students to these latest developments is critical to the successful training of future pharmacists, because these therapeutic modalities and options are likely to be clinically significant in the future. All these principles and appli-cations need to be integrated in a single textbook, so that the student devel-ops a better and overall understanding of the principles involved in dosage
xxxiv Preface
form design and drug delivery. This book covers an in-depth discussion on what physiochemical parameters can be used for the design, development, and evaluation of biotechnological dosage forms for delivery of proteins, peptides, oligonucleotides, and genes.
What’s new in the third edition of Pharmaceutical Dosage Forms and Drug Delivery? This edition is significantly revised and expanded in the content matter of each chapter—to make sure the most recent progress in the field and pharmaceutical research is captured adequately—and expanded to include additional chapters that provide contemporary practices. These new chapters include “Drug Discovery” and “Drug Development” as expanded separate chapters, “Organ Specific Drug Delivery,” and “Radiopharmaceuticals.”
You have an updated, contemporary, new book that can serve as a textbook for Pharm. D. students and a valuable resource for novice in the pharmaceutics and drug delivery fields.