Table Of ContentPharmacology and Toxicology N M
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Pharmaceutical Dosage Forms ra h
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and Drug Delivery
Second Edition
Completely revised and updated, this second edition of Pharmaceutical
Dosage Forms and Drug Delivery elucidates the basic principles of PPhhaarrmmaacceeuuttiiccaall
pharmaceutics, dosage form design, and drug delivery. The authors
integrate aspects of physical pharmacy, biopharmaceuticals, drug
delivery, and biotechnology. The book highlights the increased attention
that the recent spectacular advances in dosage form design and drug
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delivery, gene therapy, and nanotechnology have brought to the field.
See what’s new in the Second Edition:
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• Additional author Ajit S. Narang brings an industrial practitioner C aanndd
perspective with increased focus on pharmacy math and statistics,
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and powders and granules
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• Reorganized into the following three parts: Introduction,
D
Physicochemical Principles, and Dosage Forms
• Chapters on pharmaceutical calculations, compounding principles, E DDrruugg DDeelliivveerryy
D
and powders and granules provide a complete spectrum of
I
application of pharmaceutical principles T
• Expansion of review questions and answers clarifies concepts for I
O
students and adds to their grasp of key concepts covered in
N
the chapter
SECOND EDITION
• Coverage of complexation and protein binding aspects of physical
pharmacy includes the basic concepts as well as recent progress
in the field
Although there are numerous books on the science of pharmaceutics
and dosage form design, most cover different areas of the discipline Ram I. Mahato
and do not provide an integrated approach to the topics. The integrated
approach of this book not only provides a singular perspective of the
Ajit S. Narang
overall field, but it supplies a unified source of information for students,
instructors, and professionals, saving them time and money.
K12224
ISBN: 978-1-4398-4918-7
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Pharmaceutical
Dosage Forms
and
Drug Delivery
SECOND E DITION
Pharmaceutical Dosage Forms and Drug Delivery, Second Edition
Ram I. Mahato and Ajit S. Narang
Pharmacy : What It Is and How It Works, Third Edition
William N. Kelly
Essentials of Law and Ethics for Pharmacy Technicians, Third Edition
Kenneth M. Strandberg
Essentials of Human Physiology for Pharmacy, Second Edition
Laurie Kelly McCorry
Basic Pharmacokinetics
Mohsen A. Hedaya
Basic Pharmacology: Understanding Drug Actions and Reactions
Maria A. Hernandez and Appu Rathinavelu
Managing Pharmacy Practice: Principles, Strategies, and Systems
Andrew M. Peterson
Essential Math and Calculations for Pharmacy Technicians
Indra K. Reddy and Mansoor A. Khan
Pharmacoethics: A Problem-Based Approach
David A. Gettman and Dean Arneson
Pharmaceutical Care: Insights from Community Pharmacists
William N. Tindall and Marsha K. Millonig
Essentials of Pathophysiology for Pharmacy
Martin M. Zdanowicz
Quick Reference to Cardiovascular Pharmacotherapy
Judy W. M. Cheng
Essentials of Pharmacy Law
Douglas J. Pisano
Pharmacokinetic Principles of Dosing Adjustments: Understanding the Basics
Ronald D. Schoenwald
Pharmaceutical and Clinical Calculations, Second Edition
Mansoor A. Khan and Indra K. Reddy
Strauss’s Federal Drug Laws and Examination Review, Fifth Edition Revised
Steven Strauss
Inside Pharmacy: Anatomy of a Profession
Raymond A. Gosselin and Jack Robbins
Understanding Medical Terms: A Guide for Pharmacy Practice, Second Edition
Walter F. Stanaszek, Mary J. Stanaszek, Robert J. Holt, and Steven Strauss
Pharmaceutical
Dosage Forms
and
Drug Delivery
SECOND E DITION
Ram I. Mahato
Ajit S. Narang
Boca Raton London New York
CRC Press is an imprint of the
Taylor & Francis Group, an informa business
CRC Press
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No claim to original U.S. Government works
Version Date: 20110831
International Standard Book Number-13: 978-1 -4398-4919-4 (eBook - PDF)
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I dedicate this book to my wife, Subhashini, and my children, Kalika
and Vivek, for their love and support; my mother, Sarswati, for
believing in me; and my students and mentors who have always
helped me in my quest for learning and achieving higher goals.
Ram I. Mahato
I dedicate this book to the sacrifices of my parents, Tirath Singh and
Gurdip Kaur, and my wife, Swayamjot; to the love of my brother,
Supreet, and sons, Manvir and Arjun; and to the encouragement
and confidence bestowed on me by my teachers and mentors
that has always inspired me to be and do the very best.
Ajit S. Narang
Contents
List of Figures ........................................................................................................xxv
List of Tables .........................................................................................................xxxi
Foreword ............................................................................................................xxxiii
Preface..................................................................................................................xxxv
Acknowledgments ..............................................................................................xxxvii
Authors ................................................................................................................xxxix
Part I Introduction
Chapter 1 Drug Development and Regulatory Process ........................................3
Learning Objectives ..............................................................................3
1.1 Introduction ...............................................................................3
1.2 Identification of New Therapeutic Moieties ..............................5
1.2.1 Plant Sources ................................................................6
1.2.2 Organic Synthesis .........................................................6
1.2.3 Use of Animals .............................................................6
1.2.4 Genetic Engineering .....................................................6
1.2.5 Gene Therapy ...............................................................7
1.3 Preclinical Development............................................................7
1.4 Clinical Develo pment ................................................................8
1.4.1 Phase I Clinical Trials ..................................................8
1.4.2 Phase II Clinical Trials .................................................8
1.4.3 Phase III Clinical Trials ...............................................9
1.5 Formulation Development .........................................................9
1.6 Regulatory Interface ................................................................10
1.6.1 Investigational New Drug Application .......................10
1.6.2 New Drug Application ...............................................11
1.6.3 Approval and Post-Marketing Surveillance ...............11
1.6.4 Abbreviated New Drug Application ...........................12
1.6.5 Accelerated Development/Review .............................12
1.6.6 Role of FDA’s Advisory Committees .........................12
Review Questions ...............................................................................13
Further Reading .................................................................................13
Chapter 2 Pharmaceutical Considerations ..........................................................15
Learning Objectives ............................................................................15
2.1 Introduction .............................................................................15
2.2 Advantages of Pharmaceutical Dosage Forms ........................15
ix
x Contents
2.3 Influential Factors in Dosage Form Design .............................16
2.3.1 Molecular Size and Volume .......................................17
2.3.2 Drug Solubility and pH ..............................................18
2.3.3 Lipophilicity and Partition Coefficient ......................20
2.3.4 Polymorphism ............................................................21
2.3.5 Stability ......................................................................23
2.3.6 pK /Dissociation Constants ........................................24
a
2.3.7 Degree of Ionization and pH-Partition Theory ..........28
2.3.7.1 Limitations of pH-Partition Theory ............28
Review Questions ...............................................................................29
Further Reading .................................................................................30
Chapter 3 Biopharmaceutical Considerations .....................................................33
Learning Objectives ............................................................................33
3.1 Introduction .............................................................................33
3.2 Diffusion ..................................................................................34
3.2.1 Drug Transport across a Polymeric Barrier ...............34
3.2.1.1 Molecular Diffusion ...................................34
3.2.1.2 Pore Diffusion .............................................35
3.2.1.3 Matrix Erosion ............................................35
3.2.2 Principles of Diffusion ...............................................35
3.2.2.1 Fick’s First Law ..........................................35
3.2.2.2 Fick’s Second Law ......................................36
3.2.3 Diffusion Rate ............................................................37
3.2.3.1 Diffusion Cell .............................................37
3.2.3.2 Spherical Membrane–Controlled Drug
Delivery System ..........................................39
3.2.3.3 Pore Diffusion .............................................39
3.2.3.4 Determining Permeability Coefficient .......40
3.2.3.5 Lag Time in Nonsteady State Diffusion .....40
3.2.3.6 Matrix (Monolithic)-Type
Nondegradable System ...............................41
3.2.3.7 Calculation Examples .................................41
3.3 Dissolution ...............................................................................42
3.3.1 Noyes–Whitney Equation ...........................................43
3.3.1.1 Calculation Example ...................................43
3.3.2 Factors Influencing Dissolution Rate .........................44
3.4 Absorption ...............................................................................46
3.4.1 Passive Transport ........................................................48
3.4.1.1 Simple Diffusion .........................................48
3.4.1.2 Carrier-Mediated Transport ........................48
3.4.1.3 Channel-Mediated Transport ......................48
3.4.2 Fick’s Laws of Diffusion in Drug Absorption ............49
3.4.3 Active Transport .........................................................50
Contents xi
Review Questions ...............................................................................50
Further Reading ................................................................................52
Chapter 4 Pharmacy Math and Statistics ............................................................53
Learning Objectives ............................................................................53
4.1 Introduction .............................................................................53
4.2 Systems of Measure .................................................................53
4.2.1 Volume and Weight Interconversions .........................54
4.2.2 Temperature Interconversions ....................................55
4.2.3 Accuracy, Precision, and Significant Figures .............55
4.3 Ratio and Proportion ...............................................................56
4.4 Concentration Calculations .....................................................57
4.4.1 Percentage Solutions...................................................57
4.4.2 Concentrations Based on Moles and Equivalents ......57
4.4.3 Parts per Unit Concentrations ....................................58
4.4.4 Dilution of Stock Solutions ........................................59
4.4.5 Mixing Solutions of Different Concentrations ...........60
4.4.5.1 Alligation Medial ........................................60
4.4.5.2 Alligation Alternate ....................................60
4.4.6 Tonicity, Osmolarity, and Preparation of
Isotonic Solutions .......................................................63
4.5 Clinical Dose Calculations ......................................................66
4.5.1 Dosage Adjustment Based on Body Weight or
Surface Area ...............................................................67
4.5.2 Calculation of Children’s Dose ..................................67
4.5.3 Dose Adjustment for Toxic Compounds ....................69
4.5.4 Dose Adjustment Based on Creatinine Clearance .....71
4.6 Statistical Measures .................................................................73
4.6.1 Measures of Central Tendency ...................................73
4.6.2 Measures of Dispersion ..............................................74
4.6.3 Sample Probability Distributions ...............................75
4.6.3.1 Normal Distribution ....................................76
4.6.3.2 Log-Normal Distribution ............................76
4.6.3.3 Binomial Distribution .................................76
4.6.3.4 Poisson Distribution ....................................76
4.6.3.5 Student’s t-Distribution ...............................76
4.6.3.6 Chi-Square Distribution..............................78
4.7 Tests of Statistical Significance ...............................................78
4.7.1 Parametric and Nonparametric Tests .........................79
4.7.2 Null and Alternate Hypothesis ...................................80
4.7.3 Steps of Hypothesis Testing .......................................80
4.7.4 One-Tailed and Two-Tailed Hypothesis Tests ............81
4.7.5 Regions of Acceptance and Rejection ........................81
4.7.6 Probability Value and Power of a Test .......................82
