`

`
`
`APPLIED
`.
`Blopharmaceutics
`WPharmacokinetics
`
`fourth edition
`
`Leon Shargel, PhD
`Vice President and Technical Director
`National Association of Pharmaceutical Manufacturers
`Ronkonkoma, New York
`
`Adjunct Associate Professor
`School of Pharmacy
`' University of Maryland
`Baltimore, Maryland
`
`Andrew Yu, PhD
`Associate Professor of Pharmaceutics
`
`Albany College of Pharmacy
`Albany, New York*
`
`*Present affiliation
`HFD—52O CDER, FDA, Rockville, MD.
`(The contents of this book reflect the personal views of the authors and not that of the FDA.)
`
`McGraw-Hill
`
`Medical Publishing Division
`
`New York St. Louis San Francisco Auckland Bogota Caracas Lisbon London
`Madrid Mexico City Milan Montreal New Delhi San Juan
`Singapore Sydney Tokyo Toronto
`
`AstraZeneca Exhibit 2162 p. 2
`
`

`

`McGraw-Hill
`A Division ofThe McGraw-Hill Companies
`
`22
`
`Applied Biopharmaceutics 8c Pharmacokinetics, Fourth Edition
`
`Copyright © 1999 by Appleton 8c Lange. All rights reserved. Printed in the United States
`of America. Except as permitted under the United States Copyright Act of 1976, no part
`of this publication may be reproduced or distributed in any form or by any means, or
`stored in a data base or retrieval system, without the prior written permission of the put»
`lisher.
`
`Previous editions copyright © 1993 by Appleton 8c Lange; copyright © 1985, 1980 by
`Appleton—Century—Crofts.
`
`4567890 HPC/HPC 0987654321
`
`ISBN: 0—8385-0278—4 (domestic)
`
`Library of Congress Cataloging—in—Publication Data
`
`Shargel, Leon, 1941—
`Applied biopharmaceutics and phannacokinetics / Leon Shargel,
`Andrew Yu. ~4th ed.
`p.
`cm.
`Includes bibliographical references and index.
`ISBN 0-8385—0278—4 (case : alk. paper)
`1. Biopharmaceutics.
`2. Pharmacokinetics.
`1945— .
`II. Title
`
`1. Yu, Andrew B. C.,
`
`1. Biopharmaceutics.
`
`2. Pharmacokinetics. QV 38 8531a
`
`1999
`
`[DNLM:
`1999]
`RM301.4.S52
`615'.7—dc21
`DNLM/DLC
`
`for Library of Congress
`
`'
`
`98—49079
`
`.
`
`.-
`
`Editor-in-Chief: Cheryl L. Mehalik
`Production Service: York Production Services
`
`Art Coordinator: Eve Siege]
`Cover Design: Aimee Nordin
`Illustrator: Wendy Beth Jackelow
`
`ISBN: 0-8385-0321-7 (international)
`
`Exclusive rights by The McGraw—Hill Companies, Inc. for manufacture and export. This
`book cannot be re-exported from the country to which it is consigned by McGraw-Hill.
`The International Edition is not available in North America.
`
`AstraZeneca Exhibit 2162 p. 3
`
`

`

`
`
`
`
`EQNIENIL___________________________________
`
`Preface / XIII
`
`1. REVIEW OF MATHEMATICAL FUNDAMENTALS / 1
`Estimation and the Use of Calculators and Computers / 1
`Calculus / 6
`
`Graphs / 9
`Units in Pharmacokinetics / 16
`
`Measurement and the Use of Significant Figures / 17
`
`Units for Expressing Blood Concentrations / 18
`Statistics / 18
`Rates and Orders of Reactions / 21 1
`
`Frequently Asked Questions / 26
`
`Learning Questions / 26
`References / 28
`
`Bibliography / 28
`
`2.
`
`INTRODUCTION TO BIOPHARMACEUTICS AND
`
`PHARMACOKINETICS / 29
`
`*- Biopharmaceutics / 29
`Pharmacokinetics / 30
`
`Clinical Pharmacokinetics / 30
`
`Pharmacodynamics / 31
`
`Toxicokinetics and Clinical Toxicology / 31
`
`Measurement of Drug Concentrations / 32
`Basic Pharmacokinetics and Pharmacokinetic Models / 36
`
`Frequently Asked Questions / 43
`
`Learning Questions / 43
`References / 44
`
`Bibliography / 45
`
`3. ONE’COMPARTMENT OPEN MODEL /'47
`
`Intravenous Route of Administration of Drug / 47
`Elimination Rate Constant / 48
`
`AstraZeneca Exhibit 2162 p. 4
`
`

`

`VI
`
`CONTENTS
`
`Apparent Volume of Distribution / 49
`Clearance / 52
`
`Calculation of k from Urinary Excretion Data / 58
`
`Clinical Application / 62
`
`4
`
`Frequently Asked Questions / 63
`
`Learning Questions / 64
`
`Bibliography / 66
`
`. MULTICOMPARTMENTAL MODELS / 67
`
`Two—Compartment Open Model / 69
`
`Three-Compartment Open Model / 85
`
`Determination of Compartment Models / 88
`
`Frequently Asked Questions / 95
`
`Learning Questions / 95
`References / 98
`
`Bibliography / 98
`
`PHYSIOLOGIC FACTORS RELATED TO
`
`DRUG ABSORPTION / 99
`
`Nature of the Cell Membrane / 99
`
`Passage of Drugs Across Cell Membranes / 101
`
`Route of Drug Administration / 108
`
`Frequently Asked Questions / 125
`
`Learning Questions / 126
`References / 127
`Bibliography / 128
`
`"
`
`BIOPHARMACEUTIC CONSIDERATIONS IN DRUG
`
`PRODUCT DESIGN / 129
`
`Rate-Limiting Steps in Drug Absorption / 130
`
`Pharmaceutic Factors Affecting Drug Bioavaiiability / 131
`
`Physicochemical Nature of the Drug / 133
`
`Formulation Factors Affecting Drug Dissolution / 135
`
`In Vim Dissolution Testing / 138
`
`Compendial Methods of Dissolution / 140
`
`Methods for Testing Enteric-Coated Products / 143
`
`Meeting Dissolution Requirements / 143
`
`Unofficial Methods of Dissolution Testing / 144
`
`Problems of Variable Control in Dissolution Testing / 145
`
`
`
`AstraZeneca Exhibit 2162 p. 5
`
`

`

`
`
`
`
`CONTENTS VII
`
`In Vitro—In Viva Correlation of Dissolution / 146
`
`Failure of Correlation of In Vitro Dissolution to In Vivo Absorption / 150
`
`Biopharmaceutic Considerations / 151
`
`Pharmacodynamic Considerations / 152
`
`Drug Considerations / 152
`
`Drug Product Considerations / 152
`Patient Considerations / 154
`
`Route of Drug Administration / 154
`
`Clinical Example / 160
`
`Frequently Asked Questions / 164
`
`Learning Questions / 164
`References / 165
`
`Bibliography / 165
`
`MODIFIED—RELEASE DRUG PRODUCTS / 169
`
`Modified-Release Drug Products / 169
`
`Biopharmaceutic Factors / 172
`
`Dosage Form Selection / 174
`
`Drug Release from Matrix / 174
`
`Advantages and Disadvantages of Extended—Release Products / 175
`
`Kinetics of Controlled-Release Dosage Forms / 176
`Pharmacokinetic Simulation of Extended—Release Products / 178
`
`Types of Extended—Release Products / 180
`Considerations in the Evaluation of Modified-Release Products / 193
`
`Regulatory Studies for the Evaluation of Modified-Release Products / 195
`
`Evaluation of In Vivo Bioavailability Data / 198
`
`Frequently Asked Questions / 200
`
`Learning Questions / 200
`References / 201
`
`Bibliography / 202
`
`. TARGETED DRUG DELIVERY SYSTEMS AND
`
`BIOTECHNOLOGICAL PRODUCTS / 205
`
`Targeted Drug Delivery / 205
`
`Biotechnology / 207
`
`Bioequivalence of Biotechnology Products / 219
`
`Frequently Asked Questions / 220
`
`Learning Questions / 220
`References / 220
`
`Bibliography / 221
`
`AstraZeneca Exhibit 2162 p. 6
`
`

`

`VIII
`
`CONTENTS
`
`9. PHARMACOKINETIC MODEL OF ORAL ABSORPTION / 223
`
`Pharmacokinetics of Drug Absorption / 223
`
`Zero-Order Absorption Model / 224
`
`First-Order Absorption Model / 225
`
`Significance of Absorption Rate Constants / 242
`
`Frequently Asked Questions / 242
`
`Learning Questions / 243
`References / 244
`
`Bibliography / 245
`
`10. BIOAVAILABILITY AND BIOECMIVAIENCE / 247
`Definitions / 247
`
`Purpose of Bioavailability Studies / 249
`
`Relative and Absolute Availability / 250
`
`Methods for Assessing Bioavailability / 252
`
`Bioequivalence Studies / 256
`
`Design and Evaluation of Bioequivalence Studies / 259
`
`Bioequivalence Example / 265
`Generic Substitution / 271
`
`Frequently Asked Questions / 272
`
`Learning Questions / 273
`References / 278
`
`Bibliography / 279
`
`11. PHYSIOLOGIC DRUG DISTRIBUTION AND PROTEIN
`
`BINDING / 281
`
`'
`
`Physiologic Factors / 281
`
`Calculation of Apparent Volume of Distribution / 299
`
`Protein Binding of Drugs / 303
`
`Kinetics of Protein Binding / 306
`
`Determination of Binding Constants and Binding Sites
`by Graphic Methods / 309
`
`Clinical Significance of Drug—Protein Binding / 313
`
`Frequently Asked Questions / 320
`
`Learning Questions / 320
`References / 322
`
`Bibliography / 323
`
`12. DRUG ELIMINATION AND CLEARANCE CONCEPTS / 325
`
`Drug Elimination / 325 _
`
`The Kidney / 326
`
`Drug Clearance / 333
`
`
`
`AstraZeneca Exhibit 2162 p. 7
`
`

`

`
`
`CONTENTS
`
`IX
`
`Physiologic Approach to Clearance / 335
`Renal Clearance / 336
`
`Renal Drug Excretion / 337
`
`Drug Clearance / 340
`Determination of Renal Clearance / 341
`
`Relationship of Clearance Elimination Half—Life and
`Volume of Distribution / 347
`
`Frequently Asked Questions / 349
`
`Learning Questions / 350
`References / 351
`
`Bibliography / 351
`
`13.
`
`HEPATIC ELIMINATION OF DRUGS / 353
`
`Fraction of Drug Excreted Unchanged (fe) and Fraction of Drug
`Metabolized (1 ‘12) / 354
`Clinical Focus / 355
`
`Pharmacokinetics of Drugs and Metabolites / 355
`
`Anatomy and Physiology of the Liver / 362
`Hepatic Enzymes Involved in the Biotransformation of Drugs / 365
`Drug Biotransformation Reactions / 366
`Route of Drug Administration and Extrahepatic Drug Metabolism / 376
`First-Pass Effects / 377
`
`Hepatic Clearance / 383
`Significance of Drug Metabolism] 389
`Biliary Excretion of Drugs / 390
`
`Frequently Asked Questions / 393
`
`Learning Questions / 393
`References / 396
`
`Bibliography / 397
`
`14.
`
`INTRAVENOUS INFUSION / 399
`
`One—Compartment Model Drugs / 399
`Infusion Method for Calculating Patient Elimination Half-Life / 404
`
`Loading Dose Plus IV Infusion / 406
`Estimation of Drug Clearance and VD from Infusion Data / 412
`Estimation of k and VD of Aminoglycosides in Clinical Situations / 412
`
`Intravenous Infusion of Two—Compartment Model Drugs / 413
`
`Frequently Asked Questions / 414
`
`Learning Questions / 415
`References / 417
`
`Bibliography / 417
`
`AstraZeneca Exhibit 2162 p. 8
`
`

`

`X
`
`CONTENTS
`
`15. MULTIPLE'DOSAGE REGIMENS / 419
`
`Drug Accumulation / 419 '
`
`Repetitive Intravenous Injections / 424
`Intermittent Intravenous Infusion / 430
`
`Multiple Oral Dose Regimen / 433
`
`Loading Dose / 436
`
`Determination of Bioavailability and Bioequivalence in a
`Multiple—Dose Regimen / 437
`
`Bioequivalence Studies / 438
`
`Dosage Regimen Schedules / 441
`
`Frequently Asked Questions / 445
`
`Learning Questions / 445
`References / 446
`
`Bibliography / 447
`
`16. NONLINEAR PHARMACOKINETICS / 449
`
`Saturable Enzymatic Elimination Processes / 451
`
`Drug Elimination by Capacity—Limited Pharmacokinetics:
`One-Compartment Model, IV Bolus Injection / 454
`
`Equations for Drugs Distributed as One—Compartment Model and
`Eliminated by Nonlinear Pharmacokinetics / 467
`
`Time-Dependent Pharmacokinetics / 468
`
`Bioavailability of Drugs That Follow Nonlinear Pharmacokinetics / 469
`
`Nonlinear Pharmacokinetics Due to Drug-Protein Binding / 469
`
`Frequently Asked Questions / 472
`
`Learning Questions / 472
`References / 473
`1'
`Bibliography / 474
`
`I7. APPLICATION OF PHARMACOKINETICS IN CLINICAL
`
`SITUATIONS / 475
`
`Individualization of Drug Dosage Regimen / 475
`
`Therapeutic Drug Monitoring / 476
`
`Design of Dosage Regimens / 484
`
`Conversion From Intravenous Infusion to Oral Dosing / 485
`Determination of Dose / 487
`
`Effect of Changing Dose and Dosing Interval on CmaXOO, CmiHOO,
`and CW00 / 489
`
`Determination of Frequency of Drug Administration / 490
`
`Determination of Both Dose and Dosage Interval / 491
`
`Nomograms and Tabulations in Designing Dosage Regimens / 492
`
`AstraZeneca EXhibit 2162 p. 9
`
`

`

`
`
`CONTENTS
`
`XI
`
`Determination of Route of Administration / 498
`
`Dosing of Drugs in Infants and Children / 494
`
`Dosing of Drugs in the Elderly / 496
`
`Dosing of Drugs in the Obese Patient / 500
`
`Pharmacokinetics of Drug Interactions / 501
`
`Inhibition of Drug Metabolism / 504
`
`Inhibition of Biliary Excretion / 506
`
`Induction of Drug Metabolism / 506
`
`Altered Renal Reabsorption Due to Changing Urinary pH / 506
`
`Inhibition of Drug Absorption / 507
`
`Effect of Food on Drug Disposition / 507
`
`Adverse Viral Drug Interactions / 508
`
`Population Pharmacokinetics / 508
`
`Frequently Asked Questions / 522
`
`Learning Questions / 523
`References / 526
`
`Bibliography / 528
`
`18.
`
`DOSAGE ADJUSTMENT IN RENAL AND
`HEPATIC DISEASE / S31
`
`Pharmacokinetic Considerations / 531
`
`General Approaches for Dose Adjustment in Renal Disease / 532
`
`Dose Adjustment Based on Drug Clearance / 533
`
`Method Based on Changes in the Elimination Rate Constant / 534
`Measurement of Glomerular Filtration Rate / 535
`
`Serum Creatinine Concentration and Creatinine Clearance / 536
`LDosage Adjustment for Uremic Patients / 541
`
`Extracorporeal Removal of Drugs / 554
`
`Dialysis / 555
`
`Hemoperfusion / 561
`Hemofiltration / 561
`
`Effect of Hepatic Disease on Pharmacokinetics / 562
`
`Frequently Asked Questions / 567
`
`Learning Questions / 568
`References / 569
`
`Bibliography / 570
`
`19.
`
`RELATIONSHIP BETWEEN PHARMACOKINETIC AND
`
`PHARMACODYNAMICS / S73
`
`Pharmacodynamics and Pharmacokinetics / 573
`
`Relation of Dose to Pharmacologic Effect / 575
`
`
`
`AstraZeneca Exhibit 2162 p. 10
`
`

`

`XII
`
`CONTENTS
`
`Relationship Between Dose and Duration of Activity (tag),
`Single IV Bolus Injection / 577
`Effect of Both Dose and Elimination Half-Life on the
`
`Duration of Activity / 579
`
`Effect of Elimination Half-Life on Duration of Activity / 580
`
`Rate of Drug Absorption and Pharmacodynamic Response / 584
`
`Drug Tolerance and Physical Dependency / 585
`
`Hypersensitivity and Adverse Response / 586
`
`Drug Distribution and Pharmacologic Response / 587
`
`Pharmacodynamic Models / 590
`
`Frequently Asked Questions / 603
`
`Learning Questions / 603
`References / 604
`
`Bibliography / 605
`
`20. PHYSIOLOGIC PHARMACOKINETIC MODELS, MEAN
`
`RESIDENCE TIME, AND STATISTICAL MOMENT THEORY / 607
`Physiologic Pharmacokinetic Models / 608
`Mean Residence Time (MRT) / 619
`
`Statistical Moment Theory / 624
`
`Mean Absorption Time (MAT) and Mean Dissolution Time (MDT) / 635
`Selection of Pharmacokinetic Models / 637
`
`Frequently Asked Questions / 639
`
`Learning Questions / 639
`References / 640
`
`Bibliography / 641
`
`Appendix A Statistics / 6431‘
`
`Appendix B Application of Computers in Pharmacokineties / 653
`
`Appendix C Solutions to Frequently Asked Questions (FAQ) and Learning Questions / 667
`
`Appendix D Guiding Principles for Human and Animal Research / 727
`
`Appendix E Popular Drugs and Pharmacokinetic Parameters / 73]
`
`Appendix F Glossary / 737
`
`Index / 739
`
`
`
`AstraZeneca Exhibit 2162 p. 11
`
`

`

`BIOPHARMACEUTIC
`
`CONSIDERATIONS IN
`
`DRUG PRODUCT
`
`'
`
`DESIGN
`
`Drugs are not generally given as a pure chemical drug substance but formulated
`into a finished dosage form (drug product), such as a tablet, capsule, etc, before
`administering to a patient for therapy. A formulated drug product usually includes
`the active drug substance and selected ingredients (excipients) that make up the
`dosage form. Common pharmaceutical dosage forms include liquid, tablet, cap-
`sule, injection, suppository, transdermal systems, and topical products. Formulating
`a drug product requires a thorough understanding of the biopharmaceutic prin—
`ciples of drug delivery.
`Biopharmaceutz‘cs is the study of the in vitro impact of the physicochemical prop—
`erties‘of the drug and drug product on drug delivery to the body under normal
`or pathologic conditions. A primary concern in biopharmaceutics is the bioavail—
`ability of drugs. Bioavaz'labz'lz'ty refers to the measurement of the rate and extent of
`active drug that reaches the systemic circulation. Because the systemic blood cir—
`culation delivers the therapeutically active drug to the tissues and to the site of ac—
`tion of the drug, changes in bioavailability affect changes in the pharmacodynamics
`and toxicity of the drug. The aim of biopharmaceutics is to adjust the delivery of
`drug from the drug product in such a manner as to provide optimal therapeutic
`activity and safety for the patient.
`Biopharmaceutic studies allow for the rational design of drug products based
`on (1) the physical and chemical properties of the drug substance, (2) route of
`drug administration including the anatomic and physiologic nature of the appli-
`cation site (eg, oral, topical, injectable, implant, transdermal patch, etc), and (4)
`desired pharmacodynamic effect (eg, immediate or prolonged activity), (5) toxi-
`cologic properties of the drug, (6) safety of excipients, and (7) effect of excipients
`and dosage form on drug delivery. For example, some drugs are intended for top-
`ical or local therapeutic action at the site of administration. For these drugs, sys—
`temic absorption is undesirable. Drugs intended for local activity are designed to
`
`129
`
`AstraZeneca Exhibit 2162 p. 12
`
`

`

`130
`
`CHAPTER 6. BIOPHARMACEUTIC CONSIDERATIONS IN DRUG PRODUCT DESIGN
`
`have a direct pharmacodynamic action without affecting other body organs. These
`drugs may be applied topically to the skin, nose, eye, mucous membranes, buccal
`cavity, throat, and rectum. A drug intended for local activity may be given intra—
`vaginally, into the urethral tract, intranasally, in the ear, on the eye, or orally. Examples
`of drugs used for local action include anti-infectives, antifungals, local anesthetics,
`antacids, astringents, vasoconstrictors, antihistamines, and corticosteroids. However,
`some systemic drug absorption may occur with drugs used for local activity.
`Each route of drug application presents special biopharmaceutic considerations
`in drug product design. For example, the design of a vaginal tablet formulation
`for the treatment of a fungal infection must consider ingredients compatible with
`vaginal anatomy and physiology. An eye medication may require special biophar—
`maceutic considerations including appropriate pH, isotonicity, sterility, local irri—
`tation to the cornea, draining by tears, and concern for systemic drug absorption.
`For a drug administered by extravascular route (eg, intramuscular injection),
`local irritation, drug dissolution, and drug absorption from the intramuscular site
`are some of the factors that must be considered. The systemic absorption of a drug
`from an extravascular site is influenced by the anatomic and physiologic proper-
`ties of the site and the physicochemical properties of the drug and the drug prod-
`uct. If the drug is given by the intravascular route (eg, intravenous administration),
`systemic drug absorption is considered complete or 100% bioavailable because the
`drug is placed directly into the general circulation.
`By carefully choosing the route of drug administration and properly designing
`the drug prOduct, the bioavailability of the active drug can be varied from rapid
`and complete absorption to a slow, sustained rate of absorption or, even, virtually
`no absorption, depending on the therapeutic objective. Once the drug is systemi-
`cally absorbed, normal physiologic processes for distribution and elimination occur,
`which usually are not influenced by the specific formulation of the drug. The rate
`of drug release from the product and the rate of drug absorption are important
`in determining the distribution, onset, intensity, and duration of the drug action.
`Biopharmaceutic considerations often determine the ultimate dose and dosage
`form of a drug product. For example, the dosage for a drug intended for local ac—
`tivity, such as a topical dosage form, is often expressed in concentration or as per—
`centage of the active drug in the formulation (eg, 0.5% hydrocortisone cream).
`The amount of drug applied is not specified because the concentration of the drug
`at the active site relates to the pharmacodynamic action. However, biopharmaceu—
`tic studies must be performed to ensure that the dosage form does not irritate,
`cause an allergic response, or allow systemic drug absorption. In contrast,
`the
`dosage of a drug intended for systemic absorption is given on the basis of mass,
`such as mg or g. In this case, dosage is based on the amount of drug that is ab—
`sorbed systemically and dissolved in an apparent volume of distribution to produce
`a desired drug concentration at the target site. The dose may be based on the
`weight or surface area of the patient to account for the differences in the appar-
`ent volume of distribution. Thus, doses are expressed as mass per unit of body
`weight (mg/kg) or mass per unit of body surface area (mg/m2).
`
`RATE-LIMITING STEPS IN DRUG ABSORPTION
`
`Systemic drug absorption from a drug product consists of a succession of rate
`processes '(Fig. 6-1). For solid oral, immediate—release drug products (eg, tablet,
`
`AstraZeneca Exhibit 2162 p. 13
`
`

`

`
`BIOPHARMACEUTIC CONSIDERATIONS IN DRUG PRODUCT DESIGN CHAPTER 6.
`
`131
`
`ia
`
`
`Absorption
`.
`
`Ii particles
`
`———-————————>
`Dissolution
`
`Drug 1n
`solulion
`
`solid drug
`-
`- ‘1 -u l v
`
`Disintegration
`Release
`
`
`
`Drug in
`drug product
`..,___,_._~._.,..._-....
`
`
`
`
`
`Figure 6—1 . Rate processes of drug bioavailability.
`
`capsule), the rate processes include (1) disintegration of the drug product and sub—
`sequent release of the drug; (2) dissolution of the drug in an aqueous environ—
`ment; and (3) absorption across cell membranes into the systemic circulation. In
`the process of drug disintegration, dissolution, and absorption, the rate at which
`drug reaches the circulatory system is determined by the slowest step in the se—
`quence.
`
`The slowest step in a series of kinetic processes is called the rate—limiting step.
`Except for controlled release products, disintegration of a solid oral drug product
`is usually more rapid than drug dissolution and drug absorption. For drugs that
`have very poor aqueous solubility, the rate at which the drug dissolves (dissolution)
`is Often the slowest step and, therefore, exerts a rate-limiting effect on drug bioavail—
`ability. In contrast, for a drug that has a high aqueous solubility, the dissolution
`rate is rapid, and the rate at which the drug crosses or permeates cell membranes
`is the slowest or rate-limiting step.
`
`PHARMACEUTIC FACTORS AFFECTING
`
`DRUG BIOAVAILABILITY
`
`Considerations in designing a drug product that will deliver the active drug with
`the desired bioavailability characteristics include (1) the type Of drug product (eg,
`solution, suspension, suppository); (2) the nature of the excipients in the drug
`product; (3) the physicochemical properties Of the drug molecule; and (4) the
`route of drug administration.
`
`Disintegration
`
`For immediate-release, solid oral dosage forms, the drug product must disintegrate
`into small particles and release the drug. For monitoring uniform tablet disinte—
`gration, the United States Pharmacopeia (USP) established an Official disintegra-
`tion test. Solid drug products exempted from disintegration tests include troches,
`tablets which are intended to be chewed, and drug products intended for sustained
`release or prolonged or repeat action. The process Of disintegration does not imply
`complete dissolution of the tablet and/ or the drug. Complete disintegration is de—
`fined by the USP (23rd edition) as “that state in which any residue of the tablet,
`except fragments of insoluble coating, remaining on the screen of the test appa—
`ratus in the soft mass have no palpably firm core.” The official apparatus for the
`disintegration test and procedure is described in the USP. Separate specifications
`are given for uncoated tablets, plain coated tablets, enteric tablets, buccal tablets,
`and sublingual tablets.
`Although disintegration tests allow for precise measurement Of the formation Of
`fragments, granules, or aggregates from solid dosage forms, no information is Ob-
`tained from these tests on the rate of dissolution of the active drug. However, the
`
`
`
`AstraZeneca Exhibit 2162 p. 14
`
`

`

`132
`
`CHAPTER 6. BIOPHARMACEUTIC CONSIDERATIONS lN DRUG PRODUCT DESIGN
`
`disintegration test serves as a component in the overall quality control of tablet
`manufacture.
`
`Dissolution
`
`Dissolution is the process by which a chemical or drug becomes dissolved in a sol-
`vent. In biologic systems, drug dissolution in an aqueous medium is an important
`prior condition of systemic absorption. The rate at which drugs with poor aqueous
`solubility dissolve from an intact or disintegrated solid dosage form in the gas—
`trointestinal tract often controls the rate of systemic absorption of the drug. Thus,
`dissolution tests are discriminating of formulation factors that may affect drug
`bioavailability.
`Noyes and Whitney (1897) and other investigators studied the rate of dissolu—
`tion of solid drugs. According to their observations, the steps in dissolution include
`the process of drug dissolution at the surface of the solid particle, thus forming a
`saturated solution around the particle. The dissolved drug in the saturated solu—
`tion known as the stagnant layer diffuses to the bulk of the solvent from regions of
`high drug concentration to regions of low drug concentration (Fig. 6-2).
`The overall rate of drug dissolution may be described by the Noyes—Whitney equa-
`tion (Eq. 6.1).
`
`dC
`dt
`
`DA
`h
`
`(Cs
`
`C)
`
`(5-1)
`
`where dC/dt = rate of drug dissolution at time t, D = diffusion rate constant, A =
`surface area of the particle, C5 = concentration of drug (equal to solubility of drug)
`in the stagnant layer, C = concentration of drug in the bulk solvent, and h = thick-
`ness of the stagnant layer.
`The rate of dissolution, a? is the rate of drug dissolved per time expressed as
`concentration change in the dissolution fluid.
`The Noyes—Whitney equation shows that dissolution in a flask may be influenced
`by the physicochemical characteristics of the drug, the formulation, and the sol—
`vent. Drug in the body, particularly in the gastrointestinal tract, is considered to
`be dissolving in an aqueous environment, permeation of drug across the gut wall
`(a model lipid membrane) is affected by the ability of the drug to diffuse (D) and
`to partition between the lipid membrane. A favorable partition coefficient
`(Koil/Waler) will facilitate drug absorption.
`
`
`
`Solid drug
`particle
`
`‘
`
`Slognonl
`layer
`
`Figure 6-2. Dissolution of a solid drug particle in a
`solvent. (C; = concentration of drug in the stagnant
`layer, C = concentration of drug in the bulk solvent.)
`
`\
`/
`Bulk solvent
`
`AstraZeneca Exhibit 2162 p. 15
`
`

`

`’i
`
`133 BlOPl—lARMACEUTlC CONSIDERATIONS IN DRUG PRODUCT DESIGN CHAPTER 6.
`
`
`
`In addition to these factors, the temperature of the medium and the agitation
`rate also affect the rate of drug dissolution. In vivo, the temperature is maintained
`at a constant 37°C, and the agitation (primarily peristaltic movements in the gas—
`trointestinal tract) is reasonably constant. In contrast, in vitro studies of dissolution
`kinetics require maintenance of constant temperature and agitation. Temperature
`is generally kept at 37°C, and the agitation or stirring rate is held to a specified
`I rpm (revolutions per minute). An increase in temperature will increase the kinetic
`energy of the molecules and increase the diffusion constant, D. An increase in ag-
`itation of the solvent medium will reduce the "thickness, 12, of the stagnant layer, al-
`lowing for more rapid drug dissolution.
`Factors that affect drug dissolution of a solid oral dosage form include (1) the
`physical and chemical nature of the active drug substance, (2) the nature of the
`ingredients, and (3) the method of manufacture.
`
`PHYSICOCHEMICAL NATURE OF THE DRUG
`
`The physical and chemical properties of the solid drug particles not only affect dis~
`solution kinetics but are important considerations in designing the dosage form
`(Table 6.1). For example, intravenous solutions are difficult to prepare with drugs
`that have poor aqueous solubility. Drugs that are physically or chemically unstable
`may require special excipient, coating, or manufacturing process to protect the
`drug from degradation. The potent pharmacodynamic activity of drugs, such as es-
`trogens and other hormones, penicillin antibiotics, cancer chemotherapeutic
`agents, and others, may cause adverse reactions to personnel who are exposed to
`these drugs during manufacture and also presents a problem.
`
`. Solubility, pH, and Drug Absorption
`
`The solubility—pH profile is a plot of the solubility of the drug at various physiologic
`pH values. For designing oral dosage forms, the formulator must consider that the
`L
`
`Polymorphism
`
`TABLE 6.1 Physicochemical Properties for Consideration in Drug Product Design
`
`pKa and pH Profile
`Necessary for optimum stability and solubility of the final product.
`Particle Size
`May affect the solubility of the drug and therefore the dissolution rate
`of the product.
`The ability of a drug to exist in various crystal forms may change the
`solubility of the drug. Also, the stability of each form is important,
`because polymorphs may convert from one form to another
`Moisture absorption may affect the physical structure as well as stability
`of the product.
`May give some indication of the relative affinity of the drug for oil and
`water. A drug that has high affinity for oil may have poor release and
`dissolution from the foundation.
`
`Hygroscopicity
`
`Partition Coefficient
`
`pH Stability Profile
`
`Excipient interaction
`
`The compatibility of the excipients with the drug and sometimes trace
`elements in excipients may affect the stability of the product. it is
`important to have specifications of all raw materials.
`The stability of solutions is often affected by the pH of the vehicle;
`furthermore, because the pH in the stomach and gut is different,
`knowledge of the stability profile would help to avoid or prevent
`degradation of the product during storage or after administration.
`
`AstraZeneca Exhibit 2162 p. 16
`
`

`

`134
`
`CHAPTER 6. BIOPHARMACEUTIC CONSIDERATIONS IN DRUG PRODUCT DESIGN
`
`a
`
`natural pH environment of the gastrointestinal tract varies from acidic in the stom-
`ach to slightly alkaline in the small intestine. A basic drug is more soluble in an
`acidic medium forming a soluble salt. Conversely, an acid drug is more soluble in
`the intestine, forming a soluble salt at the more alkaline pH. The solubility—pH
`profile gives a rough estimation of the completeness of dissolution for a dose of a
`drug in the stomach or in the small intestine. Solubility may be improved with the
`addition of an acidic or basic excipient. Solubilization of aspirin, for example, may
`be increased by the addition of an alkaline buffer. In the formulation of controlled-
`release drugs, buffering agents may be added to slow or modify the release rate of
`a fast—dissolving drug. To be effective, however, the controlled—release drug prod-
`uct must be a nondisintegrating dosage form. The buffering agent is released slowly
`rather than rapidly so that the drug does not dissolve immediately in the sur-
`rounding gastrointestinal fluid.
`
`Stability, pH, and Drug Absorption
`
`The pH—stabz'lz'ty profile is a plot of the reaction rate constant for drug degradation
`versus pH. If drug decomposition occurs by acid or base catalysis, some prediction
`for degradation of the drug in the gastrointestinal tract may be made. For exam—
`ple, erythromycin has a pH—dependent stability profile. In acidic medium, as in the
`stomach, erythromycin decomposition occurs rapidly, whereas, in neutral or alka-
`line pH, the drug is relatively stable. Consequently, erythromycin tablets are en—
`teric coated to protect against acid degradation in the stomach. This information
`also led subsequently to the preparation of a less water soluble erythromycin salt
`that is more stable in the stomach. The dissolution rate of erythromycin powder
`varied from 100% dissolved in 1 hour to less than 40% dissolved in 1 hour. The
`
`slow-dissolving raw drug material (active pharmaceutical ingredient) also resulted
`in slow-dissolving drug products. Therefore, the dissolution of powdered raw drug
`material is a very useful in vitro method for the prediction of a bioavailability prob-
`lem of the erythromycin product in the body.
`
`Particle Size and Drug Absorption
`
`The effective surface area of the drug is increased enormously by a reduction in
`the particle size. Because dissolution is thought to take place at the surface of the
`solute (drug), the greater the surface area, the more rapid the rate of drug disso—
`lution. The geometric shape of the particle also affects the surface area, and, dur-
`ing dissolution, the surface is constantly changing. In dissolution calculations, the
`solute particle is usually assumed to have retained its geometric shape.
`Particle size and particle size distribution studies are important for drugs that
`have low water solubility. Many hydrophobic drugs are very active intravenously but
`are not very effective when given orally due to poor absorption. Griseofulvin, ni-
`trofurantoin, and many steroids are drugs with low aqueous solubility; reduction
`of the particle size decreased by milling to a micronized form has improved the
`oral absorption of these drugs. Smaller particle size results in an increase in the
`total surface area of the particles, enhances water penetration into the particles,
`and increases the dissolution rates. With poorly soluble drugs, a disintegrant may
`be added to the formulation to ensure rapid disintegration of the tablet and re—
`lease of the particles. The addition of surface—active agents may increase wetting as
`well as solubility of these drugs.
`
`AstraZeneca Exhibit 2162 p. 17
`
`

`

`W‘
`
`
`
`BIOPHARMACEUTIC CONSIDERATIONS IN DRUG PRODUCT DESIGN CHAPTER 6. 135
`
`24
`
`°
`
`100%
`o
`
`:r 20
`E\
`‘32
`: l6
`.3
`
`E E
`
`‘2
`8
`
`I
`4
`l
`'1
`0
`
`-
`
`-
`2
`
`50%
`25%
`
`0%
`-
`4
`
`.
`
`I
`
`lo
`
`12
`
`14
`
`\
`22
`24
`
`I
`
`8
`
`6
`
`After closing (hours)
`
`;
`
`C 5
`
`'6
`
`Figure 6-3. Comparison of mean blood serum levels obtained with chloramphenicol palmitate sus-
`pensions containing varying ratios of a and [3 polymorphs, following single oral dose equivalent to
`LB 9 chl