2 0 TH EDITION
`
`Remington: The
`Science and
`Practice
`of Pharmacy
`
`ALFONSO R GENNARO
`Chairman of the Editorial Board
`and Editor
`
`Williams & Connolly LLP
`
`MAR 16 2015
`
`library
`
`-
`
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 1
`
`

`

`Editor: Daniel Limmer
`Managing Editor: Matthew J. Hauber
`Marketing Manager: Anne Smith
`II'
`
`Lippincott Williams & Wilkins
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`Baltimore, Maryland 21201-2436 USA
`
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`be reproduced in any form or by any means, including photocopying, or utilized
`by any information storage and retrieval system without written permission
`from the copyright owner.
`
`The publisher is not responsible (as a matter of product liability, negligence or
`otherwise) for any injury resulting from any material contained herein. This
`publication contains information relating to general principles of medical care
`which should not be construed as specific instructions for individual patients.
`Manufacturers' product information and package inserts should be reviewed for
`current information, including contraindications, dosages and precautions.
`
`Printed in the United States of America
`
`Entered according to Act of Congress, in the year 1885 by Joseph P Remington,
`in the Office of the Librarian of Congress, at Washington DC
`
`Copyright 1889, 1894, 1905, 1907, 1917, by Joseph P Remington
`
`Copyright 1926, 1936, by the Joseph P Remington Estate
`
`" ·''
`
`qopyright 1948, 1951, by the Philadelphia College of Pharmacy and Science
`
`Copyright 1956, 1960, 1965, 1970, 1975, 1980, 1985, 1990, 1995, by the Phila(cid:173)
`delphia College of Pharmacy and Science
`
`Copyright 2000, by the University of the Sciences in Philadelphia
`
`All Rights Reserved
`Library of Congress Catalog Card Information is available
`ISBN 0-683-306472
`
`.
`.
`The publishers have made every effort to trace the copyright holders for borrowed
`material. If they have inadvertently overlooked any, they will be pleased to make
`the necessary arrangements at the first opportunity,.
`
`The use of structural formulas from USAN and the USP Dictionary of Drug
`Names is by permission of The USP Convention. The Convention is not respon(cid:173)
`. , , ,
`sible for any inaccuracy contained herein.
`Notice-This text is riot intended to represent, lior"Shall it be interpreted to be, the
`equivalent of or a substitute for the official United States Pharmacopeia (USP)
`and/or the National Formulary (NF). In the event of any difference or discrep(cid:173)
`ancy between the current official USP or NF standards of strength, quality,
`Purity, packaging and labeling for drugs and representations of them herein, the
`context and effect of the official compendia shall prevail.
`
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`at (800) 638-3030 or fax orders to (301) 824-7390. International customers
`should call (301) 714-2324.
`
`00 01 02 03 04
`12345678910
`
`--~
`
`Opiant Exhibit 2093
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 2
`
`

`

`Remington: The Science and Practice of Pharmacy . . . A treatise on the theory
`and practice of the phormoceuticol sciences, with essential
`information about phormoceuticol and medicinal agents; also, o
`guide to the professional responsibilities of the pharmacist as the
`drug information specialist of the health team ... A textboo/1 and
`reference wor/1 for pharmacists, physicians, and other practitioners of
`the phormoceuticol and medico/ sciences.
`
`EDITORS
`
`Alfonso R Gennaro, Choir
`
`Nicholas G Popovich
`
`Aro H Der Morderosion
`
`Glen R Hanson
`
`Thomas Medwicl"
`
`Roger L Schnoore
`
`Joseph G Schwartz ··
`
`H Steve White
`
`AUTHORS
`
`The 119 chapters of this edition of Remington were written by the
`
`editors, by members of the Editorial Goard, and by the authors
`
`listed on pages viii to x.
`
`Managing Editor
`-
`Editorial Assistant
`
`John E Hoover, GSc (Phorm)
`
`Gannie Grighom Pocl"er, RNC, GA
`
`Director
`
`Philip P Gerbino 1995-2000
`
`Twentieth Edition-2000
`
`Published in the 180th year of the
`PHILADELPHIA COLLEGE OF PHARMACY AND SCIENCE
`
`Opiant Exhibit 2093
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 3
`
`

`

`Remington Historicol/Diogrophicol Doto
`
`The following is a record of the editors and the dates of publication of successive editions of this boo!,, prior to the 13th
`Edition !mown as Remington's Practice of Pharmacy and subsequently as Remington's Pharmaceutical Sciences
`through the 19th Edition.
`
`First Edition, 1886
`Second Edition, 1889
`Third Edition, 1897
`Foul'th Edition, 1905
`FiHh Edition, 1907
`Sixth Edition, 1917
`
`Seventh Edition, 1926
`
`Editors
`E Fullerton Cool,
`Charles H LaWoll
`
`Eighth Edition, 1936
`
`Editors
`E Fullerton Cool,
`Charles H LaWoll
`
`Ninth Edition, 1948
`Tenth Edition, 1951
`
`Eleventh Edition, 1956
`
`Editors
`Eric W Martin
`E Fullerton Cool,
`
`TweIHh Edition, 1961
`
`Editors
`Eric W Mortin
`E Fullerton Cool,
`E Emerson Leuallen
`Authur Osol
`Linwood F Tice
`Clarence T Van Meter
`
`Thirteenth Edition, 1965
`
`Editor-in-Chief
`Eric W Martin
`Editors
`Grafton D Chase
`Herald R Cox
`Richard A Deno
`Alfonso R Gennaro
`Stewart C Harvey
`
`Fourteenth Edition~ 1970
`
`Chairman, Editorial Doard
`Arthur Osol
`Editors
`Grafton D Chase
`Richard A Deno
`Alfonso R Gennaro
`Melvin R Gibson
`Stewart C Harvey
`
`Joseph P Remington
`
`FiHeenth Edition, 1975
`
`Chairman, Editorial Doard
`Arthur Osol
`Editors
`John T Anderson
`Cecil L 13endush
`Grafton D Chase
`Alfonso R Gennaro
`Melvin R Gibson
`
`Sixteenth Edition, 1980
`
`Chairman, Editorial Doard
`Arthur Osol
`Editors
`Grafton D Chase
`Alfonso R Gennaro
`Melvin R Gibson
`
`Seventeenth Edition, 1985
`
`Chairman, Editorial Doard
`Alfonso R Gennaro
`Editors
`Grafton D Chose
`Ara H Der Morderosian
`Stewart C Harvey
`Daniel A Hussar
`Thomas Medwicl,
`
`Eighteenth Edition, 1990
`
`Chairman, Editoriaf"Board
`Alfonso R Gennaro
`
`Editors
`Grafton D Chase
`Ara H Der Marderosian
`Stewart C Harvey
`Daniel A Hussar
`Thomas Medwicl,
`
`Nineteenth Edition, 1995
`
`Chairman, Editorial Doard
`Alfonso R Gennaro
`
`Editors
`Grafton D Chase
`Ara H Der Marderosian
`Glen R Hanson
`Daniel A Hussar
`Thomas Medwicl,
`
`Managing Editor
`John E Hoover
`
`C 130yd Granberg
`Stewart C Harvey
`Robert E King
`Alfred N Martin
`Ewart A Swinyard
`
`C 130yd Gronberg
`Stewart C Harvey
`Robert E King
`Alfred N Mortin
`Ewart A Swinyard
`Gilbert L Zin!,
`
`Managing Editor
`John E Hoover
`
`Edward G Rippie
`Joseph D Schwartz
`Ewart A Swinyard
`Gilbert L Zink
`
`Managing Editor
`John E Hoover
`Editorial Assistant
`13onnie Packer
`
`Edward G Rippie
`Joseph D Schwartz
`Ewart A Swinyord
`Gilbert L Zin!,
`
`Managing Editor
`Jahn E Hoover
`Editorial Assistant
`13onnie Pacl,er
`
`Edward G Rippie
`Joseph D Schwartz
`H Steve White
`Gilbert L Zin!,
`
`Joseph P Remington
`Assisted by
`E Fullerton Cool,
`
`Associate Editors
`Ivor Griffith
`Adley 13 Nichols
`Arthur Osol
`
`Editors
`E Fullerton Cool,
`Eric W Mortin
`
`Associate Editors
`E Emerson Leuollen
`Arthur Osol
`Linwood F Tice
`Clarence T Van Meter
`
`Assistant to the Editors
`John Hoover
`
`Managing Editor
`John E Hoover
`
`Robert E King
`E Emerson Leuallen
`Authur Osol
`Ewart A Swinyard
`Clarence T Von Meter
`
`Managing Editor
`John E Hoover
`
`Robert E King
`Alfred N Martin
`Ewart A Swinyard
`Clarence T Von Meter
`
`vi
`
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`IPR2019-00694
`Page 4
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`

`

`Editorial Doard Members and Editors
`
`Alfonso R Gennaro, PhD/ University of the Sciences in Philadelphia-Professor of Chemistry. Chair, Editorial
`[3oard and Editor. Coeditor of Part 6, Pharmacodynamics, and Part 7, Pharmaceutical and
`Medicinal Agents. Coauthor of Chapter 25.
`
`Ara H Der Marderosian, PhD / University of the Sciences in Philadelphia-Professor of Pharrriacognosy and
`Medicinal Chemistry, Scientific Director, Complementary and Alternative Medicine Institute. Editor
`of Part 1, Orientation. Coauthor of Chapters 7, 49, and 103.
`
`Glen R Hanson, DDS, PhD/ College of Pharmacy and School of Medicine, University of Utah-Professor of
`Pharmacology and Toxicology. Coeditor of Part 6, Phormacodynomics, and Port 7 Pharmaceutical
`and Medicinal Agents. Author of Chapters 75, 76, and 83.
`
`Thomas Medwick, PhD / Rutgers University College of Pharmacy-Professor Emeritus, Department of
`Pharmaceutical Chemistry. Editor of Part 3, Pharmaceutical Chemistry, and Part 4, Pharmaceutical
`Testing, Analysis, and Control. Author of Chapter 24. Coauthor of Chapter 30.
`
`Nicholas G Popovich, PhD / Purdue University, School of Pharmacy and Pharmacal Sciences-Professor of
`Pharmacy Practice. Editor of Part 8A, Pharmacy Administration, Part 8[3, Fundamentals of
`Pharmacy Practice, and Part 8C, Patient Care. Coauthor of Chapter 101.
`
`Roger 1 Schnaare, PhD / University of the Sciences in Philadelphia, Philadelphia College of Pharmacy(cid:173)
`Professor of Pharmacy, Department of Pharmaceutics. Editor of Part 2, Pharmaceutics. Coauthor
`of Chapter 11 .
`
`Joseph D Schwartz:, PhD / University of the Sciences in Philadelphia, Philadelphia College of Pharmacy.
`[3urroughs-Wellcome Fund Professor of Pharmaceutics, Director of Pharmacy Research. Editor of
`Port 5, Pharmaceutical Manufacturing. Coauthor of Chapters 37 and 45.
`
`H Steve White, PhD / College of Pharmacy, University of Utah-Associate Professor of Pharmacology and
`Toxicology. Coeditor of Part 6, Pharmacodynamics, ond Part 7, Pharmaceutical and Medicinal
`Agents. Author of Chapters 74, 79, 80, 81, 84, and 88.
`
`vii
`
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 5
`
`

`

`Tobie of Contents
`
`Part 1 Orientation
`
`Scope of Pharmacy ........... .
`2 Evolution of Phormocy .......... .
`3 Ethics ond Professionalism .................. .
`4 The Practice of Community Pharmacy .... · ...... .
`5 Pharmacists in Industry . . . . . . . . . . . . . . . . . . . . . .
`6 Pharmacists in Government ................. .
`7 Pharmacists and Public Health ................ .
`8 Information P-esources in Pharmacy and the
`Pharmaceutical Sciences ................... , .
`9 Clinical Drug Literature ................... .
`10 fl-eseorch. . . . . . . . . . . . . . . . . . . . . . . . . .
`
`Part 2 Pharmaceutics
`
`11 Pharmaceutical Calculations ................. .
`12 Statistics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`13 Molecular Structure, Properties, and States of Matter .. .
`14 Complex Formation ....................... .
`15 Thermodynamics ......................... .
`16 Solutions and Phase Equilibria ................ .
`17 Ionic Solutions and Electrotytic Equilibria ......... .
`18 Tonicity, Osmoticity, Osmolality, and Osmolority.
`19 Chemical Kinetics ........................ .
`20 lnterfacial Phenomena ..................... .
`21 Colloidal Dispersions ....................... .
`22 Coarse Dispersions . . . . . . . . . . . . . . . . . . . . . . . . .
`23 P-heology .............................. .
`
`Part 3 Pharmaceutical Chemistry
`
`24 Inorganic Pharmaceutical Chemistry ........... .
`25 Organic Pharmaceutical Chemistry ............ .
`26 Natural Products .......................... .
`27 Drug Nomenclature-United States Adopted
`Names ................................ .
`28 Structure-Activity P-elationship and Drug Design .... .
`29 Fundamentals of P-adionuclides .............. .
`
`Part 4 Pharmaceutical Testing, Analysis and Control
`
`30 Analysis of Medicinals ...................... .
`31 Biological Testing ........................ .
`32 Clinical Analysis .......................... .
`33 Chromatography ......................... .
`34 Instrumental Methods of Analysis .............. .
`35 Dissolution .............................. .
`
`Part 5 Pharmaceutical Manufacturing
`
`36
`37
`38
`39
`40
`41
`42
`43
`44
`45
`46
`47
`48
`
`Separation . . . . . . . . . . . . . . . . . . . . . . . . . .
`Powders ............................... .
`Preformulation ........................... .
`Solutions, Emulsions, Suspensions, and Extracts .... .
`Sterilization ..................... .
`. ..
`Parenteral Preparations
`. . . . . . . .
`Intravenous Admixtures ................... .
`Ophthalmic Preparations ........... .
`Medicated Topicals . . . . . . . . . . . . . . . . . . . . . . . .
`Oral Solid Dosage Forms ................... .
`Coating of Pharmaceutical Dosage Forms ....... .
`Controlled-P-elease Drug-Delivery Systems .
`The Introduction of New Drugs ........ .
`
`3
`7
`19
`28
`33
`38
`47
`
`60
`70
`81
`
`91
`124
`159
`183
`198
`208
`227
`246
`263
`275
`288
`316
`335
`
`359
`385
`409
`
`441
`458
`469
`
`485
`540
`552
`587
`614
`654
`
`669
`681
`700
`721
`753
`780
`807
`821
`836
`858
`894
`903
`930
`
`49 Biotechnology and Drugs ................... .
`50 Aerosols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`51 Quality Assurance and Control ............... .
`52 Stability of Pharmaceutical Products ............ .
`53 13io6vailability and 13ioequivalency Testing ....... .
`54 Plastic Paclmging Materials .................. .
`55 Pharmaceutical Necessities .................. .
`
`Part 6 Pharmacodynamics
`56 Diseases: Manifestations and Pathophysiology
`5 7 Drug Absorption, Action, and Disposition ........ .
`58 13asic Phormacol~inetics ..................... .
`59 Clinical Phormacol~inetics ................... .
`60 Principles of Immunology ................... .
`61 Adverse Drug fl-eactions .................... .
`62 Phormacogenetics ........................ .
`63 Pharmacological Aspects of Substance Abuse ..... .
`
`Part 7 Pharmaceutical and Medicinal Agents
`64 Diagnostic Drugs and P-eagents. . . . . . . . . . . . . . . .
`65 Topical Drugs ............................ .
`66 Gastrointestinal and Liver Drugs ............... .
`6 7 l3lood, Fluids, Electrolytes, and Hematological Drugs. . . .
`68 Cardiovascular Drugs ...................... .
`69 fl-espiratory Drugs. . . . . . . . . . . . . . . . . . . . . . . . . .
`70 Sympathomimetic Drugs ................... .
`71 Cholinomimetic Drugs ... · .................. .
`72 Adrenergic and Adrenergic Neuron 131ocl~ing Drugs ..
`73 Antimuscarinic and Antispasmodic Drugs ........ .
`74 Sl~eletal Muscle P-elaxants ................... .
`75 Diuretic Drugs ........................... .
`76 Uterine and Antimigraine Drugs .............. .
`77 Hormones and Hormone Antagonists .......... .
`7 8 General Anesthetics . . . . . . . . . . . . . . . . . . . . . . . .
`79 Local Anesthetics ......................... .
`80 Sedative and Hypnotic Drugs . . . . . . . . . . . . . . . . .
`81 Antiepilei;>tic Drugs ........................ .
`82 Psychoph;rmacologic Agents ................ .
`83 Analgesic, Antipyretic, and Anti-Inflammatory
`Drugs ................................. •
`84 Histamine and Antihistaminic Drugs ............ .
`85 Central NeNous System Stimulants ............. .
`86 Antineoplastic and lmmunoactive Drugs ........ .
`8 7 Anti-lnfectives . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`88 Parasiticides ............................. .
`89 Immunizing Agents and Allergenic Extracts ...... .
`
`Part 8 Pharmacy Practice
`
`Part 8A Pharmacy Administration
`90 Laws Governing Pharmacy ................. .
`91 Phormacoeconomics ...................... .
`92 Marl~eting Pharmaceutical Core SeNices ........ .
`93 Documenting and Billing for Pharmaceutical Care
`_·SeNices ............................... .
`94 Community Pharmacy Economics and
`Management ........................... .
`95 Product P-ecalls and Withdrawals ............. .
`
`Part 8D Fundamentals of Pharmacy Practice
`
`944
`963
`980
`986
`995
`1005
`1015
`
`1053
`1098
`1127
`1145
`1156
`1165
`1169
`1175
`
`1185
`1200
`1219
`1243
`1274
`1297
`1305
`1314
`1322
`1328
`1333
`1344
`1354
`1358
`1395
`1400
`1407
`1421
`1429
`
`1444
`1464
`1471
`1477
`1507
`1562
`1567
`
`1595
`1625
`1634
`
`1640
`
`1650
`1666
`
`96 Drug Education .................... .
`
`1677
`
`xiv
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`97 The Prescription ..................... .
`98 Extemporaneous Prescription Compounding
`99 Poison Control .................. .
`100 Nutrition in Pharmacy Practice ............... .
`101 Self-Care/Diagnostic Products ................. .
`102 Drug Interactions ......................... .
`103 Complementary and Alternative Medical Health
`Care .................................. .
`104 Nuclear Pharmacy Practice ................. .
`105 Enzymes .............................. .
`106 Vitamins and Other Nutrients ................ .
`107 Pesticides .............................. .
`108 Surgical Supplies ......................... .
`109 Health Accessories ........................ .
`
`1687
`1706
`1716
`1725
`1738
`1746
`
`1762
`1781
`1792
`1796
`1825
`1846
`1857
`
`Port 8C Patient Core
`
`110 Ambulatory Patient Care ................... .
`111 Institutional Patient Care ................... .
`112 Long-Term Care Facilities ................... .
`
`1893
`1911
`1932
`
`113 The Patient: llehaviaral Determinants
`114 Patient Communication .
`. ........ .
`115 Patient Compliance ............... .
`116 Pharmacoepidemiolagy .............. .
`117 Integrated Health-Core Delivery Systems ... .
`118 Home Health Patient Care
`...... .
`119 Aseptic Technology for Home-Care
`....................... .
`Pharmaceuticals
`
`Appendixes
`
`Dose Equivalents ............... .
`Periodic Chart ............ .
`Logarithms .... .
`
`Glossary and Index
`
`1948
`1957
`1966
`1980
`1990
`2012
`
`2020
`
`2033
`2034
`2036
`
`. ............. .
`Glossary . . . . . . . . . . . . . . . .
`Index ................................. .
`
`2037
`2039
`
`xv
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`

`

`Statistics
`
`Sanford Bolton, PhD
`Visiting Professor
`Department of Pharmacy
`University of Arizona
`Tucson, AZ 85721
`
`C HAP TE R 12
`
`Statistical methods are an integral part of the development,
`evaluation, and marketing of drug products. In this chapter,
`elementary definitions and ·some common statistical applica(cid:173)
`tions to problems of pharmaceutical interest will be presented
`and discussed.
`Statistics is often thought of as a collection of numbers and
`averages, such as vital statistics, baseball statistics, or statis(cid:173)
`tics derived from the census. Indeed, this is an important
`aspect of statistical thinking, and such collections of data and
`counting do play a role in pharmacy and medicine, such as in
`marketing or disease-incidence data. However, here more em(cid:173)
`phasis will be placed on the use of statistics in presenting,
`analyzing, and interpreting data that are often, but not neces(cid:173)
`sarily always, derived from planned experiments.
`
`OVERVIEW AND INTRODUCTION
`
`Although the material in this chapter is elementary for the
`most part, those readers who have had little or no exposure to
`statistical methods may be overwhelmed by the large amount
`of information presented in a relatively small space. This in(cid:173)
`troduction presents an overview of the chapter so that the
`student can get a feeling for what is contained here. Many
`illustrations are interspersed in the didactic discussion to show
`the applications in a practical way.
`The first part of the chapter deals with introductory defini(cid:173)
`tions and methods. An understanding of this material is essen(cid:173)
`tial if one wishes to use elementary techniques intelligently, or
`if one wishes to pursue more advanced topics. Definitions in(cid:173)
`clude statistical jargon, design of scientific experiments (both
`laboratory and clinical experiments), the concept of sampling
`(including methods of obtaining samples for experiments), and
`the concept and definition of probability distributions. These
`concepts lay the foundation for the understanding of practical
`applications of statistics to scientific research. Although not
`complete, an understanding of this introductory material
`should allow the student to feel confident about applying ele(cid:173)
`mentary methods to real data.
`Some words of caution are necessary here. Real examples
`often have twists that are not obvious to the initiate, which
`make them different from simple textbook examples. At the
`beginning, students should try to seek advice from more expe(cid:173)
`rienced persons, preferably a statistician, to make sure that
`they are using the techniques in a proper manner.
`For those with some background in statistics, the initial
`portion of the chapter should serve as a quick review and an
`introduction to the material that follows. The elementary def(cid:173)
`initions include the usual measures of central tendency and
`spread, such as the mean, median, standard deviation, vari(cid:173)
`ance, coefficient of variation, and range. The nature of varia-
`
`124
`
`tion and its basis for statistical thinking is discussed, as with(cid:173)
`out variation, statistical reasoning would be unnecessary.
`Statistical approaches take the experimental variability (often
`referred to as error) into account during the analysis.
`Statistical "proof" is different from mathematical proofs. In
`statistics, one is never sure of an answer or a decision. The
`decision has a given probability of being correct. Discrete and
`continuous variables are defined and discussed. Discrete vari(cid:173)
`ables include binomial measurements, which may have a "yes
`or no" outcome (eg, accept or reject). Continuous variables can
`have any number of outcomes and include typical measure(cid:173)
`ments (eg, weight or assay).
`Definitions of a population and a sample are presented;
`these are very important concepts in statistical reasoning. Def(cid:173)
`initions and examples of bias, precision, and accuracy are in(cid:173)
`troduced. Examples are used to illustrate the fact that data
`may be precise but not accurate and vice versa.
`The analysis of any data set depends on the experimental
`design, the detailed experimental procedure. A description of
`some common designs and the manner in which data may be
`collected are presented in this chapter. The integrity of data
`from any experiment is only as good as the design and the care
`that was taken to inwlement the design. Each experiment is
`different. Design and sampling considerations are different for
`questionnaire surveys, censuses (complete sampling), and lab(cid:173)
`oratory or clinical experiments. Good experimental design
`should result in optimality, increased precision, and lack of
`bias. The random selection of objects to be included in an
`experiment and/or a(?signed to treatments is of vital impor(cid:173)
`tance in pharmaceutical and clinical research. In particular,
`controlled clinical studies should be designed as double-blind
`studies if at all possible. A controlled study is a designed study
`that includes a placebo or a positive control (eg, a known active
`drug).
`Statistical inference and estimation are cornerstones of sta(cid:173)
`tistical applications in pharmaceutical research. Statistical in(cid:173)
`ference results from the formulation and testing of a hypothe(cid:173)
`sis, the null hypothesis. In this procedure, a hypothesis is
`formulated with regard to the true, but unknown, values of
`parameters of the data distribution that is investigated in an
`experiment. For example, the average potency of a commercial
`batch of tablets may be of interest, or the mean blood pressure
`reduction of a new drug compared to an effective marketed
`product may be assessed. The experimental outcome is ob(cid:173)
`served and analyzed. Using statistical procedures that usually
`are based on the normal probability distribution, an inference
`based on probability is drawn as to whether the proposed
`hypothesis is true; eg, "Is the true average potency equal to 100
`mg?" or "Are the two comparative drugs equally efficacious?"
`Again, these inferences are not proofs. Two treatments may
`be declared to be equal, but only with a given degree of assur(cid:173)
`ance expressed in probability terms. For example, two treat-
`
`Opiant Exhibit 2093
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 8
`
`

`

`Table 12-10. The t Table
`Distribution oft Giving Both the Two-Sided or Two-Tailed Probability and the One-Sided or One-Tailed Probability
`According to Degrees of Freedom
`
`ONE TAIL
`
`p = 0.4
`
`p = 0.3
`
`P = 0.2
`
`P = 0.1
`
`P = 0.05
`
`P = 0.025
`
`P = 0.01
`
`P = 0.005
`
`STATISTICS
`
`135
`
`DF
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`40
`60
`120
`00
`
`P = 0.8
`0.325
`0.289
`0.277
`0.271
`0.267
`0.265
`0.263
`0.262
`0.261
`0.260
`0.260
`0.259
`0.259
`0.258
`0.258
`0.258
`0.257
`0.257
`0.257
`0.257
`0.257
`0.256
`0.256
`0.256
`0.256
`0.256
`0.256
`0.256
`0.256
`0.256
`0.255
`0.254
`0.254
`0.253
`
`P = 0.6
`0.727
`0.617
`0.584
`0.569
`0.559
`0.553
`0.549
`0.546
`0.543
`0.542
`0.540
`0.539
`0.538
`0.537
`0.536
`0.535
`0.534
`0.534
`· 0.533
`0.533
`0.532
`0.532
`0.532
`0.531
`0.531
`0.531
`0.531
`0.530
`0.530
`0.530
`0.529
`0.527
`0.526
`0.524
`
`P= 0.4
`1.376
`1.061
`0.978
`0.941
`0.920
`0.906
`0.896
`0.889
`0.883
`0.879
`0.876
`0.873
`0.870
`0.868
`0.866
`0.865
`0.863
`0.862
`0.861
`0.860
`0.859
`0.858
`0.858
`0.857
`0.856
`0.856
`0.855
`0.855
`0.854
`0.854
`0.851
`0.848
`0.845
`0.842
`
`P = 0.2
`3.078
`1.886
`1.638
`1.533
`1.476
`1.440
`1.415
`1.397
`1.383
`1.372
`1.363
`1.356
`1.350
`1.345
`1.341
`1.337
`1.333
`1.330
`1.328
`1.325
`1.323
`1.321
`1.319
`1.318
`1.316
`1.315
`1.314
`1.313
`1.311
`1.310
`1.303
`1.296
`1.289
`1.282
`
`TWO TAILS
`
`P= 0.1
`6.314
`2.920
`2.353
`2.132
`2.015
`1.943
`1.895
`1.860
`1.833
`1.812
`1.796
`1.782
`1.771
`1.761
`1.753
`1.746
`1.740
`1.734
`1.729
`1.725
`1.721
`1.717
`1.714
`1. 711
`1.708
`1.706
`1.703
`1.701
`1.699
`1.697
`1.684
`1.671
`1.658
`1.645
`
`P = 0.05
`12.706
`4.303
`3.182
`2.776
`2.571
`2.447
`2.365
`2.306
`2.262
`2.228
`2.201
`2.179
`2.160
`2.145
`2.131
`2.120
`2.110
`2.101
`2.093
`2.086
`2.080
`2.074
`2.069
`2.064
`2.060
`2.056
`2.052
`2.048
`2.045
`2.042
`2.021
`2.000
`1.980
`1.960
`
`P = 0.02
`31.821
`6.965
`4.541
`3.747
`3.365
`3.143
`2.998
`2.896
`2.821
`2.764
`2.718
`2.681
`2.650
`2.624
`2.602
`2.583
`2.567
`2.552
`2.539
`2.528
`2.518
`2.508
`2.500
`2.492
`2.485
`2.479
`2.473
`2.467
`2.462
`2.457
`2.423
`2.390
`2.358
`2.326
`
`P = 0.01
`63.657
`9.925
`5.841
`4.604
`4.032
`3.707
`3.499
`3.355
`3.250
`3.169
`3.106
`3.055
`3.012
`2.977
`2.947
`2.921
`2.898
`2.878
`2.861
`2.845
`2.831
`2.819
`2.807
`2.797
`2.787
`2.779
`2.771
`2.763
`2.756
`2.750
`2.704
`2.660
`2.617
`2.576
`
`below-2.262 and greater than +2.262 comprise 5% of the area.
`Conversely, it can be said that the probability of finding a t
`value between -2.262 and +2.262 is 95% for DF = 9.
`Similarly, Table 12-10 gives values for one-tailed probabil(cid:173)
`ities for P = 0.5% and 2.5%. These values correspond to the
`two-tailed probabilities of 0.01 (1 %) and 0.05 (5%). For exam(cid:173)
`ple, for 9 DF, the probability of finding at value greater than
`+2.262 (or -2.262) is 2.5%. Examples throughout the remain(cid:173)
`der of this chapter should make the use of the t table clear. In
`the current example of tablet assays, a 95% confidence interval
`can be constructed using the t distribution. The mean is 98.88
`and the sample SD is 0.954. The t value for 95% of the area for
`9 DF is 2.262. The 95% confidence interval is
`
`98.88 ± 2.262 X 0.954/ [IO = 98.88 ± 0.68
`= 98.20 to 99.56
`
`This can be interpreted to mean that the probability is
`95% that the true mean of the batch lies between 98.20 and
`99.56 mg.
`Are you surprised by the narrow limits of the interval based
`·on only 10 tablets? The reason for the tight limits is the small
`standard deviation. Note that this does not guarantee that the
`true mean, µ,, lies in this interval. As has been emphasized
`before, statistical statements and conclusions are probabilistic
`in nature.
`t TEST-In addition to estimating the mean assay of a
`batch of 10 tablets, the 10 assay values were obtained to per-
`
`form a statistical test comparing the average result to that
`expected based on the labeled potency of 100 mg. If every one of
`the 3,000,000 tablets in this batch were assayed, the average
`potency would be known. The random sample of 10 is repre(cid:173)
`sentative of the entire batch, but it is extremely unlikely that
`the sample average exactly will equat the batch average. The
`question to be asked is, in view of the variability of the 10
`assays and the average result, can it be ascertained that these
`10 tablets came from a population with an average of 100 mg?
`The solution to this question, an example of statistical infer(cid:173)
`ence, is obtained using a simple t test. This t test consists of the
`following steps, which can be considered typical in many de(cid:173)
`signed experiments.
`Construct a Null Hypothesis-A null hypothesis is an assump(cid:173)
`tion about the parameter under investigation, which is the mean value
`in this example. The null hypothesis is a statement that assumes that
`the parameter is equal to some value, usually a null value. That is, the
`hypothetical value is considered to represent a situation of no change.
`How to construct the null hypothesis is not always obvious, but a few
`examples should make this concept clearer.
`For the tablet assays, no change means that the population average,
`µ.,, is equal to the labeled potency, 100 mg. The null hypothesis is of the
`following form
`
`H0 :µ = 100 mg
`
`The statistical test allows a decision to be made: the sample of tablets
`are or are not representative of a population with mean 100 mg.
`
`Opiant Exhibit 2093
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 9
`
`

`

`Chemical Kinetics
`
`Rodney J Wigent, PhD
`Associate Professor of Chemistry
`Research Associate, Professor of Pharmaceutics
`University of the Sciences in Philadelphia
`Philadelphia, PA 19104
`
`CHAPTER
`19
`
`Thermodynamic parameters, such as LiG, LiE, LiH and LiS, are
`state functions that only depend on the initial and final states
`of a chemical process-reactants and products-and are inde(cid:173)
`pendent of the pathway taken to get to the final state from the
`initial state. Chemical kinetics is the discipline that is con(cid:173)
`cerned with the mechanism by which a chemical process gets to
`its final state from its initial state and the rate in which this
`reaction proceeds. Therefore, chemical kinetics involves the
`study of rate of chemical change and the way in which this rate
`is influenced by the conditions of the concentration of reac(cid:173)
`tants, products, and other chemical species that may be
`present, and by factors such as solvent, pressure, and temper(cid:173)
`ature. From these studies, one or more mechanisms involving a
`series of elementary processes may be postulated to explain
`how the reactants are converted to products during a chemical
`process. Applied to pharmaceutics, such information permits a
`rational approach to the stabilization of drug products, and
`prediction of shelf life and optimum storage conditions.
`This chapter is intended as a general introduction to this
`subject. A comprehensive review of experimental approaches
`and interpretation of data can be found in several texts, such as
`the book by House 1 and the compilation of information relative
`to kinetic studies on pharmaceuticals by Garrett.2
`
`REACTION RATE
`
`The rate of a reaction is the velocity with which a reactant or
`reactants undergoes a chemical change. Experimentally, the
`rate of a reaction must be determined by directly or indirectly
`following the change in the concentration of the reactants or
`products as a function of time. When there is more than one
`reactant, such changes need to be normalized according to the
`stoichiometry of the reaction. For a reaction of the type
`aA + bB + ... -> cC + dD + ...
`
`where the uppercase letters represent chemical species and the
`lowercase letters represent stoichiometric coefficients, the rate
`in which reactants go to products can be determined by follow(cid:173)
`ing the rate of the disappearance of the reactants as a function
`of time
`
`1 d[B]
`1 d[A]
`Rate=-~~= -b~
`
`(1)
`
`The brackets denote concentration (usually molar concentration
`unless otherwise indicated) and d represents the derivative func(cid:173)
`tion. The negative sign signifies that the concentration of the
`reactants is decreasing, as the rate must always be positive as
`long as the reaction is progressing from reactants to products.
`
`The rate at whi