Remington
`
`Essentials of Pharmaceutics
`
`Edited by Linda A. Felton, PhD
`Chair, Department of Pharmaceutical Sciences
`Associate Professor of Pharmaceutics
`College of Pharmacy
`University of New Mexico
`Albuquerque, NM, USA
`
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`

`

`Published by Pharmaceutical Press
`1 Lambeth High Street, London SE1 7JN, UK
`
`© Pharmaceutical Press 2012
`
` is a trade mark of Pharmaceutical Press
`
`Pharmaceutical Press is the publishing division of the Royal Pharmaceutical Society
`
`First edition published 2013
`
`Typeset by Newgen KnowledgeWorks, India
`
`Printed in the United States of America by Edwards Brothers Malloy
`
`ISBN 978 0 85711 105 0
`
`All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or
`transmitted in any form or by any means, without the prior written permission of the copyright holder.
`
`The publisher makes no representation, express or implied, with regard to the accuracy of the information
`contained in this book and cannot accept any legal responsibility or liability for any errors or omissions that
`may be made.
`
`A catalogue record for this book is available from the British Library.
`
`This book is adapted from contributions published in Remington: The Science and Practice of Pharmacy 22nd edition.
`
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`

`

`Chapter 16
`
`
`
` Tonicity, osmoticity, osmolality,
`osmolarity
` Andrew Ingham, MRPharmS, PhD and
`Cathy Y. Poon, PharmD
`
`Chapter 17
`
`
`Chemical kinetics
`Rodney J. Wigent, PhD
`
`277
`
`301
`
`Chapter 18
`
`
`Chapter 19
`
`
`
`Chapter 20
`
`
`Chapter 21
`
`
`317
`Complex formation
` Thorsteinn Loftsson, MSPharm, MSc, PhD
`and Marcus E. Brewster, PhD
`
`Interfacial phenomena
`Paul M. Bummer, PhD and
`Yvonne Perrie, PhD
`
`329
`
`Colloidal dispersions
` Bill J. Bowman, RPh, PhD,
`Clyde M. Ofner III, PhD, Hans Schott, PhD
`and Yvonne Perrie, PhD
`
`343
`
`Coarse dispersions
` James Swarbrick, DSc, PhD,
`Joseph T. Rubino, PhD, RPh and
`Orapin P. Rubino, PhD
`
`Chapter 22
`
`
`Rheology
`Lawrence H. Block, PhD
`
`Chapter 23
`
`
`Powders
` Yi-Bo Wang and
`Robert O. Williams III, PhD
`
`Chapter 24
`
`
`
` Solutions, Emulsions, Suspensions,
`and Extracts
`Michael M. Crowley, PhD
`
`101
`
`Chapter 25
`
`
`
`133
`
` Sterilization Processes and Sterility
`469
`Assurance
` James Agalloco, BEChE, MSChE, MBA,
`William G. Lindboem, Jr., PhD and Russell
`E. Madsen, MS
`
`Chapter 26
`
`
`Parenteral Preparations
`Michael J. Akers, PhD
`
`371
`
`393
`
`411
`
`435
`
`495
`
`533
`
`Contents
`
`Preface v
`About the editor vii
`Contributors ix
`
`1
`
`9
`
`29
`
`37
`
`51
`
`63
`
`81
`
`93
`
` Information resources in pharmacy and
`the pharmaceutical sciences
` Robin H. Bogner, PhD and
`Sharon Giovenale, MSLS
`
`Analysis of medicinals
`Raymond D. Skwierczynski, PhD
`
`Quality assurance and control
` John H. Parker, PhD and
`John E. Enders, PhD, MBA
`
`Stability of pharmaceutical products
` Allan D. Bokser, PhD and
`Patrick B. O’Donnell, PhD
`
`Bioavailability and bioequivalence
`Steven B. Johnson, PharmD
`
`Dissolution
` Vijai Kumar, MS, MBA and
`Praveen Hiremath, PhD
`
` Modern-day drug discovery and
`development
`Rick G. Schnatz, PharmD
`
`The New Drug Approval Process
` Linda A. Felton, PhD and
`Dennis W. Raisch, PhD, RPh
`
` Metrology and pharmaceutical
`calculations
` Roger L. Schnaare, PhD and
`Shelly J. Prince, PhD
`
`Statistics
` Sanford Bolton, PhD and
`Richard Hirsch, PhD
`
`Chapter 1
`
`
`
`Chapter 2
`
`
`Chapter 3
`
`
`Chapter 4
`
`
`Chapter 5
`
`
`Chapter 6
`
`
`Chapter 7
`
`
`
`Chapter 8
`
`
`Chapter 9
`
`
`
`Chapter 10
`
`
`Chapter 11
`
`
`
` Molecular structure, properties and
`states of matter
` Thomas Rades, PhD,
`Keith C. Gordon, PhD and
`Kirsten Graeser, PhD
`
`177
`
`Chapter 27
`
`
`
` Pharmaceutical Compounding – USP
`<797> Sterile Preparations
` Catherine Cone, PharmD, BCPS,
`Linda A. Felton, PhD, Amy Bachyrycz,
`PharmD
`
`Chapter 12
`
`
`Thermodynamics
`Timothy S. Wiedmann, PhD
`
`Chapter 13
`
`
`Solutions and phase equilibria
`Pardeep K. Gupta, PhD
`
`Chapter 14
`
`
`Separation methods
`Loyd V. Allen, Jr., PhD, RPh
`
`207
`
`219
`
`241
`
`Chapter 15
`
`
`Ionic solutions and electrolytic equilibria 257
`Barbara R. Conway, PhD
`
`Chapter 28
`
`
`Ophthalmic Preparations
` Masood Chowhan, PhD, John C. Lang,
`PhD, Paul Missel, PhD
`
`541
`
`Chapter 29
`
`
`Medicated Topicals
`Lawrence H. Block, PhD
`
`Chapter 30
`
`
`Oral Solid Dosage Forms
` Ahmed Adel Sakr, PhD and
`Fars K. Alanazi, PhD
`
`565
`
`581
`
`v
`
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`

`

`vi
`
`CONTENTS
`
`Chapter 31
`
`
`
`Chapter 32
`
`
`
`Chapter 33
`
`
`Chapter 34
`
`
`Chapter 35
`
`
` Coating of Pharmaceutical Dosage
`Forms
`Stuart C. Porter, PhD
`
` Oral Modified-Release Drug Delivery
`Systems
` Ali R. Rajabi-Siahboomi, PhD,
`Manish S. Rane, PhD and
`Linda A. Felton, PhD
`
`Aerosols
` John J. Sciarra, PhD and
`Christopher J. Sciarra, BS, MS Industrial
`Pharmacy
`
`633
`
`611
`
`Chapter 36
`
`
`Pharmaceutical Excipients
`William J. Reilly, Jr., MBA
`
`Chapter 37
`
`623
`
`
`
` Basic pharmacokinetics and
`pharmacodynamics
` Raymond E. Galinsky, PharmD and
`Craig K. Svensson, PharmD, PhD
`
`Chapter 38
`
`
`Drug action and effect
`Donald N. Franz, PhD
`
`Chapter 39
`
`
`
` Drug absorption, distribution,
`metabolism and excretion
`Michael R. Franklin, PhD
`
`Biotechnology and Drugs
` Ara H. DerMarderosian, PhD and
`Zhiyu Li, PhD
`
`Pharmaceutical Packaging
` C. Jeanne Taborsky, BSChem and
`Kathleen Deiss, RN
`
`651
`
`Chapter 40
`
`
`
`667
`
`Index
`
` Pharmacokinetics/pharmacodynamics
`in drug development
`George L. Drusano, MD
`
`683
`
`705
`
`727
`
`739
`
`755
`
`763
`
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`

`

`Chapter 4
`Stability of Pharmaceutical Products
`
`Allan D. Bokser, PhD and Patrick B. O’Donnell, PhD
`
`IntroductIon 37
`
`regulatory requIrementS 38
`
`Product StabIlIty 39
`
`PredIctIng Shelf lIfe 45
`
`aPProxImatIonS In aSSeSSIng
`Product StabIlIty 45
`
`PharmaceutIcal contaInerS 47
`
`cloSureS 48
`
`IntroductIon
`
`Stability of a pharmaceutical product may be defined as the
`capability of a particular formulation, in a specific container/
`closure system, to remain within its physical, chemical, mi-
`crobiological, therapeutic, and toxicological specifications at
`a defined storage condition. Pharmaceutical products are ex-
`pected to meet their specifications for identity, purity, quality,
`and strength throughout their defined storage period at specific
`storage conditions. Assurances that the packaged product will
`be stable for its anticipated shelf life must come from an accu-
`mulation of valid data on the drug in its commercial package.
`These stability data include selected parameters that, taken to-
`gether, form the stability profile.
`The stability of a pharmaceutical product is investigated
`throughout the various stages of the development process. The
`stability of a drug substance is first assessed in the preformula-
`tion stage. At this stage, pharmaceutical scientists determine
`the drug substance and its related salts stability/compatibility
`with various solvents, buffered solutions and excipients consid-
`ered for formulation development. Suitable analytical methods
`must be employed in order to ensure the likelihood that this
`assessment will be successful. Optimization of a stable formula-
`tion of a pharmaceutical product is built (using statistical de-
`sign) upon the information obtained from the preformulation
`stage and continues during the formulation development stages.
`Typically, the first formulation development stage may be
`for preclinical studies or as late as the preparation of a “first
`in human” formulation which is often a non-elegant formula-
`tion optimized for short-term dose-ranging clinical studies. The
`second major formulation development stage occurs to support
`Phase II clinical studies (proof of concept phase). The pharma-
`ceutical product developed at this stage is usually the prototype
`for the commercial product. Therefore, the pharmaceutical
`product will be formulated based in part on the stability infor-
`mation obtained from the previous formulations and must meet
`stability requirements for longer-term clinical studies. In the fi-
`nal formulation development state for Phase III clinical studies,
`the formulation must be truly representative of what the com-
`mercial pharmaceutical product will be in order to avoid delays
`in approval. In addition to building on the clinical requirements
`of the drug, the commercial pharmaceutical product must also
`incorporate the commercial or the final market image of the
`product, which includes the container closure system. The sta-
`bility of this product must be demonstrated to the appropriate
`regulatory agencies in order to assign an expiration period and
`date for the product. This expiration period allows for the as-
`signment of an expiration date based on the manufacture date
`of each lot of drug product.
`Once a pharmaceutical product has gained regulatory ap-
`proval and is marketed, the pharmacist must understand the
`proper storage and handling of the drug. In some cases, a phar-
`macist may need to prepare stable compounded preparations
`from this product.
`
`Most drug products are not shipped directly from the man-
`ufacturer to a pharmacy. Typically, a drug product is shipped
`from a manufacturer to a distribution center. From the distri-
`bution center the drug product is then shipped to a wholesaler.
`From the wholesaler, the drug product may be shipped to the
`distribution center for a pharmacy chain or directly to the phar-
`macy. Finally, the drug product is dispensed by the pharmacy
`to the patient. Dispensing of the drug product may be at a hos-
`pital, a clinic, and a traditional “brick and mortar” pharmacy or
`from a mail-order pharmacy. Therefore, the stability typically
`must also assess the robustness of the drug product through its
`supply chain. It is not unusual for temperature excursions to
`occur during these transfers of control.
`Inventory control, or holding, of each drug is important for a
`wholesaler or pharmacy. A drug must be within its expiration
`dating throughout its use by the patient. Solid oral dosages may
`be dispensed in the commercial packaging or in a pharmacy
`supplied container closure system. Most prescriptions are sup-
`plied to patients for up to 30 or 90 days by traditional and mail-
`order pharmacies, respectively. Inventory control of product by
`wholesalers and pharmacies must assess how much dating must
`remain on a product for it to be useful for its customer. This
`causes the actual holding of a product to be shorter than the
`expiration date. Under normal circumstances it is unusual for a
`pharmacy to accept any product with less than 6 month dating
`remaining on a product.
`Much has been written about the development of a stable
`pharmaceutical product. Comprehensive treatments of all as-
`pects of pharmaceutical product stability have been published
`by Connors et al.1, Carstensen2 and more recently by Allen.3
`This chapter will outline the appropriate steps from prefor-
`mulation to drug approval to assure that the pharmaceutical
`product developed is stable. Requirements for compounded
`products will also be discussed.
`The United States Pharmacopeia (USP) General Chapter
`<1191>4 defines the stability of a pharmaceutical product as
`“extent to which a product retains, within specified limits, and
`throughout its period of storage and use (i.e., its shelf life), the
`same properties and characteristics that it possessed at the
`time of its manufacture.” There are five types of stability that
`must be considered for each drug (Table 4-1).
`The use of kinetic and predictive studies for establishing
`credible expiration dating for pharmaceutical products is now
`accepted worldwide. Scientifically designed studies using reli-
`able, meaningful, and specific stability-indicating assays, ap-
`propriate statistical concepts, and a computer to analyze the
`resulting data are used to determine an accurate and realistic
`shelf life. In this way the maximum amount of valid information
`is obtained to establish a reliable, defendable expiration date
`for each formulation. The assigned expiration date is a direct
`application and interpretation of the knowledge gained from
`the stability study.
`Although there are exceptions, 90% of labeled potency
`generally is recognized as the minimum acceptable potency
`
`37
`
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`

`veterinary drugs, are updated periodically in light of current
`knowledge and technology.
`
`comPendIa
`The USP also contains extensive stability and expiration dat-
`ing information. Included are a discussion of stability consid-
`erations in dispensing practices and the responsibilities of both
`the pharmaceutical manufacturer and the dispensing pharma-
`cist. It now is required that product labeling of official articles
`provide recommended storage conditions and an expiration
`date assigned to the specific formulation and package. Official
`storage conditions as defined by the USP 349 are as follows:
`
`• Freezer – a place where temperature is maintained ther-
`mostatically between –25°C and –10°C.
`• Cold – any temperature not exceeding 8°C and refrigera-
`tor is a cold place where the temperature is maintained
`thermostatically between 2 and 8°C.
`• Controlled Cold Temperature – temperature maintained
`thermostatically between 2° and 8°C.
`• Cool is defined as any temperature between 8 and 15°C.
`• Room Temperature – the temperature prevailing in a
`working area.
`• Controlled Room Temperature – temperature maintained
`thermostatically between 20 and 25°C.
`• Warm – any temperature between 30 and 40°C.
`• Excessive Heat – any heat above 40°C.
`• Protect from Freezing – where, in addition to the risk
`of breakage of the container, freezing subjects an article
`to loss of a product to a loss of strength, potency or to
`destructive alteration its characteristics, the container
`label should bear appropriate instructions to protect the
`product from freezing.
`• Dry Place – denotes a place that does not exceed 40%
`average relative humidity (RH) at Controlled Room Tem-
`perature or the equivalent water vapor pressure at other
`temperatures.
`
`Most drug products are stored at controlled room tempera-
`ture and are labeled as such. As is noted above in USP 34, the
`definition of controlled room temperature was a “temperature
`maintained thermostatically between 20 and 25°C (68 and
`77°F).” This definition was established to harmonize with in-
`ternational drug standards efforts. The usual or customary tem-
`perature range is identified as 20 to 25°C, with the possibility of
`encountering excursions in the 15 to 30°C range and with the
`introduction the mean kinetic temperature (MKT).
`The mean kinetic temperature is calculated using the follow-
`ing equation:
`
`
`
` 
`
`−
`
`∆
`/
`H RT
`n
`
`−
`1
`
`e
`
`+
`
`e
`
`−
`
`∆
`/
`H RT
`n
`
`−
`
`∆
`/
`H RT
`1
`
`e
`
`+
`
`−
`
`e
`
` 
`
`In
`
`
`
`Tk
`
`=
`
`(1)
`
`
`
`
`
`∆
`/
`H R
`∆
`/
`+
`+
`H RT
`
`2
`−
`n
`
`
`
`in which Tk is the mean kinetic temperature; ΔH is the heat of ac-
`tivation, 83.144kJ·mole–1; R is the universal gas constant, 8.3144
`× 10 - 3 kJ· mole–1· degree–1; T1 is the value for the temperature
`(in degrees Kelvin (°K)) recorded during the first time period, T2 is
`the value for the temperature recorded during the second time pe-
`riod, e.g., second week; Tn–1 is the value of the second to last time
`period, and Tn is the value for the temperature recorded during
`the nth time period. Typically, the time period is in days or weeks.
`Mean kinetic temperature determine the thermal expose of
`a material. This allows an acceptable estimation to assess if a
`temperature excursion (or series of excursions) adversely af-
`fected a material.
`FDA and ICH Guidelines provide recommendations for
`
`1. the design of stability studies to establish appropriate
`expiry and product storage requirements
`
`38
`
`PHARMACEUTICAL ANALYSIS AND QUALITY CONTROL
`
`Type of Stability
`Chemical
`
`Physical
`
`Microbiological
`
`Table 4-1. types of Stability
`Conditions Maintained Throughout the Shelf Life
`of the Drug Product
`Each active ingredient retains its chemical
`integrity and labeled potency, within the
`specified limits.
`The original physical properties, including
`appearance, palatability, uniformity,
`dissolution, and suspendability are retained.
`Sterility or resistance to microbial growth
`is retained according to the specified
`requirements. Antimicrobial agents that
`are present retain effectiveness within the
`specified limits.
`The therapeutic effect remains unchanged.
`No significant increase in toxicity occurs.
`
`Therapeutic
`Toxicological
`
`level over the shelf life of a drug product. Exceptions to this
`minimum potency include drugs with active pharmaceutical
`ingredients that have a narrow therapeutic thresholds and
`biologics.
`The stability of a commercial pharmaceutical product is
`expressed as an expiration date (expiry). Expiration dating is
`defined, therefore, as the time in which a drug product in a
`specific packaging configuration will remain stable when stored
`under recommended conditions. This date is usually calculat-
`ed by adding the established expiration period to the date of
`manufacture. The date of manufacture is many times defined as
`the date in which the active pharmaceutical ingredient is first
`combined with a drug product excipient.
`An expiration date, which is expressed traditionally in
`terms of month and year, denotes the last day of the month.
`In the United States, the expiration date shall appear on the
`immediate container and the outer retail package. However,
`when single-dose containers are packaged in individual car-
`tons, the expiration date may be placed on the individual
`carton instead of the immediate product container. If a dry
`product is to be reconstituted at the time of dispensing, expi-
`ration dates are assigned to both the dry mixture and the re-
`constituted product. Tamper-resistant packaging is to be used
`where applicable.
`
`regulatory requIrementS
`
`Stability study requirements and expiration dating are covered
`in the Current Good Manufacturing Practices (cGMPs),5 the
`USP,6 and the FDA and ICH guidelines.
`
`good manufacturIng PractIceS
`The GMPs5 as stated in US 21 CFR part 211.166 requires that
`there shall be a written testing program designed to assess the
`stability characteristics of drug products. The results of such
`stability testing shall be used to determine appropriate stor-
`age conditions and expiration dating. The latter is to ensure
`that the pharmaceutical product meets applicable standards of
`identity, strength, quality, and purity at time of use. Regulatory
`agencies of other regions have similar requirements. For ex-
`ample Canadian regulations require that every distributor and
`importer shall monitor, by means of a continuing program, the
`stability of the drug in the package in which it is sold.7 The Eu-
`ropean Union GMPs states “after marketing, the stability of the
`medicinal product should be monitored according to a continu-
`ous appropriate program that will permit the detection of any
`stability issue (e.g., changes in levels of impurities or dissolu-
`tion profile) associated with the formulation in the marketed
`package.”8 These regulations, which apply to both human and
`
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`

`2. the submission of stability information for investigational
`new drugs, biologics, new drug applications, and biologi-
`cal product license applications.
`
`Thus, the guidelines represent a framework for the experi-
`mental design and data analysis as well as the type of docu-
`mentation needed to meet regulatory requirements in the
`drug-development process.
`The International Conference on Harmonization of Technical
`Requirements for Registration of Pharmaceuticals for Human
`Use (ICH) is an ongoing project that brought together regulatory
`authorities and experts from the pharmaceutical industry from
`three regions of the world; Europe, Japan, and the US since its
`inception in 1990. The first conference (ICH1) took place in
`November 1991 in Brussels, and the second conference (ICH2)
`in Orlando, FL, in October 1993. These conferences continue
`to provide an open forum for discussion and resulted in the
`creation of an extensive set of guidelines dealing with the many
`aspects of safety, quality, and efficacy of medicinal products.
`The following ICH Harmonized Tripartite Guidelines related to
`stability are summarized below.
`
`• Q1A (R2) provides the general requirements for Sta-
`bility Testing of New Drug Substances and Products.
`The main thrust of the stability guideline centers on
`criteria for setting up stability protocols, shown in
`Table 4-2. ICH Q1A is considered the parent guideline for
`stability.10
`• Q1B provides the general requirements for assessing the
`intrinsic photostability characteristics of new drug sub-
`stances and drug products.11
`• Q1C provides the reduced general requirements for
`stability testing of new drug products dosage forms that
`use active ingredients already approved in another dosage
`form.12
`• Q1D provides approaches that allows for bracketing and
`matrixing designs for stability testing. This is especially
`important when a new drug product is to be commer-
`cialized with multiple strengths in multiple packaging
`configurations.13
`• Q1E provides acceptable approaches for evaluating stabil-
`ity data to assess the shelf life of the product in a registra-
`tion application.14
`• Q1F was withdrawn. It provided definitions for testing
`conditions to register drugs marketed in Climatic Zones
`III and IV.15 However, countries in Climatic Zone IV
`believed that a larger safety margin was required than
`presented in this guidance.
`
`It should be noted that all ICH guidelines provide approaches
`that are now common in the industry for assessing stability of
`a drug substance or drug product. However, these guidelines
`also make it clear that alternative approaches can be used when
`there are scientifically justifiable reasons.
`
`Table 4-2a. Stability Protocols
`
`Conditions
`Long-term testing 25°C ± 2°C/60%
`RH ± 5%
`Accelerated testing 40°C ± 2°C/75%
`RH ± 6%
`Alternate testinga 30°C ± 2°C/65%
`RH ± 5%
`
`Minimum Time
`Period at Submission
`12 month
`
`6 month
`
`12 month
`
`Required if significant change occurs during 6-mo storage under
`conditions of accelerated testing.
`
`Durations (Months)
`6
`9
`12
`X
`X
`X,
`Y
`O
`
`O
`
`O
`
`0
`R*
`
`1
`
`X
`
`3
`X
`
`O
`
`X
`
`STABILITY Of PHARMACEUTICAL PRODUCTS
`
`39
`
`Table 4-2b. example Stability Pull Schedule for a Solid
`oral dose for Zone I and II
`Storage
`Conditions
`
`18
`X
`
`24
`X
`
`36
`X
`
`25 °C/60
`% RH
`30 °C/65
`% RH
`X,
`40 °C/75%
`Y
`RH
`*from Release testing if testing is within 30 days of stability set down
`R= Release Tests; Appearance (visual); Identity; Assay (HPLC);
`Impurities (HPLC); Dissolution (USP <711>); Moisture Content
`(Karl fischer); Uniformity of Dosage Unit
`X = Tests at Every Stability Pull; Appearance (visual); Assay (HPLC);
`Impurities (HPLC); Dissolution USP <711>
`O = Pull and test only after 40 °C/75% is out of specification;
`Appearance (visual); Assay (HPLC); Impurities (HPLC); Dissolution
`Y = Additional tests periodically performed; Moisture Content (Karl
`fischer)
`
`The FDA and ICH guidelines are readily available on the in-
`ternet. The pharmaceutical scientist can now access a complete
`listing of both FDA and ICH publications. To view the publi-
`cations, go to: http://www.fda.gov/Drugs/GuidanceComplian-
`ceRegulatoryInformation/Guidances/default.htm for the FDA
`guidance webpage, and http://www.ich.org/products/guidelines/
`quality/article/quality-guidelines.html for the ICH guideline
`webpage.
`
`Product StabIlIty
`
`Many factors affect the stability of a pharmaceutical product
`including the intrinsic stability of the active ingredient(s), the
`potential interaction between active and inactive ingredients,
`the manufacturing process, the dosage form, the container-
`liner-closure system and the environmental conditions encoun-
`tered during shipment, storage and handling and length of time
`between manufacture and usage.
`Classically, pharmaceutical product stability evaluations
`have been separated into studies of chemical (including bio-
`chemical) and physical stability of formulations. Realistically,
`there is no absolute division between these two arbitrary divi-
`sions. Physical factors—such as heat, light, and moisture—may
`initiate or accelerate chemical reactions, whereas every time
`a measurement is made on a chemical compound, physical di-
`mensions are included in the study.
`One type of time-related chemical stability failure is a de-
`crease in therapeutic activity of the preparation to below some
`arbitrary labeled content. A second type of chemical stability
`failure is the appearance of a toxic substance, formed as a deg-
`radation product upon storage of the formulation. The numbers
`of published cases reflecting this second type are few. However,
`it is possible, though remote, for both types of stability failures
`to occur simultaneously within the same pharmaceutical prod-
`uct. Thus, the use of stability studies with the resulting applica-
`tion of expiration dating to pharmaceuticals is an attempt to
`predict the approximate time at which the probability of occur-
`rence of a stability failure may reach an intolerable level. This
`estimate is subject to the usual Type 1 or alpha error (setting
`the expiration too early so that the product will be destroyed
`or removed from the market appreciably earlier than actually
`is necessary) and the Type 2 or beta error (setting the date too
`late so that the failure occurs in an unacceptably large pro-
`portion of cases). Thus, it is obligatory that the manufacturer
`clearly and succinctly defines the method for determining the
`
`Opiant Exhibit 2306
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 7
`
`

`

`40
`
`PHARMACEUTICAL ANALYSIS AND QUALITY CONTROL
`
`degree of change in a formulation and the statistical approach
`to be used in making the shelf life prediction. An intrinsic part
`of the statistical methodology must be the statements of value
`for the two types of error. For the safety of the patient a Type 1
`error can be accepted, but not a Type 2 error.
`One type of time related physical stability failures may affect
`the availability or rate of drug release of a product. This type
`of physical stability failure may cause the active ingredient not
`to be released or a higher rate of drug release (dose dumping).
`Another type of time related physical stability failures are ap-
`pearance related. These may just cause the drug product not
`to appear pharmaceutically elegant or may be an artifact of an-
`other physical or chemical stability failure.
`In this treatment, physical and chemical stability are dis-
`cussed along with those dosage form properties that can be
`measured and are useful in predicting shelf life. The effect of
`various physical and chemical phenomena of pharmaceuticals
`also is treated.
`Knowledge of the physical stability of a formulation is very
`important for three primary reasons. First, a pharmaceutical
`product must appear fresh, elegant, and professional, for as long
`as it remains on the shelf. Any changes in physical appearance
`such as color fading or haziness can cause the patient or con-
`sumer to lose confidence in the product. Second, since some
`products are dispensed in multiple-dose containers, potency of
`the active ingredient over time must be ensured for each indi-
`vidual dose. A cloudy solution or a broken emulsion can lead to
`a non-uniform dosage pattern. Third, the active ingredient must
`be bioavailable to the patient throughout the expected shelf life
`of the preparation. A breakdown in the physical system can
`lead to non-availability or “dose dumping” of the medication
`to the patient. In the case of metered-dose inhaler pulmonary
`aerosols, particle aggregation may result in inadequate lung de-
`position of the medication.
`The chemical causes of drug deterioration have been clas-
`sified as incompatibility, oxidation, reduction, hydrolysis,
`racemization, and other mechanisms. In the latter category,
`decarboxylation, deterioration of hydrogen peroxide and
`hypochlorites and the formation of precipitates have been
`included.
`
`PharmaceutIcal doSage formS
`As the various pharmaceutical dosage forms present unique sta-
`bility problems, they are discussed separately in the following
`section.
`tablets
`Stable tablets retain their original size, shape, weight, and color
`under normal handling and storage conditions throughout their
`shelf life. In addition, the in vitro availability of the active ingre-
`dients should not change appreciably with time.
`Excessive powder or solid particles at the bottom of the con-
`tainer, cracks or chips on the face of a tablet, or appearance of
`crystals on the surface of tablets or on container walls are indi-
`cations of physical instability of uncoated tablets. Hence, the ef-
`fect of mild, uniform, and reproducible shaking and tumbling of
`tablets should be studied. The recommended test for such stud-
`ies is the determination of tablet friability as described in the
`USP. Tablet Friability USP <1216> describes the recommended
`apparatus and the test procedure. After visual observation of
`the tablets for chips, cracks, and splits, the intact tablets are
`sorted and weighed to determine the amount of material worn
`away by abrasion. In general, a maximum weight loss of not
`more than 1% of the weight of the tablets being tested is con-
`sidered acceptable for most products. The results of these tests
`are comparative rather than absolute and should be correlated
`with actual stress experience. Packaged tablets also should be
`subjected to cross-country shipping tests as well as to various
`drop tests.
`Tablet hardness (or resistance to crushing or fracturing) can
`be assessed by commercially available hardness testers. As
`
`results will vary with the specific make of the test apparatus
`used, direct comparison of results obtained on different instru-
`ments may not necessarily be made. Thus, the same instrument
`should be used consistently throughout a particular study.
`Color stability of tablets can be followed by an appropriate
`colorimeter or reflectometer with heat, sunlight, and intense ar-
`tificial light employed to accelerate the color deterioration. It is
`still not unusual for color assessment to be performed visually.
`Caution must be used in interpreting the elevated temperature
`data, as the mechanism for degradation at that temperature
`may differ from that at a lower temperature. It is not always
`proper to assume that the same changes will occur at elevated
`temperatures as will be evidenced later at room temperature.
`Cracks, mottling, or tackiness of the coating indicates evidence
`of instability of coated tablets.
`Typically, dissolution is the in vitro test performed to esti-
`mate bioavailability for a tablet regardless of the solubility of
`the active ingredients. Disintegration has been relegated to an
`in-process test or used to help dissolution. Dissolution tests
`should be run in an appropriate medium at 37°C. Actual dis-
`solution conditions, including medium, are developed during
`the clinical development phase of a product. The dissolution
`method developed has to demonstrate a correlation that is
`relevant to the bioavailability of the dosage form. Dissolution
`profiles are examined during development to provide sufficient
`information to define a single sample time point with a mini-
`mum concentration for immediate release product. Controlled
`release drug products require a dissolution profile with concen-
`tration ranges at set sampling points for product assessment.
`When no significant change (such as a change in the polymor-
`phic form of the crystal) has occurred, an unaltered dissolution-
`rate profile of a tablet formulation usually indicates constant in
`vivo bioavailability.
`Uniformity of weight, odor, texture, drug and moisture con-
`tents, and humidity effect may also be studied during a tablet
`stability test.
`gelatin capsules
`Hard gelatin capsules are the type used by pharmaceutical man-
`ufacturers in the production of the majority of their capsule
`products. The pharmacist in the extemporaneous compounding
`of presc