Parenteral Medications
`"OIIIIIIB 1
`Second Edition, Revised and Expanded
`
`Edited by Kenneth E. Avis,
`Herbert A. liebermnn, and lean lnchmun
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`AstraZeneca Exhibit 2103 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017—00904
`
`

`

`Parenteral Medications
`ttolumet
`Serond Edition, Revised and Expanded
`
`Edited by
`
`Kenneth E. Avis
`
`The University of Tennessee
`Memphis, Tennessee
`
`Herbert A. liebermnn
`
`H.H. Lieberman Associates, inc.
`Consultant Services
`
`Livingston, New Jersey
`
`leon larhmun
`
`Lachman Consultant Services
`
`Wesrbunt, New York
`
`Marcel Dekker, Inc.
`
`New York I Basel - Hong Kong
`
`AstraZeneca Exhibit 2103 p. 2
`
`

`

`Library of Congress C'atatoging - “1— Publication Data
`
`Pharmaceutical dosage forms, parenteral medications I edited by
`Kenneth E. Avis, Herbert A. Lieberman, and Leon Leohman. -- 2nd ed. .
`rev. and expanded.
`p.
`cm.
`
`Includes bibliographical references and index.
`ISBN 0-3243—8576-2 (v. 1 : elk. paper)
`1. Parenteral solutions.
`2. Pharmaceutical technology.
`Kenneth E.
`II. Lieberman, Herbert A.
`III. Leohman. Leon.
`[DNLM: 1. Infusions. Parenteral.
`WB 354 P536]
`RSZDIJ‘STPéS 1992
`615'. 19--dc20
`DNLMIDLC
`
`2. Technology, Pharmaceutical.
`
`I. Avis,
`
`for Library of Congress
`
`91 -38063
`CIP
`
`This book is printed on acid—free paper.
`
`Copyright © 1992 by MARCEL DEKKER, INC. All Rights Reserved
`
`Neither this book nor any part may be reproduced. or transmitted in any form
`or by any means; electronic or mechanical, includingphotoeopying. micro-
`filming, and recording, at by any information storage and retrieval system,
`without permission in writing from the publisher.
`
`MARCEL DEKJCER, INC.
`270 Madison Avenue, New York, New York 10016
`
`Current printing (last_ digit):
`10 9 S 7 6 5 4 3 2 ]
`
`PRINTED IN TEE UNITED STATES OF AMERICA
`
`AstraZeneca Exhibit 2103 p. 3
`
`

`

`Contents
`
`Preface
`Contributors
`
`Contents of Pharmaceutical Dosage Forms: Parenteral Medications,
`Second Edition, Revised and Expanded, Volumes 2 and 3
`Contents of Pharmaceutical Dosage Forms: Tablets, Second Edition.
`Revised and Expanded, Volumes 1-3
`Contents of Pharmaceutical Dosage Forms: Dispense Systems,
`Volumes 1 and 2
`
`E.E:-
`
`xiii
`
`xv
`
`xvii
`
`Chapter 1 The Parenteral Dosage Form and Its Historical Development
`
`1
`
`Kenneth E. Arts
`
`1. The Dosage Farm
`11.. History of Parenteral Medications
`Appendix A: Glossary of Terms
`Appendix 3': Highlights in the History of
`Parenteral Medications
`References
`
`Chapter 2
`
`Parenteral Drug Administration: Routes. Precautions,
`Problems, Complications, and Drug Bel-Wary Systems
`
`Richard J. Dame. Michael J. Alters. and
`Salvatore J. Tums
`
`Introduction
`I. General Indications for Parenteral
`
`Administration of Drugs
`ll. Pharmaceutical Factors Affecting Parenteral
`Administration
`
`Specific Routes of Administration
`III.
`IV . Distribution of Parenterally Administered Agents
`
`1
`4
`12
`
`19
`15
`
`1'?
`
`1’?
`
`18
`
`19
`
`21
`39
`
`vii
`
`AstraZeneca Exhibit 2103 p. 4
`
`

`

`viii
`
`Contents
`
`V'. Precautions. Problems. Hazards, and
`Complication Associated with Parenteral Drug
`Administration
`
`VI. Methods and Devices for Drug Delivery Systems
`VII.
`Summary
`References
`
`_
`
`Chapter 3 Biopharmaceutics of Injectable Medications
`
`So! Motola
`
`I.
`
`Introduction
`
`II. Physioochemical and Physiological Factors
`Affecting Drug Absorption by Injection: An
`Overview
`
`111. Application of Pharmacokinetics to Biopharmr
`centic Investigations: Pharmacokinetic Models
`"IV. Examples of BiopharmaeeuticlPharmaeokmetio
`Principles
`V. Regulatory Considerations for Bioequivalence
`Studies
`
`VI. Bioequivolence Study of Two Injeotable Forms
`of the Same Drug
`Summary
`References.
`
`VII.
`
`Chapter 4
`
`Preformulation Research of Parenteral Medications
`
`So! Morale and Shreamm N. Aghorkor
`
`I .
`
`Introduction
`
`II. Drug Substance Physieochemical Properties
`III. Accelerated Stability Evaluation
`IV. General Modes of Drug Degradation
`V. Preformulatlon Studies for Proteins and Peptides
`VI.
`Preformulation Screening of Parenteral
`Packaging Components
`Summary
`VII.
`VIII. Preformulation Worksheet
`
`References
`
`Chapter 5
`
`Formulation of Small Volume Parenterals
`
`Patrick P. DeLuca and James C. Boylon
`
`I .
`
`Introduction
`
`Formulation Principles
`II.
`III. Container Effect-e. on Formulation
`1V. Stability Evaluation
`V.
`Process Effects
`References
`
`41
`
`49
`56
`5'?
`
`59
`
`59
`
`60
`
`7'?
`
`9%
`
`108
`
`109
`111
`112
`
`115
`
`115
`
`115
`140
`150
`154
`
`158
`183
`163
`
`169
`
`1'?3
`
`17 3
`
`174
`22?"
`234
`244
`245
`
`AstraZencca Exhibit 2103 p. 5
`
`

`

`Contents
`
`ix
`
`Chapter 6
`
`Formulation of Large Volume Parenterals
`
`Levit J. Demorest and Jeffrey G. Hamilton
`
`I.
`II.
`III.
`IV.
`V.
`
`Introduction ‘
`
`Concepts of Formulation
`Formulation Development
`Sqution Quality
`Summary
`References
`
`Chapter 7
`
`Parenteral Products of Peptides and Proteins
`
`YuHChong John Wang
`
`I.
`II.
`III.
`IV.
`
`V.
`
`Introduction
`
`
`Characteristics of Proteins and Peptides
`Formulation Principles
`Compatibility with Packaging Components and
`Infusion Sets
`Formulation of Market Products
`References
`
`Chapter 8
`
`Sterile
`
`Diagnostics
`
`Leif E.
`
`Olsen
`
`Introduction
`
`II.
`III.
`IV.
`
`VI.
`VII.
`
`Diagnostic Products Defined
`Sterile Diagnostics
`Definitions
`
`Aseptic Manufacturing Considerations
`Validation Program
`Conclusion
`References
`
`Chapter 9
`
`Glass Containers for Parenterals
`
`R. Poul Abendroth and Robert N. Clark
`
`I.
`II.
`III.
`
`IV .
`V .
`VI .
`VII.
`VIII.
`
`Introduction
`The Nature of Glass
`
`United States Pharmacopeia Glassware
`Classifications
`The Manufacture of Glass Containers
`Chemical Performance
`Mechanical Performance
`
`The Container and Closure as a System
`Quality Assurance
`References
`
`249
`
`249
`250
`273
`280
`281
`281
`
`283
`
`283
`284
`302
`
`310
`312
`317
`
`321
`
`323.
`321
`322
`325
`330
`351
`359
`359
`
`351
`
`381
`381
`
`362
`369
`375
`380
`380
`382
`384
`
`AstraZeneca Exhibit 2103 p. 6
`
`

`

`a:
`
`Contents
`
`Chapter 10 Use of Plastics for Parenteral Packaging
`
`John M. Anes. Robert S. Nose, and
`Charles H. White
`
`I.
`II.
`III.
`IV.
`V.
`VI.
`
`Introduction
`Fundamentals
`Fabrication Processes
`
`Important Criteria for Selection of Plastics
`Plastics Used in Parenteral Packaging
`Quality Assurance of Parenteral Containers
`References
`
`Chapter 11 Elastomeric Closures for Parenterals
`
`Edward J. Smith and Robert J. Nash
`
`II
`
`II.
`III.
`IV.
`V.
`VI .
`VII.
`VIII.
`IX .
`
`XI.
`
`Elaetomeric Parenteral Packaging Components:
`A Physical Description
`Physical Description of Rubber
`Types of Rubber Used in Parenteral Packaging
`Closure Design
`Rubber Compdunding
`Vulcanization Process
`Closure Manufacture and Control
`
`Closure Design Qualification
`Regulatory Considerations
`Interaction of Drug Formnlations with
`Rubber Closures
`
`Contemporary Closure-Related Issues
`References
`
`Chapter 12 Parenteral Products in Hospital and Home Care
`Pharmacy Practice
`
`John W. Levchuk
`
`1.
`II.
`
`III.
`IV.
`
`V.
`VI.
`VII.
`
`Introduction
`
`The Preparation of Sterile Dosage Forms in the
`Hospital and in Home Care
`Dispensing and Compounding Processes
`Technology of Sterile Compounding in the
`Hospital Pharmacy
`Clinical Supply and Use of Sterile Products
`Quality Assurance
`Conclusion
`
`Appendix: Abbreviated Sequence for Preparing a
`Series of Extemporaneously Compounded LV.
`Admixtures
`References
`
`Index
`
`387
`
`387
`. 389
`398
`407
`422
`439
`443
`
`445
`
`445
`450
`451
`462
`463
`470
`477
`494
`503
`
`505
`50'?
`503
`
`513
`
`513
`
`513
`524
`
`532
`547
`552
`562
`
`56 3
`566
`
`569
`
`AstraZencca Exhibit 2103 p. 7
`
`

`

`4 P
`
`reformulation Research of
`Parenteral Medications
`
`Sol Motola"
`
`Whitehall Laboratories, Hammonton, New Jersey
`
`Shreeram N. Agharkar
`
`Bristol—Myers Squibb Company. Syracuse. New York
`
`I.
`
`INTRODUCTION
`
`Preformulaiion research relates to pharmaceutical and analytical investigations
`that both pressed and so
`.
`. ormu a on eve went e
`a
`r
`sage
`
`forms. Expenmen s are designed to generate
`a a
`aracterizing speci c,
`pharmaceutically important. physicochemical preperties of the drug substance
`and its combination with selected solvents, excipients, and packaging com—
`ponents. These studies are carried out under stressed conditions of tempera-
`ture, light, humidity, and oxygen in order to accelerate and detect potential
`reactions. Taking into account early pharmacological and biopharmaceutlcal
`data, preformulation studies yield key information necessary to guide the term—
`ulator and analyst toward the development of an elegant, stable dosage form
`with good bioavailability. Prior to development of the clinical and marketed
`dosage form, preformulation studies yield basic knowledge necessary to de-
`velop suitable formulations for toxicological use.
`Due to important research leads in a highly competitive field, rapid pro—
`gress is essential, and clinical studies should be initiated as soon as possible.
`Thus an expeditious preformulation program {i.e. , one typically taking 6 to
`10 weeks to complete) is generally required.
`If clinical program acceleration
`is desired, it may be necessary to streamline studies and develop crucial de—
`cision-making data in shorter time periods. Should interim results indicate
`that a more stable or more soluble drug form is needed, expansion of the
`original program will be necessary. Additionally, areas of particular interest
`may arise, such as the elucidation of a reaction mechanism or the investigation
`of unusual solubility phenomena. Such studies may be of prime importance
`and are often addressed either initially or as second-phase preformulation
`studies, depending on their potential impact on the overall program.
`
`*C'ur'r'ent affiliation: Wyeth-Ayerst Laboratories, Radnor, Pennsylvania
`
`115
`
`AstraZeneca Exhibit 2103 p. 8
`
`

`

`115
`
`Metals and Aghar'lcar
`
`The general subject of preformuletion research has been described in de-
`tail by several investigators [1- 5] and is in wide use throughout the pharma-
`ceutical industry. These presentations have dealt mainly with studies designed
`for solid dosage forms. Some specific applications have been made to certain
`areas of parenteral interest [6,7] . The objective of this chapter is to outline
`methods used in developing preformuletion data necessary to characterize
`significant physicochemical properties of new drugs important to a paren-
`teral formulation development program.
`
`ll. DRUG SUBSTANCE PHYSICOCHEMICAL PROPERTIES
`
`Typical physicochemical properties of drug substances that either characterize
`or may exert significant influence on the development of a parenteral formula-
`tion are listed in Table 1.
`
`A. Molecular structure and Weight
`
`These are the most basic characteristics of. a drug ubstance and are among
`the first items to be known. From the molecular structure the investigator
`can make initial judgments regarding potential properties and functional group-
`reactivities, as described in Section IV.
`
`B . Color
`
`Color is generally a function of a drug's inherent chemical structure relating to
`a certain leVel of unsaturation. Color intensity relates to the extent of conju—
`gated unsaturation as Well as the presence of chromophores such as ~NH2, -N03,
`and -CO- (ketonel, which intensify color. Some compounds may appear to have
`color although structurally saturated. Such a phenomenon can often be due to
`the presence of minute traces of highly unsaturated, intensely colored. impurities
`andior degradation products. Thesse substances may be prone to increased
`color formation under stress conditions of heat, oxygen. and light. A signifi-
`cant color change can become a limiting factor to the shelf life of s parenteral
`product even before a significant change in chemical stability is noted.
`
`Table l Physicochemical Properties of Drug Substances
`
`Molecular structure and weight
`
`Solubility
`
`Color
`
`Odor
`
`pH solubith profile
`
`Polymorphism potential
`
`Melting point
`
`Solvate formation
`
`Thermal analytical profile
`
`Absorbance spectra
`
`Particle size and shape
`
`Light stability
`
`Hygrosco'picity potential
`
`Thermal stability
`
`Ionization constant
`
`pH stability profile
`
`Optical activity
`
`Asnaancca Exhibit 2103 p. 9
`
`

`

`Pre formulation Research
`
`1 1 ‘7
`
`The drug substances color should he recorded by s subjective description,
`as well as by an objective means such as by comparison with standard color
`chips [8] , or by spectrophotometric analysis if the compound‘s color intensity
`in solution is proportinsl to concentration. The American Public Health Assn“
`cistion (APHA) color standards [9} can be used effectively to quantitate
`changes in solution color with time. Visible absorbsnce of APHA color stand~
`srds (diluted appropriately) can be measured spectrophotometrically {10]
`to
`
`monitor more accurately the color of solution test samples. An example plot
`
`is shown in figure 1.
`
`Ci Odor
`
`The odor of a new drug substance should be examined by cautiously smelling
`the headspsce of the drug container which has been previously closed to allow
`volatiles to concentrate. The presence and description of any odor should be
`recorded. The substance may exhibit an inherent odor characteristic of major
`functional groups present (i.e. , sulfurcus or garlic—like for sulfides, sulfoxides,
`or sulfhydryl-contsining compounds, or smmoniacsl as for amines). Alternaw
`tively, a drug may be void of characteristic odor or it may have an odor of
`residual solvent. The presence of a solvent odor should be reviewod with the
`synthesis chemist to determine whether the sample has been sdeQustely dried.
`
`D. Particle Size, Shape, and Crystallinity
`
`The particle size of s weter~soluble drug is not of concern unless it exists in
`large aggregates and an increase in rate of solution is desired to reduce menu-
`factoring time. Under such circumstances milling through on appropriate size
`sieve [11] may be sufficient.
`
`soc
`
`37.5
`
`b
`'U
`I
`b
`
`n
`250 e
`fl
`
`U’
`c
`
`"
`
`125
`
`D
`
`2O
`
`4O
`
`60
`
`30
`
`100
`
`% Certified APHA Color S1ancsrc (500 units)
`
`0.4
`
`0.3
`
`EC
`
`Q g
`
`..
`a:
`.-..
`E
`
`"j
`v 02
`3
`
`5.E
`
`D
`
`3 0.1
`q
`
`0
`
`0
`
`
`Figure 1 Typical visible absorbsnce readings at 4100 nm for certified APHA
`color standard (500 units) at various dilutions versus APHA color number.
`
`AstraZeneca Exhibit 2103 p. 10
`
`

`

`ll 8
`
`Mo talc and A ghorkor
`
`Particle size and shape characteristics can be determined by microscopic
`evaluation using either an optical adorescope, preferably with polarizing at—
`tachments, or by a scanning electron microscope. The morphological charac-
`teristics of the drug substance should be recorded either by a sketch or,
`more accurately. by a photomicrograph which acts as a permanent record for
`comparison with future batches. A good estimate of particle size and particle
`size range can be obtained by viewing several fields of a representative sam-
`ple of drug- substance.
`A polarizing microscope is also used to determine whether a compound is
`crystalline or amorphous. Crystalline materials refract polarized light and are
`thus visible when polarization attachments in the ocular and. objective are
`crossed at a 90° angle (crossed polars”) , whereas amorphous or glassy- sub-
`stances become invisible.
`
`Optical microscopes usually operate at useful magnifications of up to illllthE
`with a resolution limit in the vicinity of 1 mo. The scanning electron micro-
`scope provides magmfications up to 200,000! with a resolution of approximate-
`ly 25 3 to determine detailed particle surface morphology as well as. individ-
`ual particle surface characteristics. Whereas the optical microscope provides
`only a two-dimensional View, the seaming electron microscope adds the dimen-
`sion of depth by tilting- the stage to several angles of view during operation.
`Thus what may appear to be a combination of acicular and plate-shaped struc-
`tures under a polarizing microscope could in reality only be a field of flat.
`plates of various sizes with some on edge, as shown in Figure 2. This ability
`to resolve various shapes helps the investigator determine whether a sample
`is morphologically homogencOus. Mixtures of morphological forms either within
`a sample or between samples could indicate the existence of hydrates, solvstes,
`or polymorphic forms which could later significantly affect properties such as
`solubility, stability. and bioaVaflability.
`
`E . Melting Point
`
`The melting point of a substance is thermodynamically defined as the tempera-
`ture at which the solid and liquid phases are in equilibrium as described in
`Equation ( 1).
`
`ssolid r—Jsliquid
`
`m
`
`A melting-point determination is a good first indicatiOn of purity since the
`presence of relatively small amounts of impurity can be detected by a lowering
`as Well as widening in the melting-point range. Methods for detErmining the
`melting- range or temperature are described in detail for various compounds
`[12] . Any peculiar behavior of a substance undergoing melting, such as dra-
`matic change in volume, melting and recrystallization, gas evolution. color
`change, or other physical change, should he recorded and investigated fur-
`ther. Such behavior could be indicative of significant changes, such as a
`polymorphic transition, desolvation, oxidation, or decarboxylation.
`
`F. Thermal Analytical Profile
`
`During- synthesis and isolation. a sample may have been exposed to changes.
`in the temperature environment which may be exhibited as a thermal profile
`
`AstIaZeneca Exhibit 2103 p. 1 I
`
`

`

`Preformulotion Research.
`
`119
`
`when the sample is heated between ambient temperature and its melting point.
`When no thermal history exists, the sample will neither absorb nor give off
`heat prior to its melting point. The basic technique used to study this phe-
`nomenon is called differential thermal analysis (DTA). Essentially, the sample
`is heated in the presence of a sensitive thermocouple while a second, balanced
`thermocouple electrically connected in series opposition is heated at the same
`rate in the presence of an inert reference material. The reference substance
`is one that does not undergo thermal transition within the range of tempera-
`tures to be used. The data are plotted on rectilinear paper with the ordinate
`equal to the difference in temperature between sample and reference, AT,
`and the abscissa equal to the temperature T . Although differences in conven-
`tion exist, this treatment will indicate exothermic reactions above and endo-
`thermic reactions below the baseline.
`If a flat signal results. no differential
`change in temperature (aT) occurred between sample and reference. When a
`sample shows a defined exotherm (heat liberation) 0r endotherm (heat absorp-
`tion) resulting- from physical or chemical changes as a function of temperature,
`these phenomena are indicative of phase transitions. Examples of character-
`istic endothermic transitions that can be detected by this technique are:
`fu-
`sion or melting, crystalline structure changes such as polymorphic transitions,
`sublimation. boiling, and desolvation. An. exothermic effect is seen when crys-
`tallization occurs. Examples of thermal analysis profiles of melts with and
`without decomposition are. shown in Figures 3 and 4. Decomposition upon melt-
`ing is noted when the signal drops below the original baseline following the
`melting endotherm.
`A similar process which examines this phenomena is called differential
`Scanning calorimetry (DSC) . With this technique, the area under the output
`curve is directly proportional to the total amount of energy (q) absorbed or
`liberated from the sample. The abscissa is proportional to the rate of heat
`transfer (dqldt) at any given time. The loss of surface moisture and a de-
`composition melt is evident in the DEC curve shown in Figure 5.
`The thermal analytical method used to detect the existence and stability
`of solvated drug molecules is called thermogrovimetric analysis (TGA).
`In
`this technique relative weight loss is studied between the sample and a refer-
`ence during the heating cycle. The reference chosen is one known not to
`undergo weight loss over the temperature range desired. Weight loss can
`occur as. a result of the loss of sample surface moisture or by molecular desol-
`vation or decomposition. Combined DTA and TGA curves for amphotericin B
`showing intermediate phase transition (DTA) , weight loss, and decomposi-
`tion (TGA) are shown in Figure 6. An overview of thermal analytical methods
`described above is available for further information [17] .
`
`G . Hygroscopicity
`
`A compound is hygroscopic if it picks up a significant amount of moisture
`under a specific condition of temperature and humidity. A high degree of
`hygroscopicity may adverser affect the physical and chemical properties of
`a drug substance, making it either pharmaceutically difficult or unsatisfactory
`to work with.
`
`Hygroscopicity studies are usually carried out over a range of humidity
`conditions relevant to the general laboratory and manufacturing areas as" well
`as uncontrolled storage environment. A low-humidity condition can be used
`
`Asuacheca Exhibit 2103 p. 12
`
`

`

`120
`
`Motels and Aghcrkar
`
`
`
`Figure 2 Microscopic examination of an experimental drug. Views through
`an optical microscope (a) and a scanning electron microscope (b) at various
`stage angles as noted.
`(Courtesy of E. B. Vedas, Merck Frosst Canada. Inc. .
`Pointe Claire-Dowel, Quebec, Canada.)
`
`to determine whether a hydrate will lose water under such storage. Saturated
`solutions of certain salts stored in sealed containers, such as desiccators,
`are used to establish well- defined humidity conditions; examples are shown
`in Table 2.
`
`To carry Out a study. samples of compound are accurately weighed into
`tared containers and placed at various humidity conditions for periods up to
`2 weeks. Weight gain or loss is measured at predetermined intervals until
`equilibrium is reached. An assessment is made regarding the relative weight
`gain as well as color and general flowability. Chemical analysis is often per-
`formed should physical change indicate possible chemical degradation. A hy-
`groscopicity classification is shown in Table 3. Thus from hygroscopicity
`studies the investigator can determine environmental humidity conditions neces—
`sary to maintain initial properties.
`If the drug is very hygroscopic or deter-
`mined to be unstable in the presence of moisture, the drug would have to be
`stored under dry conditions and worked with under low humidity. Close ex—
`amination of the quantity of moisture gained during these experiments is in“
`portant in determining whether hydrate formation is occurring.
`
`AstraZeneca Exhibit 2103 p. 13
`
`

`

`

`

`Match: and Agharkm-
`
`H CONH—Q—Cfla
`’i
`2
`
`'
`
`50
`
`?5
`
`103
`
`125
`
`1
`
`US
`
`200
`
`225
`
`It
`
`122
`
`END!)—0-
`
`«Ir—HO
`
`Figure 3 Structure and differential thermal analysis scan of ergonovine maleate
`with decomposition (USP reference standard, lot L).
`(From Ref. 13.)
`
`cm3
`
`Cl
`
`93"
`
`"92'
`
`
`
`Figure It Structure and differential thermal analysis scan of ketamine.
`Ref. 14.)
`
`("From
`
`AstraZer-leca Exhibit 2103 p. 15
`
`

`

`Preformulatian Research
`
`123
`
`Rmnwaz
`0
`
`0
`
`NH?
`
`NH?
`
`/§Z;§/NH:2
`
`H0
`
`0
`
`0
`
`TEMPERATURE
`
`
`
`
`
`ENDOTHERM‘—‘5—a-EXGTHERM
`
`0
`
`100
`
`200
`
`300
`
`400
`
`TEMPERATURE,
`
`0(3
`
`Figure 5 Structure sand, differential scanning calorimetry scan 0f gentamicin
`sulfate (USP reference standard).
`(From Ref. 15.)
`
`mculr’sec
`
`
`
`1mm
`
`---I—--
`
`'
`
`I
`210
`
`90%
`
`36%
`
`TGA
`
`AMPHQTERICfN B
`
`o
`
`HQ
`
`d0
`
`30
`
`3 20
`
`160
`
`200
`
`240
`
`280
`
`TEMPERATURE 1
`
`“C
`
`Figure 5 Structure, differential thermal analysis, and thermogravimetric anal~
`ysis scan of amphotericin 13.
`(From Ref. 16.)
`
`AstraZeneca Exhibit 2103 p. 16
`
`

`

`1 24
`
`Mo talc and A gh crkor
`
`Table 2 Saturated Salt Solutions for Humidity Control
`
`Percent relative
`Temperature
`
`humidity
`(0C)
`
`Potassium acetate, Kc2H302
`
`Calcium chloride, CsClz-EHZO
`Potassium thiocysnsts, KSCN
`
`Sodium nitrite, NsN02
`
`Sodium acetate, Ns02H302-3H20
`
`20
`
`31
`47
`
`56
`
`76
`
`20
`
`24,5
`20
`
`20
`
`20
`
`
`
`90Zinc sulfate, AnSOévTHZO 20
`
`
`
`Source: Ref. 18.
`
`H . Absorbsnce Spectra
`
`Molecules with structural unsuturation are solo to absorb light within a spo~
`cific frequency range. As mentioned previously, the degree of unsaturation
`coupled with the presence of chromophnrss will influence the extent of absorp-
`tion and whether ultraviolet (409-190 nm) or visible (800400 nm) light will
`be ubsorbccl. The ultraviolet and Visible spectra of compounds in soiution
`or not highly specific; however, they are very suitable for quantitative ans“
`lyticsl work and serve as additional information for compound identification.
`The ultraviolet or visible spoctrum can be oetsrmined by placing approximate-
`ly s 10 to 20 pg ml‘1 solution of the compound in a 1 cm cell, and recording
`the spectrum versus the appropriate solvent blank in the spectral range 190
`to 800 nm. An example of the ultraviolet spectrum of ohlorothiazicls is shown
`in Figure 7. Absorbsncc maxima are evident at 228, 292, and 31!] nm.
`
`Tobie 3 Hygroscopicity Classification
`
`Class IMNonhygroscopic: Essentially no moisture increases occur at relativo
`humiditics below 90%. Furthermore, the increase in moisture content after
`
`storage for 1 week above 90% relative humidity (RH) is less than 20%.
`
`Class IIwSlightly hygroscopic: Essentially no moisture increases occur at
`relative humiditiss below 80%. The increase in moisture content after storage
`for 1 week above 80% RH is less than 40%.
`
`Class Iilwldoderctcly hygroscopic: Moisture content does not increase above
`5% after storage at relative humiditiss below 60%. The increase in moisture
`content after storage for 1 week above 80% RH is less than 50%.
`
`Gloss I V-nVsry hygroscopic: Moisture increase may occur at relative humidi—
`tics as low ss 40 to 509*. The increase in moisture content after storage for
`1 week above 90% RH may exceed 30%.
`
`Source: Ref. 1 9.
`
`AstraZeneca Exhibit 2103 p. 17
`
`

`

`Preformulction Research
`
`125
`
`ABSOEBANCE
`
`220
`
`250
`
`300-
`
`340
`
`WAVELENGTH. nm
`
`Figure 7 Structure and ultraviolet absorbsnce spectrum of chlorothazide.
`(From Ref. 21.)
`
`Relationships- used to compare and quantitate ultraviolet and visible ab-
`sorbance of compounds in solution are shown in Equations (2) and (3).
`
`A
`“Fe.
`
`__A..
`“be
`
`(2)
`
`(3)
`
`In Equation (2) , the quantity :1, called absorptivity. is related to the absorp—
`tion of a compomd of concentration c (in g! 1000 1111) through a sample cell of
`in centimeters and thus has the units liters per gram-centimeter. When the
`concentration is expressed in moles per liter, the absorptivity becomes molar
`ebsorptivity e, and is expressed in leters per mole centimeter.
`Both values should be recorded for each solvent system of interest. For
`quantitative use. either a or e is determined. For a compound in solution the
`molar concentration of an unknown quantity of the same drug can be deter-
`mined by knowing- the absorbence at the wavelength and the cell path length.
`Real-ranging Equation (3) yields Equation (4) .
`
`—_-*}_.
`c—be
`
`(4)
`
`The infrared (IR) spectrum (run between 2.5 and 15 pm) is highly specific
`for each chemical structure, with small structural differences resulting in
`significant spectral changes. Samples can be prepared as a solution. as a
`dispersion in mineral oil (Nujol mull), cr'as a potassium bromide (KB-r) pellet.
`
`Astra-Zeneca Exhibit 2103 p. 18
`
`

`

`12:3
`
`2.5
`100
`
`microns
`
`Motels and Agharkar
`
`3.0
`
`4,0
`
`5.0
`
`6.0
`
`7.0
`
`5.0 9.010
`
`12 I4
`
`80
`
`a O
`
`{L O
`
`M O
`
`Transmittance
`
`accnJ
`
`coma
`
`0
`
`CH,OCCH3
`
`4000
`
`350.0
`
`3000
`
`2500
`
`2000 1800
`
`1600
`
`1400
`
`1200 1000
`
`000 850
`
`Wavenurnber (cl-n")
`
`Figure 8 Structure and infrared spectrum of cefotaxime- in KBr with peaks of
`several functional groups identified.
`(Adapted from Ref. 22.)
`
`After running a spectrum. significant peaks relating to major functional groups
`are identified; spectra of subsequent samples of the same compound are com-
`pared with the original.
`If IR spectral differences are found. the reason for
`and source of change should be investigated. This technique is used to de-
`tect batch-to-batch variations, as an identity test, and for the detection of
`polymorphs and solvates. KBr and Nujol mull spectra of cefotaxime acid are
`shown in Figures 8 and 9, respectively. Peaks corresponding to various func-
`tional groups are identified by letters a—j on the KBr spectrum with assigned
`frequencies listed in Table 4.
`
`I. Solubility
`
`Solubility is of prime importance for developing solutions that can be injected
`either intravenously or intramuscularly.
`In general, solubility is a function
`of chemical structure: salts of acids or bases represent the class of drugs
`having the best chance of attaining- the degree of water solubility desired.
`Other compound classes, either neutral molecules or very weak acid and bases
`which cannot be solubilized in water within the desired pH range, may require
`the use of nonaqueous solvents. A list of such solvents used for solubility
`studies as well as eventual use in products is shOWn in Table 5.
`
`Solubility Measurement
`
`The analytical method used in obtaining solubility measurements may vary
`according to the drug moiety.
`If the drug‘s. structure has unsaturated conju-
`gation, enabling it to absorb Visible or ultraviolet light, spectrophotometric
`analysis can he performed. A predetermined excess of drug is placed into
`suitable ampuls (or flasks) containing a small volume (2-5 ml) for each solvent
`
`AsUacheca Exhibit 2103 p. 19
`
`

`

`microns
`
`1
`
`6.0
`7““
`
`7.0
`1
`
`8.0 9.010
`‘1“"1'7
`
`12
`
`14
`
`2.5
`100
`
`3.0
`
`4.0
`-r-—-
`
`5.0
`“1—”
`
`
`
`Transmittance
`
`4000
`
`3500
`
`3000
`
`2500
`
`2000 1000
`
`1600
`
`1400
`
`1200
`
`1000
`
`800 050
`
`Wavenumber (cm“)
`
`Figure 9
`22.)
`
`Infrared spectrum 0f eefotaxime in Nujol mull.
`
`(Adapted from Ref.
`
`Table 1} Infrared Frequency Assignments for Cefotaxime
`
` Frequency (cm'l)
`
`Assignment
`
`0
`
`b
`c
`
`d
`
`0
`
`f
`
`g
`
`11
`i
`
`j
`
`3420
`
`WNHZ
`
`3340 (broad)
`
`—NH, —NI—I2
`
`2940
`1760
`
`1730
`
`1050
`
`1620
`
`1540
`
`“SHOE-12
`—C=O lactam
`
`0
`
`"CEO carboxylie, DwngHB
`
`O
`
`—y3--NH2
`
`0
`—ngH, owN—, "Cmc—
`0
`—g—-N—
`
`13851355
`1180
`
`—O-C0-—CH3
`0:0 in ester
`
`CMO stretching
`1050
`
`Adapted from Ref. 22.
`
`12?
`
`AstraZeneca Exhibit 2103 p. 20
`
`

`

`128
`
`Motoch and Aghorkcr
`
`Table 5 Examples of Nonaqueous
`Solvents Used in the Parenteral
`Product Formulation
`
`Polyethylene glycol 400 and 600
`
`Propylene glycol
`
`Glycerin
`
`Ethyl alcohol
`
`Fixed oils
`
`Ethyl oleate
`
`Benzyl bensoate
`
`Source: Ref. 20.
`
`tested. The ampuls are sealed and placed on a suitable shaker or rotator at a
`controlled temperature (mg. . 25 or 37°C) for several days to attain equilib-
`rium. At selected time internals samples are withdrawn by an appropriate
`means (syringe. pipet), filtered through a 5111311 micrometer-size (example,
`0. 2—0.45 1.1m) filter, and analyzed for drug in solution using the appropriate
`ultraviolet or visible assay methodology. For example, the absorbanoe is read
`versus a solvent blank at a predetermined. Wavelength. Using the appropriate
`Beer's law reference curve as shown in Figure in, the concentration is either
`estimated from the curve or can be calculated using a previously determined
`molecular absorptivity.
`Solubility determination of compounds that do not absorb ultraviolet or
`visible light can be attempted by transferring filtered aliquot solutions onto
`previously tared weighing- pans, evaporating the solvent, and drying to con-
`stant weight under low-temperature conditions.
`
`Due to limits in the amount of new drugs available at the first stages of
`preformulation studies. it is sufficient to determine approximate solubility
`values for highly- solu‘ole compounds.
`In such cases a minimal volume of solv-
`ent is used and fixed amounts of drug added (Le. , 150 lug—1 m1 of solvent).
`Should this still yield an unsaturated solution, a value (3.3-. , >15%J will be
`sufficient to denote high solubility at this stage. Equilibrium solubility can be
`determined when more compound is available, if important for a particular
`solvent.
`
`It is also very important to run solubility determinations. at refrigeration
`temperature (2- 8°C) using solvents demonstrating a high potential for use in
`formulation studies. This is done to establish the range of concentration usable
`within the range 2 to 25°C without risking saturation and crystal growth dur--
`ing stability studies.
`
`pH—Solubility Profile
`
`Compounds. with either acidic or basic functionality will show differences in
`solubility characteristics with changes in soluticIn pH in accord with their ioni—
`zation constants. These differences are often large and important in attaining
`
`Astra-Zoneca Exhibit 2103 p. 21
`
`

`

`
`
`Prefomnulation Research
`
`129
`
`
`
`Absorbance of sample
`
`.
`
`Conaentraunn of sanpie
`
`1.0
`
`0.8
`
`0.6
`
`Absorbance 0.4
`
`0.2
`
`0
`
`0,2
`
`(3.4
`
`0.6
`
`0.8
`
`1.0
`
`Concentration
`
`Figure 10 Hypothetical Beer's law curve relating abaorbance and concentration.
`
`the concentrations desired for formulations. pH~solubility prafiles can be
`established by running equilibrium selubflit'y experiments within the range
`3 t0 4 pH units can both sides of the pKa or gal-(El.
`The relationship between solubility of an acidic drug and pH can be de-
`fined with