Parenteral Medications
`tlolumet
`Second Edition, Revised and Expanded
`
`Edited by Kenneth E. Avis,
`Herbert A. Lieberman, and Leon luchmun
`
`
`
`
`
`Serumconcentrationimuu,-me;
`
`40
`
`Ed 0
`
`M O
`
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`
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`
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`
`1
`Astrazeneca Ex. 2103 p.
`Mylan Pharms. Inc. v. Astrazeneca AB IPR2016-01316
`
`

`

`Parenteral Medications
`VIIIIIIIIB 1
`Second Edition, Revised and Expanded
`
`Edited by
`
`Kenneth E. Avis
`
`The University of Tennessee
`Memphis, Tennessee
`
`Herbert A. Lieberman
`
`H.H. Lieberman Associates, inc.
`Consultant Services
`
`Livingston, New Jersey
`
`Leon lutbman
`
`Lachman Consuitant Services
`
`Westbur}; New York
`
`Marcel Dekker, Inc.
`
`New York I Basel 0 Hong Kong
`
`Astrazeneca Ex. 2103 p. 2
`
`

`

`Library of Congress Cataloging -1n— Publication Data
`
`Phalmaceutical dosage forms. parenteral medic-art-ions I edited by
`Eienneth E. Avis. Herbert A. Lieberman, and Leon Lachman. -- ‘End ed. _,
`rev. and expanded.
`p.
`cm.
`Includes bibliographical references and index.
`ISBN 0-B24?-85'if3—-2 (V. 1 :- alk. paper)
`1. Parenteral solutions.
`2-". Pharmaceutical technology.
`Kenneth E.
`II. Iieberman, Herbert A.
`III. Lao-htoan. Leon.
`
`I. Avis,
`
`[DNLM:. 1. Infusions. Par'enteraI.. 2. ‘Technology, Pharmaceutical.
`WB 354 P5Sfi]
`RS201._P3TP48 1992
`615'. 19--de2D
`DNLM.-’DL(.-I
`for Library of Dongress
`
`91 -38083
`CIP
`
`This book is printed on acid-free paper.
`
`Copyright© 1992 by MARC}?-L DEKKEII, INC. All Righu Reserved
`
`Neither this book not any part may be reproduced or transmitted in any form
`or by any means. electronic or mechanical. including photocopying, micro-
`filming, and recording, or by any information storage and retrieval -system,
`without permission in writing from the publisher.
`
`MARCEI. DEKKER, INC.
`270 Madison Avenue, New York, New York [0016
`
`Current printing [last digit]:
`ID 9 8 7 6 5 4- 3 2 I
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`Astrazeneca Ex. 2103 p. 3
`
`

`

`Contents
`
`Preface
`Contributors
`Parenteral‘ Medications,
`Contents of Pharmaceutical Dosage Forms:
`Second Edition, Revised and Expanded, Volumes 2 and 3
`Tablets, Second Edition,
`Contents of Pharmaceutical Dosage Forms:
`Revised and Expanded, Volumes 1-3
`Contents of Pharmaceutical Dosage Forms:
`Ilisperse Systems.
`Volumes 1 and 2
`
`ii.Ea"
`
`JEV
`
`xvii.
`
`Chapter I. The Parenteral Dosage Form and Its Historical Development
`
`Kenneth E. Avis
`
`I.. The Dosage Form
`I]. History of Parenteral Medications
`Appendix A: Glossary of Terms
`Appendix '13: Highlights in the History of
`Parenteral Medications
`References
`
`Chapter 3
`
`Parenteral Drug Administration: Routes, Precautions,
`Problems, Complications, and Drug Delivery Systems
`
`Richard J. Burns, Michael J. Alters. and
`8aIvatore- J. Tm-no
`
`Introduction
`I. General Indications for Parenteral
`
`Administration of Drugs
`11 . Pharmaceutical Factors Affecting Parenteral
`Administration
`
`111.
`IV.
`
`‘Specific Routes of Administration
`Distribution of Pareuterally Administered Agents
`
`IADIDA1-‘
`
`14
`15
`
`1'7
`
`1?
`
`18
`
`19
`21
`-39
`
`vi!
`
`AstraZeneca Ex. 2103 p. 4
`
`

`

`vlti
`
`Contents
`
`V. Precautions, Problems, Hazards. and
`Complications Associated with Parenteral Drug
`Administration
`
`W. Methods and Devices for Drug Delivery Systems
`VII.
`Summary
`References
`
`Chapter -3
`
`Biopharmaceutics of Injectable Medications
`
`Sol Motola
`
`1.
`
`Introduction
`
`1!.
`
`Phyaicochemical and.Phys1olog1ca1 Factors
`Affecting Drug Absorption by Injection: An
`U'V'E1‘V'i9W
`
`III. Application of Pharmacokinetics to Biopharma-
`ceutic Investigations: Pharmacokinetic Models
`IV. Examples of Biopharmaceuticflharmacokinetic
`Principles
`V. Regulatory Considerations for Bioequivalence
`Studies
`
`VI. Bioequivaience Study of Two Injectable Forms
`of the same Drug
`Summary
`References
`
`VII.
`
`Chapter 4
`
`Preformulation Research of Parenteral Medications
`
`Sol Match: and Shreeram N. Agharkcr
`
`I.
`
`Introduction
`
`11.. Drug. Substance Physieochemical Properties
`III. Accelerated stability Evaluation
`IV. General Modes of Drug Degradation
`V.
`Preforlmflation Studies for Proteins and Peptides
`VI. Preformulation Screening of Parenteral
`Packaging Components.
`Summary
`VII.
`VIII. Preformulation Worksheet
`References
`
`Chapter 5
`
`Forrnulstion of Small Volume Parenterala
`
`Patrick P. Dellucc and James C.. Boylan
`
`Introduction
`I.
`IL Formulation Principles
`III. Container Effects on Formulation
`11?.
`Stability Evaluation
`V.
`Process Effects
`References
`
`41
`49
`55
`5’?
`
`59
`
`59
`
`60
`
`77
`
`98
`
`108
`
`I119
`111
`112
`
`115
`
`115
`116
`140
`I50
`154
`
`158
`183
`163
`
`169
`
`173
`
`173
`I'M
`227
`234
`244
`245
`
`Astraleneca Ex. 2103 p. 5
`
`

`

`Contents
`
`inc
`
`Chapter 6
`
`Formulation of Large Volume Parents-rals
`
`Levit J. Demorest and Jeffrey G. Hamilton
`I.
`II.
`III.
`IV.
`V.
`
`Introduction ,
`Concepts of Formulation
`Formulation Development
`Solution Quality
`Summary
`References
`
`Chapter 7
`
`Parenteral Products of Peptides and ?roteins
`
`Yu~Chang 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
`
`III.
`IV.
`
`VI.
`VII.
`
`Diagnostic Products Defined
`Sterile Diagnostics
`Definitions
`
`Aseptic Manufacturing Considerations
`Validation Program
`Conclusion
`References
`
`Chapter 9
`
`Glass Containers for Parenterais
`
`R. Paul 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
`
`2419
`
`249
`250
`273
`280
`281
`281
`
`283
`
`283
`284
`302
`
`310
`312
`317
`
`321.
`
`321
`321
`322
`325
`330
`351
`359
`359
`
`351
`
`361
`361
`
`362
`369
`375
`380
`380
`382
`384
`
`Astrazeneca Ex. 2103 p. 6
`
`

`

`1.‘
`
`Contents
`
`Chapter 10 Use of Plastics for Parenteral Packaging
`
`John M. Anes, Robert S. Nose, and
`Charles H. White.
`
`Introduction
`I.
`II. Fundamentals
`III. Fabrication Processes
`
`Important Criteria for Selection of Plastics
`IV.
`V. Plastics Used in Parenteral Packaging
`VI. Quality Assurance of Parenteral Containers
`References
`
`Chapter 11 Elastomeric Closures for Pa.-renterals
`
`Edward J. Smith and Robert J. "Noah
`
`1. Elastomeric Parenteral Packaging Components:
`A Physical Description
`Physical Description of ‘Rubber
`11.
`III. Types 01’ Rubber Used in Parenteral Packaging
`IV. Closure Design
`V. Rubber Compounding
`VI.
`vulcanization Process
`VII. Closure Manufacture and Control
`
`VIII. Closure Design Qualification
`IX. Regulatory Considerations
`X.
`Interaction of Drug Formulations with
`Rubber Closures
`
`XI. Contemporary Closure-Related Issues
`References
`
`Chapter 12 Parenteral Products in Hospital and Home Care
`Pharmacy Practice
`
`John W". Levchuk
`
`1.
`
`Introduction
`
`.11. The Preparation of Sterile Dosage Forms in the
`Hospital and in Home Care
`111. Dispensing and Compounding Processes
`IV. Technology of sterile Compounding in the
`Hospital Pharmacy
`1?. Clinical Supply and Use of Sterile Products
`VI. Quality Assurance
`VII. Conclusion
`
`Appendix: Abbreviated Sequence for Preparing 9.
`Series of Extemporaneously compounded IN’.
`- Admixturas
`References
`
`Index
`
`387
`
`387
`. 389
`398
`407
`422
`439
`443
`
`-145
`
`445
`450
`451
`482
`463.
`470
`477
`494
`503
`
`505
`507
`508
`
`513
`
`513
`
`513
`524
`
`532
`54'?
`552
`583.
`
`563'
`566
`
`569
`
`Astraleneca Ex. 2103 p. '7
`
`

`

`4 P
`
`reformulation Research of
`
`Parenteral Medications
`
`Sol Mo1:o|a*
`
`Whitehall Laboratories, Hommonton, New Jersey
`
`Shreeram N. Aghar-Igar
`
`Br:'stot—.Myer-s Squibb Company, Syracuse. New York
`
`I.
`
`INTRODUCTION
`
`Preformulation research relates to pharmaceutical and analytical investig‘atione
`
`tharhoth 5;.-med and sufififi Ermflljtion Eevgpment egomag iiosage
`
`
`c,.
`aracterising speci
`a a
`forms. Exp men s are designed to generate
`pharmaceutically important, physieochemical properties 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 biopharmaceutical
`data, preformulation studies yield key information necessary to guide the form-
`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 uitable 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 prefiormulation
`studies, depending on their potential impact on the overall program .
`
`‘Current affiliation: Wyeth-Ayerst Laboratories, Radnor. Pennsylvania
`
`115
`
`Astraleneca Ex. 2103 p. 8
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`

`

`116
`
`Match and Aghorkor
`
`The general subject of preformulation research has been described in de-
`tail by several investj.'gators- [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 preformulation data necessary to characterize
`significant physicochemicsl properties of new drugs important to a paren-
`teral formulation development program.
`
`ll. DRUG SUBSTANCE PHYSICDCHEMICAL 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 substance and are among
`the first items to be lmown. From the molecular structure the invesfifiator
`can make initial judgments regarding potential properties and functional group
`reactivities. as described in section IV.
`
`3. 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 -NHZ, -NO 3,
`and -GC|~ (ketone) . 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 °o1ored impurities
`andfor degradation products. These substances may be prone to increased
`color formation under stress conditions of heat, oxygen, and light. A signifi-
`cant color chsngc can become a. limiting factor to the shelf life of a parenteral
`product even before a significant‘ change in chemical stability is noted.
`
`Table ‘I Physicochemical Properties of Drug Substances
`
`Molecular structure and weight
`
`Solubility
`
`Color
`
`Odor
`
`pH solubility profile
`
`Polymorphism potential
`
`Melting point
`
`Solvate formation
`
`Thermal analytical profile
`
`Absorbance spectra
`
`Particle size and shape
`
`Light -stability
`
`Hygroscopioity potential
`
`Thermal stability
`
`Ionization constant
`
`pl-I stabflity profile
`
`Optical activity
`
`AstraZene.ca Ex. 2103 p. 9
`
`

`

`Preformulcticn Research
`
`11 7
`
`The drug sut;>stsnce's color shcauld be recorded by s subjective description,
`as well as by an objective means such as by comparison with standard color
`chips [8], or by spectrcphctemetric analysis if the comp0und‘s celor intensity
`in soluticn is prcpcrticnel ta concentration. The American Public Health Asses
`ciation (APHA) color standards [93 can be used effectively to quantitate
`changes in solution cclcr with time. Visible absorbance of APHA color stsnd~
`eras (diluted spprcpriatsiy) can be measured spectrcphotometrically [10] t0
`monitor more accurately the color of solution test samples. An example plot
`is shown in figure 1.
`
`C. Oder
`
`The odor cf a new drug substance should be examined by cautiously smelling
`the heedspace cf the drug container which has been previously closed to allow
`volatiles ts concentrate. The presence and description of any odor should be
`recerdecl. The substance may exhibit an inherent ecicr characteristic of msjcr
`functional groups present (i.e. . sulfurcus er g:arlic—1ike fer sulfides, sulfexides,
`or sulfliydrykconteizning compounds, or ammcniacal as for amines). A1te1'na—
`tively, e drug‘ may be veid of characteristic odor DI‘ it may have an odor cf
`residual solvent. The presence of :1 solvent odor should be reviewed with the
`synthesis chemist to determine whether the sample has been adequately dried.
`
`D. Particle Size, Shape, and Crystaliinity
`
`The particle size of s weter~se1ub1e drug is not of concern unless it exists in
`large aggregates and an increase in rate of solution is desired to reduce menu—
`featuring time. Under such circumstances milling threugh an appropriate size
`sieve [11] may be sufficient.
`
`sac
`
`37,5
`
`15
`
`2
`3»
`0
`
`250 %
`;
`§
`3'
`"
`
`125
`
`D
`
`ca
`
`0.3
`
`EE
`
`Q 3
`
`..
`
`°=
`'5‘
`'~’
`
`-'3 02
`§
`.3’
`5
`3 01
`-1
`
`0
`
`Q
`
`lL......,
`20
`
`W
`40
`
`1
`60
`
`80
`
`100
`
`“:3 Certified APHA Cclcr S1ano:3erti (500 units)
`
`Figure 1 Typical visible absorbsnce readings at 400 nm ft‘) certified APHA
`color standard (500 units) at various dilutions versus APHA color number.
`
`Astrazeneca Ex. 2103 p. 10
`
`

`

`118
`
`Motels and Agharkor
`
`Particle size and shape characteristics can be determined by microscopic
`evaluation using either an optical microscope, preferably with polarizing et-
`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. Cryrstalline materials retract 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 1000*
`with a resolution limit in the vicinity of 1 ‘pm. The scanning electron micro-
`scope provides magnifications 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 scanning electron ‘microscope adds the dimen-
`sion of depth by tilting the stage to severe] angles of View during operation.
`‘Thus what may appear to be a combination of soioulsr 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 homogeneous. Mixtures of morphological for-ms either within
`a sample or between samples could :indicate the existence of hydrates, solvates,
`or polymorphic forms which could later significantly affect properties such as
`solubility, stability. and biosvsilability.
`
`E . Melting Point
`
`The melting point of 8. substance is thermodynamically defined as the tempera-
`ture at which the solid and liquid phases are in equilibrium as described in
`Equation (1).
`
`S
`
`_-.s
`solid t-— liquid
`
`(1)
`
`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 rang-e.. 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 circ-
`matic change in volume, melting and recrystallization, gas evolution, color
`change. or other physical change, should be recorded and investigated fur-
`ther. Such behavior could be indicative of significant changes, such as a
`polymorphic transition, deaolvation. 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
`
`Astralenoca Ex
`
`.2103 p. 11
`
`

`

`Prcformulctton 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,
`.31‘.
`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) or 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-
`tallisation 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 (1350). with this technique. the area under the output
`curve is directly "proportional to the total amount of energy ((1) absorbed or
`liberated from the sample. The abscissa is proportional to the rate of heat
`transfer Kdqfdt) at any given time. The loss of surface moisture and a de-
`composition melt is evident in the D56 curve shown in Figure 5.
`The thermal analytical method used to detect the existence and stability
`of solvated drug molecules is called ther-mogrc-vimetric analysis (TGA).
`In
`this technique relative weight loss is studied between the sample and a refer-
`ence durlng 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 rnoiature or by molecular desol-
`vation or decomposition. Combined DTA and TGA curves for amphoterirfin 5
`showing intermediate phase transitions (DTA) , weight loss, and decomposi-
`tion CTGA) are shown in Figure 6. An overview of thermal analytical methods
`described above is available for further information [17] .
`
`C . Hygroscoplcity
`
`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 adversely affect the physical and chemical properties of
`a drug substance, making it either phsrmaceuticslly 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
`
`Astraleneca Ex. 2103 p. 12
`
`

`

`120
`
`Motels and Aghurkor
`
`Figure 2 Microscopic examination of an experimental drug. Views through
`an optical microscope Ca) and a scanning electron microscope (b) at various
`stage angles as noted.
`(Courtesy of E. B. Vedas, Merck Frosst Canada, Inc.,
`Pointe Claire-Dorval, 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-
`groseopicity 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 im-
`portant in determining‘ whether hydrate formation is occurring.
`
`AstraZeneca Ex. 2103 p. 13
`
`

`

`

`

`Match: and Aghar-ker
`
`122
`
`t i
`
`r;
`
`em ——I:§—CI-I3
`cuzou
`
`' H...
`
`"ff‘°°2*'
`He-co,H
`
`
`
`50
`
`T5
`
`IE0
`
`I15
`
`150
`
`N5
`
`III!
`
`225
`
`‘c
`
`Figure 3 Structure and‘ differential thermal analysis scan of ergonovine rnaleete
`with decomposition [USP reference standard, lot L).
`(From Ref. 13.)
`
`
`
`Flgure a structure and differential thermal analysis scan of Iqetamme.
`Ref. 14.)
`
`(From
`
`Astraleneca Ex. 2103 p. 15
`
`

`

`
`
`-0>
`
`-c
`LL!
`Lu
`:1
`?
`=
`:-
`<3
`“
`0.
`1
`=
`us
`"' 2cc
`l.l.l
`:I:
`1-
`
`Oc
`
`:zI
`
`.I.l
`
`EI
`
`0
`
`100
`
`200
`
`300
`
`400
`
`TEMPERATURE,
`
`°C
`
`Figure 5 Structure and differential scanning calorimetry scan of gentamicin
`sulfate (USP 1=efe1'ence standard) .
`(From Ref. 15.)
`
`
`TGA
`
`210
`
`AMPHQTERIQN ES
`
`100%
`
`90%
`
`83yfl
`
`-10
`
`80
`
`3 2%
`
`160
`
`200
`
`340
`
`380
`
`TEMPERATURE,
`
`“c
`
`Figure 5 Structure, differential thermal analysis. and thermogravimetric aI1al~
`ysis scan of amphotericin 13.
`(From Ref. 15.)
`
`Astrazeneca Ex. 2103 p. 16
`
`Preformulatian Research
`
`123
`
`a,crmna2
`D
`
`mu-:2
`
`0
`
`NH:
`
` /NR2
`
`HG
`
`Q
`
`0
`
`E“
`
`II
`
`J
`
`

`

`124
`
`Mo tale and Agh arkar
`
`Tame 2 Saturated Salt Solutions far Humidity Cnntrol
`
`Percent relative
`humidity
`
`Temperature
`(DC)
`
`20
`
`31
`47
`
`55
`
`76
`90
`
`Potassium acetate , K(.‘2H3'D2
`
`Calcium chloride, CaC12 -EH20
`Patassium thiocyanate, KSCN
`
`Sodium nitrite, NQNO2
`
`Sodium acetate , NaG2H3O2-3H2O
`
`Zinc sulfate, $11304 v'?H2D
`
`Source; Ref. 18.
`
`H . Absorba nce Spectra
`
`28
`
`24. 5
`20
`
`20
`
`20
`20
`
`Molecules with structural unsaturation are able to absorb light within a spe~
`cific frequency range. As mentioned previuusly, the degree of unsaturation
`coupled with the presence of ehromophnres will influence the extent of absorp-
`tion and whether ultraviolet (400-190 nm} 92- visible (800400 nm} light will
`be absorbed, The ifltraviolet and visible spectra. ef cnmpounda in snlution
`are not highly apeeific; however, they are very suitable for quantitative ana-
`lytical work and serve as additional information for camponnd identification.
`The ultraviolet or visible spectrum can be zietermined by placing approximate-
`ly a 10 to 26 pg mJ”1 solution 0f 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 chlcrnthiazide is shown
`in Figure 7. Absorbance maxima are evident at 228, 292, and 31!] nm.
`
`Tabie 3 Hygroseepicity Classification
`
`Class I-~Nonhy-groscopic: Essentially no moisture increaaes occur at relative
`humidities below 90%. Furthermore, the increase in meisture content after
`storage for 1 week above 90% relative humidity (RH) is less than 20%.
`
`Class Ilwslightiy hygroscopic: Essentially no moisture increases occur at
`relative humidities below 30%. The increase in moisture cement after storage
`far 1 week above 80% RH is less than 40%.
`
`Class III-21/Iodemtely hygroscopic: M-Distnre content does not increase above
`5% after storage at relative humiditiese below 60%. The increase in moisture
`ccmtent after storage for 1 week above 80% RH is less than 50%.
`
`Class I V-‘Very hygroscopic: Moisture increase may occur at relative humidi-
`ties as low as 40 to 50%. The increase in moisture content after storage for
`1 week above 90% RH may exceed 3(}%.
`
`Source: Ref. 19.
`
`Astrazeneca Ex
`
`.2103 p. 17
`
`

`

`Preformulatton Research
`
`125
`
`AESDR
`
`BANCE
`
`220
`
`260
`
`300
`
`340
`
`WAVELENGTH. nm
`
`Figure 7 Structure and ultraviolet ebso:-hence spectrum of chlorothesicle.
`(From Ref. 21.)
`
`Relationships used to compare and quantitate ultraviolet and visible ab-
`sorbsnce of compounds in solution are shown in Equations (2) and (3) .
`
`Hg
`
`...A_
`Eflbc
`
`:2)
`
`(3)
`
`In Equation. (2) , the quantity :1, called ebscrptivity, is related to the absorp-
`tion of a. compound of concentration c (in g:'10flD ml) through a sample cell of
`13 centimeters and thus has the units liters per grant-centimeter. when the
`ooncentrafion is expressed in moles per liter , the absorptivity becomes molar
`ahsorptivity E, and is expressed in leters per mole centimeter.
`Both values should be recorded for each solvent system of interest. For
`qusntitative use, either a or e is determined. For a compound in solution the
`molsr concentration of en unknown quantity of the same drug cen be deter-
`mined by knowing the sbsorbance at the wavelength and the cell path length.
`Rear:-anging Equation (3) yields Equation (4).
`
`A
`<==g';
`
`(4)
`
`The infrared (IR) spectrum (run between 2. 5 and 15 um.) is highly specific
`for each ehernical structure, with small structural differences resulting in
`significant spectral changes. Samples can be prepared as a solution, as a
`dispersion in mineral oil Cliujol mull) , or‘ as n potassium bromide (KB:-) pellet.
`
`Astra."-Seneca Ex. 2103 p. 18
`
`

`

`133
`
`2.5
`
`3.0
`
`6.0
`
`Motels and Aghcrkar
`
`microns
`5.0
`
`6.0
`
`7.0
`
`8.!) 9.01.0
`
`1.2
`
`‘III
`
`Transmittance
`
`4000
`
`3500
`
`3000
`
`2.500
`
`2000
`
`1300
`
`1000
`
`1400
`
`1200
`
`‘I000
`
`000 550
`
`Wavenumber torn")
`
`Figure 8 Structure and infrared spectrum of cefotaxime in KB: with peaks of
`several functional groups identified.
`(Adapted from Ref. 22.)
`
`After running a spectrum. significant peeks relating to major functional groups
`are identified; spectra of subsequent samples of the same compound are com-
`pared with the original.
`Ii’ 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 oi’
`polyraorphs 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 IKBr spectrum with assigned
`frequencies listed in Table 4.
`
`1. Solubility
`
`Solubility is of prime importance for developing solutions that can be injected
`either intravenously or intrarnusouiarly.
`In general, solubility is a function
`of chemical structure; salts of acids or bases represent the dass 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-
`gflfifln. enabling‘ it to absorb visible or ultraviolet light. spectrophotometric
`analysis can be performed. A predetermined excess of drug is placed into
`suitable ampuls (or flasks) containing a small volume (2-5 ml) for each solvent
`
`Astraleneca Ex. 2103 p. 19
`
`

`

`2.5
`100
`
`3.0
`
`microns
`5.0
`-"-1
`
`4.0
`‘T
`
`3.0
`1
`
`7.0
`r
`
`14
`‘I2
`3.0 9.0 10
`1
`I -:jI—-r*
`
`3500
`
`3000
`
`2500
`
`2000 1800
`
`1600
`
`1400
`
`1200
`
`‘I000
`
`800 650
`
`Wavenumber (cm“)
`
`Infrared spectrum «ref cefotaxime in Nujol mull.
`
`(Adapted from Ref.
`
`6,0 '
`
`60
`
`40
`
`20
`
`Transmittance
`
`0 4
`
`000
`
`Figure 9
`22.)
`
`Table 1}
`
`Infrared Frequency Assignments for Cefotaxime
`
`Frequency (cm'1)
`
`Assignment
`
`El
`
`13
`c
`
`d
`
`e2
`
`f
`
`g
`
`h
`i
`
`j
`
`3420
`
`~=-WNHZ
`
`3340 (broad)
`
`—-NH, --NH2
`
`2940
`1760
`
`1730
`
`1650
`
`1520
`
`1540
`
`-“S-“CH2
`—C=D lactam
`
`0
`
`-C=0 carboxylie, 0--1CiJ--CH3
`
`0
`
`—g--NR2
`‘R
`—CwNl-I, ~««C—-2N-—, -c==c—
`
`0
`—g-N-
`
`l385««1355
`1180
`
`1050
`
`-O--CO--CH3
`C=O in ester
`
`C -«O stretching
`
`Adapted from Ref. 22.
`
`127
`
`Astrazeneca Ex. 2103 p. 20
`
`

`

`128'
`
`Mo talc and A'gharkor'
`
`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
`
`Bensyl benzoate
`
`Source: Ref. 20.
`
`tested. The arnpuls are sealed and placed on a suitable shaker or rotatar at 8
`controlled temperature to-3'. . 25 or 37°C!) for several days to attain equilib-
`rium. At selected time intervals samples are withdrawn by an appropriate
`means (syringe. pipet), filtered through a small micrometer-size (example.
`0..2—0.45 um) filter, and analyzed for drug in solution using the appropriate
`ultraviolet or visible assay methodology. For example, the absorbance is read
`versus a solvent blank at a predetermined wavelength. Using the appropriate
`Beer's law reference curve as shown in Figure 10. 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
`vislble 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 firs’: stages of
`preformulation studies, it is sufficient to determine approximate solubility
`values for highly soluble compounds.
`In such cases a minimal volume of solv-
`ent is used and fixed amounts of drug added (Le. , 150 mg‘-1 ml of solvent).
`Should this still yield an unsaturated solution. a value (e-.g. , 3-15%) will be
`sufficient to denote high solubility at this stage. Equilibrium solubility can be
`determined when more compound is available, it‘ important for a particular
`solvent.
`
`It is also very important to run solubility determinations at refrigeration
`temperature £.9- 8°C) using solvents demonstrating a high potential for use in
`formulation studies.
`'.l‘h1s.ia done to establish the range of concentration usable
`the range 2 to 25°C without rislclng 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 solution pH in accord with their ioni-
`zation constants.
`‘These differences are often large and important in attaining
`
`Astraleneca Ex. 2103' p. 21
`
`

`

`Preformulation Research
`
`1.0
`
`129
`
`0.8
`
`Absorbance of sample
`
`0.2
`
`0.6
`
`Absorbancc 0.4
`
`0
`
`0.2
`
`0.4
`
`0.6
`
`05
`
`1.0
`
`Concentration
`
`Figure 10 Hypothetical Beer's law curve relating absorbance and concentration.
`
`the concentrations desired for formulations. pH~s-olubilityr profiles can be
`established by running equilibriuun solubility experiments within the range
`3 to 4 13}! units on both sifles of the {mg or pK§1.
`The relationship between solubility of an acidic drug and pH can be de-
`fined with respect to its pKa using Equation (5):
`
`pH = piia +109;
`
`{C51
`
`:ca1
`
`where
`
`(5)
`
`piia m negativ