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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`
`O
`
`
`
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`
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`_L
`__
`
`I.
`
`J
`
`1
`5
`
`1
`8
`
`Time {hours}
`
`__§_
`1t,_
`
`1
`Astrazeneca Ex. 2111 p.
`Mylan Pharms. Inc. v. Astrazeneca AB IPR2016-01326
`
`

`
`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. 2111 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. 2111 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 Po:-ms:
`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
`II. 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. Bums, Michael J. Alters. and
`Salvatore J. Tm-so
`
`Introduction
`I. General Indications for Parenteral
`
`Administration of Drugs
`11 . Pharmaceutical Factors Affecting Parenteral
`Administration
`
`111.
`IV.
`
`‘Specific Routes of Administration
`Distribution of Psrcuterally Administered Agents
`
`IADIDA1-‘
`
`14
`15
`
`1'7
`
`1?
`
`18
`
`19
`21
`-39
`
`vi!
`
`AstraZeneca Ex. 2111 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. 2111 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. 2111 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. 2111 p. 7
`
`

`
`5 F
`
`ormulation of Small Volume
`
`Parenterals
`
`Patrick F. DeLuca
`
`University of Kentucky College of Pharmacy. Lexington. Kentucky
`
`James C. Boylan
`
`Abbott Laboratories, Abbott Park. Illinois
`
`I.
`
`INTRODUCTION
`
`Whereas a parenteral can be defined as a sterile drug. solution. or suspension
`that is packaged in a manner suitable for administration by hypodermic injec-
`tion, either in the form prepared or following the addition of a. suitable solv-
`ent or suspending agent [1]. the term small volume parenteral (SVP) has been
`officially defined by the United States Phermacopeia (USP) [2] as " .
`.
`. -an
`injection that is packaged. in containers labeled as containing 1130 ml or less."
`The USP categorizes sterile preparations for parenteral use according to the
`physical state at’ the product as follows:
`
`1.. Solutions or emulsions of medicaments suitable for injection
`2. Dry solids or liquid concentrates containing no additives which, upon
`the addition of suitable solvents, yield solutions. conforming in all
`respects to requirements for injections
`3. Preparations the some as described in class 2 but containing one or
`more additional substances
`
`4. Suspensions of solids in a suitable medium which are not to be injected
`intravenously or into the spinal column
`5. Dry solids which, upon the addition of suitable vehicles, become
`sterile suspensions
`
`Although the term sterile pharmaceuticals is applicable to all injections (radio-
`phsnnaceuticals included), ophthalmic preparations. and irrigating solutions.
`this chapter emphasizes the formulation of injectable dosage forms.
`The successful formulation of an injectable preparation requires a broad
`knowledge of physical, -chemical, and biological principles as well as expertise
`in the application of these principles. Such knowledge and expertise are re-
`qui.red to effect rational decisions regarding the selection of:
`(1) a suitable
`
`.173
`
`Astrazeneca Ex. 2111 p. 8
`
`

`
`174
`
`DeLuco and Boylan
`
`vehicle (aqueous, nonaqueous, or cosolvent); (2) added substances ("anti-
`microbial agents, antioxidants. buffers. chelating agents. and tonicity con-
`tributors); and (3) the appropriate container and container components.
`In-
`herent in the above decisions is the obligatory concern for product safety,
`effectiveness, stability. and reliability. This chapter focuses on the physics}-
`chemical aspects of preparing a stable product in a -suitable container rscogv
`nising that safety must be established through evaluation of toxicity. tissue
`tolerance. pjrrogenicity. sterility. and tonioity. and efficaey must he demon-
`strated through controlled clinical investigations.
`The majority of parenteral products are aqueous solutions, preferred be-
`cause of their physiologic compatibility and versatility with regard to route
`of administration. However, cosolvents or nonaqueous substances are often-
`required to effect solution or stahilitsr. Furthermore. the desired properties
`are -sometimes attained -through the use of" a suspension or an emulsion. Al-
`though each of these dosage forms have distinctive characteristics and formu-
`lation requirements. certain physical-chemical principles are common. Those
`common principles will be discussed in a -general manner and the differences
`distinctive of each system will be emphasized.
`It is important to recognise
`that the pharmaceutical products derived from biotechnology are -on the in-
`crease and the formulation of these products requires some unique skills and
`novel approaches. An attempt will be made to cover some of the formulation
`approaches for proteins and peptides.
`
`II.
`
`A.
`
`FORMULATION PRINCIPLES
`
`Influence of the Route of Administration
`
`Since parenteral preparations are introduced directly into the intra-- or extra-
`cellular fiuid compartments. the lymphatic system. or the blood. the nature
`of the product and the desired pharmacological action are factors determining
`the particular route of administration to be employed. The desired route of
`administration. in turn, places certain requirements and limitations on the
`formulations as well as the devices used for administering the dosage forms.
`Consequently. a variety of routes of administration (see Chap. 2) are cur-
`rently used for parenteral products.
`One of the most important considerations in formulating a parenteral prod-
`uct is the appropriate volume into which the drug should be incorporated.
`The intravenous route is the only route by which large volumes (i._e. . greater
`than 10 ml) can be administered, although the rate of.‘ administration must be
`carefully controlled. Volumes up to 10 ml can be administered intraspinally,
`while the intramuscular route is normally limited to 3 ml, subcutaneous to 2
`ml and intrsdermal to 0.2 ml.
`The choice of the solvent system or vehicle is directly related to the in-
`tended route of administration of the product.
`Intravenous and intraspinal
`injections are generally restricted to dilute aqueous solutions". whereas oily
`solutions, cosolvent solutions, suspensions, and emulsions can be injected
`intrsmuscularly and subcutaneously.
`
`Isotonicity is another factor that must be taken into consideration. Al~
`though isotonic solutions are less irritating, cause less tcoticity and eliminate
`the possibility of hemolysis, it is not essential that all injections be isotonic.
`In fact, for subcutaneous and intramuscular injections hypertonic solutions-
`
`Astrazencca Ex
`
`.2111p.9
`
`

`
`Formulation of Small Volume Parenteral:
`
`175
`
`are often "used" to facilitate absorption of drug due to local effusion of tissue
`fluids. With intravenous solutions isotonicfity becomes less important as long
`as administration is slow enough to permit" dilution or adjustment in the blood.
`However, intraspinal injections. must he isotonic because of slow circulation
`of the cerebrospinal fluid in which abrupt changes of osmotic pressure can
`give rise to severe side effects.
`New routes of administration include intrasrticular, directly into the sync-
`vial fluid for rheumatoidal diseases and even intradigitel, between the fingers,
`in order to ‘better target the lymphatics. The parenteral routes of adminis-
`tration will influence the design of novel dosage forms and drug delivery sys-
`tems especially as more potent agents from biotechnology are developed.
`
`B. Selection of the Vehicle
`
`Most parenteral products are aqueous solutions. Chemically, the high dielec-
`tric constant of water makes it possible to dissolve ionisahle electrolytes and
`its hydrogen-bonding potential facilitates the solution of -alcohols . aldehydes,
`ketones, and amines. Water for Injection, USP. is the solvent of choice for
`making parents-rsls.
`It must he prepared fresh by distillation or by reverse
`osmosis and contain no added substance. When it is not possible to use a-
`wholly aqueous solution for physical or chemical reasons, the addition of
`solubilising agents or cosolvents may be necessary. For instance. nonpolar
`substances (i.e. . slkaloidsl bases) possess limited solubility in water and it
`is necessary to add a- cosolvent such as glycerin. ethanol, propylene glycol
`or polyethylene glycol.
`In other cases. to prevent chemical degradation (i.e. .
`hydrolysis, oxidation. decarboxylation, or racemization) water may have to
`be eliminated partially or totally. Most proteins and peptides require an
`aqueous environment, and the addition of salt, buffer, or other -additives for
`solubility purposes often leads to conformational changes. Consequently.
`"parenteral product formulators should be aware of not only the nature of the
`solvent and solute in parenterals but also the solvent-solute interactions and
`the route of administration
`
`Solubility and Solubilizction
`
`The solubility of a substance at a given temperature is defined quantitatively
`as the concentration of the dissolved solute in a saturated solution (i.e. , the
`dissolved solute phase). Generally, drugs are present in solution at unsatu-
`rated or subsaturated concentrations; otherwise. crystallisation of the drug
`can occur as a result 01’ changes in pH or temperature or by seeding from
`other ingredients or particulates in the solution. To enhance the solubility
`of drugs, in addition to using‘ organic solvents that are miscible with water
`as cosolvents, other techniques can be employed. These include salt forma-
`tion and prodrugs, which, although capable of greatly enhancing‘ solubility,
`constitute new entities requiring additional clinical studies. Other substances
`used as solubilizers include the surface-active and complezcing agents.
`Surface-active .agents, by virtue of their association tendencies in solu-
`tion and the ability to orient into concentrated polar and nonpolar centers
`(micelles). have been used to solubilise drugs and other substances such as
`vitamins, hormones, sulionamides. dyes. resins. and volatile oils. These
`surfactants are powerful wetting agents and form colloidal dispersions that
`have the appearance of a true solution.
`
`Astraleneca Ex. 2111 p. 10
`
`

`
`I76
`
`Debuca and Boylan.
`
`Ethylenediamine is required in aminophylline injections to maintain the
`theoghyllins in solution since aminophylline is a salt that ionizes into its CD11“
`stituent ions theophylline emit ethylenediamine.
`
`Aminophylline + 2 theophy11ine' + ethylenediamine“
`
`Ethylenecliamine, a strongly alkaline substance, is volatile and if it escapes,
`the pH will be lowered, causing theophylline ion to be converted to free theo-
`phylline (plia W 3. 8), which is only slightly soluble in water (3 mg’/ml).
`
`Theophyiline" + 15*
`
`—~
`
`theophyllina (free)
`
`Creatinine, niscinamide, and lecithin have been used for solubilizing steroids
`in the free slsohol form. The use of the stilt or ester of these steroids. or
`vitsmins eliminates the need to use eelubilizers but requires other additives
`to ensure stability.
`A brief description of the phenomenon of solubility will be helpful to the
`formulator in selecting the best solvent or agent to overcome difficulties that
`arise in the preparation of pharmaceutical dosage forms containing poorly
`soluble drugs. with psrentersls, the drug and other dissolvevzi substances
`should remain solubilizecl throughout the shelfdife of the product.
`
`Solubility Expressions. Solubility of El substance can be expressed in a
`number of ways. Generally, the concentration is expressed as percent (wlv) ,.
`that is, grams per 100 ml of solution, but molarity and molality have been
`used. Molarity is defined as the number of moles per 1000 ml of solution.
`Molality is the number of moles of solute per 1000 g of solvent and, therefore,
`being a weight relationship, is not influenced by temperature. The USP lists
`solubility in terms of the number of milliliters of solvent required to dissolve
`1 g of substance.
`If exact solubilities are not known, the USP provides gen-
`era} terms to describe a given range. These descriptive terms re listed in
`Table 1.
`
`Table 1 Expressions for Approximate Solubility
`
`Term
`
`Very soluble
`
`Freely soluble
`
`Soluble
`
`Spsringly soluble
`
`Slightly soluble
`
`Very slightly soluble
`
`Relative amount of
`solvent to dissolve
`
`1 part of solute
`
`<1
`
`1-10
`
`10- 30
`
`30-1UU
`
`100~1000
`
`1OIJO~1D,430C|
`
`Practically insoluble or insoluble
`
`>1{J,G0fl
`
`Astrazeneca Ex. 2111 p. 11
`
`

`
`Formulation of Small Volume Porenterols
`
`1??
`
`Measuring Solubility. Methods for determining the solubility of drug sub-
`stances in various solvents have been described 13-61. The phase solubility
`technique is especially applicable to determining the solubility of pure sub-
`stances and also detecting the presence of impurities [6] .
`In this method,
`successively larger portions of the substance are added to the same volume
`of solvent in suitable containers which are agitated at constant temperatures,
`generally 30 i ll. 1°C.
`In those containers in which excess drug is. present
`(undissolved), samples of the supernatant are withdrswn and assayed until
`the concentration is constant (i.e. , the system has reached equilibrium). For
`a pure compound, a phase solubility diagrmn is constructed as shown in Fig-
`ure 1a. The solubility is readily determined by extrapolating the line with
`a slope of zero to the y axis.
`If an impurity exists in the substance, a phase
`solubility diagram as shown in Figure 1b results. which shows an inflection
`in the ascending line. Extrapolation of the horizontal line gives the solubil-
`ity of the substance plus the impurity of the substance on the y—a:ds_, while
`extrapolation of the ascending line gives the solubility of the impurity.
`
`Bonding Forces. For a substance to dissolve. the forces of attraction that
`hold the molecules together must be overcome by the solvent. The solubility
`will be determined by the relative binding forces within the substance (solute-
`solute interactions) and between the substance and the vehicle (so1ute—so1“vent
`interactions).
`If an environment similar to that of the or-'ystal.structu1'a can.
`be provided by the solvent, then the greater the solubility (i.e., "like dis-
`solves like").
`Ionic compounds dissolve more readfly in water by virtue of
`ion—dipo1e interactions. whereas hydrophobic substances dissolve more easily
`in organic solvents as a result of dipole or induced dipole interactions {van
`der ‘Heels, London or Debye forces).
`
` Undissoived selule
`
`
`begins appearing
`
`
`mg SOLUTEIIHI SOLVENT
`
`SOLUTECONC.mqfmI
`
`
`SOLUTECflflfimqiml
`
`
`
`
`Solubility or substitute and irnpuril;
`
`Soiubilily of mpuril-r
`
`mg SOLUTE/ml SOLVENT
`
`Figure 1 Phase solubility diagrams for a pure substance (a) and a substance
`containing‘ an impurity (In) .
`
`Astraleneca Ex. 2111 p. 12
`
`

`
`H8
`
`DeLuoc end Bcylcn
`
`The solubility" of the drug substance is due in large part to the polarity
`of. the solvent. often expressed in terms of dipole moment, which is related
`to- the dielectric constant. Solvents with high dielectric constants dissolve
`ionic compounds and are water soluble. whereas solvents with low dielectric
`constants are not water soluble and do not dissolve ionic compounds. The
`former are classified as polar solvents [e.g. , water, glycerin, and methanol} ,
`‘While the latter are nonpolar (e.g_. . chloroform, benzene, and the oils).
`‘Sol-
`vents with intermediate dielectric constants (e.g., acetone and butanol) are
`classified as sernipolsr. The dielectric constants of most pharmaceutical sol-
`vents are known [7,3] and values for a number of binary and tertiary blends
`have been reported [9] and, if not reported. can be readily estimated [1fl].
`Table 2 is a listing of the dielectric constants of some liquids used in pharma-
`ceutical systems.
`The solubility profiles of a number of pharmaceuticals as a function of
`dielectric constant have been reported by Paruta and coworkers and others
`[ll-17] . By determining the solubility of a substance in a system at various
`dielectric constants. a graph such as that shown in Figure 2 can be constructed
`to determine the dielectric constant that will provide the required solubility.
`As can be seen from the plot. to obtain the maximum concentration a dielec-
`tric constant of around 40 is required. Not all mixtures will show a maximum 3
`but such a plot illustrates the required dielectric constant to obtain the de-
`-sired concentration. For example, if a d:l.e1ec1.'I'ic constant {d.c.) of 60 was
`selected, a mixture of water (d.c. 1'8. 5). polyethylene glycol (PEG) -1011
`
`Tsbie 2 Dielectric Constants of some Solvents at 25°C
`
`Solvent
`
`Water“
`
`Glycerin‘
`
`N , N- Dimethylacetamidea
`
`Dielectric constant
`
`?8.5
`
`40.1
`
`3'? . B
`
`Propylene glycol“
`
`32.01 (30°)
`
`Methanol
`
`Ethanol“
`
`N—Propano1
`
`Acetone
`
`Benzyl alcohol“
`
`Polyethylene glycol 400“
`
`Cottonseed oil“
`
`Benzene
`
`Dioxane
`
`asolvents used in parentersls
`
`31.5
`
`24. 3
`
`30.1
`
`19.1
`
`13.1
`
`12.5
`
`3.. u
`
`2.3
`
`2. 2
`
`Astraleneca Ex. 2111 p. 13
`
`

`
`Formulation of Small Volume Parenterals
`
`179
`
`am Salsbrflry
`
`I
`
`IT‘!
`SOLUBIL
`
`I0
`
`20 30 40 50 60 ?0
`DIELECTRIC CONSTANT
`
`Figure 2 Hypothetical plot of solubility of a substance versus dielectric con-
`stant in various mixtures of dioxsne and water.
`
`(d.c. 12.5) and ethanol (d.c. 24.3) could be used. Selecting an amount of
`ethanol necessary to dissolve the drug ('e.g. . 10%]. the percentages of PEG
`-400 and water can be calculated as follows:
`
`(10) (24.3) + (X) (178.5) + (90 - X‘) (13.5) = (100) (60)
`
`where X is the percentage of water required and is calculated to be 73.5%.
`Therefore, the vehicle to provide a dielectric constant of 60 will have the fol-
`lowing composition:
`
`Ethanol
`PEG 500
`
`fig!)
`
`10%
`16.5%
`
`73. 5%
`
`Since dielectric constant is a measure of the polarisability and dipole mo—
`ment of a compound, several researchers have explored other parameters. and
`polarity indexes [18] which are included by molecular volume, solvent and
`solute interactions, and specific interactions such as hydrogen bonding.
`Hildebrand and Scott [3] introduced solubility parameters to predict solu-
`bility of regular solutions; Since pharmaceutical systems deviate from regular
`or ideal solutions. Martin and co-workers [19] modified the Hildebrand ap-
`proach to include hydrogen-bonding and dipolar interactions. The molecular
`surface area of the solute and interfacial tension between solute and solvent
`
`were used by Amidon [20] and Yalkowsl-zy [21] to predict solubility. These
`approaches were especially applicable to systems in which the intermolecular
`forces between solvent and solute were different. Figure 3 shows the solu-
`bility as a function of -solvent concentration. The slope of the line is a meas-
`ure of the activity in the solvent and was found to be related to several param-
`eters of solubility including‘ interfaclal tension and hydrogen bonding [18,22] .
`Hydrogen bonding. the strongest type of dipo1e- dipole interaction, is
`characterised by a- positive center in the hydrogen atom {proton donor). Be-
`cause of its small size. the hydrogen atom can approach the negative center
`(electron donor) of a neighboring dipole more closely than any other atom.
`As a result of this spatial maneuverability. both intramolecular bonding {i.e. ,
`
`Astraleneca Ex. 2111 p. 14
`
`

`
`DeLuca and Boylan
`
`‘[80
`
`10°
`
`
`
`SOLUBILITY.molesil
`
`105
`
`103
`
`0
`
`so
`so
`40
`20
`PROPYLENE GLYCUL. ‘In
`
`too
`
`Figure 3 Log‘-linear solubility relationship for a series of alkyl p-a.rninobenzo—
`ates-glycol-water. {From Yalkowslcy. S. H. , Flynn, G. L., and Amidon, G.
`L., J. Pharm. Sci. , 61:983 (1972).]
`
`Cal-|s—0—-H---O:
`
`H
`
`”
`
`T
`
`©C*9
`
`0- H‘
`
`i~“t'31'm°1°°“19-1' H b°1'1diI1g
`
`intramolecular H bonding
`
`Astrazeneca Ex. 2111 p. 15
`
`

`
`Formulation of Small Volume Par-enter-ols
`
`181'
`
`between groups within a single molecule) and the intermolecular type (Le. ,
`among molecules) can occur- The latter is responsible for association in most
`solvents and dissolution of most drugs.
`Generally, the proton is donated by a carbonyl. hydroxyl. amine or amide
`group. The hydrogen from 3-H or C-—H can also form hydrogen. ‘bonds, but
`generally the bonds are weak. The proton attached to a halogen is generally
`quite active. HF forms strong hydrogen ‘bonds. Typical electron contribu-
`tors are oxygen. nitrogen and halogen atoms found in alcohol-, ethers, alde-
`hydes, ketones. amide and N-heterocyclic compounds. Some examples of hy-
`drogen bonding with water follow:
`
`H
`H
`F!
`|
`|
`|
`?...H_O... -H—o- --H—?.---9
`R
`H
`
`alcohol
`
`‘:1
`‘I.
`R-G=D---H-0-H" -D=C-H
`
`lnatooe
`
`F|sN- “H-0' --NR3
`
`amine
`
`Alcohols dissolve in water by hydrogen bonding. up to an alkyl chain
`length of five carbon atoms. Phenols dissolve in water and alcohol and. as
`the number of hydmxyl groups increase, the water solubility i enhanced
`because of the increased opportunity for hydrogen bonding. Most aromatic
`carhoxylic acids , steroids, and cardiac glycosides are not water soluble but
`dissolve in alcohol. glycerin, or glyools by hydrogen bonding‘. Since the
`overall conformation of proteins is most influenced by hydrogen bonding.
`wster—the solvent of choice for most proteins-contributes to the hydrogen
`bonding and. therefore. can have a strong influence on protein conformation.
`Dipole-ion interactions are responsible for the dissolution of ionic crystal-
`line substances in polar solvents (i.e. . water or alcohol).
`Ions in aqueous
`solution are generally hydrated. (surrounded by water molecules) by as many
`water molecules as can spatially fit around the ion. The attributes of a good
`solvent for electrolytes include:
`(13 a high-dipole moment; (2) a small molec-
`ular size ; and (3) a high dielectric constant to reduce the force of attraction
`between the oppositely charged ions in the crystal. Water possesses all of
`these characteristics and is. therefore .. a good solvent for electrolytes. The
`cation of the electrolyte is attracted to the neg-sure-oinygen atom, while the
`anion attracts the hydrogen atoms to the dipolsr water molecules.
`Generally, when electrolytes dissolve in. water, heat is generated because
`the ion-dipole interaction energy exceeds the sum of the ion—ion interaction
`energy of the solute and the dipole-dipole interaction energy of the solvent.
`Examples of a negative heat of solution are anhydrous rnsgnesium sulfate and
`sodium hydroxide. Where the ion- dipole. energy is less than the sum of the
`energies holding the solute and solvent molecules together, heat is absorbed
`from the surrounding area to make "up for the energy deficit. Electrolytes
`showing a positive heat of -solution include potassium iodide -and sodium bro-
`
`Astraleneca Ex. 2111 p. 16
`
`

`
`183
`
`DeLuca and Boylan
`
`mide. Hydrated salts generally show a positive heat of solution-. Citric acid,
`sorbitol, and mennitol have positive heats of solution so that during dissolu-
`tion the solution becomes cool. when reconstituting dry products containing‘
`large amounts of these substances. which is quite common in freeze—d1-ied
`products. it is necessary to be aware of this phenomenon and warm the solu-
`tion prior to injection.
`Many complexes result because of an ion-induced dipole interaction. For
`example. iodine is solobilized in a solution of potassium iodide in the following
`manner:
`
`I+K"1' +1:
`2
`
`+1-
`3
`
`Although the iodine molecule is electrically neutral. a temporary polarity may
`result from electronic movements within the molecule. Such movements induce
`
`dipoles in neighboring molecules and are responsible for maintaining benzene
`and carbon tetrachloride in the liquid state. The iodide complex forms be-
`cause the strong electrical field of the electrolyte in solution induces a dipole
`in the polarizable iodine molecule. Eenaene is a neutral molecule that is read-
`ily polarisable and soluble in alcohol.
`Symmetrical molecules. such as benzene and carbon tetrachloride. possess
`a zero dipole moment and are nonpolar.
`-Solubility of such molecules or their
`existence in a liquid state is due to van der Waals forces.
`In the manner de-
`scribed earlier. an induction effect occurs in these electrically neutral mole-
`cules, and the molecules orient themselves with surrounding molecules so that
`negative and positive poles are together. Such orientation is referred to as
`resulting from induced dipole-induced dipole interactions. These very weak
`attractions are sometimes called London forces, because they were first de_-
`soribed by London in 1930. They are responsible for dissolution of hydropho-
`bic substances in nonpolar solvents [e.g. , wax in carbon tetrachloride and
`paraffin in petroleum henzin) .
`If the solute and solvent in nonpolar systems
`are similar in size and structure. they can be mixed without any appreciable
`heat of solution.
`If the heat of solution is zero. the solution is referred to
`as an ideal solution.
`
`Another type of van der Waals force is that resulting from induced dipole-
`dipole interact-‘ions. also called Debye interactions.
`In this case, a -dipolar
`molecule is capable of inducing an electrical dipole in a nonpolar molecule-.
`A molecule that resonates. such as benzene. can be polarized by a dipolazr
`substance such as methyl alcohol.
`‘Other examples of such interacfions include
`mixtures of chloral hydrate in carbon tetrachloride and phenol. in mineral oil.
`Examples of drugs marketed in water-miscible systems include digitoxin,
`phenytoin, and diaseparn. These injections are formulated in a water—miscib1e
`system containing -glycols and alcohol and adjusted to a suitable pH. other
`cosolvents used in psrenterals include gly-cei-in in deslanoside, dirnethy1aceta-
`mide in reserpine and dimstliylsulfoidde in chemotherapeutic agents under-
`going clinical testing. Propylene glycol is used most frequently as a coco]-
`vsnt, generally in concentrations of 40%. However, one product {Lorazepu1n)
`uses a complete cosolvent system, 80% propylene glycol and 20% polyethylene-
`glyool; the latter two sol-vents have [.1359 significantly higher than the other
`solvents mentioned. although tissue irritation has been implicated with all
`
`Astraleneca Ex
`
`.2111 p. 17
`
`

`
`Fbnnulotion of Small Volume Porsnterols
`
`133
`
`the -cosolvcnts when administered in high concentrations via the intramuscu-
`lar and subcutaneous routes. Although such systems are stable in individual
`containers, care must be exercised upon administration. For example, pheny-
`toin is dissolved as the sodium salt in a vehicle containing 40% propylene glycol
`and 10% ethanol and adjusted to a pH of 12 with sodium hydroxide. However,
`if this solution is added to a large volume intravenous solution and the pH is
`lowered to a value close to the pKa of the drug tplia = 8.3), precipitation of
`the drug can occur-. This is due to the fact that in aqueous systems at pH
`below 11,