`tlolumet
`Second Edition, Revised and Expanded
`
`Edited by Kenneth E. Avis,
`Herbert A. Lieberman, and Leon lurhmun
`
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`30
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`Time (hours)
`
`Astrazeneca Ex. 211 l p. 1
`Mylan Pharms. Inc. V. Astrazeneca AB IPRZOI6-01325
`
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`B08398 FOI‘IIIS:
`
`Parenteral Medications
`ttolumet
`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 lachman
`
`Lachman Consultant Services
`
`We-stbury, New York
`
`Marcel Dekker, Int;
`
`New York - Basel 0 Hong Kong
`
`Astrazeneca Ex. 21 l l p. 2
`
`
`
`Library of Congress Cataloging - in - Publication Data
`
`Pharmaceutical dosage forms, parenteral medications I edited by
`Kenneth E. Avie, Herbert A. Lieberman, and Leon Lachrnan. -- 2nd ed. ,
`rev. and expanded.
`p.
`cm.
`
`Includes bibliographical references and index.
`ISBN 0-8247-8576-2 (V. 1 : alk. paper)
`1. Parenteral solutions.
`2. Pharmaceutical technology.
`Kenneth E.
`II. Lieberman, Herbert A.
`III. Lachman, Leon.
`[DNLM: 1. Infusions. Parenteral.
`WB 354 P536]
`RS2D1.P37P48 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 not any part may be reproduced or transmitted in any form
`or by any means, electronic or mechanical, including photocopying. micro-
`filrning, and recording, or by any information storage and retrieval system,
`without permission in writing from the publisher.
`
`_
`MARCEL DEKKER, INC.
`270 Madison Avenue, New York, New York 10016
`
`Current printing (last digit):
`10 9 S 7 6 5 4 3 2 1
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`Astrazeneca Ex. 2111 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: Disperse Systems.-,
`Volumes 1 and 2
`
`1ii
`xi
`
`xiii
`
`xv
`
`xvii
`
`Chapter 1 The Parenteral Dosage Form and Its Historical Development
`
`1
`
`Kenneth E. Avis
`
`I. The Dosage Form
`I1. History of Parenteral Medications
`Appendix A: Glossary of Terms
`Appendix B‘: Highlights in the History of
`Parenteral Medications
`References
`
`Chapter 2
`
`Parenteral Drug Administration: Routes. Precautions,
`Problem, Complications, and Drug Delivery Systems
`
`Richard J. Duma.-. Michael J. Aka.-rs. and
`ScI'uatore- .1’. Turns
`
`Introduction
`I. General Indications for Parenteral
`
`II.
`
`Administration of Drugs
`Pharmaceutical Factors Affecting Parenteral
`Administration
`
`III. Specific Routes of Adminitratison
`IV. Distribution of Parenteraliy Administered Agents
`
`1
`4
`12
`
`1-!
`15
`
`17
`
`1'?
`
`18
`
`1 9
`
`21
`3-9
`
`vii
`
`Astrazeneca Ex. 21 1 1 p. 4
`
`
`
`1.-iii
`
`Contents
`
`V". Precautions. Problems, Hazards, and
`Complications Associated with Parenteral Drug
`Administration
`
`VI. Methods and Devices for Drug Delivery Systems
`VII.
`Summary
`References
`
`_
`
`Chapter 3 Biopharmaceutics of Injectabls Medications
`
`So! Motola.
`
`I.
`
`II.
`
`Introduction
`
`Physicochernical -and Physiological Factors
`Affecting Drug Absorption by Injection: An
`Overview
`
`III. Application of Pharmacokinetics to Biophar1'na-
`ceutic Investigations: Pharmacokinetic Models
`IV. Examples of Bic-pharmaceutic lPhar1necokinetic
`Principles
`V. Regulatory Considerations for Bioequivalenee
`Studies
`
`VI. Bioequivalence Study of Two Injeotable Forms
`of the Same Drug
`Summary
`References
`
`VII.
`
`Chapter 4
`
`Preformulation Research of Parenteral Medications
`
`So! Motoia and Shreerom N . Agharkar
`
`I .
`
`Introduction
`
`11. Drug Substance Physieochemical Properties
`III. Accelerated Stability Evaluation
`IV . General Modes of Drug Degradation
`V.
`Preformulation 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 Effects on Formulation
`IV.
`Stability Evaluation
`V.
`Process Effects
`References
`
`4_1
`
`49
`56
`5'?
`
`-59
`
`59
`
`60
`
`7'?
`
`98
`
`108
`
`109
`111
`112
`
`1.15
`
`11 5
`
`116
`140
`150
`154
`
`158
`163
`163
`169
`
`1'33
`
`1':'3
`
`174
`22'?‘
`234
`244
`245
`
`Astrazeneca Ex. 21 1 1 p. 5
`
`
`
`Contents
`
`ix
`
`Chapter 6
`
`Formulation of Large Volume Parenterals
`
`Levi: 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 Proteins
`
`Yu~«Chnng John Wong
`
`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. Poul Abendroth and Robert N. Clark
`
`1.
`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 Ex. 2111 p. 6
`
`
`
`X
`
`Contents
`
`Chapter 10 Use of Plastics for Parenteral Packaging
`
`John M. Aries, 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 Elastomerio Closures for Parenterals
`
`Edward J. Smith and Robert J’. Nash
`
`II
`
`II.
`III.
`IV.
`V.
`VI .
`VII.
`VIII.
`IX .
`X .
`
`XI.
`
`Elastomeric Parenteral Packaging Components:
`A Physical Description
`Physical Description of Rubber
`Types of Rubber Used in Parenteral Packaging
`Closure Design
`Rubber Compounding
`vulcanization Process
`Closure Manufacture and Control
`
`Closure Design Qualification
`Regulatory Considerations
`Interaction of Drug‘. Formulations with
`Rubber Closures
`
`Contemporary Closure-Related Issues
`References
`
`Chapter 12 Parenteral Products in Hospital and Home Care
`Pharmacy Practice
`
`John W. Levohulc
`
`I.
`II.
`
`III .
`IV .
`
`V0
`VI‘
`VII.
`
`Introduction
`
`The Preparation of Sterile Dosage Form: 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 I.V.
`Admixtures
`References
`
`Index
`
`387
`
`38.7
`. 389
`398
`40?
`422
`439
`443
`
`445
`
`4415
`450
`£151
`462
`463
`470
`477
`494
`503
`
`505
`507
`508
`
`513
`
`5-13
`
`513
`524
`
`532
`54'?
`552
`562
`
`56 3
`56.6
`
`569
`
`Astrazeneca Ex. 21 1 1 p. 7
`
`
`
`5 F
`
`ormulation of Small Volume
`
`Parenterals
`
`Patrick P. DeLuca
`
`University o f 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 Pharmacopeia (USP) [2] as " .
`.
`. an
`injection that is packaged in containers labeled as containing 100 ml or less."
`The USP categorizes sterile preparations for parenteral use according to the
`physical state of 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 same 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-
`pharmaceuticals included), ophthalmic preparations, and irrigating solutions,
`this chapter emphasizes the formulation of injectable dosage forms.
`The successful formulation of an injectsble 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-
`quired to effect rational decisions regarding the selection of:
`(1) a suitable
`
`173
`
`Astrazeneca Ex. 2111 p. 8
`
`
`
`174
`
`DeLuco and Baylor:
`
`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 physical-
`chemical aspects of‘ preparing a stable product in a suitable container recog-
`nizing that safety must be established through evaluation of toxicity, tissue
`tolerance, pyrogenicity, sterility. and tonicity. and efficacy must be 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 stability. 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 formulafion
`approaches for proteins and peptides.
`
`II.
`
`FORMULATION PRINCIPLES
`
`A‘
`
`Influence of the Route of Administration
`
`Since parenteral preparations are introduced directly into the intra- or extra-
`cellular fluid 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 intradermal 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
`intramuscularly and subcutaneously.
`lsotonicity is another factor that must be taken into consideration. Al-
`though isotonic solutions are less irritating, cause less toxicity and eliminate
`the posibility of hemolysis, it is not essential that all injections be isotonic.
`In fact. for subcutaneous and intramuscular injections hypertonic solutions
`
`Astrazeneca Ex.2111 p.9
`
`
`
`Formulation of Small Volume Porenterals
`
`175
`
`are often used to facilitate absorption of drug due to local effusion of tissue
`fluids. With intravenous solutions isotonicity becomes less important as long
`as administration is slow enough to permit dilution or adjustment in the blood.
`However, intraspinal injections must be 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 intraarticular, directly into the syno—
`vial fluid for rheumatoidal diseases and even intradigital, 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 ionizable electrolytes and
`its hydrogembonding potential facilitates the solution of alcohols, aldehydes,
`ketones, and amines. Water for Injection, USP, is the solvent of choice for
`making parenterals.
`It must be 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
`solubilizing agents or cosolvents. may be necessary. For instance, nonpolar
`substances (i.e. , alkaloidal 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 Soluhilization
`
`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, crystallization of the drug‘
`can occur as a result of 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 greafly enhancing solubility,
`constitute new entities requiring additional clinical studies. Other substances
`used as solubilieers include the surface-active and complexing 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, sulfonamides, dyes, resins, and volatile oils. These
`surfactants are powerful wetting agents and form colloidal dispersions that
`have the appearance of a true solution.
`
`Astrazcneca Ex. 2111 p. 10
`
`
`
`I76
`
`DeLuco and Boylcm
`
`Ethylenediemine is required in sminophylline injections to msjntsin the
`theoyghylline in solution since sminophylline is e salt that ionizes into its con“
`stituent ions theophylline and ethylenediamine.
`
`Aminophylline + 2 theophylline” + ethy1endiemine2'*
`
`Ethylenediamine, 5: strongly alkaline substsnee, is volatile and if it escapes,
`the pH will be lowered, causing; theophylline ion to be converted to free their
`phyllin (plia W B. 8), which is only slightly soluble in water (8 mgfml) .
`
`Theophylline" + s*' + theophylline (free)
`
`Creatinine, niecinamide, and lecithin have been used for solubilising steroids
`in the free alcohol form. The use of the salt or ester of these steroids or
`
`vitamins eliminates the need to use soluoilizers but requires other additives
`to ensure stability.
`A brief description of the phenomenon of solubility will be helpful to the
`formulstor in selecting the best solvent or agent to overcome difficulties that
`arise in the preparation of pharmaceutical dosage forms containing poorly
`soluble drugs. with perentersls, the drug and other dissolved substances
`should remain solubilized throughout the shelfdife of the product.
`
`Solubitity Expressions. Solubility of e substance can he expressed in a
`number of ways. Generally, the concentration is expressed es percent (w Iv} ,
`that is, grams per 100 ml of solution, but molerity and molality have been
`used. Molsrity 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 end, therefore,
`being a weight relationship , is not influenced by temperature. The USP lists
`solubflity 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-
`ere} terms to describe :3. given range. These descriptive terms are 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
`
`30~1GU
`
`100-1800
`
`lOUUI—1f.},{l€]f3
`
`Prsotieelly insoluble or insoluble
`
`>1{],[l{]i3
`
`Astrazeneca Ex. 2111 p. 11
`
`
`
`Formulation of Small Volume Parenterols
`
`17?
`
`Measuring Solubility. Methods for determining the solubility of drug sub-
`stances in various solvents have been described [3- 6] . The phase solubility
`technique is especially applicable to determining the solubility of pure sub-
`stances and also detecting the presence of impurities [B] .
`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 0.1°C.
`In those containers in which excess drug is present
`(undissolved) , samples of the supernatant are withdrawn and assayed until
`the concentration is constant (i.e. . the system has reached equilibrium). For
`a pure compound, a phase solubility diagram is constructed as shown in Fig-
`ure la. 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-axis. 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 (solute-solvent
`
`If an environment similar to that of the crystal structure can
`interactions).
`be provided by the solvent. then the greater the solubility (i.e. , "like dis-
`solves like").
`Ionic compounds dissolve more readily in water by virtue of
`ion-dipole interactions, whereas hydrophobic substances dissolve more easily
`in organic solvents as a result of dipole or induced dipole interactions (van
`der Waals, London or Debye forces) .
`
`E""5.
`33"
`E
`
`E5
`8
`Lu
`9-
`:3
`
`En’
`”‘
`
`_ _ _ _ _ ..
`
`
`
`Undissulved salute
`begins appearing
`
`mg SOLUTE./ml SOLVENT
`
`
`
`.
`Solubility of substance and irnpurily
`
`
`
`E
`gs
`%Ou
`Lu
`I-‘
`::
`an
`5|
`Snlublilly of impurity
`
`
`
`mg SOLUTEI'I11| SOLVENT
`
`Figure 1 Phase solubility diagrams for a pure substance (a) and a substance
`containing an impurity (b).
`
`Astrazcneca Ex. 2111 p. 12
`
`
`
`l?3
`
`DeLuoa and Boylan
`
`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
`constant 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 semipolar. The dielectric constants of most pharmaceutical sol-
`vents are known [7,8] and values for a number of binary and tertiary blends
`have been reported [9] and, if not reported, can be readily estimated [10].
`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 ccrworkers and others
`[11~17] . 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 4D is required. Not all mixtures will show a maximum,
`but such a plot illustrates the required dielectric constant to obtain the de-
`sired concentration. For example, if a dielectric constant 131.0.) of 60 was
`
`selected, a mixture of water (d.c. 78.5), polyethylene glycol (PEG) 400
`
`Table 2 Dielectric Constants of Some Solvents at 25°C
`
`Solvent
`
`Water“
`
`c1'yt-em".-na
`
`N , N-Dimethylacetamidea
`
`Dielectric constant
`
`78.5
`
`40.1
`
`37. 8
`
`Propylene glycol”
`
`32.01 {3fl°)
`
`Methanol
`
`Ethanol“
`
`N-Propanol
`
`Acetone
`
`Benzyl alcohol”
`
`Polyethylene glycol 4003
`
`Cottonseed oil“
`
`Benzene
`
`Dioxane
`
`asolvents used in parenterals
`
`31.5
`
`24.3
`
`20.1
`
`19.1
`
`13.1
`
`12.5
`
`3.0
`
`2.3
`
`2.3
`
`Astrazcneca Ex. 2111 p. 13
`
`
`
`Formulation of Smell Volume Pcrenter-als
`
`179
`
`He: Salarbswly
`
`/
`
`SOLUBILITY
`
`I0
`
`20
`
`30 40 50
`
`60 ‘F0
`
`DIELECTRIC CONSTANT
`
`Figure 2 Hypothetical plot of solubility of a -substance versus dielectric con-
`stant in various mixtures of dioxane 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) (34.3) + (X) (78.5) + (90 - X) (12.5) = (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
`rec sou
`
`H 20
`
`10%
`13.5%
`
`73.5%
`
`Since dielectric constant is a. measure of the polerizability -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 [31 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 Am-idon [20] and Yalkowsky [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 a a function of olvent 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-
`eter of solubility including interfacial tension and hydrogen bonding [18, 22] ..
`Hydrogen bonding, the strongest type of dipole-dipole interaction, is
`characterized 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. ,
`
`Astrazcneca Ex. 2111 p. 14
`
`
`
`Del-uca and Boylan
`
`180
`
`10°
`
`
`
`SOLUBILITY.males}!
`
`105
`
`103
`
`o
`
`so
`so
`40
`20
`PROPYLENE GLYCO L. '5
`
`100
`
`Figure 3 Log—1inear solubility relationship for a series of alkyl p-aminobenzo—
`ates-glycol-water.
`[From Yalkowsky, S. H. , Flynn, G. L., and Amidon, G.
`L., J. Pharm. Scz'., 61:983 (1972).]
`
`C2Hs.-0-H---0:
`
`H
`
`H
`
`5‘
`C--'.-.--
`
`Q 9
`
`0 __ H '
`
`intermolecular H bonding
`
`intramolecular H bonding
`
`Astrazeneca Ex. 21 11 p. 15
`
`
`
`Formulation of Small Volume Pcrentersls
`
`181
`
`between groups within a single molecule) and the intermolecular type (i.e. ,
`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 carboxyl, hydroxyl. amine or amide
`group. The hydrogen from 5-H or 0-H can also form hydrogen bonds. but
`generally the bonds are weak. The proton attached to a halogen is generally
`quite active.
`I-IF forms strong hydrogen bonds. Typical electron contribu-
`tors are oxygen, nitrogen and halogen atoms found in alcohol, ethers, alde-
`hydes, ketones, amide and N-heterocyolic compounds.
`some examples of hy-
`drogen bonding with water follow:
`
`F!
`|
`T
`T
`?___H,_o_ _ ,H_0. _.H_['). . -
`9
`H
`
`H
`|
`||‘
`n—c=o- - -H—0—H- —-O=C-R
`
`H
`I
`RaN*--H--O- --NR:
`
`alcohol
`
`Isetone
`
`I
`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 hydroxyl groups increase. the water solubility is enhanced
`because of the increased opportunity for hydrogen bonding. Most aromatic
`carboxylic acids, steroids, and cardiac glycosides are not water soluble but
`dissolve in alcohol, glycerin. or glycols by hydrogen bonding. Since the
`overall conformation of proteins is most influenced by hydrogen bonding,
`water--the solvent of choice for most prote_ins—cont1'ibutes to the hydrogen
`bonding and. therefore, can have a strong influence on protein conformation.
`l'.‘Iipole—iorl 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:
`(1) a high—dipo1e 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 negative—oxyg-en atom, while the
`anion attracts the hydrogen atoms to the dipolar 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 magnesium 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-
`
`Astrazcneca Ex. 2111 p. 16
`
`
`
`182
`
`DeLucc and Boylun
`
`mide. Hydrated salts generally show a positive heat of solution. Citric acid,
`sorbitol, and mannitol 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 freese~dried
`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 solubilized in a solution of potassium iodide in the following
`manner:
`
`+—
`I2+I{I
`
`+~
`+ K13
`
`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 polarisable iodine molecule. Benzene is a neutral molecule that is read-
`ily polarizable 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-
`scribed 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 benzin) .
`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 interactions, 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 dipolar
`substance such as methyl alcohol. other examples of such interactions 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 diazepam. These injections are formulated in a water- miscible
`system containing‘ glycols and alcohol and adjusted to a suitable pl-l. Other
`cosolvents used in parent-erals include glycerin in deslanoside, dirnethylaceta-
`mide in reserpine and dirnethylsulfoxide in chemotherapeutic agents under-
`going clinical testing. Propylene glycol is used most frequently as a cosol-
`vent, generally in concentrations of 40%. However, one product (Lorazepam)
`uses a complete cosolvent system, 30% propylene glycol and 20% polyethylene
`glycol; the latter two solvents have LD 53 significantly higher than the other
`solvents mentioned, although tissue irritation has been implicated with all
`
`Astrazcneca Ex. 2111 p. 17
`
`
`
`Formulation of Small Volume Parentsrels
`
`183
`
`the cosolvents 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 pita of the drug (pita = 8.3) _, precipitation of
`the drug can occur. This is due to the fact that in aqueous systems at p