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`Parenteral Medications
`tlolumet
`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
`
`Westbury, New York
`
`Marcel Dekker, Inc.
`
`New York 0 Basel 0 Hong Kong
`
`ALKERMES EXH. 2001
`ALKERMES EXH. 2001
`Luye v. Alkermes
`Luye v. Alkermes
`IPR2016-1095 & IPR2016-1096
`IPR2016-1095 & IPR2016-1096
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`Library of Congress Cataloging — in- PUbliCati°n Data
`
`Pharmaceutical dosage forms , parenteral medications / edited by
`Kenneth E. Avis, Herbert A. Lieberman, and Leon Lachman. -- 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 P5361
`RS201.P37P48 1992
`615‘. 19--dc20
`DNLM /DLC
`for Library of Congress
`
`I. Avis,
`
`2. Technology, Pharmaceutical.
`
`91 ‘33063CIP
`
`
`
`i"30va ?2v?2s“
`
`This book is printed acid-free paper.
`Copyright © 1992 MARCEL DEKKER, INC. All Rights Reserved
`,
`.
`Neither this boficnor 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.
`
`MARCEL DEKKER,-INC.
`270 Madison Avenue, New York, New York 10016
`
`Current printing (last digit):
`10 9 8 7 6 5 4 3 2 1
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`
`
`
`
`
`
`us.Cobyiightlaw;
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`ThematerialonthispagewascopiedfromthecollectionoftheNationalLibraryofMedicinebyattiirdpartyandmaybeprotectedby
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`
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`
`
`Contents
`
`
`
`..4,
`
`,
`
`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
`
`X1
`
`xiii
`
`XV
`
`XVii
`
`Chapter 1 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 B: Highlights in the History of
`Parenteral Medications
`References
`
`'
`
`Chapter 2
`
`Parenteral Drug Administration: Routes, Precautions,
`Problems, Complications, and Drug Delivery Systems
`
`Richard J. Duma, Michael J. Akers, and
`Salvatore J. Turco
`
`Introduction ‘
`I. General Indications for Parenteral
`
`II.
`
`Administration of Drugs
`Pharmaceutical Factors Affecting Parenteral
`Administration
`
`Specific Routes of Administration
`III.
`IV. Distribution of Parenterally Administered Agents
`
`1
`
`1
`4
`12
`
`14
`15
`
`17
`
`17
`
`18
`V
`19
`
`21
`39
`
`vii .
`
`
`
`viii
`
`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 Injectable Medications
`
`Sol Motola
`
`I.
`
`II.
`
`Introduction
`
`Physicochemical and Physiological Factors
`Affecting Drug Absorption by Injection: An
`Overview
`
`III. Application of Pharmacokinetics to Biopharma—
`ceutic Investigations: Pharmacokinetic Models
`IV. Examples of Biopharmaceutic /Pharmacokinetic
`Principles
`V. Regulatory Considerations for Bioequivalence
`Studies
`
`VI. Bioequivalence Study of Two Injectable Forms
`of the Same Drug
`Summary
`References
`
`VII.
`
`Chapter 4
`
`Preformulation Research of Parenteral Medications
`
`Sol Motola and Shreer-am N. Agharkar
`
`I .
`
`Introduction
`
`II. Drug Substance Physicochemical 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
`Preformulation Worksheet
`References
`
`VII.
`VIII .
`
`Chapter 5
`
`Formulation of Small Volume Parenterals
`
`Patrick P. DeLuca and James C. Boylan
`
`I .
`
`Introduction
`
`Formulation Principles
`II.
`III. Container Effects on Formulation
`
`-Stability Evaluation
`IV.
`V. Process Effects
`References
`
`41
`49
`56
`57
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`59
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`59
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`60
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`77
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`98
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`108
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`109
`111
`112
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`115
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`115
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`116
`140
`150
`154
`
`158
`163
`163
`169
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`173
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`173
`174
`227
`234
`244
`245
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`Contents
`
`Chapter 6
`
`Formulation of Large Volume Parenterals
`
`Levit J. Demor-est 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-Chang John Wang
`
`I.
`II.
`III.
`IV.
`
`V.
`
`Introduction
`Characteristics of Proteins and Peptides
`Formulation Principles
`Compatibilityiwith Packaging Components and
`Infusion Sets
`Formulation of Market Products
`References
`
`Chapter 8
`
`Sterile
`
`Leif E.
`
`I.
`II.
`III.
`IV.
`V.
`VI.
`VII.
`
`Diagnostics
`Olsen
`
`Introduction
`
`Diagnostic Products Defined
`Sterile Diagnostics
`Definitions
`
`Aseptic Manufacturing Considerations
`Validation Program
`Conclusion
`References
`
`Chapter 9 Glass Containers for Parenterals
`
`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
`
`249
`
`249
`250
`273
`280
`281
`281
`
`283
`
`283
`284
`302
`
`310
`312
`317
`
`321
`
`321
`321
`322
`325
`330
`351
`359
`359
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`361
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`361
`361
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`362
`369
`375
`380
`380
`382
`384
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`ThematerialonthispagewascopiedfromthecollectionoftheNationalLibraryofMedicinebyathirdpartyandmaybeprotectedlbyCopyrightlaw.
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`ac
`
`Contents
`
`Chapter 10 Use of Plastics for Parenteral Packaging
`John M. Anes, Robert S. Nase, and
`Charles H. White
`
`I.
`II.
`III.
`IV.
`V.
`VI.
`
`Introduction
`Fundamentals
`Fabrication Processes
`Important_ Criteria for Selection of Plastics
`Plastics Used in Parenteral Packaging
`Quality Assurance of Parenteral Containers
`References
`‘
`
`Chapter 11 Elastomeric Closures for Parenterals
`
`Edward J. Smith and Robert J. Nash
`
`I.
`
`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. Levchuk
`
`I.
`II.
`
`III.
`IV.
`
`V.
`VI.
`VII.
`
`Introduction
`
`The Preparation of Sterile Dosage Forms in the
`Hospital and in Home Care
`Dispensing and Compounding Processes
`Technology of Sterile Compounding in the
`Hospital Pharmacy
`Clinical Supply and Use of Sterile Products
`Quality Assurance
`Conclusion
`
`Appendix: Abbreviated Sequence for Preparing a
`Series of Extemporaneously Compounded I.V.
`Admixtures
`References
`
`Index
`
`387
`
`387
`389
`398
`407
`422
`439
`443
`
`445
`
`445
`450
`451
`462
`463
`470
`477
`494
`503
`
`505
`507
`508
`
`513
`
`513
`
`513
`524
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`532
`547
`552
`562
`
`563
`566
`
`569
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`Formulation of Small Volume
`Parenterals
`
`Patrick P. 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 dru_g, 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 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-
`quired to effect rational decisions regarding the selection of:
`(1) a suitable
`
`173
`
`
`
`174
`
`DeLuca 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 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 recognize
`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.
`
`ll. 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.
`Isotonicity is another factor that must be taken into consideration. Al-
`though isotonicvsolutions are less irritating, cause less toxicity and eliminate
`the possibility of hemolysis, it is not essential that all injections be isotonic.
`In fact, for subcutaneous and intramuscular injections hypertonic solutions
`
`
`
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`Formulation of Small Volume Parenterals
`
`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 hydrogen—bonding 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 Solubilization
`
`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 greatly enhancing solubility,
`constitute new entities requiring additional clinical studies. Other substances
`used as solubilizers 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 solubilize 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.
`
`
`
`176
`
`DeLuca and Boylan
`
`Ethylenediamine is required in aminophylline injections to maintain the
`theophylline in solution since aminophylline is a salt that ionizes into its con-
`stituent ions theophylline and ethylenediamine.
`
`Aminophylline + 2 theophylline’
`
`+ ethylenediamine2+
`
`Ethylenediamine, 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 (pKa '\a 8. 8), which is only slightly soluble in water (8 mg"/ml).
`
`Theophylline_ + H+ —>
`
`theophylline (free)
`
`Creatinine, niacinamide, and lecithin have been used for solubilizing steroids
`in the free alcohol form. The use of the salt or ester of these steroids or
`vitamins eliminates the need to use solubilizers 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 parenterals, the drug and other dissolved substances
`should remain solubilized throughout the shelf-life of the product.
`
`Solubility Expressions. Solubility of a substance can be expressed in a
`number of ways. Generally, the concentration is expressed as percent (w/V) ,
`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-
`eral terms to describe a given range. These descriptive terms are listed in
`Table 1.
`
`Table 1 Expressions for Approximate Solubility
`
`Term
`
`Very soluble
`
`Freely soluble
`
`Soluble
`
`Sparingly soluble
`
`Slightly soluble
`
`Very slightly soluble
`
`Relative amount of
`solvent to dissolve
`
`1 part of solute
`
`<1
`
`1-10
`
`10-30
`
`30-100
`
`100- 1000
`
`1000-10,000
`
`
`
`Practically insoluble or insoluble >10,000
`
`
`
`
`
`
`
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`
`Formulation of Small Volume Parenterals
`
`177
`
`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 [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 O. 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 lb 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
`interactions).
`If an environment similar to that of the crystal structure can
`be provided by the solvent, then the greater the solubility (i.e. , "like dis-
`solves 1ike").
`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).
`
`_ _ _ . _ _
`
`
`
`
`Undissolved solute
`begins appearing
`
`mg SOLUTE/ml SOLVENT
`
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`Figure 1 Phase solubility diagrams for a pure substance (a) and a substance
`containing an impurity (b).
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`178
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`DeLuca 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
`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 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 co—workers 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 40 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 (d.c.) 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 Dielectric constant
`
`Watera
`
`Glycerina
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`N , N-Dimethylacetamidea
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`78. 5
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`40. 1
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`37. 8
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`Propylene glycola
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`32. 01 (30°)
`
`Methanol
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`Ethanola
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`N—Propanol
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`Acetone
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`Benzyl alcohola
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`Polyethylene glycol 4003
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`Cottonseed oila
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`Benzene
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`31. 5
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`24. 3
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`20 . 1
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`19. 1
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`13. 1
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`12. 5
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`3. 0
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`2 . 3
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`2. 2
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`Formulation of Small Volume Parenterals
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`179
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`SOLUBILITY
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`DIELECTRIC CONSTANT
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`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) (24.3) + (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
`PEG 500
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`H 20
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`10%
`16.5%
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`73 . 5%
`
`Since dielectric constant is a measure of the polarizability 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 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 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 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. ,
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`180
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`100
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`DeLuca and Boylan
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`SOLUBILITY,moles/I
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`Figure 3 Log‘-linear solubility relationship for a series of alkyl p-arr§inobenzo—
`ates—g1yco1—water,
`[From Yalkowsky, S. H. , Flynn, G. L. , and Am1don, G.
`L., J. Pharm. Sci., 61:983 (1972).]
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`Formulation of Small Volume Parenterals
`
`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 S——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:
`
`alcohol
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`ketone
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`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 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:
`(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—oxygen 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 sumvof 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-
`
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`182
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`DeLuca and Boylan
`
`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 freeze-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:
`
`12 + K+I
`
`+ K+I3
`
`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. 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,