Pharmaceutical
`Dosage FOI'IIIS:
`Parenteral Medications
`VolumeI
`Second mien, Revised and Expanded
`
`
`
`MAIA Exhibit 1014
`
`MAIA V. BRACCO
`
`IPR PETITION
`
`
`
`
`MAIA Exhibit 1014
`MAIA V. BRACCO
`IPR PETITION
`
`

`

`Pharmaceutical
`: ”08398 HII'IIIS:
`Parenteral Medications
`Volume 1
`Second Edition, Revised and Expanded
`
`New York - Basel 0 Hong Kong
`
`
`' Wfifififfi'fl
` WELE‘TES UNIVERSITY
`‘fifllfiflES-BAS‘RE, PA
`
`Ediled by
`
`Kenneth E. Avis
`The University of Tennessee
`Memphis, Tennessee
`
`Herbert A. liebermun
`H.H'. Lieberman Associates, Inc.
`Consultant Services
`Livingston, New Jersey
`
`lean Luthman
`Lachman Consultant Services
`Wesrbury, New York
`
`Marcel Dekker, Inc.
`
`
`
`
`

`

`
`
`Library of Congress Cataloging —‘in — Publication Data
`
`Pharmaceutical dosage forms. parenteral medications I edited by
`Kenneth E. Avis, Herbert A. Lieberman, and Lean Lachman. ~- 2nd ed. .
`rev. and expanded.
`p.
`cm.
`Includes bibliographical references and index.
`ISBN WWW-8576401.
`1 :
`2111:. paper)
`I. Parenteral solutions.
`2. Pharmaceutical technology.
`Kenneth E.
`II. Lieberman. Herbert A.
`III. Lechman. Leon.
`
`I. Avis.
`
`[DNLM: l. Infusions. Parenteral.
`WB 354 P536]
`RS201.P37P43 1992
`615'. 19~—dc20
`DNLM/DLC
`
`for Library of Congress
`
`2. Technology, Pharmaceutical.
`
`91 - 33063
`CIP
`
`This book is printed on acid—free paper.
`
`Copyright © 1992 by MARCEL DEKKER, INC. All Rights Reserved
`
`Neither this book nor any part may be reproduced or transmitted in any form
`or by any means. electronic or mechanical. including photocopying, micro—
`filming, and recording, or by any infonnalinn storage and retrieval system.
`withcm pennism'on in writing from the publisher.
`
`MARCEL DEKKER. INC.
`270 Madison Avenue, New York, New York lOOl6
`
`Curt-em printing (last digit):
`10 9 8
`T 6 5 4 3 2
`|
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`
`
`
`

`

`
`
`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 £01109!ng 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 Pharmacopoeia (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. Dr).r solids which. upon the addition of suitable vehicles. become
`sterile suspensions
`
`Although the term sterile pharmaceuticals is applicable to all injections (radios
`pharmaceuticals included), ophthalmic preparations, and irrigating solutiOns,
`this chapter emphasizes the formulation of lnjectable dosage forms.
`The successful formulation of an injectablc 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
`
`I73
`
`-173-
`
`-173-
`
`
`
`
`

`

`
`
`”'4
`
`DeLuco and Boylcm
`
`vehicle (aqueous, ncnaqueous, or cosolvent); (2) added substances (enti-
`microbisl agents, antioxidants, buffers, chelating agents, and tonicitzr 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 s stable product in a suitable container recoge
`nizing that safety must be established through evaluation of toxicity. tissue
`tolerance, pyrogenicity, sterility, and tonicity, and efficacy must be demonv
`stratcd 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. HDWEveI‘, cosolvents or nonoqueous 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. Ale
`though each of these dosage forms have distinctive characteristics and formu-
`lation requirements, certain physicalichemical 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 intre— 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 on r—
`t'ently used for parenteral products.
`One of the most important considerations in formulating a psrcntersl 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 1.0 Int) can be administered, although the rate of administration must be
`carefully controlled. Volumes up to 10 ml can be administered intraspincllly.
`while the intramuscular route is normally limited to 3 ml, subcutaneous to 2
`ml and introdermal to 0.2 ml.
`The choice of the solvent system or vehicle '15 directly related to the in-
`tended routc of admimstration 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
`intramusculerly and subcutaneously.
`file
`Isotonicity is another factor that must be taken into consideration.
`though isotonic solutions 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 hyper-tonic solutions
`
`-174-
`
`-174-
`
`
`
`
`

`

`Formulation of Small Volume Purentemls
`
`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,
`intraapinal injections must be isotonic becausa of slow circulation
`of the cerebrospinol 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—
`‘viaJ 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 theI Vehicle
`
`the high dielec—
`Most parenteral products are aqueous solutions. Chemically,
`tric constant of water makes it possible to dissolve ionizublc electrolytes and
`its hydrogen-bonding potential facilitates the solution of alcohols, aldehyde-s,
`ketones, and amines. Water for Injection. USP, is the solvent of choice for
`makingr parentersls.
`It must be prepared fresh by distillation or by reverse
`osmoeis 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 (Le. . alkaloids] bases) possess limited solubility in water and it
`is necessary to add a cooolvent such as glycerin, ethanol. propylene glycol
`or polyethylene glycol.
`In other cases, to prevent chemical degradation (i.e. .
`hydrolysis, oxidation. decsrboxylstion, or rsoemization) 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 Solubilizclion
`
`The solubility of a substance at a given temperature is defined quantitatively
`as the concentration of the dissolved solute in a saturated solution (Le. . the
`dissolved solute phase). Generally. drugs are present in soluticm at unsatus
`rated or subsaturated concentrations; otherwise, crystallization of the drug
`can occur as a result of changes in pull 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 forms?
`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.
`
`-175-
`
`
`
`-175-
`
`
`
`
`

`

`176
`
`DeLuca und Boylon
`
`Ethylenediamine is required in aminophylline injections to maintain the
`theophylline in solution since ominophylline is a salt that ionizes into its cons
`stituent ions theophylline and ethylenediamine.
`
`Aminophylline + 2theophylline'
`
`+ ethylenediamine2+
`
`Ethylenediamine, a strongly alkaline substance, is volatile and if it escapes.
`the pH will be lowered. causing theophvlline ion to be converted to free theo-
`phylline‘ (pl-Ca m 3.8). which is only slightly soluble in water (8 mg/ml).
`
`The-ophyllinei
`
`1' P“ + theophylline (free)
`
`Creatinine. niacinamide. and lecithin have been used for solubilizing steroids
`in the tree 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
`i'ormulator in selecting the best solvent or agent to overcome difficulties that
`arise in the preparation of pharmaceutical dosage forms containing poorly
`soluble drugs. With parental-ads. 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 m1 of solution. but molarity and molality have been
`used. Molarily is defined as the number of moles per 1000 m1 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 I Expressions for Approximate Solubility
`
` Term
`
`Relative amount of
`solvent
`to dissolve
`1 part of solute
`
`Very soluble
`
`Freely soluble
`Soluble
`
`Sparinpl-ly soluble
`
`Slightly soluble
`
`Very slightly.r soluble
`
`Practically insoluble or insoluble
`
`<1
`
`1— 10
`10-30
`
`30 100
`
`10071000
`
`NOD-10,000
`
`40,000
`
`
`
`-176-
`
`-176-
`
`
`
`
`

`

`
`
`Formulation of Small Volume Porenterols
`
`l7?
`
`Measuring Solubility. Methods for determining the solubility of drug sub-
`stances in various solvents have been described [It-ti]. The phase solubilityr
`technique is especially applicable to determining the solubility of pure sub-
`stances and also detecting the presence of impurities [G].
`In this method,
`successively larger portions of the substance are added to the same volume
`or solvent in suitable containers which are agitated at constant temperatures.
`generally 30 1 0.1°C.
`In those containers in which excess drug in present
`tundlssulved). samples of the supernatant are withdrawn and noseyed until
`the concentration is constant (Le. , the system has reached equilibrium). For
`a pure compound. a phase solubility diagram is constructed as shown in Fig-
`ure la.
`’l‘he 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 on 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 ti.e.. "like dis-
`solves Like" }.
`Ionic compounds diesolve 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
`dcr Whole. London or Dehye forces).
`
`
`
`Sfllu’mlll}
`
`______
`Undassalvt'li some
`
`begins uppcorrnq
`
`
`mg SULUIEIMI SOLVENT
`
`E3
`
`..
`E
`
`g
`0
`U._
`D_l
`
`UL
`
`D m
`
`Boylun
`
`the
`:s can
`
`rapes .
`:2 {1160*
`
`teroids
`; or
`itivee
`
`to the
`as that
`nasty
`mees
`
`d in a
`t. (wlv) ,
`«zen
`on.
`ere-fore .
`SP Lists
`issolve
`es gen—
`ted in
`
`:‘E
`Soluhll-IT cl subtlflnte and openly
`E»
`U ______
`
`ZOuh
`
`.)._
`.3
`'1‘!
`5'
`
`
`
`59mm”; cl 1mm“
`
`mg sown rm.
`SOLVENT
`
`Figure I Phase solubility diagrams for a pure substance (is) and a substance
`containing an impurity (b).
`
`-177-
`
`-177-
`
`
`
`
`

`

`
`
`1378
`
`DcLuca and Boylun
`
`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 nanpclar (e.g. . chloroform , benzene, and the oils). Sol-
`vents with intermediate dielectric constants (e.g. , acetone and butanvol) are
`classified as semipolar. The dielectric constants of most pharmaceutical sol-
`vents are known [7,83 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 eta-workers and others
`ill-17] . By determining the solubility of a substance in a system at various
`dietectric constants. a graph such as that shown in Figure 2 can be constructe
`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 49 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 (El.c.) of ED 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
`
`Water8
`
`Glycerina
`
`N. N—Dimet11.],rliicctstnidea
`
`Propylene gljvrml‘El
`Methanol
`
`Eti‘tanola
`
`NiPi-opanol
`Acetone
`
`Henry] identified3
`
`Polyethylene glycol 4009
`Cottonseed oil'El
`
`'38. 5
`
`40.1
`
`3'3. 8
`
`32.01 (30")
`31. 5
`
`24. 3
`
`20. l
`19. 1
`
`[3.]
`
`12. 5
`3. 0
`
`Benzene
`2.3
`Dioxonc 2. 2
`
`a
`.
`Solvents used in pare-Morals
`
`-178-
`
`-178-
`
`
`
`
`

`

`
`
`Formulation of Small Volume Parentercls
`
`n5.
`
`Hal 5mg». 0-
`
`1’
`
`SOLUBlLlT‘l‘
`
`I'll. mum —O- l
`
` ID El) 50 4'3 50 60 ff-
`
`
`
`
`U:ELEUP.I£ CONSTANT
`
`Figure 2 Hypothetical plot of solubility of a substance versus dielectric con-
`stant in various mixtures of dioxane and water.
`
`(LLc. 12.5) and ethanol (d.c. 24.3) could be used. Selecting an amount of
`ethanol necessary to dissolve the drug te.g.. 10%). the percentages of PEL'.
`£00 and water can be calculated as follows.
`
`(Ill) (24.3) * (X) {73.5) + (90 - X) (12.5) : (100)
`
`(61])
`
`where X is the percentage of water required and is calculated to be 73.5%.
`Therefore.
`lhe vehicle to provide a dielectric constant 0! till will have the [ol-
`Iowlng' composition:
`
`Ethanol
`PEG 500
`H20
`
`10%
`16.5%
`73.5%
`
`Since dielectric constant is a measure of the polarizablllty and dipole mo—
`ment or a compound. several researchers have explored other parameters and
`polarity indexes [13] 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 idea] solutions. Martin and co-workers [I9] modified the Hildebrand “p,
`preach to include hydrogen—bonding and dipole: 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 it shows the solu-
`bility as a function of solvent concentration. The slope of the line is u 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 [15.22].
`Hydrogen bonding. the strongest type of dipole-dipole interaction. is
`characterized by a positive center in the hydrogen mam (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.
`A5 a result of this spatial maneuverability. both intramoleculur bonding (Le. .
`
`-179-
`
`
`
`-179-
`
`
`
`
`

`

`f
`
`130
`
`100
`
`DeLuca and Boyia.
`
`1c?
`
`u-__._....‘.__...
`
`
`
`SDLUBILITY,males/l
`
`10-5
`
`1
`
`D
`
`BO
`60
`40
`20
`PRO'PYLENE GLYCOL. '36
`
`100
`
`Figure 3 Log-linear solubility relationship for a series of alkyl piaminoben:
`ates—glycol-water.
`[From YaJkowsky, S. H., Flynn, G. L... and Amldon. G
`L.. J. Phur‘m. Sci. , 51:983 (19?2).]
`
`H|
`
`Ca:
`
`Q ,9
`
`0—H
`
`.
`
`,
`
`;
`
`ems—o-H-uq
`
`I
`
`H
`
`H
`
`L
`
`mzermoiecular H bonding
`
`intramolecular H bonding
`
`-180-
`
`
`
`-180-
`
`
`
`
`

`

`
`
`[an
`
`
`
`
`
`
`
`
`
`Formulation of Small Volume Porenterols
`
`181
`
`between groups within a single molecule) and the intermolecular type (i.e. 2
`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 eontribw
`tors are oxygen, nitrogen and halogen atoms found in alcohol. others. alde-
`hydes, ketones, amide and N-heterocyclic compounds. Some examples of hy-
`drogen bonding with water follow:
`
`alcohol
`
`ketone
`
`amine
`
`Fl
`I
`l:
`l:
`0---H-o- --H—0---H-C|l-- —
`l
`H
`
`IF
`
`H
`I
`I?
`n—c-o---H—o—H-~o=c—n
`
`Hl
`
`RaN---H-O- “NR:
`
`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 proteinsnconlributes 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 (Le. , 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 at good
`solvent for electrolytes include:
`(1) 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 negativesoxygen 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-
`
`
`
`-181-
`
`-181-
`
`
`
`
`

`

`
`
`182
`
`DeLuco and Boylan
`
`mide. Hydrated salts generally show a positive heat of solution. Citric acid,
`sorbilol, and mannitol have positive heats of solution so that during dissolus
`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 calm
`tion prior to injection.
`Many complexes result because of an ion—induced dipole interaction. For
`example, iodine is solubilized in :1 solution of potassium iodide in the following
`manner:
`
`4- ~
`
`+ -
`
`I2 + K I
`
`-r 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 polsrizsble 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 it liquid state is due to van dcr Wouls 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 nonpolsr 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 Wards 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 nonpolsr molecule.
`A molecule that resonates. such as benzene, can bc polarized by a dipole:
`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 pH. Other
`cosolvents used in parenterals include glycerin in deslanuside, dimethyiacetar
`mide in reserpine and dimethylsulfozo'de 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 (Lorazepsm)
`uses a complete cosolvent system. 30% propylene glycol and 20% polyethylene
`glycol;
`the latter two solvents have LD50 significantly higher than the other
`solvents mentioned. although tissue irritation has been implicated with all
`
`-182-
`
`-182-
`
`
`
`
`

`

`
`
`
`an
`
`”3
`
`
`
`Faimulotion of Small Volume Porenlemla
`
`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, phony;
`toin is dissolved as the sodium salt in a vehicle containing 40% propylene glycol
`and 10% ethanol and adjusted to a pH of !2 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 (pita : 8.3) . precipitation of
`the drug can occur. This is due to the fact that in aqueous systems at pH
`below 11, the amount of undissociated phenyloin exceeds its solubility [23].
`The dielectric constant of 60, however. solvates the sodium salt by hydrogen
`bonding and van der Weeds forces and reduces the risk of precipitations upon
`addition to an infusion solution prior to intravenous administration [24].
`Nevertheless, such preparations should be administered slowly into the sys—
`temic circulation because rapid injection could result in the precipitation of
`the drug in the blood stream [25]. The influence of pH on solubility of pheny—
`toin will he demonstrated later.
`
`Effect of pH. Most drug substances are weak electrolytes and, therefore,
`exist in solution in the dissociated and undissociated forms. The ratio of these
`forms is determined by the pH of the solution. As a result, properties such
`as solubility, partition coefficient, and chemical stability, which are markedly
`different for the undissociated and dissociated forms. will be influenced by pH.
`Many of the organic electrolytes used in parenteral systems contain a basic
`nitrogen atom in the molecules. These include antihistamines, alkaloids,
`local
`anesthetics, and so on. which are practically insoluble in water but dissolve
`readily in dilute solutions of acids due to salt formation. The addition of alkali
`to these solutiOns increases the pH and causes free-base to precipitate.
`Ex—
`amples are atropine sulfate, ephedrine sulfate, lidocaine hydrochloride, and
`pyribenzemine hydrochloride.
`
`H H
`H H H
`I
`l
`I
`I
`I
`©?-IC—lll-CHJ = Q—EII—(i': —N+- CH3+ OH
`1
`O C
`H
`0 C H
`H H:
`H H:
`
`_
`
`ephedrine cation in dilute acid
`
`In compounds containing an electron withdrawing group, such as oxygen.
`a positive center is created, which in turn attracts electrons from an adjacent
`nitrogen . and if a hydrogen atom is attached, the N-w-l-l bond is weakened.
`As a result, in alkaline solution a more soluble onion is formed. This is illus~
`traled for phenobarbital and aull’anilamide. The addition of acid to the solu-
`
`_
`
`Cal-is
`
`/’
`
`c
`
`/ \
`
`0ll
`C H N
`I
`C=O
`c — N
`u
`{1,
`C2"!
`H
`phenobarbital anion
`
`f
`
`Na
`
`—
`
`HzN-Q—SCHNH
`sulfanilamlde anion
`
`*
`Na
`
`-183-
`
`
`
`
`
`
`
` ,
`‘,
`.1.t.
`,-
`'_
`
`
`
`m
`
`
`
`-"mm-")3...
`
`
`
`-183-
`
`
`
`
`

`

`
`
`I 84
`
`fistula: and Boylan
`
`tions above will cause the free acid form to precipitate. Even the addition
`of a salt of a strong acid such as morphine sulfate will cause precipitation.
`To calculate the solubility of a weak alsotronto as a function of pH. it
`is necessary to express the equilibrium in solution for a week acid or was]:
`bale:
`
`HA
`
`HOH
`._.‘__
`
`+
`
`H
`
`_
`
`+ A
`
`s
`
`.—_-
`
`1311* + 05
`
`(1)
`
`(2)
`
`In Equation (1} . (HA) represents the concentration of weak acid present in
`undissociatsd form at equilibrium. and (A') represents the concentration of
`dissociated (or salt} form present at equilibrium.
`In Equation (2), (B) is
`the slightly soluble undissoclatad basic substance and (El-1+] is the dissoci-
`ated salt form. The concentration of the undissociated forms (HA) and (B)
`will remain essentially constant. Therefore, So. the solubility of the undisso-
`ciated form, can represent the concentration of (HA) or (B) in solution. For
`a weak sold the dissociation constant K3 for the equilibrium between species
`may be written as
`
`= (mu-3
`(HA)
`
`Ks
`
`Resrronging yields
`
`(HA)
`
`_
`[A ) = K
`
`8041+)
`
`{3)
`
`{4)
`
`Total drug; solubility, S. will be the sum of undissociated and dissociated forms.
`
`s ={HAJ +(A')
`
`or
`
`5:50*Ka
`
`S
`
`f
`(H)
`
`(5)
`
`(a)
`
`Therefore. the total solubility of a weak sold electrolyte is a function of the
`hydrogen ion concentration. The solubility equation may be expressed in
`logarithmic form by rearrangement:
`
`log (5 - so) = log Kn + log sfl — log (11*)
`
`01'
`
`pH = sz + log
`
`
`3-50
`50
`
`(7}
`
`(8)
`
`E0
`
`Th
`
`01'
`
`Bin-
`tern
`
`-184-
`
`-184-
`
`
`
`
`

`

`
`
`nylon
`
`on
`m.
`it
`ea}:
`
`(1}
`
`(2)
`
`1! in
`m of
`is
`mai-
`(3)
`ndisso-
`.. For
`ecics
`
`(3)
`
`{4)
`
`ed forms.
`
`{5)
`
`(5)
`
`Jf the
`i in
`
`(7)
`
`(B)
`
`
`
`
`
`Formulation of Small Volume Pcrenterols
`
`185
`
`Considering the earlier example, phenytoin. which is formulated as the:
`sodium salt, the following equilibria occur:
`
`+
`_ non
`+
`Na phenytoin :‘ Na + phenytoin
`
`7
`
`Phenytoin' + HOH .:- phenytoin(u) + on“
`
`(9)
`
`(10)
`
`These equilibria indicate that a high OI—l- concentration is required in order
`to keep the reaction in the direction of the soluble dissociated species. The
`aqueous solubility of the undissociated phenytoin is [1.016 mg—ml’1 [25] and
`at pH values below 5, phenytoin exists essentially in the practically insoluble
`undissociated spccies. Using Equation (3) , in which so is the aqueous solu-
`bility of undissociated phenytoin and S is the total concentration of phenytoin
`in solution (i.e-. phenytoin' and phenytoinwp, the pH required to maintain
`a concentration of 50 mg ml'1 in solution can be determined:
`
`pH
`
`.
`- 1.34110
`8.3+log1’823x ID
`1.34 x 10—5
`
`—1
`
`-5
`
`pH=s.3+log 22:74:11.?
`
`(11)
`
`(12}
`
`Therefore, in wotcr for injection 0 pH of 11.7 is required. At this pH the
`phenytoin is 99. 97% dissociated.
`1n the commercial preparation the hydro"
`alcoholic solvent maintains the solution at a lowar pH due to the dielectric
`effect discussed earlier.
`For a weak base the dissociation constant Kb for the equilibrium between
`species may be written as
`+
`_
`Kb = (EH ()5!!!
`
`(13)
`
`)
`
`Rearranging yields
`
`(E)
`+ _
`(EH ) - Kb (OH')
`
`(14)
`
`The total solubility, S. is the sum of the dissociate