Pharmaceutical
`Dosage Forms:
`Parenteral Medications
`Volume 1
`Second Edition, Revised and Expanded
`
`
`
`MAIAExhibit 1014
`
`MAIA V. BRACCO
`
`IPR PETITION
`
`
`
`
`MAIA Exhibit 1014
`MAIA V. BRACCO
`IPR PETITION
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`

`New York ¢ Basel * Hong Kong
`
`Pharmaceutical
`Dosage Forms:
`Parenteral Medications
`Volume1
`Second Edition, Revised and Expanded
`Edited by
`Kenneth E. Avis
`The University of Tennessee
`Memphis, Tennessee
`Herbert A. Lieberman
`AH. Lieberman Assaciates, Inc.
`Consultant Services
`Livingston, New Jersey
`Leon Lachman
`Lachman Consultant Services
`Westbury, New York
`
`} wursuuversry|
`
`
`WILIES UNIVERSITY
`
` WILMES-BAORE, PA
`
`Marcel Dekker, Inc.
`
`
`
`
`

`

` Library of Congress Cataleging -in- Publication Data
`
`MARCEL DEKKER, INC.
`270 Madison Avenue, New York, New York 10016
`
`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 information storage and retrieval system,
`without permission in writing from the publisher.
`
`Current printing (last digit):
`W098 7654371
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`Pharmaceutical dosage forms, parenteral medications / edited by
`Kenneth E. Avis, Herbert A. Lieberman, and Leon Lachman. -- 2nd ed. \
`rev. and expanded.
`p.
`em.
`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,
`Il. Lachman, Leon.
`[DNLM: 1. Infusions, Parenteral.
`WB 354 P536]
`RS201.P37P48 1992
`615', 19-de20
`DNLM /DLC
`for Library of Congress
`
`I. Avis,
`
`2. Technology, Pharmaceutical.
`
`91 - 38063
`CIP
`
`
`
`
`

`

`
`
`5 F
`
`ormulation 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 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 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-
`
`-173-
`
`
`
`
`

`

`DeLuca and Boylan
`
`vehicle (aqueous, nonagueous, or cosolyvent); (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 physica
`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
`eommon 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.
`
` 174
`
`Il. 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
`earefully controlled. Wolumes up to 10 ml can be administered intraspinally,
`while the intramuscular route is normally Limited to 3 ml, subcutaneous to 2
`m] 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. L[ntravenous and intraspinal
`injections are generally restricted to dilute aqueous solutions, whereas oily
`solutions, cosolvent solutions, suspensions, and emulsions can he injected
`intramuscularly and subcutaneously.
`Isotonicity is another factor that must be taken into consideration. Al-
`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 hypertonic solutions
`
`-174-
`
`-174-
`
`
`
`
`

`

`
`
`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
`
`the high dielec-
`Most parenteral products are aqueous solutions. Chemically,
`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 [njection, 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 4
`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 ta
`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 conformations! 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.
`
`-175-
`
`-175-
`
`
`
`
`

`

`176
`
`DeLuca and Boylan
`
`Ethylenediamine is required in aminophylline injections to maintain the
`theophylline in solution since aminophylline is a salt that ionizes inta 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 (pK, »% 8.8), which is only slightly soluble in water (8 mg/ml)-
`
`Theophylline + Ht + theophylline (free)
`
`Creatinine, niacinamide, and lecithin have been used for solubilizing steroids
`in the free aleohol 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 numberof milliliters of solvent required to dissolve
`1g of substance.
`If exact solubilities are not known, the USP provides gen-
`eral terms to describe 4 given range. These descriptive terms are listed in
`Table 1.
`
`Table 1 Expressions for Approximate Solubility
`
` Term
`
`Relative amount of
`solvent
`to dissolve
`1 part of solute
`
`Very soluble
`
`Freely soluble
`Soluble
`
`Sparingly soluble
`
`Slightly soluble
`
`Very slightly soluble
`
`Practically insoluble or insoluble
`
`<1
`
`1-10
`10-30
`
`30-100
`
`LOO-1000
`
`1000-10,000
`
`>10,000
`
`
`
`-176-
`
`-176-
`
`
`
`
`

`

`
`
`Formulation vf 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 + 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
`interactions).
`If an environment similar to that of the crystul structure can
`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).
`
`
`
`Boylan
`
`the
`=s con-
`
`sapes,
`ze theo-
`
`teroids
`30r
`itives
`
`to the
`es that
`rly
`inces
`
`dina
`t (wiv),
`een.
`on.
`erefore,
`SP lists
`issolye
`es pren-
`ted in
`
`mg SOLUTE/mi SOLVENT
`
`
`Sofubility of impurity
`mg SOLUTE /m)
`SOLVENT
`
`a-
`
`= S
`
`wr
`s
`
`Figure 1 Phase solubility diagrams for a pure substance (a) and a substance
`containing an impurity (b).
`
`-177-
`
`Ec
`
`o Solutalitya
`
`Undsssolved solute
`Ss
`begins oppeoring
`o
`oo
`
`ad-
`=>=f
`So
`v7
`
`
`&=
`
`Solubility of substance ond impurity
`SSeS © sts
`
`=o2h
`
`-177-
`
`
`
`
`

`

`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
`eonstants are not water soluble and do not dissolve ionic compounds. The
`former are classified as polar solvents (e.¢., 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 bimary 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 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 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), polyethyleme glycol (PEG) 400
`
`Table 2 Dielectric Constants of Some Solvents at 25°C
`
`
`
` Solvent Dielectric constant
`
`Water@
`
`Glycerin®
`
`N,N-Dimethylacetamide®
`
`Propylene glycol?
`Methanol
`
`Ethanol®
`
`N-Propanol
`Acetone
`
`Benzyl aleohol®
`
`Polyethylene glycol 4004
`Cottonseed oil®
`
`78.5
`
`40.1
`
`37.8
`
`32.01 (30°)
`31.5
`
`24.3
`
`20.1
`19.1
`
`13.1
`
`12.5
`3.0
`
` 178
`
`Benzene
`2.3
`Dioxane ae2
`
`a
`.
`Solvents used in parenterals
`
`-178-
`
`-178-
`
`
`
`
`

`

`
`
`Formulation of Small Volume Parenterals
`
`! 3 6
`
`Mor Soludelity
`
`SOLUBILITY
`
`(% Wolter ———» )
` 10 20 SW 40 50 60 70
`
`
`
`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 ond 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 ta be 73.5%.
`Therefore,
`the vehicle to provide a dielectric constant of 60 will have the fol-
`lowing composition:
`
`Ethanol
`PEG 500
`HO
`
`10%
`16.5%
`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 appronch 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.,
`
`-179-
`
`1d
`
`-179-
`
`
`
`
`

`

`106
`
`o
`
`80
`60
`40
`20
`PROPYLENE GLYCOL, %
`
`100
`
`Figure 3 Log-linear solubility relationship for a series of alkyl p-aminoben:
`ates-glycol-water.
`[From Yalkowsky, S. H., Flynn, G. L., and Amidon, G
`L., J. Pharm, Sci., 61: 983 (1972).]
`
`H|
`
`c=
`
`ey ?
`
`‘O-H
`
`C2Hs—O=H---O
`
`f
`
`H
`
`H
`
`intermolecular H bonding
`
`intramolecular H bonding
`
`-180-
`
`180
`
`DeLuca and Boyla:
`
`102
`
`104
`
`
`
`SOLUBILITY,moles/|
`
` Aereee
`
`-180-
`
`
`
`
`

`

`
`
`lan
`
`3enzoO-
`ai
`
`
`
`
`
`
`
`
`
`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
`
`ketone
`
`amine
`
`R
`(
`--H—-O---H-O---
`H
`
`q
`"
`Q---H-O-
`
`'R
`
`H
`I
`iH
`R-C =0---H-O-H---O=C—R
`
`H
`|
`RaN---H—O- --NAg
`
`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 aleohol, 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) s 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
`eation 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 jon-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 icdide and sodium bro-
`
`-181-
`
`
`
`-181-
`
`
`
`
`

`

`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:
`
` 182
`
`I+KT
`2
`
`KT
`3
`
`?
`
`Although the iodine molecule is electrically neutral. a temporary polarity may
`result from electronic movements within the molecule. Such movements induce
`dipoles in neighboring molecules and are responsible for maintaining benzene
`and carbon tetrachloride in the liquid state. The iodide complex forms be-
`cause the strong electrical field of the electrolyte in solution imduces a dipole
`in the polarizable iodine molecule. Bemzene is a neutral moleewle 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
`reaulting 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-
`bie 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 amy 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 pH. Other
`cosolvents used in parenterals include glycerin in deslanoside, dimethylaceta-
`mide in reserpine and dimethylsulfoxide in chemotherapeutic aments 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, 80% propylene glycol and 20% polyethylene
`glycol;
`the latter two solvents have LD59 significantly higher than the other
`solvents mentioned, although tissue irritation has been implicated with all
`
`-182-
`
`-182-
`
`
`
`
`

`

` “
`
`
`
`
`
`
`
`
`
`
`
`
`
`Fensiemivlnsial
`
`Formulation of Small Volume Parenterals
`
`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 pK, of the drug (pK, = 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 phenytoin exceeds its solubility [23].
`The dielectric constant of 60, however, solvates the sodium salt by hydrogen
`bonding and van der Waals 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 be 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
`farms 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
`anestheties, 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 [ree-base to precipitate. Ex-
`amples are atropine sulfate, ephedrine sulfate, lidocaine hydrochloride, and
`pyribenzamine hydrochloride.
`
`-
`
`HL
`
`(H
`
`ro-O-=-=z 3
`
`+
`—-N— CH; + OH
`
`xmO-O-=zr
`ZmoO-0—=
`Ot» —O
`
`H
`
`xro-O0-=z
`
`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—H bond is weakened.
`As a result, in alkaline solution a more soluble anion is formed. This is illus-
`trated for phenobarbital and sulfanilamide. The addition of acid to the solu-
`
`mals
`
`sg
`
`‘—
`i
`H
`
`phenobarbital anion
`
`nn-(_\)-soend
`
`~
`
`4
`
`Na
`
`sulfanilamide anion
`
`-183-
`
`
`
`
`
`ng
`
`ty
`ice
`
`1 n
`
`e
`ad-
`
`-183-
`
`
`
`
`

`

`
`
`184
`
`DeLuca 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 electrolyte as a function of pH, it
`is necessary to express the equilibrium in solution for a weak acid or weak
`base:
`
`HOH |
`HA z= HA
`
`B =< BH'+oOn
`
`(1)
`
`(2)
`
`In Equation (1), (HA) represents the concentration of weak acid present in
`undissoclated form at equilibrium, and (A~) represents the concentration of
`dissociated (or salt) form present at equilibrium.
`In Equation (2), (B) is
`the slightly soluble undissociated basic substance and (BH*) is the dissoci-
`ated salt form, The concentration of the undissoclated forms (HA) and (B)
`will remain essentially constant. Therefore, Sq, the solubility of the undisso-
`ciated form, can represent the concentration of (HA) or (B) in solution. For
`a weak acid the dissociation constant Kg for the equilibrium between species
`may be written as
`
`. YA)
`GHA)
`
`RA
`
`Rearranging yields
`
`(A7) =K
`
`(HA)
`(H’)
`
`(3)
`
`(4)
`
`Total drug solubility, 5, will be the sum of undissociated and dissociated forma.
`
`S = (HA) +(A’)
`
`or
`
`5
`S=S,+k,—
`(H )
`
`(5)
`
`(6)
`
`Therefore, the total solubility of a weak acid electrolyte is a function of the
`hydrogen ion concentration. The solubility equation may be expressed in
`logarithmic form by rearrangement;
`
`log (S - S,) = log K, + log Sy - log cH’)
`
`or
`
`pH = pK, + log
`
`s-S
`
`
`8p
`
`(7)
`
`(8)
`
`Re
`
`Th
`
`or
`
`Sin.
`ter:
`
`-184-
`
`-184-
`
`
`
`
`

`

`
`
`
`
`
`
`aylan
`
`an.
`it
`aak
`
`cl)
`
`(2)
`
`vt in
`om of
`is
`30ci-
`(B)
`ndisso-
`cs For
`ecies
`
`(3)
`
`(4)
`
`ed forms,
`
`(3)
`
`(6)
`
`of the
`iin
`
`(7)
`
`(8)
`
`Formulation of Small Volume Parenterals
`
`185
`
`Considering the earlier example, phenytoin, which is formulated as the
`sodium salt, the following equilibria occur:
`
`“
`Na phenytoin
`
`,
`_HOH
`=— Na + phenytoin
`
`.
`
`Phenytoin + HOH ==> phenytoin) + OH
`
`(9)
`
`(10)
`
`These equilibria indicate that a high OH 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 0.016 mg-ml- 1 [26] and
`at pH values below 5, phenytoin exists essentially in the practically insoluble
`undissociated species. Wsing Equation (8), in which So is the aqueous solu-
`bility of undissociated phenytoin and § is the total concentration of phenytoin
`in solution (i,e., phenytoin” and phenytoin,,)), the pH required to maintain
`a concentration of 50 mg mi~1 in solution can be determined:
`
`4
`- 1.34 x 10
`pH = 8.3 4 log 2:823 x 10
`1.34* 10°
`
`1
`
`-5
`
`pH
`
`8.3 + log 2874 = 11.7
`
`era
`
`(12)
`
`Therefore, in water for injection o pH of 11.7 is required. At this pH the
`Phenytoin is 99.97% dissociated.
`In the commercial preparation the hydro-
`aleoholic solvent maintains the solution at a lower pH due to the dielectric
`effect discussed earlier.
`For a weak base the dissociation constant Kp for the equilibrium between
`species may be written as
`
`BH*t)(OH-
`By ona
`
`Rearranging yields
`
`_
`+.
`(B)
`(BH) = Ky (OH)
`
`a)
`
`(14)
`
`The total solubility, S, is the sum of the dissociated and undissociated forms:
`
`5S = (BH*) + (B)
`
`or
`
`So
`s= So + Ky, (oH)
`
`(15)
`
`(16)
`
`Since Ky, = (OH) (H*) , the hydroxyl ion concentration can be expressed in
`terms of the hydrogen ion concentration:
`
`-185-
`
`-185-
`
`
`
`
`

`

`log (5 5) log K, + log (H*)-log K,,log 56 (
`
`_
`+)
`+
`=
`=
`
`
`or
`
`
`
` 18