`Dosage For•:
`Parenteral Medications
`Volume1
`
`Second Elltion, Revised cnl Expanded
`
`Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare SA, et al.
`U.S. Patent No. 8,729,094
`Reddy Exhibit 1042
`
`Exh. 1042
`
`
`
`tical
`Ph
`Dosa F
`Parenteral Medications
`VOIUD1e1
`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
`
`r ·1
`
`- --
`- ·· ··-·- ·-- -. r ;-T ·-
`E.S. f. ,~kEY LIBRA .• Y
`WJU~ES UNIVERSITY
`V•/!U<~S-BA?RE. P.A
`
`Marcel Dekker, Inc.
`
`New York • Basel • Hong Kong
`
`j
`j
`!
`i
`
`i L
`
`Exh. 1042
`
`
`
`J(yf~t'/
`. /~1 ,. -~ .~ .. r
`
`/
`
`I
`.VI t
`
`·I
`
`I . . ,
`' ' •
`
`Library of Congress Cetafeging - In - Publication Data
`
`Pharmaceutical dosage fol'IIQJ , parenteral medic ations I 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 - Z (v. 1: aile paper)
`1. Parenteral solutions. 2. Pharmaceutical technology. 1. A vis ,
`Kenneth E . II. Lieberman, Herbert A,
`Ill • Lachman, Leon.
`[DNLM : 1. Infusions, Parenteral. 2. Technology, PharmaceuticaL
`WB 354 P536]
`RS20l. P37P48 1992
`615'. 19--dc 20
`DNLM /DLC
`for Library of Congress
`
`91 - 38063
`CIP
`
`This book: is printed on acid-free paper.
`
`Copyright @ 1992 by MARCEL DEKKER, INC. All Rights Reserved
`
`Neither this book nor any part may be reproduced or transmitted in any form
`or by my means, electronic or mechanical, including photoropying, micro-
`filmine, 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
`
`CUfTcnt printing (last digit):
`10 9 8 7 6 5 4 3 2 I
`
`..
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`Exh. 1042
`
`
`
`5
`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 drug, solution, or suspension
`that is packaged in a manner suitabl e 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 bee·n
`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 s pinal column
`5. Dry solids which, upon the addition of suitable vehicles, become
`sterile suspensions
`
`Although the term sterile pharmaceu ticals 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
`knowledg·e 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
`
`Exh. 1042
`
`
`
`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, s tability, 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
`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 bioteclhnology are on the in-
`crease and the formulation of these products requires some unique skills and
`novel approaches. An attempt will be made to cover some of the formulation
`approaches for proteins and peptides.
`
`II. 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 n ature
`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 a dministration (see Chap. 2) are cur-
`rently used for parenteral products.
`One of the most important conside·rations 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 mi.
`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 ::~olutions, whereas oily
`solutions, cosolvent solutions, suspensions, and emu~sions can be 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 iisotonic.
`In fact, for subcutaneous and intramuscular injections hypertonic solutions
`
`Exh. 1042
`
`
`
`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. Select ion 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 aqu eous 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 o. 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 c:oncentrated polar and nonpolar centers
`(miceUes ) , 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.
`
`Exh. 1042
`
`
`
`' ,,
`]·
`
`176
`
`DeLuca and Boylan
`
`Ethylenediamine is req uire<i 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 (pK8 "' 8. 8), which is only slightly soluble in water ( 8 mg /ml).
`
`Theophylline + H+ +
`
`theophylline (free)
`
`Creatinine, niacinamide , and lecithin have been used for soluibilizing 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 s electing 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 t he 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 i'elationship, is not influenced by temperatul.'e. The USP lists
`solubility in terms of the number of milliliters of solvent req uiired 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 so·luble
`Freely soluble
`Soluble
`Sparingly soluble
`Slightly soluble
`Very slightly soluble
`Practically insoluble or insoluble
`
`Relative amount of
`solvent to dissolve
`1 part of solute
`
`< 1
`1-10
`l 0-30
`30- 100
`100-1000
`1000- 10,000
`>10, 000
`
`Exh. 1042
`
`
`
`Boyl an
`
`the
`:s con-
`
`)apes,
`~e theo-
`).
`
`.teroids
`3 or
`itives
`
`to the
`es that
`•rly
`lllces
`
`din a
`t (w /v ) ,
`•een
`.on.
`erefore,
`SP lists
`issolve
`es gen-
`ted in
`
`Formulation of Small Volume Parenterals
`
`177
`
`Measuring Solubility. Methods for determining the solubility of d r~ sub-
`stances in various solvents have been described ( 3- 6] . The phase solubility
`technique is especiaJly applicable to determining the solubility of pure sub-
`stances a nd also detecting the presen ce 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 agit ated at constant t emperatures,
`gener ally 30 ± O.l°C. In those containers in which excess drug is present
`(undissolved), samples of the supernatant are withdrawn and assayed until
`the concentr ation is constant {i.e., the s y stem has r eached equilibrium). For
`a pur e compound, a phase solubility diagram is con structed 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 Figur e lb results, which shows an inflection
`in the ascending line. Extrapolation of the horizontal line gives t he solubil-
`ity of the s u bstance plus the impurity of the s u bst ance on the y-axis, while
`extr apolation of the ascending line gives the solubility of the impurity.
`Bonding Forces. For a s ubstance to dissolve, the forces of attraction that
`hold the molecules together must be o vercome by the solvent. The solubility
`will be determined by the relative binding forces within the substance (solute-
`solute interactions) and between the substance and t he vehicle (solute-solvent
`interactions). If an environment similar to that of the crystul structure can
`be provid ed 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 solvent s as a result of dipole or induced dipole Interactions (van
`der Waals, London or De bye forces) .
`
`Undossol,tlll solute
`beqons opp~orinq
`
`mg SOLUTE! ml SOLVENT
`
`ond ompurily
`
`€ ..... 00 e
`
`'-' z
`0
`'-'
`w
`1-::::. _,
`0
`V>
`
`mg SOLUTE /ml SOLVENT
`Fig ure 1 Phase solubility diagrams for a pure s u bstance (a) and a substan ce
`containing an impurity (b).
`
`Exh. 1042
`
`
`
`178
`
`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
`constan ts 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 semi polar. 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 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), polyethylene glycol (PEG) 400
`
`Table 2 Dielectric Constants of Some Solvents at 25°C
`
`Solvent
`
`Dielectric constant
`
`Watera
`Glycerin8
`N, N- Dimethylacetamidea
`Propylene glycoJ8
`Methanol
`Ethanol8
`N-Propanol
`Acetone
`Benzyl alcohols
`Polyethylene glycol 4009
`Cottonseed oila
`Benzene
`Dioxane
`8 Solvents used in parenterals
`
`78.5
`40.1
`37.8
`32.01 (30°)
`31.5
`24.3
`20.1
`19. 1
`13.1
`12.5
`3.0
`2.3
`2.2
`
`Exh. 1042
`
`
`
`Fonnulat1on o{ Small Volume Parenterals
`
`J79
`
`Not Solv6ddf
`I
`
`( '4 WO I ! r - )
`
`10 20 30 40 ~0 60 70
`DIELECTRIC CONSTANT
`
`Figure 2 Hypothetical plot of solubility of a substance vers us 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 per cent ages of PEG
`400 ~md water c..n be c!l1culated (I.S follow::>;
`(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
`H2<)
`
`10%
`16.5%
`73.5%
`
`Since dielectric constant is a measure of the polarizabillty nnd dipole mo-
`ment or a compound, several res.earchers have explored other parameters and
`polarity indexes [18] which are included by molecular volume, solvent and
`solute interaction s, 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] modJOed the Hildebrand ap-
`proach to include hydrogen-bonding and dipolu interactions. T he molecular
`s urface area of the solute and interfacial tension between solute nnd solVent
`were used by Amidon I 20] and Yalkowsk:y ( 21] to predict solubility. These
`approaches were especially applicable to systems in which the intermolecular
`forces between solvent and solute were different. Fig-ure 3 shows the solu-
`bility os 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 118,221.
`llydrogen bonding, the strongest type of dipole- dipole interaction. is
`characterized by 8 positive center in the hydrogen atom (proton donor). Be-
`cause of it s s mall size, the hydrogen atom can opprooch the negative center
`(elect ron donor ) of a neig hboring dipole more closely than any other atom.
`As 8 r esult of this s patial maneuverability, both intramolecular bonding (i.e. ,
`
`Exh. 1042
`
`
`
`180
`
`DeLuca and Boylai
`
`PROPYLENE Gl VCOL,%
`
`Figure 3 Log-linear- solubility relationship for a series of alkyl p-aminobem
`ates-glycol-water. [From Yalkowsky, S. H., Flynn, G. L., and Amidon, G
`L., J. Pharm. Sci., 61:983 (1972).]
`
`Intermolecular H bonding
`
`intramolecular H bonding
`
`Exh. 1042
`
`
`
`!an
`
`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, ketone s, amide and N - heterocyclic compounds. Some examples of hy-
`drogen bonding with water follow :
`
`R
`H
`H
`I
`I
`I
`0-- -H-0- · -H-0· · -H-0· · ·
`I
`I
`R
`H
`
`alcohol
`
`H
`H
`I
`I
`R-C•O ·- ·H-0-H· · ·O=C- R
`
`ketone
`
`H
`I
`R3N-·-H-0· · ·NRa
`
`amine
`
`Alcohols dissolve in water by hydrogen bonding, up to an alkyl chain
`length of five carbon atoms. Phenols dissolve in water and alcohol and, as
`the number of hydroxyl groups increase , the water solubility is enhanced
`because of the increased opportunity for hydrogen bonding. Most aromatic
`carboxylic acids, steroids, and cardiac glycosides are not water soluble but
`dissolve in alcohol, glycerin , or glycols by hydrogen bonding. Since the
`overall conformation of proteins is most influenced by hydrogen bonding,
`water-the solvent of choice for most proteins- cont ributes to the hy<;)rogen
`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 solv,ents (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-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 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 !on- 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-
`
`:>enzo-
`. , G.
`
`Exh. 1042
`
`
`
`182
`
`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:
`
`+ -
`I 2 + K I
`
`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 iocline 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 inducer! 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 De bye 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 ag.ents 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 20'1; polyethylene
`glycol; the latter two solvents have LD 50 significantly higher tllan the other
`solvents mentioned, although tissue irritation has been implicated with all
`
`Exh. 1042
`
`
`
`l,
`
`ng
`
`lY
`1ce
`le
`
`ole
`ld-
`
`ess
`ir
`.e-
`
`hat
`.S
`lk
`
`>ho-
`l
`ms
`·le
`)
`
`•ole-
`
`!lude
`>il.
`.n,
`ible
`.r
`eta-
`
`l -
`am)
`
`:1er
`
`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 pKa of the drug· (pKa = B. 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
`forms is determiMd 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
`pyribenzamine hydrochloride.
`
`0~ ~
`
`C-C-N-CHJ
`I
`I
`I
`0 C H
`H HJ
`
`H H H
`-
`I
`I+
`~=~ C-C -N- CHJ + OH
`I
`I
`I
`0 C H
`H H1
`
`0 1
`
`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-
`
`0
`-
`II
`C6HS
`/C--N
`'-..c
`~=o
`"".
`I
`/
`CzHs
`C - - N
`H
`H
`0
`phenobarbi~ anion
`
`Na ..
`
`+
`Na
`
`sulfanilamide anion
`
`Exh. 1042
`
`
`
`184
`
`DeLuca and Boylan
`
`tiona 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 8 weak electrolyte as 8 function of pH, it
`is necessary to express the equilibrium in solution for a weak acid or weak
`base:
`
`(1)
`
`(2)
`
`In Equation (1), (HA) r epresents the concentration of weak acid present in
`undissoclated form at eq uillbrium, and (A-) represents the concentration of
`dissociated (or salt) form present at equJUbrium. In Equation (2), (B) is
`the slightly soluble undissociated basic substance and (BH+) is the dissoci-
`ated salt form. T'he concentration of the undissociated forms (HA) and ( B)
`will remain essentially constant. Therefore, s 0, the solubility of the und.isso-
`ciated form, can represent the concentration of ( HA) or (B) in solution. For
`a weak acid the dissociation constant Ka for the equllibr:l!um between species
`may be written as
`
`-
`
`K
`a
`
`(H+)(A - )
`(HA)
`
`Rearranging yields
`
`(A-)=K (HA)
`a (H+)
`
`( 3)
`
`( 4)
`
`Total drug solubility, S, will be the sum of undissoclated and dissociated forms.
`
`S = (HA) +(A-)
`
`or
`
`so
`S=S +K - -
`a (H+)
`0
`
`( 5)
`
`(6)
`
`Therefore. the total solubUity 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 - s0) =log Ka +log s 0 - log ( H )
`
`( 7)
`
`or
`
`pH = pK
`
`8
`
`s - s 0
`+ log - 8- -
`0
`
`( 8)
`
`T
`t<
`
`a·
`u
`b
`ir
`8
`
`T l
`p~
`a!<
`ef
`
`sp
`
`Re
`
`Th.
`
`or
`
`Sin·
`terr
`
`Exh. 1042
`
`
`
`.on
`Jn.
`it
`:!Sk
`
`(1)
`
`( 2)
`
`1t in
`mof
`is
`;oct-
`(B)
`ndi sso-
`.. For
`ecies
`
`(3)
`
`( 4)
`
`ed forms.
`
`( 5)
`
`( 6)
`
`Jf the
`1 in
`
`(7)
`
`( 8)
`
`Formulation of Small Volume Pm·enterals
`
`185
`
`Considering the earlier example, phenytoin, which is formulated as thy
`sodium salt, the following equilibria occur:
`
`HOH
`-
`+
`-
`+
`Na phenytoin ~ Na + phenytoin
`
`Phenytoin- + HOH ~ phenytoin(u) + O H
`
`( 9)
`
`(10)
`
`Th.ese equilibria indicate that a high OH- concentration is required in order
`to ]{eep 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 practicalJy insoluble
`undissociated species. Using Equation (8), 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 phenytoin(u)>, the pH required to maintain
`a concentration of 50 mg mi- l in solution can be determined:
`
`pH = 8 . 3 +log 1.823 x 10-l- 1.34 x 10-s
`1. 34 X lQ~ S
`
`pH= 8.3 +log 2874 = 11.7
`
`( lt)
`
`(12)
`
`Therefore, i