Editor: Donna Balado
`Managing Editor: Jennifer Schmidt
`Marketing Manager: Christine Kushner
`
`Copyright © 1999 LippincottW1lliams & Wilkins
`
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`Baltimore, Maryland 21201-2436 USA
`
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`
`All rights reserved. This book is protected by copyright. No part of this book may be re-
`produced in any form or by any means, including photocopying, or utilized by any infor-
`mation storage and retrieval system'without written permission from the copyright owner.
`
`The publisher is not responsible (as a matter of product liability, negligence, or otherwise)
`for any injury resulting from any material contained herein. This publication contains in-
`formation relating to general principles of medical care which should not be construed as
`specific instructions for individual patients. Manufacturers’product information and pack-
`age inserts should be reviewed for current information, including contraindications,
`dosages, and precautions.
`
`Printed in the United States ofAmerica
`
`Library of Congress Cata1oging-in-Publication Data
`
`Ansel, Howard C., 1933-
`Pharmaceutical dosage forms and drug delievery systems / Howard C.
`Ansel, LoydV. Allen, ]r., Nicholas G. Popovich. —— 7th ed.
`p.
`cm.
`Includes bibliographical references and index.
`ISBN 0-683-30572-7
`2. Drug delivery systems.
`1. Drugs—-Dosage forms.
`II. Popovich, Nicholas G.
`III. Title.
`[DNLM: 1. Dosage Forms.
`2. Drug Delivery Systems. QV 785 A6181 1999]
`RS200.A57
`1999
`615’.1—dc21
`DNLM/DLC
`for Library of Congress
`
`1. Allen, LoydV.
`
`99—17498
`CIP
`
`The publishers have made every effort to trace the copyright holders for borrowed material. Ifthey
`have inadvertently overlooked any, they will be pleased to make the necessary arrangements at
`the first opportunity.
`-
`
`The use of portions of the text of USP23/NF18, copyright 1994, is by permission of the USP
`Convention, Inc. The Convention is not responsible for any inaccuracy of quotation or for
`any false or misleading implication that may arise from separation of excerpts from the
`original context or by obsolescence resulting from publication of a supplement.
`
`To purchase additional copies of this book call our customer service department at (800)
`638-3030 or fax orders to (301) 824-7390. International customers should call (301)
`714-2324.
`
`99 00 01 02
`1 2 3 4 5 6 7 8 9 10
`
`Astrazeneca Ex. 2096 p. 2
`
`

`
`
`
`Contents
`
`Preface
`
`Acknowledgments
`
`Section I. PRINCIPLES OF DOSAGE FORM DESIGN AND DEVELOPMENT
`
`I
`
`2
`
`3
`
`4
`
`5
`
`Introduction to Drugs and Pharmacy
`
`New Drug Development and Approval Process
`
`Dosage Form Design: Pharmaceutic and
`Formulation Considerations
`-
`
`Dosage Form Design: Biopharrnaceutic and
`Pharmacokinetic Considerations
`
`Current Good Manufacturing Practices and Good
`Compounding Practices
`
`Section II. SOLID DOSAGE FORMS AND MODIFIED-RELEASE DRUG DELIVERY SYSTEMS
`
`6
`
`7
`
`8
`
`Powders and Granules
`
`Capsules and Tablets
`
`»
`
`Modified~Release Dosage Forms and Drug Delivery Systems
`
`Section III. SEMI-SOI.ID AND TRANSDERMAI. SYSTEMS
`
`9
`
`I0
`
`Ointments, Creams, and Gels
`
`Transdermal Drug Delivery Systems
`
`v
`
`vii
`
`1
`
`23
`
`60
`
`101
`
`142
`
`164
`
`179
`
`229
`
`_
`
`'244
`
`263
`
`ix"
`
`Astrazeneca Ex. 2096 p. 3
`
`

`
`x
`
`Contents
`
`Section IV. PHARMACEUTICAL INSERTS
`
`I I
`
`Suppositories and Inserts
`
`Section V. LIQUID DOSAGE FORMS
`
`I 2
`
`I3
`
`S olutions
`
`Disperse Systems
`
`Section VI. STERILE DOSAGE FORMS AND DELIVERY SYSTEMS
`
`I 4
`
`I 5
`
`I6
`
`Parenterals
`
`Biologicals
`
`Ophthalmic Solutions and Suspensions
`
`Section VII. NOVEL AND ADVANCED DOSAGE FORMS, DELIVERY SYSTEMS, AND DEVICES
`
`Radiopharmaceuticals
`
`Products of Biotechnology
`
`Novel Dosage Forms and Drug Delivery Technologies
`
`Systems and Techniques of Pharmaceutical Measurement
`
`I 7
`
`I8
`
`I9
`
`Appendix
`
`Index
`
`279
`
`296
`
`346
`
`397
`
`450
`
`469
`
`487
`
`503
`
`535
`
`552
`
`563
`
`Astrazeneca Ex. 2096 p. 4
`
`

`
`Section V. Liquid Dosage Forms
`
`SOLUTIONS
`
`Chapter at cl Glance
`
`Solubility
`Inorganic Molecules
`Organic Molecules
`Some Solvents For Liquid Preparations
`Distillation Method
`
`Ion-exchange method
`Reverse Osmosis
`
`Preparation of Solutions
`Oral Solutions and Preparations for Oral
`Solution
`
`Dry Mixtures for Solution
`Oral Solutions
`
`Oral Rchydration Solutions
`Oral Colonic Lavage Solution
`Magnesium Citrate Oral Solution
`Sodium Citrate and Citric Acid Oral Solution
`
`Syrups
`Components of Syrups
`Sucrose and Non-Sucrose Based Syrups
`Antimicrobial Preseroatioe
`Flaoorant
`Colorant
`
`Preparation of Syrups
`Solution with the Aid oflieat
`Solution by Agitation without the Aid of
`Heat
`
`Addition of Sucrose to a Medicated Liquid or
`to a Flavored Liquid
`Percolation
`Elixirs
`
`Preparation of Elixirs
`Nonrnedicated Elixirs
`Medicated Elixirs
`Antihistarnine Elixirs
`
`Barbiturate Sedatioe/Hypnotic Elixirs
`PllEflOlJfll'l7llttl Elixir
`
`Digoxin Elixir
`Tinctures
`
`296
`
`Proper Administration and Use of Liquid
`Perora! Dosage Forms
`Topical Solutions and Tinctures
`Topical Solutions
`Sprays
`Aluminum Acetate Topical Solution
`Aluminum Suliacetate Topical
`Solution
`
`Calcium Hydroxide Topical Solution
`Coal Tar Topical Solution
`Hydrogen Peroxide Topical Solution
`Chlorhexidine Gluconate Solution
`
`Pooidone-Iodine Topical Solution
`Tln'mer'osal Topical Solution
`Vaginal and Rectal Solutions
`Vaginal Douches
`Retention Enemas
`Evacuation Enemas
`
`Topical Tinctures
`Iodine Tincture
`
`Compound Benzoin Tincture
`Thimerosal Tincture
`
`Special Application Solutions
`Nasal Preparations
`Nasal Decongestant Solutions
`Inhalation Solutions
`
`Examples ofMedicated inhalation
`Solutions
`inhalants
`
`Amyl Nitrite inhalant
`Propylhexedrine lnhalanr
`Proper Administration and Lise ofNasal
`Drops and Sprays
`Nasal Route for Systemic Ejjlects
`Otic Solutions
`
`Cerumen~Removing Solutions
`Anti-infective, Anti-inflammatory, and
`Analgesic Ear Preparations
`
`Astra2'.eneca Ex. 2096 p. 5
`
`

`
`Proper Administration and Use qfOtic
`Drops
`Topical Oral (Dental) Solutions
`Miscellaneous Solutions
`Aromatic Waters
`Diluted Acids
`Spirits
`Nonaqueous Solutions
`Liniinents
`Collodions
`Collodion
`
`Flexible Collodian
`Salicylic Acid Collodion
`Extraction Methods for Preparing
`Solutions
`Methods of Extraction
`Maceration
`Percolation
`
`Example Preparations Prepared by
`Extraclion Processes
`Fluidextracts
`Extracts
`
`IN PHYSICOCHSEMICAL terms, solutions may be pre-
`pared from any combination of solid,
`and
`gas, the three states of matter. For example, a solid
`solute may be dissolved in either another solid, a
`liquid, or a gas, and with the same being tmefor a
`liquid solute and for a gas, nine types of homoge-
`neous mixtures are possible. In pharmacy, however,
`interest in solutions is for the most part limited to
`preparations of a solid, a liquid, and less frequently
`a gas solute dissolved in a liquid solvent.
`In pharmaceutical terms, solutions are ‘liquid
`preparations that contain one or more chemical
`substances dissolved in a suilable solvent or InI'.'K-
`ture of mutually miscible solvents"(1). Because of a
`particular pharmaceutical so1ul:ion's use, it may be
`classified as an oral solut:'oo, our solution, ophthalmic
`solution, or topical.’ solution. Still other solutions, be-
`cause of their composition or use, may be classified
`as other pharmaceutical dosage forms. For exam-
`ple, aqueous solutions containing a sugar are clas-
`sified as syrups; sweetened hyctroalooholic (combi-
`nations ofwater and ethanol) solutions are termed
`elixirs; solutions of aromatic materials are termed
`spirits if the solvent is alcoholic or oromoticroateis if
`the solvent is aqueous. Solutions prepared by ex-
`tracting active consfituenis from crude drugs are
`termed tinctures orfluid extracts, depending on their
`method of preparation and their concentration.
`Tinctures may also be solutions of chemical sub-
`stances dissolved in alcohol or in a hydroalcoholic
`solvent. Certain solutions prepared to be sterile and
`pyrogen-Eree and intended for parenteraladminis-
`tration are classified as injections. Although other
`examples could be cited, iris apparent that a solu-
`tion, -as a distinct type of pharmaceutical prepara-
`tion, is much further defined than is the physica-
`chemical definition of the term solution.
`
`Oral .5olLrtion5. syrups, elixlrs, spirits and tinc-
`turesare prepared and used for the specific effects
`of the medicinal agents present. In these prepara-
`tions, the medicinal agents. are intended to provide
`
`systemic effects.The fact that theyare administered
`in solution form usually means that their absorp-
`tion. [tom the gashointestihal tract into the sys-
`temic circulation may‘ be expected to occur more
`rapidly than from suspension or solid dosage forms
`of the same medicinal agent.
`Solutes other than the medicinal agent are usu-
`ally present in orally administered solutions.These
`additional agents usually are included to provide
`color, flavor. sweetness, or stability to the solution.
`In formulating or compounding a p
`'
`-solution. the pharmacist must utilize information
`on the solubility and stability of" each of the solutes
`present with regard to the solvent or solvent sys-
`tem employed. Combinations of medicinal or
`phannaceutlc agents that will result in chemical or
`physicalirlteractions aifeciingthe therapeutic qual-
`ity or pharmaceutic stabilityof the product must be‘
`avoided.
`
`For single-solute solutions and especially for
`multiple-solute solutions, the pharmarzist must be
`aware of the solubility characteristics of the solutes
`and the features of the common pharmaceutical
`solvents. Each chemical agent has its own solubil-
`ity in a given solvent. For many medicinal agents,
`their solubilities in the usual solvents are stated in
`the USP as well as h! other reference books.
`
`Solubility
`Attractive forces between atoms lead to the for-
`mation ot molecules and ions. The intermolecular
`
`forces, which -are developed between like mole-
`cules, are responsible for the physical state (i.e.,
`solid, liquid, or gas) of the substance under given
`conditions, as temperature and pressure-. Under or-
`dinary conditions. most organic compounds, and
`thus most dnlgsubstances, form molecular solids.
`When I:nOlE£l.llE5 interact, attractive forces and re-
`pulsive Eoroes are in efl’ect.'I'he attractive forces cause
`the molecules to cohere, whereas the repulsive
`
`Astrazeneca Ex. 2096 p. 6
`
`

`
`2.98
`
`Solutions
`
`forces prevent molecular interpenetration and de-
`struction. When the attractive and repulsive for:
`are equal, the potential energy between two mole-
`cules is minimum and the system is most stable.
`Dipole: molecules frequently tend to align
`themselves with other dipolar molecules such that
`the negative pole of one molecule points toward
`the positive pole of the other. Large groups of mol-
`ecules may be associated through these weal: at-
`tractions known as dipole-dipole orvan derwaals
`forces. In addition to the dipole: irtteractions, other
`atiracfions occur between polar and nonpola: mol-
`ecules and ions. These indude ion-dipole forces
`and hydrogen bonding. The latter is of particular
`interest. Because of small size -and large electrosta-
`ticfield, the hydrogen atom can move in close to an
`electronegative atom, forming an electrostatic type
`of association referred to as a hydrogen bond or hy-
`drogen
`Hydrogen bonding involves strongly
`electronegative atoms as oxygen. nitrogen, and flu-
`orine. Such a bond ezdsts in water, represented by
`the dotted lines:
`
`H/p\l-LE
`../"\...
`
`Hydrogen bonds also exist between some alcohol
`molecules. esters, carbcooylic acids, aldehydes, and
`polypeptides.
`When a solute dissolves, the substances inter-
`molecular forces of attraction must be overcome by
`forces of attraction between the solute and solvent
`
`molecules. This involves breakingthe solute-solute
`forces and the solvent-solvent forces to achieve the
`solute—solvent attraction.
`
`The solubility of an agent in a particular solvent
`indicates the maximum concentration to which a
`
`solution may be prepared with that agent and that
`solvent. When a solvent. at a given temperature.
`has dissolved all of the solute it can, it is said to be
`saturated. To emphasize the possible variation in
`solubility between two chemical agents and there-
`fore in the amounts of each required to prepare a
`saturated solution, two oflicial aqueous saturated
`soluiions are cited as examples, Calcium Hydroidde
`Topical "Solution USP, and "Potassium Iodide Oral
`Solution,.U5P. The first solution, prepared by agi-
`
`tating an excess amount of calcium hydroxide with
`purified water, contains only about 1.40 mg of dis-
`solved solute per 100 mL of solution -at 25"C,
`whereas the latter solution contains about 100 g of
`solute per 100 mL of solution, over 700 times as
`much solute as present in the calcium hydroxide
`topical solution. It is apparent from this compari-
`son. that the maximum possible concentration to
`which a pharmacist may prepare a solution Varies-
`greatiy and is dependent, in part, on the chemical
`constitution of the solute. Through selection of a
`_dl£ferent.solut_>i1izing agent or a different chemical
`salt form of the medicinal agent, alteration of the
`pH ofa solution, or substitution, in part or inwhole,
`of the solvent, at pharntacist can in certain instances
`dissolve greater quantifies of a solute than would
`ot-herwise be possible. For example, iodine gran-
`ules are soluble in water only to the extent of 1 g
`in about 3000 ml, of water. Using only these
`two agents, the maximum concentration possible
`would be approximately 0.03% of iodine in aque-
`ous solution. However. through the use ofan aque-
`ous solution of potassium or sodium iodide as the
`solvent, much larger amounts of iodine may be dis-
`solved as the result of the formation of a water
`
`soluble complex with the iodide -salt.'I'his reaction
`is taken advantage of, for example, in Iodine 'Ibpi-
`cal Solution, USP, prepared to contain about 2% of
`iodine and 2.4% of sodium iodide.
`
`Temperature is an important factor in determin-
`ing the solubility of a drug and in preparing its so-
`lution. Most chemicals absorb heat when they are
`dissolved and are said to haves positive first oj'.so-
`luticn. resulting. in increased solubility with an in-
`crease in temperature. A few chemicals have a neg-
`atioe heat of -solution and exhibit a decrease in
`solubility with arise in temperature. Other factors,
`in addition to temperature, affect solubility. These
`include the various chemical and other physical
`properties of both the solute and the solvent, fac-
`tors of pressure, the acidity or basicity of the solu-
`tion. the state of subdivision of the solute, and the
`physical agitation applied to the solution during
`the dissolving process. The solubility of a pure
`chemical substance at a given temperature and
`pressure is oonstant; however. its rate of solution,
`that is, the speed at which it dissolves, depends on
`the particle size of the substance and the extent of
`agitation.Tl1e finer the powder, the greater the sur-
`face area. that comes in contact with the solvent,
`and the more rapid the dissolving process. Also, the
`greater the agitation, the more unsaturated solvent
`passes over the dnig, and the faster the formation
`of the solution.
`
`Astrazeneca Ex. 2096 p. 7
`
`

`
`The solubility of a substance in a given solvent
`may be deterrttined by preparing a. saturated solu-
`tion of it at a specific tarnperatuns and d.etermi:ning
`by chemical analysis the amount of Cliemical dis"-
`solved in a given weight of solution. B]! simple cal-
`culation, the amount ofsolvent required to dissolve
`the amount of solute can be determirted. The solu-
`
`bilityrnay then be expressed as grants ofsolute disr
`solving in milliliters of solvent--for examplefl g of
`sodium chloride dissolves in 23 ml. of water.”
`When the exact solubility has not been detarrnined,
`general expressions of relative solubility may be
`used. These terms are defined in the USP as pre-
`sented inTablc 12.1
`A great many of the important organic medicinal
`agents are either weak acids or weak bases, and
`their solubility is dependent to a large measure on
`the pH of the solvent. These drugs react either with
`strong acids orstrong bases to form water—solubie
`salts. For instance, the weak bases, includingrnany
`of the alkaloids (atropine, codeine, and morphine),
`antiltistaounes (diphenyhydramine and tdpelen—
`namine], local anesthetics (cocaine, procaine, and
`tetracaine), and other important drugs are not very
`water-soluble, but they are soluble in dilute solu-
`tions of acids. Pharmaceutical mamtfecturers have
`
`prepared many acid salts of these organic bases to
`enable the preparation of aqueous solutions. it
`must be recognized, however, that ifthe pH of the
`aqueous solutions of these salts is changed by the
`addition of alkali, the free base may separate from
`solution unless it has adequate solubility in water.
`Organic medicinals that are weak acids include the
`barbiturate drugs (as phenobarbital and pentobar-
`bital) and the sulfonamides (as. sulfadiazine and
`sulfacetamicle). These and other weak acids form
`water-soluble salts in basic solution and may sepa-
`rate irom solution by a lowering of the pH. Table
`12.2 presents the comparative solubflities of some
`typical examples ofweak acids and weak bases and
`their salts.
`
`Table 12.1. Relative Terms of Solubility (2)
`
`Descfiptitis “om:
`
`Very soluble
`Freely soluble
`Soluble
`Sparlngty soluble
`Slightly soluble
`Very slightly soluble
`Practically insoluble
`or insoluble
`
`Parts ofsolvoofioqsired
`for] Portofsolote
`
`Less than 1
`From I to 10
`From 10 to 30
`From 30 to 100
`From 100 to 1000
`From 1000 to 10,000
`10,000 and over
`
`Solutions
`
`299
`
`Table 12.9. Witter and Alcohol Solubilities of Some
`Selected Weak Acids, Weak Bases, and Their Sill:
`
`Number ofml. ofSoIoent
`Required to Dissolve
`1 s vffims
`Alcohol
`
`Water
`
`ass
`05-
`120
`30
`25-
`5,090
`16
`1,000
`1
`200
`1
`13,000
`2
`
`2
`5
`2
`1.280
`325
`.210
`565
`8
`10
`soluble
`15
`sparingly soluble
`sliglitly soluble
`
`Dntg
`
`Atropine
`Atropine sulfate
`Codeine
`Codeine sulfate
`Codeine phosphate
`Morphine
`Morphine suliate
`Phenobarbital
`Phenobarbital sodium
`Procaine
`Procaine hydrorliloricle
`Sulfadiazine
`Sodium sulfadiafine
`
`Although there are no exactrules for predicting
`unerringly the solubility of a dternical agent in a
`particular
`liquid,
`experienced pharmaceutical
`chemists can estimate the general solubility of a
`chemical compound based on its molecular struc-
`ture and functional groups. The information gath-
`ered on a great number of individual chemical
`compounds has led to the characterization of the
`solubilities of groups of compounds, and though
`there may be an occasional inaccuracy with respect:
`to an
`member of-a group of compounds,
`the generalizations nonetheless serve a useful
`fiu'u:ti.on.As demonstrated by the data in Table 12.2"
`and othersimilar data, salts of organic compounds
`are more soluble in water than are the correspond-
`ing organic bases. Conversely, the-cu-ganicbasesare
`more soluble in organic solventaincluding alcohol,
`than are the corresponding salt forms. Perhaps the
`most written guideline for the prediction of solo-
`bility is that"l.ike dissolves like,"meaning that a sol-
`vent having a chemical structure most similar to
`that of the intended solute will be most likely to
`dissolve it.'I'hus-, organic compounds are more sol-
`uble in organic solvents than in water. Organic
`compounds may, however, be somewhat water-
`soluble if they contain polar groups capable of
`forming hydrogen bonds with water. In fact. the
`greater the number of polar groups present, the
`greater will likely be the organic compound’s solu-
`bility in water. Polar groups include OH. CHO,
`COH, Cl-IOI-I, CI-I201-I, COOH. N02, C0, NH,‘
`and SO3H.The introduction of halogen atoms into
`
`Astrazeneca Ex. 2096 p. 8
`
`

`
`300
`
`Solutions
`
`a molecule tends to decrease water-solubility be-
`cause of an increasein the molecular weight of the
`compound without a proportionate increase in po-
`larity. An increase in the molecular weight of an or-
`ganic compound without a change in polarity re-
`sults in decreased solubility in water. Table 12.3
`demonstrates some of these generalities through
`the use of specific chemical examples.
`As with organic compounds. the pharmacist is
`aware of some general patterns of solubility that
`apply to inorganic compounds. For instance, most
`salts of monovalent cations such as sodium, potas-
`sium, and ammonium are water soluble, whereas
`the divalent cations like calcium, magnesium. and
`barium usually form water-soluble compounds
`with nitrate. acetate, and chloride anions but not
`with carbonate, phosphate, or hydroxide anions.'Ib
`be sure, there are certain combinations of anion
`and cation that would seem to be similarin make-
`
`up but that do not have similar solubility character-
`For instance, magnesium sulfate (Epsom salt)
`is soluble, but calcium sulfate is only slightly solu-
`ble; barium sulfate is very insoluble (1 g dissolves in
`about 400,000 mL of water) and is used as an
`opaque media for x-ray observation of the intesti-
`nal tract, but barium sulfide and barium sulfite are
`
`not as insoluble, and their oral use can result input-
`soning; mercurous chloride (HgCl) is insoluble and
`was formerly used as a cathartic. but mercuric chlo-
`ride (I-IgCl¢) is soluble in water and is a deadly poi-
`son if taken intemally.There are many instances in
`which solubilities of certain drugs and their differ-
`entiation from other drugs -are critical to the phar-
`macist in order that he or she might avoid com-
`pounding failures or therapeutic disasters.
`
`Table 12.3. Solubilities of Selected Organic
`Compounds-in Water as a Demonslration of
`Chemical Shucttlre-Solubility Relationship
`
`Compound
`
`I-‘onnula
`
`Benzene
`Benzolc acid
`Benzyi alcohol
`Phenol
`Pyrocatechol
`Pyrogallol
`Carbon tetracliloride
`Chloroforrn
`Methylene chloride
`
`qt-I,
`C5H5CC-‘OH
`Cal-l5CI-I101-I
`C,H,OH
`C6!-l,,(Ol-I),
`Cgl-l3(C}l'I}3
`CC!‘
`CHCl3
`CI-I20,
`
`Number ofmll
`qfWater
`Required to
`Diaalve I g of
`Compound
`
`1430
`275
`25
`15
`2.3
`
`'
`
`2.000
`200
`50
`
`For organic as well as for inorganic solutes, the
`ability of a solvent to dissolve them depends on
`its effectiveness in overcoming,‘ the electronic
`forces that hold the atoms of the solute together
`and the corresponding lack of resolute on the
`part of the atoms themselves to resist the solvent
`action. During the dissolution process, the mole-
`cules of the solvent and the solute become
`
`‘uniformly lrtixed and cohesive forces of the atorns
`are replaced by new forces due to the attraction
`of the solute and solvent molecules for one
`another.
`
`The student may find the following general rules
`of solubility useful.
`
`Inorganic Molecules
`1. If both the cation and anion of an ionic com-
`
`pound are monooalent, the solute-solute attrac-
`tive forces are usually easily overcome, and
`therefore, these compounds are generally water
`soluble. (Examples, NaCL LiBr. Kl, Nl-l§NO3,
`NaNO;J
`2. If only one of the two-ions in an ionic com-
`pound is monoualent, the solute-solute interac-
`tions are also usually easily overcome and the
`compounds are water soluble.
`(Examples:
`BaCL_,, Mglg, Na2SO‘.. Na_-.,P0a)
`3. If both the cation and anion are multioelent. the
`solute-solute interaction maybe too meat to be
`overcome by the solute-solvent interaction
`and the compound may have poor water solu-
`bility. (Examples: C'.aS0,,, BaSO, BiPO§ Ex-
`ceptions: ZnSO.. FeSO.,)
`4. Common salts of alkali metals (Na, K, Li, Cs,
`Rb) are usually water soluble.
`(Exception:
`T-lac‘-'33)
`5. Ammonium and quaternary ammonium salts
`are water soluble.
`6. Nitrates, nitrites, acetates, chlorates, and lac-
`
`tates are generally water soluble. (Exceptions:
`silver and rnercurous acetate)
`‘.7. Sulfates, sulfites, and thiosulfates are generally
`water soluble. (Exceptions: calcium and bar-
`ium salts)
`-8. Chlorides. bsornides, and iodides are water
`soluble. (Exceptions: salts of silver and mer-
`curous ions)
`9. Acid salts corresponding to an insoluble salt
`will be more water soluble than the original
`salt.
`
`10. Hydroxides and oxides of compounds other
`than alkali" metal cations and the ammonium
`
`ion are generally water insoluble.
`
`Astrazeneca Ex. 2096 p. 9
`
`

`
`Solutions
`
`301
`
`1‘L Sulfides are water insoluble except for their
`alkali metal salts.
`
`12. Phosphates, carbonates, silicates, borates, and
`hypochlorites are water insoluble except for
`their alkali metal salts and ammonium salts.
`
`Some Solvents For
`
`Liquid Preparations
`
`The following agents find use as solvents in the
`preparation of solutions.
`
`Organic Molecules
`
`1. Molecules having one polar functional group
`are usually soluble to hotel chain lengths offive
`carbons.
`
`2. Molecules having branched chains are more
`soluble than the corresponding straight-chain
`compound.
`3» Water solubility decreases with an increase in
`molecular weight.
`4. Increased snuctural similarity between solute
`and solventis accornpanieclbyincreased solu-
`bility.
`
`It is the pharrnacist's knowledge of the chemical
`characteristics of drugs that permits the selecfion of
`the proper solvent for a particular solute. However.
`in addition to the factors of solubility: the selection
`is based on such additional solvent characteristics
`
`as clarity, low toxicity, viscosity, compatibility with
`other Eormulative ingredients, chemical" inertness,
`palatability, odor‘. color, and economy. In most in-
`stances, and especially for solutions to be taken
`orally, used ophthalrnically, or injected, water is the
`preferred solvent because it comes closer to meet-
`ing the majority of the above criteria than the other
`available solvents. In many instances, when water
`is used as the primary solvent, an atodliary solvent
`is also employed to augment the solvent action of
`water or to contribute to a product's chemical or
`physical stability. Alcohol, glycerin, and propylene
`glycol, perhaps the most used auxiliary solvents,
`have been quite efiective in contributing to the de-
`sired characteristics of phanrlaoeutical solutions
`and in maintaining their stability.
`Other solvents, such as acetone, ethyl oxide, and
`isopropyl alcohol, are too toxic to be permitted in
`pharmaceutical preparations to be taken internally,
`but they are useful as reagent solvents in
`chemistry and in the preparatory stages ofdrug de-
`velopment, as in the extraction or removal of active
`constituents from medicinal plants. For purposes
`such as this, certain solvents are otficiallyrecognlzed
`in the compenctia. A number of fixed oils, such as
`corn oil, cottonseed oil, peanut oil, and sesame oil,
`serve useful solvent functions particularly ir1 the
`preparation of oleaginous injections and are recog-
`nized in the official compendia for this purpose.
`
`Alcohol, use (EthylAIco}rol,.
`Ethanol, c,H5oH)
`Next to water. alcohol is the most useful solvent
`in pharmacy. It is used as a primary solvent for
`many organic con1potrnds.'lbgether with water it
`forms a hydroalcoholic mixture that dissolves both
`alcohol-soluble and water-soluble substances a
`feature especially useful in the extraction ofactive
`constituents from crude drugs. By varying the pro-
`portion of the two agents, the active constituents
`may be selectively dissolved and extracted or al-
`lowed to remain behind according to their particu-
`lar solubility characteristics in the 1nenstnrum.Al-
`cohol. USP, is 94.9 to 96.0% C‘,H50t-I by volume
`{i.e., vfv) when determined at 15.56°C, the U.S.
`Government's standard temperature for alcohol
`determinations. Deliydmted Alcohol, USE contains
`not less than 99.5% C11-I501-I by volume and is uti-
`lized in instances in which an essentially water-free
`alcohol is desired.
`
`Alcohol has been well recognized as a solvent
`and excipienl in the formulation of oral pha.rI'na.-
`ceutiml products. Certain drugs are insoluble in
`water and must be dissolved in an alternate vehi-
`cle. Alcohol is often preferred because of its misci-
`bility with water and its ability to dissolve many
`water-insoluble ingredients,
`drug sub-
`stances, tlavorants, and antimicrobial preservatives.
`Alcohol is frequently used with other solvents, as
`glycols and glycerin, to reduce the amount of alco-
`hol required. It also is used in liquid. products as an
`antimicrobial preservative alone or as a copreserv-
`atlve with parabens, benzoates, sorbates, and other
`agents.
`However, aside from its pharmaceutic advan-
`tages as a solvent and preservative, concern has-
`been expressed over the undesired pha'rmacologic'
`and potential toxic efl'ects of alcohol when ingested
`in pharmaceutical products particularly by child-
`ren. Thus, the FDA has proposed that manufactur-
`ers of OTC oral drug products restrict, insofar
`as possible, the use of alcohol and include appro-
`priate warrrings in the labeling. For OTC oral prod-
`ucts intended for children under 6 years of age, the
`recommended alcohol-content limit is 0.5 93; Ear
`
`products intended for children 6 to 12 years of age,
`the recommended limit is 5%; and for products
`
`Astraloneca Ex. 2096 p. 10
`
`

`
`30?.
`
`Solutions
`
`recommended for children over 12 years of age and
`for adults, the recornmended limit is 10%.
`
`Diluted Alcohol, NF
`
`Diluted Alool1ol..NF, is prepared by mixing equal
`volumes of Alcohol, USP, and Purified Water, USP.
`The final volume of such
`is not the sum of
`
`the individual volumes of the two oomponents, but
`due to contraction of the liquids upon mixing, the fi-
`nal volume is generally about 3% less than what
`would normally be expected. Thus when 50 mL of
`each component is combined, the resulfing product
`measures approximately 97 mL. It is for this reason
`that the strength of Diluted Alcohol, NI-', is not ex-
`actly half that of the more concentrated alcohol, but
`greater, approximately 49 ‘it. Diluted alcohol
`is a useful hydroalcoholic solvent in various phar-
`maceutical processes and preparations.
`
`Alcohol, Rubbing
`
`Rubbingfillcohol contains about 70% of ethyl al-
`cohol by volume, the remainder consisting of wa-
`ter. denaturants with or without color additives and
`perfume oils, and stabilizers. In each 100 mL, it
`must contain not less than 355 mg of sucrose oc-
`taacetate or 1.4 mg of denatoniurn benzoate, bitter
`substances that discourage accidental or abusive
`oral ingestion. The denaturants employed in rub-
`bing alcohol are according to the Internal Revenue
`Service, .'U.S- Treasure Department, Formula 23-I-I,
`which is composed of 8 parts byvolume of acetone,
`1.5 parts by volume of methyl isobutyl kebone, and
`100 parts byvolume of ethyl alcohol.The use of this
`denaturant mixture makes the separation of ethyl
`alcohol from the denaturants avirtuallyimpossible
`task with ordinary distillation apparatus. This dis-
`courages the illegal removal and use as a beverage
`of the alcoholic content of rubbing. alcohol
`The product is volatile and Elarrunable and should
`be stored in tight containers remote from Ere. It is
`employed as a rubefacient extemally and as a sooth-
`ing rub for bedridden patients, a gemiicide for in-
`struments, and a skin cleanser prior to injection. It is
`also usedas a vehicle for topical preparations,
`Synonym: Alcohol Rubbing Compound.
`
`Glycerin, USP (Glycerol),
`CH2OH-CHOH-CH2OH'
`
`Glycerin is a clear synipy liquid with a sweet
`taste. It is miscible both with water and alcohol. As
`
`a‘ solvent. it is comparable with alcohol, but because
`
`ofits viscosity, solutes areslowly soluble in it unless:
`it is rendered less -viscous by heating.
`has
`preservative qualities and is often used as a stabi-.
`lizer and as an auxiliary solvent in conjunction with
`water or alcohol. It is used in many internal prepa-
`rations.
`
`Isopropyl Rubbing Alcohol
`
`Isopropyl Rubbing Alcohol is about 70% by vol-
`ume isopropyl alcohol, the remainder consisting of
`water with or without color additives, stabilizers,
`and perfume oils. It is used externally as a 1'ubefa-
`cient and soothing rub and as a vehicle for topical
`products. This preparation and a commercially
`available 91% isopropyl -alcohol solution are com-
`monly employed by diabetic patients in preparing
`needles and syringes for hypodermic injections of
`insulin and for disinfecting the slcin.
`
`Propylene Glycol, LISP,
`ch,cHr0H)cH,oH
`
`liquid, is miscible
`Propylene glycol, a
`with water and alcohol. It is a useful solvent with a
`
`wide range of applications and is frequently substi-
`tuted for glycerin in modern pharmaceutical for-
`mulations.
`
`,
`
`Naturally occurringwater exerts-its solvent effect
`on most -substances it contacts and thus is impure
`and contains varying amounts of dissolved inor-
`ganic salts, usually sodium, potassium, calcium,
`magnesium, and iron, chlorides; sulfates, and bi—
`carbonates, as well as dissolved and undissolved
`organic matter and rnicroorganlsms. Water found
`in most cities and towns where water is purified for
`drinking purposes usually contains less than 0.1%
`oftotal solids, determined by evaporating a 100 mL
`-sample of water to dryness and weighing the
`residue (which would weigh less than 100 Ingl-
`Drinlcing water must meet the United States Pub—
`Iic Health Service regulations with respect to bac-
`teriological purity. Acceptable drinking water
`should be clear, colorless, odorless, and neutral or
`only slightly