`

`Editor: Donna Balado
`Managing Editor: jennifer Schmidt
`Marketing Manager: Christine Kushner
`
`Copyright © 1999 Lippincott Wllliams & Wilkins
`
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`
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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 Cataloging-in-Publication Data
`
`Ansel, Howard C., 1933—
`Pharmaceutical dosage forms and drug delievery systems / Howard C.
`Ansel, Lode. Allen, Jr, 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.
`11. Popovich, Nicholas G.
`III. Title.
`[DNLM: 1. Dosage Forms.
`2. Drug Delivery Systems, QV 785 A618i 1999]
`RS200.A57
`1999
`615’.1—dc21
`DNLM/DLC
`for Library of Congress
`
`1. Allen, Lode.
`
`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 Exhibit 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: Biopharmaceutic 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-SOLID AND TRANSDERMAL SYSTEMS
`
`9
`
`IO
`
`Ointments, Creams, and Gels
`
`Transdermal Drug Delivery Systems
`
`v
`
`vii
`
`1
`
`23
`
`60
`
`101
`
`142
`
`164
`
`179
`
`229
`
`_
`
`'244
`
`263
`
`ix'
`
`AstraZeneca Exhibit 2096 p. 3
`
`

`

`x
`
`Contents
`
`Section IV. PHARMAEEUTICAL INSERTS
`
`II
`
`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 ADVANEED DOSAGE FORMS, DELIVERY SYSTEMS, AND DEVIEES
`
`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 Exhibit 2096 p. 4
`
`

`

`Section V. Liquid Dosage Forms
`
`' SOLUTIONS
`
`
`
`Chapter at a Glance
`
`Solubility
`Inorganic Molecules
`Organic Molecules
`Same Solvents For Liquid Preparations
`Distillation Method
`Ion-exchange method
`Reverse Osmosis
`
`Preparation of Solutions
`Oral Solutions and Preparations for Oral
`Solution
`
`Dry Mixturesfor Solution
`Oral Solutions
`
`Oral Rehydration Solutions
`Oral Colonic Lavage Solution
`Magnesium Citrate Oral Solution
`Sodium Citrate and Citric Acid Oral Solution
`
`Syrups
`Compont of Syrups
`Sucrose and Non—Sumse Basod Sympa
`Antimicrobial Presematioe
`Flavorant
`Colorant
`
`Preparation of Syrups
`Solution with the Aid of Heat
`Solution byAgitation without the Aid of
`Heat
`
`Addition ofSuorose to a Medicated Liquid or
`to a Flavored Liquid
`Percolation
`Elixirs
`
`PIEPaIfithEI‘l of Elixirs
`Nonmedicated Elixirs.
`Medicated Elixirs
`Antihistamine Elixirs
`
`Proper Administration and Use of Liquid
`' Peroral Dosage Forms
`Topical Solutions and Tinctures
`Topical Solutions
`Sprays
`Aluminum Acetate Topical Solution
`Aluminum Subacetate Topical
`Solution
`
`Calcium Hydroxide Topical Solution
`Coal Tar Topical Solution
`Hydrogen Peroxide Topical Solution
`Chlorhexidine Gluconate Solution
`
`Pavilions-iodine Topical Solution
`'l‘liimerosal Topical Solution
`Vaginal and Rectal Solutions
`Vaginal Douches
`Retention Enemas
`Evacuation Enema
`
`Topical Tinctures
`lodlne Tlncture
`
`Compound Benzoin Tinctures
`Thimerosol Tincture
`
`Special Application Solutions
`Nasal Preparations
`Nasal Deoongestant Solutions
`Inhalation Solutions.
`
`Examples ofMedicated inhalation
`Solutions
`inhalants
`
`Amyl Nitrite Inhalant
`Propylliaxedrine Inhalant
`Proper Administration and Use ofNasal
`Drops and Sprays
`Nasal Route for Systemic Efiizcts
`Otic Solutions
`
`Barbiturate Sedation/Hypnotic Elixirs
`Phenobarbital Elixir
`Cemmen-Remooing Solutions
`Digoxin Elixir
`Anti—infective, Anti-inflammatory, and
`Tinctures
`Analgesic Ear Preparations
`
`
`296
`
`AstraZencca Exhibit 2096 p. 5
`
`

`

`Proper Administration and Use ofOtic
`
`Topical Oral (Dental) Solutions
`Miscellaneoas Solutions
`Aromatic Waters
`Diluted Acids
`Spirits
`Nonaqueous Solutions
`Liniment's
`Collodions
`ColIndian
`
`Flexible Collodiorr
`Salicylic Acid- Canadian
`Extraction Methods for Preparing
`Solutions
`Methods of Extraction
`Mammal-ion
`Percolation
`
`Example Preparations Prepared by
`Extraction Processes
`Fluidextracts
`Extracts
`
`IN PHYSICOCHEMCAL terms, solutions may he 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. 3.
`liquid, oragas, andwiththesame beingtmefora
`liquid solute and for a gas, nine types of homoge-
`neous mixtures are possible. In phamnacy, however,
`mterest in solutions is for the most patt' 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 suitable solvent or mix-
`
`ture of mutually miscible solvents”(1). Because of a
`particular pharmaceutical solution’s use, it may be
`classified as an oral solution, oiic 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 hydroalcoholic (combi-
`nations ofwater and ethanol) solutions are termed
`Elixirs,- solutions of aromatic materials are termed
`spirits if the solvent is alcoholic or mficwalefs if
`the solvent is aqueous. Solutions prepared by so
`tracting active constituents from crude drugs are
`termed
`orfluid och-och depending on their
`method of preparation and their concentration.
`Tinctures may also be solutions of chemical sub-
`stances dissolvod in alcohol or in a hydroalcoholic
`solvent. Certain solutions prepared to be sterile and
`pyrogenvfree and intended for parmteral-adnfinis-
`tration are classified as injections. Although other
`examples could be cited, it is apparent that a solu-
`tion, as a distinct type of pharmaceutical prepara-
`tion, is omch further defined than is the physioo-
`chemical definition of the term solution.
`
`Oral solutions, sytups, elirdrs, spirits and tinc-
`nlresare prepared and need for the specific effects
`of the medicinal agents present. In these prepara-
`tions, the medicinal agents are intended to provide
`
`:systernic etieaa'l'he fact that theyare admirlisteted
`in solution fonn usually means that their absorp-
`tion from the gastrointestinal tract into the sys-
`temic circulationmaybe expected to occurmote
`rapidly than from suspension or solid dosage forms
`of the same medicinal agent.
`Salutes other than the medicinal agent are usu-
`ally presentin acaflyadnfinistered solutions.'l‘hese
`additional agents usually are included to provide
`color, flavor, sweetness, or stability to the solution.
`In fountdadng or compoimding a pharmaceutical
`solution, the pharmacist must utilise information
`on the solubility and stability ofeach of the solutes
`present with regard to the solvent or solvent sys-
`tem employed. Combinations of medicinal or
`pharmaceutic agents that will result in chemical or
`physical interactions affording the therapeutic qual-
`ity or pharmaceutic stability of the product must be
`avoided.
`
`For single-solute solutions and especially for
`multiple-solute solutions, the pharmacist must be
`aware of the solubility characteristics of the solutes
`and the {echoes of the common pharmaceutical
`solvents. Each chemical agent has its own solubil-
`ity in a given solvent, For mny medicinal agents,
`their solubilities in the usual solvents are stated in
`the USP aswell as in other reference books.
`
`Solubility
`Attractive forces between atoms lead to the for—
`mation of molecules and ions. The intermolecular
`
`tomes, which are developed between like make
`coins, are responsible for the physical state (i.e.,
`solid, liquid, or gas}. of the substance under giVEn
`conditions, as temperature and pressure; [Rider or-
`dinary conditions. must organic compounds, and
`thus most drugsubotances, form molecular solids.
`When molecules interact,
`forces and re-
`pulsive forces are in edcct.'l'he attractive forces came
`the molecules to cohere, whereas the repulsive
`
`AstraZencca Exhibit 2096 p. 6
`
`

`

`298
`
`Solutions
`
`forces prevent molecular interpenetration and de-
`struction. When the attractive and reptdsive forces
`are equal, the potential energy between two mole—
`colesis minimum and the systemis most stable.
`Dipole: molecules frequently tend to align
`themseIVes with other dipole: 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 weak at-
`tractions known as dipole-dipole or van der Wallis
`forces. In addition to the dipolar interactions. other
`attractions occur between polar and nonpolar mol-
`ecules and ions. These include ion-dipole forces
`and hydrogen bonding. The latter is of par-Hotter
`interest. Because of small size and large electrosta-
`dcfield the hydrogen stomcanmovein closeto an
`electronegative atom, forming an electrostatic type
`of association referred to as a hydrogen bond or hy-
`drogen budge. Hydrogen bonding irWoh-res strongly
`electronegative atoms as oxygen, nitrogen. and flu-
`orine. Such a bond exists in water. represented by
`the dotted lines:
`
`a
`sh.
`.r‘
`I'L
`o
`3&1
`1-1” \H
`Water
`
`Hydrogen bonds also exist between some alcohol
`molecules. esters. carboxylic acids. aldehyd, and
`polypeptides.
`till-ten a solute dissohres. the substances inter-
`molecular forces oE attraction must be overcome by
`forces of attraction batsmen the solute and solvent
`
`molecules'I'his involves breekiogthe solute—solute
`forces and the solvent-solvsnt forces to achieve the
`solute-solvent attraction.
`
`The solubility of an agent in a particular solvent
`indicates the moximron concenlretiorr 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 twa chemical agents and there-
`fore in the amounts of each required to prepare a
`saturated solution. two oflicial aqueous saturated
`solutions are cited as examples, Calcium Hydroidde
`Topical Solution U312 and Botassium Iodide Oral
`Solution. USP. The first solution, prepared by agi-
`
`tating an excess amount of caldmn hydmodde With
`purified water, contains only about 140 mg of dis-
`solved solute per 100 rnL 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 poasr'ble concentration to
`which a pharmacist may prepare a solution varies
`greatly and is dependent. in part, on the chemical
`constitution of the solute. Through selection of a
`different solubillzing agent or a difierent chemical
`salt form of the medicinal agent, alteration of the
`pH ofa solution or substitution, in part or inwhole,
`of the solvent, a pharmacist can in certain instances
`dieson greater quantifies of a solute than would
`otherwise be possible. For example, iodine gren-
`ules are soluble in water only to the extent of 1 g
`in about 3000 mL of water. Using only these
`two agents, the madmum concentration possible
`would be approximately 0.03% of iodine in aque-
`oussolution. 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 tonnatton of a water-
`
`soluble complex with the iodide salt.This reaction
`is taken advantage of, for example. in Iodine ’lbpi—
`cal Solution, USP. prepared to contain about 2% of
`iodina and 2.4% of sodium iodide.
`
`Thmperamre is an important Eactorin determin-
`ingthe solubility of a- drug and in proper-tog its so—
`Iution Most chemicals absorb heat when they are
`dissoltIed and are said to have a positive heat ofso-
`lotion. resulting in increased solubility with an in-
`crease in temperature. A fen: chemicals have a seg—
`olive heat of solution and exhibit a decrease in
`solubility with a rise in temperature. Other factors,
`in addition to temperature, effect solubility. These
`include the various chemical and other physical
`properties of both the solute and the solvent, fac-
`tors of pressure-,.the acidity or basicityot the solu—
`tion. the state of subditdsiOn 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 constant; howover, its one of solution,
`that is. the speed at which it dissolves, depends on
`the particle size of the substance and the torrent of
`agitation.'[he liner 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 drug and the faster the formation
`of the solution.
`
`AstraZeneca Exhibit 2096 p. 7
`
`

`

`Solutions
`
`299
`
`Table 12.2.. Water and Alcohol Soluhimies of Some
`Selected Weak Acids, Weak Bases. and Their Salli
`
`Numberqu ofSoloent
`Required to Dissolve
`1 g ofDmg
`
`W s
`
`2
`5
`2
`1.280
`325
`.210
`565
`8
`10
`soluble
`‘15
`sparingly soluble
`slightly Still-lb!!!
`
`ome
`Atropine sulfate
`Codeine
`Codeine sulfate
`Codeine phosphate
`Morphine
`Morpholo- sulfate
`Phenobarbital
`thobarbital sodium
`Promote
`Procaine hydrochloride
`Sulfadiazine
`Sodium sulfadiazine
`
`455
`0.5
`120
`30
`2.5
`5.000
`16
`1,000
`1
`200
`'1
`13,000
`2
`
`Although there are-no exactntlesfor
`unerringly the solubility of a cherrucal agent in a
`particular
`liquid,
`atpetienoed pharmaceutical
`chemists can estimate the general solubility of a
`chemical compound based on its molecular struc-
`ture and flmctional groups. The infarct-radon gath—
`ered on a great number of indhrldual charities]
`compounds has led to the characterization of the
`solubilities of groups of compounds, and though
`there may be an occasional inaccurath respect:
`to an individual member of a group of compounds
`the generalizations. nonetheless serve a useful
`function. As demonstrahed by the data in Table 12.2
`and other similar data, salts of organic compounds
`are more soluble in water than are the correspond-
`ing organic bases. Conversely the organic basos are
`more soluble in organic sobents. including alcohol.
`than are the corresponding salt forms. Perhaps the
`most written guideline for the predictiou of solu-
`bility is [haf'like dissolveslikefmeaning that a sol-
`vent having a chemical structure most similar to
`that of the intended solute will be most likely to
`dissolve it'll-nus, 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 pressnt, the
`greater will likely be the organic compound’s solu-
`bility in water. Polar groups include 0H,. CHO.
`COH, CHOH, CHpH, COOH. N02. C0,
`and. 50311.1}!!! introduction of halogen atoms into
`
`AstraZencca Exhibit 2096 p. 8
`
`The solubility of a substance in a given solvent
`may be determined by preparing a saturated solu-
`tion of it at a specific tempetahn'e and determining
`by chemical analysis the amount of chemical dis-
`solved in a g‘Ven weight of solution. By simple cal-
`culation, the amount ofsolvent required to dissolve
`the amount of solute can be detemiirtEthe solu-
`
`biliryrnay then be expressed as grams of solute dis-
`solving in milliliters of solvent~—for example,“1 g of
`sodium chloride dissolves in 18 ml. of water.“
`
`When the exact solubility has not been determined,
`general expressions of relative solubility may be
`used. These terms are defined in the USP as- pre-
`sonfiecl in Table 12.1 (2;
`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 ofthe submit. These drugs react eitherwith
`strong acids or strong bases to form watervsoluble
`salts. For instance, the weak bases, includinng
`of the alkaloids (atropine, codeine, and morphine).
`antihistamines (diphenyhydrarnine and tripelen—
`nominal, local anesthetics. (cocaine, procaine, and
`belracaine), and other important drugs are not very
`water-soluble, but theyI are soluble in dilute solu-
`tions of acids. Pharmaceutical manufacturers have
`
`prepared many acid salts of these orgardc bases to
`enable the preparation of aqueous solutions. it
`must be recognized, however, that if the pH of the
`aqueous solutions of these salts is changed by the
`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 peatobar-
`bital) and the sulfonarnides (as sulfadiazine and
`sulfacetamide). These and other weak acids form
`water-soluble salts in basic solution and may sepa-
`rate b'om solution by a lowering of the pH. Table
`12.2 presents the comparative solubilities of some
`typical examples otweak acids and weakbasesand
`their salts.
`
`Table 12.1. Relative Teams of Solubility (2}
`
`Descripfim'lbmz
`
`Very soluble
`Freely soluble
`Soluble
`
`Spar-lusty soluble
`Slightly soluble
`Very slightly soluble
`Practically insoluble
`or insoluble
`
`Parts ofSol‘vent Required
`furl PmrofSolute
`
`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
`over
`
`

`

`300
`
`Solutions
`
`a molecule tends to decrease water-solubility be—
`cause of an increase in 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 ofspecific 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 watensoluble compounds
`With rfitrate, acetater and chloride anions but not
`with carbonate, phosphate, or hydroxide anions.'1b
`be sure, there are certain combinations of anion
`and cation that would seem to be similar in make-
`
`up but that do nothave similar solubility character-
`istics. Fori‘nstance, magnesium sulfate (Epsom salt)
`is soluble,I but calcium snifate is only slightly Bolo-
`ble; barium sulfate is very insoluble (1 g dissolves in
`about 400,000 mi. of water) and is used as an
`opaque media for x-ray observation of the intesti-
`nal tart-neti but barium sulfide and barium sulfite- are
`
`not as insoluble, and their oral use can result in poi-
`soning; mercurous chloride {HgCD is insoluble and
`was tonnerly used as a cathartic, but mercuric chlo-
`ride (HgClz) is soluble in water and is a deadly poi-
`son if taken internally.There are many instances in
`which solubilitles 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 Demonstration of
`Chemical Shawna—Solubility
`
`Compound
`
`Formula
`
`Benzene
`Benzoic acid
`Benzyl alcohol
`Phenol
`
`CGHE
`Cal-{4200}!
`Cgl-IECE-IQOH
`Csl-ISOH
`
`oregano
`Carbon tetrachloride
`Chloroform
`Methylene chloride
`
`CsHsloms
`CCI,
`C}ng
`CREE,
`
`Monber :3me
`ofWater
`Required to
`Diesel»: 1 g of
`Compound
`
`1430
`2175
`25
`15
`
`:3
`2.000
`200
`51]
`
`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
`
`tmiformly mbted and cohesive forces of the atoms
`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 usefiil.
`
`Inorganic Molecules
`1. If both the cation and anion of an ionic com-
`
`pound are monmlau, the solute-solute attrac~
`rive forces are usually easily overcome, and
`therefore, these compounds are generallywater
`soluble. (Examples, NaCL LiBt. Kl, NH‘NO,
`NaNOzJ
`2. If only one of the two ions in an ionic com—
`pound is monmient the solute-solute interac-
`tions are also usually easily overcome and the
`compounds are Water soluble.
`(Examples:
`Bach, Mglz, NaZSOy NaaPO‘)
`3. If both the cation and anion are malevolent, the
`solute-solute interaction maybe too great to be
`overcome by the solute-solvent interaction
`and the compound ma.)r have poor mter solu—
`{Exarnplen CaSD‘, BaSOg, BiPOd; Ex-
`ceptions: 21150,, FeSOQ
`4. Common salts of alkali metals (Na, K, Li, Csi
`Rb) are usually Water soluble (Biosphere
`Locos)
`5. Ammonium and quaternary ammonium salts
`are water sohible.
`6. Nitrates, nitrites, acetates, chlorates, and lac-
`
`tates are generally water soluble. (Exceptions:
`silver and mercurous acetate)
`7. Sulfates, sulfites, and tluosulfates are generally
`“rater soluble. (Exceptions: calcium and bar-
`ium salts)
`8. Chlorides-l bromides.I and iodides are water
`soluble. (Emeptions: salts of silver and mer-
`cu'rous ions)
`9. Acid salts corresponding to an insoluble salt
`will be more water soluble than the original
`salt.
`
`10. Hydroiddes and oxides of cumpounds other
`than alkali metal cations and the ammonium
`
`ion are generally water insoluble.
`
`AstraZeneca Exhibit 2096 p. 9
`
`

`

`Solutions
`
`301
`
`1L Sulfides are water insoluble except for their
`aficali metal salts.
`
`12. Phosphates, carbonates, silicates, boretes, and
`hypomlorites 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 pole: funcfitmal group
`are usually soluble to total chain lengths of Eye
`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 sit-smite! similarity between solute
`and solvent is accompanied by increased solu-
`bility.
`
`It is the pharmacist knowledge of the chemical
`characteristics of drugs that permits the selection of
`the propersolvent fora particular solutel-Iowever,
`in addition to the factors of solubility the selection
`is based on such additional solvent characteristics
`
`as clarity, low toadclty, 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 cphmalnucalh’, or injected, water is the
`preferred solvent because it cornea closer to meet-
`ing the majority of the above miseria than the other
`available solvents, In many instancos, when water
`is used as the primary solvent, an auxiliary 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
`giycol, perhaps the most used corollary solvents,
`have been quite eflecfiw in contributing to the de-
`sired characteristics of pharmaceutical solutions
`and in maintaining their stability.
`Other solvents, such as acotone, ethyl crude, and
`isopropyl alcohol, are too toadc to be pennitted in
`pharmaceutical preparations to be taken internally,
`but they are useful as reagent solvents in organic
`chemistry and in the preparatory stages of'drug de-
`Velopment, as in the extractions: removal of active
`constituents from medicinal plants. For purposes
`such as this, certainsolvents are officially recognized
`in the compendia. A mtmber of fixed oils, such as
`corn oil, cottonseed oii. peanut oil, and sesame oil,
`some useful solvent Emotions particularly in the
`preparation of oleaginous injections and are recog-
`nized in the oflicial compendia for this purpose.
`
`Alcohol, use (EthylAlcohol,
`Ethanol, cszom
`Next to water, alcohol is the most useful solvent
`in pharmacy. It is used as a primary solvent for
`many organic componmds. Together with water it
`forms a hydroalcoholic mixture that dissolves'both
`alcohol—soluble and water-soluble substances a
`feature especially usufixl 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 accordingto their particu-
`lar' solubility characteristics in the menstruum. Al-
`cohol, USP, is 94.9 to 96.0% QH50H by volume
`(i.e., WV) when determined at 15.56‘C, the US.
`Government's standard temperature for alcohol
`determinations. Dehydrated Alcohol, USP, contains
`not loss than 99.5% Czl-isCJI-I by volume and is uti-
`lized in instances in which an essentiallywater—foee
`alcohol is desired.
`
`Alcohol has been Well recogniZed as a solvent
`and enipient in the formulation of oral pharma-
`ceutical products. Certain dnrga are insoluble in
`water and must be dissolved in an alternate vehi-
`
`deAlcohol is often preferred because of its misci-
`bilitywith watermle abilityto dissolvemany
`water-insoluble ingredients, including drug sub-
`stances, flavorants, and
`presenzetives.
`Alcohol is frequently used with other solvents, as
`glycols and glycerin. to reduce-the amount of alco—
`hol required. It also is used in
`products as an.
`antimicrobial preservative alone or as a copreserv-
`ative with parabens, benzoates, sorbates, and other
`agents.
`Howaver, aside from its pharmaceutic advan-
`tages as a solvent and preset-same, concern has
`been expressed over the undesired pharmemlogic
`and potential toad: efl’ects of alcohol when ingested
`in pharmaceutical products particularly by child-
`ren'l‘hus, theFDAhas proposed that: manufactur-
`ers of OTC oral drug products resn-ict. insofar
`as possible, the use of alcohol and include appro-
`priate warnings in the labeling. For OTC oral prod-
`ucts intended for d'tildren. under 6 years of age, the
`recommended alcoh01~content limit is 0.5%; for
`
`products intended for children 6 to 12 years of age,
`the recommended limit is 5%; and for products
`
`Astra-Zoneca Exhibit 2096 p. 10
`
`

`

`302
`
`Solutions
`
`recommended forchildren over 12 years of age and
`for adults, the recommended limit is 10%.
`
`Diluted Alcohol, NP
`
`Diluted Alcohol, NE is prepared by mixing equal
`volumes of Alcohol, USP, and Purified Waten USP!
`The finalvolumeofsuch mbeturesisnotthesumof
`
`the individual volumes of the two components, 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 resulting product
`measures approximately '97 mL. It is for this reason
`that the attengtb of Diluted Alcohol, NE is not ex-
`actly half that of the more concentrated alcohol, but
`slightly greater, approfimately 49 it. Diluted alcohol
`is a useful hydroalooholic solvent in various phar-
`maceutical processés and preparations.
`
`Alcohol, Rubbing
`
`RubbingAlcohol contains about 70% of ethyl al-
`cohol by volume, the remainder consisting of wa-
`ter, denaturants With or without COIor additives and
`perfume oils, and stabilizers. In each 100 mi, it
`must contain not less than 355 mg of sucrose oc-
`taecetate or 1.4 mg of denatonium benzoate, bitter
`substances that discourage accidental or abusive
`oral ingestion. The denaturants employed in rub-
`bing alcohol areaocording to the Internal Revenue
`Service, US. 'lteasure Department, Fonnula 23-H,
`which is composed oft! parts byvolumeof acetone,
`15 parts byvolurne of methyl isobutyl ketone, and
`100 parts byvolume of ethyl alcohol.'I'he use of this
`denaturant mixmre makes the separation of ethyl
`alcohol from the denaturants a
`impossible
`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 flammable and should
`be stored in tight containers remote from fire. It is
`employed as a rubefacient maternally andasa sooth-
`ing rub for bedridden patients, a genrficide for in-
`struments, and a skin cleanser prior to injection. It is
`also used as a vehicle for topical preparations.
`Symonym: Alcohol Rubbing Compound.
`
`Glycerin, LISP (Glycerol),
`mon'CHOH-CHzofl
`
`Glycerin is a clear syrupy 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 are slowly soluble in it unless:
`it is rendered less viscous by heating. Glycerin has.
`presarvative qualities and is often used as a staid-,-
`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% byvol-
`ume isopropyl alcohol. the remainder consisting of
`water with or without color additives, stabilizers,
`and perfume oils. It is used externally as. a robot:-
`cient and soothing rub and as a vehicle for topical
`products. This preparation and. a commercially
`available 91% is'optopyl alcohol solution are com—
`monly employed by diabetic patients in preparing
`needles and syringes for hypodermic injections of
`insulin and for disinfecting the-skin
`
`Propylene Glycol, USP,
`ChautZ'HiOIDCHZOH
`
`Propylene glycol, a viscous liquid, is miscible
`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.
`
`Purified Water, use H20
`
`Naturally occurring water exerts-its solvent effect
`on most substances it contacts and thus is import
`and contains varying amounts of dissole inor-
`ganic salts, usually sodium. potassium, calcium.
`magnesium, and iron, chlorides, sulfates, and bi—
`carbonates, as well as dissolved and undissohred
`organic matter and microorganisms. Water found
`in most cities and towns where water is purified for
`drinking purposes usually contains less than 0.1%
`of total solids, determined by evaporating a 100 ml.
`sample of water to dryness and weighing the
`residue (which would weigh less than 100 mg).-
`Drlnlring Water must meet the United StateS Pub—
`lic Health Service regulations with respect to bar:-
`teriological purity. Acceptable drmking water
`should be clear, colorless, odorless, and neutral or
`only slightly acid or alkaline, the deviation ham
`neutral being due to the nature of the dissolved
`solids and gases (carbon diordde contributingto the
`acidity and ammonia to the alkalinity of water).
`Ordinary drinking