Editor: Donna Balado
`Managing Editor: Jennifer Schmidt
`Marketing Manager: Christine Kushner
`
`Copyright © 1999 LippincottW1lliams & Wflkins
`351 West Camden Street
`Baltimore, Maryland 21201-2436 USA
`
`227 East Washington Square
`Philadelphia, PA 19106
`
`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, 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.
`Il. Popovich, Nicholas G.
`Ill 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, LoydV.
`
`99-17498
`CIP
`The publishers have made every efiort 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 excerpm 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 O2
`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-SOLID AND TRANSDERMAL SYSTEMS
`
`_
`
`9
`
`TO
`
`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
`
`II
`
`Suppositories and Inserts
`
`Section V.
`
`LIOUID DOSAGE FORMS
`
`I 2
`
`I3
`
`Solutions
`
`Disperse Systems
`
`Section VI. STERILE DOSAGE FORMS AND DELIVERY SYSTEMS
`
`T4
`
`T5
`
`T6
`
`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
`
`T7
`
`T8
`
`T9
`
`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 af a Glance
`
`Solubility
`Inorgmic 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 Mfxturesfar Solution
`Oral Solutions
`
`Oral Rehycirotion Solutions
`Oral Colonic Lavage Solution
`Mogrrosium Citrate Om! Solution
`Sodium Citrate and Citric Acid Oral Solution
`
`Syrups
`Components of Syrups
`Sucrose and Nor:~Sucroso Boson‘ Syrups
`Antimicrobial Preseroatioe
`Flooormu
`Colo:-out
`Preparation of Syrups
`Solution with the Aid of.l-loot
`Solution by Agitation zoithout the Aid of
`Heat
`
`Addition of Sucrose to o Medicated Liquid or
`to o Flavored Liquid
`Percolation
`Elixirs
`
`Preparation of Elixirs
`Norunedicated Elixirs
`Medicated Elixirs
`Autihistomioe El:‘xirs
`
`Bo:-lriturote Sedotioe/Hypnotic Elixirs
`Phenobarbital Elixir
`
`Digoxin Elixir
`Tinctures
`
`295
`
`Proper Administration and Use of Liquid
`Peroral Dosage Forms
`Topical Solutions and Tinctures
`Topical Solutions
`Sprays
`Aluminum Acetate Topical Solution
`Aluminum Subocotaie Topical
`Solution
`
`Calcium Hydroxide Topical Solution
`Cool Tor Topical Solution
`Hydrogen Peroxide Topical Solution
`Chlorhexidine Glut-onote Solution
`
`Pooidorwlodine Topical Solution
`Thfmerosol Topical Solution
`Vaginal and Rectal Solutions
`Vaginal Douohes
`Retention Enemos
`Eoocuation Eoemos
`
`Topical Tinctures
`Iodine Tiucture
`
`Compound Benzoin Tiucture
`Thiroerosal Tiucture
`
`Special Application Solutions
`Nasal Preparations
`Nasal Decougostonr Solutions
`Inhalation Solutions
`
`Examples of Medicated lnholotion
`Solutions
`Iuholonis
`
`Amyl Nitrite lrrlzolarzt
`Propylhexedriue Irrluzlont
`Proper Administration and use of Nasal
`Drops and Sprays
`Nosol Routefor Systemic Eflkcfs
`Otic Solutions
`
`Cerumen-Removing Solutions
`Anti-infective, Anti-inflammatory, and
`Analgesic Ear Preparations
`
`Astrazeneca Ex. 2096 p. 5
`
`

`
`Solutions
`
`29'?’
`
`Proper Administration and Use of Otis
`Drops
`Topical Oral (Dental) Solutions.
`Miscellaneous Solutions
`Ar-omaticwalaers
`Diluted Acids
`.
`_
`Spirits
`_
`Nonequeoussolut-.-one
`
`Lmrrne’'
`nts
`Collodions
`Callodian
`
`Flexible Colladion
`Salicylic Acid Collodion
`Extraction Methods for Preparing
`Sohrfioris
`Methods of Exn-action
`Msceratian
`Percolation
`
`Example Preparations Prepared by
`Extraction Processes
`Pluidextracts
`Extracts
`
`INPm'5!COCl-mvltCA.Lteru1s,solulior1s maybe pre-
`pared from any corobination of solid, liquid, and
`gas, the threestares of matter. For example, a solid
`solute may be dissolved in either another solid, as
`oragas, andwitlrthesarrnebeirigtrue flora
`liquid solute and for a gas. nine types of ho.1:noge-
`neous mixtures arepossible In pharmacy. however.
`interest insolutions is for the most part
`to
`preparations of a solid, a liquid, and less Irequently
`a gassolute 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}.Be-cause ota
`particular pharmaceutical solutiorrs use, it may be-
`classitied as an erelsolnticrl. atic solution, ophthalmic
`solution, or topll solution. Still other solutions, ‘be-
`cause of their composition oruse, maybeclassified
`as other phmzrnaceuticel dosage forms. For exam-
`ple. aqueous solutions containing a sugar are clas-
`sified assynqtrs; sweetened hyclroalcaholie (combi-
`nations ofwater and ethanol} solutions are termed
`eliiciw; solutions of aromatic materials" are termed
`spirits if the solve-ntis alcoholicor erontaticwctersif
`the solvent is aqueous. Solutions prepared by ex-
`tracting active constituents from crude drugs are.
`termed tinctures orfiuid ertreda. dependingon their
`method of preparation and their concentration.
`Iincturm may take be solutions of chemical aub-
`stsnoes dissolved in.-alcohol or in a lryclroalcoholic
`solvent. Certainsolutions prepared tobesterileand
`pyrogen-free and intended for parenteral adminis-
`tration are classified as
`Although other
`eararnples could be- cited, it is apparent that nsolu-
`ticrn, as a distinct type‘ of pharmaceutical prepara-
`tion, is rrmch further defined than is the physics-
`chernical definition of the term salvlion.
`Oral solutions. Sffrups, elixirs, spirits and tinc-
`lures are prepared and used tor the specific effects
`of the
`agents present. In these prepara-
`tions, the medicinal agents are intended to provide
`
`systemic eiieets.'I‘he fact that they areadrninisteted
`in solution form usually means that their absorp-
`lion from the gastrointestinal tract into the sys-
`temic circulation maybe expectedtooccur more
`rapidlyflianfromsuspensionorsoliddosage forms
`of the same rrtedicinal agent.
`Solutes other than the medicinal agent are usu-
`allypresent in orally
`solutions.T_h.ese
`aadditional agents usually are included to
`color, flavor, sweetness, or stability to the solution.
`In formulating -or compounding la phamiaceulical
`solution, the pharntadst must utilize inionnation
`on the solubility and stability of each of the solutes
`prment with regard to the solvent or solvent sys-
`tem employed Combinations of medicinal or
`pharrrraceulic agenls that will result in Chcrnical or
`physical interactions attesting the therapeutic qual-
`ityorphannaceulicstahilityofthe product mustbe
`avoided.
`For 5'ingle—solute solutions and especially for
`multiple-solute solutions, the pharmacist must be
`aware of the solubility characteristics of the solutes
`and the features of the common pharrnaceufical
`solverus. Each chemical agent has its own solubil-
`ity in a given solvent. For marry medicinal agents-,.
`their solubilities in the usual solvents are stated in
`the USP aswellas in elite: referencebool-ts.
`
`"Solubility
`Attractive forcesbetween ahornsleadtothe for-
`mation of molecules and ions. The lntenr1ol'ecula.t
`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 drug substances, form molecularsolids.
`Wher1mo1eculesinteract,attractiveforoesa.rv.'lre-
`pulsive£orcesareinefl‘ect.The attract-Iveforcescause
`the molecules to cc-here, whereas the repulsive
`
`Astraleneca Ex. 2096 p. 6
`
`

`
`198
`
`Solutions
`
`fioroes pretrent molecular mterpenetration and. de-
`struction. When the attractive and repulsive forces
`areequaL the potential energyhetweentwooto1e—
`culesisminimumandthesystemismoststable.
`Dipolar molecules firequently tend to- aligra
`themselves 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 weal: at-
`tractions known as dipole-dipole or van do" Waals
`foroesln addition. to the dipolarintecaclions. other
`attntctions OCCI.1J.'bEtW'¢E1'l polar and nonpolar mol-
`ecules and ions. The include ion-dipole forces-
`and hydrogen bonding. The latter is of particular
`interest. Because of small size and large electrosta-
`ticfield. the hydrogen atom canrnovein closetoan
`electronegative atom. forming an electrostafic type
`of association referred to as a hydrogen bond or hy-
`drasen bridge Hydrogen bonding involves strand!
`electronegative atoms as cmygven, nitrogen. andflu-
`orine. Such a bond exists in water, represented by
`the dotted lines:
`
`pagan‘
`H/0¥\l-Iwflafl/oxfl
`
`Hydrogen bonds also most between some alcohol
`molecules, esters. carboxylic acids, aldehydes, and
`polypeptides.
`When asolute dissolves, the substance’s inter-
`molecular forces of aflzraction must be overcome by
`forces of attraction between the solute and solvent
`
`molecules.'I‘hts involves breaking the 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 beprepared with that agent and that
`‘solvent. When a solvent, at -it given temperature,
`hasdissolvedallof the solute it can, itis saidtobe
`saturated. To emphasize the pos_s1'ble variation in
`solubility between two chemical agents and there-
`forein the amounts ofeach required to prepare a
`saturated solution. two oficial aqueous. saturated
`solutions are cited as examples. Calcium Hydroxide
`'E)pical Solution, USP, and Potassium Iodide Oral
`Solution. USP. The first solution. prepared by agi-
`
`tating an excess arnounr of calcium hydroxide with
`purified water. contains only about 140 mg of dis-
`solved solute per 1.0!} 1:111. of sol1_.:tio_n.at 25°C,
`whereas the latter solution contains about 100 g of
`solute per 100 ml. ofsolution, over 700 t‘nnes.as
`much solute as
`in the calcium hydroxide
`topical solution. it is apparent from this compari-
`son that the rnaximurn possible concentration to
`which a phamlaciat may prepare a solution varies
`greatly and is dependent. in part. on the chemical
`constitution of the solute. Through selection. of a
`diffiexent solubilizing agent or a difierent chemical
`salt EDEEI1 of the medicinal agent, alteration of the
`pH ofa solution, or substitution. in part or in whole,
`ofthesolvent, apharmadstceninceflain instances
`dissolve g-eater-q1.1sntities of a solute than would
`otherwise be possible. For example, iodine gran-
`ules are soluble in water only to the extent of ‘I g
`In about 3000 ml. of water. Using only these
`two agents. the maximum concentration possible
`would be approximately D.tJ3% of iodine in aque-
`oussolution.l-lowever. tl1tt}ugh'the use ofan aque-
`ous solution of potassium or sodium iodide as the
`solvent, much larger amounts otiodirte may be dis—
`solved as the result of the formation of a water-
`
`soluble complex with the iodide salt.Tbis reaction
`is taken advantage of, for example, in Iodine Topi-
`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 ofa drugand inpreparing its so—
`lution. Most chemicals absorb hear when they are
`dissohtedand are said to have apositfce heal‘ ofs'o-
`lsrtifltl. resulting in increased solubility with an in-
`crease in tem:perature.A few chemlcalshave snag»
`eons hear of solution and exhibit -a decrease in
`solubility with a rise In lierrlperstute. Other factors,
`in addition to ternperattire, a.EEec1_: sol_ubillty.'I'hese
`include the various chemical and other physical
`properties ofboth the solute and the solvent, fic-
`tors of pressure, the acidity“ or basicity-of the solu-
`tion, the state ofsubdivlsion of the solute, and the
`physical agitation applied to the solution during
`the dissolving process. The solubility of a pure
`chemical substance at 3 given temperature and
`pressure is oorlstalllii however, its rate qf solution,
`thatis. the speedatwhichit dissolves, depenclson
`thepatticleslze ofttresubetanceandtheextentof
`agitation.'I'l1e finer the powder. the greater the sur-
`face area that comes in contact with the solvent-,.
`andthe more rapidthedissolvingprocess.Also, the
`greater die sgitatiora, the more unsaturated solvent
`passes over the drug, and the faster the formation
`of the solution.
`
`Astraleneca Ex. 2096 p. '7
`
`

`
`Tltesolubilityofasubstanoeinaglvensolvertt
`may be deterrnined by preparing a saturated solu-
`tion ofitet aspecific temperature andcletermining
`bychetnical analysis the
`oichcmical dis-
`solved in a given weight of solution. By simple cal-
`culation, the amount of solvent requiredto dissolve
`the amount of solute can be determined. The solu-
`bility may then be expressed as grams ofsolule disr
`solvingin roilliliters ofsolvent—t'or examplefl got
`sodium chloride dissolves in 2.8 ml. of water.‘
`When theexactsohibilityhssnot been determined,
`general expressions of relative solubility may be
`LL-sed."Ihese terms are defined fir the USP as pre-
`sented inTahIe 12.1 (2).
`Agreatmanyofthe important orgsnicmeclicinal
`agents are either weak acids or weak bases, and
`their solubility is-dependent to a large measure on
`thepH of fire solve'nt.'i'l-iese drugs react either 'Wlfh
`strong acids -or strong bases to form water-soluble
`salts. For instance, Ehe weak bases, includingmany
`of the alkaloids (atropine, codeine, rand niotphine),
`antihistamines (dnahenyhydrarnine and tu‘pelen-
`namlne], local anesthetics (cocaine, procaine, and
`tetracaine), and otherirnportanl drugs are not very
`water-soluble, but they are soluble in dilute solu-
`tions oi
`manufacturers have
`prepared manyacidsalts ofthese organic 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
`addition of alkali, the free base may separate from
`solufion unless it has adequate solubilltyin water.
`Organic tnedicinals that are weak acids
`the
`barbiturate drugs (as phenobarbital and pentobar-
`bital) and the sulfonarnides (as sulfadiazine and
`sulfacetan1ide).These and other weak acids form
`waler—soluble salts in basic solution and maysepa-
`rate from solution by a lowering of the pH. ‘Fable
`1512 presents the comparative solubilities of sortie
`typical examples ofweak adds and weakhascs and
`their salts.
`
`Table 12.1. Relative Terms of Solubility {II
`
`Drsoiptivciirnn
`Very soluble
`Freely soluble
`Soluble
`Spatingiy -soluble
`Slightlysoluble
`Very slightly soluble
`Practically insoluble
`or tnsoluhle
`
`Parts ofsofimrl Rsqzurcd
`for1Htr£o[Sahrte
`Less than 1
`From 1 to 10
`From in to as
`From 30 to 100
`From 1.00 to 1000
`Fmm 100010 1o,mc
`10.000 and over
`
`'SalufimS
`
`199
`
`Table 122. Water a.nd'Aloohol Snlnhilities of Some
`Selected Weak Acids, Weak lilies, and Their Salts
`
`Number q,FmL of'SalDent
`Request to Dissalw
`I so‘We
`Alcohol
`
`Water
`
`455
`0.5
`120
`an
`2.5
`5,000
`16
`1,000
`1
`200
`1
`13.000
`2
`
`2'
`5
`2
`1,280
`325
`2-10
`5
`
`B
`10
`soluble
`15
`sparingly soluble
`slightly soluble
`
`Drug
`
`Atropine
`Atropine sulfate
`Codeine
`-Codeine sullate
`Codeine phosphate
`Morphine
`Morphine sulfate
`P1-renobarbital
`Phenobarbital sodium
`Ptocaine
`Procaine hydrochloride
`Sulladiaxlrur
`Sodium-sulfadiazinc
`
`Although there are no exact rules" for predicting
`unerringlythesolubilltyofa chemical agent ins
`particular
`liquid, experienced pharmaceutical
`chemists can estimate the general solubility ofa
`chemical compound based on its molecular struc-
`ture and functional groups.The infiormation 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 individual member of a group of compounds,
`the generalizations nonetheless serve a useful
`function.Asclen1onstratedbythedata in'Ii«1ble 12.2
`and other similar data, salts of organic compounds
`are more soluble in water than are the correspond-
`ingorganic bases. Conversely, the organicbases are
`more soluble in organic solvents,
`than are the corresponding salt forms. Perhaps the
`most written guideline for the prediction ofso1u-
`bilityis I:hal"l:1ce dissolves lil:e,"meam‘n glhat-a sol-
`vent having a chemical mucture most similar In
`tl1atof.tl"(e irlmrlded solutewillbc most likely to
`dissolve it.Thus, organic compounds are more sol-
`ublein organirzsolvcnts thaninwater. Organic
`compounds may, however.‘ be somewhat water-
`soluble if they contain polar groups capable of
`fanning hydrogen bonds with wate1_'.l.n fact. the
`greater the number of polar groups present. the
`greater will likely be the organic compound’: solu-
`bility in water. Polar groups include 0H. CH0,
`COH» CHOH. Cl-I3CIH, C001-I, N01, C0, NH,’
`and S031-I.'l'hc introduction ofhalogen atoms into
`
`Astraleneca Ex. 2096 p. 8
`
`

`
`3011
`
`Solutions
`
`a molecule tends to decrease wster—solubil:lty be-
`cause of an increase in the molecular weight of the
`compotuicl without aproportionate increase. in po-
`1arity.Aninctc-sse inthc 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 rnonovalent 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 hydrozdcle anions. ‘R:
`be sure. there are certain corubinnfions of anion
`and cation that would seem to be similar in make-
`
`up but that do nothave similar solubility character-
`istics. For instance, magnesiumsulfate (Epsomsalt)
`is soluble, but calcium sulfate is only slightly solu-
`ble; barium sulfite isveryinsoluble (1 gdissolves in
`about 400,000 mi. 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
`notasinsoluble,andtheirora1usecanresu1tmpoi-
`sorting; mercurous chloride Cl-_IgCl} is insoluble and
`mass Eonnerly used as a cathartic, but mercuric chlo-
`ride (HgCL_,) is solublein waterandisa deadly/poi-
`son if taken lntema1l'y.'l'11ere are many instances in
`which solubilities of certain drugs and their differ-
`entlstioniromotlzietdnlgs are criticalto tl.'lE‘pl’liIl‘-
`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 at Demonstration of
`Chemical Structure-Solubility Relationship
`
`Compound
`Benzene
`Benzoic acid
`Benzyl alcohol
`Phenol
`P-.vr°'=Ab=c'h°|
`Flwsallul
`Carbon tetrachloride
`Chloroform
`Methylene chloride
`
`Formzda
`QH.
`C5!-_l,CCl0H
`C,H,CH3OH
`C,.}-I501-I
`CeH4(01'D2
`CsHz(°H3a
`CCI,
`CHCI5
`Cl-I301
`
`Number ofmi.
`oflvflrtcr
`Required to
`Dissolve 1 gof
`Compound
`1430
`2?5
`25
`15
`33
`17
`2,000
`200
`50
`
`For organic as well as for inorgarnic 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 ll'.10_11:I3 themselves to resist the -solvent
`action. During the dissolution process, the mole-
`cules of the solvent and the solute become
`
`uniformly mixed 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 geneusl rules
`of solubility useful.
`
`Inorgrmic Molecules
`1. lfboll:thecationartdanionofanionicoom-
`pound are momoalsnt, the solute-solute attrac-
`tive form are usually easily overcome, and
`therefore, these oompounds are generally water
`soluble. (Examples, Nacl, Liar, 1:1, memo,
`NaNO,)
`2. IEonlyoneofthetwoio'nsinanionicoom-
`pound is
`the solute-solute interac-
`tions are also usually easily overcome and the
`compounds -are water soluble.
`(Examples:
`Ba‘-‘la: M812: N92504: NasP04J
`3. Ifboth the cationand anionare multiuclenr, the
`solttte—solui:e interaction maybe too great to be-
`overcome by the solute-solvent interaction
`and the compound may have poor water solu-
`bility. (Examples: CaSO‘, BaSCl,,, BiP0,; Ex-
`ceptions: ZnSO.,, F950,)
`4. Comrnonsalts ofalkalimetals (Na,K,I..i, Cs,
`Rb) are usually water soluble.
`(Exception:
`I-ECO.-J
`S. Ammonium and quaternary ammortium salts
`are water soluble.
`l‘\l‘tl:rates, nitrites, acetates, chlorates, and tan-
`tates are generally water soluble. (Exceptions:
`silver and mercurous acetate)
`7. Sulhtes, gulfites, and thlosulfates are generally
`water soluble. (Exceptions: calcimn and bar-
`ium salts)
`8. Chloridtrs, bromides, and iodidm are water
`soluble. (finceptionszz salts of silver and mer-
`curousions)
`9. Acid salts corresponding to an insoluble salt
`will be more water soluble than the original
`salt.
`
`I5.
`
`10. I-lydroxidea and oxides of compounds other
`llzart alkali metal cations and the antmonium
`
`generally water insoluble.
`
`Astraleneca Ex. 2096 p. 9
`
`

`
`Solutions
`
`301
`
`11. Sulfides are water insoluble except for their
`alkali metal salts.
`
`12.
`
`carbonates, silicates, isolates, and
`hypochlofites are water insoluble except for
`their alkali metal salts and amrnortium salts.
`
`Some Solvents For
`
`Liquid Preparations
`
`Thefollowing agents linclusesssolventsin the
`preparation of solutlorrs.
`
`Organs‘: Molecules
`
`‘.l. Molecules having one pole: functional group
`are usually soluble to total chainlengths of Eve
`carbons.
`'
`2. Molecules having branched chains are more
`soluble than the corresponding straight-chain
`compound.
`3. Meter solubility decreases wiflr an increase in
`molecular weight.
`4. Increased structural sirnilarity between solute
`and solvent is aoootnpsnied by increased solu-
`bility.
`
`It is the pharmocisfs lrnowledge of the chemical
`characteristics ofdrugs that permits the selection of
`the proper solvent Eoraparticularsolutel-lowevet.
`in addition to the factors of solulbility. the selection
`is based on such additional solvent characteristics
`
`as clarity, low tO'.\ClCl'l.'fi viscosity. cornpalibility with
`other fotmulafive ingredients. chemical inertness.
`palatability. odor. color, and economy. In most in»
`stances, and especially for solutions to be taken
`orally, used ophthalmically, or injected, wateris the
`preferred solvent because it comes closer to meet-
`ing the ntajority of the above criteria than the other
`available solvents. In many instances, when water
`is used as the primary solvent, an aurdliary 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 pharmaceutical solutions
`and in maintaining their stability.
`Other solvents, such as acetone. ethyl or-tide, and
`isopropyl alcohol. are too tordc to be permitted" in
`phannaceutical preparations to be taken intanally.
`buttheyareusefulasreagerusolvenlsinorganlc
`cherrristry anclin the preparatorysiages of drug de-
`velopment, asin the exlracfionorrernoval ofactive
`-oorestinlents from medicinal plants. For purposes
`such asthis. certatnaolvents are officiallyrecognlzed
`lnthecompendla.Anurnbero£fixedoils,sI.tchas
`oomoil, oottorrseedofl, peanutoil, andsesatne-oil,
`serve useful solvent functions particularly in the
`preparation of oleaginous injections -and are recog-
`nlmedin the offidalcompendla Eorthis purpose.
`
`Alcohol. IISP (Ethyl Alcohol,
`Ethanol, C,H50H)
`Next to water alcohol is the most useful solvent
`inpharrr1acy.ItisusedassprimarysolventEo1'
`many" organic compounds. Together with water it
`forms a ltydroalooholic mixttrre that dissolves both
`alcohol-soluble and water-soluble substances, a
`feature pecially useful in the extraction of active
`constituents from crude drugs. Byvarying the pro-
`portion of the two agents, the active constituents
`may be selectively dissolved and attracted or al-
`lowed to remain behind according to their particu-
`lar solubility characteristics in the menslruum. Al-
`-cohol. USE is 94.9 to 96.0% C21-I501-I by volume
`(i.e.. vhr) when deliermined at l5.56“C_, the U.S.
`Government's standard temperature fior alcohol
`detenninatlons. Dehydrated Alcohol. USE contains
`not less than 99.5% CAI-l50H byvohtme and is uti-
`lizedininstancesinwhichan essentially water-free
`alcohol is desired.
`
`Alcohol has been well recognized as a solvent
`and encipient in the formulation of oral phonon-
`ceutical 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 roam?
`waier—insolubIe ingredients, including drug sub-
`stanoes,i1avorants,eud antimicrobial preservatives.
`Alcohol Is frequently used with other solvents, as
`glycol: and glycerin. to reduce the amount of alco-
`hol required. It also isusedin liquid products as an
`antimicrobial preservative alone one a copreserv-
`arise with paflbens, benzaoatest sorbatm, and other
`agents.
`However, aside from its pharmaceutic advan-
`tages as a solvent and preservative, concern has
`been expressed over the undesired phannaeologic
`andpotentlal toxic effects ofalooholwheningested
`in phannaceutical 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 warnings in the labeling. For OTC oral prod-
`ucts intended for children under 6 years of age. the
`recommended alcohol-content limit is 0.5%; fior
`products intended for children 6 to 12 years of age,
`the recommended l‘uru‘t is 5%; and for products
`
`Astraleneca Ex. 2096 p. 10
`
`

`
`392.
`
`Soiutiolts
`
`Ireuommendedfornhildxen over123/ears ofsgesnd
`for acl1.Il1s,'the recommended limit is 10%-
`
`Diluted Alcohol, NP
`
`Diluted .Alcol'1ol.NF, is prepared by'I:cu'xir\g equal
`volumes of Alcohol. USB and Purified VVatel'. USE‘.
`The finalvohinte cci-suchrnixturesisnotthesurn of
`the individual irolumesof the two components, but
`duenooontraction oitheliquirkupon mixir|g,tl-1e fi«
`nalvolumeis gerrerullyab0'ut39b1essthanw'hut
`would normally be expected. Thus when 50 mt. oi
`each component "is combined, the resulting product
`measures approximately 97 mi... It is for this reason
`that the strength of Diluted Alcohol, NE is not ex-
`actlyhalfthat ofthe more concentrated alcohol, but
`slightly greater: 1PP“3'X5n'|ateI}' 4996. Diluted alcohol
`is a useful ltyllroalcoholic solvent in various phar-
`maceutical processes and preparations.
`
`Aicatwl, Rubbing
`
`Rublririgiklcohol contains about 70% ofethyl el-
`coho! by volume, the remainder consisting ofwu—
`ter, denaturantswith orwitiiout 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 denatonium benzoate, bitter
`substances that discourage accidental or abusive
`oral ingestion. The dsnahirants employed in rub-
`bing alcohol are according to the Internal Revenue
`Service, US». Treasure Department, Formula 23-I-I,
`which iscomposed of 8 parts byvotume of acetone,
`1.5 parts byvolurne of:nethy1isobutyllr.etone,sr|_d
`100 parts byvolume of ethyl alcoholfllie use otthis
`denaturant mixture makes the separation of ethyl
`alcohol from -the denahirants avirtually itnpossible
`task with ordinary distillation apparatus. This dis-
`courages the illegal removal and use as a beverage
`of the alcoholic content of rubbing alcohol.
`The productisvolatile and flammable and should
`be stored in tight oontairrers nemote from Ere. It is
`employeclas anibefacient extemsilyand asa sooth-
`ing mb for bedfidden-patiems, agennicide tor in-
`struments. andaslcin cleanserptiortoinjection. Iris
`3150135211 asavehiclefortopicalpreparafions.
`Synonym: Alcohol Rubbing Compound-
`
`GI-year-in, IISP {GIyceraI):
`CH3.OH- CHOH' C'H2_OH
`
`Glycerin is it clear syrupy liquid with a sweet
`taste, It is miscflzlle both with waterand alcohol. As
`a sohrent, it is comparable with alcohol, but because
`
`of ilsvisoosity, solutesare slowtysotuble initunless»
`it is tenderer! lm viscous hyheefing. Glycerin has‘;
`preservative qualifies and is often used as a stabs.
`lizerandas an auxiliary solventin conjunction with.
`watetora1oohDLItisusedinmanyintemal prepay:
`rations.
`
`Isapropyl R-ulJbingAlcoiro!
`
`lsopropyl Rubbingfilccd-tol is about 70% by-val.
`urns isopropyl-alcohol. the remainder consisting of
`water with or without color additives. stabilizers,
`and perfurne oils. It is used'e>'ctemel1y as a rubetas
`dart and sootl1i.ng.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
`fiorhypodennic injections of
`
`1nsuJ1n'' and to: disinfecting the skin.
`
`Propylene Glycol, USP,
`ch,cH(0rDcH,oH
`
`Propylene glycol, a viscous liquid, is miscible
`with water and aloo11oI.1t is a useful solvent with a
`
`wide range ofapplications and is frequently substi-
`tuted for glycerin in modern pharmaceutical for-
`mulations.
`
`Purified Water, use, H20
`
`Naturallyoucuningwaterexertsitssolvent ei3FEC‘l’
`on most substances it contacts and thus is-impure
`and contains varying amounts of dissolved inor-
`prlic salts, usually sodium. potassium, calcium,
`magnesium, and iron, chlorides, sulfates, and bi-
`carbonates, as well as dissolved and undisrolved
`organic matter and microorganisms. Water found
`inmost cities andtowns where water is-purified for
`diinltingpiri-poses usually contains less than 0.1%
`oftotal solids, delnennined by evaporatinga 100 mL
`ample of water to dryness and weighing the
`residue {which would weigh less than 100' mg).
`Drinking water must meet the United States Pub-
`lic Health Service regulations with respect to bac-
`tcrioiogical purity. Acceptable dfinldng water
`should be clear, colorless. odorless, and neutral or
`only slightly acid or alkaline, the deviation from
`ncutral'bei:ttgdueto tlienatureofthedissolved
`solids and gases [carbon dioxide r.onn:ibutingto.the
`eciditysnd arrrrnonia to the sllrali