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 at a 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 Rehyclration 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
`I-‘laoorant
`Colo:-ant
`Preparation of Syrups
`Solution with the Aid oft-teat
`Solution by Agitation zoitlront the Ala‘ of
`Heat
`
`Addition of Sucrose to a Medicated Liquid or
`to a Flavor-ea‘ Liquid
`Percolation
`Elixirs
`
`Preparation of Elixirs
`Norunedicated Elixirs
`Medicated Elixirs
`Arztlhistarnine Elixirs
`
`Barlriturate Sedatioe/Hypnotic Elixirs
`Phenobarbital Elixir
`
`Digoxin Elixir
`Tinctures
`
`295
`
`Proper Administration and Use of Liquid
`Perot-al Dosage Forms
`Topical Solutions and Tinctures
`Topical Solutions
`Sprays
`Alumirturn Acetate Topical Solution
`Aluminum Subacelale Topical
`Solution
`
`Calcium Hydroxide Topical Solution
`Coal Tar Topical Solution
`Hydrogen Peroxide Topical Solution
`Cnlorlrexidine Gluconale Solution
`
`Pooi:ione—loa'ine Topical Solution
`Thirnerosal Topical Solution
`Vaginal and Rectal Solutions
`Vaginal Douche-5
`Retention Enernas
`Evacuation Enernas
`
`Topical Tinctures
`Iodine Tlncture
`
`Compound Benzoin Ttncture
`Thirnerosal Tincture
`
`Special Application Solutions
`Nasal Preparations
`Nasal Decongestant Solutions
`lnlzalation Solutions
`
`Examples of Medicated inhalation
`Solutions
`Inltalants
`
`Arnyl Nitrite lnltalonl
`Propylhexedrine lnltalant
`Proper Administration and llse of Nasal
`Drops and Sprays
`Nasal Routefor Systemic Effects
`Otic Solutions
`
`Cerumert-Removing Solutions
`Antz‘—infectloe, Anti-inflammatory, and
`Analgesic Ear Preparations
`
`AstraZeneca Ex. 2096 p. 5
`
`

`
`Solutions
`
`29'?’
`
`Propcraidminislration and use qf Dtic
`D"P5
`Topical Oral (Dental) Solutions.
`Miscellaneous Solutions
`Aromatic We lets
`Diluted Acids
`irits
`
`onaqueous “Solutions
`
`Lmime’'
`nts
`Collodions
`Collodion
`
`Flexible Colladfon
`
`_ Salicylic Acid Coiiadion
`Extraction Methods for Preparing
`Solutions
`Methods of Extraction
`Maceratiort
`Percolation
`
`Example Preparations Prepared by
`Extraction Processes-
`Fluidextracta
`Extracts
`
`IN rI~orstcot:H1=.~ocAL tem1s,solul:io11s maybe pre-
`pared from any combination of solid, liquid. and
`gas, the three states of matter. For example, a solid
`solute may be dissolved in either another solid, at
`liquid, oragas, aridtvifltthesamebeiltgmie fora
`liquid solute and for a gas. nine types of homoge-
`neous mixtures arepossilaleln pharmac}-,howeve1;
`interest insolutions is for the most part
`to
`_prepa.ral:ions of a solid, a. liquid. and less Itequently
`a gas solute dissolved in a liquid solvent.
`In pharmaceutical henna. solutions are "liquid
`preparations that contain one or more chemical
`substances dissolved in a suitable solvent or tl."I:l.'lt-
`tute of mutually miscible solvents” (11. Because of a
`particular pharmaceutical solutiorfs use, it may be
`clessitied as an and solution. otic solution. ophthaipu'c
`solution, or topical solution. Still O‘tl1ersolutions,l:e-
`causa of their composition oruse. maybeclassified
`as other phamaceutical dosage forms For oom-
`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
`mi:-itsifthesotventis alcol-nolicot orantalicwafetsif
`the solvent is aqueous. Solutions prepared by cat-
`tracting active constituents from crude drugs are.
`ternned.
`orflttfd extracts dependingon their
`method of preparation and their concentration.
`Iinctum may also be solutions of chemical sub-
`stances dissolved in alcohol orin a ltydroalcoholic
`so'1vent.Certainsolnlions preptuedtobesteriieand
`pytogan-fiee and intended for parenteral .adminis-
`tration are classified as injections. Although other
`ezatarnples could be- cited, it is apparent that asolu-
`tion, as a distinct type of pharmaceutical p'oepa.'ta-
`tion, is rtmch further defined than is the physico~
`chemical definition of the term solution.
`Oral solutions. syrups, 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 effects-.'.[‘he fact that they ate adrninistetad
`in solution form usually means that their absorp-
`tion from the gastrointestirtal tract into the sys-
`temic circulation maybe expected to occur more
`rapidly-than fiom-suspension or solid dosage forms
`of the same rrioiiicinal agent.
`Solutes other than the medicinal agent are usu-
`ally present in orally
`solutions.T_hese
`azdditional agents usually are included to provide
`color, flavor, sweetness, or stability to the solution.
`In formulating -or compounding a phartnaceulical
`solution, the phannadst must utilize ‘l.t1.§CI1'l'.I'lafiDrl
`on the solubility and stability of each of the solutes
`pment with regard to the solvent or solvent sys-
`tem employed. Combinations of medicinal or
`pharmaceutic agents that will result in Chomical or
`physical interactions affecting the therapeutic qual-
`ityorphannaceuticstalztilityofthe product muatbe
`avoided.
`For single-solute solutions and especially for
`multiple-solute solutions, the pharmacist must be
`aware of the solubility
`of the solutes
`and the features of the common pharrnaccufical
`solvents. Each chemical agent has its own so1ubil~
`ity in a given solvent. For many medicinal agents,
`theirsolubilities in the usual solvents are stated in
`the USP aswellas in other reference books.
`
`‘Solubility
`Attractive forces between atoms Ieadto the for-
`mation of molecules and ions. The intennol'ecui|ar
`forces, which are developed between like mole—
`cules, are responsible for the pl-grsical state (Le-.,
`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.
`When molecules interact, attractive foroes and re-
`pulstveton:esareine.tlect.?l'he attract-iveforcescause
`the molecules to cohere, whereas the repulsive
`
`Astra.Zeneca Ex. 2096 p. 6
`
`

`
`198
`
`Solmforrs
`
`£0105 prevent molecular mretpenetz-stion and de-
`struction. When Ihe attractive and repulshre forces
`areequal, the potential energybetweentwo1:nole—
`culesisminimumandthesystemismoststable.
`Dipolar molecules frequently tend to align
`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~
`lractions known as dipole-dipole or van do" Waals
`foroesln addition to the dipolarinteraclions. other
`attractions occur].-retween 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 andlarge electrosta-
`ticfield. the hydrogen atomcarunoveirl closetoan
`electronegative atom. forming an clectrostafic type
`of association referred to as a hydrogen bond or hy-
`drogen bridge Hydrogen bonding involves“ strongly
`electronegatlve atoms as oxygen. nitrogen. andflu—
`orine. Such a bond exists in water, represented by
`the dotted lines:
`
`__
`H..:°~,,_
`'-/(Kl
`
`Hydrogen bonds also moist between some alcohol
`molecules, esters, carboxylic 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.Thisinvo1ues breakirlg the solute-solute
`forces and the solvent-solvent forces to achieve the
`solute-solvent attractlort
`
`The solubility of an agent in a particular -solvent
`indicates the mdrinnnn ooncenlrtltion to which a
`solution may be prepared with that agent and that
`solvent. When a solvent, at it given tempetahjre,
`hasdissolvedall oflhe solute it can, itis said tube
`saturated. To emphasize the possible variation in
`solubility between two chemical agents and titers-
`fore in the amounts of each required to prepare a
`saturated solution. two oficial aqueous. saturated
`solutions are cited as examples, Calcium Hydroxide-
`Topical Solutictn, USP, and Fotassium Iodide Oral
`Soluiiort. USF‘. The first solutiotr. prepared l:'y.agi-
`
`tadngan excess amount of calcium hydroxide with
`purified water, contains only about 140 mg of dis-
`solved solute per 100 ml. of sol1_.1l:i.o_n at 25°C,
`whereas the latter solution contains about 100 g of
`solute per 100 ml. of solution, over 700 l:'m1es.as
`much solute as
`in the calcium hyrlroadde
`topical solution. It is apparent Erom this compari-
`son that the rnaximurn possible concentration to
`which a phamiacist niayprepare a solution varies
`greatly and is dependent in par.t,.oIr1 the chemical
`consfitufion of the solute. Through selection of a
`diffiexenl solubilizing agent or a difierent chemical
`salt form of the medicinal agent, alteration of H::.e
`pH ofa solution, or substitution, in part or in whole,
`of the solvent, a ph_armac'ist csninccrtain instances
`dissolve 9-eater -quantities of a solute than would
`otherwise be possible. For example, iodine gren-
`ules are soluble in water only to the extent ofl g
`in about 3000 mL of water. Using only these
`two agents. the maximum concentration possible
`would be approxirnately D.03% of iodine in aque-
`ousaolution.However. through the use otan aque-
`ous solution of potassium or sodium iodide as the
`solvent. much larger amounts ofiodirte may be dis-
`solved as the result of the formation of-a water-
`
`soluble complex with the iodide salt.'1'hi.s reaction
`is taken .acl:I-outage of, for example, in Iodine Topi-
`cal Solution, USP, prepared to contain about 2% of
`iodine and 2.4% ofsodium iodide.
`
`Temperature is an imponant factor’ in cIetem'Ii’n-
`ing the solubilityofa drugand inpreparingits so—
`lution. Most chemicals absorb hear when they are
`dissolvedand-aresaid to have apositfoe heat ofa'o-
`lsrtiou, resulting in increased solubility with an in-
`crease in temperanu-e.A few chemlcals have a stage
`arise hem‘ of solution and exhibit -a decrease in
`solubility with a rise in temperature. Other factors,
`in addition to
`effect solubility. These
`include the vmious chemical and other physical
`properties ofboth the solute and the solvent, fic-
`tors of pressure, the acidity or bmicity-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 mic qfsolution,
`thatis. the speedatwhichit dissolves, depends on
`thcparticlesize ofthesubstanceandthe extlentof
`agitation.'I'he finer the powder. the greater the sur-
`face area that comes in contact with the solvent,
`and the more rapid-the dissohlingprocessllklso. the
`greater die agltatiort. the more unsaturated solvent
`passes over the drug, and the faster the formation
`of the solution.
`
`AstraZeneca Ex. 2096 p. '7
`
`

`
`solvent-
`The solubility of a. 5u|::sI:a11oe in a
`may be determined by preparing a saturated solu-
`tion of itat a specific temperature and determining
`by chemical analysis the amount of chemical dis-
`solved in a given weight of solution. By simple cal-
`culation, the amount of solvent required to dissolve
`the amount of solute can be determined.The solu-
`bility may then be expressed as gains ofsolute disr
`soivingin milliliters ofsolvent—for examplefl g-of
`sodium chloride dissolves in 2.8 ml. of water.’
`When theexaetsohibilityhasnot been determined,
`general expressions of relative solubility may be
`1.I.sed."Ihese terms. are defined in the USP as pre-
`sented inTabIe 12.1 [2]-
`Agreatmanyoftlie important orgsnicmedicirnal
`agents are either weak acids or weal: bases, and
`their solubilityis dependent to a large measure on
`thepl-I oftl1eao1vant.Ti-iese drugs react either with
`strong acids -or strong bases to form water-soluble
`salts. For instance, Ehe weak bases, includingmany
`of the alkaloids (atropine, codeine, and niorphine),
`arttlhistarrtines (dm e and tn‘pelen-
`namlne), local anesthetics (cocaine, procaine, and
`tetracaine), and otlreritrtportant drugs are not very
`weter-soluble, but they are soluble in dilute solu-
`tions of acids.
`manufacturers have
`prepared many acid salts of these 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 ofalkali, the free base may separate from
`solution unless it has adequate solubilityin water,
`Organic medicinals that are weak acids include the
`barbimtate drugs (as phenobarbital and pentobar-
`bitali and the sulfonainides (as sultadiazine and
`sulfacetemide). These and other weak acids form
`water-soluble sales in basic solution and maysepa-
`rate from solution by a lowering of the pH. Table
`1522 presents the colnparative solubilities of sortie
`typical examples-oiweak acids and weakbases and
`their salts.
`
`Table 12.1. Relative Terms of Solubility {II
`
`Elesoiplhzlenn
`
`Very soluble
`Freeiy soluble
`Soluble
`Sparlngly -soluble
`Slightlysoluble
`Very slightly soluble
`Practically insoluble
`or insoluble
`
`Parts ofsoforlrl Reqnked
`for 1 Part ofsolute
`
`Less than 1
`Front 1 to m
`From ‘it! to 30
`From 30 to 100
`From1.00to1OOI1
`From into to 1o,mo
`10,000 and over
`
`Solutions
`
`199
`
`Table 122. Water and!)-leohol Solulailit-ies of Home
`Selected Weak Acids, Weak Eases, and ‘Their Salts
`
`Number ofml. ofsalolrnt
`Rovuttrad to Dissalw
`1 so‘ the
`Alcohol
`
`Witter
`
`455
`0.5
`120
`an
`2.5
`5,000
`16
`1,000
`:1
`200
`1
`13.000
`2
`
`2
`5
`2
`1,280
`325
`210
`5:55
`B‘
`1D
`soluble
`15
`sparingly soluble
`slightly soluble
`
`Drug
`
`Atropine
`Atropine sulfate
`Codeine
`-Codeine sullate
`Codeine phosphate
`Morphine
`Morphine sulfate
`Phenobarbital
`Phenobarbital sodium
`Procaine
`Pi-oczine hydrochlotide
`Sulladiaaine
`Sodium aulfadiaeine
`
`Although there are no exact rules" for predicting
`unerringly the solubility of a chemical 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.Tl1e infiormadon 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.As demonstrated by the data in‘1hb1e 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 bases are
`more soluble in organic solvents.
`than are the corresponding salt forms. Perhaps the
`most written guideline for the prediction of solu-
`bilityis l:l:1at”like dissolves lll':E,"mEal‘lfl'1g that a sol-
`ttenthfivingachemlcalstruchiremostsimilarto
`tliatofthe intended solutewillbe most likely to
`dissolve it.Thus, organic compounds are more sol-
`uble in organic solvents than in water. Organic
`compounds may, however.‘ be somewhat water-
`Suluble if they contain polar groups capable of
`loaning hydrogen bonds with water. In fact. the
`greater the number of polar groups present. the
`greater will likely be the organic compounds solu-
`bility in water. Polar groups include 0H. CH0.
`COPL CHOH4 ('_‘H3OH.- C001-I, NO, C0, NH,‘
`and S051-l.'I'he introduction of halogen atoms into
`
`Astraleneca Ex. 2096 p. 8
`
`

`
`3011
`
`Solutions
`
`a molecule tends to decrease water-solubil:lty be
`cause of an increase in the molecular weight of the
`cornpouncl without a proportionate increase in po-
`larity.Anincnease inthe 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 sodiulzn, 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 hydrozdde
`‘lb
`be sure. there are certain combinations of anion
`arid cation that would seem to be similar in make-
`
`up but that do not have similar solubility character-
`istics. For instance, magnesiumsulfate (EPSDtl'l salt)
`is soluble, but calcium sulfate is only slightly solu-
`ble; barium sulhte isveryinsolubie (1 gdiesolves 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
`notasinsoluble, and theirora1usecanresultinpoi-
`sorting; rnercurous chloride Cl-_IgCl) is insoluble and
`was founerly used as a cathartic, but mercuric chlo-
`ride (HgCL_,) is soluble in waterandisa deadlypoi—
`son if taken lute-mall'y.‘1‘here are many instances in
`which solubilitias 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. Solubillties of Selected Organic
`Compounds in Water as a Demornslralion-of
`Chemical Structure-Solubility Relationship
`
`Compound
`Benzene
`Beuzoic acid
`Benzyl alcohol
`Phenol
`P-yroeatech ol
`1’rr°s111°1
`Carbon tetrachloride
`Chloroforrn
`Methylene chloride
`
`Formula
`QH.
`Cal-_l,CCIOH
`c,H,cH,o1-I
`Cg}-I503
`C‘!-I, (OI-D,
`C¢Hz(0H3a
`CC),
`CPICI3
`t:H,c1,
`
`Number ofml.
`oflrlrhtrr
`Required to
`Dissolve I gqf
`Compound
`1430
`1?5
`25
`15 _
`2.3
`17
`zooo
`200
`so
`
`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 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 general rules
`of solubility useful.
`
`Inorgrlnic Molecules
`1. lfbotlt the cation and anion ofan ionic oom-
`pound are monooalent, the solutessolute attrac-
`tive foroes are usually easily overcome, and
`therefore, these compounds are generally water
`soluble. (Examples, Nacl, LiBr, 1:1, NH,No,,
`NaNO,)
`2. Ifonlyone ofthetwo ions in an ionicoom-
`pound
`the solute—solute interac-
`tions are also usually easily overcome and the
`compounds -are water soluble.
`(Examples:
`Baal! M31a.Nez50« NaaP04J
`3. Ifboih the cationand anionare multitJeI'ent, the
`solute-solute interaction maybe too great to be-
`overcome by the solute-solvent interaction
`and the compound may have poor water solu-
`bility. (Examples: C2330‘, BaSO,,, BiP0,: Ex-
`ceptions: Z1150‘, Fe-S0,.)
`4. Common salts of alkali-rnetals (Na, K, Li, :2,
`R13) are usually water soluble.
`(Exception:
`“$303)
`5. Ammonium and quaternary ammonium salts
`are water soluble.
`IS. Nitrates. ttltrites, acetates, chlnrates, and lac-
`tates are generally water soluble. (Exceptions:
`silver and Inercurous acetate)
`'1'. Sulfates, sulfates, and thlosulfates are generally
`water soluble. (Exceptions: calcium and bar-
`ium salts)
`8. Cl1lorides,. bromides, and iodida are water
`soluble. (Exceptions: salts of silver and mer-
`curousions)
`9. Acid salts. corresponding to an insoluble alt
`will be more water soluble than the original
`salt.
`
`10. I-Iydroxides and oxides of compounds other
`than alkali metal cations and the arnmoniurn
`
`water insoluble.
`
`Astrazeneca Ex. 2096 p. 9
`
`

`
`Solctiavls
`
`301
`
`11. Sulficles are water insoluble except for their
`alltali metal salts.
`
`12. Phosphates, carbonates, silicates isolates, and
`hypochlodtes are water insoluble except for
`their alkali metal salts and amrnonlum salts.
`
`Some Solvents For
`
`Liquid Preparations
`
`Thefoflowixigagerltsfirtduseassolwzentsin the
`preparation of solutions.
`
`Organs’: Molecules
`
`‘.l. Molecules having one polar functional group
`are usuallysoh1ble.tototalcl1ai11Ie.ngtlzs offive
`carbons.
`'
`
`2. Molecules having branched chains are more
`soluble than the cmresponding Stra1'g;l1t-chain
`compound.
`3. Vi-hear solubility decreases ‘with an increase in
`molecular weight.
`4. Increased structural similarity between solute
`and solvent is accompanied by increased solu-
`bility.
`
`It is the pham-uacist's knowledge of the chemical
`characteristics ofdrugs thatpermits the selection of
`the proper scilvent for a particular solute. However;
`in addition to the factors 0! solubility, the selection
`is based on such additional solvent characteristics
`
`as "clarity, low toxicity, viscosity, compatibility with
`other forntulative ingredients. chemical inertness.
`palatability, odor. color, and economy. In most in-
`stances. and especially for solutions to be taken
`orally, used ophlhalmically, or inieclecl, waleris the
`preierred solvent because it comes closer to meet-
`irtg the majority of the above criteria than the other
`available solvents. in many instances, 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 chernical or
`physical stability. Alcohol, glycerin. and propylene
`glycol, perhaps the most used.
`solvents,
`have been quite eifective in contributing to the de-
`sired characteristics of pharmaceutical solutions
`and in maintaining their stability.
`Otlter solvents, such as acetone. ethyl mode, and
`isopropyl alcohol. are too toidc to be permitted" in
`phannaceutical preparations to be taken inte.-.11al1y,
`btlttheyareusefulasrcagentsolvenlsinotganlc
`cherrllsl-ry and in the preparatory stages of drug cle-
`veloprnent, asin the exliacfionorremoval ofactivle
`-oorstiruents from medicinal plants. For purposes
`such as-this, cenairisolventsareofficlallgrrecognlzed
`irithecoInpe:ndia.AnL:mbero£fixedoils,5uchas
`cornoil, cottonseeclofl, peanut oiJ.,andsese1ne-oil,
`serve usefill solvent functions particularly in the
`preparation of oleaginous injections and are recog-
`nlzedin the officialcompendla Eorthisputpose.
`
`Alcohol. use (Ethyl Alcohol,
`Ethanol, c,H5oH)
`Next to warm; alcohol is the most useful solvent
`inphannacjcltisuseclassprimarysolventfcr
`many" organic con1pounds.'Ibgether with water it
`forms a 1-ryclroalcoholic mixture that dissolves both
`alcohol-soluble and water-soluble substances, a
`feature especially useful in the extraction of active
`corlslituents from crude drugs. Byvarying 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 rncnstruum. Al-
`-cohol. USP. is 9-L9 to 96.0% Czl-1501-I by wailtune
`[leg Viv) when determined at l5.56"'C, the U.S.
`Government’s standard temperature fior alcohol
`detenrninatlons. Dehydrated Alcohol, USE contains
`not less than 99.5% Q1!-l5OH byvolnme and is uti-
`lized in instances in whichan essentially water-free
`alcohol is desired.
`
`Alcohol has been Well recognized as a solvent
`and encipient in the formulation of oral pharma-
`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 mam
`water—insolubIe ingredients, including drug sub-
`stanoes, ilavorants, and antimicrobial preservatives.
`Alcohol Is frequently used with other solvents, as
`glycol: and glycerin, to reduce the amount of alco-
`holrcquired. ltalso isusedin liquid produclsas an
`antiinicrobial preservative alone one a copaeserv-
`some with parabans, benzaoalasp sorbatess, and other
`agents.
`l-iowevaer, aside from its pharmaceutic advan-
`tages as a solvent and preservative, concern has
`been expressed over the undesired phannacologic
`andpotentlal toxic effects of alcohol wheningested
`in phannaceuxical products particularly by child-
`ren.Thus, the FDA has proposed that -
`ers of OTC oral drug products restrict, insofar
`aspossible, the use of alcohol and include appro-
`priate warnings in the labeling. For OTC oral prod-
`ucts intended for cldldren under 6 years of age, the
`recommended alcohol-content limit is 0.5%; liar
`products intended for children 6 to 12 years of age,
`the recommended limit 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:ibut