`

`Editor: Donna Balado
`Managing Editor: jennifer Schmidt
`Marketing Manager: Christine Kushner
`
`Copyright © 1999 Lippincott Wllliams & Wilkins
`
`351 West Camden Street
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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 2097 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 2097 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 2097 p. 4
`
`

`

`DISPERSE SYSTEMS
`
`
`
`Chapter at a Glance
`
`Suspensions
`Reasons for Suspensions
`Features Desired in a. Pharmaceutical
`Suspension
`Physical Foal-ores of the Dispersed Phase of
`a Suspension Dispersion Medium
`Preparation of Suspensions
`Sustained-Release Suspensions
`Extemporaneous Compounding of
`Suspensions
`Packaging and Storage of Suspensions
`Examples of Oral Suspmsiom
`Aniacid Oral Suspensions
`Antibacterial Oral Suspensions
`Examples of Other Suspensions
`Otis Suspensions
`Rectal SuSpensions
`Dry Powders for Oral Suspension
`Emulsions
`Purpose of Emulsions and. of
`Emulsificafion
`Theories of Emulsification
`Preparation of Emulsions
`Emulmfling Agents
`The HLB S stem
`Methods qyfimulsion Preparation
`Continental or Dry Gum Method
`English or Wet Gum Method
`Bottle or Forbes Battle Method
`Auxiliary Methods
`In Situ Soap Method
`Microemulsions
`Stability of Emulsions
`Aggregation and Coalesceme
`Examples of Oral Emulsions
`Mineral Oil Emulsion
`Castor Oil Emulsion
`Simethicone Emulsion
`
`345
`
`Gels and Mag-mas
`Colloidal Dispersions
`Terminology Related to Gels
`Classification and Types of Gels
`Preparation of Magmas and Gels
`Examples of Ceiling Agents
`Gel Formulation Considerations
`Examples of Magrrlas and Gels
`Bentonfle Magma, NF
`Aluminum Hydroxide Gel, USP
`Milk ofMagnesia, LISP
`Starch Glycerile
`Lubricating Jelly Pomula
`Clear Aqueous Gel with Dimhimne
`Poloxamer Gel Base
`Proper Administration and Use of
`Disperse Systems
`Aerosols
`AdVantages of the Aerosol Dosage
`Form
`The Aerosol Principle
`Aerosol Systems
`Two-phase Systems
`Three—phase Systems
`Cammssed Gas Systems
`Aerosol Container and Valve Assembly
`Containers
`Valve Assembly
`Metered Dose Inhalers (MDIS)
`Filling Operations
`Cold Filling
`Pressure Filling
`Testing the Filled Containers
`Packaging, Labeling, and Storage
`Pro
`Administration and Use of
`maceutical Aerosols
`Tapical Aerosols
`Vaginal and Rectal Aerosols
`
`AstraZencca Exhibit 2097 p. 5
`
`

`

`11-55 .CHAPI'ER includes the main types of liquid
`preparations containing undissolved or immiscible
`drug distributed throughout a vehicle. In these
`Preparations, the substance distributed is referred
`to as the dispersed phase and the vehicle is termed
`the dispersing phase or dispersion medium. 'lbgether,
`they produce a dispersed system.
`The particles of the dispersed phase are usually
`solid materials that are insoluble in the
`medium. In the case of emulsions. the dispersed
`phase is a liquid substance which is neither soluble
`no: miscible with the liquid of the dispersing phase.
`The emulsificationprocess resxdtsirr the dispersion of
`liquid drug as fine droplets throughout the dispersing
`phase.l11tlrecase ofan aerosolthedispersedphase
`may be air thatis present as small bubbles throughout
`a solution or an emulsion. Dispersions also consist of
`droplets ofa liquid (solution orsuspension)
`The particles of the dispersecl phase Vary widely
`in sizefrom large particles visible to the naked eye
`down to particles of colloidal dimension, falling be-
`tween 1.0 nm and 0.5 pm in size. Dispersions con-
`touring coarse particles. usually 10—50 urn in siza.
`are referred to as coarse dispersions and include the
`nopensions and emulsions. Dispersions containing
`particles of smaller sine are termed fine dispersions
`(as-10 um). and, lithe particles are in the colloidal
`range. mlloidol dispersions. Mgmas and gels repre—
`sent such fine dispersions.
`Largely because of their greater size. dispersed
`particles in a coarse dispersion hate a greater ten-
`dency to separate tram the dispersion medium than
`do the particles of a fine dispersion. Most solids in
`dispersion tend to settle to the bottom of the con—
`tainer because of their greater density than the dis-
`persion medium, whereas most emulsified liquids
`for oral use are oils and generally have a leSSer den-
`siiythan the aqueous mediuminwhich theyare dis
`persed and tend to rise toward the top of the prepa-
`ration. Complete and uniform redistribution of the
`di5persed phase is essential to the aourrate adminis-
`tration of unifonn doses. For a properly prepared
`dispersion,
`this should be accomplished by the
`moderate agitation of the container.
`The locusofthischapterisondispersionso!
`drugs administered orally or topicallyJI‘he same ba-
`sic pharmaceutical characteristics apply to those dis-
`persion systems administered by other routes of ad-.
`mnustrsfion. Included among these are ophthalmic
`suspensions, and sterile suspensions for injection.
`
`Suspensions
`
`Dispose Systems
`
`347
`
`as the SWM) disuibuted somewhat uniformly
`throughout a vehicle in which the drug eidu'bits a
`minimum degree of solubility Some suspensions
`are available in ready-to-use form—that is, already
`dislributed through a liquid vel'dcle With or Mthout
`stabilizers and other phaonaceutical additives (fig.
`13.1). Other proparations are available as dry pow~
`clots intended forsuspensionsin liquidvehicles.This
`type ofproduct generally is a powder rnixnire con-
`taining the drug and suitable suspending and dis-
`persing agents. which upon dilution and agitafion
`with a specified quantity of vehicle (generally puri-
`fied water) results in the formation of a suspension
`suitable for administration. Figure 13.2 demon-
`strates the preparation of this type of product. Drug
`that are unstable it maintained for attended periods
`of timein the presence ofan aqueousvehicle (for ex-
`ample. rnany antibiotic drugs) are most frequently
`supplied as dry powder moms for reconstitution
`at the time of dispensingThis type of preparation is
`designatedintheUSPbyatitieofthe fiorm“...for
`Oral Suspension"Prepared suspensions not requir-
`ing reconstitution at the time of dispensing are sim-
`ply designated as“. . . Oral Suspension.”
`
`Reasons for Suspensions
`
`There are several reasons for preparing mispen-
`sions. For one thing, certain drugs are chemically un—
`stable when in solution but stable when suspended.
`lninslamessudrasttmmesuspensioniosures
`chemical stability while pen-hitting liquid therapy. For
`many patients, the liquid form is preferred over the
`solidlounofthesarne drugbecausedthe easeof
`swallowingliquid's and [he fierdbilny in the adminis-
`tradonofarangeofdoses.’lhisisparticularlyadvan—
`tageous forkrfantsmhildren andthe elderly.'1he dis-
`advantage of a disagreeable taste of certain drugs
`
`
`
`Suspensions may be defined as preparations con-
`taining finely dirdded drug particles (referred to
`
`Fig. 13.1 Examples ofsome memorial oral Suspension
`
`AstraZencoa Exhibit 2097 p. 6
`
`

`

`341B
`
`Disperse Systems
`
`
`
`Fig. 13.2 Commercial mmbiotic preparationfir oral suspen-
`sionfiliowfng reconstitution with purified water. On the left is
`the dry powder mixture, and on the right the suspension afier
`fermentation with the specified amount ofpunfied water:
`
`when given in solution form is overcome when the
`drug is administered as undissolved particles of an
`oral suspension. In fact, cherru‘cal forms of certain
`poor—tasting drugs have been specifically developed
`for their insolubility in a desired vehicle for the sole
`purpose of preparing a palatable liquid dosage form.
`For example, the water—insoluble ester form of chlo-
`rarnphenicol, chloramphenicolpahnitate, was devel-
`oped to prepare a palatable liquid dosage form of the
`cl'iloramphenicol, the result being the development
`of Chlorampherficol Palmitate Oral Suspension USP!
`By the creation of insoluble forms of drugs for use in
`suspensions, the diffith tasteemaskhig problems of
`deVelolarnentel pharmacists are greatly reduced, and
`the Selection of the flavoran'ts to be used in a given
`suepension may be based on taste preference rather
`than on a particular flavorant’s ability to act as a
`masking agent for an unpleasant tasting drug. Forthe
`mostpart, oral suspensions are aqueous preparations
`with the Vehicle flavored and sweetened to suit the
`
`anticipated taste preferences of the intended patient.
`
`Features Desired in a
`
`Pharmaceutical Suspension
`
`There are many considerations in the develop-
`ment and preparation of a phannaceutically ele-
`
`gant suspension. In addition to therapeutic efficacy,
`chemical stability of the oomponents of the formu-
`lation, permanency of the preparation, and esthetic
`appeal of the preparation—desirable qualities in
`all pharmaceutical preparations—a few other fea-
`tures apply more specifically—to the pharmaceutical
`suspension:
`
`‘1. A properly prepared pharmaceutical suspension
`should settle slowlyand should be readily redis-
`persed upon the gentle shaking of the container.
`2. The characteristics of the sospension should be
`such that the particle size of the suspensoid re«
`mains fairly constant throughout long periods
`of undisturbed standing.
`3. The suspension should pour readily and evenly
`from its container.
`
`These main features of a mispension, which de-
`pend on the nature of the dispersed phase, the dis-
`persion medium. and pharmaceutical adjuncts. will
`be discussed briefly.
`
`Sedimentation Rate of the
`
`Particles of a Suspension
`
`The ondousflctm’s involved in the rate ofoeiocity of
`settling of the potholes of“ suspension are embodied in
`the equation ofStakes’ into, which is presented in the ac-
`companying Physical Pharmacy Capsule.
`Stokes’ equation was derived for an ideal situa-
`tion in which uniform, perfectly spherical particles
`in a very dilute suspension settle without effecting
`turbulence in their downward course, without col-
`lision of the particles of the Suspensoid._and with-
`out chetnical or physical attraction or affinity for the
`dispersion medium. Obviously. Stokes’ equation
`does not apply precisely to the usual pharmaceuti-
`cal suspension in which the suspensoid is irregu-
`larly shaped, of various particle diameters, and not
`spherical. in which the fall of the particles does re
`suit in both turbulence and collision, and also in
`which there may be a reasonable amount of affine
`ity of the particles for the suspension medium.How-
`ever, the basic concepts bf the equation do give a
`valid indication of the factors that are important to
`the suspension of the particles and a clue to the pos-
`sible adjustments that can be made to a formulation
`to decrease the rate of particle sedimentation.
`From the equation it is apparent that the veloc-
`ity of fall of a suspended particle is greater for larger
`particles than it is for smaller particles, all other fac-
`tors remainirig constant. By reducing the particle
`size of the dispersed phase, one can expect a slower
`rate of descent of the particles. Also, the greater the
`
`AstraZeneca Exhibit 2097 p. 7
`
`

`

`
`
`Disposefiysm
`
`349
`
`
`
`Physical Pharmacy Capsule 13.1 Sedimentation Rate 8; Stokes' Equation
`
`Stokes’ Equation:
`
`where
`
`3 = filo-JAR
`dt
`lB'q
`
`dx/dt is the rate of settling,
`d is the diameter of the particles,
`pi is the density of the particle.
`p. is the density of the medIUm,
`g is the gravitational constant, and
`11 is the viscosity of the medium.
`
`A number of factors can be adjusted to enhance the ph ical stability of a suspension, including the di-
`ameter of the particles and the density and viscosity of t e medium. The effect of changing these is illus-
`trated in the following example.
`EXAMPLE I
`_
`A powder has a density of l .3 g/CC and is available as acpowder with an average particle diameter of
`i
`2.5 microns (assuming the particles to be spheres). Accor ng to Stoke's Equation, this powder will set—
`tle in water [Viscosity of i cps assumed) at a rate of".
`
`[2.5 x iO-‘HLS — 1.0”980} =
`18 x 0’0]
`
`1.02 x '10
`
`_4
`
`cm/seo
`
`if the-particle size of the wder is reduced to 0.25 p. and water is still used as the‘dispersion medium,
`the powder will now sette at a rate of:
`
`3‘ 10-5213 —
`is X 0.0T
`
`___
`
`x 10—6 cmfsac
`
`As is evident, a decrease in particle size by a factor of 10 results in a reduction in the rate of settling by
`a factor of 100. This enhanced effect is a result of the "cl" factor in Stakes Equation being squared.
`
`Now, ifa different dispersion medium, sUch as glycerin, is used in place of water, a further decrease in
`settling Will result. Glycerin has a density of 1.25 glue and a viscostty at 400 cps.
`
`The larger particle size powder [2.5 u.) will settle at a rate of:
`mi!
`_
`[2.5 x10 } [1.3
`18.4
`
`1.2511930) mus x wean/m
`
`The smaller particle size (0.25 M Powder will now settle at a rate of:
`
`[2.5 X l0‘5[2|1.3 - l.25“980| =
`18x4
`
`-10
`4.25MB crn/sec
`
`A summary of these results is shown in the Following table:
`
`Condition
`
`Rate of Settling {cm/sec}
`
`2.5 apowder in water
`0.2.5 p. powder in water
`2.5 a. powder in glycerin
`0.25 p. powder in glycerin
`
`1.02 x 10"
`1.02 X 10“
`4.25 x it)"5
`4.25 x 10""
`
`As is evident from this table, a change in dispersion medium results in the greatest change in the rate of
`settling of particles. Particle size reduction also can contrlete significantly to suspension stability. These
`factors are important in the formulation of physically stable suspensions.
`
`AstraZencca Exhibit 2097 p. 8
`
`

`

`35:1
`
`DisperseSysiems
`
`density of the particles, the greater the rate of de-
`scent, provided the density of the vehicle is not al—
`tered. Because aqueous vehicles are used in phar~
`maceutical oral scepensions, the density of the
`particles is generally greater than that of the vehi-
`Cieli a desirable feature, for if the particles were less
`dense than the vehicle, they would tend to float,
`and floating particles would be quite difiicult to dis-
`tribute unifom'lly in the vehicle. The rate of sedi-
`mentation may be appreciably reduced by increas-
`ing the viscosity of the dispersion medium, and
`within limits of practicality this may be done. How-
`ever, a product having too high a fiscosity is not
`generally desirable, because it pours with difficulty
`and it is equally difficult to redisperse the suspen-
`soidfiherefore, iftheviscosity ofa suspensionisin-
`creased, it is done so only to a modest extent to
`avoid these difficulties.
`
`The viscosity characteristics of a suspension may
`be altered not only by the vehicle used, but also by
`the solids content.As the proportion ofsolid parti-
`cles is. increased ina suspensim‘ll so is the viscosity.
`The viscosity of a pharmaceutical preparation may
`
`be determined through the use of a BrookfieldVis-
`cometer. whidi measures viscOSity by the force re-
`quired to rotate a spindle in the fluid being tested
`0’13— 13-3)-
`_
`For the most part, the physical stability of a phar-
`maceutical suspension appears to be most approv
`pliately adjusted by an alteration in the
`phase rather than through great changes in the dis-
`persion medium In most instances, the dispersion
`medium is supportive to the adin dispersed
`phase. These adiusbnents mainly are conoemed
`with particle size, uniformity of particle size, and
`separation ofthe particles so that theyare not liker
`to become greatly larger or to form a solid cake on
`standing.
`
`Physical Features of the Dispersed
`Phase of a Suspension
`
`Probably the most important single oonsideralion
`in a discussion of suspensions is the size of the drug
`particles. In most good pharmaceutical suspensions.
`the pertiCIe diameteris between 1 and 50 urn.
`
`Synchronous motor
`
`Speed-selector knob
`
`
`
`Oil-Off toggle switch
` Clutch lever
`
`
`
`Pointer
`
`
`
`Jewel healing support
`
`Spindie coupling not
`
`Immersion mark
`
`Spindle body
`
`Removable
`splndle guard
`
`Sample
`container
`
`Big 13.3 Stile-inane rimming ofthe Bmkfieldllismmeten {Courtesy gramme Engineering mummies.)
`
`AstraZeneca Exhibit 2097 p. 9
`
`

`

`Particle size reduction is generally accomplished
`by dry-milling prior to the incorporation of the dis-
`persed phaso into the dispersion medium. One of
`the most rapid, convenient, and inexpensive meth-
`ods of producing fine drug powders of about 10 to
`50 um size is nricropuluoization. Micropulverisers
`are '
`speed, atnitim'l or impact mills which are
`efl'icient in reducing powders to the size neceptable
`for most oral and topical suspensions. For still finer
`particles, under 10 pm, the process offluid energy
`grinding. sometimes referred to asjet-millingor mi-
`«seizing,
`is quite effective. By- this process, the
`shearing action of high velocity compressed air
`streams on the particles in a confined space pro-
`duces the desired ultrafine or rrlicronized particles.
`The particlurs to be stimulated are swept into vio-
`lent turbulence by the sonic-and supersonic veloc-
`ity of the air streams. The particles are accelerated
`into high velocities and collide with one another,
`resulting in fragmentation and a decrease in the
`size ofthe particles; This. method maybe employed
`in instances in which the particles are intended for
`parenteral or ophthalmic stupensions. Particles of
`extremely small dimensions may also be produced
`byspraywdrying techniques. A spray dryer is a cone-
`shaped piece of apparatus into which a solution of
`a drug is sprayed and rapidly dried by a current of
`warmed, dry air circulatingin the cone. The result-
`ing dry powder is then collected. It is not possible
`for a community pharmacist to achieve the same
`degree of particle-size reduction with such simple
`commuting equipment as the mortar and pestle.
`However. many minimized rings are commer-
`cially available and when needed may be pur-
`chased by the pharmacist in bulls quantities.
`As shown by Stokes’ equation, the reduction in
`the particle size of a suspensoid is beneficial to the
`stability of the suspension in that the rate of sedi-
`mentation of the solid particles is reduced as the
`particles are decreased in size. The reduction in
`particle size produces slow. more uniform rates of
`settling. However. one should avoid reducmg the
`particle size to too great a degree of fineness, since
`fine particles. havo a tendency to form a compact
`cake upon settling to the bottom of the container.
`The msult may be that the cake resists breakup
`upon shaking. and forms
`aggregates of parti-
`cles which are of larger dimension and less Sus-
`pendable than the original suspensoidThe particle
`shape of the suspensoid can also affect taking and
`product stability. It has been show that meni—
`cal barrel-shaped particles of calcium carbonate
`produced more stable seepensions than did asym—
`metrical needle-shaped particles of the same agent.
`
`Dispose System
`
`351
`
`The needle-shaped particles formed a tenacious
`sediment-cake on standing which could not be re-
`distributed whereas the barrel-shaped particles did
`not cake on standing (1).
`To avoid the fiormation of a cake, measures must
`be taken to prevent the agglomeration of the parti-
`cles into laryr crystals or into masses. One com—
`mon method of preVenting the rigid cohesion of
`small
`of .a suspension is through the in—
`tentional lormation of a less rigid or loose aggrega-
`tion of the particles held together by comparatively
`weak particle—to-particle bonding forces. Such. an
`aggregation of particles is termed afloc or afloccule,
`with flocculated particles forming a type of lattice
`structure that resists complete settling (although
`flocs settle more rapidly than fine. individual parti-
`cles) and thus are loss prone to compaction than
`unflooculated particles. The flocs settle to form a
`higher sediment volume than unflocoilated parli-
`c'les. the loose structure of which permits the ag-
`gregates to break up easily and distribute readily
`with a small amount of agitation.
`There are several methods of preparing floc-
`culatod
`suspensions.
`the
`choice
`depending
`onthenrpeofdrugirwolvedandthetype ofproduet
`desired. For instance,
`in the preparation of an
`oral suspension ofadrug, clays such as cfihited ben—
`tonite magma are oormnonly employed as the
`flocoilating agont. The structure of the bentonibe
`magma and of other clays used for this purpose also
`assists. the suspension
`helping to support the doc
`onceformed.When claysareunsuitable asagents,as
`in a parenteral suspension, frequently a fine of the
`dispersed phase can be produced by an alteration in
`the pHofthepreparafion (generally totheregion of
`curds-tum drug solubility). Electrolytes. can also act
`as tlocoilati'ng agents, apparently by reduong the
`electrical barrier between the particles of the sus-
`pensoidandiormingabridgesoastolinkthemto—
`gather. The carefully determined concentration of
`norlionic and ionic surface-active agents (surfac-
`tants) can also induce the flocculation of particles in
`suspension and irurease the sedimentationvolume.
`
`Dispersion Medium
`
`Chonfirnes, as with highly flocculated suspEn-
`sions. the particles of a suspension settle too rapidly
`to be consistent with what might be tanned a phar—
`rriaceutioall}r elegant preparation. The rapid settling
`hinders the accurate measurement of dosage and
`from an esthetic point of View produces too on-
`sightly a supernatant layer. in many of the commer-
`cial suspensions, suspending agents are added
`
`Astra-Zoneca Exhibit 2097 p. 10
`
`

`

`352
`
`Disperse Systems
`
`to the dispersion medium to lend ita structure to
`assist in the suspension of the dispersed phase.
`Ctrboxymethyicellulose, methylcellulose, n'tiu'ocrys-
`talline cellulose. polyvinyl pyrrolidone, xanthan
`gum. and bentonlte are a few of the agents em—
`ployed to thicken the dispersion medium and help
`suspend the suspensoid. When polymeric sub—
`stances and hydrophilic colloids are used as sus-
`pending agents, appropriate tests must be per»
`formed to show that the agent does not interfere
`with the availability for therapeutic eEtects of
`the suspension‘s medicinal substance. These mate-
`rials can bind certain medicinal agents, rendering
`them unavailable or more slowly available for their
`therapeutic function. Also, the amount of the sus—
`pending agent must not be such to render the sus-
`pension too viscous to agate (to distribute the
`susporsoid) or to pour. The study of the flow char-
`acteristics is termed rheology. A summary of the
`concepts of rheologyis found in the accompanying
`Physical Pharmacy Capsule 13.2.
`Support of the suspensoid by the diapersion
`medium may depend on several factors: the density
`of the suspensoid, whether it is flocculated, and the
`amount of material requiring support.
`The solid content of a suspension intended for
`oral administration may vary considerably, depend-
`ing on the dose of the drug to be adofinisbered, the
`volume of product desired to be administered, and
`also on the ability of the dispersion medium to sup-
`port the concentration of drug while maintaining
`desirable feanues of fiscosity and flow. The usual
`adult oral suspension is frequently designed to sup-
`ply the dose of the particular drug in a convenient
`measure of 5 mL or one 'teaspoonfrd. Pediatric sus-
`pensions are formulated to deliver the appropriate
`dose of drug by administefing a close-calibrated
`number of drops. Figure 13.4 shows conunonly
`packaged oralsuspensions adrrdnlsteredaspediatdc
`drops. Some are accompanied by a calibrated drop-
`
`
`
`Fig. 13.4 Examples of oral pediatric suspensions showing
`package designs ofa built-in dropper device and a calibrated
`dropper accompanying the medication container:
`
`per, whereas other packages have the drop capabil—
`ity built into the container. On administration the
`drops maybe placed directly into the infant’s mouth
`orminedwithasmwportionoffoodbecausemany
`of the suspensions of antibiotic drugs intended for
`pediatric use are prepared in a highly flavored.
`sweetened, colored base, theyare bequentlyreferred
`to by their manufacturers and also popularly as
`“SWAPS,”EVEI1 thoughinfact they are suspensions.
`
`Preparation of Suspensions
`
`1n the proparatlon of a suspension, the pharma-
`cist must be acquainted with the characteristics of
`both the intended dispersed phase and the disper-
`sion medium. In some instances the dispersed
`phase has an affinityfor the vehicle to be employed
`and is readilyflwettedfiyit upon its addition. Other
`drugs are not penetrated easily by the vehicle and
`have a. tendency to dump together or to float on top
`of the vehicle. In the latter case, the powder must
`first be wetted by a so-called "wetting agent” to
`make the powder more penetrable by the disper-
`sion medium. Alcohol, glycerin, and other hygro~
`soopic liquids are employed as wetting agents when
`an aqueous vehicle is to be used as the dispersion
`phase. They function by displacing the air in the
`crevices of the particles, dispersing the particles,
`and subsequently allowing the penetration of dis-
`persion medium into the powdenln the large-scale
`preparation of suspensions the wetting agents are
`mixedwiththeparticlesbyanappsratus suchasa
`colloid mill; on a small scale in the pharmacy} they
`are mixed witha mortar and pestle. Once the pow-
`deriswetted, thedispersionmedium (towhichhave
`been added all of the fiomiulation's soluble compo—
`nents such as colorants, flavorants, and preserva-
`tives) is added in portions to the powder. and the
`mixture is thoroughly blended before subsequent
`additions of vehicle,A portion of H18 vehicle is used
`to wash the mixing equipment free of suspensoid,
`and this portion is used to bring the suspension to
`final volume and insure that the suspension con-
`tains the desired concentration of solid matter. The
`
`final product is then passed through a colloid mill or
`other blender or
`device to insure uniformity.-
`Whenever appropriate,
`suitable preservatives
`should be included in the formulaticn of suspensions
`to preserve against bacterial and mold contamination
`An example formula for an oral suspension fol-
`lows (Z). In the example, the suSpensoid is the
`antacid aluminum hydroxide, the pres ervatiVes are
`methylparaben and propylp araben, with syrup and
`sorbitol solution providing the viscosity as well as
`the sweetness.
`
`Asuacheca Exhibit 2097 p. 1 l
`
`

`

`
`
`DisperseSystems
`
`353
`
`Physical Pharmacy Capsule 131
`
`Rheoloy
`
`Rheology is the study of flow and involves the viscosity characteristics of powders, iluids, and semisolids.
`Materials are divided Into two general categories depending upon their tlow characteristics: Newtonian
`and non-Newtonian. Newtonian tlow is characterized by a constant viscosity, regardless at the shear
`rates applied. Non-Newtonian Flow is characterized by a change in viscosity characteristics with in-
`creasing shear rates. Non-Newtonian Flow includes plastic. pseudoplastic and dilatant Flow.
`
`Newton's Law at Flow relates parallel layers at liquid, with the bottom layer fixed, when a force is placed
`on the top layer and the top plane moves at constant velocity and each lower layer moves with a veloc-
`ity directly proportional to its distance from the stationary bottom layer. The velocity gradient, or rate at
`shear (clv/dr), is the difference of velocity dv betWeen twa planes of liquid Separated by the distance dr.
`The Force {F'/A] applied to the top layer that is required to result in Flow (rate at shear, G! [5 called the
`shearing stress
`The relationship can be expressed.
`
`.51 _ i
`A _ 11 dr
`
`where n is the viscosity coefficient, or viscosity. This relationship is often written
`
`,_ F
`‘1 ' a
`
`where F = F’/A and G = dv/d r. The higher the viscosity at a liquid, the greater the shearing stress re-
`quired to produce a certain rate of shear. A plot at F vs G yields a rheogram. A Newtonian fluid will plot
`as a straight line with the slope at the line being 11. The unit at viscosity is the poise, which is the shear-
`ing force required to produce a velocity at l cmg’sec between two parallel planes at liquid, each 1 cm2
`in area and separated by a distance at 1 cm. The most convenient unit to use is the centipoise, or cp
`(equivalent to 0.01 poise].
`
`These basic concepts can be illustrated in the following two graphs.
`
`RateofShear
`
`Z t
`
`Viscose);
`
`Shearing Stress
`
`Shear Ftate
`
`EXAMPLE 1
`What is the shear rate when on oil is rubbed into the skin with a relative rate of motion between the tin-
`gers and the skin at about 10 cm/sec and the tilrn thickness [5 about 0.02 cm?
`
`_ 10 cm/sec _
`_1
`G «- —-——-—-—o‘02 « 500 sec
`
`AstraZeneca Exhibit 2097 p. 12
`
`

`

`35¢
`
`Dispose Systems
`
`
`
`Rheology (Continued)
`
`The viscosity of Newtonian materials can be easily determined using a capillary viscometer, such as the
`Ostwald Pipet, and the following relationship:
`
`11’ = kid
`
`where 11' = viscosity,
`k = a coefficient, including such factors as the radius and length of the capillary, volume of the
`liquid flowing, pressure head, etc,
`i = time, and
`cl = density of the material.
`The official compendia, the USP-NF, utilize Kinematic Viscosity, which is the absolute viscosity divided by
`the density of the liquid, as follow;
`
`Kinematic viscosity = 1179
`The relative viscosity of a liquid can be obtained by utilizing a co illary viscometer and comparin data
`with a second liquid of known viscosity, provided the densities o the two liquids are known, as to lows:
`
`mm 2
`
`n‘f’n'a = [Pfl/lpalal
`
`At 25"C, water has a density of 1.0 /cc and a viscosity of 0.895 cps. The time of flow of water in a
`capillary viscometer is 15 sec. A 50
`aqueous solution of glycerin has a flow time of 750 sec. The den-
`sity of the glycerin solution is i .2 i s gfcc. What is the vixosity of the glycerin solution?
`, E [U.895]l750}[i.216] =
`-
`unis:
`“'4 “P5
`
`“
`
`EXAMI'LE 3
`
`The time of flow between marks on an Oslwalcl viscometer using water [p = l} was 120 sec at 20°C.
`The time for a liquid (p = 1.05} to flow through