Editor: Donna Balado
`Managing Editor: Jennifer Schmidt
`Marketing Manager: Christine Kushner
`
`Copyright © 1999 LippincottW1lliams & Wilkins
`
`351 West Camden Street
`Baltimore, Maryland 21201-2436 USA
`
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`
`All rights reserved. This book is protected by copyright. No part of this book may be re-
`produced in any form or by any means, including photocopying, or utilized by any infor-
`mation storage and retrieval system'without written permission from the copyright owner.
`
`The publisher is not responsible (as a matter of product liability, negligence, or otherwise)
`for any injury resulting from any material contained herein. This publication contains in-
`formation relating to general principles of medical care which should not be construed as
`specific instructions for individual patients. Manufacturers’product information and pack-
`age inserts should be reviewed for current information, including contraindications,
`dosages, and precautions.
`
`Printed in the United States ofAmerica
`
`Library of Congress Cata1oging-in-Publication Data
`
`Ansel, Howard C., 1933-
`Pharmaceutical dosage forms and drug delievery systems / Howard C.
`Ansel, LoydV. Allen, ]r., Nicholas G. Popovich. —— 7th ed.
`p.
`cm.
`Includes bibliographical references and index.
`ISBN 0-683-30572-7
`2. Drug delivery systems.
`1. Drugs—-Dosage forms.
`II. Popovich, Nicholas G.
`III. Title.
`[DNLM: 1. Dosage Forms.
`2. Drug Delivery Systems. QV 785 A6181 1999]
`RS200.A57
`1999
`615’.1—dc21
`DNLM/DLC
`for Library of Congress
`
`1. Allen, LoydV.
`
`99—17498
`CIP
`
`The publishers have made every effort to trace the copyright holders for borrowed material. Ifthey
`have inadvertently overlooked any, they will be pleased to make the necessary arrangements at
`the first opportunity.
`-
`
`The use of portions of the text of USP23/NF18, copyright 1994, is by permission of the USP
`Convention, Inc. The Convention is not responsible for any inaccuracy of quotation or for
`any false or misleading implication that may arise from separation of excerpts from the
`original context or by obsolescence resulting from publication of a supplement.
`
`To purchase additional copies of this book call our customer service department at (800)
`638-3030 or fax orders to (301) 824-7390. International customers should call (301)
`714-2324.
`
`99 00 01 02
`1 2 3 4 5 6 7 8 9 10
`
`Astrazeneca Ex. 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: Biopharrnaceutic and
`Pharmacokinetic Considerations
`
`Current Good Manufacturing Practices and Good
`Compounding Practices
`
`Section II. SOLID DOSAGE FORMS AND MODIFIED-RELEASE DRUG DELIVERY SYSTEMS
`
`6
`
`7
`
`8
`
`Powders and Granules
`
`Capsules and Tablets
`
`»
`
`Modified~Release Dosage Forms and Drug Delivery Systems
`
`Section III. SEMI-SOI.ID AND TRANSDERMAI. SYSTEMS
`
`9
`
`I0
`
`Ointments, Creams, and Gels
`
`Transdermal Drug Delivery Systems
`
`v
`
`vii
`
`1
`
`23
`
`60
`
`101
`
`142
`
`164
`
`179
`
`229
`
`_
`
`'244
`
`263
`
`ix"
`
`Astrazeneca Ex. 2097 p. 3
`
`

`
`x
`
`Contents
`
`Section IV. PHARMACEUTICAL INSERTS
`
`I I
`
`Suppositories and Inserts
`
`Section V. LIQUID DOSAGE FORMS
`
`I 2
`
`I3
`
`S olutions
`
`Disperse Systems
`
`Section VI. STERILE DOSAGE FORMS AND DELIVERY SYSTEMS
`
`I 4
`
`I 5
`
`I6
`
`Parenterals
`
`Biologicals
`
`Ophthalmic Solutions and Suspensions
`
`Section VII. NOVEL AND ADVANCED DOSAGE FORMS, DELIVERY SYSTEMS, AND DEVICES
`
`Radiopharmaceuticals
`
`Products of Biotechnology
`
`Novel Dosage Forms and Drug Delivery Technologies
`
`Systems and Techniques of Pharmaceutical Measurement
`
`I 7
`
`I8
`
`I9
`
`Appendix
`
`Index
`
`279
`
`296
`
`346
`
`397
`
`450
`
`469
`
`487
`
`503
`
`535
`
`552
`
`563
`
`Astrazeneca Ex. 2097 p. 4
`
`

`
`DISPERSE SYSTEMS
`
`Chapter at a Glance
`
`Suspensions
`Reasons for Suspensions
`Features Desired in a Pharmaceutical
`Suspension
`Physical Features 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 Suspensions
`Antacid Oral Suspensions
`Antibacterial Oral Suspensions
`Examples of Other Suspensions
`Otto Suspensions
`Rectal Suspensions
`Dry Powders for Oral Suspension
`Emulsions
`Purpose of Emulsions and of
`Emulsification
`Theories of Emulsification
`Preparation of Emulsions
`Emulsifying Agents
`The HLB S stem
`Methods 0 Emulsion Preparation
`Continental or Dry Gum Method
`English or Wet Gum Method
`Bottle or Forbes Bottle Method
`Auxiliary Methods
`In Situ Soap Method
`Miaroemulsions
`Stability of Emulsions
`Aggregation and Coalesceuoe
`Examples of Oral Emulsions
`Mineral Oil Emulsion
`
`Castor Oil Emulsion
`Simethicone Emulsion
`
`34:6
`
`Gels and Magmas
`Colloidal Dispersions
`'l‘ermino1ogy Related to Gels
`Classification and Types of Gels
`Preparation of Magmas and Gels
`Examples of Gelling Agents
`Gel Formulation Considerations
`Examples of Magmas and Gels
`Benlonite Magma, NF
`Aluminum Hydroxide Gel, USP
`Milk ofMagnesia, LISP
`Starch Glycerite
`Lubricating Ielly Formula
`Clear Aqueous Gel with Dimethioone
`Poloxamer Gel Base
`Proper Administration and Use of
`Disperse Systems
`-
`Aerosols
`Advantages of the Aerosol Dosage
`Fomt
`The Aerosol Principle
`Aerosol Systems
`Two-phase Systems
`Three—phase Systems
`Compressed Gas Systems
`Aerosol Container and Valve Assemlilly
`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
`
`Topical Aerosols
`Vaginal and Rectal Aerosols
`
`Astrazeneca Ex. 2097 p. 5
`
`

`
`T1-as Cl-{AFTER 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. Together,
`they produce a dispersed system.
`The particles of the dispersed phase are usually
`solid materials that are insoluble in the dispersion
`medium. In the case of emulsions, the dispersed
`phase is a liquid substance which is neither soluble
`nor miscible with the liquid of the dispersing phase.
`The emulsification process results in the dispersion of
`liquid drug as fine droplets throughout the dispersing
`phase. In the case of an aerosol. the dispersed phase
`may be air that is present as small bubbles tliroughout
`a solution or an emulsion. Dispersions also consist of
`droplets of a liquid (solution or suspension) in air.
`The particles of the dispersed phase vary widely
`in size, from large particles visible to the naked eye
`down to particles of colloidal dimension, falling be-
`tween 1.0 nm and 0.5 um in size. Dispersions con-
`taining coarse particles, usually 10-50 um in size,
`are referred to as coarse dispersions and include the
`suspensions and emulsions, Dispersions containing
`particles of smaller size are termed fine dispersions
`(05-10 um), and, if the particles are in the colloidal
`range, colloidal dispersioris. Magmas and gels repre-
`sent such Eine dispersions.
`Largely because of their greater size, dispersed
`particles in a coarse dispersion have a greater ten-
`dency to separate from 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-
`sity than the aqueous medium in which they are dis-
`persed and tend to rise toward the top of the prepa-
`ration. Complete and uniform redistribution of the
`dispersed phase is essential to the accurate adminis-
`tration of uniform doses. For a properly prepared
`dispersion,
`this should be accomplished by the
`moderate agitation of the container.
`The focus of this chapter is on dispersions of
`drugs administered orally or topically.The same ba-
`sic pharmaceutical characteristics apply to those dis-
`persion systems administered by other routes of ad—.
`ministration. Included among these are ophthalmic
`suspensions, and sterile suspensions for injection.
`
`Suspensions
`
`Disperse Systems
`
`347
`
`as the suspensoid) distributed somewhat uniformly
`throughout a vehicle in which the drug exhibits a
`minimum degree of solubility. Some suspensions
`are available in ready-to-use form—that is, already
`distributed through a liquid vehicle with or without
`stabilizers and other phannaceufical additives (Fig.
`13.1). Other preparations are available as dry pow-
`ders intended for suspensions in liquid vehicles.This
`type of product generally is a powder mixture con-
`taining the drug and suitable suspending and dis-
`persing agents, which upon dilutjon and agitation
`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. Drugs
`that are unstable if maintained for extended periods
`oftime in the presence of an aqueous vehicle (for ex-
`ample, many antibiotic drugs) are most frequently
`supplied as dry powder mixtures for reconstitution
`at the time of dispensing.This type of preparation is
`designated in the USP by a title of the form ". . .for
`Oral 5uspension.”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 suspen-
`sions. For one thing, certain drugs are chemically un-
`stable when in solution but stable when suspended
`In instances such as this, the suspension insures
`chemical stability while perrnitting liquid therapy. For
`many patients, the liquid form is preferred over the
`solid form of the same drug because of the ease of
`swallowing liquids and the flexibility in the adminis-
`tration of a range of doses. This is particularly advan-
`tageous for infants, children and the elderly. The dis-
`advantage of a disagreeable taste of certain drugs
`
`
`
`Suspensions may be defined as preparations con-
`taining finely divided drug particles (referred to
`
`Fig. 13.}
`
`Examples ofsome commercial oral suspensions.
`
`AstraZeneca Ex. 2097 p. 6
`
`

`
`348
`
`Dispersc Systems
`
`
`
`Fig. 13.2 Comrrterciel antibiotic preparrru'on for em! suspen-
`sioitfollowutg nsconstitution with purified water On the la
`is
`the dry powder mixture. and on the right the suspension after
`reconstitution wit}: the specified ruuount ofpunficd water:
`
`when given in solution form is overcome when the
`drug is administered as undissolve-:1 particles of an
`oral suspension. In fact, chemical 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-
`rampheiucol, chloramphenicol palrnitate, was devel-
`oped to prepare a palatable liquid dosage form of the
`chloramphenicol, the result being the development
`of Clilorampherucol Palrnitate Oral Suspension, USE
`By the creation of insoluble forms of drugs for use in
`suspensions, the difficult taste—masl<i.ng problems of
`developmental pharmacists are greatly reduced, and
`the selection of the flavorants to be used in a given
`suspension may be based on taste preference rather
`than on a particular Flavor-ant's ability to act as a
`masking agent for an unpleasant tasting drug. For the
`most part, 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 pharmaceutically ele-
`
`gant suspension. In addition to therapeutic efficacy,
`chemical stability of the components of the formu-
`lation, permanency of the preparation, and esthetic
`appeal of the preparation—desirable qualifies in
`all pharmaceutical preparations——a few other fea-
`tures apply more specifically to the pharmaceutical
`suspension:
`
`ix}
`
`1. A properly prepared pharmaceutical suspension
`should settle slowly and should be readily redis-
`persecl upon the gentle shaking of the container.
`The characteristics of the suspension should be
`such that the particle size of the suspensoicl 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 suspension, 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 21 Suspension
`
`'l'lie various factors involved in the mic ofoelocity of
`settling of the particles ofn suspension are embodied in
`the equation ofstoltes’ low, which is presented in the ac-
`comprrnyirrg 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 chemical 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-
`sult in both turbulence and collision, and also in
`which there may be a reasonable amount of affin-
`ity of the particles for the suspension medium. How-
`ever, the basic concepts of 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 remajning 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
`
`Astraleneca Ex. 2097 p. 7
`
`

`
`
`
`Dispense Systrrns
`
`349
`
`
`
`Physical Pharmacy Capsule 13.1 Sedimentation Rate 8: Stokes’ Equation
`
`stokes’ Equation:
`
`where
`
`3 = dz“? _ E 19
`dt
`l8-n
`
`dx/clt is the rate of settling,
`d is the diameter of the particles,
`p, is the density of the particle.
`pa is the density of the medium,
`9 is the gravitational constant, and
`-:1 is the viscosity of the medium.
`A number of factors can be adjusted to enhance the physical stability of a suspension, including the di-
`ameter of the particles and the density and viscosity oft e medium. The effect of changing these is illus-
`trated In the following example.
`
`EXAMPLE I
`_
`_
`A powder has a density of l .3 9/cc and is available as acrowder with an average
`l
`2.5 microns (assuming the particles to be spheres). Accor ng to 5tol<e's Equation,
`tle in water [viscosity of T cps assumed] at a rate of:
`
`rticle diameter of
`is powder will set-
`
`(2.5 x '|0"}2[l.3 — l.O]l9B0_[ =
`18 x 0.0]
`
`_
`1.02 X 10 ‘cm/sec
`
`If the particle size of the powder is reduced to 0.25 p. and water is still used as theidispersian medium,
`the powder will now settle at a rate of:
`
`2.5 x to-521.3 -1.0 930 =1 02 x wgcm/Sac
`l8><0.0l
`
`As is evident, a decrease in particle size by a factorot 10 results in a reduction in the rate of settling by
`a Factor of 100. This enhanced effect is a result of the "d" factor in Stokes 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 g/cc and a viscosity of -400 cps.
`
`The larger particle size powder [2 .5 1.1.) will settle at a rate of:
`2.5:-no-42'_1.3—1-2.5 980 ___4_25Xw_3cm/sac
`18.4
`
`The smaller particle size (0.25 p.) powder will now settle at a rate of:
`
`(2.5 X l0‘5[3|'l-3 — i.25l|980] =
`18 x4
`
`_ -
`4.25 X 10 1“ crnfsec
`
`A summary of these results is shown in the following table:
`
`Condition
`
`Rate of Settling {cm/sec}
`
`2.5 p. powder in water
`0.25 p. powder i.n water
`2.5 p. powder in glycerin
`0.25 p. powder in glycerin.
`
`1.02 X 10"
`1.02 X 10"
`4.25 X 1.0"‘
`4.25 X 10‘1‘'
`
`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 contribute significantly to suspension stability. These
`factors are important in the formulation of physically stable suspensions.
`
`Astrazeneca Ex. 2097 p. 8
`
`

`
`358
`
`Disperse Systems
`
`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 suspensions, the density of the
`particles is generally greater than that of the vehi-
`cle, a desirable feature, for if the particles were less
`dense than the vehicle, they would tend to float,
`and fioatingparticleswould be quite difficult to dis-
`tribute uniformly 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 viscosity is not
`generally desirable, because it pours with difficulty
`and it is equally difficult to redisperse the suspen-
`soid.'i'here fore, if the viscosity of a suspension is in-
`creased, it is done so only to a modest extent to
`avoid these difflculdes.
`
`The viscosity characteristics of a suspension may
`be altered not only by the vehicle used, but also by
`the solids content.As the proportion of solid parti-
`cles is increased in a suspension, so is the viscosity.
`The viscosity of a pharmaceutical preparation may
`
`be determined through the use of a Brook.fieldVis-
`oometer. which measures viscosity by the force re-
`quired to rotate a spindle in the fluid being tested
`{P15 13-3)-
`.
`For the most part, the physical stability of a phar-
`maceutical suspension appears to be most appro-
`priately adjusted by an alteration in the dispersed
`phase rather than through great changes in the dis-
`persion medinm. In most instances, the dispersion
`medium is supportive to the adjusted dispersed
`phase. These adjustments mainly are concerned
`with particle size, uniformity of particle size, and
`separation of the particles so that they are not likely
`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 consideration
`in a discussion ofsuspensions is the size ofthe drug
`particles. In most good pharmaceutical suspensions.
`the particle diameter is between 1 and 50 p.n'L
`
`Synchronous motor
`
`Speed-selector knob
`
`On-off toggle switch
`
`
`
` Clutch lever
`
`
`
`Pointer
`
`
`
`Jews: bearing support
`
`Spindle coupling -out
`
`Immersion mad:
`
`3Pifldl8 b0dY'
`
`Fig 13.3 Schematic drawing of the Hmokfislii llisoometsr. [Courtney afflraolgfield Engineering Laboratories.)
`
`Astrazeneca Ex. 2097 p. 9
`
`

`
`Particle size reduction is generally accomplished
`by city-millingprior to the incorporation of the dis-
`persed phase into the dispersion medium. One of
`the most rapid, convenient, and inexpensive meth-
`ods of ptoducingfirle drug powders of about 10 to
`50 um size is micropuloerizaiian. Micropulverizers
`are high-speed. attrition or impact mills which are
`efficient in reducing. powders to the size acceptable
`for most oral and topical suspensions, For still finer
`particles, under 10 urn, the process offluid energy
`grinding. sometimesreferred to as jet-niillirtgor mi-
`cronizfng,
`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 mlcronlzed particles.
`The particles to be micronized 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 fra-gmentation and a decrease in the
`size ofthe particles;This method maybe employed
`in instances in which the particles are intended for
`parenteral or ophthalmic suspensions. Particles of
`extremely small dimensions mayalso be produced
`by spray-drying techniques. A spraydtyer is a cone-
`shaped piece of apparatus into which a solution of
`a drug is sprayed and rapidly dried bya 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
`comminuting equipment as the mortar and pestle.
`However, many rnicronizecl drugs are commer-
`cially available and when needed may be pur-
`dnased by the pharmacist in bull: quantities.
`As shown by Stokes’ equation, the reduction in
`the particle size of a suspensoicl 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 reducing the
`particle size to too great a degree of fineness, since
`fine particles have a tendency to form a compact
`cake upon settling to the bottom of the container.
`The result may be that the cake resists breakup
`upon shaking, and forms rigid aggregates of parti-
`cles which are of larger dimension and less sus-
`pendable than the original suspensoid.The particle
`shape of the suspensoid can also affect raking and
`product stability. It has been shown that symrnetri--
`cal barrel-shaped particles of calcium carbonate
`produced more stable suspensions than did asym-
`metrical needle-shaped particles of the same agent.
`
`Dispose Syrians
`
`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 Cl).
`To avoid the formation of a cake, measures must
`be taken to prevent the agglomeration of the -pa.rti-
`cles into larger crystals or into masses. One com-
`mon method of preventing the rigid cohesion of
`small particles of a suspension is through the in-
`tentional .l'ormatlon of a less rigid or loose aggrega-
`tion of the particles held together by comparatively
`weak particle-to-particle bonding forces. Such an
`aggregation ofpanicles 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 less prone to compaction than
`unflocculated particles. The flocs settle to form a
`higher sediment volume than unflocculated parti-
`cles, the loose structure of which permits the ag-
`gregates to break up easily‘ and distribute readfljr
`with a small amount of a.g-itation.
`There are several methods of preparing floc-
`culated
`suspensions,
`the
`choice
`depending
`onthe type ofclrug involved and the type ofproduct
`desired. For instance,
`in the preparation of an
`oral suspension ofa drug, clays such as o‘ilute-cl ben-
`tonlte magma are oornmonly employed as the
`tlocculating agent. The structure of die bentonite
`rnagrna and of other clays used for this purpose also
`assists. the suspension by helping to support the floc
`once fon:ned.When clays are unsuitable asagents, as
`in a parenteral suspension, frequently a Eloc of the
`dispersed phase canbe proclucedby an alteration in
`thepl-Iofthepreparation (generallyto theregion of
`minimum drug solubility). Electrolytes can also act
`as ilocculating agents, apparently by reducing the
`electrical "barrier between the particles of the sus-
`pensoidaridfornungabridge so as to1'rnlcthemto-
`gether. The carefully cletenninecl concentration of
`nonionic and ionic surface-active agents (surfac-
`tants) can alsoinduce the flocculation of particles in
`suspension and increase the sedimentationvolume.
`
`Dispersion Medimn
`
`Ofbentilnes, as with highly flocculated suspen-
`sions. the particles of a suspension settle too rapidly
`to be consistent with what might be termed a phar-
`rnaceutically elegant preparation. The rapid settling
`hinders the accurate measurement of dosage and
`from an esthelir: point of view produces too on-
`sightly a supernatant layer. In many of the commer-
`cial suspensions,. suspending agents are added
`
`Astrazeneca BX. 209'? p. 10
`
`

`
`352
`
`Disperse Systems
`
`to the dispersion rnedium to lend it a structure to
`assist in tire suspension of the dispersed phase.
`Carboxymethylcellulose, methylcellulose, m.icrocrys-
`talline cellulose, polyvinyl pyrrolidone, xanthan
`gum, and bentonite 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 effects of
`the suspensions 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 agitate (to distribute the
`susperrsoid) or to pour. The study of the flow char-
`acteristics is termed rheology. A summary of the
`concepts of rheology is found in the accompanying
`Physical Pharmacy Capsule 13.2.
`Support of the suspensoid by the dispersion
`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 administered, the
`volume of product desired to be aclministered, and
`also on the ability of the dispersion medium to sup-
`port the concentration of drug while maintaining
`desirable features of viscosity 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 teaspoonful. Pediatric sus-
`pensions are formulated to deliver the appropriate
`dose of drug by administering a dose-calibrated
`number of drops. Figure 13.4 shows commonly
`packaged oral suspensions administered as pediatric
`drops. Some are accompanied by a calibrated drop-
`
`
`
`Fig. 13.4 Examples of oral pediatric suspensions showing
`package designs cfa built-in dropper device and a calibrated
`dropper accompanying the meriictitioir mmairrer.
`
`per, whereas other packages have the drop capabil-
`ity built into the container. On administration the
`drops may be placed directly into the infants mouth
`or mixed with a small portion of food. Because many
`of the suspensions of antibiotic drugs intended for
`pediatric use are prepared in a highly flavored,
`sweetened, colored base, they are frequently referred
`to by their manufacturers and also popularly as
`“syrups,” even though in fact they are suspensions.
`
`Preparation of Suspensions
`in the preparation of a suspension, the pharma-
`cist must be acquainted with the characteristics of
`both the intended dispersed phase and the disper-
`sion medium.
`ln some instances the dispersed
`phase has an atfinity for the vehicle to be employed
`and is readily”wetted”by it upon its addition. Other
`drugs are not penetrated easily by the vehicle and
`have a tendency to clump 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 mediurn. Alcohol, glycerin, and other hygro-
`scopic 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 powder. In the large—scale
`preparation of suspensions the wetting agents are
`mixed with the particles by an apparatus such as a
`colloid mill; on a small scale in the pharmacy, they
`are mixed with a mortar and pestle. Once the pow-
`der is wetted, the dispersion medium (to which have
`been added all of the forniulatiorfs 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 the 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 mixing device to insure uniformity.
`V\7l'1.enever appropriate,
`suitable preservatives
`should be included in the formulation of suspensions
`to preserve againstbacterial and mold contamination.
`An example formula for an oral suspension fol-
`lows (2). In the example, the suspensoid is the
`antacid aluminum hydroxide, the preservatives are
`methylparaben and propylparaben, with syrup and
`sorbitol solution providing the viscosity as well as
`the sweetness.
`
`Astrazeneoa Ex. 2097 p. l 1
`
`

`
`Disperse Systems
`
`333
`
`
`
`Physical Pharmacy Capsule 132
`
`Rheology
`
`Rheology is the study of flow and involves the viscosity characteristics of powders, Fluids, and sernisolids.
`Materials are divided into two general categories depending upon their flow characteristics: Newtonian
`and non-Newtonian. Newtonian How is characterized by a constant viscosity, regardless of 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, pseudoplostic and dilotant flow.
`
`Newton's Law of Flow relates parallel layers of 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 of
`shear (dv/dr), is the difference of velocity dv between two 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 of shear, G] is called the
`shearing stress [F]. The relationship can be expressed.
`
`EL _ fl
`A " 11 dr
`
`where -:1 is the viscosity coefficient, or viscosity. This relationship is often written
`
`5 L
`G
`
`“
`
`where F = F’/A and G = dv/clr. The higher the viscosity of a liquid, the greater the shearing stress re-
`quired to produce a certain rate of shear. A plot of F vs G yields a rheogram. A Newtonian fluid will plot"
`as a straight line with the slope of the line being '11. The unit of viscosity is the poise, which is the shear-
`ing force required to produce a velocity of 'l cm/sec between two parallel planes at liquid, each 1 cm3
`in area and separated by a distance of 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.
`
`is
`5
`-a
`.3
`a:
`
`.-.3‘
`E
`>-
`
`Shearing Stress
`
`Shear Ftate
`
`EXAMPLE 1
`What is the shear rate when an oil is rubbed into the skin with a relative rate of motion between the fin-
`gers and the slcin of about 10 cmfsec and the film thickness is about 0.02 cm?
`
`s = l—‘°g-’g§‘*—‘— = 500 sec'l
`
`Astrazcneca Ex. 2097 p. 12
`
`

`
`35-1
`
`Dispense 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:
`
`1:’ = ktd
`
`where n’ = viscosity.
`it = a coefficient, including such factors as the radius and length at the capillary, volume at the
`liquid flowing, pressure head, etc,
`t = time, and.
`d = density at the material.
`The otticial compendia, the USP-NF, utilize Kinematic Viscosity, which is the absolute viscosity divided by
`the density at the liquid, as follows:
`
`liiinernatic viscosity = 11',’p
`The relative viscosity at :1 liquid can be obtained by utilizing o co illary viscometer and comparin data
`with a second liquid of known viscosity, provided the densities a the two liquids are known, as to laws:
`
`sxnmns 2
`
`n’/'I1's = lptl/lostsl
`
`At 25°C, water has a density at 1.0 /cc and a viscosity of 0.395 cps. The time of flow at water in a
`capillary viscometer is 15 sec. A 50 aqueous solution at glycerin has a flow time at 750 sec. The den-
`sity of the glycerin solution is 1 .2 i 6 g/cc. What