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. 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-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. 2097 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. 2097 p. 4
`
`

`
`I3
`
`
`
`Chapter at cl Glance
`
`Suspensions
`Reasons for Suspensions
`Features Desired in a Pharmaceutical
`Suspension
`Physical I-‘eat-ores of the Dispersed Phase of
`a. Suspension Dispersion Medium
`1'-‘reparation of Suspensions
`Sustained-Release Suspensions
`Externporaneous Compounding of
`Suspensions
`Packaging and Storage of Suspensions
`Examples of Oral Suspensions
`Antacfd Oral Sus ensions
`Antibacterial Ore Suspensions
`Examples of Other Suspensions.
`Ofic Susperrsions
`Rectal Suspensions
`Dry Powders for Oral Suspension
`Emulsions
`Purpose of Blnulsions and of
`Emulsification
`Theories of Emlllsification
`Preparation of Emulsions
`Emulsififing Agents
`The HLB 5 tom
`Methods
`Emulsion Preparation
`Continental or Dry Gum Method
`English or Wet Gum Method
`Bottle or Forbes Bottle Method
`Aux:'l:'.¢ry Methods
`In Situ Soap Method
`Microzmzalsfons
`
`Stability of Emulsions
`Aggregation and Coolescenoe
`Examples of Oral Emulsions
`Mineral Oil" Emulsion
`Castor Oil Emulsion
`Simzthicone Emulsion
`
`3&6
`
`Gels and Magmas
`Colloidal Dispersions
`Terminology Related to Gels
`Classification and Types of Gels
`Preparation of Magrnas and Gels
`Examples of (Selling Agents
`Gel Formulation Considerations
`Examples of Magrnas and Gels
`Bentonite lvlog-mo, NF
`Aluminum Hydroxide Gel, LISP
`A/[ilk ofMagr1es1'o, LISP
`Starch Glyceriie
`Lubricating jelly Formula
`CleirrAqueous Gel with Dimethimms
`Poloxomer Gel Base
`Proger Adnfirlistraiion and Use of
`D1sperse Systems
`Aerosols
`Advantages of the Aerosol Dosage
`Form
`The Aerosol Principle
`Aerosol Systems
`Two-phase Systems
`T'hree~plmse S
`ems.
`Compressed
`Systems
`Aerosol Container and Valve Assembly
`Containers
`Voloe Assembly
`Metered Dose Inhalers (MDISJ
`Filling
`erations
`Cold F: ling
`Pressure Fflli
`
`Containers
`Testing the F1’!
`Packaging. Labeling, and Storage
`Pro
`1' Administrafion and Use of
`I’ maceutical Aerosols
`Topical Aerosols
`Vaginal and Rectal Aerosols
`
`Astrazeneca Ex. 2097 p. 5
`
`

`
`T1-I15 Cl-IAPTER 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 niiscible with the liquid of the dispersing phase.
`The emulsification prooess results in the dispersion of
`liquid drug as fine droplets throughout the dispersing
`phase. In the case of an aerosol, the dispersed phase
`maybe air that is present as small bubbles throughout
`a solution or an emulsion. Dispersions also oonsist 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 urn in size. Dispersions con-
`taining coarse particles, usually 10-50 pm in size,
`are referred to as coarse dispersions and include the
`suspensions and emulsions. Dispersions containing
`particles of smaller size are termedfine dispersions
`(0.5-10 um). and, if the particles are in the colloidal
`range, colloidal dispersions. Magmus and gels repre-
`sent such fine 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-
`telnet because of their greater density than the dis-
`persion medlurn, 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 ad.rn.1'.nis-
`ttation of uniforrn 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 irijectlon.
`
`Suspensions
`Suspensions may be defined as preparations con-
`taining finely divided drug particles (referred to
`
`Diapers: Systems
`
`347
`
`as the suspettsoid) distributed somewhat uniformly
`throughout a vehicle in which the drug exhibits a
`minimum degree of solubility. Some suspensions
`are available in ready—to-use fort-n—that is, already
`distributed through a liquid vehicle with or without
`stabilizers and other pharmaceutical additives (Fig.
`13.1). Other preparations are available as dry pow-
`ders intended for suspensions in liquid vehicleslhis
`type of product generally is a powder mixture con-
`taining the drug and suitable suspending and dis-
`persing agents, which upon dilution and agitation
`with a specified quantity of vehicle (generally puri-
`fied water) results in the formation of a suspension
`suitable for adrninistration.
`‘Figure 13.2 demon-
`strates the preparation of this type of product. Drugs
`that are unstable if mairitained for extended periods
`of time in the presence of an aqueous velucle [for ex-
`ample, many antibiotic drugs) are most frequently
`supplied as dry powder mixmres for reconstitution
`at the time of dispensing.’l‘his type or’ preparation is
`designated in the USP by a title of the form ". . . for
`Oral Suspension." Prepared suspensions not requir-
`ing reconstitution at the time of dispensing are sim-
`ply designated as ”. .
`. Oral Suspension."
`
`Reasons for Suspensions
`
`The're are several reasons for preparing suspen-
`sions. For one tl'n'ng, certain drugs are chemically un-
`stable when in solution but stable when suspended.
`In instances such as this, the suspension insures
`chemical stability while perrruttingliqtud 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 acln-tints-
`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
`
`
`
`Fig. 13.1 Examples ofsome commercial unit suspensions.
`
`Astrazeneca Ex. 2097 p. 6
`
`

`
`3-I38
`
`Dtspersc Systems
`
`
`
`COJiIl'H£P't‘i(Il itmibioric preparation for oral suspen-
`Fig. 13.2
`sioirfliilowing recanstimrion tr.-itlr purified ureter On the left is
`the dry powder rriiriure, and on the right the snispcnsion after
`rrrconstitntiott with the mcified mnottnl afpunflfied water.
`
`when given in solution form is overcome when the
`drug is adrninistered as undissolved 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-
`rarnphenjcol, chloramphenicol palrnitate, was devel-
`oped to prepare a palatable liquid dosage form of the
`Chloramphenicol, the result being the development
`of Chlorarnphenicol Palmitate Oral Suspension, USP.
`By the creation of insoluble forms of drugs for use in
`suspensions, the difficult taste—rnasl:ir1.g problems of
`developmental pharrriacists 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 partictilar flavoranfs 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 pharrnaccutically ele-
`
`gant suspension. In addition to therapeutic efficacy,
`chemical stability of the components of the formu v
`lation, permanency of the preparation, and aesthetic
`appeal of the preparat:'on—de5irable qualifies in
`all pharmaceutical preparations-—a few other fea-
`tures apply more specifically to the pharmaceutical
`suspension:
`
`1. A properly prepared phannaceutical suspension
`should settle slowly and should be readily redis-
`persed upon the gentle shaking of the container.
`2. The characteristics of the suspension 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 suspension, which de-
`pend on the nature of the dispersed phase, the dis-
`persion mediurn, and pharmaceutical adjuncts, will
`be discussed briefly.
`
`Sedimentation Rate of the
`
`Particles of a Suspension
`
`‘iii: rmriousfacrars involved in the rate ofoelociry of
`settling of the pm'ti'clcs oft: suspension me eiiibodicd in
`the equation of5tolces‘ law, which is presented in the oc-
`crmipanyirtg Physical Pliarmocy Capsule.
`Stokes’ equation was derived for an Ideal situa-
`tion in which uniform, perfectly spherical particles
`in 2: 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 docs 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 remaining 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 Ex. 2097 p. 7
`
`

`
`
`
`Dispersesysterns
`
`349
`
`Physical Pharmacy Capsulels.-.1
`Sedimentation Rate 8; Stokes’ Equation
`
`
`
`
`' "
`
`stakes’ Equation:
`
`where
`
`dx/dt is the rate of settling,
`d is the diameter of the particles,
`p, is the density of the particle,
`P‘ is the density at the medium,
`9 is the gravitational constant, and
`11 is the viscosity at the medium.
`A number at factors oan be adjusted to enhance the phisicol stability of a suspension, including the di-
`ameter ot the particles and the density and viscosity of t e medium. The eltect of changing these is illus-
`trated in the following example.
`EXAMPLE I
`
`.
`
`A powder has a density of 1.3 g/cc and is available as a powder with on average particle diameter at
`2.5 microns lassuming the particles to be spheres]. According to Stol:e‘s Equation, this powder will set-
`tte in water lvisoosfly of I cps assumed] at a rate of:
`
`_
`[25 X l0"‘[7-ll.3 - l.Dll98D[ _
`.|8x0.O]
`—i.Cl2><iO ‘cm/sec
`
`If the particle size at’ the powder is reduced to 0.25 p. and water is still used as the dispersion medium,
`the powder will now settle ata rate cl‘.
`-
`'
`-h
`0
`_
`—
`
`%———l—l————-ll——l-25" l°;';:<l03.0, ' 0 93° -1.02 >410 ‘cm/sec
`
`-As is evident, a decrease in particle size by a factor at 10 results in a reduction in the rate of settling by
`a factor of I00. This enhanced effect is a result at the “d” Factor in Stakes Equation being squared.
`Now, if a 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 {25 p.] will settle at a rate of:
`
`|2.5 SK iO“‘[3|l.3 — l.25[l93D| =
`18.4
`
`_
`4.25 X10 9 orn/sec
`
`The smaller particle size {(3.25 p.} powder will now settle at a rate of:
`
`2.5 x 10-52 1.3 -1.25 93:: :4” X. ,0_,,,Cm/M
`13- K -4
`
`A summary of these results is shown in the Following table:
`
`Corrdiflan
`
`Rate of Sefliing fcrn/sec]
`
`2.5 p. powdel-in water
`0.25 p. powder in water
`2.5 is powder in glycerin
`0.25 p. powder in glycerin
`
`1.02 x 19"
`1.02 X 10“
`4.25 x 10'‘
`4.25 X 10''"
`
`As is evident from this table, a change in dispersion medium results in the greatest change in the rate oi
`settling of portides. Particie size reduction also can contrtbufh significantly to suspension stability. These
`Factors are important in the formulation at physically stable suspensions.
`
`Astraleneca Ex. 2097 p. 8
`
`

`
`350
`
`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 floating particles wouldbe quite difficult to dis-
`tfibute uniformly in the vehicle. The rate of sedi-
`mentation may be appreciably reduced by increas-
`ing the viscosity of the dispersion mediurn, and
`within limits of pracficalitythis maybe done. How-
`even a product having too high a viscosity is not
`generally desirable, because it pours with difficulty
`and it is equally ditficult to redisperse the suspen-
`soid.'1'heretore, itthe viscosity ofasuspensionisi.n-
`creased,itisdoneso onlytoamodestextentto
`avoid these difficulties.
`
`The viscosity characteristics ofa 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 Brookfi.eldVis-
`cometer, which measures viscosity by the fame re-
`quired to rotate a spindle in the fluid being tested
`{Fig 13.3).
`For the most part, the physical stability of a phar-
`macetttical suspension appears to be most appro-
`priately adjusted by an alteration in the dispersed
`phase ratherthan through great changes in thedis-
`persion medium. In most instanoes, the dispersion
`medium is supportive to the adjusted dispersed
`phase. These adjustments mainly use concerned
`with particle size, uniformity of particle size, and
`separation of the particles so that they/are not likely
`to become greatiylargerorto forms solid cake on
`standing.
`
`Physical Features of the Dispersed
`Phase of .1 Suspension
`
`Probably the mosticoportant single oonsideration
`in a discussion ofsuspensions isthe size ofthe drug
`particles. In
`pharmaceutical suspensions.
`the particle diameterisbetweeiii and50 p.m.
`
`Synchronous motor
`
`Speed selector knob
`
`On-oil toggle switch
`
`
`
`clutch lever
`
`
`Knuded out
`
`Handle
`
`Painter
`
`
`
`Jewel bearing support
`
`Spindle ooupfing nut
`
`Immersion marl:
`
`Sphdle body
`
`Fig. 13.3 Sdtematic drawing ofthe Braalrficld Visrometrn rcburtesy offlmaatfield Engineering LobDralmis_'.J
`
`Astraleneca Ex. 2097 p. 9
`
`

`
`Particle size reduction is generally accornplished
`by dry—rru'llir1g prior to the incorporation of the dis~
`persecl phase into the dispersion medium. One of
`the most rapid, convenient, and inexpensive meth-
`ods ofproducing fine drugpowders ofabout 10 to
`5|] pm size is micmpultwermfion. Micropulverizers
`are high-speed, attrition or iznpactmills which are
`eflicient in reducing powders to the size acceptable-
`figrmostoraland topical suspensions. For still finer
`particles, unda 10 pm, the process-offiuid ertcrgy
`grinding. sometimes referred to asjst-nn‘Ur"ng or mi-
`crunizing, is quite effective. By this process, the
`shearing action of high velocity oornpressed air
`streams on the particles in a oonfined space pro-
`duces the desired ultrafine or inicronized particles.
`The
`to be rnicronized 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 of the
`method may be employed
`in instances in which the particles are intended for
`parenteral or ophthalmic suspensions. Particles of
`extremely small dimensions may also be produced
`by spray-drying 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 circulating in the cone."i‘l1e result-
`ing dry powder is then collected. It is not poible
`for a ootnrnunlty pharmacist to achieve the same
`degree of particle-size reduction with such simple
`equipment as the mortar arid pestle.
`However. many
`drugs are commer-
`cially available. and when needed may be pun
`chased by the pharmacist in bulk
`As shown by Stokcs’eq:uatiort. the reduction in
`tltepartirzlesizeofasuspensoidisbeneficialtothe
`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 shotlld avoid reducing the
`particle size to too great a degree of fineness, since
`fine particles have a tendency to torm a compact
`cake upon settlingto the bottorn of the container.
`The result may be that the cake resists breakup
`upon shaking. and forms
`aggregates -of parti-
`cles wltich are oflarger dimension and less sus-
`pendable than the original suspensoid.'l'ne particle
`shape of the suspensoid can also affect coking and
`product stability. It hasbeen shown that syrnmetr't—
`cal barrel-shaped particles of calcium carbonate
`produced more stable suspensions than did asym-
`metrical needle-shaped partides of the-some agent
`
`Diapers: Systems
`
`3'51
`
`The needle-shaped particles formed a tenacious
`sediment-cake on standingwhich could not be re—
`distributed whereas the barrel-shaped
`did
`not cake on standing {'1}.
`‘It: avoid the formation of a cake, measures must
`be taken to prevent the agglornetalion of the parti-
`cles into larger crystals or Into masses. One corn-
`mon method of preventing the rigid cohesion of
`small particles of a suspension is through the in-
`tenlional formation of a less rigid or loose aggrega-
`tion or the particles held together by comparatively
`weak particle-to-parl'ide bonding forces. Such an
`agregation of particles is termed aflac or aflocmle;
`with tlocculated particles forming a type of lattice
`structure that resists complete settling (although
`floss settle more rapidly than line. individual parti-
`cles) and thus are less prone to compaction than
`untlocculsred particles. 'I'he Elots settle to form a
`higher sediment ‘volume than untlooculatsd parti-
`cles. the loose structure of which permits the ag-
`gregates to break up easily and distribute readily
`with a small amount of agitation.
`Thercaresevetaltnethodsofp.repar:ing£loc-
`culated
`suspensions,
`the
`choice
`depending
`onthetjlpeofdrugirnrolvedandtrtetype nfproduct
`desired. For instance,
`in the preparation of an
`oIa1sLIspensionofadn.1g,c1ays suchas diluted ben-
`torfiterrtagrnaarecommonlyemployedasthe
`floccttlating agent. The structure of die bentonite
`magmaarld ofotherclaysused forthispurpose also
`assists the suspension by helping to-support the floc
`once fonnedwlmndaysareunsuitable asa'gents.as
`in a parenteral suspension. Erequenfly a Hot: of the
`dispersed phase can be produced by an alteration in.
`the pH of the P.YEP3ratioIt {genet‘a.l.ly to tlte-region-of
`minirrrum drug solubility}. Electrolytes can also act
`as Elocorlating agents. apparently by reducing the
`electrical barderbelweern the particles of the sus-
`pettsoidartdfonnirtgabridgesoas l:ol.’Inktl1err1to-
`gather. The carefully
`conccntrafion of
`nonionic and ionic surface-active agents (surfac-
`tants) can alsoinduce theflocculafion ofparticles in
`suspension and increase the scdirnentation volume.
`
`Dispersion Medium
`
`oftentimes, as with highly Elocculated suspen-
`sionnthe particles of a suspension settle too rapidly
`to be-ooosisterttwitlt what might be termed a phar-
`mateutical1y.elegantprepa.rafion..The rapid settling
`hinders the accurate measurement of dosage and
`from an esthelir point of view produces too un-
`gghtly a supernatant layer. in many of the commer-
`cial suspensions. suspending agents are added
`
`Astraleoeca Ex. 2097 p. 10
`
`

`
`352
`
`Disperse Systems
`
`to the dispersion medium to lend it a sI1'ur:tu.re to
`assist in the suspension of the dispersed phase.
`Carboxymethyleellulose, tnethylcellulose, mic1'ocrys-
`talline cellulose, polyvinyl pyrrolidone, xanthan
`gum, and bentonite are a few of the agents em-
`ployed to thicken the dispersion medhirn and help
`suspend the suspensoid. When polyrneric sub-
`stances and hydmphilic 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 slowiy available for their
`therapeutic function. Also. the amount of the sus-
`pending agent must not be such to render the sus-
`pension too visoous to agitate (to distribute the
`suspensoidl 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 Elocculated, and the
`amount of material requiring support.
`The solid content of a suspension intended for
`oral administration rnayvaiy 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 particu.la.t’ drug in a convenient
`measure of 5 ml. or one teaspoonful. Pediatric sus-
`pensions are formulatecl to deliver the appropriate
`close of drug by administering a dose-calibrated
`number of drops. Figure 13.4 shows commonly
`packaged oral suspensions adrnlnistered as pediatric
`drops. Some are accompanied by a calibrated drop-
`
`
`
`Fig. 13.4 Eramples of oral pediatric suspeusioirs showing
`package designs of :1‘ Emil:-in dropper device and a cnlibmrcd
`dropper ccwnrpxmyirrg H19 medioutiorr container
`
`per, whereas other packages have the drop capabil-
`ity built into the container. On administration the
`drops may be placed directly into the infanfs 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. in some instances the dispersed
`phase has an affinity for the vehicle to be employed
`and is rea.dily”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 medium. Alcohol, glyoerin, 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 we-tted. the dispersion medium (to whidi have
`been added all of the formulation’s soluble compo-
`nents such as oolorants, fiavorants, 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. "lite
`
`final product is then passed through a colloid mill or
`other blender or mixing device to insure unifonnity.
`Whenever
`appropriate.
`suitable
`preservatives
`should be included in the formulation of suspensions
`to preserve against bacterial and mold corltaminaiiion.
`An example formula for an oral suspension fol-
`lows (2). In the example. the suspensoid is the
`antacid aluminum hydroxide, the preservatives are
`methylparabcn and propylparaben. with syrup and
`sorbitol solution providing the viscosity as well as
`the sweetness.
`
`Astraleneca Ex. 2097 p. 11
`
`

`
`353
`Disperse Systems
`
`
`U PhysicalPharmacyCapsule132
`
`Rheology
`
`Rheology is the study at How and involves the viscosity characteristics of powders, tiuids, and semisaiids.
`Materials are divided into two general categories depending upon their How characteristics: Newtonian
`and non-Newtonian. Newtonian tiaw 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. it-ton-Newtonian flow includes plastic, pseudoptastic and dilotant Flow.
`
`Newton's Law of Flow relates parallel layers of liquid, with the bottom layer fixed, when a Force is placed
`an the top layer and the tap plane moves at aonstant velocity and each lower layer moves with a veloc-
`ity directly proportional to its distance item the stationary bottom
`The velocity gradient, or rate of
`shear idv/dr], is the diiterence of velocity dv between two planes of liquid separated by the distance ctr.
`The Force {F'/Al applied to the top layer that is required to result in itaw (rate of shear, G) is called the
`shearing stress [F]. The relationship can be expressed.
`
`E- i
`Avfldr
`
`where 1' is the viscosity coefficient. or viscosity. This relationship is often written
`F
`.‘''=(;
`
`where F = F’/A and G = dv/dr. 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 tine with the siope at the line being 11. The unit at viscosity is the poise, which is the shear-
`ing force required to produce a velocity at i cm/sec between two parollei planes at liquid, each 1 cm3
`in area and separated by a distance of 1 cm. The most convenient unit to use is the ceniipoise, or op
`[equivalent to 0.01 poise].
`
`These basic oonoepts can be illustrated in the toilowing two graphs.
`
`RateatShear
`
`Kb
`
`Viscosity
`
`Shearing Stress
`
`Shear Rate
`
`EXAMPLE ‘I
`What'is the shear rate when an oil is rubbed into the skin with a relative rate oi motion between the fin-
`gers and the skin of about 10 crn/sec and the Film thickness is about 0.02 cm?
`
`e= =5oosm-t
`
`Astraleneca Ex. 2097 p. 12
`
`

`
`35-1
`
`Dispcrse System
`
`Rheology (Continued)
`
`The viscosity of Newtonian materials oan be easily determined using a capillary viscometer, such as the
`Osiwald Pipet, and the iallawing relationship:
`
`11’ = ldcl
`
`where 'r|'= viscosity.
`is = a coefficient, including such factors as the radius and length at the capillary, volume at the
`liquid flowing, pressure head, etc,
`I = time, and.
`cl = density at the material.
`
`The official cornpendia the USP-NF, utilize Kinematic Viscosity, which is the absolute viscosity divided by
`the density at the liquid, as follows:
`
`Kinematic viscosity = 1179
`The relative viscosity ata liquid can be obtained by utilizing a co illory viscometer and aornparin data
`with a second liquid at known viscosity. provided the densities o the two liquids are known, as icalavvs:
`11’/11‘. = lptl/{n.t.l
`
`sxmusz
`
`At 25°C, water has a density of 1.0 /‘cc and a viscosity of 0.8?5 -cps. The time of flow of water in a
`capillary visoometer is 15 sea. A 50 aqueous solution at glycerin has a "How time at 750 sec. The den-
`sity oi the glycerin solution is 1 .216 9/oc. What is the viscosity at the glycerin solution?
`
`“
`
`i1ii15i
`
`'
`
`“F”
`
`EXAMPLE 3
`The time at Flaw between marks an an Ostwald viscometer u