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. 2083 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. 2083 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. 2083 p. 4
`
`

`
`
`
`DOSAGE FORM DESIGN:
`
`BIOPI-IARIVIACEUTIC
`
`
`
`AND PHARMACOKINETIC
`CONSIDERATIONS
`
`Chapter at a Glance
`
`General Principles of Drug
`Absorption
`Passive Dzfifilsion
`Specialized Transport Mechanisms
`Dissolution and Drug Absorption
`Surface Area
`Crystal or Amorphous Drag Form
`Salt Forms
`Other Factors
`
`Bioavailability and Bioequivalence
`FDA Bioamilability Submission
`Requirements
`Blood 1'or Serum or Plasma) Cmtcentratiom
`Time Curve
`
`Routes of Drug Administration
`Oral Route
`Dosage Fcmms Applicable
`Absorption
`Rectal Route
`Parenteral Route
`
`Dosage Forms Applicable
`Subcutaneous Injections
`Intraxnuscular Injections
`Inn-avenous Injections
`Intzmderrnal Injections
`Epicutaneous Route
`Ocular, Oral and Nasal Routes
`Other Routes
`
`Parameters for Assessment and Comparison
`ofBioava1'IabiIii_y
`Peak Height
`Time of Peak
`Area Under the Scrum ConceI1t1'al:ion Time
`Curve
`
`Bioequioalerrce of Drug Products
`
`Fate of Drug After Absorption
`Drug Metabolism (Bfotransformation)
`Excretion of Drugs
`Pharrnacolonetic Principles
`Half-Life
`Concept of Clearance
`Dosage Regimen Considerations
`
`AS DISCUSSED in the previous cltapten the biologic
`response to a drug is the result of an interaction be-
`tween the drug substance and functionally impor-
`tant cell receptors or enzyme systems.'I'he response
`is due to an alteration in the biologic processes that
`were present prior to the drugs adrm’nistralion.'Ihe
`magnitude of the response is related to the con-
`centration of the drug achieved at the site of its ac-
`
`I:ion.This drug concentration depends on the dosage
`of the drug adm:i.n.istered, the extent of its absorp-
`tion and distribution to the site, and the rate and ex-
`tent of its elimination from the body. The physical
`and chemical constitution of the drug substance-
`particularly its lipid solubility, degree of ionization,
`and molecular 5ize—detem'u'nes to a great extent
`its ability to affect its biological acfivity. The area of
`101
`
`Astrazeneca Ex. 2083 p. 5
`
`

`
`102
`
`study embracing this nelationship between the
`Physical, chemical, and biological sciences as they
`applytodmgs,doeage£orms,andtodmgacfionha.s
`beeny'venthedesczipttvebem1biop!u:msowuin
`Ingenera1,Eoradrugtoe'xertitsbiologicefEect,it
`must be transported by the body fluids, uaverse
`the required biologic membrane barriers, escape
`widespremidjshzibutiontounwanll.-tlareamexxdure
`metabolic attack, penetrate in adequate concentra-
`tiontothesitesofection, andioteracthmaspecific
`fashion, causing an altemtion ofoellular fum:tion.A
`simplified diagram oefthis complexseries of events
`between a drug's adnamistraflortarldits e]J':o1inn-
`tlon is presented in Figure 4.1.
`The abeorptiotx, dis!-.-ibution, blotranefiomtaflon
`(metabolism), and elimination ola drug from the
`bodyaredynamicprooessesthatoonfinuefiomthe
`time-adtugistakenmmtilallofthedrughasbeen
`:emovedfI'omthehody.Therotesatwhid1tl1ese
`
`anclthe
`processes ooourafiect the onset.
`duration ofthe drugs activity within the body.The
`area of study which eluctdatea the time course of
`drug concentration in the blood and tissues is
`termed m. It is the study of the ki-
`netics of absorption, d1'sl:n'bufion, metabolism and
`excretion (ADMB) of thugs and their L‘OIl'E$pDtld-
`ing phaxmacologic, therapeutic, or toxic response
`inmin'ua]sa1'LdmaI1.fi1Ithe1;.einceorLecln.1gr:1a;.r
`alter the absorption, distrzihution, metabolism or
`excretion of another drug. ph also
`maybeappliedinthestudyofinteractionsbetween
`dmee
`Onoe adrugis admi.nistseredarIddJ:ugabsorp-
`tionbeginsthedmgdoesnotremaininasingle
`bodylocaticm. but ratheris distributed Eh.tougl'1.out
`the body until its ultimate eiixnination. For in-
`stancefoflawingfimoraladmjrdsuauonofadtug
`and its entry into the gastrointestinal tract. a por-
`
`
`
` Oral
`
`administratlon
`
`Gatrointsstinal
`tract
`
`
`
` Excretion
`
`
`
`
`Intravenous
`injection
`
`
`
`Circulatory
`systems
`
`tntramusculer
`Injection
`
`
`
`Subcutaneous
`lniection
`
`Fig.4.}. Sd:mmfiowruamtmofmwq'dmrmmnmehEm;ad.naemefidm§qflaflm&odnhb#mmbyw-
`ionsroutes.
`
`Astraleneca Ex. 2033 p. 6
`
`

`
`Dccegrfcrm
`
` 'md Pkcmuwkfncfl‘: Camidemfiwu
`
`W3
`
`nonn§thedmgisabsorbedintotheci:cuIaIaorysys—
`temfrom-whichitisdistribuhedtoti'Leva1imJsotl1er
`body fluids, tissues, and organs. From these sites
`flaednlsmayremm to the-circulatorysystemand
`beeicctetedtlttoughthekzldncyasauchorlhedrug
`may be metabolized by the liver or other cellular
`sites and be excreted cs metabolites. As shown
`in Figure 41. drugs adrni.n.is’ce:ed by intravenotx
`injecfinnareplaceddixeciiyintoflgedmflatmy
`sysheny {hereby
`the absorption process-,
`whiehisrequiredfxcmal1otherrcutescfadminis—
`lmtion
`eflects
`'I'1xeva:icusbodyl'ccations:o whidzadxugtraw
`glsmeybe viewed aseeparate counparixnentmeech
`containing some fraction of the administered dose
`e£d.mg.’I'he |:I:ansfercfdrugE|'omtI1e bloodto other
`bcdylccations is generallya mpidpmcess andis
`new.-wible; thatis. the drug-meydiffuee backinto
`thedrcuiaficn.'Ihe drugintheblcod therefinre ex-
`isisin Mm the drugfi'H:heot11.ercom-
`part:ner.1irs. However, in this equiflbfium state, the
`concentraflon otthe drug in the bloudmay be quite
`diffiezent (greaterorleaser) than the ccncerauauon
`ofthe clrugin I-he ctl-n.erccrnpar|men!s.Thi.q isdue
`large.lytofl1ep1iysiocl1e1t1ica1properfles ofthe-d:u_g
`anditsr!eEulI:antabi1i’tyti0le&vetheb]oodandtra—
`vc:sethebio1ogica1me1nbranes.Ccn:aindrugsma5v
`leavethe circulatorysysnemrapidlyand mmpletebg.
`w=hereas0thetdmg5maydososlowlyandudthdif-
`ficu1ty.A. number of drugs become bound to blood
`proteins, panicclarlythe a1h11mins,andcn1ya mall
`Eracfion of the dmgadrrlinistered may acluallybe
`fiaundatlccationsoussidcofthecirculatoxysystern
`at a-given ti1ne.‘l‘he transferoidrugfzcm one
`comparlment to enotlier is mathenleflcafly asso-
`I:'iatedwit.'n aspedficrate constant deacribingthet
`parfinzlar transfer. Generally. the tale of transfer
`of a drug from one ccrmpartrnent to another is
`proportional to the concentration 01’ the drug in
`the mmparhnent front which it Eidis: the greater
`the conceniration, the greater is the amount of
`dtugtcansfer.
`Metaboflsmisflxemajorplntnssbywlfichfiareiyl
`
`bcd3LIz1tl'ieprccescc£u1etabo1isn1adnJ.gsubc_Iance
`may be
`into
`ac-
`tive or
`both the drug
`aubslance and lie m.etabo]ite(s) areactive and exert
`phanznamlogic elfecrs. For example, the
`d:ug;nazepam(C.erdrax)meIabolize5,iI:part,tocx—
`azepam (Serax), which also has antiaxuéely efieem
`Insome irnstancesaphanrnacolqgicallyimclivednzg
`{tetmedaprcdrngimzybe admirfisteredforiiie
`known efifects of its active metabolites. Dipivcfric,
`
`fincaantpleisapzodnagofepirlephdxtefcmwedby
`the eslaerification of epinephrine and pivalic acid.
`Clhis enhances the
`characber ofthe drug,
`nndasaccnsequenceits penetration intotheani:e—
`riot chamber of the eye is 17 I':imes that-afepineplb
`rine.Wi.thinthe-eye,HC1isconveri:edby
`enzyrnaticlwdroiysistoepirnephxixve.
`Themalebclismofadrugtoinactiveproductsis
`usuellyan iiievetsfble pxocesswhich r:I.t|mi.mtesJ'n
`Ehem¢:refiflnDfthe'dxug&Umthebody,usue]ly1Pia
`the u1i.ne.Thep may calculate an
`efi:nir:a.tionra1eccnatant(termcdk.,) faradmg
`to describe its rate of eiimincfion from the body.
`The term elftrnimlim refiets to both metabolism
`
`ande:-acretion.Fcrdn:gstha£areadminiete1edin-
`tmrencusly, and foe:-e£cr_e involve no absorption
`process, the task is much less. complex than f_ur
`dmgsadnninistezedoraIlycrbyot11errcutes.Inii1e
`lntterin3tances,d.rugab5orptionanddruge1in1jna-
`lion are occurring simttltaneously but at different
`races.
`
`General Principles
`of Drug Absorption
`
`Bfioreanadnfilfietereddrugcanauiveatiissite
`ofacrlon in effective concentrations, it must sur-
`mount a number of barriers. These barriers are
`
`chiefly a succession of biologic membtanes such
`as those of the pet:oin1es1i:1a1 epithelium, Jung,
`b1oo<1,andb:ain-BodymembIaIlesaregenera1l'y
`classified as th:_ee main types: (41) those composed
`ofseue:a1Iayerso£ceIla,a5tl1eafl|;(bJt1'losecom-
`pceedcfaalng1e-layercfceI]s,astheincestina1ep-
`Itheli1m1:and{c)thoseofle3athanonecel1inthick-
`ness,astheme1nh.ranec£asin3_1ecel1.Inmcst
`instances adrugsubstance mustpascmore than
`oneo£tI1.esem_.embnne tglpesbefoceitread-nesim
`siteO£ac!ion.Forin3tance,adn.tgtaIcenora]1yrrnJst
`fizstixaverecthegasttointestirlalmernlranes (storm
`ac1'L,s1na1landlaIge311tesflrLe}:S'3inentra.nceinra
`fliegerteraldrmslaficrypasstofiteorgan-ortissue
`withwhich ithas afini1y,gainentI:anceincoihat
`tissue.andthenenteIh1toit9individJ1a1oeJ]s.
`Although the chelznistry of body men-nbranes
`differs on_e- from another, the membrarles may be
`viewed in -general "as a. bimolecuiar lipoid (fat-
`contain1'.ng)!ayeIa:ltached unhoth sides to apro-
`teinlayer. Drugs arethoughttopcnetrace thse bi-
`ologic membranes in two general ways: 1)bypas-
`and2)thmughspecializedttanspoIt
`mecl1a11isn'|s.IrVithinenchofti1esemaincatcgo::ies,
`more cleazdydefined pxuceeseshevebeenascctbed
`tcdrugtransfex.
`
`Astrazeneca Ex. 2083 p. 7
`
`

`
`10%
`
`Passive Diflilsiou
`The term passive drjfiirsionis used to descdbe the
`passage of (drug) molecules through a membrane
`whichbehaveeinertlyin thatitdoesnotactively
`participate in the process. Drugsabcorbed accord-
`ingtotl'Iismethoda:E saidtobepasaiodyabsotfied.
`The absorption prooeaeis driven by the concentra~
`lion gradient (is, the
`in conoenhafion)
`Eldfitlng across the membrane, with theoassage of
`drug molecules oocuning_p1in1arilyfromtheside of
`high drug conoentratiommost drugs pass through
`biologic membranes by diffimion.
`Paaorve‘ drfiusr‘‘on is described by.FicIt’afimt km
`which states that the rate of difluslon or transport
`across a membrane (dddt) is
`to the
`difference in dnrg concentration on both sides of
`the membrane:
`
`—§=v<crc-9
`
`lnwhich Q and Cgrefierto the drugoonoentratloria
`on each side of the membrane and P is a perme-
`ability ooeflicient or constant The term C, is cus-
`tomarily used to represent the compartment with
`the greater concentration of drug and thus the
`transport Of drug proceeds from oornparunent one
`(e-.3., absorption site) to ootnpartment two (e.g.,.
`blood).
`'
`Because the concentration of drug at the site of
`abmlpfion {C1)isueuallymuchgreaterthanon the
`otheraide offlxe membrane, due to therapid dilu-
`tion ofthc drug in the blood and in subsequent
`distribution to the tissues, for practical purposes
`thevalue of'C, — C, maybetaken simplyas thatof
`C1 and the equation written in the standard fiorm
`for a first orderrate equation:
`
`+fi=Pc:
`
`The gastroirttesfizul ahsoqifion of most drugs from
`solution occursitlthis rnarmcrinaccovdancewith
`therateis enton
`drug concentration, i.e_., doubling the dose doubles
`the transfer rate. The magi-etude of the pen:neabil~
`ityconstaznt. dependaonthe diffusioncoeficlentof
`the drug. the thiclcneas and area of the absorbing
`membrane, anclthe penneal:-ility offl‘r.emeInb1a.r1e
`to the parficular drug.
`Because of the lipoid nature of the cell mero-
`braneitiahighljrpernteablemlipid solublesulr
`etances.'I'he rate of'di.ffua'1on ofa drugmos the
`menibrane depends not only upon its r._'onoentm-
`Iionbutalsouponthetelativecxtentofitsaffirdty
`for lipid and rejection of water (hhigh lipid partition
`
`ooe$denI:)."l'he .grea1:eriI:.afl':b-nity for lipid" and the
`morehydrophobicitiathefasterwillbeitsrate-of
`penetration into the lipidvrich membrane. Er)r|11ro-
`rnycin base, for example, possesses a higher parti-
`tionooe££icier1tfl1ano&1erexytluo:rayti:mou:1po1mds.
`e.g.. estolatc, gluceptate. Consequenfly, the base is
`tltcpneferredagentfortlne topicaltreaorrentofamc
`wd-tare penctrafion into the skin is desined.
`Because biologic cells are also permeated by
`water and lipid-inoohlble substances, it is thought
`that the membrane also contains water-filled pores
`orcltannelstliatperniitthepassage ofthese types
`o£subatances.AswaterpaasoainbuIkao'ass a
`porous membrane. any dissolved solute molecu-
`larlyarnall enouglttotcaversetheporespassesin
`hyfiltmtion. Aqueous pores wryinfle from mem-
`branetomiembzaneandtl-nusin theirirtdividual
`perrneability r:hatactefistica for certain drugs and
`other substances.
`Therrtaforilyofdrugstodayareweakcnganic
`acids or bases. Knowledge of their individual ion‘-
`iaafion or
`clraracteristica is important.
`beca1JsetheiIabeorptionisgavemedtoala.tgeex-
`tent M theirdegtoes ofionization astheya.repre-
`sented to the membrane-barriers. Cell membranes
`are more permeable to the unionized forms of
`drugs than to their ionized forms, mainly because
`ofthe greaterlipid solubflltyofthe urdonizedforms
`andto the highly charged nature of the cell mem-
`brane which results in the binding or repelling of
`the ionized drug and thereby decreases cell pene-
`traliort Mao, ions become hydrated through asso-
`ciation with water molecules. resulting in larger
`particles thantlmeundissodatedmolecule andagain
`decreased penetrating capability.
`flwdegreeofadrugsiorfizafiondependsboth
`on the pH ofthe solution inwhich it is presented
`to the biologic membrane and on the pic, or dis.-
`socialion constant, of the drug (whetheran acid-or
`base-).The concept o£pK,is derived Erornthe Hen-
`derson-E-iasselbalch equation and is:
`Farm: acid:
`
`.
`' nixed
`salt}
`PH ' PK" J" mg u1llilomaed°;1r:h(Eadd)
`Ibra bass.”
`
`= £m
`PH PK‘ + 103
`ionized cone. (salt)
`
`Since tl'LepHofbody£luidsvariec(stomacl1,pH_1;
`lumen of the lntestlrte. pH 6.6; blood plasma. pl-I
`7.4},theabsorpfionofadrugErumvariousbodyElu—
`idswilldifierarulrrraydictatetosotrieextentflie
`type of dosage form and the route of adminis1ra-
`Eon preferred fora given
`
`AstraZene.ca Ex- 2083 p. 8
`
`

`
`Dcs@PonnIJzsfgr1:Bio;1iw1nauuflcm|dPhmw:ncakine!ic Cousidemlims
`
`105
`
`Byteanangingthe equaticmforan acid:
`
`unio
`
`mncentra 0 1
`
`_
`PK’ H PH #105
`one-can thematically deteunine the relative extent
`towh.ichadmgremainsm1Ionizedunderva1ious
`conditions ofpI'L'I1JisIs.p_a:11:L1la:ly119efulwhen
`applied In condilzloras nfhudy fluids. For instance, if
`aweakncidhavh'|gapI(_,.df44.-sassnntedtobeirm
`anemdmnma-ntc:EgtIicjuicnviti1apHofLthe
`leftside oft11ee:[ualiunwouIdyie1dti1enuml:Iat3,-
`w]:IichwouLdIrtaaI1thattl1e:atiaofu:niorLimdto
`iorlizeddrugpatficleswutxldbeaboutlflflfl mi",
`andgastricabsotpfionwouldbeeaa:eIlent.Atthe
`pHofp1as1I1at1'LereVenIewDuldbetrue,andinthe
`blood the dmgwouldbe lawly-in the ibruized
`£ug:m.'lhb1e 4.1 presenls the :Efi-.ctnEpI-[on th¢iun-
`izafion of weak eleclmlytes, and Table 4.2 offers
`some representafive pK, values of nomxmn drug
`substances.
`_
`Fromtheequationandfmm'lhh1e4.1,itmaybc
`seenthatndmgsubatanccis-halfionizadatapfi
`value. which is equal to its p.K,.ThuspK. may be de-
`finedasthepl-Iatwl'dchadrugis50‘H:ionized.For
`e_:arnple. phenobarbital has a 9K, Value of about
`'7.4,andinplasma (pH 7.4] itiapmaentasionized
`anduniaru'zedfi:m'm'n-aqualammmts. I-Iaweven a
`drugsubstance nannotreach thebloodplaamafor
`disuibutionfluoughoutthebodytmlessitisplaced
`theredi1ectIytl1roI.:ghi111mvenm:ainjectiono:isfa-
`Vnrably absorbed from 5 site alongiis mute of mix):
`as the gaslrointwtional tract, and allovwed ta paaa
`inhothegenera1circIJ]a,fiDm.Assho1mi11TabIe4.2,
`phenobarbital, a weak acid, with: pfi, of Hwauld
`
`'I‘l1¢fE£fectolpI-Ionthelunizatiunuf
`TdIIle§._1.
`wgak E|nI‘.l:ro_lyfl.'8' pl‘.-1:1: as Unirmized
`Lflflbaknm
`§fPkal:A.ciai
`99.9
`0.100
`-3.0
`99.0
`0.990
`-2.0
`90.9
`9.09
`-1.0
`83.4
`16.6
`-0.7
`76.0
`226.0
`-0.5
`61.3
`38.7
`-0.2
`50.0
`50.0
`0
`38.?
`61.3
`+0.2
`24.0
`7&0
`+0.5
`‘:06
`00.4
`+0.5’
`9.09
`90.9
`+1.0
`0.990
`09.0
`+2.0
`0.100
`99.9
`+3.0
`
`
`‘Repdnhadwflh pennlasinn from Duluisio yr." Swin-
`t0aky‘N.Am]1’lm.cm 1965;137:149.
`
`III‘. Values fllrfiumemtldlc and
`Tabla 0.2.
`Elfiillnfllsl
`
`Acids:
`
`Aoetyisalizylk add
`‘Barhlual
`
`Bases:
`
`Benzylpexfidllin
`Bari: add
`Dicounnaml
`Phenobarbital
`Phenylnin
`Sulfarfilamida
`Iheuphylljne
`T11.lopa1ta!
`Iblbutannide
`Wufafin
`Arrqahetanflne
`Apomarphme
`Atrop1‘.ne
`Ca£EeJ11e
`Gulmdiucpodde
`Cocaine
`Cudeim
`Guanemidine
`Morphine
`Pmcalzie
`Qtllnine
`lhsezpirte
`
`PK.
`
`3.5
`7.9
`
`2.0
`9.2
`5.7
`7.4
`B-3
`10.4
`9.0
`7,6
`5.5
`4.8
`9.8
`7.0
`9.?
`0.8
`4.6
`3.5
`7.9
`113
`7.9
`9.0
`3.1
`6.6
`
`belargely undissodateditxthegaslricerwixozunexat
`ofpH1andwmLldlikelybewe1labsorbed.Ad:u,g
`m.ayent2:thecimu3afionrapid1yandathighcon~
`cernmfions if membrane penetraticm is easily ac-
`compl.tshedoratalawratea.ndIowlave1ifthed:1.tg
`.isnotreadflyabem‘bed£romitsruute-ofentcy-.'I11e
`pH of-the drug’: cturent environment influences the
`me and the degree ufiis further
`be-
`causeitbeo:Irnesmarear1e$1miun1zedar|dthem—
`flute more or1esslipid—pet1eJtrafi'ngLu-Lderaome can-
`-diu‘nnofpHthan1md;eranother.Ifantmionizad
`maieculeisabletodiffizsethroughtheliptdbatrier
`and I'.E'.n'I.a.i1'\ unionized in the new env1mnme:nt.it
`mayremmtoitsfaxmerlocafionorgoonto-anew
`one.Hi:wevenifinfhenewemfrnnmaentitisg:eafly -
`ionizedduemtflemfluenceoffitepfloftheseound
`fluid,tk]Jketywl]1beunahletou0sSthe:rIembrane
`with its former ability. Tfms a concentmiou gradi-
`ent of a drug usuallyis neached at equflibfium on
`each side eta-meunbmne dueru diffexantdegteesnf
`ionizafi.onoccurzingoneachside.Asnmma:yofthe
`concepts ofdieasuciationliorzizafioruis fmmdinthe
`physical pharmacy capsule Errlitleii "pKa.¥Dimo<':ia-
`tionCur|sta:'1ts”11\C11apber3.
`Itia often desirabie Eorphazmaceutical scientists
`to make structural modifinaiions In organic drugs
`
`AstraZene.ca Ex- 2083 p. 9
`
`

`
`106
`
`Dsssgsfom Design: Biephamua-nlicandPh Considerations
`
`and thereby favorably alter their lipid solubility.
`partition ooeficienlz, and dissociation oonstsnts
`while
`the same basic phannecologic
`acfivity.'I'hese effiorts frequently result in increased
`absorption. better therapeutic response,a.ud lower
`dosage.
`
`.Spet.-ialized Transport Mechanisms
`
`to the passive transfer of drugs
`In contrast
`' and other substances across a biologic membrane,
`oertainsubs’sinces,.i11eludingsomedn1gser1dbio—
`logic metabolites are conducted across a membrane
`through one ofseveral poshilated specialized trans-
`port mechanisms. This type of transfer seems to
`aocountiorthosesubstenceamartynaturallyooeur
`ringas amino acidsandglucose, thataretoo lipid-
`insohibletodissolveirttheboundaxyandtoolarge
`fOflDwDrfil!:ertfuU11ghtl1epD1Es;'I‘l'tist)Ipeofttan5-
`port is thought to involve membrane components
`&1atmaybeer\z)nna!0a'sD1ne0thertypeota3_!eI1tca~
`pableoffonriii-Lgacomp1exwiti1ti1edt'ug{orother
`agent} atthesu:Eaeememhrane,.aEte:whichthe
`oomplexrnovee auossthemembranewhere=the
`dmgisreleaaechwitltthe ca.'o.'ierretuIningtothe
`original s1_.u:Eaoe. Figure 4.2 presents. the simplified
`scheme of this process. Speeializedlzanspert maybe
`difierenliated from passive tranéerinthat the for-
`merpaocessmaybeoome‘sstu:ated“aslt1ean1o:ant
`ofearrierpteseiitforagivenstihstsncebeoomes
`completely boundwiih thatsubetanceresultingin a
`de1ayinthe"fen'yin3”or
`Other
`ieamresofspecialized trsnspoxtinclude the speci-
`licitybyaearnierforaparticillartypeofchemitml
`
`armature so that if two substances are transported
`by the samemechanism.onewi]1 competitively in-
`hibit the transport of the other. Furtheo the trans-
`port mechanism is inhibited in general by sub»
`stance that interfere with cell metabolism. The
`
`tennactivcimnsport. asasul:u:lassificationofspe—
`cialized transport. denotes aprocesswiththeaddi-
`tionsl feature of the solute or drug being moved
`across the membrane against a concentration gra-
`dient, that is, from a solution of lower ooncentra-
`tion to one ofahigher concentrafiononiftlie solute
`is an ion, against an eleclzochenlicsl potential gra-
`dient. In contrast to active transpot-_I,_,Fsc;'litated dif-
`fi.:s:'¢m'J'.s a specialized transport mechanism having
`all of the above characteris1:’cs' except that the -solute
`is .not_1.-ransierred against a concentration gradient
`andmayattain thesameooncentration inside the
`cell as that on the outside.
`Manybody nutxients, as sugars and amino acids,
`are transporhscl across the membranes of the gas-
`trointestinal tract bycarrierprocessss. Certain vita-
`mirIs,as tl1iam'111e,niacin,1'iboE[avin andvitarnin B5,
`and drug substances as methyldopa and 5-fiuo1=-
`ouracil, require active transport mechanisms for
`their absorption.
`Irlvestigalions of intestinal lranspoel have often
`uti1izedi:1si&4(attt1esite)erI'1Itrioo (in-tl-1ebody)an—
`imal models oraroitaa (oulfldethebody) transport
`models; h€l'W2V’Ei‘_.l'ECE1'IIIYOE.l.1 cu1!1.meu1oclelsofhu-
`man small-intestine absorptive cells have become
`available to investigate traruspout across intestinal
`epifi1elium(1).Bofl1passivea.nd t1‘anspurt—mediated.
`studies havebeen conductedto irlveeligate mecha-
`nisms as well as rates of transport.
`
`Dissolution and Drug Absorption
`
`Foradrugtobe a.bsoi'bIed,I'i mnstfi.rstbedis-
`solved in the fluid at the absorption site. Fox in-
`stan.oe,adrugadn'Linisteredoxallyintab1etorcsp-
`sulefmncszmotbeabsorbedursilthednagparticles
`are dissolved by thefiulds at-some point within the
`g3Sl1‘0i!ltEStln&1tI3Ct.Initl5ial1C£SinwI‘licl'1t1'le50l-
`ubflity Dis drtrgis dependent upon either anaddic
`orbssicmediiin-tthednlgwouldbedtesolvediri
`thestomaeh orintet.-tinestespectively (Flg.4.3).The
`procm bywhidtadrugpartidedissnlvesistemled
`tiissolutiorc
`As a drug particle tmdecgoes-di$o1ution, the
`dtugmoieeulnnthesuxiaeearetl-Lefirsttuenter
`into solution creating a satmated layer of
`solutionwhich envelopsthesnrfaoeofthesolid
`dmgpar1i:1e.Thislay'erofsoIutionis_refer:edtaas
`titedzfusionIaysr.Ftomthisdi£f1isicst1ayeothe
`
`Astraleneca Ex. 2083 p. 10
`
`c
`
`e
`
`I I
`
`I
`
`:
`
`o—a-fc >ro
`
`outside
`
`membrane
`
`Inside
`
`Fig.4.! Actiuetransporlvnsckauism.Dreprssmfsedrug
`msIetuis;C'rep1ssmtst§2eeurrierbl:hem1nb:wnsflVIsd§fisd
`fitnu O'R£lHy W!AusUPhs:-m I9m¢?:56flJ
`
`

`
`Biaphwmamuicmtdflmmflmfiufic Cmlsiilentiimts
`
`‘LIJ7
`
`fotho-1D hours. although thereissubstantia1vari-
`alionbetweenpeople,andc'veninthesan1epe:son
`o::d.lEfenentoocasiot1s.Vhz-Iaousiasclirliqueshavebeen
`usedto determine gastlic entptying time and the
`gastcoixwtestlnal passage ofdrug from various oral
`dosay forms, including the
`of dosage
`Emnsiabe1edwitl13anut1a-entittirtgradionudides
`lhmugh gmtrna sclnligtaphy (2; 3). The gastric
`errlptyingtinteforadrugismostmpidwith a fast-
`ingstomach. becoming slower as the food mutant
`is
`Changes in gastric emptying time
`andfor in intestinal motility ‘can affect dmg transit
`time and thus the-oppcuiunity ford:u_g-dissolution
`arldabsorptinn.
`Thesecharqges ::anbe.a£fectedbydrugs thepa-
`tientmayhetaJs:i11g.Cerlait1dn1gswiti'1antichoiin-
`ergic
`e-.g., ditryclominc HCL am.itl.'ipty-
`line HCI, have the ability to slow-dawn gastric
`emptying.'Ihiscanenl-nancetheiateofabsotption
`ofdmgsrlonnallyahsorhetl fromthe stomach, and
`reduce the rate of absorption of drugs that are'p:'i-
`maxily absorbed from the small
`Altemav
`tively, drugs which enhance gastric motility, e;g.,
`1a:catives,.ma}*canseso:tt1ed:11gstomovesoquick1y
`Enough the
`system past their
`absorptive siteatsuch ante toreduce-thssmount
`of drug actually absorbed. This effect has been
`demonstrated with digoxim whose absorption is
`significantly decreased by sccelemfing gastroin-
`testinalmotfiity.
`The agingprooess itselfmayalsoirufluence gas-
`hointurtina] absorption. In the el'd.et1y. gastric acid-
`ity, the number ofahsorpfive oells, intestinalblood
`flow, the rate of gasuie emptying and irttesiinal
`motility are all decreased. However, drugs in which
`absorption depends on passive processes are not
`affecredbyfinesefactmts asmuchas those'thatde-
`pend on active transport"m a.g., cal»
`dum..iro11.thiamine,arLdsugars.Adecresseingas—
`tricemptyingtimewouldbeadvantageousfoxthose
`d:ugsthata!eabsoIba,d&m1thes1nmachbutdi5-
`advantageotmfotthosedsugswlficiiateptoneto
`.3;-id degradation, alga,
`Elythfalrlyti-11, or
`inaclivalaedbystmriach enzymes, e.g..L-dopa.
`The dissolution of a substance maybe fies-cribed
`bythe modififid Noyes-Whitney equation:
`dc
`dt
`
`k5(-1.
`
`C9
`
`inwhich clddtis the rate ofdissolution, kis media-
`soiulionrateoonsfan-1;-Sisthasuizfaoeareaofthe
`solid, C, is the saturation oonoentnstion
`ofdruginthe diftusionlayat (which maybe ap-
`proximated by the maximum -solubility of flte drug
`
`Astraleneca Ex. 2083 p. 11
`
`
`
`
`1
`
`I
`
`Sfflfllll IIH I III}
`‘ uuclnx
`
`IFKIEVEIIE {MAI
`hrscénltluo mm
`-I.IuIUIl In (It
`
`minus
`ILIIIH
`
`1313.63 iatamndofildiags-mxshatoivwgflwdlgadoesysmn
`.fndwii?_1gtheiao!£ioa':shwofwdtr:dmgahtorptfionn1Idlheir
`rrs;ra:£mep1-[rattles
`
`drugrrloleclzlespassthzoughoutthedissolvingfluid
`andma1:eoontschnriththebiologlcmen1brsnesand
`absorpfimertsuesfisthemoleoalasofdrugcorifixnae
`to leave the difiusionlayer, the layer '3 nzplenishcd
`wifiIdissoivoddrug&nmtt1esu:faoeoEttIed:ugpar-
`licleandtheproowofabsotptionoontinues.
`Ifthep:ocessofdissoII:lionforagivendu.tgpar'-
`tix:1eis'rapiIILCIriE.ti'led.mgisadI:1inisteIedasaao-
`lufionandremainspreseritinthebodyassuctyttie
`rateatwhichthedrugbecomesabsorbadwouldhe
`primarily dependenmpon its ability to ‘traverse the
`membrane barrier. HGWEVEI; ifthe rate ofdissohr
`tionforadrugpa.rfic1eisslowtasmaybeduetot11e
`p characteristics of the dmg sub-
`stmccortitedosagefornafimdissoluiion process
`itself wouldbe a rate-limitingstep in thenbsotp-
`lion process. Slowly soluble drugs such as digwdrt,
`mnynot nnlybe absorbed ataslow rate, theymay
`be incompletely absorbed. or, in some cases largely
`unabsorbed following oral adtrlixiishafion, due to-
`the natural limitation of time that theymay remain
`within the stomach or the irltestinal tract. 'i'hu.s,
`poorly soluble drugs or pooriy Eozmulated thug
`products-mayresult in a drug's incon1ple'ta-a1:'I9orp-
`Iionand itspassagemnchanged. outoflfna system
`
`Undernonnalcircumstancasadrugmaybetov
`pected to remain in the stomach for 2 to § hours
`fgnstricernpt1.rfnglinIe)andi:tthesma1li:1tesI:ines'
`
`

`
`103
`
`DosagcForm
`
`and Pbarriwrokfitefic
`
`in the solvent since the diffusion layeris considered
`sstuteted],andc,istheconcentrstionofth.ednrgin
`theelissoluti.onmediu1nsttimet{c, — c,isthecon-
`centmtion gradient).'I‘he rate of dissolution is gov-
`erned iry the rate of diffusion of solute molecules
`through the ditfuslonlayerintothe bodyoftheso-
`lution. The equation reveals that the dissolution
`rate of a drug may be increased by increasing the
`surface area (reducingthe particle size} ofthe drug.
`by increasing the solubility of the drug in the diffu-
`sion layer, and byfactors embodiedin the dissolu-
`lion rate constant, it, including the inrensityof agi-
`
`tafionufthesolventaridthe-dr£Ei:sron''
`coefficren"tof
`the dissolving drug. Fora given drug, the diffusion
`ccefiticient and usually the conceritration of the
`drugfi1thedi£fusionlsyerwiIlinrreasewithirrcrcas-
`ing temperature. Also, irzcreasing the rate of estra-
`tion ofthe dissoluingrnedtumwill'i:ncreesetherste
`o1’d:issolution.AredtIc'tior1intl'ievlscosiiyofthesol-
`vent employed is another means which mayheused
`toenhanoe:1'1edissoIutionrateofa.drug.Chsngesirr
`tliepl-Iortltenshlne ofthe solventwhich influence
`tllesolirbilltyofitliedrugmaybeusedm-sdvahtage
`in increasing dissolution rate. ‘B£fervescent,.buffered
`aspirintablet fcrrnulatiorisuss some of these princi-
`ples to their advantage. Due to the alkaline adju-
`vanIstrithetablet.thesolubillty.oftlteaspirlrLis
`enhancedwitliln thedifii.Isior!slleyet.and t11eevolu-
`Lion of carbon dloadde agltates the solvent system,
`i.e.. gastric juices. Consequently, the rate of aspirin
`aboorbedlnto thebloodstreamisfastertltantlut
`
`achieved from a- conventional aspirin tablet formu-
`Iatlcllfl. Ifthls defies! fmmis accept8l:.Ile'to the pa.-
`flerititprouidesaqtfickeruwarefortticpafieruto
`gainrelieffirom atroublescme headst:he.Many
`m will utilize a particular ernorphous,
`ctyslnlline, salt oresterltrrm ofadmg thstwill ex-
`lnihitthe seluhilitycharacterisfics neederlto achieve
`the de5J'redd'mscilutio.n Mm ad.l1'Iil1-
`lstered. Some ofthesefsctorsfl1nta.Efectdr'ugdisso—
`lution briefly are dismissed in the following parts-
`whereas others will be discussed in
`
`sucoeeclingchapters in vdtich they-are relevant.
`of a
`The cheuiical and physical
`drug substance that can affect drugidrug product
`safety,e£ficacy, andste.bilityrrmstbe-careh:1lyde-
`Einedbyappropriatestandardsinanapplicationfor
`I-'DAa_pprovalertdtl1en subststriedartdcontrolled
`throughoutproduct manufacture.
`
`Surface Area
`
`When at drug particle is reduced to elargcr num-
`ber of mullet particles. the total surface area cre-
`
`For drug substances that are
`ated is
`poorly or slowlysoluble,-. this generally results in an
`increase in the rim of dimo1ution."l'l'1i.s is eitplained
`in the Physical Pharmacy C‘apsule,"'TParticle Size,
`‘Surface Area and Dissohlfion Rate.‘
`Increased therapeutic response to orally ad-
`minislereddnlgsduebosrnallerparficlesizelnie
`been reported for a number of drugs, among them
`theoplryiline, a xarrlhine derivative used to treat
`bronchial asthma; griseorulvin, an antibiotic with
`arriifungel activity; sulfisoxazole, an enlzi-infective
`sulfonzunide, and nitrofiucnsoin, a urinary anti-
`
`infeciive drug."Ib actw‘ ‘e increased surface area.
`pharmaceutical manufacturers frequently use mi-
`m‘onirsd.powcle1s. in their solid dosage form prod~
`uds. Mlcronized powders consist of drugpartlclss
`reducedinsize to aboutsmicrons andsrnallei-.A
`
`sllghtveiistion orithisis-socorriplisliedbyblendiaig
`and rncltingthe poorly water-soluble powders with
`a water-soluble polymer, such as polyethylene gly-
`col (PEG). In the molten state and ifthe d1'l13-d.is-
`solves in this carrier (PEG), a. molecular dispersion
`ofthe drug_i.n the csn'