Editor: Donna Balado
`Managing Editor: Jennifer Schmidt
`Marketing Manager: Christine Kushner
`
`Copyright © 1999 LippincottW1lliams & Wilkins
`
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`
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`
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`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
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`
`99 00 01 02
`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-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. 2083 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. 2083 p. 4
`
`

`
` DOSAGE FORM DESIGN:
`
`. BIOPHARNLACEUTIC
`l AND PHARMACOKINETIC
` CONSIDERATIONS
`
`Chapter at a Glance
`
`General Principles of Drug
`Absorption
`Passive Diffusion
`Specialized Transport Mechanisms
`Dissolution and Drug Absorption
`Surface Area
`Crystal or Amorphous Drug Form
`Salt Forms
`Other Factors
`
`Bioavailability and Bioequivalence
`FDA Bioaoaiiabiiity Submission
`Requirements
`Blood Ior Serum or Plasma) Concentration-
`Time Curve
`
`Routes of Drug Administration
`Oral Route
`
`Dosage Forms Applicable
`Absorption
`Rectal Route
`Parenteral Route
`Dosage Forms Applicable
`Subcutaneous Injections
`Intramuscular injections
`Intravenous Injections
`Intradermal Injections
`Epicatarieous Route
`Ocular, Oral and Nasal Routes
`Other Routes
`
`Parameters for Assessment and Comparison
`of Bioaoailabiiity
`Peak Height
`Time of Peak
`Area Under the Serum Concentration Time
`Curve
`
`Bioequioalence of Drug Products
`
`Fate of Drug After Absorption
`Drug Metabolism (Biotransformation)
`Excretion of Drugs
`Pharntacokjnetic Principles
`Half-Life
`Concept of Clearance
`Dosage Regimen Considerations
`
`A5 DISCUSSED in the previous chapter, the biologic
`response to a drug is the result of an interaction be-
`tween the drug substance and functionally impor-
`tant ceil receptors or enzyme systems.The response
`is due to an alteration in the biologic processes that
`were present prior to the drugs administrafion.The
`magnitude of the response is related to the con-
`centration of the drug achieved at the site of its ac-
`
`tion.This drugconcentration depends on the dosage
`of the drug administered, 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-—
`particulariy its lipid solubility, degree of ionization,
`and molecular size—determ.i.nes to a great extent
`its ability to affect its biological activity. The area of
`101
`
`Astrazeneca Ex. 2083 p. 5
`
`

`
`102
`
`Dosage Form Design: Biaplzamraceutic and Plrennecalcirrstic Cmstéunfions
`
`study embracing this relationship between the
`physical, chemical, and biological sciences as they
`app1ytodrugs,dosage£on:ne, andtodrugaciicnhas
`been ghren the descriptive term
`In general. for a clrugto exert its biologic efiect, it
`must be transported by the body fluids, traverse
`the required biologic membrane barriers, escape
`widespread distribution to unwanted areas, endure
`metabolic attack, penetrate in adequate concentra-
`tion to the tes of action, and interact in a specific
`fashion, causing an alteration of cellular £uncfion.A
`simplified diagram of this complex series of events
`between a clrug’s administration and its elimina-
`tionis presented in Figure 4.1.
`'I'he absorption, distribution, biotransforrnation
`(metabolism), and elimination of a drug from the
`body are dynamic processes that continue from the
`times drugis taken until all of the drughas been
`removed from the body. The rates at which these
`
`process occur affect the onset, intensity, and the
`duration of the drug's activity within the body.'I'he
`area of study which eluddates the time course of
`dnig concentration in the blood and tissues is
`termed phannecokinetirrr. It is the study of the ki-
`netics of absorption, distribution, metabolism and
`excretion (ADME) of drugs and their correspond-
`ing pharmacologic, therapeutic, or toxic response
`in animals and man. Further, since one drug may
`alter the absorption, distribution, metabolism or
`excretion of another drug, phamrlacoldnetlcs also
`maybe applied in the study of interactions between
`drugs.
`and drugabsorp-
`Onceadrugis
`|ionbegins,tl:1edrugdoesnotremair1inasingle
`body location. but rather is distributed throughout
`the body until its ultimate elimination. For in-
`stance, following the oral adrrrirtistralion of a drug
`and its entry into the gastrointestinal tract, a pot-
`
`Oral
`administration
`
`
`
`
`Gastrointestinal
`tract
`
`
`
`Intravenous
`
`injection
`
`
`
`
`Excretion
`injection Subcutaneous
`
`Circulatory
`systems
`
`
`
`
`Metabolic
`sites
`
`intramuscular
`
`injection
`
`Fig. 4.1 Sclzsmafirrepressntation ofeaenls ofabsorption, metabolism, amiexoretion ofdmgs afio-flrmradrnfiristrefionbyoan
`iousrautes.
`
`Astrazcncca Ex. 2083 p. 6
`
`

`
`Darcy: Form Design: Biapharmcondic and
`
`103
`
`tion of the drugis absorbed into the circulatory sys-
`tem fromvdiicltitisdistributedtothevariousother
`body fluids. tissues, and organs. From these sites
`the drug mayreturn to the circulatory system and
`beexcneted tluoughthe kidneyassuchorthe drug
`may be metabolized by the liver or other cellular
`sites and be eiccretedas rnetabo]ites.Assho'wr'l
`in Figure 4.1, drugs administered by intravenous
`
`which isrequired from all other routes of adminis-
`tration for systemic efifects.
`Thevarious body locations to which a drug trav-
`els may be viewed as separate oompartoients, each
`containing some fraction of the administered dose
`o£d.nrg.'l'hc transferof d.n1gfrom.the blood to other
`body locafions is generally a rapid process and is
`reversible; that is. the drug may diffuse back into
`the circulation. The dniginthebloocl therefore ex-
`ists in equilibriumwith the drugin the other com-
`partments. I-Iowever. in this
`state, the
`concentration of the drug in the blood may be quite
`different (greater or lesser) than the concentration
`of the drug in the other compart.ments.'I'his is due
`largelyto the physiochemical properties ofthe drug
`and its resultant ability to leave the blood and tra-
`versethebiologlcal membranes. Certain drugsrnay
`leave the circulatory system rapidly and completely:
`whereasotherdrugsrnajrdoso slowlyemdw-ithdif—
`ficulty. A number of drugs become bound to blood
`proteins, particularlythealbumins, andonlyasmall
`fraction of the drug administered may actually be
`found at locations outside of the circulatory system
`at a given time.'l11e transfer of drug from one
`compartment to another is mathematically asso-
`ciated with a specific rate constant describing that
`particular transfier. Generally, the rate of transfer
`of a. drug from one compartment to another is
`proportional to the concentration of the drug in
`the cornpartment from which it exits; the greater
`the concentration, the greater is the amount of
`drug transfer.
`Metabolismis themajorprocessbywhichforaign
`substances, irieludingdnrgsareelirnirietedhom the
`body. In theproofmetabolisma drugsubstance
`may be biotransformed into pharmacologically ac‘-
`tive or inactive metabolites. Often. both the drug
`substance and its metabolite(s} are active and exert
`phannscologic efiects. For example, the antlaroriety
`drug prazepam (Cenlrax) metabolizes, in part, to our-
`azeparn (Serax), which also has anliarvtlety effects.
`Insome instances a pharrnacologioally inactive drug
`(termedaprodmg)maybeado'lir1isteredforfl1e
`known effects of its active metabolites. Dipivefrln,
`
`for example, is aprodrugof epinephflne formed by‘
`the esterificalion of epinephrine and pivalic acid.
`‘Ibis enhances the lipophilic character of the drug,
`and as a consequence itspenetrai:lon into the ante-
`rior chamber of the eye is 17 times that of epineph-
`eye, dipivefiinl-IClis converbedby
`enzymatic lrydrolysis to epinephrine.
`The metabolism of a drug to inactive procluctsis
`usually‘ an irreversible process which culminates in
`the excretion of the drugfrom the-body, usually via
`the u:cine.‘l'ne phamiacokineticist may calculate an
`elimination rate constant {termed ltd) for a drug
`todescribeitsrare ofelinrinationfromthe-body.
`The term elimination refers to both metabolism
`
`and excretion. For drugs that are administered in-
`travenously. and therefore involve no absorption
`process, the task is much less complex than for
`drugs administered orally orby other routes. In the
`latterirlstances, drug absorption and drug e1irn.i.na-
`tlon are occurring simultaneously but at different
`rates.
`
`General Principles
`of Drug Absorption
`
`Before an administereddrugoan arrive atits site
`of action in effective concentrafions, it must sur-
`mount a number of ban-lers. These barriers are
`
`chiefly a succession of biologic membranes such
`as those of the gastrointestinal epithelium, lungs,
`blood, and brain. Body membranes are generally
`classified as three main types: (a) those composed
`ofseverallayers ofcells, as the skin; Cb) those com-
`posed of a single layer of cells. as the intestinal ep-
`itheliurn; and (c) those ofless than one oell in thick-
`ness, as the membrane of a single cell. In most
`instances a. drug substance must pass more than
`one of these membrane typ before it reaches its
`site of action. For instance, a drug taken orally must
`first traverse the gastrointestinal membranes (stom-
`ach, small and large intestine), gain entrance into
`the general circulation, pass to the organ or tissue
`withwtuch ithas affinity; gain entranceintothat
`tissue, and then enter into its individual cells.
`
`Although the chemistry of body rnernbranes
`differs one Erom another, the membranes may be
`viewed in general as a bimolecular lipoid (fat-
`containing) layer attached on both sides to a pro-
`tein layer. Drugs are thought to penetrate these bi»
`ologic membranes in two general ways: 1) by pas-
`sive diffusion, and 2} through specialized transport
`rnechanisms. Within each of these main categories,
`more clearlydefirted processes have been ascribed
`to drug transfer.
`
`Astrazeneca Ex. 2083 p. 7
`
`

`
`104
`
`Dodge firm: Design:
`
`and Phmmumlfiwfic Considerations
`
`Passive Difilmion
`
`The term pessioe.ri1fi'i¢sion is used to describe the
`passage of (drug) molecules through a membrane
`which behaves inertly in that it does not actively
`participate in the process. Drugs absorbed accord-
`ing" to this method are said to be
`absorbed
`The absorption processis driven by the concentra-
`tion gradient (i.e., the differences in concentration)
`existing-across the membrane, with the passage of
`dntg molecules occurring primarily from the side of
`high drug concentration. Most drugs pass through
`biologic membranes by diffusion.
`Passive di.EfiJsiocn is described by .Fick"s first law,
`which states that the rate of diffusion or transport
`across a membrane (dcfdt) is proportional to the
`difference in drug concentration on both sides of
`the membrane:
`
`"cE=P(Ci"C2)
`
`in which Qand CZ:-eferto the drug conoerrtraiiorts
`on each side of the membrane and P is a perme-
`ability" coefficient or const-ant.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 cornpartrnent one
`(e.g., absorption site) to compartment two (e.g-._.
`blood):
`'
`Because the concentration of drug at the site of
`absorption (C3) is usually much greater than onthe
`other side of the memmane, due to the rapid dilu-
`tion of the drug in the blood and its subsequent
`to the tissues, for practical purposes
`the value ofC._, -- C1-maybetaken simplyas thatof
`C1 and the equation written in the standard form
`for a liter order rate equation:
`.
`dc
`_.Et..=pCI
`
`The gastrointestinal absorption ofmost drugs from
`solution oocurs in this manner in accordance with
`firs: order kinetics in which the rate is dependent on
`drug concentration, i.e., doubling the dose doubles
`the transfer rate. The magnitude of the permeabil-
`ity constant, depends on the diffusion ooeflicient of
`the drug. the thickness and area of the absorbing
`melnbrene, and the permeability of the membrane
`to the parficular drug.
`Because of the lipoid nature of the cell mem-
`brane... it is
`permeable to lipid soluble sub-
`stances.'I'herate ofdiffusion ofa drugacroes the
`membrane depends not only upon its concentra-
`tion but also upon the relative extent ofits altinity
`for lipid and rejection ofwater (a
`lipid paflifion
`
`forlipid and the
`coeEicient).The greater its
`morehydrophobicitis,the festerwiilbe iterate of
`penetration into the l.ipid~nch membrane. Erythro-
`mycin base, for example, possesses a higher parti-
`fioncoeflideritflranotlmererytluooxycincompounds,
`e.g., estolate, gluoeptate. Consequently, the base is
`the preferred agent for the topical treatment of acne
`where penetration into the skin is desired.
`Because biologic cells are also permeated by
`water and l.ipid—i.nsoIub1e substances, it is thought
`that the membrane also contains water-filled pores
`or channels that permit the passage of these types
`of substances. As water" passes in bulk across a
`porous membrane, any dissolved solute. molecu-
`larly small enough to traverse the pores passes in
`byfiltration. Aqueous poresvaryin size from mem-
`brane to membrane and thus in their individual
`
`permeability characterisfics for certain drugs and
`other substances.
`
`The majority of drugs today are weak organic
`acids or bases. Knowledge of their individual ion‘-
`ization -or dissociation characteristics is important,
`because their absorption is governed to alarge ex-
`tent by their degrees of ionization as they are pre-
`sented to the membrane barriers. Cell membranes
`
`are more permeable to the unionized forms of
`drugs than to their ionized forms, mainly because
`of the greaterlipid solubility of the unionized forms
`and to the highly charged nature of the cell mem-
`brane which results in the binding or repelling. of
`the ionized drugand thereby decreases oell pene-
`tration. Also, ions become hydrated through asso-
`ciation with water molecules, resulting in larger
`particles than the u.ndissociated.mo1ecu1e and again
`decreased penetrating capability.
`The degree of 3. drugs ionizafion depends both
`on the pH of the solution in which it is presented
`tothebio1ogicrnembraneandonthepI<,,ordis-
`sociation cornstant, of the
`(whether an acid or
`base).'I'he concept ofpK‘
`derived from the Hen-
`derson-Hasselbalch equation and is:
`For an acid‘
`
`= .
`PH PK‘ + log unionized conc. (acid)
`For a base:
`
`=
`PH PK‘ + 1°g
`
`ml-‘;___ni=ede°.gt1s-_C.l=_a:el
`ionized cone. (salt)
`
`Since the pH body fluids varies (stomach, pH 1;
`lumen of the Intestine, pH 6.6; blood plasma. pi-I
`7c.:),ttflL1e
`ofadéugfromvarrous bodyEtl£.1:
`i w d:ffie.r' an my ‘crate. to some extent
`type of dosage form and the route of adrnirI.i5ira-
`tion preferred for a given drug.
`
`Astrazcneca Ex. 2083 p. 8
`
`

`
`Daaqgfiarm Desigm Bfopimmmmmt:m Considerations
`
`105
`
`By rearranging the equation for an acid:
`
`Pg_ _ PH =hg
`ionized concentration (salt)
`
`one can theoretically deterrnine the relative extent
`to which a drug remains unionized under various
`conditions of pH. ‘This is particularly useful when
`applied to conditions of body fluids. Forinstance, if
`aweakacid havingapk, oftlis assumed tube in
`anezrvironrrientofgastzicjuicewithapl-Io£1,the
`left side of the equafion would yield the number 3,
`which would mean that the ratio of unionized to
`
`ionizeddrugparfideswouldbeaboutlflflfltc-1.
`and gastric absorption would be excellent. At the
`pH of plasma the reverse would be true, and in the
`blood the drug would be largely in the ionized
`fonn.Tab1e 4.1 presents the effect ofpl-I on 'theion-
`of weal: electrolytes. and Table 4.2 offers
`some representative pK_ values of oornmon drug
`substances.
`
`From the equation and froxnTable 4.1. it may be
`seenthatadrugsubstanceishaltionizedatapfl
`value wbichis equal toitspK,.'I'huspK_ maybe de-
`fined as the pH at which adrug is'5D% ioni2.ed.For
`example, phenobarbital has a pK_ Value of about
`7.4. and in plasma (pH 7.4) it is presenter ionized
`and unionized forms in equal amounts. However. a
`drug substance cannot reach the blood plascrna for
`distribution throughout the body unless it is placed
`there directly through intravenous injection. or is fa-
`vorably absorbed train 3 site along its route ofentry.
`as the gastrointestionaltract, anclallowed topass
`into the general circulation. As shown in'Iable 4.2,
`phenobarbital, aweak acid.with a pK, of?.4 would
`
`Effect of pH on the Ionization of
`Table 4.1.
`Week Elecholybes‘ pK§-pl-I ‘JG Uniorlized
`{fWeak Acid
`0.100
`0.990
`9.09
`1.6.6
`24.0
`38.7
`50.0
`61.3
`76.0
`33.4
`90.9
`99.0
`99.9
`
`{fWzal= Base
`99.9
`99.0
`90.9
`83.4
`76.0
`61.3
`50.0
`38.7
`24.0
`16.6
`9.09
`0.990
`0.100
`
`-3.0
`-2.0"
`"-1.0
`-0.7
`-0.5
`-0.2
`0
`+0.2
`+0.5
`+0.7
`+1.0
`+2.0
`+3.0
`
`‘Reprinted with permission from Doluisio ]T, Swin-
`tosky N. Am I Pharm 1965;137:149.
`
`Tah1e4.2. pK,ValnesfurSnIIIeAcidlcand
`Basicncrup
`
`Acids:
`
`Bases:
`
`acid
`
`Baabiul
`Benzgyliaeliidllin
`Boric acid
`Dioournaml
`Phenobarbital
`Phenyhain
`Sulfanilernide
`
`Theoph)fl1i.’ne
`'fl'liop-'ental
`lblbutamide
`Wiriafin
`
`Arnphetamine
`Apotlinrphine
`Alroph-re
`Caffeine
`
`dflondiamepmdde
`Cocaine
`Codeine
`Guanetllldirle
`
`Morphine
`Pmcaine
`Quinine
`Reserpine
`
`EK-
`
`3.5
`7.9
`2.6
`9.2
`5.7
`7.4
`6.3
`10.4
`
`9.0
`7,5
`5.5
`4.8
`
`9.8
`7.0
`9.7
`0;B
`
`4.6
`8.5
`7.9
`11.3
`
`7.9
`9.0
`3.4
`5.5
`
`be largely undissociated inthe gastric ernrirorunent
`ofpH1andwoulcllikeIybewellabsorbecLAdrug
`mayentertbe circulation tapidlyand at high con-
`centrations if membrane penetration is easily ac-
`oomplishedoratalowrateandlowlevelifthedrug
`isnotneadflyabsorbedfiomilsrouteofentrytlhe
`pH ofthe drugs curnentenvironment intluencesthe
`rateanclthedegreeofitsfI.Irtherdistributionbe-
`canseitbeoon1esmoreor1essunionizedandthere-
`
`fore more orlesslipid-penetrafinguncler some con-
`difionofpfittlanunderattotlietlfanunioltized
`molecule is able to diffuse through the lipidbarrier
`andnemainurdonizedintl1enewerwi:onment,it
`rnayreturntoitsfomlerlocafionorgoontoanew
`one.I-Iowever.i:Eir1thenewer-wixonmerntitisgreetly -
`ionizodduetotheiruflueneeofthepfloftheseoond
`fluid,it]ikelywillbeunableto¢:osstl1emembrane
`withfts former abi]ity.TtnJsa concennation gradi-
`e.ntofadrugusua1l'_yisreschedatequilibrium0n
`eachsideofamernbranednetodiflerentdegreesof
`ionizaflonoccuIringoneachside.Asun1maryofthe
`concepts ofdissociafiarnfioriizatiortisfoundirtthe
`physical phannacycapsule e.trlitled"'pI<.aIDissom-
`tionConstan1s"'inCl'Iapter3.
`It isoften desirable scientists
`toinalcestrlictlxralrrtodifioationsiriorgariicdrugs
`
`Astrazcneca Ex. 2083 p. 9
`
`

`
`106
`
`Dosage Form Design’ Bioplmrmaceutic andP c
`
`structure so that if two substances are transported
`by the same mechanism one will competitively in-
`hibit the transport of the other; Further. the trans-
`port mechanism is inhibited in general by sub-
`stances that interfere with cell metabolism The
`
`term active transport, as a s-ubclassification of spe-
`cialized transport. denotes a process with the addi-
`tional feature of the solute or drug being moved
`across the membrane against a concentration gra—
`client, that is, Erom a so]:ution of lower concentra-
`tion to one of a higherconcentration or. if the solute
`is sn ion. against an electrochemical potential gra-
`d1ent..In contrast to active transport, fizciiitated dif-
`fusion is a specialized transport mechanism having
`all of the above characteristics except that the solute
`is not transferred against a concentration
`and may attain the same concentration inside the
`cell as that on the outside.
`
`Many bodynutrients, as sugars and amino acids,
`are transported across the membranes of the gas-
`trointestinal tract by carrier processes. Certain vita-
`mins, as thi.a.1:nine, niacin, riboflavin and vitamin B5,.
`and drug substances as methyldopa and 5-fluor-
`ourecfl, require active transport mechanisms for
`their absorption.
`Investigatiorts of intestinal transport have often
`ufilizedinsitu-(atthesite) orinbiua (inthebody)-an-
`imal models or or visa (outside the body) transport
`models; however, recently cell culture models-of hu-
`man small-intestine absorptive cells have become
`available." to investigate transport across intestinal
`epithelium (1). Both passiveand tiransport-mediated
`studies have been conducted to investigate mecha-
`nisms as well estates of trattsport
`
`Dissolution and Drug. Absorption
`
`Fora clrugto be absorbed, itrnustfirstbe dis-
`solved in the fluid at the absorption site. For in-
`stance. a drug
`orally in tablet or cap-
`sule fonncannotbeabsorbeduntilthe drugpartides
`are dissolved by the fluids at some point within the
`gastroirttesflnal tract. In instanceain which the sol-
`ubility of a drugis dependent upon either an acidic
`or basic medium, the drug would be dissolved in
`the stomach orintestinesrespectiuely (Fig. 4.3) .'I'he
`process by-which a drug particle dissolves-istermed
`dissolution.
`
`As a drug particle undergoes dissolution, the
`drugrnolecules onthesurfaceare the firstboenter
`into solution creating a saturated layer of drug-
`solution which erwelops the surface of the solid
`drug particle.Tl'Iis layer of solution is referred to as
`thedrfiiJaionloyenFromthisdiih1sion1ayet,the
`
`Astrazeneca Ex. 2083 p. 10
`
`and thereby favorably alter their lipid solubility,
`partition coefficients, and dissociation constants
`while maintaining the some basic pharmscologic
`act.-ivity.‘I'hese eflortsfrequently result in increased
`absorption, better therapeutic response, and lower
`dosage.
`
`‘
`
`Specialized TmnsportMecham'sms
`
`to the passive transfer of drugs
`E1 contrast
`and other substances across a biologic membrane,
`certain substances, including some drugs and bio-
`logic metabolites, are conducted across a membrane
`through one ofseveral postulated specialised trans-
`parrmechaniszrisslhistypeoftransferseeuisto
`accountfor those substances, many naturally occur-
`ring as amino acids and glucose, that are too lipid-
`insoluble to dissolve in the boundary and too large
`toftoworfi1tcrthroughthepores.Tl1istypeo£trans-
`port is thought to involve membrane components
`thatmaybeenzymesorsome othertypeofagentce-
`pable of forming a complex with the drug (or other
`agent) at the surface membrane, after which the
`complex moves across the ‘membrane where the
`drug is released. with the carrier returning to the
`original .surface_ Figure 42 presents die simplified
`scheme ofthisprorzess. Specialized transport maybe
`difierendated Erom passive transfer in that the for-
`mer process may becorne“'saturated"as the amount
`of carrier present for a given substance becomes
`completely bound
`that substance resulting in a
`delay in the“'ferrying“or transport process. Other
`features of specialized transport include the speci-
`ficitybyacarrierforapariioflartypeofchernical
`
`\§.Z.“
`
`I I
`
`c
`
`‘ii
`
`I I II
`
`u—>:<
`
`I
`| membrane
`
`I
`|
`
`outside
`
`inside
`
`Fig.4.}! Aci'i1'Jeimr:sportmeshanis:n.D reprererrisadnag
`moieculofirupresenlstisedm-iov-in themembmne. [Modified
`flora O‘Reilly Writ.-st} Phone 1966;-1?:56£l.J
`
`

`
`Dcsage'P0rm Design: Biopliarmateutic andP : Corsica-nations
`
`107
`
`for 4 to 1D hours, although there is substantial vali-
`ationbetween. people, and evenin-the same person
`ondi&erentcccasions.Va1:ior:stec11r1iqueshavebeen
`usedtodeterminegastrlcexnpt}-ingfirneandthe
`passage of drug from va'rious oral
`dosage fOl.'l'l'|5; inchidirlg, the traclting of dosage
`forms labeled with gamina-en'dtting_radionucJid.es
`through gamma scintigraphy (2. 3). The gastric
`emptying time for a drug is most rapid with a last-
`ing stomach, becoming sloweras the food content
`is increased. Changes in gastric emptying time
`andlor in intestinal motility can affect drug transit
`time and thus the opportunity tor drug dissolution
`and absorption.
`These changes canine affectedby drugs the pa-
`tient maybe taking. Certain drugswith anticholin-
`ergic properties, e.g., dityclornlne HCL amitripty-
`linei-ICL,havetheabi1itytos1owdowngast:ic
`emptying.'Il1i5 can enhance the rate of absorption
`of drugs normally absorbed from the stomach, and
`reduce the rate of absorption of drugs that are pri-
`marily absorbed from the small intestine. Alterna-
`tively, drugs which enhance gastric motility, e.g.,
`laxatives, may cause some drugs to move so quickly
`through the gastrointestinal system and past their
`absorptive site at such a rate to reduce the amount
`of drug actually absorbed. 'I'his effect has been
`demonstrated with digoadn, whose absorption is
`sigtificarrtly decreased by accelerating gastroin-
`tesfixtal motility.
`The aging process itself may also influence gas-
`trointestinal absorption. In the elderly, gastric acid-
`ity, the number of absorptive cells, intestinal blood
`flow, the rate of gastric emptying and inbestirial
`motility are all decreased. However. d_ru_.gs inwhich
`absorption depends on passive processes are not
`affected by these factors as much as those that de-
`pend on active transport mechanisms, e.g., cal-
`dum,iron, thiamine, andsugars.Adecreaseingas-
`hie emptying time would be -advantageoils for those
`drugs that are absorbed from the stomach but dis-
`advantageous for those drugs which are prone to
`acid degradation. e.g., penicfllins, e.rytl1ro_myt:'m, or
`inactivated
`stomach enzymes, e.g., L-dopa.
`The dissolution of a substance may be described
`by the modified Noyes-Whitney equation:
`
`3 = '
`.1.
`rats
`
`-—a
`
`ca
`
`inwhich dcidtis the rate of-dissolution, k is the dis-
`solution rate constant, 5 is the surface area of the
`dissolving solid, as is the saturation concentration
`ofdrugin the diftuaionlayer (which may be ap-
`proximated by the maximum solubility of the drug
`
`,
`
`Astrazeneca Ex. 2083 p. 11
`
`
`
`’"-"W5
`BILL Iuoaen
`HUI
`Ifi 5-'!'1
`
`lsgiumu‘
`COLON
`
`II"!-HIIII‘
`ILIUH
`
`'
`
`srouaerl Ian mat
`nae: ns
`
`'
`
`TMHIVEISE EGLHIU
`etscanoma DOIAH
`JIJI-lltllfl ‘IN I3!
`
`3-tBMO.ItI canon
`
`Fig. 4.3 Arartomiosl
`the locations involved in drug-cbsmptioa and their
`rsspaon'o£.pl-Inoiua.
`
`drug molecules pass throughout the dissolving fluid
`and make oontactwiflr the biologic membranes and
`absorption ensues..As the molecules ofdrugcondnue
`toleavethe difiiusionlayer-,the1ayeri.S replenished
`with dissolved drug Eromthe surface ofthe drug par-
`ticle and the process ofabsorption continues.
`lfthe process of dissolutionfora given drug par-
`ticleisrapid, orif the-drugis-administered as a so-
`lution and remains present "in the bodyas such, the
`rateatwhich the drugbccomes absorbed would be
`primarily dependent upon its abflity to traverse the
`membrane barrier. However, if the rate of dissolu-
`fionforadnigparfideisslovuasmaybeduetothe
`physiochemical characteristics of the drug sub-
`stance or the dosage form, the dissolution process
`itself would be a rate-lirrtiting step in the "absorp-
`tion process. -Slowly soluble drugs such as digoadn,
`may not only be absorbed at a slow rate, they may
`be "incompletely absorbed, or, in some-cases largely
`unabsorbed following oral administration, due to
`the natural limitation of time that theymay remain
`the stomach or the intestinal
`Thus.
`
`poorly soluble drugs or poorly fionnulated drug
`products may result in a dn1g’s incomplete absorp-
`tion andits passage. unchanged, out otthe system
`via the feces.
`
`Undernorrnalcircumshmces ii drugmay bee):-
`pectedtorerrtaininthestomachforzto-4ho1:rs'
`(gastric emptying time) and in the small intestines
`
`

`
`108
`
`Dosage Form Design: Biophxtnmuzutic and Pfiamtacakineric Considerations
`
`in the-solvent since the diffusion layeris considered
`saturated), and qis the concentration of the drugin
`the dissolution medium at tin-Let (cs — q is the con-
`centration gradient).The rate ofdissolution is gov-
`erned by the rate of difiusion of solute molecules
`tlirougi the diffusion Iayerinto the body ofth.eso-
`lutlon. The equation reveals that the dissolution
`rate of a drug may be increased by inczeasingtl-1e
`surface area (reducing the particle size) ofthe drug,
`by increasingthe solubility of the drug in the diffu-
`sion layer, andby factors embodied in the dissolu-
`tion rate constant, it, including the intensity of agi-
`tation of the solvent and the diffusion coefficient of
`the dissolving drug. For a given drug, the diffusion
`coefficient and usually the concentrafion of the
`clnrginthe diffusionlayerwillint:easewithir1creas-
`ing temperature. Also, increasing the rate of agita-
`tion ofthe
`willincrease the rate
`of dissol'ution.Areductlon in fneviseofityof die sol-
`vent employed is another means which maybe used
`to enhancethe dissolution rate of adrug. Changesin
`the pH or the nature ofthe solventwhich influence
`the solubility of the drug maybe used to advantage
`in increasing flsolution rate. Effervesoerui, buflered
`tablet formulations use some of these princi-
`ples to their advantage. Due to the alkaline adju-
`vants in the tablet, the solubility of the aspirin is
`enhanoedwithin the diffusionallayerandfiie evolu-
`tion of carbon dioxide agitates the solvent Systeni,
`i.e., gastric juices. Consequently, the rate of aspirin
`absorbed into the bloodstream is faster than that
`
`achieved from a conventional aspirin tablet formu-
`lation. If this dosage form is acceptable to the pa-
`tient, it provides" a quicker means for the patient to
`gain relief from a_ troublesome headache. Many
`manufacturers will utilize a particular amorphous,
`crystalline, saltoresterform ofa dmgtharwill ex-
`hibit the solubility characteristics. needed to achieve
`the desired dissolution characteristics when admin-
`istered. Some of these factors that affect drugdisso-
`lution briefly are discussed in the
`para-
`gaphawhereasofltersvdllbediscussedin
`succeeding chapters in which theyarerelevant.
`The chemical and physical characteristics" of a"
`drug substance that can affect drugfdrug product
`safety, efficacy, and stability must be carefully de-
`fmedbyappropriate standardsin anapplicationfor
`FDA approval and then substained and controlled
`throughout product manufacture.
`
`Surface Area
`
`When a drugparticle is reduced to a larger num-
`ber