Pharmaceutics: The Science of
`Dosage Form Design
`
`EDITED BY
`Michael E. Aulton BPharm PhD MPs
`
`Reader in Pharmacy, Leicester Polytechnic, Leicester, UK
`
`1>-r::JI:>
`r::Jr::Jr::J
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`c:=:::;;r
`CHURCHILL LIVINGSTONE
`EDINBURGH LONDON MELBOURNE AND NEW YORK 1988
`
`Par Pharm., Inc.
`Exhibit 1009
`Page 001
`
`

`

`-
`
`CHURCHILL LIVINGSTONE
`Medkal Division of Longman Group UK Limited
`Distributed in the United States of America by
`Churchill Livingstone Inc., 1560 Broadway, New
`York, N.Y. 10036, and by associated companies,
`branches and representatives throughout the world.
`
`©Michael Aulton 1988
`
`All rights reserved. No part of this publication may
`be reproduced, stored in a retrieval system, or
`transmitted in any form or by any means, electronic,
`mechanical, photocopying, recording or otherwise,
`without the prior permission of the publishers
`(Churchill Livingstone, Robert Stevenson House, 1-3
`Baxter's Place, Leith Walk, Edinburgh EH1 3AF).
`
`First published 1988
`Reprinted 1989
`
`ISBN 0-443-03643-8
`
`British Library Cataloguing in Publication Data
`Pharmaceutics: the science of dosage form
`design.
`1. Pharmaceutics
`I. · Aulton, Michael E.
`615' .19
`RS403
`
`Library of Congress Cataloging in Publication Data
`Pharmaceutics: the science of dosage form design.
`Replaces: Cooper and Gunn's tutorial pharmacy.
`6th cd. 1972.
`Includes bibliographies and index.
`1. Drugs - Design of delivery systems. 2. Drugs
`- Dosage forms. 3. Biopharmaceutics.
`4. Pharmaceutical technology. 5. Chemistry,
`Pharmaceutical. 6. Microbiology, Pharmaceutical.
`I. Aulton, Michael E.
`[DNLM: 1. Biopharmaceutics. 2. Chemistry,
`Pharmaceutical. 3. Dosage Forms. 4. Technology,
`Pharmaceutical. 5. Microbiology, Pharmaceutical.
`QV 785 P5366]
`RS420.P48 1987
`
`86-25888
`
`615.5'8
`
`Produced by Longman Group (FE) Ltd
`Printed in Hong Kong
`
`Par Pharm., Inc.
`Exhibit 1009
`Page 002
`
`

`

`~~
`··?!
`i~
`if
`""
`~~
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`r~
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`fCJ
`
`·~ ··~
`
`I The design of dosage forms
`
`PART ONE Physicochemical
`principles of pharmaceutics
`2 Rheology and the flow of fluids
`3 Solutions and their properties
`4 Surface and interfacial phenomena
`5 Solubility and dissolution rate
`
`Contents
`
`Preface
`'
`1
`Contributors
`J Acknowledgements
`About this book
`
`~~
`
`i 6 Disperse systems
`
`7 Kinetics and stability testing
`
`~
`·~
`f
`
`PART TWO Biopharmaceutics
`8 Introduction to biopharmaceutics
`9 Factors influencing bioavailability
`10 Assessment of bioavailability
`11 Dosage regimens
`
`PART THREE Drug delivery systems
`12 Packs for pharmaceutical products
`13 Prefonnulation
`14 Solutions
`15 Suspensions
`16 Emul~ions
`17 Powders and granules
`18 Tablets
`19 Capsules
`20 Therapeutic aerosols
`21 Parenteral products
`22 Topical preparations
`23 Suppositories and pessaries
`
`vii PART FOUR Pharmaceutical
`ix microbiology
`xi 24 Fundamentals of microbiology
`xili 25 The action of physical and chemical
`agents on micro-organisms
`26 Principles of sterilization
`27 Microbiological contamination and
`15
`preservation of pharmaceutical
`preparations
`17
`38 28 Pharmaceutic~! applications of
`so
`microbiological techniques
`62
`PART FIVE Pharmaceutical
`81
`technology
`119
`29 Materials of fabrication and corrosion
`129 30 Heat transfer and the properties of
`131
`steam
`135
`31 Filtration
`174 32 Mixing
`191
`33 Particle size analysis
`34 Particle size reduction
`213
`35 Particle size separation
`215
`36 Powder flow
`223
`37 Granulation
`254
`38 Drying
`269
`39 Tableting
`282
`40 Tablet coating
`300
`41 Encapsulation
`304
`322 42 Design and operation of clean rooms
`43 Sterilization practice
`341
`359 44 Packaging technology
`381
`Index
`412
`
`423
`425
`
`452
`472
`
`479
`
`491
`
`509
`511
`
`525
`538
`550
`564
`581
`591
`600
`616
`629
`647
`669
`678
`686
`700
`712
`
`725
`
`Par Pharm., Inc.
`Exhibit 1009
`Page 003
`
`

`

`·-· I
`...
`.,.
`--••
`·-
`
`9
`
`S G Proudfoot
`
`Factors influencing bioavailability:
`factors influencing drug absorption from the
`gastrointestinal tract
`
`DRUG ABSORPTION FROM THE
`GASTROINTESTINAL TRACT
`Structure of the gastrointestinal tract
`Mechanisms of drug transport across the
`gastrointestinal/blood barrier
`Passive diffusion
`Carrier-mediated transport
`Active transport
`Facilitated diffusion or transport
`I on-pair absorption
`Convective absorption (pore transport)
`Pinocytosis
`PHYSIOLOGICAL FACTORS INFLUENCING DRUG
`ABSORPTION FROM THE GASTROINTESTINAL
`TRACT
`Surface area of the gastrointestinal absorption
`sites
`pH of gastrointestinal fluids
`Gastric emptying rate
`Intestinal motility
`Drug stability in the gastrointestinal tract
`Hepatic metabolism
`Influence of food and diet
`Alteration in the rate of gastric emptying ·
`. Stimulation of gastrointestinal secretions
`Competition between food components and drugs
`for specialized absorption mechanisms
`Complexation of drugs with components in the
`diet
`Increased viscosity of gastrointestinal contents
`Food-induced changes in blood flow to the ·liver
`Miscellaneous physiological factors influencing
`gastrointestinal absorption
`PHYSICOCHEMICAL FACTORS INFLUENCING DRUG
`ABSORPTION FROM THE GASTROINTESTINAL
`TRACT
`'
`Drug dissociation constant and lipid solubility
`pH-partition hypothesis of drug absorption
`
`Absorption of a weak acidic drug
`Absorption of a weak basic drug
`Limitations of the pH-partition hypothesis
`Dissolution rate of drugs
`Absorption from solution or following rapid
`dissolution of solid drug particles
`Absorption following the slow dissolution of solid
`drug particles
`Factors influencing the dissolution rates of drugs
`in the gastrointestinal tract
`Physiological conditions
`Particle size
`Crystal form
`Solubility of drug in the diffusion layer
`(salt forms)
`Complexation
`Adsorption
`Chemical stability of drugs in the
`gastrointestinal fluids
`DOSAGE FORM FACTORS INFLUENCING DRUG
`ABSORPTION FROM THE GASTROINTESTINAL
`TRACT
`Influence o( excipients
`Diluents
`Surfactants
`Viscosity-enhancing agents
`Influence of the type of dosage form
`Aqueous solutions
`Aqueous suspensions
`Soft gelatin capsules
`Hard gelatin capsules
`Tablets
`Uncoated tablets
`Coated tablets
`Enteric coated tablets
`
`135
`
`Par Pharm., Inc.
`Exhibit 1009
`Page 004
`
`

`

`136 BIOPHARMACEUTICS
`
`DRUG ABSORPTION FROM THE
`GASTROINTESTINAL TRACT
`
`The various factors which can influence drug
`release from dosage forms and absorption into the
`systemic circulation will be considered in this
`chapter by reference to the peroral (i.e. gastro(cid:173)
`intestinal) route of administration. This route is
`chosen as the example, since the majority of drugs
`are administered orally and the vast majority of
`orally administered drugs are intended to be
`absorbed from the gastrointestinal tract. Thus, a
`
`STOMACH
`(gastric contents pH 1-3)
`
`I
`Tablet _______ ,.._
`
`detailed consideration of the factors which can
`influence the absorption of drugs from this region
`is warranted.
`In order that the reader may gain an insight into
`the numerous factors which can potentially influ(cid:173)
`ence the rate and extent of appearance of intact
`drug into the systemic circulation, a schematic
`illustration of the steps involved in the release and
`gastrointestinal absorption of a drug from a tablet
`is presented in Fig. 9.1. It is evident from this
`diagram that the rate and extent of appearance of
`intact drug into the systemic circulation depends
`
`SMALL INTESTINE
`(intestinal contents pH 5-7)
`
`-
`
`Tablet
`
`t Aggregates
`
`-
`
`-
`
`-
`
`-
`
`- OJ.
`
`•••
`•••
`
`t Aggregates
`~ gra~~les - -GASTRic ..._ ~
`J.
`;';5 t
`L;)
`EMPTYING
`~ f
`. Ljj
`RATE
`- ._ a:
`...... Fine particles - - - -
`Fine particles - -
`~ I
`~
`I
`g;
`~ DISSOLUTION
`DISSOLUTION
`t
`t
`.,.,. __ ..... 1_-!,._~ INTESTINAL
`
`or - - - - - - •
`granules
`INTESTINAL
`TRANSIT
`RATE
`-
`- - - _.
`
`Drug in
`solution - - - - - - - - ._
`I
`
`..__ ..... ~~ ABSORPTION
`I
`
`Drug in
`solution - - - - - - - - •
`
`METABOLISM
`
`Intact drug
`
`+
`
`Liver
`
`f
`
`+
`
`HEPATIC
`METABOLISM____.,. Metabolites
`(Frrst pass
`effect)
`
`Intact drug.
`in
`systemic
`circulation
`
`~
`
`Pharmacological
`effect
`
`Urine
`
`Fig. 9.1 Schematic illustration of steps involved in the appearance of intact drug in the systemic circulation following peroral
`administration of a tablet. Potential rate-limiting steps with respect to drug bioavailability are shown in italic capitals. (After
`Barr, 1972)
`
`(<I:,....;;
`
`Par Pharm., Inc.
`Exhibit 1009
`Page 005
`
`

`

`·-
`
`••• I
`...
`
`••
`
`on a succession of rate (kinetic) processes. The
`slowest step in this series of rate processes, which
`is known as the rate-limiting step, will control the
`overall rate and extent of appearance of intact
`drug in the systemic circulation. The particular
`rate-limiting step may vary from drug to drug.
`Thus for a drug which exhibits a very poor
`aqueous solubility, the rate at which the drug
`dissolves in the gastrointestinal fluids is often the
`slowest step and therefore exhibits a rate-limiting
`effect on a drug bioavailability. In contrast, for a
`drug which has a high aqueous solubility, its
`dissolution rate will be rapid and the rate at which
`the drug crosses the gastrointestinal membrane
`may be the rate-limiting step. Other potential rate(cid:173)
`limiting steps include the rate of release of the
`drug from the dosage form (especially important
`in the case of controlled released dosage forms),
`the rate at which the stomach emp~ies the drug
`into the small intestine, the rate at which drug is
`metabolized by enzymes in the intestinal mucosal
`cells during its passage into the mesenteric blood
`vessels and the rate of metabolism of drug during
`
`FACTORS INFLUENCING BIOAYAILJ\BILITY
`
`137
`
`its initial passage through the liver, i.e. the 'first
`pass' effect.
`
`Structure of the gastrointestinal tract
`
`The gastrointestinal tract consists of three major
`anatomical regions: the stomach, the small intes(cid:173)
`tine and the large intestine (colon). The small
`intestine includes the duodenum, jejenum and
`ileum. As a drug descends through these regions
`of the gastrointestinal tract, it encounters different
`environments whth respect to pH, enzymes, elec(cid:173)
`trolytes, fluidity and surface features, all of which
`can influence drug absorption (see later in this
`chapter).
`The gastrointestinal tract is basically a hollow
`muscular tube composed of four concentric layers
`of tissue named from the innermost to the outer(cid:173)
`most as the mucosa (or mucous membrane), the
`submucosa, the muscularis externa and the serosa.
`These are shown diagrammatically in Fig. 9.2. Of
`these four
`layers,
`the mucosa
`is
`the most
`important with respect to the absorption of drugs
`
`Intestine wall
`Muscularis mucosa -r----_-_ ..... _+t---~------,
`+ +
`+
`
`INTESTINAL
`LUMEN
`
`VILLUS
`
`Lamina propria
`
`l l
`
`PERITONEAL
`CAVITY
`
`4
`
`lllrii~~~II--
`
`Arte~
`
`Serosa
`
`Capillary
`
`Mucosa
`
`Muscularis
`extern a
`
`Submucosa
`
`Fig. 9.2 Diagrammatic representation of the small intestine showing the absorption of a drug from the intestinal lumen into a
`blood capillary. (After Smith 1964)
`
`Par Pharm., Inc.
`Exhibit 1009
`Page 006
`
`

`

`.....
`
`••
`
`138 BIOPHARMACEUTICS
`
`from the lumen of the gastrointestinal tract. The
`mucosa contains
`the cellular membranes and
`regions through which a drug must pass in order
`to reach the blood (or lymph). Figure. 9.2 shows
`that the mucosa, itself, consists of three layers: the
`lining epithelium, the lamina propria and the
`muscularis mucosa. The epithelium lining the
`lumen of the gastrointestinal tract comprises a
`single layer of columnar and some specialized
`secretory cells (e.g. mucus secreting goblet cells).
`Of these cells only
`the columnar cells are
`concerned with absorption. The layer underlying
`is
`the
`lamina propria which
`the epithelium
`contains connective
`tissue, blood and
`lymph
`vessels. The final layer comprising the mucosa is
`the muscularis mucosa which is a relatively thin
`layer of muscle fibres.
`In the stomach the mucosa contains many folds
`which increase the total surface area over that
`afforded by a fiat smooth lining. Although the
`stomach does not function primarily as an absorp(cid:173)
`tion organ, its excellent blood supply and the fact
`that a drug can potentially reside in the stomach
`for 30 minutes up to several· hours in contact with
`a reasonably
`large epithelial surface, provide
`cQllditions which are conducive to the absorption
`of certain drugs, e.g. weak acidic drugs.
`The small intestine is the most important site for
`drug absorption in the gastrointestinal tract. The
`outstanding anatomical feature of the small intes(cid:173)
`tine is the tremendously large epithelial surface
`area through which drug absorption can take
`place. This large epithelial surface area results
`from the existence of (a) folds in the intestinal
`mucosa known as the folds of Kerckring, (b) villi
`and (c) microvilli. Villi are finger-like projections
`which arise from
`the entire mucosal surface
`(including the folds of Kerckring) of the small
`intestine. Villi range in length from 0.5 to 1.5 mm
`and there are estimated to be 10-40 villi per mm2
`of intestinal mucosa. Figure 9.2 shows that each
`villus is covered by a single continuous layer .of
`epithelium (i.e. the epithelial lining of the intes(cid:173)
`tinal mucosa) which is made up primarily of the
`columnar absorption cells and the mucus-secreting
`goblet cells. In terms of drug absorption from the
`small intestine the columnar cells are extremely
`important since it is the anatomical structure of
`the apical surface of each columnar cell (i.e. the
`
`cell surface facing the intestinal lumen) which
`further increases the epithelial surface area of the
`small intestine that is available for drug absorp(cid:173)
`tion. Figure 9.3 shows that the apical surface of
`each cell consists of numerous minute slender
`projections, approximately 1 p,m long, known as
`microvilli. Microvilli appear to be microtubular
`projections of the apical cell membrane of each
`columnar cell. The microvilli (between 700 and
`1000 per columnar cell), together with the villi
`and folds of Kerckring, are estimated to increase
`the surface area available for absorption by 600
`times that which would be available if the inner
`surface of the small intestine was fiat.
`Intimately associated with the microvilli is a
`coating of fine filamentous material composed of
`mucopolysaccharides. This coating is known as
`the glycocalyx. In addition to the glycocalyx there
`are two further layers of material between the
`microvilli and the luminal contents of the small
`intestine, i.e. a layer of protective mucus secreted
`by the goblet cells and the so-called 'unstirred
`aqueous layer'. Figures 9.2 and 9.3 show that the
`absorption of a drug from the lumen of the intes(cid:173)
`tine into the blood draining the villi involves the
`passage of drug through several barriers and
`regions. Thus drug molecules in the lumen of the
`small intestine must first diffuse through the
`unstirred aqueous layer, the mucous layer and the
`glycocalyx in order to reach the microvilli, i.e. the
`apical cell membrane of the columnar cell. The
`apical cell membrane of each epthelial cell lining
`the gastrointestinal tract appears to be tightly
`· bound to that of adjacent epithelial cells. This so(cid:173)
`called 'tight junction' between the cell membranes
`of adjacent epithelial cells (see Fig. 9.3) is thought
`to act as a barrier to the intercellular passage of
`drug molecules from the intestinal lumen to the
`lamina propria. Thus a drug molecule must cross
`the apical cell membrane into the interior of a
`columnar cell. After diffusing through the fluids
`within this cell, a drug molecule must cross the
`basal cell membrane of the columnar cell. On
`emerging from the columnar cell the molecule
`must cross the underlying basement membrane
`into the lamina propria. Finally, after diffusing
`through ~he tissue region of the lamina propria,
`drug molecules must cross the endothelium of one
`of the blood capillaries present in this region.
`
`Par Pharm., Inc.
`Exhibit 1009
`Page 007
`
`

`

`FACTORS INFLUENCING BIOAVAILABlLITY
`
`139
`
`DRUG IN SOLUTION
`
`INTESTINAL LUMEN
`
`+
`--··- --------------t- ---- ----- ----r Unstirred aqueous
`
`Glycocalyx ~ -- - - - - - - -- -
`·
`
`- - - - - - - - - -
`
`- - - - - - - -
`
`layer
`- - -
`~ Mucus layer
`
`Apical cell
`membrane
`
`Microvillus
`
`Basal membrane
`
`Basement
`membrane
`
`Lamina
`propria
`
`Tight junction
`
`columnar
`absorption cell
`of lining
`epithelium
`
`space
`
`, @.load capillary
`
`Fig. 9.3 Diagrammatic representation of intestinal columnar absorption cells in the lining epithelium showing a pathway of
`drug absorption from the intestinal lumen to a blood capillary lying in the lamina propria
`
`•r-1
`
`•!Z!!!'
`i
`
`~: _,_
`l"'
`j:
`J~
`l
`~­
`J.
`
`Drug molecules would then be carried away in the
`blood to the systemic circulation via the liver.
`Most drugs reach the systemic circulation via the
`blood stream of the capillary metwork in the villi.
`However, it is possible that the absorption of
`highly lipid-soluble drugs, particularly if admin(cid:173)
`istered in an oily vehicle, may occur via fat
`absorption pathways. In such cases, drug removal
`from the villi would involve the central lacteals
`and the lymphatic circulation.
`Although the above description of drug absorp(cid:173)
`tion refers specifically to the small intestine,
`absorption from other areas of the gastrointestinal
`tract would also involve the passage of drug
`through similar barriers and regions. Thus the
`term gastrointestinal absorption will be used in
`this chapter to encompass the separate processes
`by which drug passes from the lumen of the
`gastrointestinal tract into columnar absorption
`cells and its movement through and out of these
`cells into the blood vessels via the lamina propria.
`The large intestine like the stomach lacks villi
`(and microvilli). However, the large intestine
`serves as a site for the absorption of drug which
`has not been completely absorbed in the more
`proximal regions of the gastrointestinal tnict, i.e.
`
`the stomach and small intestine. Incomplete drug
`absorption in the more proximal regions may be
`due to the physicochemical properties of the drug
`itself (e.g. very
`low aqueous solubility and
`dissolution rate) or as a result of the intended slow
`release
`of
`drug
`from
`a
`prolonged/
`sustained/controlled
`release dosage
`form.
`In
`general if a large proportion of an orally admin(cid:173)
`istered dose of drug reaches the large intestine, it
`is likely that the drug will exhibit poor bioavail(cid:173)
`ability (Gibaldi, 1984).
`
`Mechanisms of drug transport across the
`gastrointestinal/blood barrier
`
`It is apparent from the previous section that
`absorption of a drug from the lumen of the
`gastrointestinal tract into the blood involves the
`passage of drug molecules across several cellular
`membranes and fluid regions within the mucosa,
`i.e. the gastrointestinal/blood barrier. The epithe(cid:173)
`lium lining the gastrointestinal tract is considered
`to constitute the main cellular barrier to the
`absorption of drugs from the gastrointestinal tract
`(Blanchard, 1975). The permeability character(cid:173)
`istics of this epithelial layer appear to be directly
`
`Par Pharm., Inc.
`Exhibit 1009
`Page 008
`
`

`

`140 BIOPHARMACEUTICS
`
`the properties of the apical cell
`to
`related
`membrane of the columnar absorption cell and
`thus gastrointestinal
`absorption becomes
`a
`special case of the general biological phenomenon
`of membrane transport (Levine, 1971). The api(cid:173)
`cal cell membrane exhibits
`the characteristic
`trilaminar membrane structure upon electron
`microscopic examination and is composed largely
`of protein and
`lipid. Although
`the precise
`molecular structure of a cell membrane is not
`known, the apical cell membrane of the columnar
`absorption cell appears to behave, with respect to
`the absorption of drugs 'and nutrients, as a
`'lipoidal' membrane penetrated periodically by
`submicroscopic aqueous filled channels or pores.
`Water-soluble substances of small molecular size
`(radius less
`than 0.4 nm), such as urea, are
`absorbed by simple diffusion through the water
`filled channels. Most drug molecules, however,
`are too large to pass through these channels and
`the apical cell membrane (and hence the gastroin(cid:173)
`testinaVblood barrier) behaves like a
`'lipoidal
`sieve' with respect to the absorption of drugs.
`Thus the barrier allows the passage of lipid(cid:173)
`soluble drugs in preference to
`lipid-insoluble
`drugs. The majority of drugs appear to cross the
`apical cell membrane of the lining epithelium
`(and
`other
`cell membranes within
`the
`gastrointestinaVblood barrier) by the mechanism
`known as passive diffusion. This and other mech(cid:173)
`anisms by which some drugs are absorbed will be
`considered.
`
`Passive diffusion
`
`In this process the apical cell membrane of a
`columnar absorption cell plays a passive role and
`does not participate actively in the transport
`process. The rate of drug transport is determined
`by the physicochemical properties of the drug, the
`nature of the membrane and the concentration
`gradient of drug across
`the membrane. The
`process of passive diffusion, shown in Fig. 9.4,
`initially involves partition of a drug between the
`aqueous fluid in the gastrointestinal tract and the
`lipoidal-like cell membrane of the lining epithe(cid:173)
`lium. The drug in solution in the membrane then
`diffuses across
`the membrane followed by a
`second partition of drug between the membrane
`and
`the aqueous fluids within
`the columnar
`absorption cells. The drug would cross the other
`cell membranes
`in
`the gastrointestinaVblood
`barrier by this sequence of steps and thus would
`eventually enter the blood of the capillary network
`in the lamina propria. If we considered that the
`cell membranes and fluid regions making up the
`gastrointestinaVblood barrier could be represented
`by a single
`'membrane'·,
`the gastrointestinal
`membrane, separating the aqueous gastrointestinal
`fluid from the capillary blood supply in the lamina
`propria, then the stages involved in the gastro(cid:173)
`intestinal absorption of a drug by passive diffusion
`could be represented by the model shown in
`Fig. 9.4.
`Passive diffusion of drugs across the gastro-
`
`GASTROINTESTINAL
`FLUID
`
`GASTROINTESTINAL
`MEMBRANE
`
`BLOOD
`
`Drug in
`solution
`
`.....
`
`.....
`
`Drug in solution
`carried away by
`circulating blood
`
`r
`I
`
`Partition
`
`Diffusion
`
`Partition
`
`Fig. 9.4 Diagrammatic representation of gastrointestinal absorpti~n via passive diffusion (bold arrows indicate direction of net
`movement of drug)
`
`Par Pharm., Inc.
`Exhibit 1009
`Page 009
`
`

`

`intestinaVblood barrier can often be described
`mathematically by Pick's first law of diffusion.
`Accordingly the rate of appearance of drug in the
`blood at the site of absorption is given by
`
`dm = D A (K1Cg - K 2Cb)
`dt
`h
`
`(9.1)
`
`where dm/dt is the rate of appearance of drug in
`the blood at the site of absorption, D is the effec(cid:173)
`tive diffusion coefficient of the drug in
`the
`gastrointestinal (g.i.) 'membrane', A is the surface
`area of the gastrointestinal 'membrane' available
`for absorption by passive diffusion, K 1 is the
`apparent partition coefficient of the drug between
`the gastrointestinal 'membrane' and the gastro(cid:173)
`intestinal fluid i.e.
`
`concentration of drug inside 'membrane' at
`g.i. fluid/membrane interface
`concentration of drug in g.i. fluid
`
`Cg is the concentration of drug in solution in the
`gastrointestinal fluid at the site of absorption, K 2
`is the apparent partition coefficient of the drug
`between the gastrointestinal 'membrane' and the
`blood, cb is the concentration of drug in the blood
`at the site of absorption, and his the thickness of
`the gastrointestinal 'membrane'.
`Hence K 1Cg and K 2Cb represent the concen(cid:173)
`trations of drug
`inside
`the gastrointestinal
`membrane at the g.i. fluid/membrane interface
`and g.i. membrane/blood interface respectively.
`The expression
`
`represents the concentration gradient of drug
`across the 'membrane'.
`Eqn 9.1 indicates that the rate of gastrointes(cid:173)
`tinal absorption of a drug by passive diffusion
`depends on the surface area of the 'membrane'
`that is availabl,e for drug absorption. This is
`compatible with the observation that the small
`intestine, particularly the duodenum, is the major
`site for drug absorption due principally to the
`presence of villi and microvilli which provide an
`enormous surface area for absorption. Eqn 9.1
`also indicates that the rate of drug absorption
`
`FACTORS INFLUENCING BIOAVAILApJLITY
`
`141
`
`depends on a large concentration gradient of drug
`existing across the gastrointestinal 'membrane'. It
`is of interest to note that the concentration
`gradient of drug across the membrane is influ(cid:173)
`enced by the apparent partition coefficients exhi(cid:173)
`bited by
`the drug with respect
`to
`the g.i.
`'membrane'/g.i.
`fluid
`interface and
`the g.i.
`'membrane'/blood interface. It is important that
`the drug has sufficient affinity (solubility) for the
`'membrane' phase that it can partition readily into
`the gastrointestinal 'membrane', i.e. K 1 should
`exceed unity. In addition, after diffusing across
`the 'membrane' the drug should exhibit sufficient
`solubility for the blood such that it can partition
`readily out of the 'membrane' phase into the
`blood, i.e. K 2 should be less than 1. Drug on
`entering the blood in the capillary network in the
`lamina propria will be carried away from the site
`of absorption by the rapidly circulating gastro(cid:173)
`intestnal blood supply and will become diluted by
`
`1 distribution in a large volume of blood, i.e. the
`systemic circulation,
`2 distribution into body tissue and other fluids of
`distribution, and
`3 by metabolism and excretion.
`
`In addition, proteins in the blood may bind
`drug molecules and thereby further lower the
`concentration of 'free' (diffusible) drug in the
`blood. Consequently the blood acts as a 'sink' for
`absorbed drug and ensures that the concentration
`of drug in the blood at the site of absorption is
`low in relation to the concentration of drug in
`solution in the gastrointestinal fluids at the site of
`absorption, i.e. Cg » Cb. The 'sink' conditions
`provided by the systemic circulation ensures that
`a large concentration gradient is maintained across
`the gastrointestinal 'membrane' during the absorp(cid:173)
`tion process. The passive absorption process is
`driven solely by the concentration gradient of the
`diffusible species of the drug which exists across
`the gastrointestinaVblood barrier. Under such
`that K 1Cg » K 2Cb and
`conditions
`thus
`(K1Cg - KzCb) approximates to K 1Cg, Eqn 9.1
`may be rewritten in the form
`
`(9.2)
`
`••
`
`Par Pharm., Inc.
`Exhibit 1009
`Page 010
`
`

`

`142 BIOPHARMACEUTICS
`
`For a given drug and 'membrane' under specified
`conditions, D, A, K 1 and h may be regarded as
`constants which can be
`incorporated
`into a
`combined constant known as the permeability
`constant, P. Hence Eqn 9.2 becomes
`
`at the site of absorption favours the formation of
`a large fraction of the drug in aqueous solution
`that is unionized. These observations form the
`basis of the pH-partition hypothesis (see later in
`this chapter).
`
`(9.3) Carrier-mediated transport
`
`where
`
`dm = p C
`dt
`g
`
`p = D A K 1
`h
`
`Eqn 9.3 is an expression for a first order kinetic
`process and indicates that the rate of passive drug
`absorption will be proportional to the concen(cid:173)
`tration of absorbable drug in solution in the
`gastrointestinal fluids at the site of absorption. In
`practice, the gastrointestinal absorption of most
`drugs by passive diffusion follows first order
`kinetics.
`It has been assumed that the drug in aqueous
`solution on each side of the gastrointestinal/blood
`barrier (see Fig. 9.4) existed entirely in the form
`of a single absorbable (via passive diffusion)
`species which exhibited definite partition
`coefficients for ·distribution between
`
`1 the aqueous gastrointestinal fluids and
`lipoidal 'membrane', and
`2 the blood and the lipoidal 'membrane'.
`
`the
`
`However, many drugs are weak electrolytes which
`exist in aqueous solution as two species, namely
`the unionized and ionized species. Since it is the
`unionized form of a weak electrolyte drug which
`exhibits greater lipid solubility compared to the
`corresponding ionized form, the gastrointestinal
`'membrane' (like other membranes) is permeable
`preferentially to the unionized species. Thus the
`rate of passive absorption of weak electrolyte
`drugs is related to the fraction of total drug that
`exists in the unionized form in solution in the
`gastrointestinal fluids at the sice of absorption.
`This fraction is determined, by the dissociation
`constant of the drug (i.e. its pKa value) and by the
`pH of its aqueous environment in accordance with
`the Henderson-Hasselbalch equations for weak
`acids and bases. The gastrointestinal absorption of
`a weak electrolyte drug is enhanced when the pH
`
`Active transport Most drugs are absorbed
`from the gastrointestinal tract by passive diffusion.
`However, a few lipid-insoluble drugs (such as 5-
`fluorouracil) and many substances of nutritional
`interest are absorbed by active transport mech(cid:173)
`anisms. In contrast to passive diffusion, active
`transport involves active participation by
`the
`apical cell membrane of the columnar absorption
`cell (and presumably also by
`the other cell
`membranes constituting the gastrointestinal/blood
`barrier) in the gastrointestinal absorption of a
`drug. A 'carrier' which may be an enzyme or some
`other component of the cell membrane is respon(cid:173)
`sible for effecting the transfer of drug by a process
`which is represented in Fig. 9.5.
`Figure 9.5 shows that the drug molecule or ion
`forms a complex with the 'carrier' in the surface
`of the apical cell membrane of a columnar absorp(cid:173)
`tion cell involved in the active transport of the
`particular drug. The 'drug-carrier' complex then
`moves across the membrane and liberates the drug
`on the other side of the membrane. The carrier
`(now free) returns to its initial position in the
`surface of the cell membrane adjacent to the
`lumen of the gastrointestinal tract to await the
`arrival of another drug molecule or ion.
`Active transport is a process whereby materials
`can be
`transported against a concentration
`gradient across a cell membrane, i.e. transport can
`occur from a region of lower concentration to one
`of higher concentration. Therefore active trans(cid:173)
`port is an energy consuming absorption process.
`In the case of the gastrointestinal absorption of
`drugs by active transport, transfer of drug occurs
`in the direction of the gastrointestinal lumen to
`the blood and not normally in the reverse direc(cid:173)
`tion, i.e. drug absorption by active transport
`across the gastrointestinal/blood barrier does not
`normally occur against a concentration gradient of
`the drug. The carrier system is generally a 'one(cid:173)
`way' transport system.
`
`•
`
`Par Pharm., Inc.
`Exhibit 1009
`Page 011
`
`

`

`f
`[1
`e
`l
`
`FACTORS INFLUENCING BIOAVAILABILITY
`c··
`
`143
`
`Intestinal
`lumen
`
`Apical cell membrane of
`columnar absorption cell
`
`Cell interior
`
`~ DRUG+CARRIER.
`
`/
`
`I
`
`/
`DRUG - - - - ._ CARRIER
`~
`' ' ...... _
`
`CARRIER
`'
`
`CARRIER
`
`I
`
`/
`
`..-"'
`
`'
`'
`
`l
`
`DRUG ____ _.
`
`Fig. 9.5 Diagrammatic representation of active transport of a drug across a cell membrane
`
`There appear to be several carrier-mediated
`active transport systems in the small intestine.
`Each carrier appears to be highly selective with
`respect to the chemical structure of the substance
`which it will transport. Thus if a drug structurally
`resembles a natural substance which is actively
`transported then that drug is also likely to be
`transported by the same carrier mechanism. For
`instance the drug levodopa, which is structurally
`related to the amino acids tyrosine and phenyl(cid:173)
`alanine, is absorbed by the same active transport
`system that is used to transport these amino acids
`from the lumen of the small intestine into the
`blood. Each carrier system is generally concen(cid:173)
`trated in a specific segment of the gastrointestinal
`tract. The substance which is transported by that
`carrier will thus be absorbed preferentially in the
`location of highest carrier density. For instance,
`more riboflavin is absorbed from the proximal
`portion of the small intestine than from the large
`or upper intestine.
`Unlike passive absorption, where the rate of
`absorption is directly proportional to th