REVIEW
`
`IV-IVC Considerations in the Development of
`Immediate-Release Oral Dosage Form
`
`SHOUFENG LI,1 HANDAN HE,2 LAKSHMAN J. PARTHIBAN,1 HEQUN YIN,3 ABU T.M. SERAJUDDIN4
`
`1Pharmaceutical Development Section, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover,
`New Jersey 07936
`
`2Absorption, Distribution, Metabolism and Excretion (ADME) Section, Novartis Pharmaceuticals Corporation,
`One Health Plaza, East Hanover, New Jersey 07936
`
`3Exploratory Clinical Development Section, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover,
`New Jersey 07936
`
`4Science, Technology and Outsourcing Section, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover,
`New Jersey 07936
`
`Received 23 July 2004; revised 25 November 2004; accepted 28 January 2005
`
`Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20378
`
`ABSTRACT: Predictive scientific principles and methods to assess in vivo performance of
`pharmaceutical dosage forms based on in vitro studies are important in order to minimize
`costly animal and human experiments during drug development. Because of issues
`related to poor solubility and low permeability of newer drug candidates, there has in
`recent years been a special focus on in vitro–in vivo correlation (IV-IVC) of drug products,
`particularly those used orally. Various physicochemical, biopharmaceutical, and physio-
`logical factors that need to be considered in successful IV-IVC of immediate-release oral
`dosage forms are reviewed in this article. The physicochemical factors include drug
`solubility in water and physiologically relevant aqueous media, pKa and drug ionization
`characteristics, salt formation, drug diffusion-layer pH, particle size, polymorphism of
`drug substance, and so forth. The biopharmaceutical factors that need to be considered
`include effects of drug ionization, partition coefficient, polar surface area, etc., on drug
`permeability, and some of the physiological factors are gastrointestinal (GI) content, GI
`pH, GI transit time, etc. Various in silico, in vitro, and in vivo methods of estimating drug
`permeability and absorption are discussed. Additionally, how IV-IVC may be applied to
`immediate-release oral dosage form design are presented. ß 2005 Wiley-Liss, Inc. and the
`American Pharmacists Association J Pharm Sci 94:1396–1417, 2005
`Keywords:
`in vitro in vivo correlation; formulation; bioavailability; oral absorption;
`permeability; solubility; dissolution; particle size; in silico modeling; in vitro models;
`animal models
`
`INTRODUCTION
`
`Correspondence to: Abu T.M. Serajuddin (Telephone: (862)
`778-3995, Fax: (973) 781-8487;
`E-mail: abu.serajuddin@novartis.com)
`
`Journal of Pharmaceutical Sciences, Vol. 94, 1396–1417 (2005)
`ß 2005 Wiley-Liss, Inc. and the American Pharmacists Association
`
`The rate and extent of drug absorption after oral
`administration of a dosage form are dependent
`on various physicochemical and physiological
`factors.1– 3 The physicochemical factors include
`ionization constant, partition coefficient, solubi-
`
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`lity, dissolution rate, crystal form, surface area,
`etc., of drug substances as well as the nature and
`properties of dosage forms. Some relevant phy-
`siological
`factors are: solubility of
`the drug
`substance in gastrointestinal (GI) environment,
`drug permeability through GI membrane, GI pH
`profile, GI transit time, presence of bile salts and
`other physiological surfactants, effect of food, and
`so forth. Since the pioneering works by Edwards4
`and Nelson5,6 in the 1950s in correlating dissolu-
`tion rates of aspirin and theophylline, respec-
`tively, with their in vivo appearance after oral
`administration, there have been a gradual in-
`crease in publications related to the influence of
`in vitro characteristics of drug substances and
`drug products on their in vivo performance. Early
`studies on in vitro–in vivo correlation (IV-IVC)
`were reviewed by Dakkuri and Shah7 and by
`Abdou.8
`IV-IVC has attained a much greater signifi-
`cance in pharmaceutical dosage form development
`and especially in immediate-release formula-
`tions during the past decade. As indicated by
`Serajuddin9 in a commentary in 2002, widespread
`application of combinatorial chemistry and high
`throughput screening in recent years has drama-
`tically increased the lipophilicity of new drug
`candidates and, as a consequence, the aqueous
`solubility decreased substantially. A look at drugs
`that were the subjects of intense scientific and
`regulatory scrutiny in 1970s and 1980s because of
`bioavailability issues show that most of them had
`aqueous solubility in the range of 20–100 mg/mL.
`In the present days, the situation has changed so
`much that drug candidates with intrinsic solubi-
`lity of less than 1 mg/mL are very common. Special
`IV-IVC considerations are needed to cope with this
`situation during drug development. To address
`issues related to low drug solubility and drug
`permeability, there have also been various scien-
`tific and regulatory initiatives over the past few
`years to classify drug molecules in different
`categories based on their physicochemical proper-
`ties10 and then address their in vivo performance
`accordingly.11,12
`The objective of the present review is to take a
`fresher look into various IV-IVC considerations
`necessary for the development of
`immediate
`release oral dosage forms. In particular, issues
`related to physicochemical properties and perme-
`ability of candidates will be discussed, and how
`such issues may be addressed by in silico model-
`ing and in vivo experimentations will also be
`considered.
`
`IV-IVC CONSIDERATIONS
`
`1397
`
`PHYSICOCHEMICAL PROPERTIES
`
`Most of the models or tools utilized in predicting
`oral absorption during dosage form development
`are heavily dependent on physicochemical proper-
`ties of drug candidates. Some of these models are:
`the pH-partition hypothesis13 utilizing ionization
`and partition coefficient of drugs as a function of
`pH; absorption potential (AP)14 based on physico-
`chemical properties; mass balance15,16 based on
`solubility and assuming that the small intestine
`as a tube; and compartmental absorption, such as
`mixing tank and compartmental absorption and
`transit (CAT) models.17– 19 The Rule of Five,20
`which provides experimental and computational
`approaches to estimate solubility and perme-
`ability in drug discovery and early development
`settings,
`is also dependent on chemical and
`physical properties of new drug molecules. Some
`of the physicochemical properties that influence
`rate and extent of drug absorption and relevant
`to oral dosage form development are discussed
`below.
`
`Solubility
`
`Solid drug substances must dissolve before
`absorption, and the rate of dissolution depends
`on drug solubility. However, the solubility of a
`compound must be considered together with its
`dose for an evaluation of its AP. Johnson and
`Swindell21 proposed a relatively simple approach
`for estimating maximum absorbable dose (MAD):
`MAD ¼ S  Ka  SIWV  SITT
`where S is solubility (mg/mL) at pH 6.5, Ka is
`intestinal absorption rate constant (min1) ob-
`tained from rat intestinal perfusion experiment
`that has been considered to be similar to human
`Ka, SIWV is small intestinal water volume (mL),
`which is considered to be 250 mL, and SITT is the
`residence time of drug in small intestine, gener-
`ally assumed to be 3 h. The MAD concept serves
`as an initial guide to ascertain whether a
`compound might have potential dissolution and
`absorption issues and whether considerations for
`special dosage forms to overcome or minimize
`such issues have to be made.
`In calculating MAD and, practically, for any
`other estimation of drug absorption, questions
`usually arise with respect to what drug solubility
`to use. In drug discovery settings, kinetic solubility
`based on the kinetics-driven turbidimetric light
`scattering method is generally used,20 while
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`1398
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`LI ET AL.
`
`thermodynamic equilibrium solubility values are
`usually measured for dosage form development.
`Further, the ‘‘in vivo solubility’’ in the GI tract,
`which is a function of concentration of lipids,
`surfactants and mixed micelles present in intest-
`inal fluids, might be more relevant to in vivo
`settings and for IV-IVC.22 –24 For compounds with
`logP > 3, it has been recommended that solubility
`and dissolution rate in simulated gastric and
`intestinal fluids or in human GI aspirates should
`be used for IV-IVC, since regular in vitro dissolu-
`tion media used for quality assurance purposes do
`not contain bile salts, lecithin, lipid digestion
`products, etc.25 For instance, when solubilities of
`danazol (logP 4.5) were compared in simulated
`gastric fluid (SGF), simulated intestinal fluid
`(SIF), and human aspirates, the solubility in
`human aspirates was found to be much higher
`than that in buffers alone.26 However, when dif-
`ferent concentrations of bile salts, lecithin, and
`sodium lauryl sulfate were added to buffers, the
`solubility varied widely depending on nature and
`concentration of the added components. Therefore,
`in the determination of solubility for in vivo
`relevance, consideration must be given to thecom-
`position of solvents used.
`
`pKa
`
`Solubility of a weak acid or a weak base is de-
`pendent on its ionization constant and intrinsic
`solubility (S0; solubility of unionized or non-
`protonated species) and, therefore, a function of
`pH of the dissolution medium. There are some
`excellent reports on the pH-dependence of drug
`solubility.27 –29 Both pKa and S0 are important in
`dictating what would be the drug solubility under
`gastrointestinal (GI) pH conditions; a relatively
`low pKa of an acidic drug or a relatively high pKa
`of a basic drug do not necessarily assure high drug
`solubility in the GI pH range unless the intrinsic
`solubility is also high. Figure 1A shows simulated
`pH-solubility profiles of four basic drugs where
`pKa is kept constant at 8.0 and S0 ranges from 0.1
`to 100 mg/mL. For the compound with S0 of 0.1 mg/
`mL, the solubility in the typical intestinal pH
`condition of 6 to 7 would be in the range of 1–
`10 mg/mL only, and the solubility must be lowered
`below 4 to obtain a solubility of 1 mg/mL and
`higher. One aspect of the pH-solubility profile
`that is not shown in Figure 1A is the solubility
`of the salt form. The pKa does not keep on
`increasing with a decrease in pH, as shown in
`Figure 1A,
`indefinitely; at a certain pH, the
`
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`Figure 1.
`(A) Theoretical pH-solubility profile of a
`weak base with pKa of 8.0 and different intrinsic
`solubility. (B) Theoretical pH-solubility profile of a weak
`base with So of 0.1 mg/mL and different pKa values.
`
`total solubility exceeds the solubility of its salt
`form, preventing any further increase.29 As
`expected, the solubility is also dependent on the
`pKa value; Figure 1B shows the simulated pH-
`solubility profiles of four free bases as a function
`of pKa values, where the S0 value has been kept
`constant.
`The pH gradient inherent to the GI tract in-
`fluences and gives rise to areas of preferred
`absorption. Drugs with pKa values in the range of
`1 to 8 undergo considerable changes in the
`equilibrium between their ionized and unionized
`species as they transit through different regions
`of GI tract having different pH conditions. This
`effect, coupled with the solubility differences
`shown in Figure 1, gives rise to pH-dependent
`absorption. For example, the dissolution of a basic
`drug, ketoconazole, at pH 6 after 1 h is only 10%,
`while at pH < 3 more than 85% dissolves in less
`than 5 min.30 This pH-dependence was evident
`in vivo when ranitidine was coadministered with
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`ketoconazole to raise the gastric pH to 6; the Cmax
`of ketoconazole decreased from 8.2 to 0.6 mg/mL
`and the AUC decreased from 37.1 to 1.6 mg/h/mL.31
`Similarly, a decrease of almost 85% in Cmax and
`AUC values of cinnarizine was observed in
`subjects with elevated gastric pH as compared to
`those exhibiting low gastric acidity.32 Although it
`is often assumed that a basic drug dissolves well
`under the gastric environment, these examples
`illustrate that the actual amount dissolved could
`indeed be variable and depends on such factors as
`the pH and the gastric residence time. One way of
`improving the situation, as discussed under the
`next heading in this article, is to administer a
`base in its salt form, which usually has a higher
`dissolution rate.
`Potential effects of pKa on drug solubility,
`dissolution rate, and absorption need to be inves-
`tigated at the early stage of drug development.
`When dissolution is the issue, appropriate for-
`mulation strategy to ensure the desired disso-
`lution rate at the absorption site is necessary. Ho
`et al.33 demonstrated the interplay of pH, pKa,
`partition coefficient, concentrations of
`ionized
`versus unionized species, and permeability coeffi-
`cients of aqueous boundary layers for a series of
`beta blockers by using cell culture monolayers.
`Structural modification of drug molecule can
`ensure optimal drug absorption. Derivatization
`into prodrugs or substitution of isosteres may also
`improve oral absorption of ionizable lipophilic
`molecules.34
`
`Salt Formation
`Since the early studies by Nelson,5,6 there have
`been numerous reports on the effect of salt forma-
`tion on drug dissolution35– 40 and its potential
`effect on bioavailability. A salt usually provides a
`higher dissolution rate than that of its free acid or
`base form by modifying pH and solubility in the
`diffusion layer at the surface of dissolving solid.
`Earlier work on physicochemical and biopharma-
`ceutical aspects of pharmaceutical salts were
`reviewed by Berge et al.35 It may also be pointed
`out here that, under certain GI pH conditions, a
`free base may have higher dissolution rate than
`that of its salt form. For example, Serajuddin and
`Jarowski39 reported that the dissolution rate of
`the free base form of phenazopyridine at pH 1 is
`higher than that of the hydrochloride salt; how-
`ever, if the full GI pH range (1–7) is considered,
`the salt still provides a superior pH-dissolution
`profile.
`
`IV-IVC CONSIDERATIONS
`
`1399
`
`Because of pH-dependent solubility, there is a
`potential that free acid or base forms may pre-
`cipitate out during the dissolution of salts under
`certain GI pH conditions. Depending on pKa and
`solubilities of free forms, the precipitation of free
`acid occurs at a relatively lower pH, i.e., in the
`stomach, while the free base could precipitate at a
`relatively higher pH, i.e., in the intestine. This
`may be exemplified by the dissolution of phenytoin
`sodium under GI pH conditions. Phenytoin is
`an acidic compound with a pKa of 8.4 and the
`solubility of 37 mg/mL at 378C between pH 1 and
`6.41 Therefore,
`it is expected that after oral
`administration as a sodium salt at a dose of 100
`to 300 mg, it would precipitate out in its free acid
`form under the acidic environment of the stomach.
`It had been suggested that the precipitation of
`phenytoin acid in a very finely divided state would
`facilitate its rapid redissolution and faster absorp-
`tion,42 and later it was confirmed that it is indeed
`the case.41 Figure 2 shows that when a 100-mg
`phenytoin sodium capsule was dissolved in 500 mL
`of a pH 2 medium, an equilibrium was established
`(20% dissolved) in <10 min and the excess drug
`precipitated out as free acid. However, when an
`additional 500 mL of medium was added to the
`dissolution vessel, a new equilibrium was estab-
`lished in <5 min. Figure 2 also shows that there
`
`Figure 2. Dissolution profiles of fast-release pheny-
`toin sodium formulation (100 mg) in (&) water and (~)
`pH 2.1 medium at 378C. Each data point represents the
`average of three determinations. (Reproduced from Ref.
`41 with permission of copyright owner.)
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`1400
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`was no precipitation of phenytoin when water by
`itself was used as the dissolution medium, because
`the pH of the medium increased gradually with the
`dissolution of salt. This is, however, not the case in
`GI fluids where acidity, buffering action, etc.,
`would keep pH relatively lower that could cause
`drug precipitation.
`Despite the high dissolution rate of phenytoin
`sodium and the rapid redissolution rate of pheny-
`toin acid that precipitated out in the stomach,
`phenytoin sodium dosage forms have been the
`subject of extensive IV-IVC studies. It was noted
`that there was a greater incidence of side effects if
`the innovator’s product was substituted with an
`equivalent dose of products from other manufac-
`turers,43 which was due to 2–3 mg/mL higher
`steady state plasma level from the non-innovators’
`products.44 To address this issue, the FDA classi-
`fied the innovator’s product as an ‘‘extended’’ or
`slow-release dosage form and the others as
`‘‘prompt’’ or fast-release dosage form.45,46 How-
`ever, considering the long half life (22  9 h)
`and Michaelis–Menten parameters of phenytoin,
`Sawchuk and Rector47 determined that any varia-
`tion in the release rate of phenytoin from dosage
`forms should not influence its steady state plasma
`level unless the extent of absorption is changed.
`They did not see any difference in plasma level
`when a situation assuming instantaneous absorp-
`tion of phenytoin was compared with a situation in
`which a continuous constant rate of absorption
`occurred. Indeed, Arnold et al.48 and, later Ser-
`ajuddin and Jarowski,41 demonstrated that there
`is a potential for incomplete release and, as a
`result, lower bioavailability of phenytoin from
`certain phenytoin sodium products. This example
`of phenytoin sodium highlights the importance
`of selecting not only a salt form but also of an
`appropriate dosage form for a drug to attain
`optimal plasma concentration and bioavailability.
`A similar situation may also arise for the salts of
`basic drugs, especially under intestinal pH condi-
`tions. If higher dissolution rate for a salt form cannot
`be ensured, a free base form may even be preferred.49
`If other factors remain constant, the dissolution
`rate of a compound should determine the rate of
`build-up of blood levels with time and the max-
`imum levels obtained. Nelson has reported that
`the rank order of dissolution rates correlated well
`with clinically determined blood levels.5 Correla-
`tion of urinary excretion rates and dissolution
`rates of tetracycline and some of its acid salts was
`also demonstrated by Nelson.6 Relative bioavail-
`ability of the vasodilator naftidrofuryl in oxalate
`
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`
`and citrate salt forms has shown that the rate of
`absorption is higher for the citrate than for the
`clinically used oxalate form of the drug.50 Lin
`et al.,51 on the other hand, reported no enhance-
`ment in bioavailability when salts of a basic
`antihypertensive agent, having significantly dif-
`ferent intrinsic dissolution rates, were compared.
`
`Diffusion Layer pH
`
`The effect of diffusion layer pH has been men-
`tioned above in relation to the dissolution of free
`acids and bases versus their salts. Such an effect
`should also be considered in assessing the dis-
`solution of one particular form of a compound (for
`example, free acid) under different pH conditions.
`It was reported that the diffusion layer pH on the
`dissolving surface of benzoic acid (pHh ¼ 0) would
`remain practically constant around 3 while the
`pH of unbuffered bulk media may range from 3
`to 11,36,37 and, as a result, the dissolution rate
`within such a wide pH range would also remain
`practically unchanged. A self-buffering effect to
`maintain steady state pH in the diffusion layer
`may vary from compound to compound, depend-
`ing on solubility and/or pKa values. Figure 3
`shows the effect of the pH of dissolution medium
`on the dissolution of three compounds having
`similar pKa values, namely benzoic acid, 2-
`naphthoic acid, and indomethacin.36 In this figure,
`the increase in dissolution rate (flux) relative to
`that of the unionized species (N/N0) has been
`plotted. Despite pH-dependent solubility of all
`three compounds studied, pH of dissolution
`medium (bulk pH) had minimal effect on the
`
`Figure 3. Relative flux (N/N0) versus pHbulk for
`several carboxylic acids at 258C. N0 is the respective
`flux at pH 2. (Reproduced from Ref. 36 with permission of
`copyright owner.)
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`dissolution of benzoic acid and 2-naphthoic acid,
`while a more pronounced effect was noticed in the
`dissolution of indomethacin. Indomethacin has
`much lower solubility values at different pH
`than that of the other two acids and, as a result,
`its self-buffering effect in the diffusion layers is
`limited. The buffer capacity of a dissolution
`medium also plays a critical role in modulating
`microenvironmental pH of a drug substance and,
`therefore, its dissolution rate.
`pH and drug solubility in the diffusion layer of a
`particular compound may be calculated theoreti-
`cally.36,38 Serajuddin and Jarowski37 described a
`practical method of estimating diffusion layer pH
`of drug substance as the thickness of the layer
`approaches zero (pHh ¼ 0) and thereby predicting
`its dissolution rate under different pH conditions.
`The authors established that the pH of a saturated
`solution of a drug substance (acid, base, or salt) in a
`particular medium is equivalent to pHh ¼ 0, and,
`therefore, the drug solubility at this pH would
`represent Cs,h ¼ 0, i.e, solubility in the diffusion
`layer as the thickness of the layer approaches zero.
`The flux (J) in the same medium is then deter-
`mined experimentally by determining dissolution
`rate from a constant surface area. After the
`determination of J/Cs,h ¼ 0 from these two data,
`the pHh ¼ 0 in a second medium would be deter-
`mined. The measurement or theoretical calcula-
`tion of saturation solubility at this new pH and
`then solving for J as per the equation, J/Cs,h ¼ 0 ¼ k,
`under sink condition, would give the dissolution
`rate in the second medium. The authors suggested
`that this method may also be applicable to dissolu-
`tion media containing buffering agents because
`any change in buffer type, buffer capacity, etc.,
`would be reflected in pHh ¼ 0.
`As apparent from the above discussion, various
`acidic and alkaline components added to dissolu-
`tion media or dosage forms would influence drug
`dissolution because of their effects on diffusion
`layer pH. However, one area that has not been
`explored adequately is the effect of counterions
`added to dissolution media or present in GI fluid
`on dissolution of pharmaceutical salts, where a
`common ion effect is not apparent. Li et al.52
`recently reported that the dissolution rate of halo-
`peridol mesylate (methanesulfonate) is adversely
`influenced by NaCl added to dissolution media.
`The presence of chloride ion converts the mesylate
`salt to a hydrochloride salt, possibly in the dif-
`fusion layer at the surface of the solid, thereby
`making its solubility and dissolution rate suscep-
`tible to the common ion effect.
`
`IV-IVC CONSIDERATIONS
`
`1401
`
`Particle Size
`
`Amidon et al.10 described the concept of dissolu-
`tion number, Dn, in relation to drug absorption.
`Dn may be defined as:
`Dn ¼ tres
`tdiss
`
`where tres is the mean residence time of drug in
`the GI tract and tdiss is the time required for a
`particle of the drug to dissolve. The higher the Dn,
`the better the drug absorption, and a maximal
`drug absorption may be expected when Dn is
`greater than 1, i.e., tres > tdiss. However, for most
`poorly water-soluble drugs, Dn < 1 and, as a result
`a dissolution rate-limited absorption is expected.
`As will be discussed later in this paper, tres is a
`physiological factor that is difficult to change by
`dosage form design. Therefore, a more practical
`way of increasing Dn is by decreasing tdiss, that is,
`by increasing the dissolution rate. One commonly
`used method of increasing dissolution rate is by
`reducing the drug particle size.
`It may be of interest to examine how the particle
`size reduction would increase surface area and,
`consequently, the dissolution rate of drug sub-
`stances. If the size of one specific drug particle is
`reduced from a radius of r1 to a radius of r2, the
`total number of particles produced will be
`ð4=3Þpr3
`¼ r3
`1
`ð4=3Þpr3
`r3
`2
`
`1
`
`2
`
`According to this equation, if the size of a particle is
`reduced, say, by a factor of 5, the total number of
`new particles produces will increase by a factor of
`(r1)3/(r1/5)3 or 125. Despite 125 times increase in
`drug particles, the surface area will, however,
`increase by a factor of only (4pr22  125)/(4pr1
`
`2) or 5.
`Thus, it is apparent that the surface area and,
`therefore, the dissolution rate would increase only
`linearly with the decrease in particle size. For
`example, if the initial particle size of a drug sub-
`stance is 10 mm in diameter and the size is reduced
`to 3–4 mm by micronization, which might be the
`lowest limit of particle size reduction by conven-
`tional milling, only 2–3 times increase in dissolu-
`tion rate may be achieved. This is assuming that no
`conversion of drug substance to an amorphous
`form that could enhance dissolution or no agglom-
`eration of drug particles that could reduce dissolu-
`tion have occurred.
`Johnson and Swindell21 analyzed the effect of
`particle size on drug absorption as a function of
`dose as well as drug solubility (Fig. 4), where
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`Figure 4. Computed percent of dose absorbed at 6 h
`versus mean particle size, with an absorption rate
`constant of 0.001 min1: (A) at doses from 1 to 100 mg,
`with a solubility of 0.001 mg/mL; and (B) at solubility
`from 0.001 to 1.0 mg/mL, with a dose of 1 mg. (Replotted
`from data in ref. 21.)
`
`the absorption rate constant was assumed to be
`0.001 min1. For dissolution rate-limited absorp-
`tion (Dn < 1), Figure 4A shows that the fraction of
`drug absorbed will decrease with the increase in
`dose. On the other hand, if the dose is kept
`constant, Figure 4B shows that the fraction of
`drug absorbed will increase with an increase in
`drug solubility, and the particle size becomes
`practically irrelevant for drugs with a solubility
`of 1 mg/mL at a dose of 1 mg.
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`Polymorphism
`
`Since the publication of the effect of polymorph-
`ism on the absorption of chloramphenicol from
`chloramphenicol palmitate suspensions by Aguiar
`et al.,53 the interest in polymorphism in drug
`development has increased greatly. Indeed, in
`certain circles, polymorphism has become synon-
`ymous with bioavailability issues. One must,
`however, be cautious in generalizing the findings
`of Aguiar et al.53 In their study, the solubility of
`Polymorph B used was observed to be four times
`higher than that of Polymorph A, while its bio-
`availability in humans was over 20 times higher;
`however, no reason for
`the disproportional
`increase in bioavailability was given. Also, inter-
`estingly, when three different suspensions of the
`same polymorphic form (Polymorph B) having
`three different particle sizes (1, 5, and 25 mm)
`were given to humans, no difference in bioavail-
`ability was observed. The suspension with 1-mm
`particles was ‘‘well-dispersed’’ because of the
`presence of a surfactant, while those with 5 and
`25-mm particles were ‘‘highly aggregated’’ since no
`surfactant was added. Based on this consideration
`alone, the surface area of 1-mm suspension should,
`respectively, be over 5 and 25 times higher than
`that of 5 and 25-mm suspensions, and these
`differences should be reflected in dissolution rate
`and bioavailability. Since no difference in bioa-
`vailability was seen, the authors concluded that
`‘‘the polymorphic form is of much greater sig-
`nificance than the particle size.’’ An alternative
`explanation of the results obtained by Aguiar et al.
`might be necessary. Since chloramphenicol pal-
`mitate undergoes hydrolysis into chlorampheni-
`col prior to absorption, its in-situ hydrolysis in the
`gut may complicate the over-all picture of its
`intestinal absorption. Thus, the situation with
`chloramphenicol palmitate could be different
`from common cases where polymorphism influ-
`ences drug solubility and dissolution and, there-
`fore, it may not be generalized.
`Recently, Pudipeddi and Serajuddin54 reported
`that solubility values of the polymorphic forms of
`most drugs reported in the literature do not differ
`more than two times, and any two polymorphic
`forms hardly show greater than five times differ-
`ence in solubility. Such a difference may or may not
`have biopharmaceutical significance depending
`on, as discussed earlier, doses used, particle sizes,
`and individual solubility values. Therefore, any
`potential influence of polymorphism on bioavail-
`ability and the risks involved because of their
`
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`potential interconversion in a dosage form need
`to be carefully investigated during dosage form
`development. In addition to solubility, polymor-
`phism may influence physical stability and proces-
`sing parameters for a dosage form, which need to
`be addressed separately.
`Unlike polymorphism, a conversion from crys-
`talline to amorphous form or vice versa might
`have a more profound effect on drug dissolution.
`Hancock and Parks55 reported that solubility of
`amorphous drug substances could be higher by
`factors of tens or even hundreds than that of their
`crystalline forms.
`
`BIOPHARMACEUTICAL PROPERTIES
`
`Drug Permeability
`
`Besides solubility and dissolution, permeability
`of a compound plays a major role in its absorption
`after oral administration. Transcellular perme-
`ability (Pm) of lipophilic compounds depends on
`their solubility in GI membrane lipids relative to
`their aqueous solubility. This is defined as the
`ratio of the product of membrane diffusivity (Dm)
`and membrane–water partition coefficient (Kp) to
`the membrane thickness (Lm):
`Pm ¼ KpDm=Lm
`Therefore, a variation in membrane permeabi-
`lity for a particular compound will depend on the
`fluidity of membrane and partition coefficient of
`compound.56
`Models to estimate or measure permeability
`of a compound range from simple to complex. Drug
`ionization, logP, artificial membrane permeabil-
`ity, Caco-2 cell line permeability and other in vitro
`epithelial cell culture permeability, as well as
`in situ animal perfusion study and human jejunum
`permeability (Peff), have variously been used. They
`will be discussed in the following sections. In
`general, a compound is considered highly perme-
`able when its absorption is determined to be 90%
`or higher.
`
`Ionization
`
`Under the simplest scenario, considering that
`membrane uptake of unionized solute is favored
`over that of ionized solute by the membrane-to-
`water partition coefficient (Kp), membrane perme-
`ability would reflect the solute ionization curve
`at Kp ¼ 1. When Kp is higher (i.e., in the case of
`lipophilic drugs), membrane uptake of unionized
`
`IV-IVC CONSIDERATIONS
`
`1403
`
`Figure 5. Relative absorption rate for a weak acid
`(pKa ¼ 3) as a function of mucosal pH for increasing
`(membrane) permeability (Pb) with fixed
`barrier
`unstirred aqueous layer permeability (PUL). X ¼ pH
`inflection point. (Reproduced from reference 57 with
`permission of copyright owner.)
`
`drug would shift the equilibrium in order to
`replace the unionized solute removed by the
`membrane. This would shift the sigmoidal curves
`of membrane permeability versus pH towards
`basic pH for weakly acidic drugs and acidic pH for
`weakly basic drugs.57 The shifts may be described
`by changes in inflection or half-maximal pH
`points (pHmax/2) as demonstrated in the following
`equation and in Figure 5:
`pHmax=2 ¼ pKa  log½1 þ ðPm=Paqފ
`where, Paq ¼ aqueous boundary layer perme-
`ability, Pm ¼ membrane permeability. The above
`equation describes the absorption profiles of
`sufficiently lipophilic drugs. It simply states that
`half maximal rate of absorption occurs at pH
`values close to their pKa and that shifts in
`equilibrium can be accounted for based on an
`analysis of membrane permeability against aqu-
`eous boundary layer permeability. At pH values
`where the drug is fully ionized and the equation
`above has accounted for the permeability shifts, a
`non-zero permeability would suggest that per-
`meation occurs through routes other than simple
`lipid partitioning such as pore transport or
`paracellular transport. For drugs with half-max-
`imal pH points in the range