Jennifer Dressman,‘ James Butler, John Hempenstall, and Christos Reppas
`
`
`
`
`
`
`
`
`
`ince the Biopharmaceutics Classification System
`(BCS) was introduced several years ago, it has be»
`come a benchmark in the regulation of bioequiva-
`lence of oral drug products both in the United
`'
`States and abroad (1). The concept behind the BCS is that
`if two drug products yield the same concentration pro—
`file along the gastrointestinal (GI) tract. they will result
`inthe same plasma profile after oral administration. This
`concept can be summarized by the following equation
`
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`System (805) has proven to be a valuable/ 3
`tool for the regulation ofEchangesm oral/E. .
`drug products during scale-up and after
`product approvalThis article reviewers the
`criteria for classifymg drugs accord'ng.to
`the BCS and discusses further potential
`applications of the BCS, including the
`development of new drugs, the approval
`of generics, and the regulation of
`controlled-release products.
`
`
`
`gastrointestinal tract based on
`physiological as Well as drug and dosage-
`formrelated conSIderatIons She‘5 a
`professor at the Institute Of Pharmaceutical Technology.
`Johann Wolfgang Goethe University, Marie- Curie-str. 9
`Blozentrum 50439 Frankfurt, Germany. tel. 49 69 7982 9680.
`fax 49 59 7932 9594, e-mail dressmangiem,untfrankfmfie,
`Dr. Dressman is a member of the Editorial Advisory Board of
`Pharmaceutical Technology. James Butler '5 principal
`scientist. strategic technologies. at Pharmaceutical Sciences.
`GIaxoSmithKline R&D, Ware, UK. John Hem penstall is
`director of product-line extensions at Pharmaceutical
`Development, GlaxoSmithKilne R&D. Harlow. UK. Christos
`Reppas is an assistant professor at School of Pharmacy.
`The UWVBTSEW 0f Athens: Athens. Greece.
`*To Whom 3" corms’mr'dence Show be addressed‘
`
`68
`
`Pharmaceutical Technology Jun/2501
`
`in which Iis the flux across the gut wall. Pw is the permea—
`bility of the gut wall to the drug, and Cw is the concen-
`tration profile at the gut wall. In terms of bioequivalence,
`it is assumed that highly permeable, highly soluble drugs
`housed in rapidly dissolving drug products will be bio~
`equivalent and that, unless major changes are made to the
`formulation, dissolution data can be used as a surrogate
`for pharmacokinetic data to demonstrate bioequivalence
`of two drug products. The BCS thus enables manufac-
`turers to reduce the costs of approving scale-up and post-
`approval changes (SUPAC) to certain oral drug products
`(rapidly dissolving products of Class I drugs; see Table I)
`without compromising public safety interests.
`After several years of experience with the BCS, several
`issues have arisen: First, is the BCS fail safe? Second, should
`biowaivers be limited to Class 1 drugs. or could we extend
`them to other classes? Third, what about controlled~
`release dosage forms? Fourth, how early in the develop—
`ment process can we apply the BCS principles, and should
`the same cutoff values be applied to developing both new
`drug products and SUPAC applications? Although these
`issues already have been addressed to some extent in the
`.
`literatum we mus‘ contmue to gather data and ex19‘3““
`ence in order to resolve them. In this article we have tried
`to summarize current thinking and to make some sug-
`gestions about where we should head with the BCS in the
`coming years.
`
`?
`_
`'5 the 303 fall safe-
`FDA has set quite restrictive limitations on which drugs
`and drug products would be candidates for biowaivers
`under the BCS. The permeability requirement states that
`MYLAN EXHIBIT 1031
`MYLAN EXHIBIT 1031
`
`

`

`
`
`ample time to be dissolved. As long as
`these drugs meet the permeability crite-
`rion, biowaivers for products that dissolve
`rapidly at pH vaIUes typical of the small
`intestine could be considered.
`Another issue is that the requirement
`for “not less than 35% dissolution within
`
`30 min" may be too conservative in some
`dosing circumstances. Although in the
`fasted state it is quite possible that tran»
`sit time through the stomach is short
`(half-emptying times for water as short
`as 8—10 min have been reported in the lit—
`erature), if the dosage form is given with
`a meal, more than likely it will spend at
`least an hour or two in the stomach.
`Under these circumstances even slowly
`dissolving products still may show ab—
`sorption patterns that are controlled by
`gastric emptying. A case example is that
`of certain immediate-release (IR) parace—
`tamol tablets. Galia et al. showed that
`
`Panadol tablets release very slowly in sim-
`ulated fed»state conditions (milk) (8). It
`was subsequently shown by Reppas and
`Nicolaides that gastric emptying contin—
`ues to be rate limiting to absorption of
`paracetamol, even in the fed state (7).
`These results suggest that in cases in
`which the drug is routinely administered
`with meals, it may be possible to relax the
`criteria for dissolution.
`
`Can the 868 be extended to
`rapidly dissolving products of
`Class III substances?
`
`it has been suggested by Blume and Schug
`that because the absorption of Class III
`drugs is essentially controlled by the gut
`wall permeability to the drug and not by
`the drug's solubility, biowaivers for rapidly
`dissolving products of Class HI drugs also
`could be justified (8). Although in terms
`of the BCS theory this concept is clearly
`valid, some physiological issues would
`have to he addressed on a case-by—case
`basis. First, one must establish why the
`
`www.pharrnapertai.com
`
`‘3 Paracetamol formulation. 630 mg sodium bicarbonate
`+ Paracetamol formulation, 400 mg sodium bicarbonate
`A Paracetamol formulation, 375 mg sodium bicarbonate
`X Panadoi tablets
`
`D Panadol soluble, 1342 mg sodium bicarbonate
`
` I.l
`
`l l
`
`Figure 1: Mean paracetamol serum concentrations tollewmg 500 mg oral paracetamol.
`
`
`intrinsic solubility: 0.064 regimi. and pKa: 4.39
`
`Figure 2: The pH—soiubtlity profile of Ibuprofen at 37 C.
`
`(see Figure 1) even
`though the dissolution
`of the products in vitro
`was similar (4). This ex-
`ample shows that even
`though an excipient
`change may seem com-
`pletely innocuous. if the
`new excipient alters the
`GI physiology, then it
`may very well alter the
`plasma profile also.
`Regulatory authorities
`must be very careful
`about defining what
`constitutes a "major
`change" to the formu-
`lation to address the potential physiologi-
`cal issues.
`
`the permeability of the drug is common"
`surate with 290% absorption from a so-
`lution. The solubility requirement is that
`the dose~to-solubiiity ratio (D13) of the
`drug must be $250 mL over a pH range
`of l to 7.5. and the dissolution require-
`ment for the drug product is that disso-
`lution must be >85% complete within
`30 min (3). For products meeting these
`criteria. gastric emptying, rather than the
`release performance of the drug product.
`will be the key factor in determining the
`plasma profile; therefore, variability in the
`plasma profile will be under physiologi-
`cal control and not dictated by the dosage
`form.
`
`Even for rapidly dissolving products of
`Classl drugs, however. it is possible to man-
`ufacture bioinequivalent products if ex-
`cipients that modify gastric emptying are
`added. For example, Grattan et al. showed
`that the addition of sodium bicarbonate to
`the paracetamol (acetaminophen) formu—
`lation produced a faster and higher peak
`concentration of paracetamol in plasma
`
`70
`
`Pharmaceutical Technology JULY 2001
`
`llre the BBS criteria too restrictive?
`On the other hand, some drugs that are
`currently classified as Class II are consis-
`tently and completely absorbed after oral
`administration. These are typically poorly
`soluble weak acids with pKa values of $4.5
`and intrinsic solubilities (solubility of the
`un—ionized form) of 20.01 mg/mL. At pH
`values typical of the fasted state in the je-
`junum (about pH 6.5), these drugs will
`have soiubilities of E1 mg/mL, resulting
`in fast and reliable dissolution of the drug.
`
`Currently, these drugs are classified as
`Class Ii drugs because they are poorly sol-
`uble at gastric pH, in which pH<< pK.
`Figure 2 shows a typical solubility versus
`pH profile for ibuprofen (5)
`Because the small—intestinal transit time
`is more reliable, and in the fasted state.
`
`longer than the gastric residence time
`(generally on the order of 3 h), drugs with
`these physical characteristics will have
`
`

`

`
`
`
`A With 1132 mg SAPP
`A Alone
`0 All excipianis of effervescent tablet except SAPP
`o Effervescent tablet containing 1132 mg SAPP
`
`
`
`Figure 3: Mean serum ramtldine concentrations followmg 150 mg oral solution doses of
`ranitidine.
`
`permeability of the gut wall to the drug is
`low. If the permeability is low but uniform
`along the entire GI tract (including the
`proximal colon), biowalvers might be con-
`sidered. Howaver, if there is an absorption
`window or a gradient in the permeability
`of the gut wall to the drug (with decreas-
`ing permeability in distal regions), excip-
`ients that accelerate gut motility could sig~
`nificantly reduce the contact time of the
`drug with the sites at which permeability
`is favorable and therefore lower the
`
`bioavailability of the drug.
`Several compounds belonging to the
`HE receptor antagonist group are c1assi~
`cal examples of Class III drugs. It was
`shown in the literature some years ago that
`the shape of the plasma profile of cimeti-
`dine is highly dependent upon the gastric
`pH at the time of administration, with the
`characteristic double peak eliminated if
`the drug is given under elevated gastric
`pH conditions (9) , Further, excipients that
`accelerate transit in the upper GI tract
`such as sodium acid pyrophosphate (10)
`and mannitol
`(1 l) have been clearly
`shown to reduce the extent of absorption
`of ranitidine and cimetidine, respectively.
`The results from Koch et al. are shown in
`
`Figure 3 (10) . The 50% reduction in CPeak
`illustrates how important the influence of
`excipients that can alter the GI motility
`can be to the absorption of Class llI drugs.
`
`Can the BBS be applied to
`controlled-release drug products?
`Under the current definition, the BCS is
`
`applicable only to immediate—release
`dosage forms because only the perme-
`
`72
`
`Pharmaceutical Technology JULY2001
`
`ability in the Jejunum is considered. To
`extend the BCS to controlled-release (CR)
`dosage forms, one must assess the per-
`meability at all points in the GI tract where
`release of the drug is foreseen {l2}. As
`pointed out by Corrigan, it is unlikely that
`drugs with low permeability in either the
`ileum or colon will prove to be suitable
`candidates for CR dosage forms, let alone
`for blowaivers based on dissolution tests
`
`(5). He has proposed a useful subclassifi—
`cation scheme for CR products that is
`based on the site dependency of both the
`drug solubility and permeability.
`A further consideration is the selection
`
`of appropriate dissolution conditions to
`simulate the release profile of the dosage
`form as it moves through the GI tract.
`Conditions for dissolution in the stom-
`ach, the small intestine, and the colon dif-
`fer greatly. Important parameters that
`vary with location in the GI tract include
`the volume of fluid available for dissolu-
`
`tion, osmolarity of the contents, the hy—
`drodynamic (motility) conditions, and
`the secretion of various enzymes and
`other para—GI secretions that could po-
`tentially affect the release rate. Similarity
`of the dissolution profiles under all ap-
`propriate GI conditions would have to be
`shOWn for the two drug products. Al-
`though our understanding of the com—
`position of lumenal contents as they move
`along the GI tract is far better than it was
`a decade ago, a more complete charac-
`terization is still needed. Still almost to-
`
`tally lacking is an understanding of the
`relationship between the hydrodynamics
`in the gut and those in the currently avail-
`
`able dissolution testers. This thrOWs a de-
`
`gree of uncertainty into the interpreta-
`tion of dissolution results in terms of in
`
`vivo performance. eVen when the com~
`position of the lumenal contents can be
`simulated well in the in vitro tests. Al-
`
`though a problem is posed by the limi—
`tation to establishing in vivo-in vitro cor-
`relations for IR products, the problem is
`compounded for CR dosage forms be-
`cause the hydrodynamics at several sites
`within the GI tract must then be simu-
`lated. As a result, in vitro release profiles
`of CR dosage forms with different release
`mechanisms must be interpreted very
`cautiously,
`
`Application of the 368 to the
`development of new
`drug substances
`Because the BCS was originally developed
`as a basis for determining bioequivalence
`of oral drug products, it assumes that the
`drug is sufficiently well absorbed to make
`an oral dosage form feasible. When new
`drug substances are being developed,
`however, this assumption is not appro-
`priate, and one must consider other fac—
`tors than just the solubility and permea-
`bility to determine whether an oral dosage
`form can be successfully developed. An
`overview of the events in the GI tract fol—
`
`lowing oral drug administration is de~
`picted in Figure 4.
`First, it should be remembered that the
`drug substance does not have to meet the
`Class I criteria of high permeability and
`solubility for the drug to be successfully
`formulated in an oral solid dosage form.
`Many Class II and Class III drugs are avail"
`able on the market, and several that meet
`Class IV criteria are available (see Table ll).
`One problem with applying the BCS cri-
`teria to new drug substances is that, early
`in preformulatlon/formulation, the dose
`is not yet accurately known. So at this
`point, the D:S can only be expressed as a
`likely range. A helpful rule of thumb is that
`compounds with aqueous solubilities
`>100 pg/mL seldom exhibit dissolution
`ratemlimited absorption. Alternatively, one
`can estimate the maximum absorbable
`dose on the basis of the usual volumes of
`GI fluids available under the anticipated
`dosing conditions and the solubility of the
`drug. With regard to the solubility of the
`drug, it may be useful to consider the
`
`www.pharmaporia|.cem
`
`

`

`
`Drug in solution
`at uptake sites
`iii
`
`Decomposition
`Adsorption
`Complexation
`
`Decomposition
`iii
`Adsorption
`Drug in solution
`at uptake sites
`Complexatlon
`
`Figure 4: Steps In drug absorption and sources of incomplete hioava: a lily c owmg or
`administration of a solid dosage form.
`
`
`
`
`
`would lead to a quite different interpreta-
`tion of the chances for absorption in vivo.
`For promising compounds that are both
`ionizable and lipophilic, extensive solubil-
`ity experiments in biorelevant media will
`help characterize the likely solubility be
`havior in viVO. Several publications address
`the composition and applications of these
`media (6,13—16). An alternative approach
`is to use aspirates from human volunteers.
`although volumes aspirated typically are
`small and the choice of experiments and
`apparatus therefore is limited (17).
`Another issue is the use of 250 mL as
`the volume in which a dose must be dis-
`solved. This amount is a conservative es-
`timate of the volume of fluid available in
`
`physicochemical properties of the drug
`when deciding which media to use for the
`solubility determinations. For example,
`measuring solubility at all pH values rec—
`ommended by the BCS is unnecessary for
`neutral compounds in early development.
`Later, when formulations are compared,
`dissolution data for the drug product over
`the entire Gl pll range will be useful in 88*
`tablishing the robustness of release from
`the formulation under Gl conditions.
`
`Lipophilic drugs may be very poorly sol-
`uble in water and in simple buffers, but in
`the GI fluids they can often be solubilized
`by the bile to a significant extent. Increases
`in solubility of one to two orders of mag—
`nitude are possible for compounds with
`log P values of ;4. In some cases this
`
`74
`
`Pharmaceutical Technology worms:
`
`the gut under fasting-state conditions and
`is based on the volume usually ingested
`along with the dosage form in a pharma-
`cokinetic study (the so-called FDA glass of
`Water). The actual volume available is a
`composite of the ingested fluid and the se-
`cretions of the GI tract. Although these
`amounts tend to be modest in the fasted
`state, secretions in the fed state contribute
`substantially to the overall fluid volume.
`which may be as high as 1.5 L in both the
`stomach and upper small intestine. De-
`pending on whether drug administration
`is to be on an empty stomach or with
`meals, it is reasonable to adjust the volume
`used to assess the capacity of the GI fluids
`to dissolve the dose. A useful starting point
`would be to use a volume of 300 mL for
`the fasted stomach. 500 ml. for the fasting
`
`small intestine, and up to I L for the post-
`prandial stomach and small intestine.
`A further consideration is the choice of
`
`model for assessing the permeability. Ale
`though perfusions in humans will pro—
`duce the most reliable results (18) and are
`clearly the “gold standard,” these require
`too much time and money to make them
`practicable for screening new drug sub—
`stances. Many animal- and celluculture
`models have been developed, each with its
`own set of advantages and disadvantages.
`For example. the Caro 2 cells can be used
`with confidence to assess transcelluiar dif—
`fusion and can be standardized to ensure
`
`reproducible results, but they tend to un-
`derestimate paracellular and active mecha—
`nisms. cannot be employed to determine
`regional permeability within the gut, and
`tend to overestimate efflux via the Pa
`
`glycoproteins. In situ perfusions in rats.
`although they are much better in terms of
`forecasting active transport and can be
`used to determine regional permeability,
`take more time and effort to produce a re-
`liable permeability estimate. In any case,
`it is a good idea to have more than one
`permeability screen at the disposal of the
`laboratory in order to build confidence
`and robustness into the screening system.
`If the drug is poorly soluble but highly
`permeable, formulation efforts will con—
`centrate on improving the dissolution
`profile. For example, the combined effects
`of formulating the drug as amorphous
`solid dispersion and administering it in
`the fed state are shown for troglitazone
`
`in Figure 5. Combined, these two ap-
`proaches shift the solubility—dissolution
`characteristics from those of a very poorly
`soluble drug (D28 >10,000 mL) to those
`of a drug product with a D13 within the
`range of values encountered in the gut
`after meals.
`
`Figure 6 summarizes some further pos-
`sibilities for improving the absorption of
`drugs with less than optimal permeabil~
`ity and solubility characteristics. If perv
`meability rather than solubility is the
`main problem. formulation approaches
`are less numerous and less reliable. In ex-
`treme cases, it may be appropriate to con—
`sider developing another analog with
`more appropriate blopharmaceutical
`characteristics.
`Even when allowance is made for the
`differences in solubility and permeability
`
`www.pharmaportai.com
`
`
`
`
`
`
`
`
`
`
`
`

`

` scale-up and postal:-
`exciplents? required to optimize the
`
`giggling: :18 rfugugf,
`P P 0 a 3’
`Will be used increasingly
`in the early develop~
`merit of new drugs, in—
`eluding for analog se—
`lection as well as for
`initial formulation 3p“
`proaches.As our knowl»
`edge of GI physiology
`becomes more sophia
`ticated ll'lVitI‘O dissolu—
`'
`’
`no“ teas Win be able to
`better Simulate the con—
`ditioris in the GI tract;
`-
`-
`Th“ m tum Win lead to
`more powerful predic-
`tions of in vivo perfor-
`mance and ultimately to
`a significant reduction
`in the number of ani-
`
`mal and human studies
`
`formulation. Together
`with screens for other
`limitations to oral ab—
`
`
`
`E. Gaiia at 3.1.. "Evaluation of Various Dissow
`lotion Media for Predicting in Vivo Perfor-
`mance of Class} and H Compounds," Pharm.
`Res. 15 (5). 698—705 (2998).
`7. C. Reppas and E. Nicolaides, "Analysis of
`Drug Dissolution Data" in Methods for As-
`sesslng Oral DrugAbsoypilon. J. Dressman
`and H. Lennernas, Eds. Marcel Dekker, New
`York, 2000), pp. 229—254.
`8. H. Biume and B. Schug, ”The Biopharma—
`ceutics Classification System (BCS): Class II
`Drugs a“ Better Candidates for BA/BE
`Waiver?" Eur. J. Pharm. Sci. 9 (2), 117—121
`(199%
`..
`9. V. Mummaneni and }. Dressman, Gastric
`PH Influences on the Appearance of Double
`Peaks in the Plasma Cflncemratmmflm
`Profiles of Cimetidlne after Oral AdminESv
`tration in Dogs," Pharm. Res.12 (5). 780—786
`(l 995).
`10. KM. Koch et al.. "Effect of Sodium Acid ry—
`rophosphate on Raniticline Bioavaiiahllity
`and Gastrointestinal Transit Time," Pharm.
`Res. 10 (7), 1027-1030 (1993).
`D.A. Adkin. et al., "The Effect of Mannitol
`on the Oral Bioavailability of Clmetidine." J.
`Pharm. Sci. 8402114054409 (1995).
`. I. Wilding, "Evolution of the Biopharma-
`ceutics Classification System (BCS) to Mad
`ified Release (MR) Formulations: What Do
`We Need to Consider?" Eur. J. Pharm. Sci. 8
`(3), 151L159 (1999).
`i3. J, Dressman et al.. “Dissolution Testing as a
`
`5 1-
`
`12
`
`Prognostic Tool for Oral Drug Absorption:
`Immediate Release Dosage Forms." Pharm.
`Res. 15 (1), 1142 (1998}.
`14. E. Nicolaides at it” "Firecagting the IrBVivo
`formance of our ow- olubiiity
`rugs
`H T
`.
`B
`gggfimhgirsl?ggr5 gigglgfltégg (1egggiour
`t5. R. Lobenberg et a!” "Dissolution Testing as
`2133Prognostic "£001 for Oral DGrug Abslorption:
`1
`l
`"
`Phisrjhuhg:178231393; $030: am do,
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`‘
`16' 3' Dressman and 0' Reppas' In Vim) In Vivo
`Correlations for Lipcphiiic. Poorly Waterw
`Soluble Drugs,” Eon]. Pharm. Sci. 11 Suppl.
`2, $73680 (2001).
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`d
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`‘7 3 PB “50591581
`Eifmpar 501;:
`BSOd
`ability of
`anazol in
`urnan an
`imulate
`Gastrointestinal Fluids .. Pharm Res 17 (7)
`‘
`891—894 (2090)
`’
`'
`'
`18. H. Lennemas, "Human Perfusion Studies,"
`in Methods in Oral Drug Absorption, J. Dress—
`man and H. Lennerniis, Eds. (Marcel Dekker,
`New York. 2000), pp. QQul l7. PI'
`
`II
`
`4.:fil-norpnous (faSted)
`H
`Cast...”ne
`(fasted)
`
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`Figure 5: Troglltazone 200 mg: the effect of food and form on the
`potential for solubility limited bioavaiiability.
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`Nanopaniclas
`E Selebt more soluble saltlpoiymorph
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`Solid dispersions
`T‘Addlllon of surfactant to
`solid dosage form
`Liquid-filled
`capsules with
`absorption-
`enhancing
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`w
`
`Mucoadneslon,
`absorption-
`l enhancing iii
`exclpieats,
`effiux
`inhibitors
`
`Sfirptior; 3123;3031133‘183
`E 9 way or r 3V0 ution
`in the drug develop-
`men: process.
`
`.
`.
`.
`.
`.
`.
`.
`Figure 6. Possmle effects of various formulations on developablllly.
`
`requirements for oral drug product de-
`velopment vis—a-vis biowaiver criteria ac- References
`cording to the BCS. further factors still
`I. G. Arnidon etalb‘ThegreticalBasts fgr agio-
`must be considered for new drugs. These
`EgglfiicififlwtEZgDrIElEEEEZt 31:50::
`.
`.
`.
`include the POSSiblhty 0f decomposuion
`tion and InVivo Bloavailability."Pharm. Res.
`under GI conditions and the assessment
`12 (3). 4134120 (1995),
`f first- ass metabolism both in the ut
`2 C t
`f Dr
`E l
`tion FDA “(3 id n
`0
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`an or or
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`wall and the “VET- Appraislng decompo-
`for Induséry on gissoitclltiolnlgl'estingFof 1m;
`sition in the gut is relatively simple using
`231:“: 15;?“ did m “age 0““
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`biorelevant media and exposure times
`3. Center for Drug Evaluation,FDA,"Guldance
`based on ion est
`l’itici ated ex osure
`g
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`P
`p
`for industry on the Waiver of In Vivo
`times. For sensitive compounds. appro—
`Bioavailability and Bioequivalence for Im-
`priate enzymes (e.g.. P393” and 335515 ll'
`mediate Release Solid Oral Dosage Forms
`Based on a Biopharmaceutics Classification
`pesos for the stomach, pancreatic enzymes
`System" (August 2000).
`for the jejunum, and bacterial enzymes
`4. T. Grattan et al.. "A Five—way Crossover
`Human Volunteer Study to Compare the
`for the colon) must be added to the
`Pharmacokinetics of Paracetamol Following
`medium in relevant concentrations. As far
`Oral Administration of Two Commercially
`Available Paracetamol Tablets and Three De-
`velopment Tablets Containing Paracetamol
`in Combination with Sodium Bicarbonate
`or Calcium Carbonate," Eur. J. Pharm. Blo—
`pharm. 49 (3), 225—229 (2000).
`5. 0.1. Corrigan. "The Biopharmaceutics Drug
`Classification and Drugs Administered in Ex-
`tended Release OER) Formulations," Adv. Exp.
`Med. Biol. 423.1[1—128{1997).
`
`as first—pass metabolism in the gut wall is
`concerned. it may be possible to screen for
`metabolites in the permeability model de-
`pending on how the model is set up.
`
`Summary
`in summary, the BCS has proven to be an
`extremely useful tool for the regulation of
`bioequivalence of drug products during
`
`76
`
`Pharmaceutical Technology JULY 2001
`
`www.pharmaportal.com
`
`