The AAPS Journal, Vol. 11, No. 4, December 2009 ( # 2009)
`DOI: 10.1208/s12248-009-9144-x
`
`Review Article
`Theme: Pharmacokinetics, Biopharmaceutics and Bioequivalence:
`History and Perspectives
`Guest Editors: Marilyn Martinez and Lawrence Yu
`
`Prediction of Solubility and Permeability Class Membership: Provisional BCS
`Classification of the World’s Top Oral Drugs
`
`Arik Dahan,1 Jonathan M. Miller,1 and Gordon L. Amidon1,2
`
`Received 29 May 2009; accepted 15 September 2009; published online 30 October 2009
`
`Abstract. The Biopharmaceutics Classification System (BCS) categorizes drugs into one of four
`biopharmaceutical classes according to their water solubility and membrane permeability characteristics
`and broadly allows the prediction of the rate-limiting step in the intestinal absorption process following
`oral administration. Since its introduction in 1995, the BCS has generated remarkable impact on the
`global pharmaceutical sciences arena, in drug discovery, development, and regulation, and extensive
`validation/discussion/extension of the BCS is continuously published in the literature. The BCS has been
`effectively implanted by drug regulatory agencies around the world in setting bioavailability/
`bioequivalence standards for immediate-release (IR) oral drug product approval. In this review, we
`describe the BCS scientific framework and impact on regulatory practice of oral drug products and
`review the provisional BCS classification of the top drugs on the global market. The Biopharmaceutical
`Drug Disposition Classification System and its association with the BCS are discussed as well. One
`notable finding of the provisional BCS classification is that the clinical performance of the majority of
`approved IR oral drug products essential for human health can be assured with an in vitro dissolution
`test, rather than empirical in vivo human studies.
`KEY WORDS: BA/BE; biopharmaceutics classification system; biowaiver;
`molecular biopharmaceutics; oral drug product.
`
`intestinal absorption;
`
`INTRODUCTION
`
`The rate and extent of drug absorption from the gastro-
`intestinal (GI) tract are very complex and affected by many
`factors. These include physicochemical factors (e.g., pKa,
`lipophilicity, polar–nonpolar
`solubility, stability, diffusivity,
`surface area, presence of hydrogen bonding functionalities,
`particle size, and crystal form), physiological factors
`(e.g., GI
`pH, GI blood flow, gastric emptying, small intestinal transit
`time, colonic transit time, and absorption mechanisms), and
`factors related to the dosage form (e.g., tablet, capsule,
`solution, suspension, emulsion, and gel) (1–4). Despite this
`complexity, the work of Amidon et al. (5) revealed that the
`fundamental events controlling oral drug absorption are the
`permeability of the drug through the GI membrane and
`the solubility/dissolution of the drug dose in the GI milieu.
`These key parameters are characterized in the Biopharma-
`ceutics Classification System (BCS) by three dimensionless
`numbers: absorption number (An), dissolution number (Dn),
`and dose number (D0). These numbers take into account
`
`1 University of Michigan College of Pharmacy, 428 Church Street,
`Ann Arbor, MI 48109-1065, USA.
`2 To whom correspondence should be addressed. (e-mail: glamidon@
`umich.edu)
`
`both physicochemical and physiological parameters and are
`fundamental to the oral absorption process (6,7). Based on
`their solubility and intestinal membrane permeability charac-
`teristics, drug substances have been classified into one of four
`categories according to the BCS (Fig. 1). The BCS is one of
`the most significant prognostic tools created to facilitate oral
`drug product development in recent years; the validity and
`broad applicability of the BCS have been the subject of
`extensive research and discussion (8–13); it has been adopted
`by the US Food and Drug Administration (FDA),
`the
`European Medicines Agency (EMEA), and the World Health
`Organization (WHO) for setting bioavailability/bioequiva-
`lence (BA/BE) standards for immediate-release (IR) oral
`drug product approval; and the BCS principles are exten-
`sively used by the pharmaceutical industry throughout drug
`discovery and development (14–17). In this review, we
`describe and discuss the impact of the BCS and its scientific
`basis on regulatory practice of oral drug products and review
`the provisional BCS classification of the top drugs on the
`global market. The Biopharmaceutical Drug Disposition
`Classification System (BDDCS) and its association with the
`BCS are discussed as well. One important outcome of the
`provisional classification is that the clinical performance of
`the majority of approved IR oral drug products essential for
`human health can be assured with an in vitro dissolution test,
`rather than empirical in vivo human studies.
`
`1550-7416/09/0400-0740/0 # 2009 American Association of Pharmaceutical Scientists
`
`740
`
`MYLAN EXHIBIT 1029
`
`

`

`Provisional BCS Classification
`
`741
`
`Otherwise, the drug substance is considered poorly soluble. A
`drug substance is considered highly permeable if the extent of
`intestinal absorption is determined to be 90% or higher.
`Otherwise, the drug substance is considered poorly perme-
`able. The permeability classification is based either directly
`on the extent of intestinal absorption of a drug substance in
`humans determined by mass balance or in comparison to an
`intravenous reference dose, or indirectly on the measure-
`ments of the rate of mass transfer across the human intestinal
`membrane. Alternatively, animal or in vitro models that
`predict human intestinal absorption, e.g.,
`intestinal rat
`perfusion models or epithelial cell culture models, can be
`used. An IR product is characterized as rapidly dissolved if
`not less than 85% of the labeled drug amount is dissolved
`within 30 min using USP Apparatus I at 100 rpm or USP
`Apparatus II at 50 rpm in a volume of 900 ml or less of each
`of the following media: (1) acidic media, such as USP-
`simulated gastric fluid without enzymes; (2) pH4.5 buffer;
`and (3) pH6.8 buffer or USP-simulated intestinal fluid
`without enzymes. Otherwise, the drug product is considered
`to be slow dissolving.
`Up to now, The FDA has implemented the BCS system
`to allow waiver of in vivo BA/BE testing of IR solid dosage
`forms for class I, high-solubility, high-permeability drugs. As
`for class III (high-solubility low-permeability) drugs, as long
`as the drug product does not contain agents and/or excipients
`that may modify intestinal membrane permeability, in vitro
`dissolution test can ensure BE. The absorption of a class III
`drug is likely limited by its permeability, less dependent upon
`its formulation, and its bioavailability may be determined by
`its in vivo permeability pattern. If the in vitro dissolution of a
`class III drug product is rapid under all physiological pH
`conditions, its in vivo behavior will essentially be similar to
`oral solution (controlled by gastric emptying), and as long as
`the drug product does not contain permeability modifying
`agents (this potential effect is largely mitigated by the large
`in vitro dissolution test can ensure BE.
`gastric dilution),
`Hence, biowaivers for BCS class III drugs are scientifically
`justified and have been recommended (20–24).
`
`PROVISIONAL BCS CLASSIFICATION OF THE TOP
`DRUGS
`
`Since its introduction in 1995, the validity and broad
`applicability of the BCS have been the subject of extensive
`research and discussion, including an effort to draw a BCS
`classification of many drug products. In this section, we will
`review the information gathered in the literature on the BCS
`classification of the top IR oral drug products on the global
`market. The majority of the data is based on secondary
`aqueous solubility references and permeability estimations
`based on correlations with Log P and CLogP. As such, the
`classifications are provisional and can be revised as more
`experimental data become available. Also, it should be well
`recognized that more extensive solubility, dissolution, and
`permeability determinations would need to be carried out in
`order to officially classify these drugs in accordance with
`current BCS criteria, especially to support a biowaiver
`application. In addition, the BDDCS and its association with
`the BCS will be discussed as well.
`
`Fig. 1. The Biopharmaceutics Classification System as defined by
`Amidon et al. (5). The BCS classifies drugs by their solubility and
`permeability properties in order to stand for the most fundamental
`view of
`the drug intestinal absorption process following oral
`administration
`
`BCS IN REGULATORY PRACTICE
`
`Throughout the past decade, the BCS has become an
`increasingly important tool in drug product regulation world-
`wide, by presenting a new paradigm in bioequivalence.
`Bioequivalence (BE) is the critical step that connects the
`physical drug product with the clinical properties claimed on
`its label, ensuring continuing quality of
`the innovative
`products and the generic products. Before the presentation
`of the BCS, the BE standard was solely empirical, depending
`on in vivo bioavailability (BA) studies, i.e., plasma levels,
`AUC, and Cmax. By revealing the fundamental parameters
`dictating the in vivo oral drug absorption process, the BCS is
`able to ensure BE by mechanistic tools, rather than empirical
`observation; if two drug products that contain the same active
`pharmaceutical ingredient (API) have a similar GI concen-
`tration–time profile under all
`luminal conditions, than a
`similar rate, and extant of absorption is ensured for these
`products,
`i.e., they are bioequivalent. Thus, BE can be
`guaranteed based on in vitro dissolution tests that provide
`the mechanistic proof for similar bioavailability, rather than
`empirical in vivo human studies. This is the regulatory waiver
`in vivo BE, based on the scientific and mechanistic
`of
`rationale provided by the BCS. Initially, waivers of in vivo
`BE were accepted only for Scale-Up and Post Approval
`Changes (SUPAC), but later, the biowaiver principle was
`extended to the approval of new generic drug products, thus
`avoiding unnecessary human experiments and reducing cost
`and time of developing generic IR oral drug products.
`The solubility classification of a given drug is based on
`the highest dose strength in an IR product. According to the
`current FDA guidance (18,19), drug substance is considered
`highly soluble if the highest strength is soluble in 250 ml or
`less of aqueous media throughout the pH range of 1.2–6.8
`(the volume of 250 ml
`is derived from typical BE study
`protocols that prescribe administration of a drug product to
`fasting human volunteers with a glass (about 8 oz) of water).
`
`

`

`742
`
`Dahan, Miller, and Amidon
`
`BCS Classification Based on Literature Data
`
`In order to determine the broad applicability and
`significance of the BCS, we developed a provisional classi-
`fication of first the WHO Essential Medicines List (25) and
`then extended this analysis to the top 200 drugs on the United
`States, Great Britain, Spain, and Japan lists (26). Values for
`drug solubility were obtained from standard references (e.g.,
`Merck Index, USP etc.), and the maximum dose strengths
`were readily available in the list being classified, enabling the
`calculation of the dimensionless dose number (D0). D0 is the
`ratio of drug concentration in the administered volume
`(250 ml) to the saturation solubility of the drug in water
`(27), that may also be viewed as the number of glasses of
`water required to dissolve the drug dose. A dose number
`equal or lower than 1 indicated high-solubility, and D0>1
`signified a low-solubility compound. As for the permeability
`classification, ideally, this would be based on experimental
`human jejunal permeability data, or well-defined mass
`balance studies and/or comparison to an intravenous refer-
`ence dose. However, since such data is available only for a
`small number of drugs, the provisional permeability classi-
`fication was based on correlation of the estimated n-octanol/
`water partition coefficient using both Log P and CLogP of
`the uncharged form of the drug molecule (28,29). Log P and
`CLogP values were used for permeability classifications as
`these parameters are readily attainable for most drugs. The
`correlations were based on a set of 29 reference drugs for
`which the actual human jejunal membrane permeability data
`are available. Drugs exhibiting n-octanol/water partition
`coefficient value greater than metoprolol (Log P 1.72) were
`categorized as high-permeability since metoprolol is known to
`be 95% absorbed from the GI and hence may be used as a
`reference standard for the low/high class boundary (30). One
`noticeable short coming regarding the permeability prediction
`by lipophilicity correlations is that drugs whose intestinal
`absorption is carrier-mediated, either in the absorptive
`direction or exsorptive direction, will have their permeabil-
`ities underestimated or overestimated, respectively.
`Since 1977, the WHO has published a list of essential
`medicines required for basic health care based on public
`health relevance, efficacy, safety, and cost-effectiveness. A
`total of 260 drugs are included in the 12th edition of the
`WHO list from 2002 (31), 123 of which are orally adminis-
`tered drugs. This list classification was subsequently com-
`pared with the classification of the top 200 prescribed drugs in
`the United States that include 141 orally administered drugs
`(32). Only 43 IR oral drugs appear in both WHO list and top
`200 prescribed US drugs, highlighting differences in treatment
`priorities, social acceptance, and awareness between the US
`and the developing countries (25).
`Solubility classification of the drugs on the WHO list and
`the top 200 US list revealed that 67% and 68%, respectively,
`are categorized as high-solubility (D0<1). This finding was
`obtained even though a conservative approach was applied
`for the dose number calculations. A total of 43 and 49 drugs
`on the WHO list and the top 200 US list, respectively,
`exhibited solubility lower than 0.1 mg/ml; however, some of
`these drugs were classified as high-solubility based on the
`dose number (low dose compounds). This reflects the recent
`trend towards development of highly lipophilic, but high-
`
`potency drugs, leading to low dose that compensate for the
`poor water solubility (1,33).
`Based on Log P or CLogP and permeability correlations,
`a total of 43% and 50%, respectively, of the WHO list
`exhibited higher values than the reference drug metoprolol
`and, hence, were provisionally assigned as high-permeability
`drugs. For carrier-mediated absorbed drugs, e.g., glucose, L-
`leucine, phenylalanine, and L-dopa, permeability classification
`based on partition coefficient (either Log P or CLogP) was
`false-negative (as expected). Based on Log P correlations, no
`false-positives were obtained; however, based on CLogP
`correlations, furosemide and losartan, two low-permeability
`drugs, were false-positives (25). Indeed, both drugs were
`reported to be susceptible for efflux transport, furosemide by
`MRP2 (34), and losartan by P-gp and potentially MRP2 as
`well (35). Likewise, we have recently found that sulfasalazine
`is actually a low-permeability drug due to efflux process, even
`though this drug has Log P and CLogP values higher than
`metoprolol (8).
`The percentages of the drugs in IR dosage forms on the
`WHO list that were classified as class I drugs based on D0 and
`Log P or CLogP were 23.6% and 28.5%, respectively (Fig. 2).
`The corresponding percentage of drugs classified as class III
`drugs were 31.7% and 35.0% (Fig. 2), respectively, and
`regulatory approval of biowaiver for this class of drugs is
`scientifically justified and recommended by WHO (36).
`Hence, the majority of IR oral drug products on the WHO
`List of Essential Drugs are candidates for waiver of in vivo
`BE testing based on an in vitro dissolution test. The impact of
`waiving an expensive in vivo BE testing and its replacement
`by rapid and affordable in vitro dissolution standards in
`developing countries is expected to be profoundly significant.
`Similar results were obtained in a subsequent classifica-
`tion of the WHO list of Essential Medicines that was based
`primarily on human fraction absorbed (Fabs) literature data
`for the permeability assignment (37). Out of 61 drugs that
`could be reliably classified, 34% were classified as class I,
`17% as class II, 39% as class III, and 10% as class IV. In this
`analysis, hence, more than 70% of the classified drugs proved
`to be candidates for waiver of in vivo BE testing based on in
`vitro dissolution test. Of course, other drug product character-
`istics, such as the therapeutic index and the potential
`influence of
`the excipients on the rate and extent of
`absorption, should also be considered.
`In view of the fact that many of the WHO drugs are
`not on the top 200 drugs lists of the developed countries, a
`subsequent provisional BCS classification of
`the orally
`administered IR solid dosage forms in the top 200 drug
`products lists from the United States (US), Great Britain
`(GB), Spain (ES), and Japan (JP) was carried out (26).
`Criteria for solubility/permeability classification were as
`i.e., D0 calculations based on literature
`described above,
`data for solubility and partition coefficients correlation for
`the permeability. More than 50% of
`the top 200 drug
`products on all
`four lists were oral IR drug products,
`ranging from 102–113 classified drugs/list. The maximum
`and minimum dose strengths on the US, ES, and GB were
`similar,
`indicating commonality with respect
`to use and
`efficacy standards. Conversely, significantly lower doses were
`found on the JP list compared to the other countries,
`reflecting differences in therapeutic categories and higher
`
`

`

`Provisional BCS Classification
`
`743
`
`Provisional BCS Classification Based on In Silico
`Calculations
`
`It is well recognized that human permeability data are
`very expensive and difficult to obtain. In addition, at the very
`early stage of drug discovery and development, very little
`amount of the API is available for thorough evaluation of
`BCS classification. Hence, a reliable BCS classification based
`solely on an in silico approach can be extremely valuable.
`Certainly, the underlying assumptions and methods used in
`any computational approach should be carefully evaluated;
`however, the continuous progress, convenience, and feasibil-
`ity of in silico methods attract increasing interest.
`A set of 185 worldwide IR oral drug products was
`assigned with provisional BCS classification based on two in
`silico solubility estimations and three in silico permeability
`approaches: CLogP (BioLoom 5.0 and ChemDraw 8.0), Log
`P (MOE Version 2004.03), and KLog P using simplified
`approach based upon the Crippen fragmentation method that
`depends strictly on the element type in the molecule (38). An
`excellent agreement was obtained between the solubility
`classification based on in silico methods and literature values.
`The in silico permeability calculations demonstrated ~75%
`accuracy in classifying 29 reference drugs with human
`permeability data and ~90% accuracy in classifying the 14
`FDA reference drugs for permeability.
`The in silico based provisional BCS classification of these
`185 drugs showed some interesting trends;
`for a given
`solubility classification approach, the BCS classification was
`not significantly different when different in silico partition
`coefficient methods were used. The classification by the two
`solubility approaches for a given partition coefficient method,
`however, exhibited some systematic differences. The in silico
`solubility approach underestimated class I and overestimated
`class II drugs by an identical average of 4.3 ± 1%, while it
`overestimated class III and underestimated class IV drugs by
`an identical average of 7.3 ± 0.7%, compared to the
`classification using reference literature solubility (38). This
`work suggests that when the in silico method is validated, it is
`convenient, efficient, and cost-effective in the early preclinical
`drug discovery setting. Further research should continuously
`improve the accuracy and reliability of in silico-based BCS
`classification. Methods for more accurate structure-based
`prediction of solubility and permeability (e.g., polar surface
`area) should be further developed and evaluated to enable
`even more reliable in silico classifications.
`
`The Biopharmaceutics Drug Disposition Classification
`System
`
`While solubility measurements are relatively easy to
`carry out and usually there is a broad agreement when
`classifying drugs as either high- or low-solubility drugs,
`intestinal permeability is not as routinely measured, partic-
`ularly using methods and laboratory practice that would allow
`granting a FDA in vivo biowaiver. Wu and Benet (39) have
`noticed that the high-permeability characteristics of BCS class
`I and II drugs allow ready access to metabolizing enzymes
`within hepatocytes and suggested that
`there is a good
`correlation between the extent of drug metabolism and the
`
`Fig. 2. Provisional BCS classification of
`the 123 oral drugs in
`immediate-release solid dosage forms on the WHO Essential
`Medicines List, based on dose number (D0) for the solubility criterion
`and Log P/CLogP correlations for the permeability classification (25)
`
`emphasis on safety issues. According to the Japanese
`Guideline for BE studies, the volume used for D0 calculation
`is 150 ml; hence, this value was used for the classification of the
`JP list. A volume of 250 ml was used for the classification of the
`other three lists (26).
`The solubility classification of the top selling drugs in
`the four countries was very similar (~55% high-solubility
`drugs per list), despite of the fact that only 34–44 drugs on
`the JP list were in common with the US, GB, and ES lists.
`Based on D0 and CLogP correlation, the percentage of
`drugs that were classified as BCS class I drugs were 31%,
`30.4%, 30.2%, and 34.5% on the US, GB, ES, and JP,
`respectively (Fig. 3). The corresponding percentage of
`drugs classified as class III compounds were 23.0%,
`25.8%, 28.0%, and 19.5% on the US, GB, ES, and JP,
`respectively (Fig. 3). Thus, BE criteria of the majority of
`the world’s top-selling drugs may potentially be based on a
`suitable in vitro dissolution test procedure. This informa-
`tion should help pharmaceutical manufacturers to avoid
`unnecessary human experiments and reduce cost and time
`of the product development. This is of particular interest in
`countries with considerably limited health care budget.
`Hence, BCS contributes to the public health worldwide by
`significantly enhancing the efficiency in drug development
`and regulatory approval processes.
`It should be noted that the solubility criteria specified in
`the BCS classification guidelines covers the physiologically
`relevant pH range (typically pH 1.2, 4.5, and 6.8 buffers).
`However, the solubility values used in the provisional BCS
`classifications are based on drug solubility in water only.
`Thus, for ionizable drugs in which the API solid form is a salt,
`the value of solubility used for the provisional BCS classi-
`fication may not be the minimum solubility of the drug over
`the physiological relevant pH range and could, therefore,
`represent a best case scenario with regard to aqueous
`the drugs classified as high-
`solubility. In fact, 31% of
`solubility on the WHO list are salts, whereas 36% are
`free-forms. Likewise, 35–39% of the drugs classified as high-
`solubility on the US, GB, ES, and JP lists are salts, whereas
`16–24% are free-forms.
`
`

`

`744
`
`Dahan, Miller, and Amidon
`
`Fig. 3. Provisional BCS classification of oral drugs in IR solid dosage
`forms on the top 200 US, GB, ES, and JP drugs lists using dose
`number (D0) for the solubility criterion and CLogP for the perme-
`ability classification (26)
`
`permeability as defined in the BCS. This is the BDDCS,
`claiming that if the major route of elimination of a given
`drug is metabolism, then the drug is high-permeable and if
`the major route of elimination is renal and biliary excretion
`of unchanged drug, then that drug should be classified as
`low-permeability (40). The cutoff was originally set at
`≥50% metabolism but later changed to 70% or 90% of an
`oral dose in human. Additional
`implications of
`the
`BDDCS, e.g., food effect and significance of transporter/
`enzyme interplay in drug interactions, were suggested as
`well (41).
`The key questions, to what extent metabolism can be
`used as a surrogate for intestinal permeability and under what
`circumstances drug metabolism may not be viable for
`permeability predictions, were investigated. A total of 168
`drugs were classified by the BDDCS based on solubility and
`metabolism (39). Drugs with ≥50% metabolism were defined
`as extensively metabolized and thus considered high-perme-
`ability drugs. Takagi et al. (26) compared this BDDCS
`classification of 164 drugs with the BCS approach using D0
`
`Fig. 4. Comparison of the provisional classification of 164 drugs
`according to the BDDCS and the BCS. BDDCS classification was
`carried out using 50% as the cutoff for extensive metabolism and the
`BCS using metoprolol as the reference permeability drug (26)
`
`Fig. 5. The provisional BCS classification service as offered by
`Therapeutic Systems Research Laboratory (TSRL Inc., Ann Arbor,
`MI) website
`
`and CLogP. The BDDCS classification indicated that 59
`drugs are class I, 51 class II, 42 class III, and 12 drugs out of
`the 164 are class IV compounds. The BCS classification based
`on metoprolol as the reference compound indicated a total of
`42, 54, 57, and 11 drugs as class I, II, III, and IV, respectively.
`Hence, excellent agreement between BDDCS and BCS was
`obtained for the classification of class II and IV drugs but not
`for class I and III (Fig. 4). It was shown that the differences
`could be reduced depending on the choice of permeability
`(fraction absorbed) or percent metabolism dividing line for
`high/low classification (26).
`More recently, the extent of metabolism of 51 high-
`permeability drugs was evaluated (42). By using a cutoff of
`(73%) were classified as
`50% metabolism, 37 drugs
`extensively metabolized and, hence, also high-permeability,
`according to the BDDCS as well. Hence, 27% of these
`BCS high-permeability drugs were poorly metabolized
`compounds, pointing out that high permeability as defined by
`the BCS does not necessarily dictate extensive metabolism.
`The authors concluded that the extent of metabolism may be
`in supporting permeability classification only under
`useful
`certain circumstances (42).
`While permeability classification based solely upon
`metabolism might fail to correctly classify drugs that are
`highly absorbed but are excreted unchanged into urine and
`bile (e.g., amoxicillin, trimethoprim, lomefloxacin, zalcitabine,
`and chloroquine),
`lipophilicity considerations alone would
`not be able to predict active carrier-mediated transport of
`drugs. Despite these differences, the two approaches indicate
`that granting a waiver from in vivo BE studies is justified for
`the majority of drugs (26,39,40).
`
`Additional BCS Classification Sources
`
`In addition to the contributions aiming to provisionally
`classify different drug lists reviewed so far, several other
`sources are available as well. Literature search reveals that
`research articles often offer a BCS classification of
`the
`investigated drugs (43–47). Moreover, starting in 2004, a
`
`

`

`Provisional BCS Classification
`
`745
`
`series of monographs have been published in the Journal of
`Pharmaceutical Sciences, aiming to evaluate all relevant data
`available from literature sources for a given API to assess the
`risk associated with a biowaiver. For this purpose, risk is
`defined as the probability of an incorrect biowaiver decision,
`as well as the consequences of an incorrect biowaiver decision
`in terms of public health and individual patient risks. On the
`basis of these considerations, a recommendation was made as
`to whether a biowaiver is advisable or not. The monographs
`have no formal regulatory status but represent the best
`scientific opinions now available. So far, about 20 APIs
`evaluated in these monographs, and an in vivo BE waiver
`was scientifically justified and recommended for vast majority
`of them (48–50). These monographs are part of an ongoing
`project, and the details and progress of this project are
`available at www.fip.org/bcs. Additional source for BCS
`classification can be found in Therapeutic Systems Research
`Laboratory (TSRL Inc., Ann Arbor, MI) website (http://
`www.tsrlinc.com/services/bcs/search.cfm). This free service
`offers a provisional BCS classification of a large database of
`drugs, including the classification process, e.g., Log P/CLogP,
`solubility value, maximum/minimum dose strength, and
`calculated dose number (Fig. 5).
`
`CONCLUSIONS
`
`In conclusion, the majority of the world’s top-selling
`drugs may be candidates for waiver of in vivo BE testing
`based on appropriate in vitro dissolution test. The replace-
`ment of expensive in vivo testing with a simpler, more easily
`implemented, routinely monitored, and more reliable in vitro
`dissolution test would ensure clinical performance of
`approved drug products in a rapidly globalizing market.
`Moreover, the current FDA guidelines on BCS classification
`are considered highly conservative, especially with respect to
`the class boundaries of solubility, permeability, and dissolu-
`tion. New regulatory policies, with criteria and class bounda-
`ries that will allow granting an in vivo biowaiver to larger
`number of drugs, should be constructively examined
`(1,11,19,51).
`From industrial point of view, the information provided
`by the BCS classification of the top drugs on the global
`market should help pharmaceutical manufacturers of both
`new medicines and generic drug products to avoid unneces-
`sary human experiments and reduce cost and time of the
`product development. With continued industry emphasis on
`more efficient processes and decreasing drug development
`timeline, the BCS will remain an invaluable tool in the future
`as well (17,52).
`
`REFERENCES
`
`1. Dahan A, Amidon GL. Gastrointestinal dissolution and absorp-
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