Biopharmaceutical Classification System An Account-1
Biopharmaceutical Classification System An Account-1
Biopharmaceutical Classification System An Account-1
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Abstract: In 1995, Amidon and coworkers introduced the biopharmaceutical classification system (BCS) to reduce the
need for in vivo bioequivalency studies, utilization of in vitro dissolution tests as a surrogate for in vivo bioequivalence
studies. The principles of the BCS classification system can be applied to NDA and ANDA approvals as well as to scale-
up and post approval changes in drug manufacturing. Therefore, can save significant amount of product development
time of pharmaceutical companies and reduces it costs. BCS is a drug development tool that allows estimation of the
contributions of three major factors, dissolution, solubility, and intestinal permeability, which affect oral drug absorption
from immediate release (IR) solid oral products. Knowledge of BCS helps to the formulation scientist to develop a
suitable dosage forms based on mechanistic rather than empirical approaches.
This review article represents principle, goal & guidance of BCS, characteristics of various BCS class drugs, Various
type of dissolution media for various BCS class drugs, their importance & methodology of dissolution, and various
applications of BCS have been highlighted.
Key Words: BCS; Solubility; Permeability; Dissolution; Bioequivalence.
plasma profile after oral administration. This concept The classification is associated with drug dissolution
can be summarized by application of Fick’s first in and absorption model, which identifies the key
the following equation parameters controlling drug absorption as a set of
J = Pw Cw …………………. (1) dimensionless numbers: [1, 6].
Where J is the flux across the gut wall, Pw is the v The Absorption Number (An) is the ratio of
permeability of the gut wall to the drug, and Cw is the the Mean Residence Time (T res) to the Mean
concentration profile at the gut wall [ 3]. Absorption Time (Tabs) and it could be
In terms of bioequivalence, it is assumed that highly estimated using equation.
permeable, highly soluble drugs housed in rapidly An = (Tres / T abs) = (3.14R2L/Q) (R/Peff) …… . (2)
dissolving drug products will be bioequivalent and
that, unless major changes are made to the v The Dissolution number is a ratio of mean
formulation, dissolution data can be used as a residence time to mean dissolution time. It
surrogate for pharmacokinetic data to demonstrate could be estimated using equation 2.
bioequivalence of two drug products [4, 5]. Dn =(Tres/Tdiss)=(3.14 R2L/Q) / (ρ r2 /3 D Cs min)...(3)
PURPOSE OF THE BCS GUIDANCE [ 3] v The Dose number is the mass divided by an
v Expands the regulatory application of the BCS uptake volume of 250 ml and the drug’s
and recommends methods for classifying solubility. It could be estimated using equation
drugs. 2.
v Explains when a waiver for in vivo D0 = Dose/(V0 x C mins) ……………………………(4)
bioavailability and bioequivalence studies may
be requested based on the approach of BCS. v The mean residence time here is the average
of the residence time in the stomach, small
GOALS OF THE BCS GUIDANCE [ 3] intestine and the colon.
v To improve the efficiency of drug Where: L = tube length, R = tube radius, π = 3.14, Q =
development and the review process by fluid flow rate, ro = initial particle radius, D = particle
recommending a strategy for identifying acceleration, ρ = particle density, Peff = effective
expendable clinical bioequivalence tests permeability, Vo is the initial gastric volume equal to
v To recommend a class of immediate-release 250 ml which is derived from typical bioequivalence
(IR) solid oral dosage forms for which study protocols that prescribe administration of a drug
bioequivalence may be assessed based on in product to fasting human volunteers with a glass of
vitro dissolution tests . water at the time of drug administration and Csmin is
v To recommend methods for classification minimum aqueous solubility in the physiological pH
according to dosage form dissolution, along range of 1-8 [1].
with the solubility and permeability
characteristics of the drug substance.
Table 1: IVIVC expectations for IR products based on the BCS Calss [8,9]
Class Permeability/ Absorption rate IVIVC
Solubility control step
Class I High /High Gastric emptying IVIVC expected if dissolution rate is
slower than gastric emptying rate.
Otherwise limited or no correlation.
Class II High /Low Dissolution IVIVC expected if invitro dissolution rate
is similar to invivo dissolution rate, unless
dose is very high.
Class III Low /High Permeability Absorption is rate determining and
Limited or no IVIVC with dissolution.
Class IV Low /Low Case by case Limited or no IVIVC expected
Mohd Yasir et al /Int.J. PharmTech Res.2010,2(3) 1683
dissolution of this drug by the SGF medium. Water is particularly useful for forecasting the invivo
less suitable medium than the aforementioned buffers, dissolution of the poorly soluble drugs from different
because it has a nominal buffer capacity zero; formulations and for assessing potential for foods
therefore, the pH may vary during the test [19]. Ensure effects on the invivo dissolution. The dissolution rate
and Milk as dissolution media can improve the drug of the poorly soluble drug is often better in FaSSIF and
solubility includes the solubilization of drugs in the FeSSIF than in the simple aqueous buffers because of
fatty part of the fluid. Of these media contains similar the increased wetting of the drug surface and micellar
ratio of protein/ fat/ carbohydrate.Ues of ensure and solubilization of the drug by the bile components of
milk have been vigorously suggested as a media these media [19, 23]. (d) Hydroalcoholic mixtures as
suitable for simulating fed state in the stomach[20, 21]. dissolution media were popular for the dissolution of
poorly soluble drugs. Particular significance of these
Media for Class II substances media over the surfactant containing media is that they
Substances that belong to class II possess poor do not tend to foam, which makes deaeration and
aqueous solubility but are easily transported across the volume adjustment somewhat less frustrating [17, 19].
GI mucosa. Suitable biorelevant media for class II
drugs are: (a) SGFsp plus surfactant (e.g., Triton X- Media for Class III substances
100), to simulate the fasted state in the stomach. This Despite their good aqueous solubility, class III
medium is specifically useful for weak basic drugs, substances fail to achieve complete bioavailability
because these are most soluble under acidic condition. after oral dosing because of their poor membrane
Presence of surfactant in the gastric may play a role in permeability. A simple aqueous media can be used [6,
19]
the wetting and solubilization of poorly soluble acids .
in the stomach [22]. (b) Ensure and Milk as dissolution
media can improve the drug solubility include the Media for Class IV substances
solubilization of drugs in the fatty part of the fluid. Class IV drugs combine poor solubility with poor
Both of these media contains similar ratio of protein/ permeability. Therefore, similar to class III drugs, they
fat/ carbohydrate [20, 21]. (c) FaSSIF (Fasted state usually do not approach complete bioavailability. Two
simulated intestinal fluid) and FeSSIF (Fed state compendial media i.e. SGFsp & SIFsp with addition of
simulated intestinal fluid) are the recently developed to a surfactant to ensure the complete release of drug
simulate the intestinal condition. The two media are from formulation can be used [6, 17, 19].
of a method, model drugs should represent a range of measured by the shake-flask method and permeability
low (e.g., < 50%), moderate (e.g., 50 - 89%), and high by Caco-2 cells.
(≥ 90%) absorption. Gastric emptying of the dissolved drug is the rate-
limiting step for oral absorption of class I drugs with
C. Determining Drug Product Dissolution rapid dissolution. Class I drugs have favorable
Characteristics absorption properties, leading to rapid and complete
Dissolution testing should be carried out in USP absorption. Drug absorption can be mediated either by
Apparatus I at 100 rpm or Apparatus II at 50 rpm using passive transcellular diffusion or by active transport.
900 ml of the following dissolution media: (1) 0.1 N Even simple, conventional IR formulation assures
HCl or Simulated Gastric Fluid USP without enzymes; rapid and complete absorption for this class of drugs.
(2) a pH 4.5 buffer; and (3) a pH 6.8 buffer or Therefore, formulation development is fast and cheap
Simulated Intestinal Fluid USP without enzymes. For unless other issues, such as stability or production
capsules and tablets with gelatin coating, Simulated problems exist. IVIVCs cannot be found for IR
Gastric and Intestinal Fluids USP (with enzymes) can formulations of class I drugs if dissolution is faster
be used. than gastric emptying. Thus, the dissolution method
Selection of the dissolution testing apparatus (USP can be a simple and cheap quality control tool.
Apparatus I or II) during drug development should be However, if a BCS biowaiver is utilized in a regulatory
based on a comparison of in vitro dissolution and in application, dissolution should be tested in three
vivo pharmacokinetic data available for the product. different media representing the pH range of the
A minimum of 12 dosage units of a drug product gastrointestinal tract.
should be evaluated to support a biowaiver request. Dissolution controls absorption of class II drugs and a
Samples should be collected at a sufficient number of point-to-point relationship, i.e., level A IVIVC, can be
intervals to characterize the dissolution profile of the found between in vitro dissolution and in vivo
drug product (e.g., 10, 15, 20, and 30 minutes). When dissolution or absorption. Like BCS I drugs, class II
comparing the test and reference products, dissolution drugs have high permeability, and transport may be
profiles should be compared using a similarity factor active or occur by passive transcellular diffusion. If
(f2). The similarity factor is a logarithmic reciprocal absorption is limited by solubility or dissolution, it
square root transformation of the sum of squared error may be incomplete. Formulation development may be
and is a measurement of the similarity in the percent more challenging than for BCS I drugs if special
(%) of dissolution between the two curves. techniques and skills are utilized to enhance drug
solubility or dissolution. For example, nanoparticles,
f2 = 50 • log {[1 + (1/n) Σ=1n (Rt - Tt) 2]-0.5 • 100} microemulsion, cyclodextrins or lipid formulations can
be used [28, 29]. In vitro dissolution method development
Two dissolution profiles are considered similar when also requires more time and a high level of knowledge
the f2 value is > 50. if in vitro conditions are to mimic drug release and
dissolution in vivo. Several pH values, agitation
APPLICATIONS OF BCS IN ORAL DRUG speeds, and different apparatuses should be tested. An
DELIVERY TECHNOLOGY appropriate method should discriminate critical
Once the solubility and permeability characteristics of formulation or manufacturing variables of the product
the drug are known it becomes an easy task for the affecting drug dissolution in vivo. If successful, a level
research scientist to decide upon which drug delivery A IVIVC may be proven and in vitro dissolution tests
technology to follow or develop. can be used as surrogates for in vivo bioavailability
1. BCS in the drug development and bioequivalence studies.
In early drug development, knowledge of the class of a BCS III drugs have permeability limited absorption.
particular drug is an important factor influencing the Incomplete absorption due to limited permeability can
decision to continue or stops it development. rarely be solved by formulation factors, because
BCS classification can be utilized in drug candidate specific and non-toxic permeability enhancers are
selection at an early phase in drug development, during difficult to develop [28]. Instead, bioavailability may be
formulation development, and in regulatory increased by prodrug derivatization of the parent
applications [28]. The BCS class of a drug indicates the compound, improving drug distribution to the target
rate-limiting step for oral absorption: gastric emptying, tissue [30]. The prodrug can be more lipophilic than the
dissolution or intestinal permeability [1]. In the early parent drug, facilitating transcellular passive diffusion
development phase, the permeability and solubility or, alternatively, the prodrug can be designed to be a
boundaries can be set as selection criteria for new drug substrate for a transporter [31, 32]. In many cases,
candidates [29]. In vitro methods are utilized to measure permeability is high enough to achieve therapeutic
solubility and permeability. Solubility is typically drug concentrations in plasma. Then conventional
Mohd Yasir et al /Int.J. PharmTech Res.2010,2(3) 1687
immediate-release formulation is a good choice. For BCS II drugs have not been accepted as biowaiver
example, the BCS III drugs ranitidine and cimetidine candidates by the regulatory agencies, but acidic BCS
in immediate-release tablets have bioavailability of 50- II drugs have been suggested as possible candidates for
60% [33, 34,35,36]. In many cases, the prodrug approach is biowaivers in scientific publications [43, 44]. Those
not needed if therapeutic drug concentrations are publications criticize the current biowaiver guidelines,
achieved with the parent drug and with simple and which are based on equilibrium solubility and
cheap conventional formulations. An IVIVC can not dissolution tests, and in which the dynamic nature of
be found for BCS III drugs when permeability is the drug absorption is not taken into account. Acidic BCS
rate-limiting step for absorption [37]. The role of the II drugs have low solubility only in the stomach, while
dissolution method is to act as a quality control tool to solubility in the small intestine is high and the fraction
ensure batch-to-batch consistency. Dissolution method of the dose absorbed can be > 0.9. The extent of oral
development is thus easier for such class III drugs than drug absorption (i.e. AUC) may not be sensitive to
for class II drugs or controlled-release products. minor dissolution rate differences under the alkaline
BCS IV drugs have low solubility and permeability. conditions in the small intestine. In contrast, the rate of
The rate-limiting step in drug absorption can be oral absorption (i.e. Cmax) may be sensitive to
solubility, dissolution or permeability. The fraction of differences in the dissolution rates, as was pointed out
absorbed drug dose may be low and highly variable in simulation studies [45]. Solubility and dissolution of
because class IV drugs have problems in solubility and acidic BCS II drugs are site dependent, i.e., solubility
permeability. Formulation and dissolution methods is low in the acidic stomach and high in the alkaline
may be similar to those for class II drugs if dissolution small intestine. As discussed previously, gastric
is the rate-limiting factor. For permeability-limited emptying of solid drugs is a highly variable process,
absorption, class IV drugs may be developed like class since house-keeping waves occur every 1.3-2 hours
[46]
III drugs. Some class IV drugs may be unsuitable for . Thus, drug concentrations at the absorption site
oral administration if the fraction absorbed is too low may vary and minor dissolution rate differences may
and oral absorption is highly variable. However, the cause fluctuations in Cmax values.
tolerated level of variability depends on the indication For BCS III drugs, biowaivers can not be utilized in
and therapeutic index of the drug. [37] regulatory applications in the USA and Europe, but in
a report recently published by the WHO, BCS III
BCS biowaivers extensions drugs were accepted as biowaiver candidates [47]. There
During the time period spanning 2000-2007, are many scientific papers published where class III
regulatory agencies have received fewer BCS drugs are recommended as biowaiver candidates [42, 48,
49, 50].
biowaiver applications than expected. This is the case For this BCS class, the permeability rate controls
especially for new generic drug products [39,40,41]. There absorption and the bioavailability is more dependent
are a few published revisions to methodologies for on the drug (permeability) than on the formulation
classifying drugs in the BCS, and extension of (dissolution). The test and reference products will be
biowaivers to acidic class II and class III drugs has bioequivalent if absorption is permeability rate limited.
been suggested. Hopefully these will lead to BCS Class III drugs may be even better biowaiver
guideline revisions and increase BCS biowaiver candidates than class I drugs, if the effects of
applications. Methodology revisions it has been excipients on gastrointestinal transit time and
suggested that the solubility boundary for biowaiver permeability can be excluded [50].
candidates should be narrowed from pH 1-7.5 to 1-6.8 BCS III drugs which are substrates of efflux proteins
and the fraction of the dose absorbed should be and/or have extensive metabolism in the intestine
reduced from 90% to 85% [42, 38]. Currently, a drug should not be accepted as biowaiver candidates. These
product is considered rapidly dissolving if more than saturable mechanisms are dependent on drug
85% dissolves in 30 minutes. A new criterion of 60 concentration and thus in some cases even minor
minutes for the dissolving time has been suggested [38]. differences in the concentration can lead to changes in
For acidic drugs, solubility tests in conditions the rate and/or extent of absorption.
mimicking small intestinal pH may be more
appropriate than tests performed at pH 7.5 [43]. To 2. Approval of the generics
classify drug solubility, the solubility is measured in BCS is done in accordance with the FDA guidelines
aqueous buffer using a volume of 250 ml. It has been when the potential class I drug condidate enters in
suggested that the volume should be increased from human testing. If the compound meets all the criteria a
250 ml to 500 ml and that surfactants may be added to petition is send to FDA asking for the agreement with
the medium [38]. However, these revisions need the compound classification. The goal is to send to the
experimental verification before they can use. FDA prior to initiation of phase II.
Mohd Yasir et al /Int.J. PharmTech Res.2010,2(3) 1688
The BCS is used to set drug product dissolution phenytoin, theophylline, and warfarin. Because not all
standard to reduce the in vivo bioequivalence drugs subject to therapeutic drug concentration or
requirement. As subsequent R & D proceeds, pharmacodynamic monitoring are narrow therapeutic
dissolution studies are done on a new formulation in range drugs, sponsors should contact the appropriate
accordance with the FDA guidance and petition is review division to determine whether a drug should be
submitted to FDA requesting waivers of in vivo considered to have a narrow therapeutic range.
bioequivalence studies. 2. Products Designed to be absorbed in the Oral
The knowledge of BCS can also help the formulation Cavity
scientist to develop a dosage form based on A request for a waiver of in vivo BA/BE studies based
mechanistic approach rather than empirical approach. on the BCS is not appropriate for dosage forms
This allows determining the potential for invitro- intended for absorption in the oral cavity (e.g.
invivo correlation and significantly reducing the in sublingual or buccal tablets).
vivo studies.
CONCLUSION
EXCEPTION FOR BCS: BCS principles provide a reasonable approach for
BCS-based biowaivers are not applicable for the testing and approving drug product quality. BCS
following: applications for Class 2 and 3 are challenging, but at
1. Narrow Therapeutic Range Drugs the same time provides opportunities for lowering
This guidance defines narrow therapeutic range drug regulatory burden with scientific rational. BCS also
products as those containing certain drug substances provides an avenue to predict drug disposition,
that are subject to therapeutic drug concentration or transport, absorption, elimination. The BCS is the
pharmacodynamic monitoring, and /or where product guiding tool for the prediction of in vivo performance
labeling indicates a narrow therapeutic range of the drug substance and development of drug
designation. Examples include digoxin, lithium, delivery system to suit that performance.
14. Khar RK, Pandita D, “Biopharmaceutical 29. Aungst BJ, Intestinal permeation enhancers.
classification system and its importance,” J. Pharm. Sci. 2000, 89(4): 429-442.
The Indian Pharmacist. March 2005, 25- 30. 30. Steffansen B, Nielsen CU, Brodin B,
15. Guidance for industry, “Dissolution testing Eriksson AH, Andersen R and Frokjaer S,
for immediate release solid oral dosage “Intestinal solute carriers: an overview of
forms,” FDA,August 1997. trends and strategies for improving oral drug
16. Ahuja A, Baboota S, Ali J, “Dissolution: a absorption,” Eur. J. Pharm. Sci. 2004, 21, 3-
promising tool in drug delivery,” Indian J. 16.
Pharm. Sci., Nov- Dec 2005, 650-660. 31. Todd PA and Heel RC, “Enalapril a review
17. Galia E, nicolaides E, Lobenberg RD, of its pharmacodynamic and
Dressman JB, “Evaluation of various pharmacokinetic properties and therapeutic
dissolution media predicting in vivo use in hypertension and congestive heart
performance of class I and Class II drugs,” failure. Drugs, 1986, 31(3): 198-248.
Pharm Res. 1998,15, 698-705. 32. Beaumont K, Webster R, Gardner I and
18. USP-27th edition, NF-22nd edition, United Dack K, “Design of ester prodrugs to
state pharmacoepial convention, Inc., enhance oral absorption of poorly permeable
Rockville, M.D., 2004, Page No 2313-2314 compounds: Challenges to the discovery
19. Dressaman JB, Lennernas H, Oral drug scientist. Curr. Drug Metab. 2003, 4, 461-
absorption prediction and assessment, 485.
Marcel Dekker inc, Page No 159-173. 33. Bogues K, Dixon GT, Fowler P, Jenner WN,
20. Macheras P, koupparis M, Apostelelli E, Maconochie JG, Martin LE and Willoughby
“Dissolution for controlled release BA, “Pharmacokinetics and bioavailability
theophylline formulations in Milk,” Int. J. of ranitidine in humans,” Br. J. Clin.
Pharm. 2007, 36, 73-79. Pharmacol. 1980, 73, 275-276.
21. Ashby LJ, Beezer AE, Buckton G, “In-vitro 34. Garg DC, Weidler DJ, Baltodano N,
dissolution testing of oral controlled release Eshelman FN, “Pharmacokinetics of
preparation in the presence of artificial food ranitidine, a new histamine H2-receptor
stuff,” Int. J. Pharm., 1989,51, 245-251 blocker,” Br. J. Clin. Pharmacol.1981,
22. Efentakis M, Dressman JB, “Gastric Juice as 29(2): 247-248.
a dissolution medium: surface tension and 35. Jantratid E., Prakongpan S., Amidon G.L.
pH,” Eur. J. Drug Metab. Pharmacokinet. and Dressman J.B., Feasibility of biowaiver
1998, 23, 97-102. extension to biopharmaceutics classification
23. Greenwood DE, “Small intestinal pH and system class III drug products cimetidine.
buffer capacity: implications for dissolution Clin. Pharmacokinetic., 2006, 45(4): 385-
of ionizable compounds,” Doctoral 399.
dissertation, the university of Michign, Ann 36. Guidance for industry,. Immediate-release
Arbor, MI, 1994. solid oral dosage forms, scale-up and
24. USP-27th edition, NF-22nd edition, United postapproval changes: Chemistry,
state pharmacoepial convention, Inc., manufacturing, and controls, in vitro
Rockville, M.D., 2004, Page No 2303-2312. dissolution testing, and in vivo
25. Dressaman JB, Lennernas H, “Oral drug bioequivalency documentation. CDER/FDA,
absorption prediction and assessment,” August 1995
Marcel Dekker inc. , Page No 174-175, 183- 37. The European Agency for the Evaluation of
195 Medicinal Products (EMEA), Note for
26. FIP guidelines for dissolution testing of solid Guidance on the Investigation of
oral products, Pharm Ind., 1997, 59, 760- Bioavailability and Bioequivalence.
760. Committee for Proprietary Medicinal
27. L Shargel, ABC Yu, “Applied Products , 2002.
biopharmaceutics and pharmacokinetics,” 38. Polli JE, Yu LX, Cook JA, Amidon LA,
3rd edition, Appleton and Lange, Stamford, Borchardt RT, Burnside BA, Burton PS,
Connecticut, 1999. page no 365 376 Chen M-L, Conner DP,Faustino PJ, Hawi
28. Lennernäs H and Abrahamsson B, “The use AA, Hussain AS, Joshi HN, Kwei G, Lee
of biopharmaceutics classification of drugs VHL, Lesko LJ, Lipper RA, Loper
in drug discovery and development: current AE,Nerurkar SG, Polli JW, Sanvordeker
status and future extensions,” J. Pharm. DR, Taneja R, Uppoor RS, Vattikonda CS,
Pharmacol. 2005, 57, 273-285. Wilding I and Zhang G, Summary workshop
Mohd Yasir et al /Int.J. PharmTech Res.2010,2(3) 1690
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