BIOPHARMACEUTIC

S CLASSIFICATION
SYSTEM

Contents
Introduction
Overview of the Classification
system
Applications
Conclusion
References

Pendahuluan
Biopharmaceutics
Classification System (BCS)

Kerangka acuan untuk mengklasifikasikan

bahan obat berdasarkan kelarutannya dalam

air dan permeabilitas di usus

Apa pentingnya?
Penting dalam menentukan
bioavaibilitas obat

ORAL ROUTE
Penentuan rute pemberian bagi Formulator
Continues to dominate the area of drug delivery
technologies.
Batasan
Absorption and Bioavailability di lingkungan saluran cerna.
Limitations more prominent

with the advent of protein and peptide drugs

compounds emerging as a result of combinatorial chemistry and
the technique of high throughput screening

API structure
salt form and
excipients

Bioavailability of drug
is determined by

extent of drug solubility

and
permeability
drug
solubility
drug product
quality
attributes

Biopharmaceutics Classification System

Guidance provided by the U.S. Food and Drug

Administration for predicting the intestinal drug
absorption
The fundamental basis established by

Dr. Gordon Amidon (2005)

Distinguished Science Award (Aug 06 ,FIP)

First introduced into regulatory decision-making process in the

guidance document on Immediate Release Solid Oral Dosage
Forms:

Scale Up And Post Approval Changes

 Tiga faktor utama yang mempengaruhi absorpsi obat

dari bentuk sediaan padat oral lepas segera :

Dissolution
Solubility
Intestinal permeability.

The Biopharmaceutics Classification System (BCS)

(as defined by the FDA after Amidon)

Basis of BCS
Disolusi obat in vivo

SIMILAR IN VIVO
DISSOLUTION

menentukan

Konsentrasi obat
Dalam membran

SIMILAR IN VIVO ABSORPTION

sebanding

Intestinal Absorption

SIMILAR SYSTEMIC
AVAILABILITY

SOLUBILITY DETERMINATION
(37100C in aqueous medium with pH range of 1-7.5.)

A sufficient number of pH conditions

Karateristik ionisasi zat uji

Minimal dilakukan pada 3 pH yang berbeda (pH 1,2;

pH 4,5; dan pH 6,8)
Larutan buffer (standar) sesuai Farmakope
Metode uji yang direkomendasikan

Determination
of permeability
Tidak hanya berdasarkan lipophilicity (termasuk abs. in
vivo)
A. Human studies
Mass balance studies
Absolute bioavailability studies
Intestinal perfusion methods
B.In vivo or in situ intestinal perfusion in a suitable animal
model
C.In vitro permeability methods using excised intestinal
tissues
D. In vitro permeation studies across a monolayer of cultured
epithelial cells.e.g. Caco-2 cells or TC-7 cells

DISSOLUTION DETERMINATION
USP apparatus I (basket) at 100 rpm or USP apparatus
II (paddle) at 50 rpm.
Dissolution media (900 ml): 0.1 N HCl or simulated
gastric fluid, pH 4.5 buffer, and pH 6.8 buffer or
simulated intestinal fluid.
Compare dissolution profiles of test and reference
products using a similarity factor (f2).

Batasan
HIGHLY SOLUBLE jika the highest dose
strength is soluble in < 250 ml water over a pH range
of 1 to 7.5.
The volume estimate-a glassful (8 ounce)

HIGHLY PERMEABLE when the extent of

absorption in humans is determined to be > 90% of
an administered dose

RAPIDLY DISSOLVING when > 85% of the

labeled amount of drug substance dissolves within 30
minutes using USP apparatus I or II in a volume of <
900 ml buffer solutions.

BCS Class Boundaries: Objectives

Dissolution
(Product)

Solubilit
y (Drug)

Permeabili
ty
(Drug)

Rapid dissolution - ensure that in

vivo dissolution is not likely to be the
rate determining step
High solubility- ensure that
solubility
is not likely to limit dissolution and,
therefore, absorption
High permeability - ensure that
drug
is completely absorbed during the
limited
transit time through the small
intestine

BCS -Implications for drug

Application development
in early drug development and then in
the management of product change through its life
cycle
Aids fundamental understanding of the
biopharmaceutical and physical properties of the drug
Aids discriminatory dissolution method development
Can help guide the development of in-vitro/in-vivo
correlations
Can be used to obtain a biowaiver
Development of poorly soluble drugs

This classification is associated with drug

dissolution and absorption model, which
identifies the key parameters controlling
drug absorption as a set of dimensionless
numbers viz
BCS defines 3 numbers (no units)
An ~ absorption number
Do ~ dose number
Dn ~ dissolution number

Absorption Number
A function of GI Permeability to Drug Substance
Residence time in GI

Effective permeability

T
P
An
T
T
R
eff

GI

GI

ABS

Radius of GI

Time required for

complete absorption

Dose Number
A function of solubility of drug substance
Highest Dose Unit

Do

250 mL

Water

Solubility

Dissolution Number
A function of drug release from formulation
Solubility

Residence time in GI

mg/mL

Diffusivity

180 min

5x10-6 cm2/s

T
3D C

Dn

r
T
S

GI

GI

DISS

Particle Radius
m

Density
1.2 mg/cm3

Time required for

complete dissolution

IVIVC expectations for immediate release products based on BCS

Class

Solubility

Permeability

Absorption
rate
control

IVIVC expectations for

Immediate release product

High

High

Gastric
emptying

IVIVC expected, if dissolution rate is

slower than gastric emptying rate,
otherwise limited or no
correlations

II

Low

High

Dissolution

IVIVC expected, if in vitro

dissolution rate is similar to in
vivo dissolution rate, unless
dose is very high.

III

High

Low

Permeability Absorption (permeability) is rate

determining and limited or no
IVIVC with dissolution.

IV

Low

Low

Case by
case

Limited or no IVIVC is expected.

High Solubility

H igh P erm eability

Class 1
Abacavir
Acetaminophen
Acyclovirb
AmilorideS,I
Amitryptyline S,I
Antipyrine
Atropine
Buspironec
Caffeine
Captopril
ChloroquineS,I
Chlorpheniramine
Cyclophosphamide
Desipramine
Diazepam
Diltiazem S,I
Diphenhydramine
Disopyramide
Doxepin
Doxycycline
Enalapril
Ephedrine
Ergonovine
Ethambutol
Ethinyl Estradiol
FluoxetineI
Glucose

ImipramineI
Ketorolac
Ketoprofen
Labetolol
LevodopaS
Levofloxacin S
LidocaineI
Lomefloxacin
Meperidine
Metoprolol
Metronidazole
MidazolamS,I
Minocycline
Misoprostol
Nifedipine S
Phenobarbital
Phenylalanine
Prednisolone
PrimaquineS
Promazine
Propranolol I
QuinidineS,I
Rosiglitazone
Salicylic acid
Theophylline
Valproic acid
Verapamil I
Zidovudine

Low Solubility
Class 2
Amiodarone I
AtorvastatinS, I
AzithromycinS ,I
Carbamazepine S,I
Carvedilol
Chlorpromazine I
CisaprideS
Ciprofloxacin S
Cyclosporine S, I
Danazol
Dapsone
Diclofenac
Diflunisal
Digoxin S
Erythromycin S,I
Flurbiprofen
Glipizide
GlyburideS,I
Griseofulvin
Ibuprofen
Indinavir S
Indomethacin

Itraconazole S,I
Ketoconazole I
LansoprazoleI
Lovastatin S,I
Mebendazole
Naproxen
Nelfinavir S,I
Ofloxacin
Oxaprozin
Phenazopyridine
PhenytoinS
Piroxicam
Raloxifene S
Ritonavir S,I
Saquinavir S,I
Sirolimus S
Spironolactone I
Tacrolimus S,I
TalinololS
Tamoxifen I
Terfenadine I
Warfarin

High Solubility

Low Permeability

Class 3
Acyclovir
Amiloride S,I
Amoxicillin S,I
Atenolol
Atropine
Bisphosphonates
Bidisomide
Captopril
Cefazolin
Cetirizine
Cimetidine S
Ciprofloxacin S
Cloxacillin
Dicloxacillin S
Erythromycin S,I
Famotidine

Low Solubility
Class 4

Fexofenadine S
Folinic acid
Furosemide
Ganciclovir
Hydrochlorothiazide
Lisinopril
Metformin
Methotrexate
Nadolol
Pravastatin S
Penicillins
Ranitidine S
Tetracycline
Trimethoprim S
Valsartan
Zalcitabine

Amphotericin B
Chlorthalidone
Chlorothiazide
Colistin
Ciprofloxacin S
Furosemide
Hydrochlorothiazide
Mebendazole
Methotrexate
Neomycin

Applications of BCS in oral drug

delivery technology
Class I - High Permeability,
High Solubility
Achieve a target release profile associated with a
particular pharmacokinetic and/or pharmacodynamic
profile.
Formulation approaches include both control of release
rate and certain physicochemical properties of drugs
like pH-solubility profile of drug.

Class II - High Permeability,

Low Solubility
Micronisation,
Addition of surfactants,
Formulation as emulsions and microemulsions
systems,
Use of complexing agents like cyclodextrins

Class III - Low Permeability,

High Solubility

Require the technologies that address to

fundamental limitations of absolute or
regional permeability.

Peptides and proteins constitute the part of

class III and the technologies handling such
materials are on rise now days

Class IV - Low Permeability,

Low Solubility

Major challenge for development of drug

delivery system and the route of choice
for administering such drugs is parenteral
(solubility enhancers.)
Fortunately, extreme examples are the
exception rather than the rule and are
rarely developed and reach the market

Biowaiver

A biowaiver is an exemption from

conducting human bioequivalence
studies when the active
ingredient(s) meet certain solubility
and permeability criteria in vitro
and when the dissolution profile of
the dosage form meets the
requirements for an "immediate"
release dosage form.

Waiver of In Vivo Bioequivalence Study

based on
Pharmaceutical Dosage Form (Solutions)
Biopharmaceutics Classification
System
Dose. (Highest Strength should be tested)

BCS BIOWAIVER
Biowaiver for

Rapid and similar dissolution.

High solubility &High permeability.
Wide therapeutic window.
Excipients used in dosage form used
previously in approved IR solid dosage
forms.

REQUEST FOR BIOWAIVERS

Data
Supporting

:-

Rapid and Similar Dissolution

High Permeability
High Solubility

Limitations of BCS as a
Predictor of Drug
Disposition

Permeability (90% absorption) is difficult to

determine, and difficult to convince the regulatory
agency .
There is little predictability for BCS classification
drugs beyond Class 1 primarily due to the difficulty of
determining and proving 90% absorption.
many drugs are misclassified (e.g. HIV protease inhibitors
as Class 4 compounds)).

Conclusion
BCS aims to provide a regulatory tool for
replacing certain BE studies by
accurate in-vitro dissolution tests..
This increased awareness of a proper
biopharmaceutical characterization of
new drugs may in the future result in
drug molecules with a sufficiently high
permeability, solubility and dissolution
rate, and that will automatically
increase the importance of the BCS as
a regulatory tool over time

References:
Draft guidance for industry, waiver of in vivo

bioavailability and bioequivalence studies for

immediate release solid oral dosage forms
containing certain active moieties/ active
ingredients based on a biopharmaceutic
classification system, february 1999, CDER/FDA.
Amidon G.L., Lennernas H., Shah V.P., Crison
J.R.A., A theoretical basis for a biopharmaceutic
drug classification: the correlation of in vitro
drug product dissolution and in vivo
bioavailability. Pharm. Res. 12: 413-420 (1995).
Guidance for industry, immediate release solid
oral dosage forms: scale up and post approval
changes, november 1995, CDER/FDA.
Medicamento generico from website
http://www.Anvisa.Go/.

 Devane J., Oral drug delivery technology: addressing the

solubility/ permeability paradigm, pharm. Technol. 68-74,
november 1998
Amidon, G. L.,Lennerns H., Shah V. P., And crisonj. R., A
theoretical basis for a biopharmaceutics drug classification:
the correlation of in vitro drug product dissolution and in
vivo bioavailability, Pharmaceutical research, 12: 413-420
(1995)
Guidance for Industry: Dissolution Testing of Immediate
Release Solid Oral Dosage Forms, FDA CDER, 1997
http://www.fda.gov/cder/guidance/1713bp1.pdf
Guidance for Industry: Waiver of In Vivo Bioavailability and
Bioequivalence Studies for Immediate Release Solid Oral
Dosage Forms Based on a Biopharmaceutics Classification
System, FDA CDER, August 2000
http://www.fda.gov/cder/guidance/3618fnl.htm

Thank y