BIOPHARMACEUTICS CLASSIFICATION SYSTEM (BCS) AND METHODS OF PERMEABILITY

1
BIOPHARMACEUTICS
CLASSIFICATION SYSTEM (BCS) AND
METHODS OF PERMEABILITY
ADVANCED BIOPHARMACEUTICS AND PHARMACOKINETICS
SUBMITTED TO:
Smt.RESHMI KRISHNA
ASSISTANT PROFESSOR
DEPARTMENT OF PHARMACEUTICS
PRESENTED BY:
LANIYA NASRIN K
SECOND SEMESTER
M PHARM PHARMACEUTICS
COLLEGE OF PHARMACEUTICAL SCIENCE,GOVERNMENT MEDICAL COLLEGE, THIRUVANANTHAPURAM

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TABLE OF CONTENTS
BIOPHARMACEUTICAL
CLASSIFICATION
SYSTEM
01
PERMEABILITY
METHODS
02
REFERENCES
03

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BIOPHAMACEUTICAL
CLASSIFICATION
SYSTEM (BCS)
• INTRODUCTION
• FACTORS AFFECTING BCS
• CLASSIFICATION
• APPLICATION
• BIOPHARMACEUTICS DRUG
DISPOSITION CLASSIFICATION
SYSTEM(BDDCS)

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BIOPHAMACEUTICAL CLASSIFICATION SYSTEM (BCS)
BCS is a scientific framework for classifying a drug substance based on its
aqueous solubility, intestinal permeability and dissolution rate
IMPORTANCE OF BCS
• Drug development tool, that is based on correlation of solubility and
permeability with the bioavailability of drugs
• For development of new dosage form
• Classification of drug based on their solubility and intestinal
permeability
• Optimized formulation development

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FACTORS AFFECTING ON BCS
SOLUBILITY PERMEABILITY DISSOLUTION
• The Maximum Amount of solute dissolved in a given solvent under
standard conditions of temperature, pressure and pH.
• Solubility is the ability of the drug to be solution after dissolution
• According to USFDA,
A drug substance is considered highly soluble
Highest single unit dose is completely soluble in 250 ml at pH 1-6.8 (37°C).
• According to WHO,
Same parameter over pH 1.2-7.5
1.SOLUBILITY

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• Permeability is a parameter of absorption
• Permeability of the drug to pass the biological membrane which is the
lipophilic.
• According to USFDA,
Drug substance is considered to be highly permeable
when the extent of absorption in human determined to be 90% or
more of an administered drug or compare to in vivo reference dose.
2.PERMEABILITY

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• The process in which solid substance solubilises in given solvent
i.e mass transfer from solid surface to liquid phase.
• To find rapid dissolving drug(When ≥85% of the labelled amount of
drug substance dissolves within 30 minutes )
• By using:
1. USP apparatus I at 100 rpm
2. USP apparatus II at 50 rpm
3. Dissolution Media [900 ml]
4. 0.1 N HCl or simulated gastric fluid (pH 1.2) without enzyme.
5. pH 4.5 buffer & pH 6.8 buffer
6. Simulated intestinal fluid without enzyme.
3.DISSOLUTION

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CLASS BOUNDARIES
HIGHLY SOLUBLE
Highest single unit dose is completely soluble in 250 ml at
pH 1-6.8 (37°C).
HIGHLY
PERMEABLE
when the extent of absorption in human determined to be
90% or more of an administered drug or compare to in vivo
reference dose.
RAPID DISSOLVING
When 85% of the labelled amount of drug substance
dissolves within 30 minutes using USP apparatus I or II
CLASS BOUNDARIES
• Used to determine whether a drug product eligible
for a biowaiver
• BIOWAIVER: when the drug substance in the test
and reference product are identical or both product
belong BCS class I

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HIGH
PERMEABILIT
Y
HIGH
SOLUBILITY
HIGH
PERMEABILIT
Y
LOW
SOLUBILITY
LOW
PERMEABILIT
Y
HIGH
SOLUBILITY
LOW
PERMEABILIT
Y
LOW
SOLUBILITY
BIOPHAMACEUTICAL CLASSIFICATION SYSTEM
CLASS I
CLASS III CLASS IV
CLASS II

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CLASS PERMEABILITY SOLUBILITY EXAMPLES
CLASS I
HIGH HIGH • Metoprolol
• Propranolol
CLASS II
HIGH LOW • Nifedipine
• Naproxen
CLASS III
LOW HIGH • Cimetidine
• Metformin
CLASS IV
LOW LOW • Taxol
• Furosemide

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CLASS I
[HIGH PERMEABLITY AND
SOLUBILITY]
Ideal for oral route
administration.
Drug absorbed rapidly.
Drug dissolved rapidly.
Rapid therapeutic action.
Bioavailability problem not
expected for immediate release
drug product.
• Eg:Metoprolol, Propranolol,
Diltiazem.
CLASS II
[HIGH PERMEABILITY
LOW SOLUBILITY]
Oral route for administration.
Drug absorb rapidly.
Drug dissolve slowly.
Bioavailability is controlled by
dosage form and rate of release
of the drug substance.
• Eg: Nifedipine, naproxen.

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CLASS III
[LOW PERMEABLITY AND
HIGH SOLUBILITY]
Oral route for administration.
Drug absorbance is limited.
Drug dissolve rapidly.
Bioavailability is incomplete if drug
is not release or dissolve in
absorption window.
• Eg:. Cimitidine, Metformin,
Insulin.
CLASS IV
[LOW PERMEABILITY AND
SOLUBILITY]
Poorly absorbed by orally
administration.
Both solubility & permeability
limitation.
Low dissolution rate.
Slow or low therapeutic action.
An alternate route of
administration may be needed.
• E g: Taxol, Cefexime Trihydrate.

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CLASS I Best suited for solid oral formulation since they have high
permeability and solubility
CLASS II Require some dose modification through size reduction,
use of surfactant etc.
CLASS III Incorporate permeability enhancers, maximize local luminal
concentration
CLASS IV Combine 2 and 3
DOSAGE FORM DEVEOLPMENT

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APPLICATION
OF BCS
To use in biowaiver consideration
To predict in vivo performance of drug product using
solubility and permeability measurements.
Aid in earliest stages of drug discovery research.
For research scientist to decide upon which drug delivery
technology to follow or develop.
For the regulation of bioequivalence of the drug product
during scale up and post approval.

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BIOPHARMACEUTICS DRUG DISPOSITION CLASSIFICATION
SYSTEM[BDDCS]
• Modification of the BCS system
• Useful in predicting overall drug disposition
• It take into account drug metabolism (hepatic clearance) and
transporters in the gastrointestinal tract for drugs that are orally
administered.
• Including routes of drug elimination and the effects of efflux and
absorptive transporters on oral drug absorption.

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CLASS SOLUBILITY METABOLISM ELIMINATION
PATTERN
EXAMPLE
CLASS I
HIGH EXTENSIVE Predominantly
eliminated by liver
Diltiazem
CLASS II LOW EXTENSIVE By liver Itraconazole
CLASS III
HIGH POOR Poor metabolism,
elimination
unchanged by renal
and biliary route
Doxycycline
CLASS IV
LOW POOR poor metabolisms,
eliminated
unchanged by renal
and biliary routes
ofloxacin

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Absorption
the process of movement of unchanged drug from the site of administration
to systemic circulation.
• It is a determinant of intestinal absorption and oral bioavailability.
• Optimizing passive diffusion is productive because it is the predominant
mechanism for absorption of most commercial drugs.
PERMEABILITY
It is the diffusion of molecule through membrane barrier/ the rate of
flow of a liquid or gas through a porous membrane

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PERMEABILITY METHODS
IN VITRO METHODS
1. Partition coefficient
2. Artificial membranes
3. Chromatographic retention
indices
4. Brush border membrane
vesicles (BBMV)
5. Isolated intestinal cells
6. Tissue techniques
7. Diffusion cell method
8. Cell culture techniques
IN VIVO
METHODS
1.Direct method
2.Indirect method
IN SITU
METHODS
1.Absorption from
small intestine
a.Doluisio method
b.Single pass
perfusion
technique
2.Absorption from
stomach

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• In vitro methods are carried out outside of the body
• Used to determine the permeability of drug using live animal tissues.
• To assess the major factors involved in the absorption process and
predict the rate and extent of drug absorption.
• Partition coefficient between an oil and water phase, log P
• It provides a measure of the lipophilicity of a molecule and can be used
to predict to what extent it will cross the biological membrane.
• Octanol is selected as an oil phase as it has similar properties to
biological membranes.
1.IN VITRO METHOD
1.A:PARTITION COEFFICIENT

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• log D is the distribution coefficient where aqueous phase is at a
particular pH
• It takes into account the ionization of the molecule at this pH.
• The log D measured at intestinal pH will give a much better idea about
extent of drug permeability across GI membrane than log P.

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• It is useful in studying passive membrane permeability as they are reproducible
and are suitable for high throughput screening.
Parallel artificial membrane permeability assay (PAMPA)
• It determines the permeability of substances from a donor compartment, through
a lipid infused artificial membrane into an acceptor compartment.
• The artificial membrane is like a phospholipid membranes supported by filter
material.
• Test compound is added to the donor compartment in buffer solution of pH 7.4
and permeation takes place through artificial membrane into the acceptor
compartment
• Aliquot collected and the concentration of drug permeated is measured by assay
techniques
• A modification of this system is immobilized liposome chromatography(ILC)
1.B. ARTIFICAL MEMBRANES

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USES
To determine the
intestinal permeability
Prediction of passive
transport
• Trans-cellular
permeability of drugs
ADVANTAGE
For screening large no.
of compounds.
• Provides information
on solubility,
lipophilicity and
ionization status of a
drug..
DISADVANTAGE
• They are based on
approximation and
over simplification of
the actual in vivo
conditions

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• IAM along with physicochemical parameters is used for
evaluation of passive intestinal absorption.
• IAM packings are prepared by covalently immobilizing
monolayers of membrane phospholipids to silica particles.
Immobilized artificial membranes
(IAM) chromatography
• Used for the prediction of passive drug absorption
• In this system retention of drug mainly depends on
hydrophobic, electronic and steric interactions
Micellar liquid chromatography (MLC)
1.C: CHROMATOGRAPHIC RETENTION INDICES

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A brush border is the name for the microvilli covered surface of simple cuboidal
epithelium and simple columnar epithelial cells, found in the small intestine.
• Both animal and human tissue can be used for this.
1.D: BRUSH BORDER MEMBRANE VESICLES (BBMV)
Intestinal
tissues are
treated with
calcium
chloride
precipitation
method using
centrifugation.
The pellets
obtained after
centrifugation
is
resuspended
in buffer which
results in the
formation of
vesicles.
Vesicles are
mixed with
drug in buffer
solution and
filtered after a
period of time.
The amount
of drug taken
up by the
vesicles gives
an account of
drug
absorption.

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1.E: USING ISOLATED INTESTINAL CELLS
Small intestine is perfused with enzyme solutions that
release the cells and the cells are treated with chelating
agents or enzymes.
The freshly isolated cells are suspended in buffer
solution. containing the drug under O2/CO2 and shaken
well.
After a specific period of time, the cells are separated by
filtration, extracted and drug absorbed is determined.

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• Small segments of small intestine are
mounted between two glass chambers
filled with buffer at 37
1.F: DIFFUSION CELL METHOD
Diffusion cell
consist of two
compartments
• Donor compartment - which contains the
drug solution and the lower end of which
contains the synthetic or natural GI
membrane that interfaces with the receptor
compartment.
• Receptor compartment - which contain the
buffer solution.

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1.G:TISSUE
TECHNIQUES
Everted small intestinal sac technique
Everted sac modification
Circulation techniques
Everted intestinal ring or slice techniques

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Isolating a small segment of the intestine of a laboratory animal
such as rat
Inverting the intestine and filling the sac with a small volume of
drug free buffer solution.
Both the segments are tied off and the sac is immersed in an
ERLENMEYER FLASK containing a large volume of buffer
solution that contains the drug.
The flask and its contents are then oxygenated and the whole
preparation is maintained at 37°C and shaken mildly.
At predetermined time intervals, the sac is removed and the
concentration of drug in the serosal fluid is determined/ assayed
for drug content
I)EVERTED SMALL INTESTINAL SAC TECHNIQUE:

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ADVANTAGES
• The epithelial cells of the mucosal surface are exposed directly to
the oxygenated mucosal fluid.
• Prolongs the viability and integrity of the preparation after removal
from the animal.
• Convenience and accuracy with respect to drug analysis.
DISADVANTAGES
• Difficulty in obtaining more than one sample per
intestinal segment

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The test animal is fasted for a period of 20-24 hr and water is allowed.
Animal is killed and the entire small intestine is everted.
Segments of 5-15 cm in length are cut from a specific region of the intestine.
The distal end of the segment is tied and the proximal end is attached to
the cannula.
The segment is suspended in a mucosal solution which contains the drug
II) EVERTED SAC MODIFICATION

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A drug free buffer is then placed in the serosal compartment.
For determining the rate of drug transfer, the entire volume of serosal solution is
removed from the sac at each time interval with the help of a syringe and
replaced with fresh buffer solution.
The amount of drug that permeates the intestinal mucosa is plotted against
time to describe the absorption profile of drug at any specific pH.

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ADVANTAGES
• Number of different solutions may be tested with a single segment of the
intestine.
• Simple and reproducible.
• It distinguishes between active and passive diffusion.
• It determines the region of small intestine where absorption is optimal, in the
case of active transport.
• Used to study the effect of pH, surface active agents, complexation and
enzymatic hydrolysis.
DISADVANTAGES
• The intestinal preparation is removed from the animal as well as from its
normal blood supply.The permeability characteristics of the membrane are
significantly altered.
• The rate of transport of drug as determined from the everted sac technique,
may be slower than in the intact animal.

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III) CIRCULATION TECHNIQUES
Isolating either the entire small
intestine of small lab animal or
a segment and circulating
oxygenated buffer containing
the drug through the lumen.
Drug free buffer is circulated on
the serosal side of the intestinal
membrane and oxygenated.
Absorption rate from the lumen
to the outer solution are
determined by sampling both
the fluid circulating through the
lumen and outside.
ADVANTAGE:
• Applicable for kinetic studies of
the factors affecting drug
absorption
• Both surface are oxygenated
• Eversion not necessary

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Entire small intestine is
isolated from the fasted
experimental animal and
washed with saline
solution
Dried by blotting with
filter paper.
The segment is tied at
one end and by placing
on glass rod it is carefully
everted and cut into
small rings.
The everted intestinal
rings are then incubated
in drug containing buffer
maintained at 37ºC with
constant oxygenation.
Under optimal
conditions, rings remain
viable for up to 2 hours
and the transport of drug
is stopped by rinsing the
rings with ice cold buffer
and drying them.
At selected time interval,
the tissue slices are
assayed for drug content
and expressed as
mol/gm/time.
IV) EVERTED INTESTINAL RING OR SLICE TECHNIQUE

38
• Simple and reproducible.
• Kinetic studies can be performed.
• Each animal can act as its own control as many rings can be
prepared from each segment of the intestine isolated
• Mechanism of drug absorption can be studied by changing the
experimental conditions
ADVANTAGES
• Extreme care is needed to maintain to viability of the tissue
throughout the experiment.
• tissue needs to be disrupted completely for the determination of
drug contents, which complicates the assay procedure.
DISADVANTAGES

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• Cell culture is the complex process by which
cells are grown under controlled conditions,
generally outside their natural environment.
• These models are based on the assumption
that passage of drugs across the intestinal
epithelium is the main barrier for drugs to
reach the circulation.
• CaCo2 cells is the most widely used cell line
and is a continuous cell line.
1.G-CELL CULTURE TECHNIQUE

40
Differentiated cells of the intestine, originating from cells of carcinoma of
colon(CaCo2 cells) are placed on synthetic polycarbonate membrane
Previously treated with an appropriate material such as collagen, which
on incubation, aids reproduction of cells while not retarding drug
permeation characteristics.
These cells differentiate spontaneously under normal culture conditions
and hence are polarized (i.e. apical and basolateral surface), have tight
junctions and brush border.
Solution of drug is placed on this layer of cultured cells and the system is
placed in a bath of buffer solution.
The drug that reaches the latter compartment is sampled and analysed
periodically.

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2.IN VIVO METHODS
• In vivo method gives us an idea about some important factor that
influence absorption such as gastric emptying, intestinal motility and the
effects of drugs on the GIT can be determined.
IN VIVO
METHOD
DIRECT
METHOD
INDIRECT
METHOD

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.
2.A:DIRECT METHOD
The drug levels in blood or urine is determined as a function of time.
blank urine or blood sample is taken from the test animal before the
experiment.
The test dosage form is administered to the animal
at appropriate intervals of time the blood or urine sample are collected and
assayed for the drug content.
From the data can determine the rate and extent of drug absorption.

43
• When the measurement of drug concentration in blood or urine is
difficult or not possible
• Then absorption studies can be done by this indirect method.
• In this method, pharmacological response of the drug is related to the
amount of drug in the body.
• The response is determined after the administration of a test dosage
form
• LD 50 appears to be dependent on the rate of the absorption of drug.
2.B:INDIRECT METHOD

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• In situ refers to those method in which the animal’s blood supply remains
intact in which the rate of absorption determined from these methods
may be more realistic than those determined from in vitro techniques.
• Acts as a bridge between in vivo and in vitro methods.
• These methods simulates the in vivo conditions for drug absorption and
are based on perfusion of a segment of GIT by drug solution and
determination of amount of drug diffused through it.
3.IN SITU METHOD

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IN SITU
METHODS
Absorption of
drug from
small intestine
PERFUSION
TECHNIQUE
Doluisio
method
Single pass
perfusion
method
INTESTINAL
LOOP
TECHNIQUE
Absorption
from stomach

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DOLUISIO METHOD
The upper and lower parts of the small intestine of
anaesthetised and dissected rat are connected by
means of tubing to syringes of capacity 10 – 30 ml.
After washing the intestinal segment with normal saline
the syringe is filled with a solution of radiolabelled drug
and a non-absorbable marker which is used as an
indicator of water flux during perfusion.
Part of the content of the syringe containing drug is
delivered to the intestinal segment which is then
collected in the second syringe and analysed for drug.
3.A:ABSORPTION OF DRUG FROM SMALL INTESTINE

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• It is generally considered superior to the
Doluisio method giving better control of
the hydrodynamics and increased surface
area.
SINGLE PASS PERFUSION TECHNIQUE
The drug solution is perfused continuously (via an
infusion pump) down a set length of intestine
through the duodenal end cannula and perfusate
collected from the ileal-end cannula, at flow rates
of between 0.1 and 0.3 ml/min.
The samples collected at outflow are assayed for
drug content.

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Fasted adult male rats are
anaesthetized, stomach is exposed
and the cardiac end is ligated.
An incision is made in the pylorus in
which the cannula is introduced and
ligated
The lumen is washed several times
with saline and subsequently with
0.1 N HCL solution containing
0.15M NaCl.
The drug solution of known
concentration is introduced into the
stomach and after 1 hour, the
solution is removed from the gastric
pouch and assayed for drug
content.
3.B:ABSORPTION FROM THE STOMACH

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PREVIOUS YEARS QUESTIONS
10 MARKS
1. Explain in vivo, in situ and in vitro methods for the determination
of permeability(Jan 2020)
5 MARKS
2. Biopharmaceutics classification systems of drugs(Jan 2019,may
2022,sep 2022,dec 2023,oct 2023)
3. Permeability study by in situ method(July 2019)
4. Explain various methods for the determination of
permeability(Feb. 2021)

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03 REFERENCES
1. Applied Biopharmaceutics and Pharmacokinetics by Leon
Shargel, Andrew B.C Yu, 7th Edition, Appleton & Lange;
2005.pg no:507-509
2. Biopharmaceutics & Pharmacokinetics; D.M. Brahmankar,
S.B. Jaiswal; 1st edition, 12th reprint; Vallabh Prakashan.pg
no:194
3. BCS and permeability. www.jiwaji.edu.
4. Biopharmaceutical classification system based biowaivers M9.
www.database.ich.org.

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