The seminar on the Biopharmaceutical Classification System (BCS) discussed its guidelines for evaluating drug solubility and dissolution, emphasizing its role in drug development and bioequivalence testing. It classified drugs into four categories based on their solubility, permeability, and absorption patterns, providing examples and methodologies for each class. The importance of dissolution testing for ensuring quality and stability in drug products was also highlighted.

1. Seminar on
Biopharmaceutical Classification system (BCS)
Guideline for Solubility and Dissolution
Center of Pharmaceutical Sciences, IST,
JNTUH, Hyderabad-500085
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
1
Presented by:
Imdad H. Mukeri
M. Pharm( Pharmaceutics)

2. Table of Contents
• Introduction to BCS Guidline for Solubility and Dissolution
• Goal of BCS
• Determination of High solubility, High permeability and Rapid
dissolution
• Factor Affecting BCS (Solubility, Permiability and Dissolution
• Biopharmaceutical Classification system (BCS)
• Dissolution Testing Apparatus as per USP
• Conclusion
• References
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
2

3. Introduction to BCS
• Biopharmaceutics Classification System (BCS) proposed in
1995 by Amidon et al and his collegues that classified
compounds based on their solubility and permeability.
• The BCS is a scientific approach based on the aqueous
solubility and intestinal permeability characteristics of the
drug substance.
• BCS has been incorporated in Guidelines for biowaiver
granting. Based on aqueous solubility and intestinal
permeability the four classes of the BCS represent four
distinct expectations of in vitro invivo correlations (IVIVC).
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
3

4. 9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
4
The classification system is based on fick’s law applied to a
membrane
Jw= PwCw
Where,
Jw = drug flux ( mass/area/time) through
the intestinal wall at any position and
time
Pw = permeability of membrane
Cw = Drug conc. At membrane

5. Introduction to BCS
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
5

6. Introduction to BCS
Release of drug substance from drug product
Dissolution of drug under physiological condition
Permeability across the GI tract
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
6
Drug absorbance from a solid dosage form following oral administration
depents on

7. Goals of BCS
• To identify the challenges of formulation Design.
• To guide decisions w.r.t IVIVC.
• To improve the efficiency of drug development and identifying
expendable clinical bioequivalence tests.
• To explain when a waiver for in vivo bioavailability and
bioequivalence may be requested.
• To assist in QC in SUPAC.
• To recommend a class of immediate-release (IR) solid oral
dosage forms for which bioequivalence may be assessed
based on in vitro dissolution tests.
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
7

8. Factors Affecting BCS
A. Solubility
B. Permeability
C. Dissolution
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
8
• Drugs are classified according to the BCS in accordance
with the solubility, permeability, and dissolution
characteristics of the drug

9. Solubility
• To determine the solubility of a drug under approximate physiologic
conditions.
• Determine of pH–solubility profiles over a pH range of 1–8
• The solubility class is determined by calculating what volume of an
aqueous medium is sufficient to dissolve the highest anticipated
dose strength.
• A drug substance is considered highly soluble when the highest
dose strength is soluble in 250 mL or less of aqueous medium over
the Ph range 1–8.
• The drug substance is not stable with >10% degradation over the
extent of the solubility assessment, solubility cannot be adequately
determined and thus the drug substance cannot be classified.
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
9

10. Determination of High solubility, High permeability
and Rapid dissolution
Hight soluble
• A drug substance is considered highly soluble when the highest
dose strength is soluble in 250 mL or less of aqueous medium
over the pH range 1 –7.5
Highly Permeable
• High permeability is consider high permeable when the absolute
bioavailability is ≥85%.
• High permeability can also be concluded if ≥85% of the administered dose
is recovered in urine as unchanged (parent drug)
Rapidly dissolving
• A drug product is consider to dissolve rapidly when 85% of the
labeled amout of drug substance dissolve within 30 minute using
USP Apparatus I & II in a volume of 900 ml buffer solution.
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
10

11. Biopharmaceutical Classification system (BCS)
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
11

12. Class I drugs (high solubility/high permeability
• The drugs of this class exhibit high absorption number and
high dissolution number.
• For those class 1 drugs formulated as IR products, dissolution
rate generally exceeds gastric emptying.
• Behave like an oral solution in-vivo. The rate-limiting step is
gastric emptying.
• These compounds are well absorbed. Absorption rate is
usually higher than the excretion rate. Example Example
Diltiazem, Metoprolol , Propanolol etc.
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
12

13. Class II drugs (low solubility/high permeability)
• The drugs of this class have a high absorption number but a
low dissolution number.
• In vivo drug dissolution is then a rate-limiting step for
absorption except at a very high dose number.
• The absorption for Class II drugs is usually slower than for
Class I and occurs over a longer period of time.
• The bioavailability of these products is limited by their
solvation rates.
• Hence, a correlation between the in vivo bioavailability and
the in vitro solvation can be found. Example: Nifedipine,
Phenytoin, verapamil etc.
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
13

14. Class III drugs (high solubility/low permeability)
• Drug permeability is the rate-limiting step for drug absorption,
but the drug is solvated very quickly.
• These drugs exhibit a high variation in the rate and extent of
drug absorption.
• Since the dissolution is rapid, the variation is attributable to
alteration of physiology and membrane permeability rather
than the dosage form factors. Example famotidine,
cimetidine, Ranitidine, Acyclovir etc.
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
14

15. Class IV drugs (low solubility/low permeability)
• The drugs of this class are problematic for effective oral
administration.
• These compounds have poor bioavailability.
• They are usually not well absorbed through the intestinal
mucosa, and a high variability is expected.
• Fortunately, extreme examples of Class IV compounds are the
exception rather than the rule, and these are rarely developed
and marketed. Nevertheless, several Class IV drugs do exist.
Example. Furosemide, Cyclosporine, Spiranotacton etc.
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
15

16. Biopharmaceutical Classification System for Drugs
Class Solubility Permiability Absorption
Pattern
Rate-limiting
step in Abs.
Example
I High High Well
Absorption
Gstric
empitying
Diltiazem
Metoprolol
Propanolol
II Low High Variable Dissolution Nifedipine
Phenytoin
verapamil
III High Low Variable Permeability Insule
Cimetidine
IV Low Low Pooly
Absorption
Case by Case Furosemide
Cyclosporine
Spiranotacton
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
16

17. Dissolution Testing Apparatus as per USP
• Dissolution is a process in which a solid substance solubilises in a given
solvent i.e. mass transfer from the solid surface to the liquid phase.
• The dissolution is based on the in vitro dissolution rate of an IR drug
(immediate release) product under specified test conditions and is
intended to indicate rapid in vivo dissolution in relation to the average rate
of gastric emptying in humans under fasting conditions.
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
17
BCS Class Dissolution Methodology
I Single point if NLT 85% Q in 15-45 minutes
Multiple point if Q < 85% in 15 minutes
II Multiple point
III Same as class I
IV Same as class II
Table: Dissolution Methodology for Immediate-Release Products Based on BCS

18. Factors that Design the dissolution test
Factors relating to dissolution
apparatus
The size of the container
(several mL to several litres),
The shape of the container
(round bottomed or flat),
Nature of agitation (stirring,
rotating or oscillating
methods)
Speed of agitation,
performance precision of the
apparatus, etc.
Factors relating to dissolution
test
water, 0.1N HCl, phosphate
buffer, simulated gastric
fluid, simulated intestinal
fluid, etc.), viscosity, volume
(generally larger than that
needed to completely
dissolve the drug under
test), temperature (generally
37oC) and maintenance of
sink
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
18

19. Need for Dissolution Testing:
 Evaluation of bioavailability.
 Batch to batch drug release uniformity.
 Development of more efficacious and therapeutically
optical dosage forms.
 Ensures quality and stability of the product.
 Product development, quality control, research and
application.
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
19

20. 9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
20
Dissolution Apparatus Types as per USP and Their
Applications

21. Apparatus 1: Rotating Basket
 first developed in the 1960s and
consists of a shaft with a stirring 40-
mesh basket
It is rotated continuously at 100–
150 rpm in typically 900 mL of
media Constant-temperature bath
set at 37°C.
It is primarily used for testing
beads, tablets and capsules.
The basket ensures the dosage
form is completely immersed in the
media.
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
21
Advantages:
Full pH change during the test
Disadvantages:
Sink condition for poorly soluble
drug

22. Apparatus 2: Paddle Method
Consists of a stainless steel or teflon
coated shaft with a paddle that is
continuously rotated typically 900 mL
of media at at 37°C
The most common operating speeds
for Apparatus 2 are 50 or 75 rpm for
solid oral dosage forms and 25 rpm for
oral suspensions.
This apparatus has been found to be
useful for immediate and modified
release forms.
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
22
Advatages: esay to use robust
Disadvantages: pH/media change is difficult and sink condition
for pooly soluble drugs.

23. Apparatus 3: Reciprocating
Cylinder
 A set of cylindrical, flat-
bottomed glass vessels equipped
with reciprocating cylinders for
dissolution testing of extended-
release products, particularly
bead-type modified-release
dosage forms.
 Agitation rate : 5–30 dpm (dips
per minute) at 37°C
 Starting at pH 1 and then pH 4.5
and then at pH 6.8
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
23
Advantage:
•Easy to change the pH
•Hydrodynamic can be influenced
by varying the dip rate

24. Appataus 4: Flow-through-Cell
The Flow Through Cell is
used for testing low solubility
drugs, those drugs prone to
rapid degradation and those
systems requiring swift pH
changes in the media at 32°C
Flow rate ranges from 4 to
32 mL/min.
Used for very limited
solubility, Microparticles,
implnts, suppositories,
controlled release formulation
.
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
24
•Easy to change media pH and maitain
sink condition
•Two different modes (i) open system
(ii) closed system

25. Apparatus 5: Paddle-over-Disk
•Used for transdermal patches.
•The paddle height is positioned 2.5
cm above the surface of the screen.
900 mL of medium is typically used.
•TempR at 32 ºC ± 0.5 ºC for patches.
•In these cases, the medium
temperature would be set
accordingly and the dosage forms
would be held below the screen.
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
25
Advantages: standard equipment (paddle) can
be used, only add a strainless steel disk asselbly
Disadvantages: Disk assembly restricts patch size

26. Apparatus 6: Rotating Cylinder
Used to test transdermal patches
and is similar to Apparatus 1.
instead of a rotating basket, there is
a rotating cylinder.
The patch is generally attached to a
piece of Cuprophan and glued to the
outside of the cylinder.
Volume : 900 ml held at tempr 32ºC
± 0.5 ºC
Rotated at a constant rate until the
active ingredient from the patch has
passed into solution.
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
26

27. Apparatus 7: Reciprocating Holder
Used for testing transdermal
patches, various modified
release dosage forms,
The test is carried a 20 - 300
mL vessel at 32°C, and
frequency is 30 cycles per
minute.
The dosage forms are inserted
into the holders, which move up
and down to agitate the media.
The five official USP
reciprocating holders are shown
figure.
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
27

28. Dissolution Acceptance Criteria
Stages Number of Dosage
Units Tested
Acceptance Criteria
1 6 No dosage unit is less than Q+5%
2 6 Average of the twelve dosage units (S1 + S2)
Q% and no dosage unit is less than Q-15%
3 12 Average of the twenty four dosage units (S1 +
S2 + S3) Q% and not more than two dosage
units are less than Q-15% and no dosage unit
is less than Q-25%
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
28
The value of Q is defined as percentage of drug content dissolved in a
given time period
This value is generally specified in USP monograph of a given drug
product. Three stages like S1, S2 and S3 of dissolution testing are allowed

29. Conclusion
• Biopharmaceutics classification system (BCS) guideline
introduce to provided a simple way to describe the
biopharmaceutics behavior of a drug.
• Solubility and permeability are among the major parameters,
which determine the fraction dose absorbed of a drug
substance and consequently its chances to be bioavailable.
• The purpose of BCS guidline is the evolution of the media
used for determining solubility and dissolution and how this
can be used in modern drug development.
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
29

30. References
• Siewert M, Dressman J, Brown CK, Shah VP, Aiache JM, Aoyagi N, Bashaw
D, Brown C, Brown W, Burgess D, Crison J. FIP/AAPS guidelines to
dissolution/in vitro release testing of novel/special dosage forms. Aaps
Pharmscitech. 2003 Mar;4(1):43-52.
• Guideline IH. Biopharmaceutics classification system-based biowaivers
M9. Int Counc Harmon Tech Requir Pharm Hum Use. 2018 Jun 7:19.
• Bou-Chacra N, Melo KJ, Morales IA, Stippler ES, Kesisoglou F, Yazdanian M,
Löbenberg R. Evolution of choice of solubility and dissolution media after
two decades of biopharmaceutical classification system. The AAPS journal.
2017 Jul;19(4):989-1001.
• Papich MG, Martinez MN. Applying biopharmaceutical classification
system (BCS) criteria to predict oral absorption of drugs in dogs:
challenges and pitfalls. The AAPS journal. 2015 Jul;17(4):948-64.
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
30

31. • Tsume Y, Mudie DM, Langguth P, Amidon GE, Amidon GL. The
Biopharmaceutics Classification System: subclasses for in vivo predictive
dissolution (IPD) methodology and IVIVC. European Journal of
Pharmaceutical Sciences. 2014 Jun 16;57:152-63.
• Blume HH, Schug BS. The biopharmaceutics classification system (BCS):
class III drugs—better candidates for BA/BE waiver?. European Journal of
Pharmaceutical Sciences. 1999 Dec 1;9(2):117-21.
• Chavda H, Patel C, Anand I. Biopharmaceutics classification system.
Systematic reviews in pharmacy. 2010;1(1):62.
• Reddy BB, Karunakar A. Biopharmaceutics classification system: A
regulatory approach. Dissolution Technologies. 2011 Feb 1;18(1):31-7.
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
31

32. Thank you
for your attention
Any question?
9/2/2022
Center of Pharmaceutical sciences, IST,
JNTUH
32