The document discusses the Biopharmaceutical Classification System (BCS), which classifies drug substances based on their aqueous solubility and intestinal permeability. The BCS has four classes based on whether a drug is highly soluble/permeable or low soluble/permeable. It provides a framework to determine if in vitro dissolution tests can replace bioequivalence studies for certain drugs. The BCS considers factors like dose/solubility ratios, dissolution rates, and permeability to classify drugs and determine regulatory applications like biowaivers for bioequivalence studies.

1. BIOPHARMACEUTICAL
CLASSIFICATION SYSTEM
By: Md Shakeeb
Ahmed
Presented to: Dr. K. K. Jamia Hamdard
Pillai

2. CONTENTS
1.INTRODUCTION
2.SIGNIFICANCE OF BCS
3.INFLUENCE OF BCS ON BIOAVAILABILITY

3. INTRODUCTION
 Route of
choice for the
formulators
 Continues to
dominate the
area of drug
delivery
technologies

4. DRUG DISSOLUTION AND ABSORPTION
disintegration dissolution permeability
formulated
Drug
product
Kdd Kid
Solubilized
drug
absorbed drug
dispersed
Drug
particles
Kp

5. BIOPHARMACEUTICAL CLASSIFICATION
SYSTEM
 A scientific framework for classifying drug substances
based on their aqueous solubility and intestinal
permeability
 Established by Gordon Amidon et al.
 BCS has gained importance worldwide as a drug product
regulation tool For scale-up and post-approval changes
 The aim of the BCS is to provide a regulatory tool for the
replacement of certain BE studies by conducting accurate
in vitro dissolution tests.

6. BIOPHARMACEUTICS CLASSIFICATION SYSTEM
(as defined by the FDA after Amidon et al.)

7. BCS CLASS MEMBERSHIP
Class I
Propranolol
Verapamil
Metoprolol
Class II
Ketoprofen
Naproxen
Carbamazepine
Low
High
Class IV
Furosemide
Hydrochlorothiazide
Class III
Ranitidine
Cimetidine
Atenolol
Vancomycin
High
Low

8. Classification of a drug depends upon its three key
parameters, that control absorption:
Solubility
Dissolution
rate
permeability
that correlate with three respective dimensionless parameters
Dose no.
Dissolution
no.
Absorption no.

9. DOSE NUMBER
A function of solubility of drug substance
Should
be less
than 1.
It is the dose concentration/solubility ratio


 




 

V
Water
C
S
D
Highest Dose Unit
Do
250 mL
Solubility

10. DISSOLUTION NUMBER
A function of drug release from formulation
• Defined as the ratio of mean residence time to mean
Should exceed 1
dissolution time
Dn= [TGI/TCD]
TGI = Residence time in GI (approx. 180 min)
TCD= Time required for complete dissolution

11. ABSORPTION NUMBER
“A function of GI Permeability to Drug Substance”
• Absorption number (An) is the time required to absorb the
• It is the ratio of the mean residence time to mean
A T n
GI
T
ABS
administered dose
absorption time.
TGI = Residence time in GI (approx. 180 min)
TABS Time required Should exceed = for complete 1
absorption

12. PERMEABILITY DETERMINATION
A. Determination of extent of absorption in humans:
• Mass balance P/K studies
• Absolute bioavailability studies
B. Intestinal permeability methods:
• In vivo intestinal perfusion studies in humans
• In vivo or in situ intestinal perfusion studies in animal
• In vitro permeability methods using excised
human/animal intestinal tissues
• In vitro permeation studies across a monolayer of
cultured epithelial cells. e.g. Caco-2 cells or TC-7 cells

13. 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).
If f2= 100 ; dissolution
profiles are identical
N= no. of dissolution time points
Rt = dissolution value of the reference drug product at time t
Tt = dissolution value of the test drug product at time t

14. SOLUBILITY DETERMINATION
“Shake flask method”
• pH- solubility profile of test drug in aqueous media
within a pH range of 1.0-7.5
• A minimum of three replicate determinations of
solubility in each pH condition
• Methods other than shake flask method (with
Justification). e g. acid or base titration methods

15. CLASS BOUNDARIES
 HIGHLY SOLUBLE; the highest dose strength should be
soluble in < 250 ml water over a pH range of 1 to 7.5.
(The volume estimate-a glassful i.e. 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.

16. BCS CLASS BOUNDARIES: OBJECTIVES
Dissolution
(Product)
Solubility
(Drug)
Permeability
(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

17. IVIVC EXPECTATIONS FOR IRP BASED ON BCS
Class Solubil
ity
Perme
ability
Absorption
rate control
IVIVC expectations for
Immediate release product
I 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.

18. High Solubility Low Solubility
High Permeability
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
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

19. High Solubility Low 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
Fexofenadine S
Folinic acid
Furosemide
Ganciclovir
Hydrochlorothiazide
Lisinopril
Metformin
Methotrexate
Nadolol
Pravastatin S
Penicillins
Ranitidine S
Tetracycline
Trimethoprim S
Valsartan
Zalcitabine
Class 4
Amphotericin B
Chlorthalidone
Chlorothiazide
Colistin
Ciprofloxacin S
Furosemide
Hydrochlorothiazide
Mebendazole
Methotrexate
Neomycin

20. CLASS – I
Class I - High Permeability, High Solubility
• Drugs dissolved rapidly
• Drugs absorbed rapidly
• Rapid therapeutic action
• Excellent property
• Ideal for oral route
• e.g. Metoprolol, Diltiazem, Verapamil, Propranolol,

21. CLASS – II
• Drugs dissolve slowly
• Drugs absorbed rapidly
• Controlled released drugs
• Oral / IV route for administration
• Ex. Glibenclamide, Ezetimibe, Phenytoin, Nifedipine

22. CLASS – III
• Dissolved rapidly
• Absorbance is limited
• Incomplete bioavailability
• Oral / IV route for administration
• Ex. Cimetidine, Acyclovir, Captopril

23. CLASS – IV
• Low dissolution rate
• Low permeability property
• Slow or low therapeutic action
• IV or other routes are required
• Ex. Hydrochlorothiazide

24. Background: About biowaivers

25. BCS BASED BIOWAIVER
A biowaiver is an exemption from conducting human
bioequivalence studies
Criteria for Biowaiver
Immediate-release solid oral dosage form
Rapid and similar dissolution.
High solubility &High permeability.
Wide therapeutic window.
Excipients used in dosage form are same as those
present in approved drug product
• Companies can potentially save thousands of dollars in
costs, and several months of time in development, if
bioequivalence studies are avoided

26. REQUEST FOR BIOWAIVERS
Data Supporting :-
Rapid and Similar Dissolution
High Permeability
High Solubility
Biowaiver: Class III compounds are eligible biowaiver if
they dissolve within 15 minutes in buffer media pH 1.2 –6.8
(75 rpm)
Biowaiver: Class II acids with D:S ratio < 250 ml at pH 6.8
and > 85 % dissolved within 30 minutes at pH 6.8 (75 rpm)

27. NO BIOWAIVER FOR:
As the BCS is only applicable to APIs which are absorbed
from the small intestine; drugs absorbed from other
sites (e.g. from the oral cavity) are not eligible for a
biowaiver
non-oral immediate release forms with systemic action
modified release products
transdermal products

28. SURROGATE MARKERS
Drug product Drug Possible surrogate
marker for
bioequivalence
Topical steroid Hydrocortisone Skin blanching
Anion exchange
resin
Cholestyramine Binding to bile acids
Antacids Mg & Al
hydroxide gel
Neutralization of acid
Topical
antifungal
Ketoconazole Drug uptake into
stratum corneum

29. SIGNIFICANCE OF BCS
Regulatory toll for replacement of certain BE studies.
It can save both time and money—if the immediate -release,
orally administered drug meets specific criteria, the FDA will
grant a waiver for expensive and time-consuming bio-equivalence
studies.
Valuable tool for formulation scientist for selection of design
of formulated drug substance.
When integrated with other information provide a
tremendous tool for efficient drug development.
Reduces cost and time of approving Scale- up and post
approval challenges.
Applicable in both pre-clinical and clinical drug development
process.
Works as a guiding tool in development of various oral drug
delivery systems.

30. BCS can be used as a key component to guide drug delivery
system design for any route of administration

31. DRAWBACKS OF BCS BIOWAIVERS
• Sponsors are sometimes reluctant to apply for
biowaivers due to the perceived lack of certainty of
acceptance by the regulatory agencies.
• Industrial implementation of BCS may also be limited
due to:
– unnecessary barriers in existing guidelines
– compartmentalization of company resources
– or a general lack of knowledge about BCS or the biowaiver
process.

32. ELIGIBLE APIs FOR WHO BCS-BASED
BIOWAIVER APPLICATIONS:
DRUG CATEGORY DRUGS ELIGIBLE FOR BIOWAIVER
APPLICATIONS
antiretroviral  Abacavir
 Emtricitabine
 Lamivudine
 Stavudine
 zidovudine
anti-tuberculosis  Ethambutol
 Isoniazid
 Levofloxacin
 Ofloxacin
 Moxifloxacin
 pyrazinamide

33. REFERNCES
 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
biopharmaceutics classification system, February 1999, CDER/FDA.
 Amidon G.L., Lennernas H., Shah V.P., Crison J.R.A., A theoretical
basis for a biopharmaceutics 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/.
 Particle size; Drug development services; Technical Brief 2011 Volume
9

34. REFERNCES
 Devane J., Oral drug delivery technology: addressing the solubility/
permeability paradigm, pharm. Technol. 68-74, November 1998
 Amidon, G. L.,Lennernäs 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
 WHO Prequalification of Medicines Programme; General notes on
Biopharmaceutics Classification System (BCS)-based biowaiver
applications; Guidance Document October 2012

35. REFERNCES
 Chi-Yuan Wu and Leslie Z. Benet, (2005); “Predicting Drug Disposition
via Application of BCS: Transport/Absorption/Elimination Interplay
and Development of a Biopharmaceutics Drug Disposition
Classification System” ; Pharmaceutical Research, Vol. 22, No. 1,
January

36. If you’re not
part of the
solution…..
©
you’re part of
the precipitate