6. BCS drug substance are classified as
below:
• Class 1: High Solubility, High Permeability
• Class 2: Low Solubility, High Permeability
• Class 3: High Solubility, Low Permeability
• Class 4: Low Solubility, Low Permeability
6/20
8. Solubility
Objective: to determine equilibrium solubility of a
drug substance under physiological pH conditions.
pH-solubility profile of test drug at 37oC in aqueous
media with a pH range of 1 to 7.5
Shake-flask or titration method
Analysis by validated stability-indicating assay
8/20
9. Permeability
Extent of absorption in humans determined by:
Pharmacokinetic studies in humans:
Mass-balance studies
Absolute bioavailability studies
Intestinal permeability methods:
In vivo intestinal perfusions studies in humans
In vivo or in situ intestinal perfusion studies in animals
In vitro permeation experiments with excised human or animal
intestinal tissue
In vitro permeation experiments across epithelial cell
monolayers
Instability in the Gastrointestinal Tract
Accounts for extent of degradation of a drug in the GI fluid prior
to intestinal membrane permeability. 9/20
10. Permeability Standards
IS = Internal standard for Permeability
studies
ES =Efflux pump substrates
10/20
11. 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 USP,
• A pH 4.5 buffer,
• A pH 6.8 buffer or simulated intestinal fluid USP.
Compare dissolution profiles of test and reference products
Using a similarity factor f2.
11/20
12. BCS BIOWAIVER (no in vivo BA/BE
needed)
Rapid dissolution relative to gastric emptying
Class 1: High solubility, High permeability
Wide therapeutic window
Excipients used in dosage form should be
used previously in FDA approved Immediate
Release (IR) solid dosage forms
Prodrugs; buccal absorption
12/20
13. No biowaiver for:
locally applied, systemically acting products
non-oral immediate release forms with systemic action
modified release products
transdermal products
13/20
14. Biowaiver Extensions ?!
Provided that ......
drug solubility is high,
permeability is limited,
excipients do not affect kinetics,
excipients do not interact ,.....
14/20
15. Biowaiver Extensions ?!
....then very rapid dissolution (e.g.>85% in 15 min)
of test and reference may ensure similar product
characteristics
because...
....absorption process is probably independent from
dissolution and not product related…
limited absorption kinetics due to poor drug
permeability and/or gastric emptying
♦ Biowaiver for BCS class III drugs (e.g. Atenolol)?!
15/20
16. Biowaiver Extensions ?!
For drugs showing ....
‘very’ high permeability
pH-dependent solubility within the physiologically
relevant pH range
.....an ‘intermediate solubility’ class is suggested
16/20
17. Data to support Biowaivers
Data supporting
High solubility
High permeability
Rapid and similar dissolution
17/20
18. Write note on drug products for which BA/BE
studies can be waived. (5 marks)
Write note on BCS based biowaivers. (5 marks)
Enlist the methods to determine the permeability
of drug substance. (2 marks)
Comment on Biowaiver extensions. (2 marks)
18/20
