Transcript Slide 1

6th Annual Science and Standards Symposium
January 16, 2013
Istanbul
Determination of Solubility and
Permeability in BCS
Erika Stippler, Ph.D.
Director
Dosage Form Performance Laboratory
BCS Concept
 Published by Amidon and co-workers 1995
 Biopharmaceutics Classification System is a
scientific framework for classifying drug
substances based on their aqueous solubility
and intestinal permeability
 The aim is to optimize the development of oral
dosage forms relying only on rate limiting
factors for absorption
Drug Release – The Rate Limiting Step
Modern Biopharmaceutics, G.L. Amidon, M. Bermejo 2003
Biopharmaceutical Drug Classification
System (BCS)
Class
I
II
III
IV
Solubility
High
Low
High
Low
Permeability
High
High
Low
Low
Solubility directly influences the dissolution behavior of oral
dosage forms in gastrointestinal tract
BCS Solubility: FDA vs. EMA
FDA
EMA
– Solubility profile in the range of
pH 1- 7.5 at 37 ± 1 °C
– Solubility profile in the range of
pH 1- 6.8 at 37 ± 1 °C
– At least 3 buffers
– At least 3 buffers (1.2, 4.5, 6.8)
– At pH=pKa, pH=pKa-1,
pH=pKa+1 (where applicable)
– At pH=pKa (where applicable)
– USP buffers
– Buffers not specified (PhEur)
– Minimum of 3 replicates
– Sufficient number of replicates
Solubility Determination
 Equilibrium solubility (thermodynamic solubility)
– Drug dissolved is in equilibrium with solid remaining on the bottom.
 Kinetic solubility (turbidimetric solubility)
– Solubility at time point X. Precipitate present but equilibrium not
necessarily reached. Supersaturation and subsaturation possible.
 Intrinsic solubility
– Equilibrium solubility of the free acid or base form of an ionizable
compound at a pH where it is fully de-ionized.
Solubility Determination: Lab-Method
Shake-flask method
(thermodynamic solubility)
Excess of solid drug exposed to
liquid
Final assay after established
equilibrium between drug dissolving
and drug precipitating at 37 °C
Takes usually 60 – 72 hours with
sampling at earlier time points
Sufficient number (n>3 with
extrapolation of regression line to yaxis)
Standard USP buffer solutions
considered to be appropriate
pH of supernatant needs to be
verified
Dose Number
function of drug substance solubility
D
 V
Do  
 C

Water
Solubility
Issues
D / Vwater >> CS ~ High Do
S





D / Vwater << CS ~ Low Do
BCS Class Boundaries
 Solubility:
 Highly
soluble drug substance
– FDA: the highest dose strength is soluble in 250 mL or less of aqueous
media over a pH range of 1 to 7.5, at 37°C ± 1°C
– EMA: the highest single dose administered is soluble in 250 mL or less
of buffer solutions of pH 1 to 6.8, at 37°C ± 1°C
– WHO: the highest dose* is soluble in 250 mL or less of aqueous media
pH range of 1.2 to 6.8, at 37°C ± 1°C
* highest dose recommended in WHO’s List of Essential Medicines or the
highest dose strength available on the market
Permeability Determination
 High permeability
– Complete absorption, generally related to high permeability
 Methodology
– Absolute bioavailability: oral BA determination using
intravenous administration as a reference
– Mass-balance studies: pharmacokinetic mass balance studies
using unlabeled, stable isotopes or a radiolabeled drug
substance
– Intestinal permeability methods:
• in vivo intestinal perfusion studies (human/animal)
– in vitro permeation studies (excised human/animal tissue)
– in vitro permeation studies on cell monolayers (e.g.Caco-2)
Absorption Number
Effective permeability
T
P 
An   T  
T
R
eff
GI
GI
ABS
Residence time in GI
Radius of GI
Time required for
complete absorption
Human Permeability vs. Fraction Dose Absorbed
Amidon G.L. et al. Pharm Res 1995 12: 413-20
BCS Class Boundaries
 Permeability
 Highly
permeable drug substance:
– FDA: the extent of absorption in humans is greater than 90% of an
administered dose
– Mass balance
– Absolute bioavailability
– Intestinal permeability
– EMA: the extent of absorption in humans is greater than 85% of an
administered dose
– Mass balance
– Absolute bioavailability
– WHO: the extent of absorption in humans is greater than 85% of an
administered dose
– based on mass-balance
– compared with an intravenous reference dose
– Alternative methods are accepted
Biopharmaceutics Classification System
Human Permeability
10
I
Gastric emptying
determines on-set of
absorption
II
Dissolution likely
to be “rate limiting”
1.0
III
IV
Absorption might be:
- incomplete
- sensitive to
certain excipients
0.1
Generally “problem”
molecules
0.01
1
10
100
1000
10000
Volume of water (ml) required to dissolve
the highest dose strength at pH 1.2 - 8
100000
Biopharmaceutics Classification System
Dissolution number
Diffusivity
Solubility
3D  C

Dn   
 r  
S
2
T 

T    

T 
mg/mL
GI
GI
DISS
Residence time in GI Trakt
Particle Radius
Density
Time required for
complete dissolution
BCS Linked to Dissolution and Absorption
 Class I
– High absorption number
– High dissolution number
– Rate limiting step is
dissolution
• If rapid then gastric emptying
rate limiting step
 Class II
– High absorption number
– Low dissolution number
– Rate limiting step is dissolution
• Except a very high dose number
– IVIVC possible
 Class III
–
–
–
–
Low absorption number
High dissolution number
Rate limiting step is permeability
BA not influenced by dosage form
but alteration of physiology
 Class IV
– Low absorption number
– Low dissolution number
– Rate limiting steps both,
permeability and dissolution
– BA highly variable
Extension of the BCS to BDDCS
 BDDCS: biopharmaceutical drug
disposition classification system
(according to Wu and Benet 2005)
– BCS Class I and II drugs are eliminated
primarily via metabolism, whereas Class
III and IV drugs are eliminated
unchanged via bile or urine
– When metabolism is the major route of
drug elimination, the drug exhibits high
permeation
– Extent of metabolism instead of extent
of absorption may be used for
categorization
• e.g. class I: > 90 % metabolized may be
substituted for > 90 % absorbed
– BDDCS allows for the prediction of
transporter-enzyme interactions
Dissolution Testing Requirements for in vitro BE
FDA
EMA
WHO
Apparatus
USP App. 1
USP App. 2
Basket
Paddle
Basket
Paddle
Dissolution
media
0.1 N HCl or SGF
Buffer pH 4.5
Buffer pH 6.8 or SIF
Buffer pH 1.0 or SGF
Buffer pH 4.5
Buffer pH 6.8 of SIF
Buffer pH 1.2
Buffer pH 4.5
Buffer pH 6.8
Use of enzymes is allowed
in case of gelatin capsules
or gelatin coated tablets
Absolutely no addition
of surfactant or
enzymes is allowed
Int. Ph. Buffers are
preferred
Volume
900 ml
900 ml or less
900 ml or less
Temperature
37°C ± 0.5°C
37°C ± 1°C
37°C
Agitation
Basket: 100 rpm
Paddle: 50 rpm
alternatives to be justified
Basket: 100 rpm
Paddle: 50 rpm
Basket: 100 rpm
Paddle: 75 rpm
Sampling time
10, 15, 20, 30 min
10, 15, 20, 30, 45 min
10, 15, 20, 30, 45, 60 min
Sample #
12
12
12
Requirements
f2 ≥ 50
50 ≤ f2 ≤ 100
50 ≤ f2 ≤ 100
Dissolution Characteristics of IR Drug Products
FDA
EMA
WHO
Very rapidly
dissolving
No definition
≥85%of the labeled
amount dissolves in
15 min
≥85%of the labeled
amount dissolves in
15 min or less
Rapidly
dissolving
≥85%of the labeled
amount dissolves in
30 min
No definition
≥85%of the labeled
amount dissolves in
30 min
Similarly
dissolving
(EMA)
No definition
≥85%of the labeled
amount dissolves
between 15 and 30 min
No definition
Test conditions
Paddle at 50 rpm or
Basket at 100 rpm in
900 ml or less of
0.1N HCl or SGF
Buffer pH 4.5
Buffer pH 6.8 or SIF
Paddle at 50 rpm or
Basket at 100 rpm in
900 ml or less of
0.1N HCl or SGF
Buffer pH 4.5
Buffer pH 6.8 or SIF
Paddle at 75 rpm or
Basket at 100 rpm in
900 ml or less of
Buffer pH 1.2
Buffer pH 4.5
Buffer pH 6.8
FDA-Requirements for BCS-based Biowaiver
 Immediate
release drug products only
 BCS-Class
I drug substance
 Rapidly dissolving IR drug product
 Test and reference drug product are pharmaceutically equivalent
 Test and reference drug product exhibit similar dissolution profiles
 Exclusions
 IR
drug products considered not to have a narrow therapeutic index
 Products designed to be absorbed in the oral cavity
+
Biowaiver with Respect to BSC Classification - FDA
I
IV
III
-
Permeability
II
-
Solubility
+
EMA-Requirements for BCS-based Biowaiver
 Restricted
for immediate release drug products considered not
to have a narrow therapeutic index
 Case
I
– Same drug substance BCS-Class I or different salt both BCS-Class I
– either very rapid or rapid in vitro dissolution
– Same excipients in similar amounts
– Similarity of dissolution profiles
 Case
II
– Same drug substance BCS-Class III
– very rapid in vitro dissolution
– Same excipients in very similar amounts
– Similarity of dissolution profiles
WHO-Requirements for BCS-based Biowaiver
 WHO
Model List of Essential Medicines immediate release solid
oral dosage forms
 Case
1
– BCS-Class I drugs
– very rapidly dissolving drug products (both test and reference)
– rapidly dissolving drug products for which similarity of dissolution profiles
was demonstrated
 Case
2
– BCS-Class III drugs
– very rapid in vitro dissolution
– Same composition regarding excipients in both test and reference
WHO-Requirements for BCS-based Biowaiver
 WHO
Model List of Essential Medicines immediate release solid
oral dosage forms
 Case
3
– BCS-Class II compounds with weak acid properties (high solubility at pH 6.8
but not at pH 1.2 or 4.5 and with high permeability)
– rapidly dissolving in pH 6.8 (both test and reference)
– similar of dissolution profiles for both test and reference product in all three
buffer media (pH 1.2, 4.5, and 6.8)
– Careful examination of type and amount of surfactant in the formulation
II
I
IV
III
-
Permeability
+
Biowaiver with Respect to BSC Classification - WHO
-
Solubility
+
Selection of the Reference Product
 The
reference product/ comparator
– is RLD in the US
– is normally the innovator product for which efficacy, safety and quality has
been established (EMA)
– the selection is made at the national level and should be justified (EMA and
WHO)
– In case the innovator cannot be identified
– WHO comparator product
– ICH innovator product
– Well selected comparator
 The
assayed content of the batch used as test product should not
differ more than 5% from that of the batch used as reference product
 More than one batch of the reference product should be investigated
Example: Amoxicillin
 Dose
strength:
 US-RLD:
875 mg
 Europe:
common dose 500 mg
 WHO-LEM: 500 mg (as trihydrate)
Solubility:
 1 g / 370 ml
 875 mg = 324 mL
 500 mg = 185 mL
BSC Classification:
 US:
Class IV
 Europe, WHO:
Class I
Permeability:
89%
Dissolution Cases
 High
solubility in both pH 1.2 and 6.8
– Conduct dissolution according to USP-NF <711> in each pH 1.2 and 6.8
– App. 1@100 rpm or App. 2@50 rpm in 900 mL
– Q=85% in 30 minutes
 High
solubility in pH 1.2 only
– Conduct dissolution according to USP-NF <711> in pH 1.2
– App. 1@100 rpm or App. 2@50 rpm in 900 mL
– Q=85% in 15 minutes
 High
solubility in pH 6.8 only
– Conduct dissolution according to USP-NF <711> in pH 6.8
– App. 1@100 rpm or App. 2@50 rpm in 900 mL
– Q=85% in 15 minutes
 Low
solubility in both pH values
– Product specific development needed
– Suggestions on surfactant usage could be included
Evaluating the results
 Products
that meet the acceptance criteria may be considered:
 To
perform optimally or
 To be optimally available for in vivo absorption
Products that do not meet the acceptance criteria are
 not
necessarily “bad” products,
 require additional studies to demonstrate proper performance
30
Summary
 The
BCS is the scientific foundation for Biowaivers
 Biowaivers can be used to approve drug products
– SUPAC
– Generic drug products
 Harmonization
among different jurisdiction regarding solubility
classification is needed
 Harmonization in selection of a Reference product