3. Concepts and Introduction
In Vivo In Vitro correlation is defined as the
predictive mathematical model that describes the
relationship between an in vitro property (such as rate
and extent of dissolution) of a dosage form and in
vivo response (such as plasma drug concentration)
USP defines IVIVC as the establishment of a
relationship between a biological property produced
from a dosage form and a physiochemical property of
the same dosage form.
4. Applications of IVIVC
I. To ensure batch to batch consistency in the physiological
performance of a drug product by use of such in vitro
values
II. To serve as a tool in the development of a new dosage
form with desired in vivo performance
III.To assist in validating or setting dissolution
specifications i.e. the dissolutions specifications are
based on the performance of product in vivo
IV.It minimizes the number of bioequivalence studies
performed during the initial approval process and during
scaling up and post approval changes
V. It assists in validating dissolution specifications
VI. Biowaiver for minor formulation and process changes
5. Limitations of IVIVC
I. The IVIVC is limited to a certain drug product.
It can be used only on that particular
formulation
II. The IVIVC cannot be used on the products
with different release mechanisms
6. Quantitative In Vitro In Vivo Correlation
A. Correlation based on the plasma level data:
Parameters used for correlating in vitro dissolution with plasma data
In vitro dissolution parameters In vivo plasma drug parameters
Time for specific amount of drug to
dissolve
AUC, Cmax
Amount dissolved at a specific time
point
Fraction absorbed, absorption rate
constant Ka
Mean dissolution time Mean residence time, mean dissolution
time, mean absorption time
Parameter estimated after modelling the
dissolution process
Concentration at time t , amount
absorbed at time t
7. B. Correlations based on the urinary excretion
data: Parameters such as amount of drug excreted
unchanged in the urine, cumulative amount of drug
excreted as a function of time.
C. Correlation based on the pharmacological
response : an acute pharmacological effect such as LD50
in animals in related to any of the dissolution parameters.
Statistical moments theory: can be used to
determine the relationship such as mean
dissolution time vs. mean residence time.
8. In Vivo In Vitro Correlation levels
Level A :
It shows relationship between fraction absorbed and fraction dissolved.
No direct comparison is possible.
It is considered as a predictive model for relationship between the entire in
vitro and in vivo response.
There exists a linear correlation 1:1.
There is point to point relationship.
It is highest level of correlation and most preferred to achieve.
0
5
10
15
20
25
1 2 3 4
Fractionabsorbed
Fraction dissolved
Level A Correlation
9. Level B:
In this the mean in vitro dissolution time is compared with
mean in
vivo residence time or mean in vivo dissolution time.
It is based on statistical moment analysis.
It is not point to point correlation.
It is least used for regulatory purposes.
0
10
20
30
1 2 3 4
MRT(invivo)
MDT ( in vitro)
Level B Correlation
10. Level C Correlation:
It is single point correlation that is established in between
one dissolution parameter like t 50% and one of the
pharmacokinetic parameters like tmax, Cmax, AUC.
It is helpful in early stages of formulation .
0
5
10
15
20
25
1 2 3 4
AUC
MDT
Level C Correlation
11. Multiple level C Correlation:
It reflects the relationship between one or several
pharmacokinetic parameters of interest and amount
of drug dissolved at several time point of dissolution.
It is similar to Level A correlation.
Level D Correlation:
It is not considered useful for regulatory purpose.
12. Class Solubility Permeability Absorption
Pattern
Examples
1 High High Well absorbed Diltiazem,
Propanolol,
Metoprolol
2 Low High Variable Nifedipine,
Carbamazepin
e, Naproxen
3. High Low Variable Insulin,
Metformin,
Cimetidine
4. Low Low Poorly
absorbed
Taxol,
Chlorthiazide,
Furosemide
The Biopharmaceutics Classification System For Drugs
13. Drug properties that determine BCS classification
Drug property influencing absorption Corresponding parameter
Solubility: a drug with high solubility is
the one whose largest dosage strength is
soluble in 250 ml or less of water over a
pH range of 1-8
Dose number: It is the mass of drug
divided by an uptake volume of 250 ml
and the drug solubility
Dissolution rate: A drug product with
rapid dissolution is the one when ≥85% of
the labelled amount of drug substance
dissolves within 30 minutes using USP
apparatus 1 or 2 in more than 900 ml
volume buffer solution.
Dissolution number : It is the ratio of
mean residence time to mean dissolution
time
Permeability : A drug with high
permeability is the one having extent of
absorption greater than 90% of the
administered dose given that the drug is
stable in GIT
Absorption Number: it is ratio of MRT to
absorption time.
14. BCS for immediate release drug products and IVIVC
expectations.
Class Solubility Permeability IVIVC
Expectations
Possibility of
predicting
IVIVC from
dissolution
data
1 High High IVIVC
expected
Yes
2 Low High IVIVC
expected
Yes
3 High Low IVIVC not
expected
No
4 Low Low IVIVC not
expected
No
15. BCS for extended release drug products and IVIVC expectations
Class Solubility Permeability IVIVC
Expectations
1a High and site
independent
High and site
independent
IVIVC Level A
expected
1b High and site
independent
Dependent on site
and narrow
absorption window
IVIVC Level C
expected
2a Low and site
independent
High and site
independent
IVIVC Level A
expected
2b Low and site
independent
Dependent on site
and narrow
absorption window
IVIVC not expected
Va Variable Variable IVIVC not expected
Vb Variable Variable IVIVC Level A
expected
16. BCS based Biowaiver to in vivo
studies
In biowaivers the in vivo bioavailability and bioequivalence studies
need not to be conducted for drug products under following
circumstances:
1. Rapid and similar dissolution
2. High solubility
3. High permeability
4. Wide therapeutic window
5. Excipients used in dosage form are same as those present in
approved drug product.
17. Dissolution
As per IVIVC perspective dissolution is proposed to be a serrogate of drug
bioavailability. Generally following types of apparatus are being used for conducting
the dissolution studies.
1. Rotating basket apparatus
2. Rotating paddle type apparatus
3. Reciprocating cylinder apparatus
4. Flow through cell apparatus
5. Paddle over disc apparatus
6. Cylinder apparatus
7. Reciprocating disc apparatus
The conditions such as the stirring speed, choice of apparatus, pH of medium, and
temperature of medium are important for conducting dissolution profile.
Dissolution medium used are: water, simulated gastric fluid (pH1.2), intestinal fluid
(pH 6.8, 7.4)buffers with pH range of 4.5 to 7.5
Water and simulated gastric fluids are used for class 1 drugs
The normal test duration for immediate release is 15 to 60 minutes with a single
time point.
20. Dissolution acceptance criteria
Q is considered as the acceptance criteria for dissolution which is defined as percentage
of drug content dissolved in a given time period.
Method of comparison of dissolution profile:
Dissolution can be determined by calculating difference factor f1 and similarity factor
f2
F1=∑(Rt-Tt)*100/∑Rt
F2= 50log [(1+1/n∑(Rt-Tt)(Rt-Tt)]-0.5*100
where n= number of dissolution time points
Rt = dissolution value of reference product
Tt= dissolution value of test drug
Comparison of dissolution profile:
Difference factor f1 Similarity factor f2 Inference
0 100 Dissolution profiles are
identical
≤15 >50 Similarity or equivalence of
two profiles
21. The evaluation of dissolution profiles
is based on following conditions:
•Minimum 3 dissolution points are measured
•Number of drug products tested for dissolution is 12
•Not more than one mean value of more than 85%
dissolved for each product
•S.D should not be more than 10%
22. Dissolution methology for immediate
release products based on BCS
BCS Class Dissolution methodology
1 Single point if NLT 85% Q in 15
minutes
Multiple point if Q is less than in 15
minutes
2 Multiple point
3 Same as class 1
4 Same as class 2
23. Stage Number of dosage units
tested
Acceptance criteria
S1 6 No dosage unit is less than
Q+5%
S2 6 Average of the twelve
dosage units (S1+S2) > Q%
and no dosage unit is less
than Q-15%
S3 12 Average of 24 dosage units
(S1+S2+S3)> Q% and not
more than 2 dosage units are
less than Q-15% and no
dosage unit is less than Q-
25%
Dissolution Acceptance Criteria
24. Dissolution acceptance criteria for extended
release
Level Number tested Acceptance criteria
S1 6 No individual value
exceeds 10% dissolved
S2 6 Average of the twelve
dosage units (S1+S2) is not
more than 10% dissolved
and no individual unit is
greater than 25%dissolved
S3 12 Average of 24 dosage units
(S1+S2+S3) ) is not more
than 10% dissolved and no
individual unit is greater
than 25%dissolved
