IVIVC

In Vitro–In Vivo Correlation:

 Definitions
• In vitro dissolution:
It is a process of release of drug from dosage form as
measured in an in vitro dissolution apparatus
• In vivo dissolution:
A process of dissolution of drug in the GI tract.
• Correlation:
A relationship between in vitro dissolution rate and in
vivo absorption rate as used in bio-equivalence guidance
• An in vitro – in vivo correlation (IVIVC) is defined as a
predictive mathematical model describing the
relationship between the in vitro property of an oral
dosage form and relevant in vivo response
• In IVIVC, "C" denotes "Correlation", which means "the
degree of relationship between two variables".
• Correlation deals with the "tightness" in how two
variables vary together.
• This term does not limit a relationship to only the linear
type, but allows for non-linear relationships as well
• IVIVC is more an in vitro–in vivo relationship than
a strict correlation.
In-vitro-in-vivo correlation (IVIVC) establishes a
relationship between

1- Biological property of the drug

Pharmacodynamic effect.
Plasma drug concentration.
2- Physicochemical property of the drug
Dissolution rate.
 
• In order to have an IVIVC, some property of the
drug release from the drug product in vitro ,
under specified conditions, must relate to in-vivo
drug performance.
• Dissolution tests should differentiate formulation
factors that may affect bioavailability of the drug.
IVIVC have been reported for modified-release
drug products, but have been difficult to predict
for immediate-release drug products.
• In some cases, dissolution tests for immediate-
release solid oral drug products may bias or
unfair and a clinically acceptable product might
perform poorly in the dissolution test.
 When a proper dissolution method is chosen,
The rate of dissolution of the product may be
correlated to the rate of absorption of the drug
into the body.
An IVIVC should be evaluated to demonstrate
• Predictability of in-vivo performance of a drug
product perceived from its in-vitro dissolution
characteristics.
• It should be maintained over a range of in-vitro
dissolution release rates and manufacturing
changes.
 Parameters for correlations
IN VITRO INVIVO

1 Dissolution rate Absorption rate or

absorption time
2 Percent drug dissolved Percent of drug absorbed

3 Amount of drug dissolved Maximum plasma

concentration, Cmax Cp
 The in-vitro dissolution
characteristics are dependent on

1- The physical properties of the active

pharmaceutical ingredient (API),
2- The drug formulation,
3- The hydrodynamics of the dissolution apparatus,
4- The dissolution medium.
• USP-NF has separate and distinct dissolution
test requirements for two different phenytoin
sodium capsules.
• For extended-release phenytoin sodium
capsules, USP-NF states that
• not more than 35% in 30 minutes
• between 30% and 70% in 60 minutes and
• not less than 85% 120 minutes
of the labeled amount of C15 H11 N2 NaO2 in the
Extended Capsules dissolves in, under the specified
dissolution conditions."
• In contrast, about tolerances for conventional
Phenytoin Sodium Capsules,
• USP states "not less than 85% of the labeled
amount of C15 H11 N2 NaO2 in the Prompt
Capsules dissolves in 30 minutes."
 Importance of IVIVC
• Correlations between in vitro and in vivo data
(IVIVC) are often used during pharmaceutical
development in order to
1-Reduce development time
2- Optimize the formulation with the fewest
possible trials in man. Reduce the requirement of
animals & human for bioavailability testing
3-For predicting in vivo results based on in vitro
data
4- Fixes dissolution acceptance criteria.
5-Replacement for further bioequivalence studies;
6-Useful for establishing upper and lower
dissolution specs for a solid oral dosage form.
7- Supports or validates the use of dissolution
method and specification.
8- Serves as the replacement of in vivo phenomena
9- Assist quality control during manufacturing and
selecting appropriate formulation.
10- To minimize the bioequivalence studies
performed during the initial approval process and
during the scaling up and post approval changes .
 categories of dissolution showing different
degrees of correlation to invivo data.

• Bases on the type of data used to establish the

relationship, three main levels are defined by the
FDA:
 Level A

• Level A is the highest level of correlation,

• a 1:1 relationship between in-vitro dissolution
and in-vivo bioavailability is demonstrated.
• Included in Level A are extended-release
dosage forms that demonstrate an in-vitro drug
release essentially independent of the
dissolution medium.
• In this case, the in-vitro dissolution curve is
compared directly to the percentage of drug
absorbed calculated from the plasma drug
concentration-time curve using a
pharmacokinetic model or a model-independent
method.
• Generally, the percentage of drug absorbed may
be calculated by direct mathematical
computational method, a process of
mathematical resolution of blood level into an
input (absorption) and an output (disposition)
component .
in vitro release profiles of three complex parenteral formulations with
different release characteristic step 4 shows a one-to-one linear
correlation. 
Whatever the method used to establish a Level A IVIVC,
The model should predict the entire in vivo time course
from the in vitro data.
Advantage of a Level A correlation

• The quality control procedure of the in-vitro

dissolution/drug release test is predictive of drug
product performance in vivo .
• A correlation of this type is generally linear and
represents a point-to-point relationship
between in vitro dissolution and the in vivo input
rate.
• In a linear correlation,
the in vitro dissolution and in vivo input curves may
be directly super imposable or may be made to be
super imposable by the use of a scaling factor.
• Nonlinear correlations
uncommon, may also be appropriate.
 Level B

• Level B IVIVC uses the principles of statistical

moment analysis.
• The mean in vitro dissolution time is compared
either to the mean residence time or to the mean
in vivo dissolution time .
 DISADVANTAGES

• Level B correlation does not uniquely reflect the

actual in vivo plasma level curve, because a
number of different in vivo curves will produce
similar mean residence time values.
• Level B is the least useful for regulatory purposes
because it does not reflect the actual in
vivo plasma level curves.
• In vitro data from a Level B correlation cannot be
used to justify the extremes of quality control.
 Level C

•  Level C IVIVC establishes a single point

relationship between a dissolution parameter,
• For example, t 50
,percent dissolved in 4 hours
%
and a pharmacokinetic parameter e.g. AUC, Cmax,
Tmax.
 DISADVATAGE

• Level C correlation does not reflect the complete shape

of the plasma concentration-time curve, which is the
critical factor that defines the performance of ER
products.
 Multiple level C

• A multiple Level C correlation relates one or

several pharmacokinetic parameters of interest
to the amount of drug dissolved at several time
points of the dissolution profile.
• Level A correlations use all the information of
the dissolution and absorption curves, in
contrast to levels B or C.
Dissolution Rate versus
Absorption Rate
• If dissolution of the drug is NOT a rate limiting,
a faster dissolution rate may result in a faster rate
of appearance of the drug in the plasma.
• It may be possible to establish a correlation
between rate of dissolution and rate of
absorption of the drug.
• The absorption rate is usually more difficult to
determine than peak absorption time.
• Therefore, the absorption time may be used in
correlating dissolution data to absorption data.
• In the analysis of in-vitro, in-vivo drug correlation,
rapid drug dissolution may be distinguished from
the slower drug absorption by observation of the
absorption time for the preparation.
• The absorption time refers to the time for a
constant amount of drug to be absorbed.
 Sustained-release aspirin
products
• In one study involving three sustained-release
aspirin products , the dissolution time for the
preparations were linearly correlated to the
absorption times .
• The results from this study demonstrated that
aspirin was rapidly absorbed and was very much
dependent on the dissolution rate for absorption.
 Correlation between time required for a given
amount of drug to be absorbed and time required
for the same amount of drug to be dissolved in vitro
for three sustained-release aspirin products
Study of Percent of Drug Dissolved
versus
Percent of Drug Absorbed
• If a drug is absorbed completely after dissolution,
a linear correlation may be obtained by
comparing the percentage of drug absorbed to
the percentage of drug dissolved.
• An appropriate dissolution medium should be
selected and use a slow dissolution stirring rate
so that in-vivo dissolution is approximated.
• Aspirin is absorbed rapidly, and a slight change in
formulation may be reflected in a change in the
amount and rate of drug absorption during the
period of observation.
• If the drug is absorbed slowly, which occurs
when absorption is the rate-limiting step, a
difference in dissolution rate of the product may
not be observed.
• In this case, the drug would be absorbed very
slowly independent of the dissolution rate.
 Limitations

• It is limited to a certain drug product.

• It can be used only that particular formulation.
• Cannot be used across the drug product with
different release pattern.
• It is unable to accurately estimate the rate of
drug absorption ,Cmax, prediction error will
found to be 20%.
 Biopharmaceutics Classification
System of Drugs

The Biopharmaceutics Classification System is a

system to differentiate the drugs on the basis of
their solubility and permeability.
 Class 1 drug

• High absorption.
• High dissolution.
• Rate limiting step is drug dissolution or gastric
empting time.
e.g. metoprolol
• IVIVC IS EXPECTED
 Class 2 drugs

• Have low solubility

• High permeability
• Ivivc expected
• e.g-phenytoin
 Class 3 drug

• Permeability is rate controlling step.

• Rapid dissolution is particularly desirable in order
to maximize the contact time between dissolve
drug and absorption mucosa.
• Eg. cimetidine
• Limited or NO IVIVC expected
 Class 4 drug

• They have low solubility

• Low permeability and significant problem in oral
dosage form.
• Limited or NO IVIVC expected
e.g. Bifonazole  (imidazole, antifungal drug)