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Write about IVIVC. 5 Mark

A simple in vitro dissolution test on the drug product will be insufficient to predict its therapeutic

Convincing correlation between in vitro dissolution behavior of a drug and its in vivo bioavailability
must be experimentally demonstrated to guarantee reproducibility of biological response.

In vitro-in vivo 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 an in-vivo
response (such as the plasma drug concentration or amount of drug absorbed).

The main objective of developing and evaluating an IVIVC is to enable the dissolution test to serve as a
Surrogate (alternative) for in vivo bioavailability studies in human beings.

The application of developing such an IVIVC are-

1. To ensure batch-to-batch consistency in the physiological performance of a drug product by use
of such in vitro values.

2. To serve as a tool in the development of a new dosage form with desired in vivo performance.
3. To assist in validating or setting dissolution specifications (i.e. the dissolution specification are

based on the performance of product in vivo).

There are two basic approaches by which a correlation between dissolution testing and
bioavailability can be developed:
i) By establishing a relationship usually linear, between the in vitro dissolution and the in vivo

bioavailability parameters-convulsion method.
ii) By using the data from previous bioavailability studies to modify the dissolution

methodology in order to arrive at meaningful in vitro-in vivo correlation-De-convulsion

Some of the often used quantive linear in vitro-in vivo correlation are-

1. Correlation based of the plasma level data: Here linear relationship between dissolution
parameters and plasma level data are established.

2. Correlation based of the urinary excretion data: Here, dissolution are correlated to the amount of
drug excreted unchanged in the urine, cumulative amount of drug excreted as a function of time,

3. Correlation based on the pharmacological response: An acute pharmacological parameter such
LD50 in animals versus dissolution parameters.

4. Statistical moments theory can also be used to determine the relationship such as mean
dissolution time (in vitro) versus mean residence time (in vivo).


In vitro-in vivo correlation Levels

Three IVIVC levels have been defined and categorized in descending order of usefulness.

Level A- The highest category of correlation, it represents a point-to-point relationship between in vitro
dissolution and the in vivo rate of absorption (or in vivo dissolution) i.e. the in vitro dissolution and in
vivo absorption rate curves are superimposable and the mathematical description for both curves is the

Advantages of level A correlation are as follows-
i. A point-to-point correlation is developed. The in vitro dissolution curve serves as a

surrogate for in vivo performance. Any change in manufacturing procedure or
modification in formula can be justified with the out the need for additional human

ii. The in vivo dissolution serves as in vivo indicating quality control procedure for
predicting dosage form’s performance.

Level B- It utilizes the principles of statistical moment analysis. The mean in vitro dissolution time is
compared to either the mean residence time or the mean in vivo dissolution time. However, such a
correlation is not a point-to-point correlation since there are a number of in vivo curves that will produce
similar mean residence time values. It is for this reason that one cannot rely upon level B correlation to
justify changes in manufacturing or modification in formula. Moreover, the in vitro data cannot be used
for quality control standards.


Level C- it is a single point correlation. It relates one dissolution time point (e. g. t50%) to one
pharmacokinetic parameter such as AUC, tmax or Cmax. This level is generally useful only as a guide in
formulation development or quality control owing to its obvious limitations.


Multiple level C- It is correlation involving one or several pharmacokinetic parameters to the amount of
drugs dissolved at various time points.