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IN VITRO IN VIVO

CORRELATIONS
BY
T.Dilip Kumar
M.S.(pharm.) Pharmaceutics
CONTENTS

Definitions
Significance of ivivc
Parameters for correlation
Levels of correlation
Development of correlation
Case study
Conclusions
References

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Definitions

In vitro dissolution: Its a process of release of drug from


dosage form as measured in an in vitro dissolution apparatus
In vivo dissolution: process of dissolution of drug in the GI
tract.
Correlation: relationship between in vitro dissolution rate and
in vivo absorption rate as used in bio-equivalence guidance
IVIVC has been defined as a predictive mathematical model
describing the relationship between an in-vitro property of a
dosage form and an in-vivo response

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Significance of ivivc

The main objective of developing and evaluating an IVIVC is


to enable the dissolution test to serve as a surrogate. It reduces
the number of bio-equivalence required for approval as well as
during scale up and post approval changes (SUPAC).
IVIVC shortens the drug development period, economizes the
resources and leads to improved product quality.
A means of assuring the bioavailability of active ingredients
from a dosage form.
Supports and or validates the use of dissolution methods and
specifications
IVIVC assists in supporting biowaivers.

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Parameters for correlations

SL. No. IN VITRO INVIVO

1. Dissolution rate Absorption rate (or


absorption time)
2. Percent drug dissolved Percent of drug absorbed

3. Percent drug dissolved Maximum plasma


concentration, Cmax
4. Percent drug dissolved Serum drug
concentration, Cp

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Dissolution rate versus absorption rate

If dissolution of drug is rate


limiting step, the faster the
dissolution rate, the faster is
the rate of appearance of drug
in the plasma. Therefore,
absorption time and
dissolution time may be
considered for correlation

Figure 1: In vitro-in vivo correlations-


Dissolution time Vs absorption time of
three sustained release products

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Percent of drug dissolved versus percent of drug
absorbed:

. Appropriate dissolution medium and a


slow stirring rate during dissolution
should be considered to mimic in vivo
dissolution.
. If the drug is absorbed completely after
dissolution, a linear correlation may be
obtained by comparing the percent drug
absorbed to the percent drug dissolved.

Figure 2: In vitro-in vivo correlations-


Percent of drug dissolved Vs percent of
drug absorbed of three sustained release
aspirin products

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Percent of drug dissolved versus maximum plasma
concentration:
A poorly formulated drug may not
be completely dissolved and
released, resulting in lower plasma
drug concentration.
The percentage of drug released at
any time interval will be greater
for more bioavailable drug
product, the peak serum
concentration will be higher for the
drug that shows highest percent of Figure 3: percent drug dissolved in 30 minutes Vs
Cmax of drug for nine products of phenytoin (100
drug dissolved. mg).

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Serum drug concentration versus percent of drug
dissolved

In a study on aspirin absorption,


serum concentration of aspirin
was correlated to percent of drug
dissolved using an in vitro
dissolution method
Dissolution of drug is rate
limiting step, and various
formulations with different
dissolution rates has difference in
serum concentration of aspirin
Figure 4:In vitro-In vivo correlations-serum drug
concentration Vs percent of drug dissolved of
aspirin

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Levels of correlation

Level A Correlation
Level B Correlation
Level C Correlation
Multiple Level C Correlation

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Level A correlation

It is estimated by two step method,


deconvolution followed by comparison
of fraction of drug absorbed to the
fraction of drug dissolved.
Defines a direct relationship between in
vivo data such that measurement of in
vitro dissolution rate alone is sufficient
to determine the biopharmaceutical rate
of the dosage form.
Figure 5: Correlation between percent
An in vitro dissolution curve can serve theophylline dissolved in vitro and
percent theophylline absorbed after
as a surrogate for in vivo performance administration of extended release
product

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Level B correlation:
Level B correlation utilizes the
principles of statistical moment
analysis.
Mean in vitro dissolution time
(MDTvitro) of the product is compared
to mean in vivo residence time
(MRT).
MRT may be calculated as the ratio of
the area under the first moment curve
(AUMC) to the AUC, where AUMC
Figure 6: Correlation of mean in vitro
is the area under the curve observed dissolution time (MDT) and mean in vivo
for the product of time and absorption time (MAT)

concentration versus time.

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Level C correlation
Level C correlation represents a single
point correlation.
One dissolution time point (t50%, t90%,
etc.) is compared to one mean
pharmacokinetic parameter such as
AUC, tmax or Cmax.
Weakest level of correlation as partial
relationship between absorption and
dissolution is established. Figure 7: Correlation between percent drug
dissolved in 45 minutes and AUC of plasma
drug-time curve .

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Multiple level C correlations

Multiple Level C correlation relates one or several


pharmacokinetic parameters of interest (Cmax, AUC, or any
other suitable parameters) to the amount of drug dissolved at
several time points of the dissolution profile.
Its correlation is more meaningful than that of Level C as
several time points are considered.

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Development of in vivo/ in vitro
correlation

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Case Studies

In Vitro-in Vivo Correlation (IVIVC) Study Of


Leflunomide Loaded Microspheres.
The parameters correlated were amount of drug dissolved to
the respective fraction of dose absorbed.
The in vitro release from leflunomide microspheres
B1,B2,B3,B4 show good sustained release property
The selected formulations were examined in In vivo rabbit
model, the Tmax of all microspheres were increased from 1 to
4hr confirming its sustaining property
Degree A level of correlation was established from the results

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CONCLUSIONS
The current IVIVC studies have focused more on the
development and validation of level A IVIVC which gives
more useful information on the relationship between in vitro
release and in vivo absorption from dosage form.
Levels B and C IVIVCs have been evaluated for several
purposes in formulation development, for example, to select
the appropriate excipients and optimize the manufacturing
processes.
Present regulatory guidelines for IVIVC is only applicable to
oral conventional and modified release dosage forms;
however, further research is necessary to develop IVIVCs for
non-oral products, inhaled medicines and dermatological
medicaments also.
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References

Leon Shargel, Susanna wu-pong, Andrew Yu. Applied


biopharmaceutics and pharmacokinetics. 6th edition, pg no- 380-
383.
Sundaramoorthi Nainar, Kingston Rajiah, Santhosam Angamuthu,
D Prabakaran and Ravisekhar Kasibhatta. Biopharmaceutical
Classification System in In-vitro/In-vivo Correlation: Concept
and Development Strategies in Drug Delivery. Tropical Journal of
Pharmaceutical Research April 2012; 11 (2): 319-329
Rabindranath pal, Manas Chakraborty, Rabindra Debnath and
Bijan K Gupta. In vitro-In vivo Correlation (IVIVC) study of
Leflunomide loaded microspheres. International Journal of
Pharmacy and Pharmaceutical Sciences, Vol. 1, Suppl 1, Nov.-
Dec. 2009
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References

Hitesh Jain , Kruti Joshi1, Shweta Gediya, Vishal Sutariya,


Hirak Shah, T. Y. Pasha. IN VITRO IN VIVO CORRELATION
(IVIVC): A REVIEW. Imperial Journal of Pharmaceutics &
Cosmetology.

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