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: It’s 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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Figure 1: In vitro-in vivo correlations-

Dissolution time Vs absorption time of

three sustained release products

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

Dissolution rate versus absorption rate

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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

drug dissolved.Figure 3: percent drug dissolved in 30 minutes Vs

Cmax of drug for nine products of phenytoin (100

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

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Figure 4:In vitro-In vivo correlations-serum drug

concentration Vs percent of drug dissolved of

aspirin

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.

An in vitro dissolution curve can serve

as a surrogate for in vivo performance

Figure 5: Correlation between percent

theophylline dissolved in vitro and

percent theophylline absorbed after

administration of extended release

product

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Level B correlation:

Level B correlation utilizes theprinciples of statistical momentanalysis.

Mean in vitro dissolution time(MDTvitro) of the product is comparedto mean in vivo residence time(MRT).

MRT may be calculated as the ratio ofthe area under the first moment curve(AUMC) to the AUC, where AUMCis the area under the curve observedfor the product of time andconcentration versus time.

Figure 6: Correlation of mean in vitro

dissolution time (MDT) and mean in vivo

absorption time (MAT)

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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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