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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
2
Definitions
3
Significance of ivivc
4
Parameters for correlations
5
Dissolution rate versus absorption rate
6
Percent of drug dissolved versus percent of drug
absorbed:
7
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).
8
Serum drug concentration versus percent of drug
dissolved
9
Levels of correlation
Level A Correlation
Level B Correlation
Level C Correlation
Multiple Level C Correlation
10
Level A correlation
11
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)
12
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 .
13
Multiple level C correlations
14
Development of in vivo/ in vitro
correlation
15
Case Studies
16
17
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.
18
References
20
21