Chemistry Reference
In-Depth Information
Figure 11.11.
Effect of temperature and relative humidity on epimer growth in tablet.
epimer growth over time as a function of temperature and relative humidity at a constant
impurity level.
A regression model was developed that predicts growth of epimer as a function of
storage temperature, time, tablet moisture content, and excipient impurity. Stepwise
linear regression was used to determine signi
cant effects. The functional form of the
regression equation was chosen based on the expected dependence of epimer growth on
temperature and time according to the following equation:
k
A
exp
E
a
=
RT
;
where
k
is the degradation rate,
A
is a constant that depends on both tablet water content
and excipient quality,
E
a
is the activation energy and is also dependent on the excipient
quality,
is temperature.
The actual and predicted increase in epimer using the model are in excellent
agreement, as shown in Figure 11.12, and the model parameter estimates are tabulated
in Table 11.11.
The regression model can be used to determine appropriate acceptance criteria for
water content in tablets and impurity content in excipient based on the following:
R
is the universal gas constant, and
T
The predictions of the regression model are also in good agreement with
traditional ICH stability data (Figure 11.13).
The model appropriately predicts that formation of epimer increases as a function
of impurity level of the excipient and storage temperature (Figure 11.13).
Finally, the model was used to project the increase in epimer as a function of tablet
water content and excipient impurity after storage at 25
C for
12 months (assuming constant tablet moisture; thus, storage humidity was not consid-
ered) (Figure 11.14). The NOR for the proposed impurity level and moisture content
combination is indicated in the shaded area on the 25
C for 24 months and 30
°
°
C/60% RH contour plot in
Figure 11.14. The DSL is chosen based on the assumption that the maximum epimer
°
