Chemistry Reference
In-Depth Information
Figure 11.10.
Design space for spray-dried dispersion particle size and bulk density at low,
target, and high tablet hardness.
This equation represents the limiting design space equation for SDD particle size and
bulk density that can be compressed to achieve acceptable dissolution; that is, the
combined SDD particle size and bulk density must produce
D
15
80% for a minimum
tablet hardness of 13 kP.
The NORs for particle size and bulk density ensure that the tablet dissolution CQA
will be met across the acceptable range of tablet hardness. The DSLs for particle size and
bulk density re
ect the ranges over which acceptable dissolution could be achieved, with
at least one acceptable combination of other parameters. For example, SDD with particle
size of 110
m can produce tablets with acceptable dissolution, provided that the bulk
density is lower than 0.38 g/cm
3
at 13 kP average hardness. The design space equation
for particle size and bulk density ensures that the dissolution CQA will be met with a
minimum average tablet hardness of 13 kP.
The NORs for SDD particle size and bulk density are both well within the DSL
ranges, at the target hardness, as shown in Figure 11.10. In addition, the spray drying
process is under excellent control for the CQAs of SDD particle size and bulk density, as
described in the spray drying model. Therefore, although SDD particle size and bulk
density are critical quality attributes controlled via the SDD control strategy, with respect
to the tablet CQA of dissolution they were de
μ
ned as key since they have the potential to
affect dissolution. However, the NOR is well within the DSL and they are well
controlled. The NORs and DSLs for the SDD particle size and bulk density, average
tablet hardness following compression, and compression processing parameters are
summarized in Table 11.8.
11.3.3 Conceptual Approach to De
ning Telaprevir Shelf Life
Although the solid dispersions may enhance aqueous solubility, they bring numerous
stability issues such as recrystallization of the amorphous material and/or reduced
chemical stability. Therefore, careful formulation design and process control is needed
(during both spray drying and downstream processing) to prevent thermodynamic and
chemical instability during processing and subsequent storage. Such instability can arise
from interactions between excipients and the amorphous dispersion. In addition,
compression, heat, and exposure to moisture, which can occur at different stages on
