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be used to guide formulation design. For example, if a compound has a
poor predicted percentage of drug absorbed, PSA can aid identifi cation of
critical parameters limiting the absorption or bioavailability of a drug.
Once the limiting factors are known, it may be possible to devise methods
to overcome these limitations (e.g. reduction of drug particle size,
addition of solubilizers, co-solvents, permeability enhancers, use of
different salt forms). In this way, researchers can save a great deal of time
and effort, and minimize loss of resources in (pre)formulation processes.
In the previously described case of GLK, PSA was performed to assess
the effect of the selected formulation parameters (i.e. effective particle
radius, drug particle density), and certain drug physicochemical properties
(i.e. solubility and permeability) on the predicted rate and extent of GLK
absorption. The selected parameters were varied in the range covering
one-tenth to ten-fold actual input parameter value, except for the human
effective permeability, which was varied from one-half to two-fold input
value. The results are presented in Figure 6.7.
According to the PSA outcomes, the percentage of GLK absorbed (F
a
)
would not be signifi cantly infl uenced by variations in drug particle density
and effective particle radius. The PSA for solubility showed that even a
10-fold decrease in solubility would not cause bioavailability problems
(F
a
>85%) (Figure 6.7a). However, it was demonstrated that larger
particles, higher density and/or lower solubility values than the ones
used for simulation would decrease the rate of GLK absorption
(Figure 6.7c). The results also indicated that variations in the input
effective permeability did not signifi cantly affect the drug absorption
profi le.
Other examples describe the use of PSA to investigate the effects
of different input parameters on GastroPlus™ predicted drug PK
performance. In our CBZ study (Kovacevic et al., 2009), PSA was used to
assess the importance of the selected input parameters (i.e. drug solubility,
dose, effective particle radius, and drug particle density) in predicting the
percentage of CBZ absorbed. The selected parameters were varied in the
range from one-tenth to ten-fold actual input parameter value. According
to the results, the extent of drug absorption was rather insensitive to the
variation in the input parameters tested. PSA for drug solubility indicated
that complete absorption (F
a
>85%) could be achieved with CBZ
solubility 2.5 times lower than the initially used input value (0.05 mg/mL
in comparison to 0.12 mg/mL), signifying that eventual CBZ
transformation to less soluble polymorph would not cause bioavailability
problems. PSA for particle radius revealed that high bioavailability would
be achieved with CBZ particle sizes up to 90 µm (25 µm was used as the
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