High P

Very High P

Figure 5. Contour plots of fraction absorbed (Fabs) for An equal to (a) 0.6, (b) 1.3, (c) 8.5 and (d) 20 representing low, moderate, high and very high permeability compounds respectively. Plots are to be used to estimate the location of an unknown compound in the biopharmaceutics landscape.

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co Cd

CO CL

TS 10

Figure 6. Particle size as a function of solubility for Dn > 10 (shaded region) such that dissolution plays a minor role in influencing bioavailability.

made with the assumption that subsequent batches of material will perform equivalently to the initial batch. One way to help assure this is to have particle size small enough such that Dn > 10. Figure 6 shows the particle size limit necessary to have Dn > 10 as a function of solubility, with the shaded region being desirable.

It is important to note that it is the effective particle size that dictates the dissolution rate. If the primary particles are very small, yet they form large aggregates in suspension, it will be the aggregate size that controls dissolution. In practice, one can sonicate the suspension to help break up aggregates. Also, if dosed as a solid (e.g., powder in a capsule), dispersion of the particles becomes an important step in the dissolution process.

If the effective particle size is small enough that dissolution is not at all rate-limiting, then fraction absorbed may be estimated from the contour plot in Figure 7, where Fabs is calculated as a function of dose number Do and absorption number An. The solubility-limited region is the upper portion of the plot where Fabs is < 0.9 and the permeability-limited region is the lower left-hand corner where the Fabs contours become parallel to the Do-axis.

Figure 7. Contour plot of fraction absorbed (Fabs) as a function of dose number (Do) and absorption number (An) if dissolution plays no role in influencing bioavailability.
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