Dissolution Limited

Dissolution rate is proportional to solubility and inversely proportional to the square of the particle radius. To enhance bioavailability, one must either reduce particle size or increase the solubility (note that increasing solubility effects both Dn and Do). As Dn becomes greater than 10, the enhancement of Fabs due to particle size reduction decreases. One can deduce this from the contour plots in Figure 5 as the contour lines begin to run parallel to the Dn-axes at or about Dn = 10. Note that this occurs in each of the plots, and so this phenomenon is independent of the permeability. The physical interpretation of Dn > 10 is that the time to complete dissolution is at least ten-fold less than the intestinal transit time.

From a formulation perspective, it is of benefit for particle size not to be a major determinant of bioavailability in order to get consistent exposure between lots of material. During lead optimization, often one has only one batch of material to evaluate, but dosing decisions for further ADME-Tox studies are often

Low P

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