Understanding the effect of API properties on bioavailability through absorption modeling

Abstract

Selection of API phase is one of the first decision points in the formulation development process. Subsequent to phase selection, the focus shifts to the API physical properties such as particle size. Oftentimes, such properties are closely monitored throughout the drug development, as they can have a direct impact on the formulation bioperformance. The purpose of this mini-review was to describe the potential for application of absorption modeling in understanding the effect of API properties on bioavailability. Examples are provided to demonstrate how absorption modeling can be applied both early on to set the formulation strategy as well as during the development process to help with setting of specifications around the API. Limitations of the existing models and areas of possible expansion of such tools are also discussed.

Fig. 1

Dissolution and absorption curves and parameter sensitivity analysis for a 50-mg dose of BCS class II compound A

Fig. 2

Comparison of predicted absorption rates (a) and regional distribution of absorption (b) for the free base and the salt of compound A

Fig. 3

Model predicted dissolution (a) and absorption (b) for the initial formulation and the new polymorph of compound B under different stomach pH values

Fig. 4

Effect of particle size on exposures for compound C following administration of a 3-mg tablet formulation to male beagle dogs (mean ± SD, n = 3). Absorption model predicted exposures are also shown

Fig. 5

Fraction absorbed for compound C as a function of dose and particle size

Fig. 6

Parameter sensitivity analysis for human fraction absorbed for aprepitant

Fig. 7

Observed and model predicted exposures for aprepitant following suspension administration to male beagle dogs at a dose of 2 mg/kg

Fig. 8

3D parameter sensitivity analysis for compound D assessing the effect of dose and API density on fraction absorbed