The purpose of this study was to investigate the suitability of physicochemical parameters of Active Pharmaceutical Ingredients (APIs) as input functions for the Advanced Compartmental Absorption and Transit Model (ACAT) to predict the oral absorption of drug products. Five different glyburide APIs were characterized using X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Raman spectroscopy, particle size and particle size distribution, specific surface area and true density measurements, as well as dissociation constant (pKa), partition coefficient (log P) and distribution coefficient (log D). The computer simulations were performed using GastroPlus™. The results of XPRD, DSC and Raman spectroscopy indicated that no significant differences in crystal form were present in the five APIs. However, significant differences in particle size and particle size distribution were observed. A basic in vitro/in vivo relationship between the APIs’ particle size and clinically observed plasma time profiles was established. The study demonstrates that in silico methods can assist the formulation scientist to set meaningful API specifications. Computer simulations could shorten the drug development process since appropriate bioawaivers, based on data from simulation studies, may be justified.