To increase the understanding of how drugs behave following oral administration to the pediatric population, the aim of the present study was to investigate the solubilization of fluconazole and ibuprofen during simulated gastro-intestinal (GI) digestion, using an immediate transfer model mimicking pediatric GI digestion. The effects of infant formula and digestion, on the drug solubilization, were studied using simulated fasted and fed state digestion media in the presence and absence of digestive enzymes. Additionally, the effect of digestion media viscosity on the solubilization process was investigated. It was found that the solubilization of fluconazole was unaffected by all tested parameters, as the entire estimated dose equivalent was solubilized in the aqueous phase throughout all digestion studies. In contrast, the solubilization of ibuprofen was affected by all the tested parameters, i.e. in the fasted state, the solubilization of ibuprofen was limited by its solubility in the aqueous phase of the simulated GI digestion media, whereas the solubilization in the fed state was affected by drug partitioning between the lipid and the aqueous phases, and therefore by the digestion of the lipid phase. Adding Nestlé Thicken Up™, containing xanthan gum as a thickening agent, to the digestion medium increased its viscosity, which in turn resulted in a reduced initial digestion rate, increased pH fluctuations, as well as high variability in all drug solubilization data as evident in large standard deviations. Furthermore, the increased digestion medium viscosity decreased the drug recovery from the combined pellet and aqueous phase. The observed viscosity effects might translate into a more variable and lower oral bioavailability.