Indirect effects of pH on drug solubility in fed state simulated intestinal fluids

The pH-mediated effect of drug ionization on solubility is well-described. However, pH can also indirectly influence solubility by altering the colloidal structures in human intestinal fluids. This study investigates the indirect pH effect on the apparent solubility of 13 uncharged drugs across a pH range of 4.5 to 7.5 in fed-state simulated intestinal fluids (SIF) composed of taurocholate and lecithin, with or without added lipids (monoolein and/or sodium oleate). A pronounced indirect pH effect on drug solubility was observed when oleate was present in the SIF, whereas monoolein had only a minor effect. Below pH 6.5, sodium oleate was converted to oleic acid, resulting in lipid droplet formation that enhanced lipophilic compound solubility in the total sample (lipid phase + micellar phase), while the micellar solubility remained similar to the reference SIF (without oleate). This resulted in an up to 50-fold increase of the ratio total/micellar drug solubility, which correlated well with drug lipophilicity or its combination with total polar surface area (R² ≈ 0.8). At higher pH, a lipid phase was not formed because the ionized sodium oleate partitioned in the micellar phase, where it significantly increased drug solubilization. These findings highlight the importance of considering indirect pH effects in solubility assessments by tuning simulated intestinal fluids composition to better reflect in vivo reality.