Background/Objectives: Recent studies have shown that the solubilisation of poorly water-soluble drugs can be enhanced by using infant formula as a lipid-based formulation. In those studies, digestion of the triglycerides in infant formula to produce more polar lipids, namely fatty acids and monoglycerides, produced a high-capacity solubilisation environment for weakly basic drugs such as clofazimine, driven mainly by ion-pairing of the fatty acid with the drug. However, digestion of lipid-based formulations is not expected to provide the same effect for nonionised or acidic drugs and in fact may present a reduced solubilisation capacity for weakly acidic drugs. Methods: In this study, a weakly acidic drug, tolfenamic acid, was dispersed in reconstituted infant formula, and the infant formula was digested under in vitro simulated intestinal conditions. The quantity of tolfenamic acid that was solubilised in the infant formula during digestion was determined by high-performance liquid chromatography and small-angle X-ray scattering. Results: Unexpectedly, digestion of the infant formula increased the solubilisation capacity for tolfenamic acid. Reconstituting infant formula at a higher fat content also increased the rate and extent of solubilisation of tolfenamic acid during digestion. The quantity of tolfenamic acid that was solubilised during digestion correlated approximately linearly with the quantity of free fatty acids produced during digestion. Conclusions: These results show that a weakly acidic drug can also exhibit digestion-driven solubilisation in a lipid-based formulation in the absence of ion-pairing and highlights the need to better understand drug response to digestion of lipid-based foods and formulations, and their versatility as a formulation option even for poorly water-soluble acidic drugs.
Eason et al. (Tue,) studied this question.