Mechanistic Insights and Dissolution Enhancement of Sulindac with Ionic Interaction through an In Situ Coamorphization Strategy

Sulindac (SUL) is a nonsteroidal anti-inflammatory drug, but its low water solubility limits its oral absorption and therapeutic application. With the in-depth study of an amorphization strategy, in situ amorphization has gained attention due to its advantages of good solubilization effect, green process, and no stability issue. In this study, an integration of theory-model-experimental techniques was used to design the in situ coamorphization combination of SUL by introducing small molecule ligands (i.e., l-lysine, l-arginine, and meglumine), and such an in situ coamorphization mechanism was investigated under a humidity-mediated environment. The study found that SUL-ligand combinations gradually underwent in situ coamorphization upon contact with aqueous media, which was influenced by molar ratios of the components, environmental temperatures, and pH values of the aqueous media. Meanwhile, compared with crystalline SUL, three combinations showed a 288.3–308.5 times increase in apparent solubility as well as a 4222.2–4944.4 times improvement in dissolution rate. Furthermore, the phase solubility test and nucleation inhibition experiment confirmed that the ionic interaction of SUL with ligands enabled long-term supersaturation of SUL during dissolution. Therefore, this study clarified the formation mechanism of in situ coamorphization mediated by water molecules and verified the in situ coamorphous strategy as a promising solubilization approach to optimize the druggability of poorly soluble ingredients.