Co-amorphization Story of Furosemide-Amino Acid Systems: Protonation and Aromatic Stacking Insights for Promoting Compatibility and Stability

Furosemide (FUR) is usually used to treat congestive heart failure and edema. Although bioavailability problems exist due to its poor solubility and unstable gastrointestinal absorption, preparing FUR/amino acid (AA) co-amorphous systems is regarded as a promising way to solve this problem. In this work, the oscillating ball milling method was successfully used to prepare the co-amorphous systems of FUR with l-cysteine, l-phenylalanine (PHE), l-arginine, l-tryptophan (TRP), and l-valine. Protonation of the secondary amino group (N2) in FUR probably results in interactions with the AA carboxyl group, which lead to excellent compatibility between FUR and AAs. The co-amorphous systems formed between FUR and PHE/TRP possess higher physical stability than other FUR/AA co-amorphous systems, which may be attributed to favorable aromatic stacking in FUR/PHE and FUR/TRP systems. Additional experiments were performed to explore the impact of co-former loadings on the stability of co-amorphous systems, which revealed that the co-amorphous systems are most stable when the molar ratios are at 0.527 and 0.423 for FUR in FUR/PHE and FUR/TRP systems, respectively. Finally, powder dissolution tests of the FUR/PHE and FUR/TRP co-amorphous systems were carried out, and the results demonstrated that the selected most stable co-amorphous systems have excellent dissolution advantage with a two-fold improvement of dissolution rate compared to pure FUR.