Novel Spherical Trimethoprim–Niflumic Acid Drug–Drug Salt Demonstrates Simultaneous Enhancement of Powder Property and Antibacterial Activity

This study aims to prepare a stable crystal-co-agglomeration (CCA) process for combining the antibiotics trimethoprim (TMP) and the anti-inflammatory niflumic acid (NFA) as well as the enhancement of powder properties. A novel TMP–NFA salt monohydrate was synthesized and characterized through multitechniques for the first time. Subsequently, the antibacterial effectiveness of TMP–NFA salt monohydrate against Staphylococcus aureus and Shigella flexneri was found to be improved (P < 0.05) compared with that of TMP at certain concentrations, achieving a synergistic effect of TMP and NFA. Based on these findings, spherical agglomerates of TMP–NFA salt monohydrate with superior powder properties including improved flowability (Carr’s index decreased by 37.5% and Hausner’s ratio decreased by 16.3%) and tabletability were produced using an efficient CCA process. Hence, the optimized spherical agglomerates of the drug–drug salt technique provide a promising approach to simultaneously enhance the powder properties and synergistic effect of active pharmaceutical ingredients. The development of such drug–drug salts holds great potential for advancing pharmaceutical formulations and therapeutic outcomes.