An Antibacterial “Drug–Drug” Cocrystal of Trimethoprim with Sulfathiazole Achieving Synchronized Dual-Drug Release and Pharmacokinetics

Achieving synchronized release and absorption of multiple active pharmaceutical ingredients with disparate properties has long been a critical challenge in the development of combination formulations. Multidrug cocrystals offer a promising strategy to address this issue. As a classic antibacterial combination, trimethoprim (TMP) and sulfathiazole (STZ) are widely used in conventional therapy. This study reports a drug–drug cocrystal composed of the two ingredients. The TMP-STZ cocrystal was characterized by SCXRD, PXRD, DSC-TG, and IR spectroscopy. Furthermore, its hygroscopicity, solubility, dissolution, and in vivo pharmacokinetics were systematically evaluated. The results demonstrate that the pronounced initial solubility difference between TMP and STZ was effectively balanced through cocrystallization, leading to consistent dissolution rates. These in vitro modifications enabled synchronized and enhanced pharmacokinetic profiles for the two drugs in vivo. The 110 min TMAX gap between TMP and STZ was eliminated (shifting from 50/160 min in the mixture to a unified 90 min in the cocrystal). These results represent a significant advancement in the application of crystal engineering to pharmacological outcomes and greatly facilitate the exploration of novel antibacterial cocrystal formulations.