Enhancing the Physicochemical Properties of Trimethoprim through Complexation with Sulfathiazole

Small-molecule drug candidates often encounter challenges related to physicochemical properties, such as poor solubility and stability. Modifying the crystal form of these compounds is a promising approach to overcoming these challenges. Herein, trimethoprim (TMP), a biopharmaceutics classification system (BCS) class II drug with low water solubility, and sulfathiazole (STZ), a polymorphic sulfa drug, were selected as model active pharmaceutical ingredients. A TMP-STZ complex was prepared using liquid-assisted grinding, yielding anhydrous and ethanol-solvated forms. Physicochemical analyses confirmed that the complexes formed stable salt crystals, reducing hygroscopicity and improving thermal stability. An ethanol solvate demonstrated enhanced stability but exhibited a decreased melting point due to desolvation. Single-crystal structure analysis revealed strong hydrogen-bonding interactions between TMP and STZ, contributing to the stability of the crystal. Structural analysis confirmed proton transfer between TMP and STZ, forming a stable salt. Reduced hygroscopicity and improved thermal stability indicate enhanced solid-state robustness of TMP. These results provide a structural basis for controlling the solid-state stability of TMP by salt formation.