Epimer-Dependent Solid-State Landscapes of Trospium and Exotrospium Halide Salts

Abstract

Trospium (TR) and exotrospium (ETR) form a closely related epimeric pair of quaternary ammonium compounds, differing only in the stereochemistry of the tropane ring system. While the solid-state chemistry of trospium has been studied mainly for its chloride salt, no crystal structures of exotrospium salts have previously been reported. Here, we investigate the epimer-dependent solid-state landscapes of TR and ETR across the halide series, using matched salt forms to distinguish the effects of counterion selection from those of stereochemical inversion. Two new TR salts and three new ETR salts were prepared and structurally characterized by single-crystal X-ray diffraction, supported by crystal-packing comparison, hydrogen-bond propensity analysis, lattice-energy calculations, morphology prediction, and CSD-Particle surface analysis. Despite their close molecular similarity, TR and ETR display markedly different solid-state behavior. TR forms anhydrous chloride, bromide, and iodide salts stabilized by direct charge-assisted O–H···halide interactions, whereas ETR forms isostructural chloride and bromide dihydrates, with only the iodide obtained as an anhydrate. These differences are reflected in molecular conformation, crystal packing, hydration behavior, predicted crystal habit, and surface descriptors. The results show that epimerization can substantially alter both bulk and surface features of pharmaceutical molecular salts and demonstrate the value of combining structural comparison with particle-level descriptors when evaluating related solid forms.