Dimer Persistence, Packing Adaptation, and Structural Choices in Solvated Rifaximin

Rifaximin solvates, obtained via cocrystallization with five glycols and four glycol ethers, display six distinct packing types (PT-I–VI), as revealed by single-crystal and powder X-ray diffraction (PXRD). Five of these packing types are unprecedented, extending the structural landscape of rifaximin well beyond the hydrated forms known to date. While the canonical rifaximin dimer, stabilized by amide···amide and water-mediated hydrogen bonds, predominates, alternative arrangements arise when solvent molecules participate in hydrogen bonding. The glycol or glycol ether stoichiometry, together with the preparation method of choice (grinding, slurry, solution), governs the crystallization outcome: low solvent content yields PT-II, whereas higher amounts favor PT-I, anhydrous PT-III, or, in specific cases, unique architectures (PT-IV, V, and VI). These findings highlight the balance between intrinsic supramolecular preferences and structural adaptability to solvent inclusion, providing a rational basis for the design of novel solvated forms.