Exploring desolvation-driven polymorph formation via multicomponent crystals of furosemide

Abstract

A controlled two-step approach for generating furosemide polymorphs through multicomponent crystal formation followed by desolvation was investigated. Furosemide was crystallised with five pyridine derivatives—pyridine (FUR·PYRw), 3-picoline (FUR·3PIC), 4-picoline (FUR·4PIC), 2,3-lutidine (FUR·23LUT), and 2,4-lutidine (FUR·24LUTw)—using slow evaporation and liquid-assisted grinding methods. Single-crystal X-ray diffraction analysis revealed 1 : 1 drug : coformer stoichiometry in all structures, while infrared spectroscopy confirmed the protonation states. Thermogravimetric analysis revealed solvent content and additional water inclusion in the pyridine and 2,4-lutidine crystals, while thermal behaviour was monitored using differential scanning calorimetry. Powder X-ray diffraction indicated that FUR·3PIC, FUR·PYRw and FUR·23LUT single crystals represent the bulk crystallisation batch, whereas crystals of FUR·4PIC and FUR·24LUTw showed differences with the bulk. The five multicomponent crystals were desolvated at ambient temperature and pressure for at least six months, then dried over silica gel desiccant for another two months. FUR·3PIC crystals showed excellent stability over eight months, and no changes in the crystal structure were observed. The desolvation of FUR·4PIC resulted in the physical mixture of known furosemide polymorphs, while the desolvation of crystals of FUR·23LUT, FUR·24LUTw, and FUR·PYRw resulted in three new solid forms, which must still be fully characterised.