Design, synthesis and analysis of multicomponent crystals of furosemide

Abstract

Furosemide (4-chloro-2-[(2-furanylmethyl)-amino]-5-sulfamoylbenzoic acid, FUR) was used to form multicomponent crystals with pyridine and its derivatives. Five multicomponent crystals of FUR were formed with pyridine (FURPYRw), 3-methyl pyridine or 3-picoline (FUR3PIC), 4-methyl pyridine or 4-picoline (FUR4PIC), 2,3-dimethyl pyridine or 2,3-lutidine (FUR23LUT), and 2,4-dimethyl pyridine or 2,4-lutidine (FUR24LUTw) via slow evaporation crystallisation method. The crystals were analysed by single-crystal X-ray diffraction, and the drug:coformer ratios were found to be 1:1 in all five multicomponent crystals. Thermogravimetry was used to verify the solvent content of the crystals, and the results of the infrared analysis supported the protonation state of the components observed in the single-crystal structures. Differential scanning calorimetry was used to follow the behaviour of the crystals under a temperature program. Powder X-ray analysis of the bulk showed that the single crystal of FUR3PIC and FURPYRw are good representations of the bulk material, while for the structures FUR4PIC, FUR23LUT and FUR24LUTw, the bulk is different, and this is very likely the result of the rapid desolvation of the material. The five multicomponent crystals were desolvated at ambient temperature and pressure to produce polymorphs of FUR in their pure forms. The crystals of FUR3PIC showed excellent stability over at least six months under ambient conditions, and no disintegration of the crystals were observed. The desolvation of FUR4PIC resulted in the physical mixture of forms I and III, while desolvation of crystals of FUR23LUT, FUR24LUTw, and FURPYRw resulted in three new solid forms. The complete identification of these new forms is a challenging task and will form the basis of another project.