Salts and Cocrystals of Furosemide with Pyridines: Differences in π-Stacking and Color Polymorphism

Furosemide (FS), a loop diuretic drug, exhibits polymorphism not only in pure entity, but also in cocrystal/salt forms. In continuation of our previous report of color cocrystals polymorphism of FS and 4,4'-bipyridine (4BPY), FS was further screened for color cocrystals by cocrystallization with other pyridines using a slow evaporative solution crystallization method. Interestingly, 2:1 molecular salt of FS and 1,2-bis(4-pyridyl)ethylene (4BPE) displayed color polymorphism in isopropanol yielding an orange (form 1I, plates) and the yellow (form 1II, blocks) crystals concomitantly. The yield of orange crystals, which appeared within 10-15 h, has always been more compared to the later formed yellow crystals, thus signifying the preference for orange crystals. The cocrystallization experiment once also yielded a yellow-colored 2:3 molecular salt (form 1III); however these crystals could not be reproduced later. Further, cocrystallization of FS and 4BPE from THF, dioxane, and their mixture produced comparatively unstable solvates, form 1IV, form 1V, and form 1VI crystals, respectively. Cocrystallization of FS with other pyridines like 1,2 bis(4-pyridyl)ethane (4BPA), 1,2 bis(4-pyridyl)propane (4BPP), 1,2 bis(2-pyridyl)ethylene (2BPE), and 1,10-phenanthroline (Phen) also gave colorless molecular salts 2, 4 and cocrystals 3 and 5 respectively. The single crystal structure analysis revealed the formation of a common sandwich motif between FS and pyridines through varying geometry p-stacking interactions in all the crystals. The significant color difference between the polymorphs could be attributed to the different levels of conjugation generated by dissimilar pi-stacking patterns between the two components. Investigation on the origin of the color difference using density functional theory calculations revealed the decrease in the highest occupied molecular orbital-lowest unoccupied molecular orbital gap for orange crystals compared to yellow crystals.