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

Abstract

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 1,10phenanthroline (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 π-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 π-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.

Engineering Cocrystals of Poorly Water-Soluble Drugs to Enhance Dissolution in Aqueous Medium

“…Color polymorphism is another interesting variation of concomitant polymorphism in which cocrystal forms of more than one color appear during crystallization. A few findings (See Section 7.4 ) on colored polymorphism of cocrystal have been reported by Gonnade and coworkers [ 257 , 258 ].…”

“…Several reports are available in the literature where the role of hydrogen bonding in altering physiochemical properties of an API has been reported [ 15 , 95 ]. However, very limited reports are available in the literature where Π…Π stacking interactions were utilized for modulating the physiochemical properties of pharmaceutical cocrystals [ 17 , 257 , 258 ].…”

Color Differences Highlight Concomitant Polymorphism of Chalcones

“…The cause of color variations in polymorphs of cocrystals, when the crystals of the components are colorless, has been rationalized in terms of the different intermolecular interactions between the component molecules in the crystal structures. 33,34 Hence, we report the preparation, crystal structures, relative stability and spectral properties of two pairs of polymorphs of chalcone isomers, and a limited polymorph screen. This experimental characterization is used to assess current methods of modelling organic polymorphs of two molecules whose charge distributions are very similar (Figure 1).…”

Solvation-Enhanced Intermolecular Charge Transfer Interaction in Organic Cocrystals: Enlarged C–C Surface Close Contact in Mixed Packing between PTZ and TCNB

“…The weak intermolecular interactions of noncovalent bonds are important driving forces to assemble the organic cocrystals with two or more competent molecules and/or ionic compounds, 1−4 for instance, π–π stacking, 5−7 halogen bonds, 8,9 hydrogen bonds, 10,11 and charge transfer (CT). 12,13 Methods based on the tuning of intermolecular interaction for organic cocrystals are advantageous in regulating the structure, simplifying operation, and reducing cost.…”