Furosemide Cocrystals with Pyridines: An Interesting Case of Color Cocrystal Polymorphism

Furosemide (FS), a loop diuretic
drug commonly used for the treatment
of hypertension and edema, exhibited color cocrystal polymorphism
with coformer 4,4′-bipyridine (4BPY) in the stoichiometry 2:1,
albeit both the API and the cocrystal former are colorless. Crystallization
from ethanol, isopropanol, ethanol–water (v/v, 1/1) mixture,
and acetonitrile yielded pale yellow (form 1I, thin needles)
and orange (form 1II, blocks) cocrystals concomitantly.
Needles appeared from solution within a day, while the blocks were
obtained after 1–2 days from the same flask, indicating that
yellow needles were formed faster and the orange blocks were perhaps
formed under thermodynamic conditions. Form 1I cocrystals
could also be produced from the variety of common solvents. Cocrystallization
of FS with 2,2′-bipyridine (2BPY) and 4-aminopyridine (4AP)
gave colorless cocrystals 2 and 3, respectively,
and did not exhibit polymorphism. The single-crystal X-ray structures,
powder X-ray diffraction, photophysical characterization, differential
scanning calorimetry, hot stage microscopy studies, and density functional
theory (DFT) calculations provide insight into the structure–property
relationship. The common structural features observed in all of the
structures is the formation of sandwich motifs comprising FS and pyridines
through π-stacking interactions. These motifs are linked differently
through hydrogen bonding interactions in all three directions. The
significant color difference between the two cocrystals dimorphs could
be attributed to the different π-stacking patterns and hydrogen
bonding interactions between molecules of FS and 4BPY in their cocrystal
structures. Investigation on the origin of the color difference using
DFT calculations revealed the decrease in HOMO–LUMO gap for
form 1II cocrystals (orange) compared to form 1I crystals (light yellow). The crystal-to-crystal thermal transformation
of form 1I crystals to form 1II crystals
of 1 suggests the role of π-stacking assemblies
in driving the self-assembly.