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

Abstract

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 πstacking 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.

Supramolecular synthon hierarchy in sulfonamide cocrystals with syn-amides and N-oxides

“…FUROS has two strong hydrogen-bonding functional groups (COOH and SO 2 NH 2 ) for crystal engineering. Binary cocrystals of FUROS with acetamide, picolinamide, nicotinamide, isonicotinamide, anthranilamide, toluamide, isoniazid, piperazine, tetramethylpyrazine, pyrazine, picolinic acid, p-aminobenzoic acid, caffeine, urea, theophylline, adenine, cytosine, bipyridines, amino pyridines, pentoxifylline and pyridine N-oxides have been reported (Goud et al, 2012;Harriss et al, 2014;Sangtani et al, 2015;Banik et al, 2016;Stepanovs & Mishnev, 2012).…”

Pharmaceutical solvates, hydrates and amorphous forms: A special emphasis on cocrystals

“…A more challenging aspect is to quantify nanocrystals in an amorphous material. Scherrer broadening (broadening of the diffraction peaks due to a reduction in crystallite size) may reduce the diffracted intensity for a crystalline material such that it becomes [205] √ (ATR) √ √ √ Nitrofurantoin cocrystal solvate, hydrates, salts [206] √ √ √ √ √ Nitrofurantoin cocrystal hydrate [126] √ √ √ √ √ Caffeine cocrystal polymorph, hydrate and solvates [116] √ [207] √ √ √ √ Salicylic acid cocrystal polymorphs [118] √ √ Felodipine cocrystal polymorph [115] √ √ √ Benzoic acid cocrystal polymorph [208] √ √ √ Glycine cocrystal polymorph [166] √ √ Vanillic acid cocrystal hydrate [125] √ √ √ √ Agomelatin cocrystal polymorph [209] √ √ √ √ Diclofenac cocrystal polymorph hydrate [104] √ √ (VT) √ √ Nicotinamide cocrystal polymorph [210] √ √ √ √ √ Phenazine cocrystal polymorph and solvate [105] √…”

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

“…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 ].…”

“…Sangtani et al [ 257 ] observed concomitant color polymorphism in Furosemide-4,4′-bipyridine (2:1) cocrystals (Forms I and II). Form I cocrystal appeared as pale yellow needles whereas form II cocrystal appeared as orange blocks [ 257 ]. Form I cocrystal was observed to crystallize at faster rate and with higher yield than the form II cocrystal.…”

“…Form I cocrystal was observed to crystallize at faster rate and with higher yield than the form II cocrystal. The authors proposed that the color polymorphism in furosemide-4,4′-bipyridine (2:1) cocrystals can be attributed to the difference in Π…Π * separation (as shown in Figure 20 ) between the benzene ring of furosemide and pyridine ring of 4,4′-bipyridine in the sandwich motifs of form I and form II cocrystals [ 257 ]. This was further supported by Dynamic Functional Theory (DFT) calculations.…”