title: Novel furosemide cocrystals and selection of high solubility drug forms.
abstract: Furosemide was screened in cocrystallization experiments with pharmaceutically acceptable coformer molecules to discover cocrystals of improved physicochemical properties, that is high solubility and good stability. Eight novel equimolar cocrystals of furosemide were obtained by liquid-assisted grinding with (i) caffeine, (ii) urea, (iii) p-aminobenzoic acid, (iv) acetamide, (v) nicotinamide, (vi) isonicotinamide, (vii) adenine, and (viii) cytosine. The product crystalline phases were characterized by powder x-ray diffraction, differential scanning calorimetry, infrared, Raman, near IR, and (13) C solid-state NMR spectroscopy. Furosemide-caffeine was characterized as a neutral cocrystal and furosemide-cytosine an ionic salt by single crystal x-ray diffraction. The stability of furosemide-caffeine, furosemide-adenine, and furosemide-cytosine was comparable to the reference drug in 10% ethanol-water slurry; there was no evidence of dissociation of the cocrystal to furosemide for up to 48 h. The other five cocrystals transformed to furosemide within 24 h. The solubility order for the stable forms is furosemide-cytosine > furosemide-adenine > furosemide-caffeine, and their solubilities are approximately 11-, 7-, and 6-fold higher than furosemide. The dissolution rates of furosemide cocrystals were about two times faster than the pure drug. Three novel furosemide compounds of higher solubility and good phase stability were identified in a solid form screen.
authors.affiliation: School of Chemistry, University of Hyderabad, Prof. C.R. Rao Road, Central University PO, Gachibowli, Hyderabad 500 046, India.
authors.forename: N Rajesh
authors.initials: NR
authors.lastname: Goud
authors.forename: Swarupa
authors.initials: S
authors.lastname: Gangavaram
authors.forename: Kuthuru
authors.initials: K
authors.lastname: Suresh
authors.forename: Sharmistha
authors.initials: S
authors.lastname: Pal
authors.forename: Sulur G
authors.initials: SG
authors.lastname: Manjunatha
authors.forename: Sudhir
authors.initials: S
authors.lastname: Nambiar
authors.forename: Ashwini
authors.initials: A
authors.lastname: Nangia
mesh_terms: D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D005665:Furosemide / Q000737:chemistry*; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D033362:Powder Diffraction; D012995:Solubility; D013055:Spectrophotometry, Infrared; D013059:Spectrum Analysis, Raman
chemical_list: D004364:Pharmaceutical Preparations; D005665:Furosemide