Novel furosemide cocrystals and selection of high solubility drug forms

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 13C solid-state NMR spectroscopy. Furosemidecaffeine was characterized as a neutral cocrystal and furosemidecytosine an ionic salt by single crystal x-ray diffraction. The stability of furosemidecaffeine, furosemideadenine, and furosemidecytosine was comparable to the reference drug in 10% ethanolwater 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 furosemidecytosine > furosemideadenine > furosemidecaffeine, 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. (C) 2011 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:664680, 2012