Furosemide, a high ceiling diuretic, decomposes on heating and is very sparingly soluble in water. The aim of this study was to identify the thermal decomposition product(s) of furosemide and to calculate the activation energy needed for this reaction. This was done to gain a better understanding of the unusually low water solubility of this drug. The main thermal decomposition product was identified by nuclear magnetic resonance (NMR), mass spectrometry (MS), and infrared (IR) analysis as 4-chloro-5-sulfamoylanthranilic acid (saluamine), and the activation energy, calculated from thermogravimetric analysis (TGA) measurements, for this reaction was 47.7 (+/- 1.93) kcal/mol. The experimentally measured activation energy was well below the normal 59 +/- 4 kcal/mol needed for the cleavage of the C-N bond to form saluamine. This could possibly be explained by the weakening of the C-N bond through the I-effect of the furane ring and the delocalization of the electrons of the aniline nitrogen in the chlorosulfamoyl benzoic acid entity of furosemide. This decomposition of furosemide indicates the breaking of intramolecular bonds before those of intermolecular bonds (separation of individual furosemide molecules). Strong inter- and intramolecular bonds are a probable cause for the poor water solubility of furosemide because, when some of the inter- and intramolecular bonds that form part of the hydrogen bond network disappeared, as in the structurally related decomposition product saluamine, the aqueous solubility increased.