New findings on degradation of famotidine under basic conditions: identification of a hitherto unknown degradation product and the condition for obtaining the propionamide intermediate in pure form.
The degradation behavior of famotidine (1) was investigated in 25% ammonia solution and in 2 M NaOH. The hydrolysis of the drug in ammonia resulted in separation of [3-[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propionamide (3), an impurity listed in British Pharmacopoeia. The treatment with 2 M NaOH resulted in formation of [3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propionyl]sulfamide (2) and 3. These products further decomposed to [3-[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propionic acid (4) and a heretofore unknown product, 5. The latter separated out in the reaction mixture as brown shiny crystals. Proton and carbon-13 nuclear magnetic resonance spectroscopy, mass spectrometry, and elemental analysis of the charcoal-treated product established the structure. The formation of 5 is postulated to involve abstraction of a proton from the alpha-carbon of intermediates 2 and 3 followed by elimination of the thiol moiety.
Singh
Saranjit
S
National Institute of Pharmaceutical Education and Research, Sector 67, S. A.S. Nagar, 160 062 India. niper@chd.nic.in
Kumar
Sanjeev
S
Sharda
Nishi
N
Chakraborti
Asit K
AK
D000577:Amides / Q000737:chemistry / Q000302:isolation & purification* / Q000378:metabolism; D002855:Chromatography, Thin Layer / Q000379:methods; D004355:Drug Stability; D015738:Famotidine / Q000737:chemistry* / Q000378:metabolism; D006635:Histamine H2 Antagonists / Q000737:chemistry / Q000378:metabolism; D006868:Hydrolysis
D000577:Amides; D006635:Histamine H2 Antagonists; D015738:Famotidine; C034666:propionamide