PHARMACEUTICAL APPLICATION OF LC-MS .1. CHARACTERIZATION OF A FAMOTIDINE DEGRADATE IN A PACKAGE SCREENING STUDY BY LC-APCI MS

The application of LC-MS to characterize low-level degradates in pharmaceutical dosage formulations is a new and challenging field. In a package screening study, a low-level degradate of famotidine (1, 3-[[[2-[[aminoiminomethyl]-amino]-4-thiazolyl]methyl]thio]-N-(aminosulphonyl)-propanimid-amide, an H-2-receptor antagonist, molecular weight: 337) was detected by HPLC in film-coated tablets packaged in child-resistant (CR) foil pouches which were stressed at 40-degrees-C/75% relative humidities (RH) for 4 months. LC-atmospheric pressure chemical ionization (APCI) mass spectrometry using positive ion mode yielded a molecular weight of 349 for the degradate, suggesting that it was formed by the addition of one carbon to the famotidine molecule. A detailed analysis of the positive product ion mass spectrum of the protonated degradate ion in a LC-MS-MS study indicated that the carbon was added to the side of N-(aminosulphonyl)-propanimid-amide of famotidine. The structure of the degradate was determined to be 2, which was confirmed by LC-APCI MS and HPLC study of the product formed from the reaction of famotidine with formaldehyde - a one-carbon reagent.