Isolation of a 2:1 hydrochlorothiazide-formaldehyde adduct impurity in hydrochlorothiazide drug substance by preparative chromatography and characterization by electrospray ionization LC-MS.

摘要: Abstract Hydrochlorothiazide drug substance (19 lots) from five different manufacturers and four countries of origin (USA, Italy, Hungary, Croatia) were analyzed for the presence impurities using a gradient elution chromatographic system, with acetonitrile–water as mobile phase. Two known hydrochlorothiazide, 4-amino-6-chloro-1,3-benzenedisulfonamide chlorothiazide, separated, well late-eluting, unknown, recurring impurity. The unknown impurity was isolated by preparative liquid chromatography followed thin-layer chromatography. It characterized electrospray ionization LC–MS 2:1 hydrochlorothiazide–formaldehyde adduct parent substance. is believed to form through double condensation reaction hydrochlorothiazide excess formaldehyde during compound's synthesis. concentration this ranged 0.02 1.1% (area%), above 0.1% USP Other Impurities threshold in 16 19 lots examined.