title: Photosensitized degradation of losartan potassium in an extemporaneous suspension formulation.
abstract: During development of an extemporaneous suspension formulation for losartan potassium, previously unknown degradation products were observed in experimental suspensions prepared in a commercial cherry syrup vehicle. These degradates increased rapidly when analytical solutions prepared from that suspension were exposed to ambient light. The structures of the degradates were determined using a combination of preparative HPLC, LC/MS, (13)C and (1)H NMR (1D and 2D), and mechanistic chemistry. Each degradate results from destruction of the imidazole ring of losartan. Formation of the two major degradates required exposure to light (UV or visible) and the presence of oxygen. Experiments using Rose Bengal (a singlet oxygen photosensitizer) and 1,4-diazabicyclooctane (DABCO; a singlet oxygen quencher) established that the major photodegradates are formed via the intermediacy of singlet oxygen. The identity of the photosensitizer in the formulation was not unequivocally determined; however, the experiments implicated the artificial flavoring in fulfilling this role.
authors.affiliation: Pharmaceutical Research & Development, Merck Research Laboratories, P.O. Box 4, West Point, PA 19846, USA. randal.seburg@cimalabs.com
authors.forename: Randal A
authors.initials: RA
authors.lastname: Seburg
authors.forename: John M
authors.initials: JM
authors.lastname: Ballard
authors.forename: Tsang-Lin
authors.initials: TL
authors.lastname: Hwang
authors.forename: Caitlin M
authors.initials: CM
authors.lastname: Sullivan
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry / Q000528:radiation effects*; D005421:Flavoring Agents / Q000737:chemistry / Q000528:radiation effects*; D007202:Indicators and Reagents; D008027:Light; D019808:Losartan / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008956:Models, Chemical; D010084:Oxidation-Reduction; D010782:Photolysis; D010879:Piperazines; D012395:Rose Bengal; D026082:Singlet Oxygen / Q000737:chemistry; D013535:Suspensions
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D005079:Excipients; D005421:Flavoring Agents; D007202:Indicators and Reagents; D010879:Piperazines; D013535:Suspensions; D026082:Singlet Oxygen; D012395:Rose Bengal; D019808:Losartan; C007306:triethylenediamine