Mechanism and kinetics of metal ion-mediated degradation of fosinopril sodium.
Fosinopril sodium (I), a new angiotensin converting enzyme inhibitor, is a diester prodrug of the active moiety II. We report here a novel transformation of fosinopril into beta-ketoamide, III, and a phosphonic acid, IV, mediated through metal ion participation. The interaction of fosinopril with magnesium ions was studied in a solution model system in which methanol was used as the solvent and magnesium acetate as the source of metal ions. Kinetic analysis indicated the degradation to be a bimolecular process, with the rate being first order in both metal ion and fosinopril concentration. The degradation products II, III, and IV effectively retarded the magnesium ion mediated reaction of fosinopril. Based on the results of 31P-NMR, 1H-NMR, Mn(II)-EPR spectroscopy experiments and mass spectrometry, a mechanism is postulated for this transformation. A key reactive intermediate has been characterized that supports the proposed mechanism. The results can account for the observed degradation profile of the fosinopril sodium in a prototype tablet formulation.
Bristol-Myers Squibb Pharmaceutical Research Institute, New Brunswick, New Jersey 08903.
A B
AB
Thakur
K
K
Morris
J A
JA
Grosso
K
K
Himes
J K
JK
Thottathil
R L
RL
Jerzewski
D A
DA
Wadke
J T
JT
Carstensen
D004578:Electron Spin Resonance Spectroscopy; D017328:Fosinopril / Q000737:chemistry*; D006868:Hydrolysis; D007700:Kinetics; D008274:Magnesium / Q000737:chemistry*; D013058:Mass Spectrometry; D000432:Methanol / Q000737:chemistry; D008958:Models, Molecular; D010759:Phosphorus Isotopes; D012997:Solvents; D013607:Tablets
D010759:Phosphorus Isotopes; D012997:Solvents; D013607:Tablets; D008274:Magnesium; D017328:Fosinopril; D000432:Methanol