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 t ransformation of fosinopril into beta-ketoamide, III, and a phosphonic acid, IV, mediated through metal ion participation. The interaction o f fosinopril with magnesium ions was studied in a solution model syste m in which methanol was used as the solvent and magnesium acetate as t he source of metal ions. Kinetic analysis indicated the degradation to be a bimolecular process, with the rate being first order in both met al ion and fosinopril concentration. The degradation products II, III, and IV effectively retarded the magnesium ion mediated reaction of fo sinopril. Based on the results of P-31-NMR, H-1-NMR, Mn(II)-EPR spectr oscopy experiments and mass spectrometry, a mechanism is postulated fo r this transformation. A key reactive intermediate has been characteri zed that supports the proposed mechanism. The results can account for the observed degradation profile of the fosinopril sodium in a prototy pe tablet formulation.