AGGREGATION BEHAVIOR OF FOSINOPRIL SODIUM - A NEW ANGIOTENSIN-CONVERTING ENZYME-INHIBITOR

Fosinopril sodium is an effective new angiotensin-converting enzyme (A CE) inhibitor that is very useful for the clinical treatment of hypert ension. After oral administration, fosinopril sodium is only partially absorbed (about one third of the drug). We studied the solution behav ior of fosinopril sodium in aqueous media by a combination of high-res olution nuclear magnetic resonance (NMR) spectroscopy and laser light scattering (LLS). LLS characterizes the self-association properties of fosinopril sodium in solution, and NMR chemical shifts provide inform ation on molecular conformation and interactions. The results revealed that fosinopril sodium has a micelle-like self-association behavior w ith a critical micelle concentration (cmc) similar to 1.5 mg/mL. Hydro phobic interactions could induce formation of micellar aggregates, whi ch had a narrow hydrodynamic size distribution, with an average diamet er of similar to 150 nm at concentrations above the cmc. The surface a ctivity and self-association of fosinopril sodium may be responsible f or its early observed concentration-dependent stability in aqueous sol ution, unexpected decrease in solubility in the presence of metal ions , as well as the limited absorption in clinical studies.