Stability of new potential ACE inhibitor in the aqueous solutions of different pH.
Angiotensin-converting enzyme (ACE) inhibitors are a group of active substances binding to an active site of ACE. Many authors who studied the structure activity relationship suggested the structural elements needed for a potent ACE inhibitor. While many authors studied the activity of ACE inhibitor substances only a few structure stability studies have been presented. In this paper the stability properties of molecule xPRIL were studied by determination of degradation path and rate of degradation in aqueous solutions with different pH (2.0, 6.8 and 12.0) and temperatures (40, 60 and 80 degrees C). The degradation of molecule through two main degradation paths was identified and confirmed by liquid chromatography and mass spectroscopy (LC-MS). Stability properties of xPRIL were determined in a stability study evaluated by high-performance liquid chromatography (HPLC). The first order kinetics of degradation reaction of xPRIL and Arrhenius equations for each pH were determined at observed conditions. xPRIL showed the highest stability at pH 2 solution. The degradation kinetics of xPRIL was compared to the degradation kinetics of enalapril maleate (EM) and perindopril (PER) in bio relevant solutions with pH 2.0 and 6.8. In addition to the stability study of xPRIL the forced degradation study of all three molecules at rigorous conditions was conducted. From the obtained results the structural element having the highest influence on stability properties of the studied molecules was identified. The fragmentation paths of xPRIL, its cyclization degradation product and its hydrolysis degradation product were identified and confirmed by MS/MS method.
Roskar
R
R
University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia.
Simoncic
Z
Z
Gartner
A
A
Kmetec
V
V
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry*; D001665:Binding Sites; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D002853:Chromatography, Liquid / Q000379:methods; D004355:Drug Stability; D004656:Enalapril / Q000737:chemistry; D017408:Guidelines as Topic; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D013058:Mass Spectrometry / Q000379:methods; D008954:Models, Biological; D015394:Molecular Structure; D020913:Perindopril / Q000737:chemistry; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D012996:Solutions; D053719:Tandem Mass Spectrometry / Q000379:methods; D013696:Temperature; D014867:Water / Q000737:chemistry*
D000806:Angiotensin-Converting Enzyme Inhibitors; D012996:Solutions; D014867:Water; D004656:Enalapril; D020913:Perindopril