Quantification of potential genotoxic impurity in sacubitril/valsartan drug substance at ppm level by LC-MS/MS

Abstract

Abstract The aim of the present research work is to provoke a validated, sensitive and highly selective LC-MS/MS method for the determination of potential genotoxic impurity namely Sacubitril Ene Ester (SEE) impurity in sacubitril/valsartan drug substance at ppm level. The LC-MS/MS method was developed on waters X-Bridge Phenyl (150mm x 4.6 mm) 3.5 µm in gradient elution at 30°C. Mobile phase-A was 10mM ammonium acetate and mobile phase-B was acetonitrile: methanol: water (60:30:10, %v/v/v) at a constant flow rate and injection volumes are of 0.8 mL/min and 10µL respectively with 30 minutes gradient run time monitored by mass spectrophotometer. Validation was performed on basis of the standard guideline “International Conference on Harmonization” (ICH) guideline Q2(R1). LC-MS/MS is able to quantitate up to 1.1ppm of SEE impurity. Under these LC and MS conditions, SEE impurity was quantified by multiple reaction monitoring pair (most stable ions) m/z of 408.1/262.2. This method has been used for testing and quantitative determination of SEE impurity in sacibitril/valsartan samples at µg levels. The developed LC-MS/MS method was validated and the resulting data found to show the specificity, linearity, accuracy and precision of the proposed methodology. Further the results show that the developed LC-MS/MS method was well suited to quantify the SEE potential genotoxic impurity.