Experimental Design Approach in HPLC Method Development: Application for the Simultaneous Determination of Sacubitril and Valsartan in Presence of Their Impurities and Investigation of Degradation Kinetics
2018
Moussa, BahiaA. | Hashem, HanaaM. A. | Mahrouse, MarianneA. | Mahmoud, SallyT.
Combination of sacubitril, a novel neprilysin inhibitor, with valsartan, an angiotensin receptor blocker, was approved by FDA as first line treatment of chronic heart failure resulting from hypertension. A selective, rapid, accurate and precise stability indicating RP-HPLC method was developed for the estimation of sacubitril and valsartan in the presence of their impurities in bulk powder and pharmaceutical dosage form. Experimental design using face-centered composite design was applied during method optimization to achieve best resolution with minimum experimental trials. The two independent variables were buffer pH and organic modifier volume in the mobile phase. Chromatographic separation was accomplished using a Zorbax Eclipse C₁₈ Cyano column (150 mm, 4.6 mm, 5 µm) and a mobile phase composed of ammonium acetate buffer (0.02 M, adjusted to pH 4 with acetic acid): acetonitrile (55:45, v/v) at a flow rate 1 mL min⁻¹. Detection was performed at 254 nm. Sharp and well-resolved peaks for sacubitril and valsartan were obtained with retention times 4.91 and 2.53 min, respectively. A complete forced degradation of sacubitril was achieved and degradation kinetics under basic conditions was studied and was found to follow first-order kinetics. Structure elucidation was performed using mass spectrometry. The method was fully validated in terms of selectivity, linearity, accuracy, precision and robustness in agreement with ICH guidelines Q2 (R1).
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