Abstract
A simple and sensitive reverse phase ultra performance liquid chromatography (RP-UPLC) method has been developed, optimized and validated for the simultaneous determination of N-Hydroxybenzotriazole (HOBt), Cinchonidine and 1,3-Dicyclohexyl urea (DCU) contents at low levels in fosinopril sodium drug substance. Efficient chromatographic separation was achieved on Acquity UPLC HSS C18column, 100 mm long with 2.1 mm i.d., 1.8 µm particle diameter, thermo stated at 30°C. Gradient elution involving binary mixture of potassium dihydrogen orthophosphate (0.01M, pH:3.0±0.05 withortho-phosphoric acid) and acetonitrile at a flow rate of 0.10 mL min-1has been used. The analytes were monitored by photodiode array (PDA) detector set at 205 nm. The drug substance was subjected to stress conditions of hydrolysis, oxidation, photolysis, thermal and humidity degradation. The method was validated for specificity, sensitivity, linearity, precision, accuracy and solution stability. The limit of detection (LOD) and limit of quantification (LOQ) for HOBt, Cinchonidine and DCU were in the range of 0.85-3.52 ppm and 2.57-10.67 ppm, respectively. The average recoveries for HOBt, Cinchonidine and DCU are in the range of 98.1% to 102.6%. The method can be used for the routine quality control analysis of fosinopril sodium drug substance.
Highlights
Fosinopril sodium [1[S*(R*)],2,4 ]-4-Cyclohexyl-1-[[[2-methyl-1-(1oxopropoxy)propoxy] (4-phenylbutyl)phosphinyl]acetyl]-L-proline, monosodium salt, is a phosphinic acid-containing ester prodrug that belongs to the angiotensin-converting enzyme (ACE) inhibitor, used for the treatment of heart failure and kidney failure due to high blood pressure and diabetes [1,2]
To improve the yield of the product, HOBt is used as condensation additive. (-)-Stereoisomer of Cinchonine commonly used in asymmetric synthesis, having acute oral toxicity of category 4 according to regulation (EC) No 1272/2008 [EU-GHS/CLP]
Analytical reagent (AR grade) N-Hydroxybenzotriazole (HOBt), Cinchonidine, 1,3-Dicyclohexyl urea (DCU), potassium dihydrogen orthophosphate, disodium hydrogen orthophosphate, hydrochloric acid, sodium hydroxide, hydrogen peroxide, ortho-phosphoric acid, HPLC grade methanol and acetonitrile were procured from E Merck India
Summary
Fosinopril sodium [1[S*(R*)],2 ,4 ]-4-Cyclohexyl-1-[[[2-methyl-1-(1oxopropoxy)propoxy] (4-phenylbutyl)phosphinyl]acetyl]-L-proline, monosodium salt, is a phosphinic acid-containing ester prodrug that belongs to the angiotensin-converting enzyme (ACE) inhibitor, used for the treatment of heart failure and kidney failure due to high blood pressure and diabetes [1,2]. In the synthesis of fosinopril sodium, N-Hydroxybenzotriazole (HOBt), 1,3Dicyclohexylcarbodiimide and Cinchonidine were used as reagents. (-)-Stereoisomer of Cinchonine commonly used in asymmetric synthesis, having acute oral toxicity of category 4 according to regulation (EC) No 1272/2008 [EU-GHS/CLP]. These residual organic impurities can come through the manufacturing process of the drug substance, the criteria for their acceptance are based on pharmaceutical studies or known safety data [3]. In view of this, monitoring of HOBt, Cinchonidine and DCU in fosinopril drug substance is essential for preserving the desired quality of active substance. For Cinchonidine variable analytical methods were reported [7,8,9,10,11,12]. For the sensitivity of detection, we have chosen an analytic liquid chromatographic technique UPLC, instead of HPLC as this technology takes full advantage of chromatographic principles to run separations using columns packed with smaller particles and / or higher flow rates for increased speed, with superior sensitivity and resolution
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