Abstract
Described is a simple, rapid, selective, and stability-indicating RP-LC method for the determination of process and degradation-related impurities of bosentan monohydrate. Chromatographic separation was achieved on Zorbax SB-Phenyl column thermostated at 35°C under gradient elution by a binary mixture of solvent A (60% phosphate buffer, pH 2.5, and 40% methanol) and solvent B (acetonitrile) at a flow rate of 1.0 mL/min. Forced degradation was carried out under acidic, alkaline, oxidative, photolytic, and thermal conditions. Significant degradation is observed in acid and alkali stress conditions. Process- and degradation-related impurities were characterized by mass spectrometry, 1H NMR, and FT-IR spectral data. Validation of the developed method was carried out as per ICH requirements. Regression analysis shows an “r” value (correlation coefficient) of greater than 0.999 for bosentan and five potential impurities. This method was capable to detect the five impurities at 0.01% of the test concentration of 1.0 mg mL-1.
Highlights
Bosentan monohydrate (4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl) pyrimidin-4-yl]benzene-1-sulfonamide monohydrate), a dual endothelin receptor antagonist (ERA) has molecular formula of C27H29N5O6 S·H2O with relative molecular mass of 569.64
Laboratory batches of crude bosentan monohydrate were analyzed for their related substances identification using the developed RP-LC method
Three related substances were detected in the crude bosentan monohydrate batch sample
Summary
Bosentan monohydrate (4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl) pyrimidin-4-yl]benzene-1-sulfonamide monohydrate), a dual endothelin receptor antagonist (ERA) has molecular formula of C27H29N5O6 S·H2O with relative molecular mass of 569.64. It is the first orally active drug approved by United States Food and Drug Administrative as Tracleer (65 mg and 125 mg) for the successful treatment of pulmonary arterial hypertension (PAH). This paper provides a simple, rapid, selective, and stability-indicating method for determining the process and degradation-related impurities in samples of the bosentan monohydrate bulk drug along with its validation as per USP and ICH guidelines [16, 17]
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