Abstract

Objective: To develop and validate macitentan with its known and unknown degradation impurities in its tablet dosage form.Methods: The RP-HPLC method for macitentan and its impurities was developed and three potential degradation impurities MCA-02, MCA-01 and degradation impurity and N-propyl derivative and N-N dimethyl derivative process impurities were separated. Chromatographic separation was achieved within 70 min on Inertsil C8 (250*4.6 mm, 5 µm) column, Using mobile phase A [Ammonium acetate (ph 4.5 adjusted with glacial acetic acid)] and mobile phase B acetonitrile in gradient elution. Other hplc parameter which was optimized flow rate 1.5 ml/min, detection wavelength 266 nm, column oven temperature 30 ° C and injection volume 20μl. macitentan was subjected to forced degradation also known as stress testing. It was validated as per ICH guidelines.Results: The drug showed extensive degradation in acidic and basic conditions, a slight degradation in oxidative condition. The developed method was statistically validated for linearity (0.45-2.25 ppm). The result of precision (%RSD<5), robustness, LOD(0.15 ppm) and LOQ(0.45 ppm) are well within limits.% Recovery at LOQ, 50%, 100% and 150% was found to be within limit 80-120 %.Conclusion: RP-HPLC method was successfully developed with satisfactory separation of macitentan and its impurities. The proposed method was found to be specific, accurate, precise and robust can be used for estimation of macitentan and its impurities and can be successfully employed in the routine analysis of macitentan.

Highlights

  • IntroductionMacitentan is chemically a {[5-(4-bromophenyl)-6-{2-[(5-bromopyrimidin-2-yl)oxy]ethoxy}pyrimidin-4-yl]sulfamoyl}(propyl) amine) with molecular weight of 588.273g/mol [1]

  • Macitentan is chemically a {[5-(4-bromophenyl)-6-{2-[(5-bromopyrimidin-2-yl)oxy]ethoxy}pyrimidin-4-yl]sulfamoyl}(propyl) amine) with molecular weight of 588.273g/mol [1].Macitentan blocks the ET1-dependent rise in intracellular calcium by inhibiting the binding of ET-1 to ET receptors

  • A survey of literature revealed that RP-HPLC, first order Derivative UV Spectroscopy, and stability indicating analytical methods have been reported for macitentan

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Summary

Introduction

Macitentan is chemically a {[5-(4-bromophenyl)-6-{2-[(5-bromopyrimidin-2-yl)oxy]ethoxy}pyrimidin-4-yl]sulfamoyl}(propyl) amine) with molecular weight of 588.273g/mol [1]. Macitentan blocks the ET1-dependent rise in intracellular calcium by inhibiting the binding of ET-1 to ET receptors. A survey of literature revealed that RP-HPLC, first order Derivative UV Spectroscopy, and stability indicating analytical methods have been reported for macitentan. It was found that there are few RP-HPLC analytical methods available, but in my work impurities to be estimated are other than the reported one. It was thought worthwhile to develop a method for estimation of impurities and related substance in macitentan using HPLC [5,6,7,8,9]

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