Macitentan (MAC) is a pulmonary arterial hypertension (PAH) drug marketed as a tablet and often has stability issues in the final dosage form. Quantitative determination of MAC and its associated impurities in tablet ...Macitentan (MAC) is a pulmonary arterial hypertension (PAH) drug marketed as a tablet and often has stability issues in the final dosage form. Quantitative determination of MAC and its associated impurities in tablet dosage form has not been previously reported. This study quantified impurities present in Macitentan tablets using a binary solvent-based gradient elution method using reversed phase-high performance liquid chromatography.The developed method w as validated per International Conference on Harmonization (ICH) guidelines and the drug product w as subjected to forced degradation studies to evaluate stability. The developed method efficiently separated the drug and impurities (48 min) w ithout interference from solvents,excipients,or other impurities. The developed method met all guidelines in all characteristics w ith recoveries ranging from 85%-115%,linearity w ith r 2≥0. 996 6,and substantial robustness. The stability-indicating nature of the method w as evaluated using stressed conditions (hydrolysis:1 N HCl at 80℃/15 min; 1 N NaOH at 25℃/45 min; humidity stress (90%relative humidity) at 25℃for 24 h,oxidation:at 6%(v/v) H2O2,80℃/15 min,thermolysis:at105℃/16 h and photolysis:UV light at 200 Wh/m2; Fluorescent light at 1. 2 million luxh). Forced degradation experiments show ed that the developed method w as effective for impurity profiling. All stressed samples w ere assayed and mass balance w as> 96%. Forced degradation results indicated that MAC tablets w ere sensitive to hydrolysis (acid and alkali) and thermal conditions. The developed method is suitable for both assay and impurity determination,w hich is applicable to the pharmaceutical industry.展开更多
基金the management of Sinotherapeutics Inc. for supporting this study
文摘Macitentan (MAC) is a pulmonary arterial hypertension (PAH) drug marketed as a tablet and often has stability issues in the final dosage form. Quantitative determination of MAC and its associated impurities in tablet dosage form has not been previously reported. This study quantified impurities present in Macitentan tablets using a binary solvent-based gradient elution method using reversed phase-high performance liquid chromatography.The developed method w as validated per International Conference on Harmonization (ICH) guidelines and the drug product w as subjected to forced degradation studies to evaluate stability. The developed method efficiently separated the drug and impurities (48 min) w ithout interference from solvents,excipients,or other impurities. The developed method met all guidelines in all characteristics w ith recoveries ranging from 85%-115%,linearity w ith r 2≥0. 996 6,and substantial robustness. The stability-indicating nature of the method w as evaluated using stressed conditions (hydrolysis:1 N HCl at 80℃/15 min; 1 N NaOH at 25℃/45 min; humidity stress (90%relative humidity) at 25℃for 24 h,oxidation:at 6%(v/v) H2O2,80℃/15 min,thermolysis:at105℃/16 h and photolysis:UV light at 200 Wh/m2; Fluorescent light at 1. 2 million luxh). Forced degradation experiments show ed that the developed method w as effective for impurity profiling. All stressed samples w ere assayed and mass balance w as> 96%. Forced degradation results indicated that MAC tablets w ere sensitive to hydrolysis (acid and alkali) and thermal conditions. The developed method is suitable for both assay and impurity determination,w hich is applicable to the pharmaceutical industry.
