A Critical Review on Selexipag: From Molecular Mechanism to Analytical Method Development

Selexipag (SLP), a pyrazine derivative with the molecular formula C26H32N4O4S, is an oral selective prostacyclin receptor (IP receptor) agonist approved by the U.S. Food and Drug Administration (FDA) in 2015 for the treatment of pulmonary arterial hypertension (PAH) in patients classified under functional class II or III. Its active metabolite, ACT-333679, exhibits approximately 130-fold selectivity towards the IP receptor, contributing to its potent vasodilatory, anti-proliferative, anti-inflammatory, and anti-thrombotic effects. Selexipag is rapidly absorbed, undergoing hepatic metabolism via carboxylesterase 1 and subsequent oxidative metabolism through CYP3A4 and CYP2C8 enzymes. The drug demonstrates a terminal half-life of 0.8 to 2.5 hours, while its active metabolite has a prolonged half-life of 6.2 to 13.5 hours. Analytical techniques for the quantification of Selexipag in bulk and pharmaceutical formulations include high-performance liquid chromatography (HPLC), LC-MS/MS, and UV-visible spectrophotometry. This study focuses on the development and validation of a rapid, precise, and accurate HPLC method for Selexipag analysis in accordance with ICH (Q2) R1 guidelines. The method was optimized for linearity, accuracy, precision, robustness, and specificity. The proposed method demonstrated excellent reproducibility and stability, making it suitable for routine quality control analysis and pharmacokinetic studies. This work aims to enhance the analytical reliability of Selexipag and contribute to improved therapeutic monitoring and patient outcomes in the management of PAH.