Development of a Stability-Indicating Purity Method for Ubrogepant Through Stress Degradation Analysis, Extraction, and Characterization of Unidentified Degradation Products Using Flash Chromatography, NMR, IR, and LC–MS

Abstract

Abstract Background Ubrogepant is a prescription medication used to prevent migraine headaches. It is currently available in tablet form. Objective The goal of this work is to investigate the drug degradation profile of ubrogepant, as well as to isolate and characterize undiscovered ubrogepant degradation products by utilizing LC–MS, NMR, and IR spectroscopic analytical techniques and, furthermore, to develop a high-resolution, sensitive, stability-indicating analytical approach for detecting and quantifying ubrogepant degradation products in its pharmaceutical formulation. Methods To identify and quantify the degradation products of ubrogepant in pharmaceutical products, a novel gradient reverse-phase HPLC (RP-HPLC) technique with a photo diode array (PDA) detector was developed by utilizing a C18 stationary phase column. The eluent comprised a mixture of acetonitrile and water with 0.1% (v/v) ortho-phosphoric acid. To establish the intrinsic stability of the ubrogepant pharmaceutical product, it was stress-tested under various degradation conditions, including water, alkaline, acid hydrolysis, photolytic, oxidative, and thermal. Flash chromatography was used to isolate the two major degradants, and the structures were determined using NMR (1H, 13C, distortionless enhancement by polarisation transfer-DEPT-135), IR, and LC–MS methods. Results The ubrogepant medication was relatively more degradable in alkaline and acidic conditions, and two unique degradation products were discovered. Based on spectroscopic and chromatographic evidence, it was conclusively demonstrated that these unique compounds were ubrogepant hydrolysis products. All degradation products were separated with a resolution greater than 2.0. The peak purity data showed that the ubrogepant peak in all of the stress samples examined was pure. Under all stress environments, ubrogepant achieved a minimum mass balance of 95%. The validated approach developed was sensitive enough to quantify ubrogepant degradation products at 0.03% of the ubrogepant test concentration. Conclusion The proposed method was found to be stability-indicating since it fits all of the regulatory authorities' typical requirements. This method is highly efficient for detecting and quantifying impurities in ubrogepant drug substances and drug products in QC laboratories. Highlights Two new degradation products of ubrogepant were successfully extracted and characterized using NMR, IR, and LC–MS spectroscopic methods. The proposed HPLC method can accurately quantify the degradation products of ubrogepant in pharmaceutical products and is sensitive enough to detect degradation products of ubrogepant as low as 0.17 µg/mL.