Forced Degradation Study of Vonoprazan Fumarate by HPLC and Characterisation of Its Degradation Products Using LC-QTOF-MS/MS.

RATIONALE:Acid-related disorders, including gastro-oesophageal reflux disease (GERD), peptic ulcers and Helicobacter pylori infection, affect millions worldwide. Vonoprazan fumarate, a potassium-competitive acid blocker, provides rapid and sustained acid suppression. Understanding its degradation behaviour is essential for ensuring drug stability, supporting formulation development and guiding quality control. METHODS:Vonoprazan fumarate was subjected to acidic and basic hydrolysis, oxidation, thermal and photolytic stress to evaluate its degradation behaviour. Degradation products were separated by reversed-phase high-performance liquid chromatography (HPLC) using a gradient program optimised for mobile-phase composition and flow rate, thereby enabling the chromatographic resolution of closely eluting degradation products. Structural characterisation was performed using liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (LC-QTOF-MS/MS) based on accurate-mass measurements and diagnostic MS/MS dissociation patterns. The method was validated for linearity, precision, accuracy, selectivity and robustness. RESULTS:Nine degradation products were detected under stress conditions: Basic hydrolysis yielded degradation product (DP)-1 and DP-8; acidic stress produced DP-1, DP-2 and DP-4; oxidation generated DP-1, DP-2, DP-7 and DP-8; and photolysis formed DP-1 to DP-6, DP-8 and DP-9. Three degradation products exhibited identical protonated molecules and closely comparable MS/MS dissociation patterns to the parent drug but differed in chromatographic retention times, with their relative distribution varying in solution- and solid-state upon UV exposure. CONCLUSIONS:This study provides a comprehensive evaluation of the forced degradation behaviour of vonoprazan fumarate by RP-HPLC and characterisation of its degradation products using LC-QTOF-MS/MS, providing insights into its degradation pathways and supporting stability assessment. Comparative solution- and solid-state photostability studies revealed distinct degradation profiles, providing further insight into the photodegradation behaviour of vonoprazan fumarate.