Optimized reversed phase liquid chromatography methodology for the determination of vonoprazan fumarate impurities: Towards Six Sigma quality standards and sustainability assessment

Abstract

Vonoprazan fumarate (VPZ), a potent potassium-competitive acid blocker, holds great promise as a therapeutic option for addressing acid-related disorders. This study introduces a refined reversed phase liquid chromatography methodology tailored for the comprehensive analysis of eight related substances, including starting materials, byproducts, and degradants within VPZ. Our approach integrates response surface methodology and tolerance analysis to achieve six sigma quality standards in chromatographic performance. By embedding specifications into the optimization process, we ensure robustness during method development. Chromatographic separation was executed using an XSelect CSH Phenyl-Hexyl column under stepped gradient conditions, employing a mobile phase comprising 0.1 % trifluoroacetic acid aqueous solution and acetonitrile. The flow rate was maintained at 1.3 mL/min, with UV absorbance at 252 nm, and a column temperature set at 25 °C. To evaluate the stability indicating ability of the method, forced degradation studies were conducted. Importantly, identified degradants did not interfere with the accurate quantification of VPZ and its associated impurities. Validation of the method was achieved through accuracy profiles. A greenness assessment was conducted using National Environmental Methods Index (NEMI), carbon footprint analysis, Analytical Greenness Calculator (AGREE), and Complementary Green Analytical Procedure Index (Complex GAPI). Additionally, blueness and whiteness assessments were conducted using the Blue Applicability Grade Index (BAGI) and Red-Green-Blue 12 (RGB 12) algorithms, respectively. The proposed method exhibited a green profile in NEMI and Complex GAPI. The carbon footprint was calculated at 0.055 kg CO equivalent per sample. The AGREE score was 0.67, BAGI was 80.0, and the whiteness score from the RGB12 algorithm was 83.5.This methodological framework holds promise for utilization in process development and quality assurance of VPZ in bulk drug manufacturing, particularly in the absence of official monographs within recognized compendia.