Evaluation of Method “Whiteness” in the Stability Analysis of Dexamethasone and PVP‐I Ophthalmic Suspensions: Synergizing LC‐MS/MS, In Silico Toxicology, and AGREE/GAPI Metrics

ABSTRACT

This study presents a holistic “White Analytical Chemistry” approach for the stability‐indicating evaluation of dexamethasone in complex povidone‐iodine (PVP‐I) ophthalmic suspensions. Moving beyond traditional validation, the method's “whiteness” was quantitatively assessed via the RGB model, balancing analytical excellence, ecological impact, and operational practicality. The redness (analytical) of the strategy is highlighted by a robust RP‐HPLC method integrated with LC‐MS/MS for the structural elucidation of degradation products. This was further augmented by in silico toxicological mapping and molecular docking against the human glucocorticoid receptor, providing a comprehensive “risk map” of degradants. The greenness (ecological) was optimized through a design of experiments (DoE) approach and the use of core‐shell column technology at a reduced flow rate (0.4 mL/min), achieving an AGREE score of 0.72 and a favorable GAPI profile. The blueness (practicality) was ensured by streamlining the routine analysis for standard UPLC‐PDA/UV systems, ensuring cost‐effective tech‐transfer for high‐throughput quality control. Ultimately, this integrative framework provides a superior safety diagnostic tool for complex ophthalmic formulations, aligning high‐tier pharmaceutical accuracy with environmental and economic consciousness.