Sustainable RP-UPLC analysis of Nirogacestat for desmoid tumors using quality-by-design and green analytical chemistry

Quality-by-Design (QbD) and Green Analytical Chemistry (GAC) are used to develop a sustainable RP-UPLC method for detecting Nirogacestat hydrobromide (NGS) in bulk and pharmaceutical formulations. The FDA-approved NGS for desmoid tumors necessitates reliable, environmentally friendly analytical techniques. QbD principles were applied to optimize NGS peak shape and resolution using Design Expert software, taking into account flow rate, temperature, and mobile phase. An ACQUITY UPLC HSS C18 Column utilized a mobile phase of 0.1% (v/v) TFA in water and methanol (71:29) at 0.29 mL/min and 27°C, with detection wavelength of 318.0 nm and a retention time of 1.761 min. The method was highly precise, with %RSD of 0.3 and 0.7 and a recovery rate of 100.26%. The LOD and LOQ were 0.34 and 1.04 μg/mL, respectively. A greenness rating was generated using ComplexMoGAPI, AGREE, the ChlorTox Scale, and the Analytical Eco-Scale, with method validation as per ICH Q2, and stability studies identified a degradation product, affirming the method's reliability. The method is simple, cost-effective, and supports quality control, aligning with GAC and QbD principles. It enhances sustainable pharmaceutical analysis by optimizing performance and minimizing environmental impact. The Efficient Valid Green (EVG) & RGBfast model framework emphasizes regulatory flexibility and quick analysis, setting a benchmark for future advancements.Abbreviations: AGREE: Analytical Greenness; AMV: analytical method validation; AQbD: analytical quality-by-design; AR: Analytical Reagent; ATP: analytical target profile; BAGI: Blue Applicability Grade Index; CAT: Critical analytical attributes; EVG: Efficient Valid Green; GAC: green analytical chemistry; LOD: limit of detection; LOQ: limit of quantitation; NGS: Nirogacestat; NTP: Number of Theoretical Plates, PRESS: predicted residual sums of squares, RSD: Relative standard deviation; SHE: Safety, Health, and Environmental, TUV: Tunable ultraviolet