Smart sequential spectrophotometric analysis of Fluconazole and its two toxic official impurities having superimposed spectra; Greenness, whiteness, blueness assessment and in silico toxicity profiling

Abstract

• A novel sequential dual amplitude difference (SDAD) technique was developed and validated according to ICH Q2 parameters. • Greenness, whiteness, blueness assessments for the SDAD method were performed for determination of fluconazole and its 2 impurities. • Toxicity profiling of the fluconazole impurities was assessed using two computational databases: preADMET and pKcsm. Owing to the health hazards of impurities presence in active pharmaceutical ingredients, even in minute amount. A smart green sustainable spectrophotometric method was developed for simultaneous determination of Fluconazole (FLU) along with its official impurities B and C. The novel sequential dual amplitude difference (SDAD) technique succeeded in resolving the severe overlapping between the three compounds and restoring their respective mother spectrum. According to international Council of Harmonization (ICH) guidelines, the developed method is accurate, precise, and selective with linearity range (50–500 µg/mL) for FLU, (0.5–6 µg/mL) for impurity B and (0.05–0.6) for impurity C. The method was successfully applied to three pharmaceutical preparations without interference from excipients. In addition, the proposed method was assessed and compared with reported chromatographic methods for its green character, sustainability, and practicality, using five tools. The spectrophotometric method was found to be the greenest with the least volume of solvents used and waste produced, moreover, it is the most practical/sustainable method. Besides, the toxicity profiling of the two impurities was predicted using two computational databases: preADMET and pKcsm. After reviewing literature, no previous analytical method to determine FLU and its two official impurities using spectrophotometry was reported.