Drug impurities are now seen as a major threat to drug safety around the world, especially when it comes to carcinogenic impurities. Here, we present the first spectrophotometric approach for the quantification of lignocaine and fluorescein in the presence of 2,6-xylidine, lignocaine’s carcinogenic impurity. The approach depends on overcoming unresolved bands through a data processing strategy employing 10 affordable, simple, and sensitive spectrophotometric methods. Fluorescein analysis (1–16 μg mL−1) was performed using direct ultraviolet spectrophotometry (D0) at 478 nm; then, the ratio subtraction method allowed the removal of interference caused by the fluorescein spectrum. From the resulting ratio spectra, 2,6-xylidine (40–160 μg mL−1) can be efficiently determined at 280 nm. However, lignocaine (72–320 μg mL−1) was analyzed using different ultraviolet-based methods, including continuous wavelet transform, ratio derivative by Savitzky–Golay filters, mean centering, second derivative of ratio spectra, ratio spectra difference spectrophotometry, extended ratio subtraction, absorbance subtraction, Q-absorbance ratio, and area under the curve. In line with International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), the presented approach was evaluated by its coefficients of determination, detection limits, quantification limits, and relative standard deviations. Similarly, the developed approach was assessed for whiteness, greenness, and sustainability using five assessment tools, including National Environmental Method Index, Eco-Scale Assessment, Complementary Green Analytical Procedure Index, Analytical Greenness Metric, and RGB12, offering promising results. Owing to the satisfactory analytical performance, besides the sustainability, affordability, simplicity, and cost efficiency of the presented methods, their application for quality control and in situ analysis in minimal-infrastructure laboratories increases, increasing the surveillance potential.
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