BACKGROUNDSpectrophotometric resolution of a mixture of several drugs is considered a cheaper, simpler, and more versatile alternative compared to costly chromatographic instruments.OBJECTIVEThe work aims to resolve the interfering spectra of ephedrine hydrochloride, naphazoline nitrate, and methylparaben in nasal preparations using smart spectrophotometric methods.METHODIn our work, derivative and dual-wavelength methods were combined to eliminate this interference, under the name of derivative dual-wavelength method. Other methods, namely successive derivative subtraction and chemometric analysis, were also able to eliminate this interference. The methods have proven their applicability as they follow the International Conference on Harmonization (ICH) requirements regarding repeatability, precision, accuracy, selectivity, and linearity. Eco-scale, GAPI, and AGREE tools were used to estimate the possible environmental effects of the methods.RESULTSAcceptable results for repeatability, precision, accuracy, selectivity, and linearity were obtained. Limit of detection (LOD) values were 2.2 for ephedrine and 0.3 for naphazoline. The correlation coefficients were above 0.999. The methods were proven to be safe for application.CONCLUSIONSThe introduced methods are cheap and easily implemented compared to chromatographic techniques. They can be used in purity-checking of raw material and estimation of concentrations in market formulations. The replacement of the published chromatographic techniques with our developed methods is useful when needing to save money, effort, and time.HIGHLIGHTSThe three components of a decongestant nasal preparation were determined using cheap, green, and versatile spectrophotometric methods that keep the advantages of chromatographic techniques, including accuracy, reproducibility, and selectivity.