The performance of different chemometric approaches was evaluated in the spectrophotometric determination of pharmaceutical mixtures characterized by having the amount of components with a very high ratio. Principal component regression(PCR), partial least squares with one dependent variable(PLS1) or multi-dependent variables(PLS2), and multivariate curve resolution(MCR) were applied to the spectral data of a ternary mixture containing paracetamol, sodium ascorbate and chlorpheniramine(150:140:1, m/m/m), and a quaternary mixture containing paracetamol, caffeine, phenylephrine and chlorpheniramine(125:6. 25:1.25:1, m/m/m/m). The UV spectra of the calibration samples in the range of200–320 nm were pre-treated by removing noise and useless data, and the wavelength regions having the most useful analytical information were selected using the regression coefficients calculated in the multivariate modeling. All the defined chemometric models were validated on external sample sets and then applied to commercial pharmaceutical formulations. Different data intervals, fixed at 0.5, 1.0, and2.0 point/nm, were tested to optimize the prediction ability of the models. The best results were obtained using the PLS1 calibration models and the quantification of the species of a lower amount was significantly improved by adopting 0.5 data interval, which showed accuracy between 94.24% and 107.76%. The performance of different chemometric approaches was evaluated in the spectrophotometric determination of pharmaceutical bows characterized by having the amount of components with a very high ratio. (PLS2), and multivariate curve resolution (MCR) were applied to the spectral data of a ternary mixture containing paracetamol, sodium ascorbate and chlorpheniramine (150: 140: 1, m / m / m), and a quaternary mixture containing paracetamol, caffeine The UV spectra of the calibration samples in the range of 200-320 nm were pre-treated by removing noise and useless data, and the frequency regions having the most useful analytical information were selected using the regression coefficients calculated in the multivariate modeling. All the defined chemometric models were validated on external sample sets and then applied to commercial pharmaceutical formulations. Different data intervals, fixed at 0.5, 1.0, and 2.0 point / nm, were tested to optimize the prediction ability of the models. The best results were obtained using the PLS1 calibration models and the quantification of the species of a lower amount was significantly improved by adopting 0.5 data interval, which showed accuracy between 94.24% and 107.76%.