Several methods are developed for the determination of two binary mixtures containing pyridoxine HCl together with either metoclopramide HCl (mixture 1) or meclozine HCl (mixture 2). The resolution of binary mixture of pyridoxine HCl and metoclopramide HCl has been accomplished by using partial least squares (PLS-1) and principal component regression (PCR) applied to zero and first order UV spectra of the mixture, respectively. In addition HPLC method depending on using RP18 column with a mobile phase consisting of acetonitrile-water (30:70, v/v, pH 3.2) with UV detection at 305 nm was developed. In mixture 2, the simultaneous determination of pyridoxine HCl and meclozine HCl was carried out by using graphical (second derivative of the ratio spectra) and numerical spectrophotometric methods (principal component regression and partial least squares, PLS-1 and PLS-2, applied to the zero order UV spectra of the mixture). The proposed methods were successfully applied for the determination of the two binary combinations in synthetic mixtures and in commercial tablets and syrup containing several light absorbing excipients.