Fenspiride hydrochloride (FNS) is used in treating chronic inflammatory diseases, most commonly as a liquid oral solution. FNS produces degradation products along with fenspiride N-oxide (FNO) and 1-phenylethyl-4-hydroxy-4-aminomethyl piperidine hydrochloride (PHAP). We aimed to develop and validate a chromatographic method in order to identify the main degradation products in the presence of other compounds from a liquid preparation. The method used a dual gradient using two buffer solutions: the first with pH 4.5 (buffer 1, pH 4.5-MeOH 90:10%, v/v) and the second with pH 2.9 (buffer 2, pH 2.9-acetronitrile-methanol, 65:15:10%, v/v/v). As mentioned, there was a modification of the organic mixture, starting with 10% methanol and ending with a mixture of acetonitrile-methanol (15:10%, v/v). The flow-rate was 1.5 mL/min. According to the elution program, experimental conditions started with 100% solution S1, which decreased to 0% and, simultaneously, solution S2 increased to 100% during the first 10 min and was maintained for a further 5 min. After 15 min, initial conditions were re-established. The linearity interval was 0.5-2 μg/mL and the minimum correlation coefficient was 0.999. The recovery factor was 100.47-103.17% and the limit of quantification was 0.19-0.332 μg/mL. Intra-day maximum precision was 4.08% for FNS and 2.65% for PHAP. This double-gradient mobile phase produced good specificity in relation to the degradation products of FNS and other constituents of the oral liquid formulation. Forced degradation studies revealed other related substances that were confirmed in mass balance analyses. Degradation products were confirmed in acidic, basic and oxidative media.