Heat, acid, base, UV radiation and oxidation stress methods were applied to study the stability of cough-cold products containing acetaminophen, phenylephrine or phenylpropanolamine hydrochloride and chlorpheniramine maleate. Liquid chromatography coupled with mass spectrometry was used to analyze the degraded samples and obtain molecular weights information. Different volatile buffers (ammonium bicarbonate and ammonium acetate) were assayed in LC/MS methods and retention times of the analytes were compared with those obtained in HPLC with UV detection employing a conventional sodium phosphate buffer to establish the possibility of results transference between the two systems.