A new rapid and sensitive method has been developed and validated for the simultaneous determination of phenylephrine hydrochloride, paracetamol, chlorpheniramine maleate and dextromethorphan hydrobromide in pharmaceutical preparations. The separation was achieved on a C18 column using a gradient mobile phase of acetonitrile–sodium perchlorate (pH 3, 0.01 M) at a flow rate of 1.4 mL min⁻¹. Detection was at 204 nm. Pseudoephedrine hydrochloride was selected as internal standard. The recovery of the drugs ranged from 97.8 to 100.9%. Central composite design was used during validation to calculate method robustness and the percentage of sodium perchlorate, temperature and flow rate were investigated as factors. The method was found to be applicable for the determination of the four compounds in sugar-coated tablets.