In the last years, supercritical fluid chromatography has largely been acknowledged as a singular andperforming technique in the field of separation sciences. Recent studies highlighted the interest of SFCfor the quality control of pharmaceuticals, especially in the case of the determination of the active phar-maceutical ingredient (API). Nevertheless, quality control requires also the determination of impurities.The objectives of the present work were to (i) demonstrate the interest of SFC as a reference technique forthe determination of impurities in salbutamol sulfate API and (ii) to propose an alternative to a referenceHPLC method from the European Pharmacopeia (EP) involving ion-pairing reagent. Firstly, a screeningwas carried out to select the most adequate and selective stationary phase. Secondly, in the context ofrobust optimization strategy, the method was developed using design space methodology. The separa-tion of salbutamol sulfate and related impurities was achieved in 7 min, which is seven times faster thanthe LC-UV method proposed by European Pharmacopeia (total run time of 50 min). Finally, full validationusing accuracy profile approach was successfully achieved for the determination of impurities B, D, Fand G in salbutamol sulfate raw material. The validated dosing range covered 50 to 150% of the targetedconcentration (corresponding to 0.3% concentration level), LODs close to 0.5 g/mL were estimated. TheSFC method proposed in this study could be presented as a suitable fast alternative to EP LC method forthe quantitative determination of salbutamol impurities.