Mixed-mode columns allow to quantitate drugs and their counter-ions in one run. Hydrophobic acidic drug and hydrophilic inorganic counter-ions are separated and quantified on an Obelisc R HPLC trimodal column. This column can be used to quantify hydrophilic basic and hydrophilic acidic drugs, hydrophobic basic and hydrophobic acidic drugs, and corresponding organic and inorganic counter-ions. Various detection techniques can be applied to obtain reliable and robust method. Mixed-mode chromatography allows to retain ionizable compounds without ion-pairing reagent. This HPLC method can be adopted as universal and robust approach for analysis basic and acidic drugs and their counter-ions. Method is compatible with various detection techniques - ELSD, UV, CAD, and LC/MS.