The European pharmacopeia provides analytical methods for the chemical characterization of active pharmaceutical ingredients (APIs). However, the complexity of some APIs exceeds the limitations of the currently prevailing physicochemical methods. Sodium bituminosulfonate (SBS) is described by the collection of key parameters of generalizing criteria such as dry matter, sulfur and sodium content, and neutrality, but techniques to unravel the complexity on a molecular level are lacking. We present a study based on online derivatization with tetramethylammonium hydroxide in combination with comprehensive two-dimensional gas chromatography coupled to an electron ionization high-resolution time-of-flight mass spectrometer (GC × GC-HR-ToF–MS) for the chemical description of SBS as well as its process intermediates. The application of GC × GC allowed the comprehensive description of the chemical components in the API and the process intermediates for the first time. Furthermore, it was possible to classify peaks regarding their elemental and structural composition based on accurate mass information, elution behavior, and mass fragmentation pattern. This work demonstrates not only the general applicability, advantages but also limitations of GC × GC for the characterization of APIs for complex drugs. Graphical Abstract