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Analysis of complex drugs by comprehensive two-dimensional gas chromatography and high-resolution mass spectrometry: detailed chemical description of the active pharmaceutical ingredient sodium bituminosulfonate and its process intermediates
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: [Figure not available: see fulltext.]
Size, concentration, and origin of human exhaled particles and their dependence on human factors with implications on infection transmission
Understanding infection transmission between individuals, as well as evaluating the efficacy of protective measures, are key issues in pandemics driven by human respiratory particles. The key is a quantitative understanding of the size and concentration of particles exhaled and their variability across the size range for a representative population of all ages, genders, and different activities. Here we present data from 132 healthy volunteers aged 5 to 80 years, measured over the entire particle size range for each individual. Conventional particle spectrometry was combined with in-line holography under well-controlled conditions for common activities such as breathing, speaking, singing, and shouting. We find age to be the most important parameter for the concentration of small exhale particles <5 µm (PM5), which doubles over a 7-year period in adolescents and over a 30-year period in adults. Gender, body mass index, smoking or exercise habits have no discernible effect. We provide evidence that particles with a diameter of <5 µm originate from the lower respiratory tract, 5–15 µm from the larynx/pharynx, and >15 µm from the oral cavity. PM5 concentration can vary by one order of magnitude within a person, while inter-person variability can span two orders of magnitude, largely explained by difference in age. We found no discernible inter-person variability for particles larger than 5 µm. Our results show that cumulative volume of PM5 is 2–8 times higher in adults than in children. In contrast, number and volume concentration of larger particles, which are produced predominantly in the upper respiratory tract, is largely independent of age. Finally, we examined different types of airborne-transmissible respiratory diseases and provided insights into possible modes of infection transmission with and without several types/fits of face masks.
Separation and quantification of imidazoles in atmospheric particles using LC-Orbitrap-MS
A method using ultra-high performance liquid chromatography coupled to a high resolution Orbitrap mass spectrometer was developed to identify and quantify imidazoles in aqueous extracts of aerosol particles. The aqueous particle extract was used without further enrichment or sample clean-up. Five columns were tested for efficient separation of ten imidazoles and the Acquity HSS T3 column was chosen for further optimization. Low limits of detection (<25 nM) and good intraday and interday repeatability (<1.6 and <6%, respectively) were achieved. Investigation of matrix effects showed that external calibration is applicable when the loading of organic carbon in the sample is below 10 µg m-3 . The developed method was applied to ten real samples, and six out of the ten test imidazoles were successfully quantified, while six further imidazoles were qualitatively identified, among them 4-imidazolecarboxaldehyde and 4-methyl-5-imidazolecarboxaldehyde. Advantages of the method are the minimal sample preparation, the short run time for each sample, and the low detection limits. These allow for a fast and reliable quantification of imidazoles even in a large number of aqueous particle extract samples.
Efficient alkane oxidation under combustion engine and atmospheric conditions
Oxidation chemistry controls both combustion processes and the atmospheric transformation of volatile emissions. In combustion engines, radical species undergo isomerization reactions that allow fast addition of O2. This chain reaction, termed autoxidation, is enabled by high engine temperatures, but has recently been also identified as an important source for highly oxygenated species in the atmosphere, forming organic aerosol. Conventional knowledge suggests that atmospheric autoxidation requires suitable structural features, like double bonds or oxygen-containing moieties, in the precursors. With neither of these functionalities, alkanes, the primary fuel type in combustion engines and an important class of urban trace gases, are thought to have minor susceptibility to extensive autoxidation. Here, utilizing state-of-the-art mass spectrometry, measuring both radicals and oxidation products, we show that alkanes undergo autoxidation much more efficiently than previously thought, both under atmospheric and combustion conditions. Even at high concentrations of NOX, which typically rapidly terminates autoxidation in urban areas, the studied C6–C10 alkanes produce considerable amounts of highly oxygenated products that can contribute to urban organic aerosol. The results of this inter-disciplinary effort provide crucial information on oxidation processes in both combustion engines and the atmosphere, with direct implications for engine efficiency and urban air quality.
Determination of highly polar compounds in atmospheric aerosol particles at ultra-trace levels using ion chromatography Orbitrap mass spectrometry
A method using ion chromatography coupled to high-resolution Orbitrap mass spectrometry was developed to quantify highly-polar organic compounds in aqueous filter extracts of atmospheric particles. In total, 43 compounds, including short-chain carboxylic acids, terpene-derived acids, organosulfates, and inorganic anions were separated within 33 min by a KOH gradient. Ionization by electrospray was maximized by adding 100 µL min−1 isopropanol as post-column solvent and optimizing the ion source settings. Detection limits (S/N ≥ 3) were in the range of 0.075–25 μg L−1 and better than previously reported for 22 compounds. Recoveries of extraction typically range from 85 to 117%. The developed method was applied to three ambient samples, including two arctic flight samples, and one sample from Melpitz, a continental backround research site. A total of 32 different compounds were identified for all samples. From the arctic flight samples, organic tracers could be quantified for the first time with concentrations ranging from 0.1 to 17.8 ng m−3. Due to the minimal sample preparation, the beneficial figures of merit, and the broad range of accessible compounds, including very polar ones, the new method offers advantages over existing ones and enables a detailed analysis of organic marker compounds in atmospheric aerosol particles.