4.2.1. Gas Chromatography

In gas chromatography (GC), ILs have found use as stationary phases. This is due to the fact that they have unique properties, such as a wide liquid phase range, low volatility (negligible vapour pressure), high viscosity, good thermal stability and variable polarities, which make them suitable for that purpose [169]. Research into using molten salts in GC started in the 1950s and now IL-based columns are used in the analysis of complex samples [29,170]. A characteristic property of ILs is that they display unusual dual nature retention behavior, separating both non-polar and polar compounds. On the one hand, ILs exhibit a similar behavior to polar stationary phases such as polyethylene glycol or cyanopropyl-substituted polysiloxanes due to their ability to display a high dipolar interaction and hydrogen bonding. On the other hand, they are able to retain non-polar solutes (i.e., alkanes and alkenes), similarly to the low polarity stationary phases such as phenyl substituted dimethyl polysiloxanes [171]. Another important feature of ILs is that varying the cation or anion might significantly affect their physical and chemical properties [169]. For example, imidazolium IL columns using the [Nf2T] anion were the most efficient [29]. ILs formed by less coordinating or nucleophilic anions, such as [Nf2T], tend to be more stable compared to those containing halide salts; in fact, the latter are characterized by a nucleophilic nature, and hence it is possible for them to undergo SN1 or SN2 reactions with the alkyl substituents of the cation. Phosphonium-based ILs, synthesized with a large alkyl chain substituent, have shown outstanding thermal stability; in particular, a dicationic phosphonium IL, namely the dicationic 1,12-di(tripropyl-phosphonium)dodecane bis(trifluoromethylsulfonyl)imide, was synthesized possessing a thermal stability of 425 ◦C [172]. In addition, it should be noted that dicationic

and tricationic ILs exhibit significantly higher thermal stability compared to monocationic-based ILs [173].

At present, IL-coated capillary GC columns are commercially available under the trade name SLB-IL (Supelco–Sigma-Aldrich, Darmstadt, Germany) (Table 4). These columns are characterized by a different polarity and can work at temperatures passing 200 ◦C and approaching 300 ◦C [174]. Studies on the synthesis and properties of new IL-stationary phases are still continuing. Yu et al. [175] analyzed the application of a new triptycene-based amphiphilic material (TP-2IL) as the stationary phase for GC separations. In research, they showed that this column exhibited good performance for analytes from an apolar to a polar nature. Particularly, it has an outstanding capability for resolving critical pairs of anilines and phenols with good peak shapes, and shows distinct advantages over the typical conventional stationary phases. IL columns find many uses in the analysis of flavors and fragrances [176,177], fatty acids [178–182] and petrochemicals [183,184]. González Peredes et al. [185] evaluated different IL columns for the separation of chlorobenzenes and developed an analytical methodology based on the use of the IL stationary phase SLB-IL82 in GC with a microelectron capture detector for the determination of chlorobenzenes in soil samples.


**Table 4.** Selected commercial IL capillary GC columns with matrix active groups.

Do et al. [186] showed that the profiling of all 136 PCDD/Fs is greatly facilitated by using IL columns or combinations including such columns. Boczkaj et al. [187] tested three capillary columns (HP-5Ms, DB-624, SLB-IL 111) in the analysis of oxygenated volatile organic compounds (O-VOCs) in postoxidative effluents from the production of petroleum asphalt. Among the capillary columns investigated, a very polar column, SLB-IL 111, with an ionic liquid as the stationary phase was found to be superior for the separation of O-VOCs, as it has a high selectivity towards n-alkanes and oxygenated volatile organic compounds.

So far, IL stationary phases have not been widely applied in the field of bioanalysis [188]. Destaillats et al. [189] applied an IL-coated SLB-IL 111 column to identify the occurrence of petroselinic acid in human skin, hair and nails. They confirmed that this column can be used to obtain a baseline resolution between petroselinic acid and cis-8 18:1 acid methyl esters.

The use of IL-based stationary phases has extended to multidimensional gas chromatography (GCxGC), ensuring future applications. For example, Zapadlo et al. [190] investigated the use of GCxGC–TOFMS with highly polar IL-based columns for the analysis of polychlorobiphenyls (PCBs). They used a non-polar/ionic liquid column series consisting of poly (50%-n-octyl-50%-methyl) siloxane

(SPB-Octyl) and the ionic liquid SLB-IL59 in the first and second dimension, respectively. As a result, a total of 196 out of 209 PCBs congeners were resolved and all dioxin-like congeners were separated with no interferences from any PCB congener.

ILs have found another significant application as a solvent in headspace gas chromatography (HS-GC), ILs are ideal solvents for HS-GC, a more sensitive method of analysis compared to direct injection. HS-GC avoids direct liquid or solid probing and greatly decreases matrix interference [29]. ILs are excellent solvents and are now used for the analysis of residual solvents in a variety of pharmaceutical products. The detection and quantitation of residual solvents/impurities in drug substances or drug products is an important measure for pharmaceutical quality assurance/quality control, because the residual solvents/impurities that were not totally removed by practical manufacturing techniques always have a potential risk to human health from toxicity. Fink et al. [191] developed a rapid, accurate, IL-based HS-GC method for the determination of water in active pharmaceutical ingredients. The HS-GC method used an IL-based capillary GC column to increase the sensitivity and ruggedness of this method. ILs are also utilized as a headspace solvent. Studies have shown that the sensitivity of the HSGC method is 100 times greater than that of volumetric Karl Fischer titration (KFT) (which is the commonly used technique to determine water content), allowing very small sample sizes (e.g., 4 mg) to be accurately and reproducibly analyzed. In comparison, a typical sample size of 500–1000 mg is used in KFT. Liu and Jiang [192] applied [C4MIM][BF4] as the matrix medium in the analysis of six solvents utilized in the synthesis of Adefovir Dipivoxil: acetonitrile, dichloromethane, N-methyl-2-pyrrolidone ([NMPyrr]), toluene, dimethylformamide (DMF), n-butyl ether. The developed method proved accurate and linear (with *R* ≥ 0.9993). All the RSDs were lower than 10%. Moreover, the comparison of [C4MIM][BF4] with DMSO as a matrix medium of headspace GC was also carried out in this study. In this research, it was indicated that DMSO, with its boiling point at 189 ◦C, has a higher vapor pressure, and the chromatographic peak of the DMSO matrix, with a much higher intensity, always occupies a wider baseline or interferes in the detection of analytes, especially at a higher equilibrium temperature. The impurities and the decomposed products of DMSO at a high equilibration temperature also became interfering substances for the detection of residual solvents.

A grea<sup>t</sup> analytical challenge for the pharmaceutical industry is the trace-level analysis of genotoxic impurities (GTIs) in drug substances. Ho et al. [193] used ILs (six compounds: ([C4MPyrr][B(CN)4]), [C4MIM][BF4], [C4MMIM][BF4], [C4MIM][Nf2T], [C4MMIM][Nf2T] and ([P6,6,6,14+][Nf2T])) as a new class of diluents for the analysis of two classes of genotoxic impurities (GTIs), namely, alkyl/aryl halides and nitro-aromatics, in small molecule drug substances by headspace gas chromatography coupled with electron capture detection (ECD) without the need for analyte derivatization. The low volatility and high thermal stability of ILs enables these compounds to be used at high headspace oven temperatures with the minimum chromatographic background. Studies have shown that increasing the headspace oven temperatures resulted in varying responses for alkyl/aryl halides and significant enhancements in the responses for all nitroaromatic GTIs. Furthermore, ILs with a conventional high-boiling organic diluent—DMSO, were compared. The chromatographic backgrounds from ILs are significantly lower than the backgrounds from DMSO. The LODs of all analytes obtained using the IL diluents were superior (5 to 500 ppb) to those obtained from pure DMSO. Research on organic solvent residues in drugs was also conducted by Ni et al. [194]. The main focus of this study was to investigate the relationship between analytes (organic solvents) and the matrix medium (ILs) by HS-GC in order to provide guidance in choosing a suitable matrix medium and next to determine the organic residual solvents in ketoconanzole to choose a suitable IL during the process of HS-GC. In research, [C4MIM][PF6] was chosen as the best headspace solvent, because an excellent separation of ethanol, dichloromethane, ethyl acetate, butyl alcohol, pyridine, DMF and DMSO was achieved. The evaluation of ILs for the analysis of residual solvents in pharmaceutical matrices was the subject of research by Laus et al. [195]. The authors chose ([C4MIM][DMP]) as the most suitable ionic liquid as solvent for the HS-GC analysis of solvents with very low vapor pressure, such as dimethylsulfoxide, *N*-methylpyrrolidone, sulfolane, tetralin, and ethylene glycol which can be found in pharmaceutical products. The limit of quantification (LOQ) of this method was from 59 (tetralin) to 113 μg/g (ethylene glycol), the accuracy was in the range of 96.6–103.7, and it showed high linearity in the tested range of 0.9890–0.9984. The developed method was applied for the detection of traces of sulfolane in a real sample of tablets containing the drug cefpodoxime proxetil. A trace of sulfolane was detected (estimated at 2 μg/g with respect to the tablet mass), which is safely below the regulatory limit of 160 μg/g. To the best of our knowledge, there are only a few reports on the use of ILs as stationary phases for GC separations in the analysis of environmental samples. One of them is the investigation performed by Reyes-Contreras et al. [171], who examined the suitability of ILs as stationary phases for GC–MS, and their application for the determination of nitrosamines and ca ffeine metabolites in wastewater samples. Studies have shown that the SLB-IL111 column enabled the baseline separation and quantification of 7 nitrosamines in a shorter analysis time compared with the commonly used cyanopropylphenyl polysiloxane. Furthermore, the SLB-IL59 column provided the elution of all the ca ffeine metabolites analyzed with the highest peak symmetry and an appropriate analysis time. Contaminants in wastewaters were also the subject of research by Domínguez et al. [169]. In this work, the application of IL stationary phases for the determination of benzothiazoles and benzotriazoles was examined. Among the IL columns evaluated, SLB-IL59 provided the total elution of all the target analytes with the highest peak symmetry and the lowest analysis time. Moreover, the lower stationary phase bleeding enabled positive identification and quantification.

In view of the properties of ILs, such as high thermal stability, high viscosity, and tunable selectivity through the modification of their chemical structure, their use, in particular as stationary phases in GC, will increase. New IL stationary phase chemistries that provide unique selectivity towards target analytes are needed to improve the separation performance and versatility of multidimensional GC [170].
