In this thesis the potential of electrokinetic chromatography (EKC) – mass spectrometry (MS) has been evaluated, including its applicability to the impurity profiling of drugs. Over the past years, capillary zone electrophoresis (CZE) and EKC have gained acceptance as separation techniques next to liquid chromatography (LC) in pharmaceutical analysis, in particular for chiral analysis and the impurity profiling of drug substances and products. The unique separation principles of CZE and EKC provide different or ‘orthogonal’ selectivities when compared to LC which ensures an important position of CE-based techniques in the field of separation technologies. This thesis demonstrates that direct coupling of EKC to MS is feasible without adapting the separation system. Identification or confirmation of separated compounds by MS is achieved, and with respect to UV detection low detection limits have been obtained. The surfactant sodium dodecyl sulphate (SDS) that is often used in micellar electrokinetic chromatography (MEKC), was found to be a notorious suppressor of the ionization efficiency. Nevertheless, coupling of MEKC to electrospray ionization mass spectrometry (ESI-MS) appears to be possible despite surfactants entering the ion source. Impurities in drugs below 0.1% (m/m) could be detected and identified. Drawbacks of ESI-MS can be circumvented using atmospheric pressure photoionization (APPI), which shows high potential for implementation in EKC–MS. Due to the gas phase ionization process, no adverse effects of the non-volatile buffer salts and SDS on the analyte ionization efficiency are observed. Non-aqueous EKC is an attractive solution for impurity profiling when the solubility of the main compound or (some of) the impurities is limited. Addition of anionic or cationic cyclodextrins (CDs) to the background electrolyte (BGE) can strongly enhance the separation of drug mixtures of basic and acidic drugs, respectively, including enantiomers. Due to the low electroosmotic flow (EOF), no CDs enter the ion source during analysis. However, the non-volatile counter-ions of the anionic and cationic CDs migrate into the ion source and affect the analyte ionization efficiency. Nevertheless, excellent detection limits (<100 ng/ml) can be obtained. The studies in this thesis show that when ESI is used, the ionization suppression by non-volatile salts and pseudo-stationary phases (PSPs) can be significant, but often not as serious as one would expect from LC–MS studies. The reason that EKC–MS systems still function relatively well in the presence of high concentrations of BGEs and PSPs, most likely is the relatively small volumetric flow from the CE capillary entering the ion source. Not so long ago, the direct coupling of EKC and MS was regarded as being not feasible. As shown in this thesis, developments in interfacing and ionization techniques offer good perspectives for improvements in EKC–MS. Based on this work, it can be stated that EKC and MS are not so incompatible after all, which might trigger the break-through of EKC and EKC–MS as powerful alternatives for pharmaceutical analysis
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