Impurity Profiling of Challenging Active Pharmaceutical Ingredients without Chromophore ; Erstellen von Verunreinigungsprofilen von anspruchsvollen Wirkstoffen ohne Chromophor

The impurity profiling of pharmaceutical ingredients can oppose many challenges. The best part of active pharmaceutical ingredients (APIs) and the related substances are detectable by UV detection, a very common detection principle. However, if an API lacks a suitable chromophore other means of detection are necessary. The corona charged aerosol detector (CAD) is a detector capable of detecting substances independent of their chemical structure. This “universal” detector has only one limitation: The analyte has to have a sufficiently low vapor pressure. Another important challenge that comes often together with the lack of a chromophore concerns the separation. These substances (e.g. most amino acids and derivatives) often contain structures that make them difficult to retain on conventional reversed phase columns. Possible solutions to overcome these challenges, like the application of the CAD and the benefit of so-called mixed-mode stationary phases in impurity profiling for pharmacopoeial purposes were explored in this work. The related substances analyzed in this thesis comprise amino acids, inorganic ions, bisphosphonic acids, basic and acidic derivatives of amino acids (esters and amides). The successful development and validation of mixed-mode liquid chromatography methods with CAD detection for carbocisteine and ibandronate sodium might help to increase the acceptance of this versatile detector in the pharmaceutical industry and in official authorities dealing with the determination of related substances. The combination of UV and CAD detection proved very useful during the analysis of Bicisate. Most of the related substances and some unidentified impurities were detectable by CAD whereas a synthesis by-product, a semi-volatile ester, was only detectable in the UV trace. The simple combination covers all relevant impurities in a single analysis. Two truly orthogonal methods regarding separation and detection for the enantiomeric purity of magnesium-L-aspartate helped to find the reason for elevated D ...