@phdthesis{Becht2022,
  author    = {Becht, Alexander Ulrich},
  title     = {New applications for spectroscopic and chemometric studies of drugs},
  doi       = {10.25972/OPUS-27534},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-275342},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2022},
  abstract  = {Spectroscopic methods were established decades ago in a wide variety of fields. This also applies to the pharmaceutical field, although they initially were mostly used for identity testing or structure elucidation only. Technical developments, such as miniaturization (NMR benchtop devices), Fourier transformations (for NMR, MIR spectroscopy) or the combination with chemometric evaluation (e.g., in Process Analytical Technology, PAT), have further increased their importance and opened up new applications. The aim of this work was to investigate further new approaches and to find new applications for already established methods and to show their benefits. By means of MIR, NIR and NMR data and their chemometric evaluation (principal component analysis, PCA; hierarchical cluster analysis, HCA; linear discriminant analysis, LDA), possibilities were presented to successfully determine the manufacturer or the pharmaceutical company of various paracetamol preparations. In the course of this, various similarities and correlations between the preparations of individual companies could also be identified. For this purpose, a suitable sample preparation was developed for each spectroscopic method, and suitable measurement parameters in order to obtain reproducible spectra for the chemometric evaluation were determined. Furthermore, the results of the two unsupervised methods (HCA, PCA) were compared with each other. The HCA was able to confirm those of the PCA for the very most part. Additionally, through these methods it was possible to characterize many of the preparations based on clusters formed by comparable tablet compositions. In order to be able to measure unmortared, whole tablets using the NIR spectrometer, an attachment was developed and manufactured using 3D printing. Its functionality was demonstrated by measuring and analyzing the tablets of two different batches of nine paracetamol preparations. The batches were clearly distinguished on the basis of a PCA and a significant difference was also demonstrated by means of statistical tests. For NMR spectroscopy, a method was developed to obtain optimized "fingerprint" spectra of drug formulations. For this purpose, a 1D DOSY measurement was elaborated, in which the signals of the active ingredient could be filtered out by the appropriate choice of measurement parameters. The chemometric evaluation can thus focus on the remaining signals of the excipients, on the basis of which the preparations of the same API can be distinguished. Especially in the case of formulations that consist largely of active ingredient, data pre processing of the spectra can thus be simplified and greater importance can be assigned to the originally very small excipient signals. A quantitative 1H NMR method was developed for the comparison of a high field spectrometer (400 MHz) with a benchtop spectrometer (80 MHz) for two finished drugs. It was shown that it is possible to obtain comparable results with both instruments, but that the influence of the excipients on the signals and the lower resolution of the benchtop instrument must be taken into account. Therefore, it was not possible to obtain comparable results without further optimization of the method for one of the active ingredients. In the investigation of various reactions between APIs and excipients using DOSY, its usefulness as a screening method in stability testing was demonstrated. For this purpose, three different APIs and excipients were stressed together and the reaction mixtures were subsequently measured using DOSY. Based on the translational diffusion coefficient, the reaction products could be identified and distinguished from the active ingredients and the excipients used. The importance of thoughtful processing could also be demonstrated. If all peak heights are selected when evaluating signals split by direct spin spin coupling, this allows the detection of hidden signals as long as not all signals have the same diffusion coefficient. The selective selection of individual peak heights in the case of split signals also enables the evaluation of signals that overlap slightly. However, the limitations of this method were also shown when two signals overlap too much and differ too little in their diffusion coefficients. Hence, it has been successfully demonstrated in the various projects that the new chemometric approaches, as well as the new applications of already established methods, enable in depth findings and thus have a clear added value.},
  subject      = {Instrumentelle Analytik},
  language  = {en}
}