Raman studies of the formation and structure of pharmaceutically relevant crystals

• Main Author: Greenan, Catherine Emma
• Published: Queen's University Belfast 2013
• Subjects: 548.3
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.601626

The pharmaceutical industry is faced with a wide range of complex problems, one of which is the relationship between different structural forms of crystalline materials of the same compound, so called polymorphism. In this Thesis Raman spectroscopy was used to search for spectroscopic evidence for the formation of nuclei as precursors to crystalline forms. This involved attempts to detect small changes in Raman spectra during crystallisation which were not associated with the simple conversion of a test compound in solution into solid crystals. However, near the start of the work it was discovered that the Raman spectra collected from a known monomorphic compound were not always reproducible, with variations in relative peak intensities, changes in band profiles and even disappearance of some peaks. Since these spectra l irregularities were not due to the presence of a new structural form, yet were similar to those which would indicate this to be the case, it was important to isolate the source of this variance and try to remove it. It was found that it was excitation of the crystals is along different crystallographic axes which was causing the marked differences in t e Raman spectra but that these effects could be significantly diminished, if not removed completely, by the collection and averaging of spectra orthogonal to each other. This has been demonstrated with two separate crystalline materials, one of which, the polymorphic compound, Carbamazepine. The second stage of this project involved the investigation of the early stages of crystal formation. Since Raman spectroscopy is sensitive to molecular arrangement, the changes seen with in the spectra during the transformation from solution to crystal may provide information on the pathway taken during crystal formation. In this work multivariate analysis, specifically principal component analysis (PCA), was used to search for small changes within the spectra of a sample undergoing crystallisation that might be associated with formation of nuclei prior to crystallisation. In this work evidence consistent with the presence of an intermediate stage were found during t he crystallisation of sucrose. It is believed this is the first time such an observation has been made using Raman spectroscopy.