Combining experimental solid-state NMR and X-ray diffraction with density functional theory calcualtion to characterise multicomponent forms of organic molecules

Structure analysis is an important step in the process of developing new solid forms of active pharmaceutical ingredients (APIs) and agrochemical ingredients (AIs) as it can provide a starting point for related structures to be designed and represents an intellectual property (IP) opportunity. This thesis investigates the complementarity of XRD and solid-state magic-angle spinning (MAS) NMR, alongside density functional theory (DFT) calculations, for the characterisation of five related pyridine based molecules, each co-crystallised with fumaric acid. Structures and stabilities were investigated using both single crystal and powder XRD at a range of temperatures, 1H MAS, 13C cross polarisation (CP) MAS solid state NMR spectra and 1H1H, 1H13C and 14N1H 2D correlation experiments and thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). DFT-based geometry optimisations were performed with the unit cell parameters both fixed and variable to investigate the convergence of structures recorded at different temperatures and calculations of the NMR parameters were conducted for both the full crystal structures and for isolated molecules from within the structures, highlighting the intermolecular interactions present. Chapter 3 identifies the loss of the base molecule, through slow evaporation, from the system, resulting in formation of crystalline fumaric acid in the affected regions. Splitting of reflections in the powder XRD patterns was linked to the existence of a second ‘polymorph’, which shows noticeable variation in unit cell parameters while maintaining the overall molecular packing. Chapter 4 investigates the co-occurrence of at least three multicomponent forms from the same crystallisation media, isolates the transitions between the structures (from hydrated to anhydrous) and identifies methods both for improving the selectivity of their formation and allowing their co-identification by NMR. In Chapter 5 the multicomponent forms of three substitutional analogue bases are compared, one of which shows evidence of polymorphism. Chapter 6 presents the trend in the 14N shift with crystal form for tertiary amine nitrogens as well as classifying common bonding patterns which, in a Cambridge Structural vi Database (CSD) search, show significant differences in incidence depending on crystal form. Two chemical environments that show significant differences between experiment and calculation are also identified.