Fingerprinting analysis of non-crystalline pharmaceutical compounds using high energy X-rays and the total scattering pair distribution function

In the development of new medicinal products, poor oral bioavailability, due to the low solubilities of many active pharmaceutical ingredients (APIs), is increasingly a barrier for treatments to be administered using tablet or capsule formulations and one of the main challenges facing the pharmaceutical industry. Non-crystalline phases such as the amorphous and nanostructured states can confer increased solubility to a drug, and therefore, have recently garnered a lot of interest from pharmaceutical researchers. However, little is known about local ordering in non-crystalline pharmaceuticals due to the lack of reliable experimental probes, hindering the clinical application of these compounds. The powerful tools of crystallography begin to lose their potency for structures on the nanoscale; conventional X-ray powder diffraction (XRPD) patterns become broad and featureless in these cases and are not useful for differentiating between different local molecular packing arrangements. In this thesis, we introduce the use of high energy X-rays coupled with total scattering pair distribution function (TSPDF) and fingerprinting analysis to investigate the local structures of non-crystalline pharmaceutical compounds. The high energy X-rays allow us to experimentally collect diffuse scattering intensities, which contain information about a sample's local ordering, in addition to the Bragg scattering available in conventional XRPD experiments, while the TSPDF allows us to view the intra- and inter-molecular correlations in real space. The goal of this study was to address some fundamental problems involving fingerprinting non-crystalline APIs using TSPDF in order to lay the groundwork for the proper use of the technique by the pharmaceutical community. We achieved this by developing the methodology as well as the exploring the scientific implications. On the methodology side, we introduced PDFGetX3, a new software program for calculating TSPDFs that simplifies the procedure and reduces user interaction. We also set a baseline for the minimum X-ray energy that is needed for fingerprinting analysis, which had implications on the type of X-ray diffractometers that can be used. On the science side, we investigated the local structures of nanocrystalline and amorphous materials as well mixtures containing crystalline and amorphous phases. First, we identified a non-crystalline sample of the mood-stabilizing drug carbamazepine as a nanocrystalline version of one of its polymorphs. Next, we found that amorphous forms created by spray drying and cryomilling a proprietary compound have the same local structure. Finally, we quantified the phase fractions of polymorphic and amorphous components in a sample of the antibiotic sulfamerazine that was recrystallizing from a cryomilling-induced amorphous state.