Impurity distributions in pharmaceutical solids

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Bourke, Timothy
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University College Cork
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The management of impurities in batches of drug products is a continual challenge facing the pharmaceutical industry. While the inclusion of many synthetic and process impurities can be reduced to safe levels by common techniques such as crystallisation, others are not so simple to remove, persisting through multiple purification attempts. In these cases, more targeted impurity rejection techniques are required. In turn, information on the nature of the impurities and their distribution within a batch of crystalline product is vital to designing an effective impurity management strategy. This research focuses on the development of techniques for determining the distribution of purification-resistant impurities within crystalline pharmaceutical products. These techniques have been shown to be applicable to systems with a range of different impurity types and levels, as well as different crystal morphologies, and require no specialised equipment to perform. Chapter one provides a summary of the impact of pharmaceutical impurities and strategies surrounding their management, background into crystal structure and morphology, and the relationship between an impurity/additive and its host material. Flufenamic acid (FFA) is introduced as the active pharmaceutical ingredient (API) basis for impure systems of study, upon which distribution determination methods can be developed. Some methods of analysis that will be used in the research are also discussed. Chapter two focuses on the selection of appropriate additives for the impure systems and the development of the analytical techniques required to characterise their behaviour. The development of a robust high-performance liquid chromatography (HPLC) method will be described, as well as the construction of calibration curves, measurement of solubility data, and the determination of effective methods of crystal production. The polymorphic behaviour of FFA is also explored. Chapter three details the development of a reliable synthetic method for the production of FFA and the selected additives, as well as detailed spectroscopic characterisation of each. An investigation into the characterisation of an impurity observed in the synthesis of FFA will also be described. Chapter four is concerned with exploring the relationship between FFA and each of the chosen additives within doped systems. To this end, the incorporation behaviour, resistance to purification, and phase behaviour of the doped system is examined. Binary phase diagrams are constructed for two of the systems. The unexpected behaviour of one of the systems is also examined in more detail. The development of the aforementioned methods of determining impurity distributions is described in chapter five. This is focused primarily on the development of a robust partial dissolution technique and its application to a wide variety of systems with different properties. A second technique designed for acicular crystals is also described. A short summary of the conclusions of the research is provided in chapter six, followed by an Appendix in chapter seven. Experimental details are presented at the end of each results chapter.
API , Crystallisation , Pharmaceutical , Impurity , Synthetic , Distributions , Flufenamic acid , Phase diagrams , Incorporation , Rejection , Partial dissolution , Stepwise dissolution , Additives
Bourke, T. 2022. Impurity distributions in pharmaceutical solids. PhD Thesis, University College Cork.