A structural database for pharmaceutical salt selection
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- University of Strathclyde
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- Salt formation is an important technique used in preclinical pharmaceutical development to modulate and optimise the physicochemical properties of a drug molecule containing an ionisable functional group. The current approach to salt selection relies on semi-empirical screening of the pharmaceutical molecule in combination with different counterions for the formation of a crystalline salt. This approach is necessitated by the limited understanding of the relationships between molecular and supramolecular structure and properties and the stoichiometry and ionisation state of the resultant crystalline solid. Presented in this work is a structural database containing 110 novel multi-component crystalline systems produced by the co-crystallisation of a library of pharmaceutically acceptable organic acid counterions with basic molecules that model the functional groups found on pharmaceutically active molecules. The structures were characterised by single crystal X-ray diffraction and their hydrogen bond interactions and molecular packing arrangements were examined using Mercury and XPac. This enabled the identification of robust hydrogen bonded synthons and supramolecular constructs for salts of secondary or tertiary amine bases in combination with different types of counterion. These observations were correlated to the molecular structures of the salt formers and a series of "salt selection rules" that can be potentially used to guide counterion selection for a novel pharmaceutical molecule were established. The applicability of these rules was assessed by the crystallisation of a validation set of 29 novel fluoroquinolone structures. Variable-temperature X-ray powder diffraction and structure determination from powder diffraction data were employed to generate four novel anhydrous salts from their corresponding hydrates. Comparison of the hydrogen bond interactions and molecular packing arrangements allowed the examination of the structural role of water in determining and stabilising the supramolecular structures of the hydrated systems.
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- This thesis was previously held under moratorium from 25th July 2011 until 25th July 2013.
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