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Polymorphism within the fenamate family: the consequences of chloro-methyl replacement

Watson, RE; (2016) Polymorphism within the fenamate family: the consequences of chloro-methyl replacement. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Both mefenamic acid (MA) and tolfenamic acid (TA) are polymorphic with three and five forms respectively. MA and TA are structurally similar molecules that differ in the replacement of a methyl on MA with a chloro group on TA. This thesis uses a joint computational and experimental approach to investigate the polymorphism of MA and TA and explores differences in the packings upon chloro-methyl replacement. To compliment an earlier crystal structure prediction (CSP) study on TA, the crystal energy landscape of MA was computed. Analysis showed there were a number of predicted structures that were competitive in energy with the known forms of MA. Isostructural relationships between MA and TA that were identified from the observed polymorphs and the predicted forms from the CSP studies were investigated in a range of templating experiments. The isostructural, not isomorphous, relationship between MA I and TA IV was explored and a solid solution series, isomorphous with MA form I, was obtained from ethanol and characterised by low temperature single crystal X-ray diffraction (SCXRD). Seeding an ethanol solution of TA with MA form I seeds nucleated a new polymorph of TA (VI) that was characterised by SCXRD and was isomorphous with MA form I. A second new form of TA (VII) was discovered, and identified by powder X-ray diffraction, when exploring the sublimation of TA onto a copper surface. Thermal analysis showed that TA VII transformed to TA I upon heating. Using a similar sublimation procedure, it was observed that if MA was sublimed onto copper, form I was obtained, yet if MA was sublimed onto glass, form II was obtained. The CSP methodology was tested by participation in the CCDC blind test and was successful in predicting the observed crystal structure of the cocrystal XXV as the global minimum.

Type: Thesis (Doctoral)
Title: Polymorphism within the fenamate family: the consequences of chloro-methyl replacement
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/1524748
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