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Computational crystal structure prediction and experimental characterisation of organic salts

Mohamed, S.; (2011) Computational crystal structure prediction and experimental characterisation of organic salts. Doctoral thesis, UCL (University College London). Green open access

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Abstract

Approximately half of all pharmaceutical drugs are marketed as salts. This thesis pioneers the application of computational crystal structure prediction to organic salts containing the commonly used chloride or carboxylate counterions, and assesses the extent to which the theoretical calculations can be used to aid experimental efforts targeting organic salts. A screen for multi-component solid forms of pyridine and 4- dimethylaminopyridine (DMAP) using a range of dicarboxylic acids led to one novel cocrystal of pyridine and six novel salts of DMAP. All novel crystal structures were solved using single crystal X-ray diffraction. At a simplistic level, salts differ from cocrystals in the position of the acidic proton within the crystal. For a selected set of structures, periodic ab initio calculations were shown to be useful in suggesting the observed N+-H (salt) or O-H (cocrystal) covalent bond as the preferred atomic connectivity. Modelling the same crystal structures by lattice energy minimisation using a distributed multipole based electrostatic model proved successful if the correct proton connectivity was used. The observed structures of a model salt, cocrystal and disordered salt-cocrystal system were found to be the most stable or almost equienergetic with the most stable structure in the predicted crystal energy landscapes. When the predictions were repeated using molecular structures with the wrong proton connectivity, the energetic ranking of the structure got worse. The computational model of crystal structure prediction was successfully used to rationalise the different polymorphic and hydration behaviour of the pharmacologically active amantadine hydrochloride and memantine hydrochloride salts. Finally, a similar methodology was applied to 1,8-naphthyridinium fumarate and the calculations performed as part of the fifth international blind test of crystal structure prediction. Overall, the success in modelling the crystal structures of carboxylate and chloride salts illustrates the promise of crystal structure prediction in aiding experimental efforts of organic salt selection.

Type:Thesis (Doctoral)
Title:Computational crystal structure prediction and experimental characterisation of organic salts
Open access status:An open access version is available from UCL Discovery
Language:English
UCL classification:UCL > School of BEAMS > Faculty of Maths and Physical Sciences > Chemistry

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