Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.569990
Title: Multi-component crystallisation approaches to controlling crystalline forms of active pharmaceutical ingredients
Author: Wales, Craig
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2013
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Abstract:
Multi-component crystallisation is investigated as a route to controlling crystalline forms of selected materials that possess pharmaceutical properties. This includes investigating the use of co-crystallisation methodology to selectively crystallise metastable polymorphs and solvated forms of these materials. This differs from the conventional use of co-crystallisation, as the aim of this aspect of the investigation is not to obtain a molecular complex of the two components, but instead for them to crystallise independently, while one component perturbs the solution environment to direct the crystallisation of the second component towards a different, often metastable, polymorph (or solvate). This co-crystallisation methodology is used as a route to crystallising new or elusive polymorphs (or solvates) of the active pharmaceutical ingredients paracetamol, piroxicam, gallic acid monohydrate and piracetam. It is also demonstrated that the use of this method can lead to crystal forms with otherwise unobtainable structural features. Co-crystallisation is also investigated as a route to controlling the ionisation state of piroxicam in the formation of molecular complexes. Molecular complexes were formed with a number of mono-substituted benzoic acids as well as with nitrogen-heterocycles and strong acids. In the molecular complexes formed, piroxicam was found to adopt the non-ionised, zwitterionic, anionic or cationic form, depending on the co-former used. Attempts are made to rationalise the occurrence of each ionisation state by consideration of the relative pKa values of piroxicam and the co-formers. The hydrogen bonded supramolecular synthons in these molecular complexes are also investigated. Co-crystallisation is also used as a route to obtaining molecular complexes of paracetamol and its derivative, 4-acetamidobenzoic acid, with nitrogen-heterocycles as co-formers. Molecular complexes of the two, with similar co-formers, are compared in terms of their hydrogen bonded supramolecular synthons. Despite having otherwise similar structural features, the phenolic hydroxyl group in paracetamol and carboxylic acid group in 4-acetamidobenzoic acid result in the formation of very different synthons and in some cases different component ratios. The susceptibility of 4-acetamidobenzoic acid to deprotonation is found to play a major role in the differences observed. Molecular complexes of paracetamol with co-formers containing multiple carboxylic acid groups are also investigated, with a view towards further crystal engineering approaches for molecular complexes of paracetamol. Piracetam complexes with carboxylic acids are investigated in a similar manner. The potential for transfer of a range of these multi-component crystallisations into a non-evaporative environment, with a view to implementing continuous crystallisation approaches, is also investigated. This transfer is found to be challenging for the systems investigated.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.569990  DOI: Not available
Keywords: Q Science (General) ; QD Chemistry ; TP Chemical technology
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