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Title: The crystallisation of pharmaceuticals using tailored supramolecular gels
Author: Andrews, Jessica Lauren
ISNI:       0000 0004 9349 0415
Awarding Body: Durham University
Current Institution: Durham University
Date of Award: 2020
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Due to ever increasing pressure for pharmaceutical companies to characterise and patent the polymorph landscape of new APIs, it is important that as many forms as possible are identified in the early stages of drug development. Novel polymorph screening techniques are required to expand the scope of traditional solution-phase methods, and access highly metastable or difficult to nucleate solid forms. This work exemplifies a modern polymorph screen, using a wide variety of experimental and computational methods to comprehensively characterise the polymorph landscape of mexiletine hydrochloride. Instead of the six forms described in previous literature, this screen revealed seven: an enantiotropic pair of anhydrous polymorphs that are stable at different temperatures, one anhydrous metastable form, three families of isostructural channel solvates, and a fourth solvate of unknown structure. Two new channel solvates, and new routes to three known forms were discovered by crystallising mexiletine within drug-mimetic supramolecular gels. As gelation was often turned off when a new polymorph crystallised within the gel, these changes in solid form are likely driven by strong interactions between the drug and gelator. The crystallisation of high temperature stable Form 2 from a gel at room temperature is a particularly striking example of the powerful stabilising effect of these tailored supramolecular gels. A complementary study into the gel-phase crystallisation of diatrizoic acid showed that the drug followed the same two-step crystallisation regime as the gelator, leading to the formation of two novel drug-gelator salt solvates. These results suggest that the polymorph landscape of the gelator has influenced the drug crystallisation, which may provide a new avenue of inquiry for the design of supramolecular gelators for pharmaceutical crystallisation. From this work, it is clear that supramolecular gels are a valuable tool for pharmaceutical polymorph screening.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available