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Title: Polymer drug dispersions : understanding structure and dynamics
Author: Hawarden, Lucy Elizabeth
ISNI:       0000 0004 5371 332X
Awarding Body: University of East Anglia
Current Institution: University of East Anglia
Date of Award: 2015
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Poor physical stability is a limiting factor in the pharmaceutical development of APIs. Amorphous drugs are attractive due to increased dissolution; however can unpredictably revert to the thermodynamically stable crystalline form. Accurate prediction of molecular level physical stability would be advantageous. Research surrounding stability prediction is evolving; but challenging, including thermodynamic, molecular and kinetic factors. This study focussed on gaining a molecular level understanding of the structure and dynamics of amorphous dispersions using three model drugs. We aimed to develop solid-state NMR methods to provide invaluable information on molecular mobility; to ultimately use NMR for the prediction of crystallisation outcomes from stability studies, leading to quicker prediction of potential storage issues, since mobility is a key factor a�ecting stability in the amorphous state. VT solid-state NMR was used to probe di�erences in local mobility between drug and polymer; and to monitor polymorphic transitions/crystallisation in high loaded dispersions. Methodologies were veri�ed using additional physicochemical approaches. We demonstrated: • Di�erences in local mobility of drug/polymer dependent on model system and drug loading. • Miscibility detection down to 2 nm, including important temperature dependent observations. VT relaxation curves could become important visual tools for quanti�cation of drug loading and prediction of miscibility during initial development. • VT NMR was a useful tool for quick and accurate prediction of high temperature stability study outcomes • Insight into crystallisation of pharmaceuticals in formulation, demonstrating mapping complex phase transitions in high loaded dispersions • Detection of di�erent dynamic features of tolbutamide, including the identi�cation of motional processes responsible for the detection of its structural transitions VT solid-state NMR has provided a signi�cant quantity of data surrounding the mobility and stability of our systems of study. These methods provide us with a valuable characterisation `toolkit' for probing molecular mobility in solid dispersions, therefore aiding the prediction of potential long term stability issues.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available