Polymer drug dispersions: understanding structure and dynamics

Hawarden, Lucy Elizabeth (2015) Polymer drug dispersions: understanding structure and dynamics. Doctoral thesis, University of East Anglia.

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Abstract

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.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Science > School of Pharmacy
Depositing User:	Users 2259 not found.
Date Deposited:	28 Jan 2016 11:44
Last Modified:	28 Jan 2016 11:44
URI:	https://ueaeprints.uea.ac.uk/id/eprint/56823
DOI:

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