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Title: Solid-state NMR studies of polymer-drug interactions in pharmaceutical formulations
Author: Guilbaud, Jean-Baptiste A. M.
ISNI:       0000 0001 3521 9166
Awarding Body: University of Liverpool.
Current Institution: University of Liverpool
Date of Award: 2007
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The development of pharmaceuticals (both drugs and their formulations) requires the characterisation of the materials in their dispensed form. Solid-state NMR is particularly appropriate for studies of such system as it does not require any pre-treatment which might affect the material properties. This methodology also provides a molecular level understanding of intra- and intermolecular bonding as well as the dynamics in pharmaceutical formulations crucial for directing their physical properties, stability, bioavailability and release kinetics of a drug in a composite. Solid-state NMR spectroscopy has been used to study the drug-polymer interactions in PLGAlpeptide guest systems. Poly(lactide-co-glycolide) (PLGA) polyesters are unique biodegradable and biocompatible polymers. They are widely applied in drug delivery devices due to their tunable physical properties. In this project, PLGAs with different lactide/glycolide ratios were used as hosts for amino acids and peptide based pharmaceuticals. The dynamics in the pure polymers and the effect of processing on the local dynamics were studied via analysis of CP-kinetics, relaxation times measurements and wide-line separation (WISE). The local dynamics characterised by solid-state NMR were correlated with the bulk properties and composition of the materials. Different aminoacids and peptides were probed to assess the dynamics occurring in the complex arginine containing polypeptide. Their local organisation was derived from the analysis of crystal structures and 2D IH_13C heteronuclear correlation (HETCOR) experiments. In the formulations, the nature of the guest and its loading level have a significant effect on the dynamics of the hosts as proven by the variable temperature TIpH time measurements, CPdynamics and WISE. Whereas arginine and ARARAF have been found to increase the local mobility in PLGA, the more complex polypeptide AZD at ca. 10% wt. tends to rigidify the system. These effects were correlated with the bulk properties of the composites. The results suggested a differentiation of the affinity of glycolide or lactide units towards different guests. Finally, the two crystalline forms of a non-steroidal and anti-inflammatory drug (indomethacin) undergoing polymorphism were characterised by solid-state NMR. Assignments of the complex Be solid-state NMR spectra are presented. Amorphous solids derived from both polymorphs were also investigated. Recrystallisation of the amorphous solid derived from the stable y-polymorph was observed. This can be prevented by dispersing the amorphous drug into an amorphous PVP polymer. In this situation, the organisation and H-bonding of the drug is altered due to the interactions between the drug and the polymer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available