Understanding structure of pharmaceutical organic solids in confined media

Nartowski, Karol (2016) Understanding structure of pharmaceutical organic solids in confined media. Doctoral thesis, University of East Anglia.

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Mesoporous silicas have attracted growing attention in pharmaceutical drug delivery due to their synthetically tailored pore diameters, large pore volume and surface area. The narrow distribution of the pores makes mesoporous silicas exciting as nano-size crystallisation chambers for studies of molecular aggregation and drug polymorphism. Determination and understanding of structure and dynamics of confined solids presents significant analytical challenge due to lack of long range ordering. In this work we demonstrate how solid-state NMR can gain molecular insight into the structures of confined pharmaceuticals which are not accessible with other techniques. Using NMR as a probe for local mobility we demonstrated differences in the molecular dynamics of confined pre-nucleating species as compared to the confined crystals and amorphous molecules embedded in seemingly uniform composites.
Indomethacin, tolbutamide and flufenamic acid were chosen as model systems. These compounds differ significantly in structural flexibility leading to a large number of polymorphs and challenges in controlling the phase transitions. Crystallisation processes from amorphous state into confined solvate and stable form V of indomethacin were monitored inside the pores of ca. 30 nm. Using 13C and 1H solid-state NMR we controlled the formation of metastable tolbutamide form V inside the pores of 3 nm, followed by its recrystallisation into the most stable form IH. Using 19F NMR and 19F T1 relaxation measurements we were able to gain molecular level insight into the crystallisation mechanisms of confined crystals, as we demonstrated the formation of a liquid-like layer on the silica surface prior to the build-up of confined crystal of flufenamic acid. All findings from NMR measurements were corroborated with PXRD, DSC and N2 adsorption proving the presence of nano confined crystals.
Combined application of nano-size crystallisation methodology and solid-state NMR spectroscopy is essential in directing molecular aggregation and answering fundamental questions on self-assembly of crystalline solids.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Pharmacy
Depositing User: Jackie Webb
Date Deposited: 06 Feb 2017 15:07
Last Modified: 06 Feb 2017 15:07
URI: https://ueaeprints.uea.ac.uk/id/eprint/62311

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