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Title: Surface energy heterogeneity mapping of pharmaceutical solids by inverse gas chromatography
Author: Smith, Robert
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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The surface energetics of model pharmaceutical powders, were D-mannitol (Ph Eur Pearlitol® 160C, Roquette, France), Racemic Ibuprofen (2-(4-isobutylphenyl)propionic acid) (Shasun, London, U.K.), Aspirin (acetyl salicyclic acid) (Sigma-Aldrich, Poole, U.K.) and Paracetamol (p-hydroxyacetanilide) (98% Sigma-Aldrich, St. Louis, MO) were evaluated using a Finite Dilution Inverse Gas Chromatography FD-IGC technique. This yielded heterogeneous surface energy distributions, which provided a continuum of energies with surface coverage. These measurements were then analysed using novel computational methods of deconvolution, to better understand the effects of heterogeneity on the fundamental site contributions to surface energetics. The modelling approach developed branches into several components: Dispersive and Specific Energetics Modelling. The Dispersive component further expanded to Iterative and Analytical forms, with extensions to both. Physical mixtures of heterogeneous unsilanised and homogeneous Methyl-silane modified Mannitol, in both blended and unblended configurations, as well as blended mixtures of two homogeneous species, Methyl-silane and Fluoro-silane modified Mannitol, were measured to investigate the effect of mixing on surface energetics measured by FD-IGC. Mannitol was used as its functionalisation allowed for the production of markedly different energy profiles with a negligible effect on surface area and mechanical properties allowing for accurate knowledge of the amount of each surface used. The effect of mixed surface chemistry was also investigated to further understand the root cause of energetic heterogeneity measured by FD-IGC, this was achieved by the dual species silanisation of Mannitol using both Methyl- and Fluoro-Silane species, this was found to produce a heterogeneity distribution bound between the energies of the two silane species used in isolation. Further, this was investigated by the induction of a heterogeneity in a homogeneous polymeric material, Polyethylene, through surface modification with Sulfuric Acid. Finally the computational approaches developed were applied to the 3 polymorphic forms of a common pharmaceutical excipient Mannitol to investigate the effects of polymorphism on surface energetics. This showed that the different polymorphs exhibit extremely different energetic behaviour, further results for a mixed-polymorph suggest that it may be possible to infer energetic contributions of unknown quantities. Such information can be used to possibly screen for unwanted polymorphic contributions and also to find more appropriate polymorphic forms for pharmaceutic uses in terms of adhesive and dissolution properties as affected by surface energetics.
Supervisor: Heng, Jerry Sponsor: Sorption Measurement Systems ; Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral