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    Approaches to Understanding the Milling Outcomes of Pharmaceutical Polymorphs, Salts and Cocrystals. The Effect of Different Milling Techniques (Ball and Jet) on the Physical Nature and Surface Energetics of Different Forms of Indomethacin and Sulfathiazole to Include Computational Insights.

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    Thesis Fiona Robinson.pdf (7.448Mb)
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    Publication date
    2012-04-18
    Author
    Robinson, Fiona
    Supervisor
    Forbes, Robert T.
    Leusen, Frank J.J.
    Keyword
    Indomethacin
    Sulfathiazole
    Ball milling
    Jet micronisation
    Inverse gas chromatography
    Attachment energy
    Cleavage plane
    Pharmaceutical polymorphs
    Salts
    Cocrystals
    Thermal characterisation
    Solid-state characterisation
    Particle size
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    Rights
    Creative Commons License
    The University of Bradford theses are licenced under a Creative Commons Licence.
    Institution
    University of Bradford
    Department
    Department of Pharmacy
    Awarded
    2011
    
    Metadata
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    Abstract
    The process of milling drugs to obtain samples with a desirable particle size range has been widely used in the pharmaceutical industry, especially for the production of drugs for inhalation. However by subjecting materials to milling techniques surfaces may become thermodynamically activated which may in turn lead to formation of amorphous material. Polymorphic conversions have also been noted after milling of certain materials. Salt and cocrystal formation is a good way of enhancing the properties of an API but little or no work has been published which investigates the stability of these entities when subjected to milling. Different milling techniques (ball and jet) and temperatures (ambient and cryogenic) were used to investigate the milling behaviour of polymorphs, salts and cocrystals. All materials were analysed by XRPD and DSC to investigate any physical changes, i.e. changes in melting point and by inverse gas chromatography (IGC) to investigate whether any changes in the surface energetics occurred as a result of milling. Another aim of this thesis was to see if it was possible to predict the milling behaviour of polymorphs by calculating the attachment energies of the different crystal facets using Materials Studio 4.0. These results were compared to the IGC data to see if the predicted surface changes had occurred. The data collected in this study showed that different milling techniques can have a different effect on the same material. For example ball milling at ambient temperature and jet micronisation of the SFZ tosylate salt caused a notable increase in the melting point of the material whereas ball milling at cryogenic temperatures did not cause this to happen. The IGC data collected for this form also showed a contrast between cryomilling and the other two techniques. The study also showed that the formation of salts and cocrystals does not necessarily offer any increased stability in terms of physical properties or surface energetics. Changes in melting point were observed for the SFZ tosylate salt and the IMC:Benzamide cocrystal. Changes in the specific surface energies were also observed indicating that the nature of the surfaces was also changing. The materials which appeared to be affected the least were the two stable polymorphs, gamma IMC and SFZ III. The computational approach used has many limitations. The software does not allow for conversion to the amorphous form or polymorphic conversions. Such conversions were seen to occur, particularly for the metastable polymorphs used, meaning that this computational approach may only be suitable for stable polymorphs.
    URI
    http://hdl.handle.net/10454/5412
    Type
    Thesis
    Qualification name
    PhD
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