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    Mechanistic Insights into the Stabilisation of Biopharmaceuticals using Glycine Derivatives. The Effect of Glycine Derivatives on the Crystallisation, Physical Properties and Behaviour of Commonly used Excipients to Stabilise Antigens, Adjuvants and Proteins in the Solid State

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    PhD Thesis (6.250Mb)
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    Publication date
    2015
    Author
    Bright, Andrew G.
    Supervisor
    Isreb, Mohammad
    Keyword
    Freeze drying
    Glycine derivatives
    Differential scanning calorimetry (DSC)
    Powder X-Ray diffraction (P-XRD)
    Raman spectroscopy
    Crystallisation
    Water loss
    Vaccines
    Adjuvant
    Stabilisation
    Amorphous
    Gordon-Taylor equation
    Solubility parameters
    Karl Fischer
    Excipients
    Proteins
    DLS (Dynamic Light Scattering)
    Polymorphs
    Vaccines
    Formulation
    Mannitol
    Sucrose
    Biopharmaceuticals
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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
    School of Pharmacy, Faculty of Life Sciences
    Awarded
    2015
    
    Metadata
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    Abstract
    This dissertation has focused on studying the effect of four glycine derivatives on the solid state properties of mannitol, glycine, and sucrose when freeze dried into blended mixtures. The primary goal was to assess their value for use in the stabilisation of vaccines in the solid state, by examining key physical and chemical characteristics, which have been documented to be beneficial to the stabilisation of biopharmaceutical formulations. The novel excipients; dimethyl glycine, and trimethyl glycine, were shown to retard the crystallisation and increase the overall glass transition temperature, of mannitol, when freeze dried as evidenced by DSC and Powder X-ray diffraction. Mannitol’s glass transition temperature increased from 100C to 12.650C and 13.610C when mixed with methyl-glycine and dimethyl glycine respectively. The glycine derivatives did not show the same effect on sucrose which remained amorphous regardless of the concentration of the other excipient. The different behaviour with the sucrose system was thought to be due to relatively high glass transition temperature of sucrose. Conversely glycine remained highly crystalline due it’s relatively low glass transition temperature. The novel excipient formulations were also assessed for their effect on the aggregation of the adjuvant aluminium hydroxide when freeze dried by Dynamic Light Scattering (DLS).The formulations containing the glycine derivatives all caused a decrease in the aggregation size of the adjuvant from ~26 μm, to 185 nm in the presence of methyl glycine. The effects of lysozyme and viral antigen on the adjuvants were also examined showing that the addition of the virus did not affect the size of the aggregates formed, however lysozyme showed significant decreases in the aggregates formed. Examination of the freezing method were also made showing that faster freezing rates produced smaller aggregates of the adjuvant. When investigating the rate at which the excipients lost water during secondary drying there was evidence of the formation of hydrates of glycine, trimethyl glycine, and mannitol has shown that the glycine derivatives have attributes which would be beneficial in stabilising vaccines in the solid state when freeze dried.
    URI
    http://hdl.handle.net/10454/15943
    Type
    Thesis
    Qualification name
    PhD
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