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Title: Structural integrity of active pharmaceutical ingredients in formulations by electron microscopy techniques
Author: S'ari, Mark Steven
ISNI:       0000 0004 7960 288X
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2018
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It has been estimated that up to 75% of drugs in development exhibit low water solubility. This can be problematic due to low solubility and slow dissolution rates, resulting in limited bioavailability of the drug. Amorphous solid dispersions (ASDs) have been developed to increase solubility by dispersing the drug within an amorphous polymer matrix. The amorphous drug must remain dispersed in the correct physical form throughout the shelf-life of the product but due to thermodynamic instability of the amorphous drug phase, phase separation and recrystallisation tend to occur. Therefore characterisation techniques that can detect phase separation and crystallisation at the earliest possible stage are desirable. This thesis outlines the use of transmission electron microscopy (TEM) to address these problems within ASDs, however, the use of TEM presents its own challenge in examining organic crystals due to electron beam damage. TEM was used to determine electron fluence limits for a range of poorly water-soluble compounds and from this predict the stability of other compounds. The electron fluence limits were determined by measuring the fading of electron diffraction patterns (typically giving critical electron fluence values of 0.1 - 15 e-/Ang^2). This information can be used to reduce electron beam induced effects such as crystal damage when trying to detect low levels of crystallinity in ASD. ASDs of felodipine and copovidone, prepared by hot-melt extrusion and spray-drying at two drug loadings of 15 and 30% felodipine were examined by powder X-ray diffraction (pXRD), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) and TEM. pXRD, DSC and FTIR identified the ASDs to be amorphous and TEM was found to be the most sensitive method in detecting crystal particles at 4% by number of areas examined and also identified the presence of multiple polymorphs of felodipine (mainly forms I and II). A similar sample was then stored at 75% and 85% relative humidity to accelerate ageing to determine the amount, size and type of nucleation and growth of crystals from the ASD. It was found that the addition of water to the system caused crystallisation to occur at the edges of ASD particles in size ranges of 10 - 1000 nm and into metastable forms (II, III and IV) of felodipine. Several preliminary experiments using different electron microscopy techniques were tested to determine the viability of TEM for providing further details on the recrystallisation of ASDs. FIB-SEM, scanning moire fringe imaging and scanning electron diffraction (SED) imaging were tested. The scanning techniques provide the most promise and are shown to be capable of imaging atomic lattice of crystalline felodipine by the moire technique and identify size and form of crystals in ASDs by SED. Overall the results show TEM to be a useful addition to the range of tools used to characterise ASDs, providing detail on the size, phase and location of the early stages of crystallisation in ASD. Further work is required to fully quantify amounts of crystalline material present and defect levels of crystals within new and aged ASDs by TEM.
Supervisor: Brown, Andy ; Brydson, Rik ; Hondow, Nicole Sponsor: EPRSC
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available