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Thermal and morphological studies of the segmented multiblock copolyesters containing 2,2,4,4-tetramethyl-1,3-cyclobutanediol and dimethyl-1,4-cyclohexane dicarboxylate were carried out using differential scanning calorimetry, small angle X-ray scattering, wide angle X-ray diffraction and dynamic mechanical analysis. Molecular origins of the thermal transitions appearing in copolyesters were assigned by the copolyester analysis at different temperatures. The hard segments in copolyesters underwent short-range and long-range ordering (crystallization) during cooling or annealing above glass transition temperature, as concluded from thermal and wide angle X-ray diffraction analysis. Annealing process affected the ordering in hard segments and annealing temperatures of 160 °C and above led to increased microphase mixing. The small angle X-ray scattering studies confirmed the microphase separated morphology of copolyesters and supported the argument of increased microphase mixing in copolyesters annealed at higher temperatures. The amount of sulfonate containing co-monomer and its presence in either hard or soft microphase affected the morphology of the copolyesters. Introduction of the sulfonate groups led to increased microphase mixing in copolyesters as well as destruction of long-range order in the hard segments. / Master of Science

This thesis investigates enhancing the thermal stabilization of a human type 5 adenoviral vector (AdHu5) through spray drying. The spray drying process was used to dry and effectively immobilize the AdHu5 within a mixture of carbohydrate or amino acid excipients into a powder form, resulting in significantly increased thermal stabilization of the viral vector. Spray dried powders were characterized by scanning electron microscopy, differential scanning calorimetry, Karl Fischer titrations, X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS) to identify the effects of temperature and atmospheric moisture on the immobilizing matrix. The best performing spray dried powder in terms of thermal stability consisted of an excipient blend of mannitol and dextran. Response surface methodology was employed to optimize production of these mannitol/dextran powders; measured responses were those relevant to industrial processing of a therapeutic material, namely powder yield for maximizing quantity, particle size for maximizing production of inhalation-deliverable powders, and adenoviral vector response for minimizing the loss of therapeutic activity. The spray drying process parameters of inlet temperature, spray gas flow rate, liquid feed rate and solute concentration in the feed were optimized resulting in a powder yield of 90%, percentage of ideally-sized particles of 50% and a near-zero viral vector titre loss of 0.25 log loss median tissue culture infectious dose (TCID50). The spray dried mannitol/dextran powders proved to have exceptional thermal stability during long term storage as minimal viral vector activity loss was observed when stored at 20°C for 90 days at low relative humidity (0.7 ± 0.3 log TCID50) in comparison to the liquid control which exhibited complete activity loss under the same storage conditions. Furthermore, viral activity of mannitol/dextran powders was retained over short term exposure (72 hours) to temperatures as high as 55°C whereas the liquid control expectedly lost all AdHu5 activity after 30 minutes. Overall, this work provides a guideline for the production of thermally stable powders and active biopharmaceuticals, such as AdHu5 vectors for vaccine applications, using the spray drying process. / Thesis / Master of Applied Science (MASc) / Many vaccines and their base components inherently deteriorate in function at moderate temperatures. Storage by refrigeration at temperatures ranging between 4°C and -80°C is the norm. Such refrigeration is costly for long term storage and significantly limits where vaccines can be sent. This reduces the availability of vaccines in locations around the world where these storage conditions are infeasible but vaccines are needed most. Spray drying, a process which forms dry powders from solution, was used; the solution contained sugars or amino acids to surround and protect the sensitive vaccine component. The produced powders from this work exhibited enhanced thermal stability compared to the control, reducing the need for refrigeration during storage and transport. The spray drying process was further optimized for industrial use by maximizing the amount of powder recovered and ensuring the particle size was appropriate for inhalable use, but most importantly, minimizing losses in therapeutic effectiveness during processing. This production of a thermally stable vaccine is advantageous because is allows for better world-wide accessibility and reduces overall production and delivery costs.

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