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Particle Formation from Evaporating Microdroplets for Inhaled Drug Delivery

  • Author / Creator
    James Ivey
  • This thesis is concerned with the mechanisms by which evaporating droplets containing dissolved or suspended solids transform into dry particles, and emphasizes applied research in the area of inhaled drug delivery. The main focus is on understanding and quantifying the relationships between the composition of the droplets, the evaporation conditions, and the resulting physical properties of the residual particles. Chapter 1 briefly introduces the basic principles of inhaled drug delivery, the importance of the drug particle physical properties, and the most commonly used delivery devices. The delivery of drugs using pressurized metered dose inhalers is described in more detail. The spray drying process is introduced at a high level, and some considerations specific to the spray drying of engineered particles for pulmonary drug delivery are presented. In Chapter 2, models are developed for the prediction of the aerodynamic particle size distribution produced by pressurized metered dose inhalers. Dimensional analysis is employed to analyze a large set of aerodynamic particle size distribution data for solution metered dose inhalers, resulting in a correlation equation for prediction of the mass median aerodynamic diameter. A stochastic model is developed to simulate the spatial distribution of a polydisperse discrete phase amongst a polydisperse spray of droplets, with the intention of evaluating the effect of aggregation on the aerodynamic particle size distribution for suspension pMDIs. A nonlinear curve fit to model results is developed which enables predictions of the aerodynamic particle size distribution for suspension metered dose inhalers as well. Chapter 3 presents a study of the effects of air relative humidity on the morphology of particles emitted by solution metered dose inhalers containing a common inhaled drug. The work demonstrates that condensed water can have a strong effect on particle morphology, with the extent determined by the formulation variables; in this case highly porous particles were produced when the metered dose inhaler was sprayed in humid air. The possible implications for the efficacy of treatment are discussed. Chapter 4 describes the design of a custom modular laboratory scale spray dryer; in combination with a novel isokinetic sampling system, its use for the characterization of atomization and collection equipment is demonstrated. Integration of a custom atomizer enables monodisperse spray drying using conventional solvents or superheated liquid propellants. Parametric particle formation studies are conducted with organic solutes in ethanol and a hydrofluoroalkane propellant which is widely used in pressurized metered dose inhalers. The dependence of particle physical properties on droplet diameter, solution concentration, solvent type, and evaporation rate are evaluated using models of particle formation. Chapter 5 reiterates the main conclusions arising from the work, and suggests possible areas for future investigations.

  • Subjects / Keywords
  • Graduation date
    Fall 2018
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3RB6WJ3S
  • License
    Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.