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Formulation Design of Spray-Dried Microparticles for Respiratory Drug Delivery
- Author / Creator
- Ordoubadi, Mani
In this thesis, several fundamental studies were conducted to tackle some of the unanswered questions in the design and engineering of inhalable microparticles produced via spray drying. Different experimental and theoretical methods were applied to understand the mechanisms that control particle formation of formulations containing solvents and excipients of the most interest.
Chapter 1 contains a brief introduction to drug delivery to the lungs in general and the appropriate tools and devices used. Next, the spray drying process is introduced and explained as one of the industrial processes employed in the production of pulmonary microparticles. The most pressing problems and questions faced by a formulator are discussed next, both with respect to overcoming the issue of emerging low-water-soluble drugs and with respect to choosing the necessary excipients to meet the physicochemical targets in the final product.
Chapter 2 focuses on the evaporation of multi-solvent microdroplets and the ensuing particle formation pertaining to the spray drying of inhalable powders containing hydrophobic active ingredients. The evaporation of such multi-solvent droplets and their internal solute transfers are theoretically modeled and compared to the measurements performed using a single-particle electrodynamic balance and a droplet chain instrument. The results show that the two parameters controlling the general morphology of the dried particles the most - namely the level of saturation and the Péclet number - change with time in a multi-solvent droplet during evaporation. This temporal variation of the parameters introduces complexities during the formulation design but vanishes at an iso-compositional state similar to the azeotrope of non-ideal mixtures.
In Chapter 3, the particle formation of L-leucine, a dispersibility-enhancing amino acid is studied extensively. Three complementary experimental methods are used: an electrodynamic balance, a monodisperse droplet chain, and a conventional lab-scale spray dryer. The shell formation kinetics of leucine in the presence of trehalose is measured using the electrodynamic balance, the particle morphologies and densities are studied using the droplet chain instrument, and spray drying is used to produce powders representative of actual industrial applications and to allow for further characterization and analytical measurements. A modified particle formation method appropriate for crystallizing components is developed to interpret the experimental measurements and observations. It is confirmed that other components can interfere with the free crystallization of the shell former. Moreover, it is observed that the surface coverage of a crystallizing shell former such as leucine shows a rather large variation for different particle sizes in the same batch of powder, which points to the mechanisms of nucleation and crystal growth in such systems. The modified particle formation theory is hence shown to be a valuable tool in the formulation design of systems containing a number of excipients and active ingredients.
In Chapter 4, the formation of trileucine-containing microdroplets is studied experimentally, and the results are explained theoretically. The kinetics of shell formation is measured using an electrodynamic balance and a droplet chain is used to measure the particle densities and examine the morphologies. Spray drying is used to produce enough powder for spectroscopy analysis. A comparison of the results to theoretical models reveals that the dispersibility enhancement of trileucine is due to two consecutive stages: the adsorption of a mono-molecular layer on the droplet surface owing to its surface activity and the early amorphous phase separation as a result of its low aqueous solubility. Based on this information, a process is proposed so that a formulator can design an excipient system to make low- or high-density particles to meet the design targets while maintaining good aerosol performance.
Chapter 5 summarizes the main conclusions of the thesis and presents some suggestions for future work.
- Graduation date
- Fall 2021
- Type of Item
- Doctor of Philosophy
- This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.