Metered Dose Inhaler Aerosols: Efficiency, Particle Engineering and Atomization

• Author / Creator

  Molaghasem Shemirani, Farzin

• The current work focuses on three different aspects of the aerosols involved in Metered Dose Inhaler (MDI) sprays. The efficiency of the drug delivery in different ambient conditions, production of monodisperse solid particles to study the heat and mass transfer processes involved, and study of flash atomization process in a propellant jet are the main topics in the present work. The aim of the first part is to investigate in vitro mouth-throat deposition and lung delivery of selected solution and suspension pMDI formulations, under a range of relative humidity, temperature and flow rate conditions. The Alberta Idealized Throat was connected to a collection filter, and placed in an environmental control chamber. The formulations selected were beclomethasone dipropionate (BDP) in 13% w/w ethanol/1.3% w/w glycerol and HFA134a propellant solution (‘BDP HFA134a’), BDP in 13% w/w ethanol and HFA227 propellant solution (‘BDP HFA227’), and Flixotide Evohaler (fluticasone propionate 250 µg/dose in HFA134a suspension). Each of these pMDI formulations were dispersed into the mouth-throat and filter assembly in triplicate, according to an experimental matrix consisting of the following conditions – air flow rates of 28.3, 60 and 90 L/min; 0%, 35% and 80% RH; operating temperatures of 20°C and 40°C. There was a general increase in mouth-throat deposition, and corresponding decrease in filter deposition (representing lung dose fraction), with increasing relative humidity for both BDP HFA134a and Flixotide pMDIs. Increasing temperature from 20 to 40°C resulted in decreased mouth-throat deposition and increased lung dose fraction for the solution pMDIs, but generally no effect for the suspension pMDI. Not only is the dose delivery of pMDI formulations affected by environmental conditions (in some cases causing up to 50% reduction in lung delivery), but solution and suspension formulations also behave differently in response to these conditions. These results have implications for dosage form design and testing, and for patient use. The second part describes an atomizer capable of generating monodisperse droplets of high vapor pressure liquids such as HFA227ea and HFA134a, which is expected to be a useful tool in future fundamental explorations of the mechanics of these highly dynamic aerosols. Hydrofluoroalkanes (HFAs) are the most common propellants in metered dose inhalers (MDIs), which are themselves the most common delivery method for pulmonary disease medications. As a result of the high vapor pressure of these fluids, generation of monodisperse droplets and their study are not possible with previously existing monodisperse atomizers due to fluid flashing when exposed to ambient conditions. The new atomizer uses a piezoelectric transducer to disintegrate the propellant jet, a cooling circuit with a low temperature limit of -30 ℃ to reduce propellant vapor pressure, and a high pressure feed system (up to 2.7 MPa) to keep the propellant in the liquid phase, thereby avoiding flash atomization. In the current setup, the diameter of the generated droplets was monitored with a laser scattering system (using Fraunhofer diffraction theory) to optimize the operating parameters of the set-up (for example, the actuation frequency and amplitude of the piezoelectric transducer). This monitoring system allowed for the measurement of droplet geometric diameter, spacing, and velocity. The capabilities of the atomizer for generating monodisperse droplets are demonstrated by a case study in which monodisperse dry particles of beclomethasone dipropionate (BDP) are generated using a solution of BDP, ethanol co-solvent, and HFA134a propellant. The parameters affecting the onset of flash atomization in cylindrical micro-jets were studied in the third part. A custom atomizer, a pressurized feed system, and a controlled flow tube were designed to produce stable jets of propellant mixtures at different initial liquid temperatures. Propellants chosen were HFA134a and HFA227ea which are used in most pressurized metered dose inhalers (MDIs). Ethanol, a common co-solvent in MDIs, was also added to the propellants at 10, 15 and 20% w/w concentrations to investigate its effect on flashing. Orifices used for the production of the jets ranged from 5 to 35 µm in diameter. A critical jet diameter above which flashing was the dominant mechanism of atomization was found at each temperature and formulation. A correlation was developed to relate the critical jet diameter to the thermo-physical properties of the formulation at different temperatures.

• Subjects / Keywords

  • Throat deposition
  • Monodisperse
  • Vibrating orifice aerosol generator
  • Propellant
  • Humidity
  • Flash atomization

• Graduation date

  Spring 2015

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R30R9M88R

• License

  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.