The Formation of Aerosol Particles from Solution-Based Pressurized Metered Dose Inhalers and Implications of Incomplete Droplet Drying: Theoretical and Experimental Comparison

Abstract

The aerosol particle size distributions of solution-based pressurized metered dose inhalers containing 15%w/w ethanol and different quantities of nonvolatile component (NVC) (drug and glycerol) were evaluated at 25 C and 55 C, using a custombuilt heating rig that preheated air prior to aerosolization. Particle size distributions were assessed using an Andersen cascade impactor and massÀweighted cumulative aerodynamic diameter distributions were compared to a theoretical model that predicts the final size distribution, based on initial droplet size, vapor pressure of the formulation containing HFA 134a and percent NVC. In general, the mass median aerodynamic diameter was proportional to NVC 1/3 , with experimental particle size distributions following theoretical values. However, when comparing theoretical vs. experimental data over the range of mass-weighted cumulative aerodynamic diameter distributions between 10 and 90%, the 55 C experimental measurements more closely fitted the theoretical equation when compared to 25 C. This was attributed to incomplete drying of some of the larger initial droplets prior to impaction. Additionally, postinduction port measurements of volumetric size distribution using laser diffraction, showed a reduction in median particle diameter at 55 C, compared to 25 C and a change from bimodal to monomodal distribution, indicating complex drying kinetics under ambient conditions.

Quality control and testing evaluation of pharmaceutical aerosols

“…Many concerns need to be measured in order to obtain a product with appropriate quality depending on the requirements of the national authorities and legislation, and the manufacturers' internal policies for production process (safety, marketing, etc.). For pharmaceutical aerosols, quality evaluation depends on several tests performed throughout the formulation development, in the process and finished product inspection phases (Zhu et al, 2015).…”

Experimental investigations of particle formation from propellant and solvent droplets using a monodisperse spray dryer

“…The formation of solid particles from evaporating solution droplets is a phenomenon of some interest in the field of aerosol science, with particular importance in pharmaceutical spray drying (Paudel et al 2013;Singh and Van den Mooter 2016) and inhaled drug delivery (Sheth et al 2017;Zhu et al 2015). The initial size and composition of the droplet and the conditions under which it evaporates determine the kinetics of the transition from droplet to residual particle, with consequences for the morphology and degree of molecular order of the dried particle (Hoe et al 2014).…”

“…Examples in pharmaceutical spray drying include bioavailability enhancement of orally administered drugs (Davis 2018), glass stabilization of biologics (LeClair et al 2016), and drug encapsulation for stabilization or modified release (Walz et al 2017). In inhaled drug delivery, particle engineering principles have been applied to optimize powder physical properties for delivery with dry powder inhalers (Kaialy and Nokhodchi 2015;Weers and Tarara 2014) and to manipulate the size (Zhu et al 2015) and physical properties (Haghi et al 2014) of particles produced from pressurized metered dose inhalers.…”