Factors influencing aerodynamic particle size distribution of suspension pressurized metered dose inhalers

Abstract

Pressurized metered dose inhalers (pMDIs) are frequently used for the treatment of asthma and chronic obstructive pulmonary disease. The aerodynamic particle size distribution (APSD) of the residual particles delivered from a pMDI plays a key role in determining the amount and region of drug deposition in the lung and thereby the efficacy of the inhaler. In this study, a simulation model that predicts the APSD of residual particles from suspension pMDIs was utilized to identify the primary determinants for APSD. These findings were then applied to better understand the effect of changing drug concentration and micronized drug size on experimentally observed APSDs determined through Andersen Cascade Impactor testing. The experimental formulations evaluated had micronized drug mass median aerodynamic diameters (MMAD) between 1.2 and 2.6 μm and drug concentrations ranging from 0.01 to 1% (w/w) with 8.5% (w/w) ethanol in 1,1,1,2-tetrafluoroethane (HFA-134a). It was determined that the drug concentration, micronized drug size, and initially atomized droplet distribution have a significant impact in modulating the proportion of atomized droplets that contain multiple suspended drug particles, which in turn increases the residual APSD. These factors were found to be predictive of the residual particle MMAD for experimental suspension HFA-134a formulations containing ethanol. The empirical algebraic model allows predicting the residual particle size for a variety of suspension formulations with an average error of 0.096 μm (standard deviation of 0.1 μm).

Fig. 1

Depiction of the Monte Carlo simulation algorithm utilized to model suspension pMDI formulations. Steps 1 to 4 are repeated until sufficient initial droplets are simulated. Particle size distribution is abbreviated as PSD. All other abbreviations can be found in text

Fig. 2

The approximate occurrence of residual particles containing 0, 1, or more than 1 drug particle (left y-axis) and residual MMAD (right y-axis) with respect to drug concentration for micronized suspended drug with a MMAD of 1.5 μm (GSD of 2.0) for a HFA-134a formulation containing 8% (w/w) ethanol and no other excipients

Fig. 3

The approximate occurrence of residual particles containing 0, 1, or more than 1 drug particle (left y-axis) and residual MMAD (right y-axis) with respect to drug concentration for micronized suspended drug with a MMAD of 2.5 μm (GSD of 2.0) for a HFA-134a formulation containing 8% (w/w) ethanol and no other excipients

Fig. 4

The proportion of atomized droplets containing suspended drug particles for formulations with 0.1 to 1% (w/w) drug for a HFA-134a formulation containing 8% (w/w) ethanol. Three different sizes of initial droplet sizes were evaluated: 9.1, 10.7, and 12.3 μm (GSD of 1.8). The MMAD of the suspended micronized drug is 2.5 μm (GSD of 2.0). No other excipients were included in the simulated formulation

Fig. 5

The percentage of simulated aerosolized droplets that contain two or more drug particles in a sample of only drug-containing particles as a function of the drug concentration and the MMAD of the micronized drug. All simulations contained micronized drug with a GSD of 1.8, 8% (w/w) ethanol in HFA-134a; no other excipients were included in the simulations

Fig. 6

The percentage of drug-containing atomized droplets that contain some number of drug particles for 0.4% (w/w) suspended drug, with 8% ethanol in HFA-134a. The purple bars represent 2.5 μm MMAD (GSD of 1.8) micronized drug with an initial droplet MMD of 8.0 or 13.0 μm (GSD of 1.8). The green bars represent 1.0 μm MMAD (GSD of 1.8) micronized drug with an initial droplet MMD of 8.0 or 13.0 μm (GSD of 1.8)

Fig. 7

A comparison of the ratio of the residual particle MMAD to the micronized drug MMAD for various sized micronized drug at different concentrations. All simulations were conducted with 8% ethanol in HFA-134a, with no additional excipients

Fig. 8

The percentage of multiplets (on the left y-axis) with the ratio of residual drug MMAD to the MMAD of the micronized drug (on the right y-axis) for a given number of particles per unit volume (PPUV). The various symbols refer to different micronized drug size (all with GSD of 1.8). Unshaded symbols correspond to the percentage of multiplets axis. Shaded symbols correspond to the MMAD ratio. All simulated formulations contained drug concentration between 0.1 and 1.2% (w/w), 8% ethanol in HFA-134a, with no additional excipients

Fig. 9

A comparison of experimental residual MMAD values derived by Andersen Cascade Impactor measurements to those values derived from Eq. 6, with 8.5% (w/w) used as the ethanol concentration for calculating the initial droplet MMD. The red dotted diagonal represents the line of unity. The model micronized drug MMAD varied from 1.22 to 2.62 μm (with varying micronized drug GSD). All formulations contained varying concentrations of drug with a nominal 8.5% (w/w) ethanol and HFA-134a. All of the aerosol vials were fitted with 50 μL Spraymiser™ valves with 0.3 mm actuator orifice diameters