A model of transient internal flow and atomization of propellant/ethanol mixtures in pressurized metered dose inhalers (pMDI)

Abstract

This article reports the extension to binary propellant/excipient mixtures of the multiphase model of transient internal flow and atomization in pressurized metered dose inhalers (pMDIs) of Gavtash and colleagues for propellant-only flows. The work considers different accounts of the effect of less volatile ethanol on the saturated vapor pressure (SVP), viscosity and surface tension of HFA-based pMDI formulations. Representation of the SVP of HFA/ethanol mixtures by Raoult's law is compared with the empirical model developed by Gavtash and colleagues as well as different theoretical mixing rules for surface tension and viscosity. For initial ethanol contents ranging from 0 to 20% by mass, the temperature, pressure and spray velocity were predicted to be almost independent of ethanol concentration when using the empirical SVP model of Gavtash and colleagues. The predicted aerosol droplet size increases with increasing concentration of ethanol. These model predictions compare favorably with phase Doppler anemometry (PDA) measurements of pMDI sprays. Exploration of model predictions with different mixing rules suggest that variations of the dynamic viscosity could result in 0.7 mm droplet size change, and different surface tension models yield around 1.5 mm droplet size change. The findings of this work challenge the view that the increase of droplet size is caused by the low volatility of excipients such as ethanol. Instead, attention is focused on composition-dependent viscosity and surface tension as potential controlling parameters with significant effect on the droplet size of HFA/ethanol sprays.

In Silico Methods for Development of Generic Drug–Device Combination Orally Inhaled Drug Products

“…One group has used theoretical mathematical formulations to produce both velocity and APSD boundary conditions at the orifice, indicating good agreement with experimental values using this approach . Recently, this same group has developed a theoretical method for predicting velocity and APSD boundary conditions for mixtures of ethanol and 1,1,1,2‐tetrafluoroethane (HFA‐134a), as illustrated in Figure . The method is based on work by Fletcher and Clark, where the behavior of constituents in the metering and expansion chambers, as shown in Figure a , is modeled using a homogeneous frozen flow model that does not permit evaporation in these regions but rather allows isentropic expansion .…”

“…Methodology used by Gavtash et al . to predict ( a ) fluid behavior in the metering and expansion chambers of ethanol/propellant mixtures and ( b ) transitional behavior through the spray orifice into an annular sheet exiting the orifice followed by droplet formation.…”

“…27,28 Recently, this same group has developed a theoretical method for predicting velocity and APSD boundary conditions for mixtures of ethanol and 1,1,1,2-tetrafluoroethane (HFA-134a), as illustrated in Figure 1. 38 The method is based on work by Fletcher 39 and Clark, 40 where the behavior of constituents in the metering and expansion chambers, as shown in Figure 1a, is modeled using a homogeneous frozen flow model that does not permit evaporation in these regions but rather allows isentropic expansion. 38,41 Upon exit from the spray orifice, atomization is predicted using the model developed by Gavtash et al 42 as displayed in Figure 1b, where the initial output is treated as a flat sheet using the linear instability sheet analysis framework as developed by Senecal et al, 43 which predicts growth of the wave-induced stabilities that are responsible for droplet breakup.…”

“…38 The method is based on work by Fletcher 39 and Clark, 40 where the behavior of constituents in the metering and expansion chambers, as shown in Figure 1a, is modeled using a homogeneous frozen flow model that does not permit evaporation in these regions but rather allows isentropic expansion. 38,41 Upon exit from the spray orifice, atomization is predicted using the model developed by Gavtash et al 42 as displayed in Figure 1b, where the initial output is treated as a flat sheet using the linear instability sheet analysis framework as developed by Senecal et al, 43 which predicts growth of the wave-induced stabilities that are responsible for droplet breakup. Further development and application of methods such as these will be beneficial for future CFD studies seeking to compare a generic MDI to the corresponding RLD because they may directly capture the influence of device and formulation changes on APSD and other in vitro metrics.…”

“…Recently, this same group has developed a theoretical method for predicting velocity and APSD boundary conditions for mixtures of ethanol and 1,1,1,2‐tetrafluoroethane (HFA‐134a), as illustrated in Figure . The method is based on work by Fletcher and Clark, where the behavior of constituents in the metering and expansion chambers, as shown in Figure a , is modeled using a homogeneous frozen flow model that does not permit evaporation in these regions but rather allows isentropic expansion . Upon exit from the spray orifice, atomization is predicted using the model developed by Gavtash et al .…”