Size Analysis of a Pressurized Metered Dose Inhaler-Delivered Solution Formulation by an Aerosizer ® -LD Time-of-Flight Aerosol Particle Size Spectrometer

Abstract

In a previous study, an Aerosizer^®-LD time-of-flight (TOF) aerosol spectrometer was shown to underestimate significantly the aerodynamic size of airborne particles produced following actuation of a suspension-based formulation delivered from a pressurized metered-dose inhaler (pMDI) via a nonelectrostatic valved holding chamber (VHC). It was postulated that the nonspecific nature of the particle detection system in terms of chemical composition was responsible for the inclusion of smaller non-drug-containing excipient particles in the measured size distribution data from this analyzer. This limitation may not apply to certain solution formulations in which the only particles remaining after the evaporation of propellant and volatile excipient (solubilizer) are composed of pure drug substance. Such a formulation (QVAR™, HFA-formulated beclomethasone di-propionate [BDP]) has recently become available, and the present investigation was therefore designed to test this hypothesis. Aerosizer^®-LD measured mass-weighted size distribution data for QVAR™ had a mass median aerodynamic diameter (MMAD) close to 1.1 μm, very similar to published data for this parameter, based on measurement of the aerosol by cascade impactor followed by drug-specific assay. However, the Aerosizer-LD underestimated the spread of the size distribution significantly. The causes are believed to be a combination of two separate effects: (1) lack of sensitivity of the particle detection system to particles finer than about 0.7 μm aerodynamic diameter and (2) preferential removal of particles larger than the MMAD, either by evaporation of residual solvent (ethanol) or by inertial/gravitational deposition in the sampling arrangement upstream of the measurement zone.