Time-of-Flight Methods for the Measurement of the Aerodynamic Particle Size Distribution of Aerosols from Orally Inhaled Products: Points to Consider

Jolyon Mitchell

Background: Particle time-of-flight (TOF) methods rapidly determine the number-weighted aerodynamic particle size distribution (APSD) of aerosols from 0.3 to >20 μm aerodynamic diameter from all classes of orally inhaled product (OIP). Software is then used to calculate the mass-weighted APSD which should be equivalent to that obtained by the slower and substantially more complicated-to-use cascade impactor (CI) methods recommended in the pharmacopoeial compendia.
Methods: We review this choice of techniques to obtain APSD-related information during the OIP life cycle, where there is regulatory freedom to do so. We also examine considerations concerning TOF- versus CI-based APSD determination for the different classes of OIP.
Results: A serious drawback to TOF analysis has been the lack of a chemical assay for the active pharmaceutical ingredient(s) in the size-characterized particles. However, this limitation may be about to be overcome if TOF analysis is combined with single particle mass spectrometry, developed originally for bio-aerosol detection and size-categorization. The correlation of measures of clinically important fine particle mass (FPM) by TOF- and CI-based analyses can be achieved by the simultaneous measurement of this metric using a single-stage abbreviated impactor add-on supplied by the manufacturer of the most frequently encountered TOF analyzer.
Conclusions: Users need to consider several potential sources of bias with TOF analysis, in particular distortion of droplets > 5 μm diameter, deviations in particle density and shape from unit density microspheres, and increased statistical ‘noise’ associated with the number-to-mass weighting conversion.

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