Table I.

Classification of Size Analysis Methods for OINDPs

Aerodynamic methods	Non-aerodynamic methods
Multi-stage cascade impactor and liquid impinger	Laser diffractometry
Full resolution CIs provide complete APSDs but are slow and labor-intensive	Rapid with high size resolution
Abbreviated impactor for simplified APSD metrics based on large and small particles (product QC) or coarse, fine, and extra-fine particles (human respiratory tract-relevant metrics)	Can be made non-invasive (no need to sample the aerosol)
	No API specificity hence inapplicable to mixtures of APIs or API + excipient(s)
	The most useful technique for size analyzing the large droplets from nasal sprays
Time-of-flight methods	Laser (phase) Doppler particle size analysis
Provide APSD directly with high size resolution, but weighting is count- rather than mass-based	Similar to LD in terms of resolution and rapidity
	No API specificity hence may be inapplicable to mixtures of APIs or API + excipient(s)
Rapid compared with cascade impaction
	Complex signal rejection criteria can make representative sampling difficult
No API specificity—hence may be inapplicable to mixtures of APIs or API + excipient(s)
	Single-particle light scattering (optical particle counting)
	Similar to LD in terms of resolution and rapidity
	No API specificity hence may be inapplicable to mixtures of APIs or API + excipient(s)
	Sampling system is needed
	Microscopy-automated image analysis
	Requires careful sample capture and preparation
	Moderately fast with automated image analysis
	Care needed to define particle boundaries
	When combined with Raman chemical imaging may provide specificity to API content

API active pharmaceutical ingredient, CI cascade impactor, LD laser diffractometry, TOF time of flight