Why aerodynamic size reflects airway deposition
- Aerodynamic particle size distribution (APSD)
- Aerodynamic particle size distribution describes how the mass of an aerosolized active substance is distributed across aerodynamic diameters. Aerodynamic diameter is the diameter of a unit-density sphere that settles at the same velocity as the particle. It reflects how inertia and gravity carry a particle through the airways, rather than how the particle looks or scatters light.1,6
Deposition in the mouth, throat, and lungs is driven by inertial impaction and sedimentation. Aerodynamic particle size distribution therefore connects a measured aerosol with its likely deposition pattern. A metered dose inhaler, dry powder inhaler, nebulizer, or nasal product may share a target diameter range but behave differently once flow, device resistance, and formulation are taken into account.3,6
This page focuses on particle size from an aerodynamic, inhalation-specific perspective. For other sizing bases, including optical and geometric diameters, see the particle size explainer. Spray pattern and plume geometry are covered in the spray and plume dynamics explainer. Aerodynamic assessment addresses a narrower question: how inhaled mass separates according to settling behavior.6
MMAD and GSD summarize the distribution
- Mass median aerodynamic diameter (MMAD)
- Mass median aerodynamic diameter is the aerodynamic diameter that divides the aerosolized active substance mass into two equal halves. Half lies in particles with larger aerodynamic diameters and half in particles with smaller aerodynamic diameters. MMAD is read from the cumulative, mass-weighted aerodynamic distribution and is most meaningful when the distribution is close to log-normal.1,6
Geometric standard deviation describes how widely the distribution spreads around the median. MMAD and geometric standard deviation can summarize an aerosol that is close to log-normal. A distribution with more than one mode, or substantial mass at either extreme, needs the full staged data rather than a single median. For that reason, reports include the underlying stage masses alongside MMAD and geometric standard deviation.1,4,6
| Metric | What it represents | Typical basis |
|---|---|---|
| Mass median aerodynamic diameter (MMAD) | The aerodynamic diameter that splits the active substance mass into equal halves | Median of the cumulative mass-weighted aerodynamic distribution |
| Geometric standard deviation (GSD) | The spread of the distribution around the MMAD | Ratio measure that applies when the distribution is close to log-normal |
| Fine particle fraction (FPF) | The portion of the dose in particles below a defined aerodynamic cut-off, commonly near 5 µm | Impactor mass below the cut-off relative to the delivered or metered dose |
| Fine particle dose (FPD) | The mass of active substance below the defined cut-off diameter | Sum of stage masses on impactor stages below the cut-off |
| Delivered (emitted) dose | The mass of active substance leaving the mouthpiece per actuation | Collected on a dose unit sampling apparatus, separate from the size split |
Fine particle fraction and fine particle dose describe material in a respirable aerodynamic size range. Fine particle fraction is the portion of the dose below a defined aerodynamic cut-off, commonly near 5 µm. Fine particle dose is the corresponding mass of active substance. The method and product determine the exact cut-off and whether the fraction is referenced to the metered dose or the delivered dose. These in vitro metrics characterize aerodynamic size; they do not directly measure lung deposition.1,4
Cascade impaction is the reference method
A cascade impactor draws the aerosol through a stack of stages with progressively finer nozzles. Particles with enough inertia strike and collect on a stage, while smaller particles follow the airflow to the next one. The active substance recovered from each stage is then assayed. The resulting stage masses show how much material falls within each aerodynamic size band and together form the aerodynamic distribution.5,6
Two impactor designs appear most often in inhaler testing. The NGI is a seven-stage impactor with a micro-orifice collector and a pre-separator. It is used with metered dose inhalers, dry powder inhalers, nebulizers, and nasal aerosols. The Andersen cascade impactor is an earlier multi-stage design that remains referenced in compendial methods. Both separate particles by aerodynamic behavior and produce stage masses that are converted into a size distribution.2,5,6
| Impactor stage | Aerodynamic cut-off diameter |
|---|---|
| Stage 1 | 8.06 µm |
| Stage 2 | 4.46 µm |
| Stage 3 | 2.82 µm |
| Stage 4 | 1.66 µm |
| Stage 5 | 0.94 µm |
| Stage 6 | 0.55 µm |
| Stage 7 | 0.34 µm |
The cut-off diameter of each stage depends on the flow rate through the impactor, so the operating flow must be specified for the product and method and held constant during testing. In the NGI, the finest particles pass through the stages and are captured by the micro-orifice collector, closing the mass balance at the small end of the distribution.2,5
Compendial frameworks for aerodynamic assessment
USP <601> sets performance quality tests for inhalation and nasal aerosols, sprays, and powders. The chapter includes aerodynamic size assessment reported through MMAD and geometric standard deviation when the distribution is log-normal. USP <1601> adds characterization tests for nebulized products, with droplet size assessed by cascade impaction at 15 L/min. In Europe, Ph. Eur. 2.9.18 covers aerodynamic assessment of fine particles. Under this method, the Andersen impactor is calibrated at 28.3 L/min, and MMAD and geometric standard deviation are derived from a log-probability plot.1,2,4
- The measured distribution depends on the operating flow rate, which is matched to the product and to the compendial method.2,5
- MMAD and geometric standard deviation assume an approximately log-normal distribution, so multimodal aerosols are better described by the full stage data.4,6
- Fine particle fraction and fine particle dose depend on the chosen cut-off diameter and on the dose reference used.1,4
- Aerodynamic results describe the emitted aerosol under the test conditions and are a characterization measurement, not a clinical deposition outcome.3,6
Abbreviated impactor measurement in routine work
Full cascade impaction provides detailed data, but it is slow. Routine and quality-control programs may instead use an abbreviated impactor measurement that retains only the stages needed to separate the aerosol into coarse and fine fractions. With efficient data analysis, this approach can track changes in fine fraction and impactor-sized mass. Full APSD is still used when the work requires characterization or product comparison.6
How ARE Labs measures APSD
ARE Labs measures aerodynamic particle size distribution by cascade impaction. The impactor, flow rate, and staging are selected to match the product and the study objective. Metered dose inhalers, dry powder inhalers, nebulizers, and nasal products require different actuation and flow conditions, so the method plan documents those conditions together with the resulting stage masses.1,2,5
Reporting may include the full staged distribution, MMAD and geometric standard deviation, or fine particle fraction and fine particle dose. Depending on program needs, the report may also include delivered-dose and breathing-simulation data. These measurements characterize the emitted aerosol under defined conditions, and ARE Labs explains what the results can and cannot support.1,4,6