Inhaled Product Characterization

The authors discuss the analysis of the resulting data, focusing on methods for the calculation of mass median ærodynamic diameter, one of the metrics routinely used for comparative testing.
Nov 01, 2011
Volume 2011 Supplement, Issue 6

Cascade impaction is mandated by the regulators for the measurement of aerodynamic particle size for all orally inhaled and nasal drug products (OINDPs). Multistage cascade impactors are used to size-fractionate a sample on the basis of particle inertia, uniquely enabling measurement of the particle-size distribution of the active ingredient, rather than of the complete formulation. The resulting information is crucial when assessing the likely deposition behavior of the drug during inhalation and is also widely taken to be an in vitro indicator of delivery efficiency.

Through development and into quality control (QC), cascade impaction generates significant amounts of data. For newcomers to the technique, understanding how to process and use data for comparative testing can be a significant challenge. On the other hand, those leading the industry are currently involved in an active debate over the best metrics for characterizing OINDP particle size and the optimal way of measuring them.

Beginning with an introduction to the technique of multistage cascade impaction, this article discusses analysis of the resulting data. A particular focus is the different calculation methods used to determine mass median aerodynamic diameter (MMAD). MMAD is one of the metrics most widely adopted as a single number descriptor of aerodynamic particle-size distribution (APSD), and the topic of a recent Pharmacopoeial Forum Stimuli article (1). We conclude with a review of current industry thinking as to the most appropriate way to characterize OINDP particle size, outlining abbreviated impactor measurement (AIM) and the thinking behind efficient data analysis (EDA).

Multistage cascade impaction

Figure 1: Flow through a cascade impactor. At each stage, particles with sufficient inertia impact on the collection plate. Smaller particles remain entrained in the airflow and are carried to the next stage. (FIGURES 1 AND 2 ARE COURTESY OF THE AUTHORS)
Multistage cascade impactors separate an incoming sample into discrete fractions on the basis of particle inertia, which is a function of particle size and velocity. These precision instruments consist of a series of stages each comprising a plate with a specific nozzle arrangement and collection surface. As nozzle size and total nozzle area both decrease with increasing stage number, the velocity of the sample-laden air increases as it proceeds through the instrument. At each stage, particles with sufficient inertia break free from the prevailing air stream to impact on the collection surface. Therefore, at any given flow rate, each stage is associated with a cut-off diameter, a figure that defines the size of particles collected. With increasing stage number, velocity increases and so stage cut-off diameter decreases.

Importantly, the cut-off diameter associated with a given stage is a function of the air-flow rate used for testing. To reflect in-use performance, nebulizers are routinely tested at 15 L/min and dry powder inhalers may be tested at flow rates up to 100 L/min. A detailed discussion of test flow rates is beyond the scope of this article but is covered in the literature (2). For data analysis, it is simply sufficient to recognize that the processing of raw data must account for the influence of the test conditions on stage cut-off diameter.

The most widely used full resolution cascade impactors (e.g., Andersen Cascade Impactor and Next Generation Impactor) separate a sample into 7–8 discrete size fractions depending on the set-up used. Analysis of each fraction, typically by high-performance liquid chromatography (HPLC), determines the amount of active collected at each stage. Once this step is complete, and the stage cut-off diameter at the sampling flow rate defined, the analyst has the raw data needed to produce an APSD for the active ingredient of the OINDP. This is a plot of cumulative mass collected on each stage against stage cut-off diameter.

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