Vitro Characterization Issues and Limitations

However, a further and much more important stability issue is that any entrained ambient air that enters the sizing instrument can be considerably drier than the humidified droplet-laden airstream emanating from the nebulizer. This 

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There are only two experimental strategies that have the potential to yield reliable predictive results for nebulized aerosols. The first is to measure the droplets in their fully hydrated state. This can be done either immediately as they exit the mouthpiece, using a real-time sizing instrument, or by reducing the evaporation kinetics sufficiently to allow measurement downstream with an offline techniqne snch as inertial cascade impaction. The second is to completely dry the aerosol, size the dry particles, and then calculate back to obtain the original size distribntion. Measuring the aerosol at intermediate hydration states between these two extremes is obviously problematic because the hydration state would have to be measured in order to correct the size distribution back to the original inhaled size. 

The latter approach—completely drying the aerosol— while valid, is diffi-cnlt to perform experimentally (29). The low solids content of pharmaceutical nebulizer solutions results in dry aerosols that are too fine for reliable enough measurements to be made to allow back calculation with any accuracy. For example a typical nebulizer droplet distribution with a mass median diameter of 3 pm generated from a 0.1% drug solution would result in a dry particle distribution with a mass median diameter of 0.1 pm. Obtaining size distribution data with any reasonable resolution at this size is very problematic. A further issue is that the solids content of the original droplets must be known in order to perform the calculation, and this can vary considerably during the course of nebulization. This technique has therefore not been used extensively. 

The former approach, attempting to measure the droplets in their fully hydrated state, has enjoyed more widespread use. Experimentally, this has been accomplished in a number of ways. The use of low-flow impactors that entrain minimal quantities of ambient air and hence maintain the quasiequilibrium humidity exiting the nebulizer is one approach (30). Adding humidified dilution air, rather than ambient air, to a high-volume cascade impactor is another. Cooling the impactor to the same temperature as the nebulizer cloud (reservoir) has also been shown to be an effective way of providing sufficient stabilization for aerosol measurement purposes (31). However, a technique that has been used extensively in conjunction with a large number of deposition studies is laser diffraction (3). As described above, this technique measures the physical diameter 

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