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An alternative method of calibration involves the dispersion of monodisperse polystyrene microparticles. This has recently been made an efficient process by the incorporation of these particles in pMDI suspensions to allow for metering of small well-dispersed boluses sufficient for use as aerosol calibration standards (63).

Dispersed

Dispersed

Figure 12 Aerodynamic particle size characterization techniques using (A) Andersen eight-stage nonviable cascade impactor and (B) four-stage liquid impinger.

Figure 12A depicts a stacked Andersen eight-stage nonviable impactor with calibrated cutoff diameters of 9.0, 5.8, 4.7, 3.3, 2.1, 1.1, 0.7, and 0.4 |im and a lower absolute filter (0.22 |im) when operated at 28.3 L/min. Figure 12B depicts a four-stage liquid impinger with calibrated cutoff diameters of 13.3, 6.7, 3.2, and 1.7 |im at 60 L/min.

Inertial impactors are calibrated at designated flow rates. This may vary depending on the instrument (28). The range of flow rates selected for early impactors was based on passive inhalation of environmental and occupational particulates. Thus, the Delron, Batelle type, six-stage impactor operates at 12.5 L/min, and the Andersen eight-stage nonviable impactor operates at 28.3 L/min [1 ACFM (actual cubic feet per minute)]. The sampling of pharmaceutical aerosols has proven more difficult than ambient particulates. After a period of debate regarding suitable inlets for the device, the USP adopted a right-angled tube as the standard for sampling pMDI output (64). When used with the Andersen impactor, the inlet is arranged immediately above the first stage of the impactor.

The next-generation pharmaceutical impactor (NGPI or NGI), is the most recent type of inertial impactor that is becoming a part of routine aerosol research because of its increased efficiency and ease of use. It has been characterized extensively, including comparison with the Andersen cascade impactor (65-71). This can be attributed to its many advantageous properties including minimal aerosol material loss and is much less labor intensive. Hence, it possesses high-throughput capability, since the solvent used for chemical analysis can be easily incorporated into the impactor prior to the experiment.

Dry powder aerosols are more complicated to sample as the commercially available devices disperse the aerosol on the patient's inspiratory flow, as described above. To challenge the efficiency of these devices, it is important to sample at multiple flow rates. The standard flow rate has become 60 L/min. Additional flow rates of 30 (28.3) and 90 L/ min have also been used. Each impactor must be calibrated at the different flow rates employed. In recent compendial specifications, the duration of sampling (four seconds) and pressure drop across the device (4 kPa) have also been suggested. This corrects for the effort on the part of a patient in a single breath.

There have been attempts to conduct in vitro experiments in a manner that gives more meaningful data with regard to lung deposition. These methods, which are loosely based on inertial impaction, utilize inspiratory flow cycles rather than fixed flow rates for sampling the aerosol. These "electronic lung" approaches give interesting results, which may prove useful in the development of aerosol products. Their suitability as quality control tools is influenced by the effect of variable flow rates on impactor calibration.

A viable bio-impactor enables experimental evaluation of aerosol particulate interactions with viable cells placed as cell cultures (specific to different lung regions and different lung disease states) (27) on each stage of the impactor. A number of excellent reviews exist, which discuss suitable pulmonary cell culture models (72-75). Immortalized (continuous) pulmonary cell lines representing distinct regions of the respiratory tract used include A549 (76-79), Calu-3 (78,80-85), and HBE14o (86-88). Primary cultures at an air-liquid interface of normal (noncontinuous) human pulmonary cells have been successful for normal human alveolar epithelial cells (77,78,84,89-92) and normal human bronchial epithelial cells (93). Recognizing the vital importance of pulmonary dendritic cells in pulmonary defense, a triple coculture (94) of dendritic cells, macrophages, and A549 cells is possible to decipher cellular-cross talk between different respiratory cells in particle uptake behavior.

General Sizing Methods

A number of alternative sizing methods are available, and these are described in Table 8. The American Association of Pharmaceutical Scientists, Inhalation Focus Group conducted a comprehensive review of available methods, which was published in a series of articles identified in the last column of the table. All of the methods described either have been or are currently employed in the development of aerosol products. However, at this time, only the inertial samplers, cascade impactors, and impingers appear in compendial standards and in regulatory guidelines (64,95-97). Other methods, such as thermal imaging, are also under development and may give complementary size information to the current methods.

Table 8 General Particle Sizing Methods

Sizing technique (Refs)

Description

Size range (Hm)

Limitations

Microscopy with image

Scanning electron

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