Cascade Impactors

Cascade impaction is one of the oldest methods for the dynamic characterization of aerosol particles. The method is used daily for the characterization of pharmaceutical aerosols, despite not currently being a pharmacopoeial requirement. The Food and Drug Administration first recognized the popularity of this type of sizing device by setting a standard for its use in the assessment of generic pharmaceutical aerosols for bioequivalence [40]. This has been superceded by pharmacopoeial and regulatory standards, as described in the last paragraph of this chapter. Other methods have been described in the literature [41-43].

Dynamic Particle Behavior

The principle on which inertial impactors operate is based on the aerodynamic behavior of aerosol particles. Fig. 6 shows a schematic diagram of particle collection by an inertial collection device. When the direction of a gas flow changes, the suspended particles continue to move in the original direction of flow until they lose inertia as a result of friction with the molecules in the surrounding medium. They are then said to "relax" into the new direction of flow, and the time taken for this to occur is known as the "relaxation time." A collections surface is placed in the path of the original direction of gas flow. Large particles will impact the surface. Small particles relax more quickly into a new direction of flow than the larger ones and, therefore, do not encounter the collection surface. The diameter at which a transition occurs from complete deposition to little or no collection of particles can be established by sampling particles of known size. This calibration will apply to known gas flows and linear velocities and assumes a fixed distance to the collection surface at each stage. Cascade impactors and impingers use these principles. Placing a series of jets and corresponding obstacles in the path of a single gas flow allows the removal of aerosol particles according to their size. Subsequently, the distribution may be reconstructed, based on the calibration for each stage. More Specifically, this is achieved by passing the gas flow through a series of orifices of decreasing diameter, thus producing an increased linear velocity, resulting in increased particle inertia. The collection surfaces may also be placed closer to the jets, or the point at which the direction of gas flow changes, at each consecutive stage.

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Figure 6 Schematic diagram of the method of collection of aerosol particles by an impactor. Solid arrows show direction of movement of airflow. Large particles impact on the collection surface, while small particles pass around it.

Figure 6 Schematic diagram of the method of collection of aerosol particles by an impactor. Solid arrows show direction of movement of airflow. Large particles impact on the collection surface, while small particles pass around it.

This does not allow particles of certain size to travel far enough or does not give them enough time to follow the new direction of flow before encountering a collection surface.

The relaxation time corresponding to the distance traveled by a particle until it follows the new direction of flow, the "stopping distance," can be derived from the equation for the terminal settling velocity [19]:

V _d2pgCc

18h where d is the aerodynamic diameter, p is unit density (I ā€” g/cm3), h is the viscosity of air, g is the acceleration due to gravity, and Cc is the slip correction factor.

The chief design parameter for impactors is the plate collection efficiency, ideally a function of a single dimensionless parameter, the ratio of the stopping distance of the particle to the width of the impactor jet. This parameter is called the Stokes number and is defined as

-ā€”dcā€”'Uo where S is the "stopping distance," Uo is the initial velocity, and dc is a critical dimension, in this case orifice diameter. The Stokes number may be thought of as the ratio of the particles "persistence" to the size of the obstacle. A well-designed impactor has a sharp cutoff at a Stokes number of 0.2, for a circular jet. Ideally, the cutoff is a step change from an efficiency of 0 to 1, as shown in Fig. 1. Ideal behavior can be achieved [44] if (1) in the region between the jet exit plane and the impaction plate the component of the air velocity parallel to the centerline of the nozzle (y) is a function of y only and (2) the y-component of the velocity of the particles at the jet exit plane is uniform across the jet. In real impactors, these conditions are only approximated. The chief departures from the ideal lie in the fluid boundary layers near the impactor walls. Particle behavior in these zones causes nonideal cutoff characteristics at large efficiencies in real devices.

The methods of handling data are based mainly on a log-normal fit to the particle size distribution data [45,46]. To eliminate some of the vagaries surrounding the derivation of the median diameter and geometric standard deviation from log-probability plots, computer methods have been developed to derive these parameters from the data [47,48]. These methods use nonlinear curve-fitting programs that result in error maps of the least mean square analysis from which the best fit can be derived. Some methods have been suggested that involve the use of a programmable pocket calculator [49].

Types of Cascade Impactors

A cascade impactor that seems to be among the most commonly used in the pharmaceutical industry is the Delron [10]. This is a Batelle-type instrument, named after the place of development. There are two models, the Delron Cascade Impactor (DCI) DCI-6 and the DCI-5. As the model numbers suggest, the DCI-6 is a six-stage and the DCI-5 a five-stage device. Each has an additional "absolute" (0.22-mm) filter to collect particles that are not deposited on each of the stages. The DCI-5 has a low airflow rate of 1.25 L/min. Conversely, the DCI-6 has a high airflow rate of 12.5 L/min. The DCI-6 seems to be the more popular model for pharmaceutical aerosol sampling. Fig. 7 shows a schematic diagram of the DCI-6. The stages are arranged vertically; thus, this type of impactor is sometimes referred to as "stacked" or "in-stack." Each stage has a single circular orifice beneath which resides a glass slide 38 mm in diameter. The nominal cutoff points for each stage of the impactor, based on a 50% collection efficiency, are 16, 8, 4, 2, 1, 0.5, and 0.2 mm [10]. It has been pointed out, however, that if the collection surfaces are coated to enhance the collection efficiency, the cutoff diameters change. Thus, the device has been reported to have cutoff diameters of 11.2, 5.5, 3.3, 2.0, 0.9, 0.5, and 0.2 mm when silicone fluid-coated glass slides were used [48]. Although this instrument is no longer mass-produced, the number in existence have given it prominence for assessing pharmaceutical aerosols.

Another cascade impactor commonly used in pharmaceutical aerosol characterization is the Andersen 1 CFM Ambient Sampler, of which a number of models exist [50-53] (Andersen Samplers, Inc., Atlanta, GA). This is also a stacked impactor, operating at an airflow rate of 1 ft3/min, or 28.3 L/min. It differs from the Delron instrument in the number of stages, the number of circular orifices at each stage, and the size of the collection surfaces. Fig. 8 illustrates the arrangement of the eight stages in the Anderson impactor. These stages are preceded by a preseparator that removes large particles (> 9.9 mm). The device uses a perforated plate rather than a single jet. This plate contains as many as 400 orifices per stage. Beneath the plate is situated a stainless steel collection plate 80 mm in diameter. The nominal cutoff diameters for each stage are 9.0, 5.8, 4.7, 3.3, 2.1, 1.1, 0.7, and 0.4 and the filter 0.2 mm [52,53]. The foregoing conditions are chosen for metered-dose inhaler and nebulizer sampling. This impactor has also been utilized at a flow rate of 60 L/min for the evaluation of dry powder inhaler performance. Since the cutoff diameters shift as a function of increased

Figure 7 Schematic of the Delron Cascade Impactor (DCI-6).

flowrate, the instrument was recalibrated by the manufacturer, stage 7 was removed, and stage ā€” 1 inserted above stage 0, to give values as follows, 6.2, 4.0, 3.2, 2.3, 1.4, 0.8, and 0.5 and the filter 0.2 mm [54]. The Marple Miller Impactor (MSP Corp.) was developed for ease of use and suitability for inhalation aerosol samples over a range of operating flowrates (30, 60, and 90L/min) [55].

The Sierra 210 Series of impactors (Andersen Samplers, Inc.) consist of 10-, 8-, and 6-stage devices. These use radial slots rather than circular jets as described in the previous examples. The device is designed to offer the advantage of a greater number of stages in the submicrometer range at a selected flowrate that effectively renders it of little relevance to pharmaceutical aerosols.

A significant effort occurred at the end of the 1990s to develop a new method of inertial sampling that had a greater application in pharmaceutical product development. This resulted in the manufacture of a the Next Generation Cascade Impactor. This device has the advantage of chambers that collect aerosol ambient air flow

Figure 8 Schematic of the Andersen Sampler. (With permission of Andersen Samplers, Inc.)

particles and that can act as vessels into which a fluid can be placed to dissolve these particles for subsequent chemical analysis. Fig. 9 shows a photograph of the new impactor [56]. Although significant for the environmental sciences, this is somewhat unnecessary for the study of pharmaceutical products. At a flow rate of 0.3 L/min, the cutoff values for stages 4-10 are 13, 8.5, 4.8, 2.9, 1.9, 1.3, and 0.58 mm, respectively. Thus, six stages are in the size range of interest. At flow rates of 10 and 21 L/min, approaching those of the Delron and Andersen devices, eight stages may be used, three of which are submicrometer and four of which are in the size range of interest. There are other cascade impactors and inertial devices, most of which find application in the fields of environmental and occupational health [57-61].

Most cascade impactors do not give data in real time. The collection surfaces must be removed from the device and subjected to chemical or gravimetric analysis. However, one impactor does give data in real time. The Model PC-2 Air Particle Analyzer (California Measurements, Inc., Sierra Madre, CA) achieves a real-time measurement by using piezoelectric quartz crystal microbalance (QCM) mass sensors to electronically weigh particles at each impactor stage [62,63]. The device has 10 stages and separates the aerosol into

Cascade Impactor
Figure 9 Next Generation Cascade Impactor, showing some of the unique design features intended to render the system automatable.

fractions between 25 and 0.5 mm. Its lower stages operate at reduced pressures to accurately separate smaller particles. Fig. 10 shows the arrangement operating portions of the device at a single stage. Only one of two unsealed crystals collects particles. The other acts as a reference to null out temperature and humidity effects. The frequency difference between the crystals is the QCM signal, and it changes in proportion to particle collection on the sensing crystal. A microcomputer process the QCM signals and provides the data output in a printout. An additional advantage of this device is that the crystals at each stage may be removed and subjected to scanning electron microscopy and energy-dispersive x-ray spectroscopy without disturbing the sample.

Figure 10 Schematic of the Quartz Crystal Microbalance Sensor System. (With permission of California Measurements, Inc.)

Limitations of Cascade Impactors

Humidity. Winkler [64] showed that in atmospheric relative humidities greater than 75% adhesion of particles to the plates is good, but in drier air, less than 75% relative humidity, there is often a loss of particles. He also studied [65] the growth of various particles with rising humidity, demonstrating the very important point that particles of mixed constitution, as found in the atmosphere, gradually increase in weight. Another complication is the effect on cascade impactor performance of the growth of particles. Hanel and Gravenhorst [66] showed theoretically that the cutoff radius can nearly double over the whole range of humidity. The number of particles per stage is not affected to the same extent, and the problem is eliminated at relative humidities less than 70% [67,68]. This effect has been used to investigate hygroscopic growth of aerosol particles [69].

Overload. The tendency to overload the collection surface in the small-particle stages in an attempt to collect measurable sample masses has been observed [67]. Attempts to avoid this problem by the use of adhesive layers or fibrous filters on the impaction plates create other, unanticipated complications [51,57,70-73].

Sampling. Sampling practices play an important role in particle size characterization using cascade impactors. Short-duration sampling may result in unrepresentative size estimates [74]. This is also the case for anisokinetic sampling [19].

Impingers

Impingers were the first devices operating on a dynamic principle to be adopted for aerosol sampling and particle characterization by the British Pharmacopoeia (BP) [75]. The data derived from these devices are intended to reflect the fraction of a pressurized inhalation aerosol emitted dose with a particle size likely to result in its deposition in the lower airways. The particles passing to the lower portion of the device are considered to be respirable. As such, this is the therapeutically desirable fraction of the aerosol. The two devices described in the BP operate on slightly different principles [75]. Apparatus A is a liquid impinger and requires solvent in both chambers to collect the aerosol. Apparatus B is a virtual impactor that uses a sintered glass disk and glass fiber filter to collect the two aerosol fractions. The liquid impinger has frequently appeared in the literature [76-80]. These devices are illustrated schematically in Fig. 11.

These types of devices are not a recent development, and the debate over their value in comparison with a cascade impactor was evident 25 years ago [5]. Knowing the respirable mass fraction of an aerosol, derived from an impinger, does not inform the investigator of the total size distribution as derived from cascade impaction. Of note, the respirable fraction as estimated by the inertial impingers, BP Apparatus A, has been correlated with the clinical performance of bronchodilator aerosols [81]. In the debate concerning the merits of the two impingers, their recommended use may need to be drug specific. Table 1 [82] shows data for the deposition of sodium cromoglycate (Intal) in vivo [83,84] and in vitro. This illustrates the capacity of the BP Apparatus B to reproduce the estimated dose of this drug to the lung, unlike Apparatus A. Two-stage impinger methods have given way to cascade impaction as a routine method of evaluating pharmaceutical aerosols. A more sophisticated impinger, the four-stage system (with cutoff diameters of 13.3, 6.7, 3.2, and 1.7 mm at a flowrate of 60L/min) has been adopted for evaluation of dry powder aerosols [85]. Its value lies in the fact

Figure 11 Diagrams of apparatus (A) twin impinger and (B) metal impinger as described Condenser Lens in the British Pharmacopoeia. (From Ref. 98, with permission of Fisons Corp.)

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