A new cascade impactor has been designed specifically for pharmaceutical inhaler testing. This impactor, called the Next Generation Pharmaceutical Impactor (NGI), has seven stages and is intended to operate at any inlet flow rate between 30 and 100 L/min. It spans a cut size (D50) range from 0.54-microm to 11.7-microm aerodynamic diameter at 30 L/min and 0.24 microm to 6.12 microm at 100 L/min. The aerodynamics of the impactor follow established scientific principles, giving confident particle size fractionation behavior over the design flow range. The NGI has several features to enhance its utility for inhaler testing. One such feature is that particles are deposited on collection cups that are held in a tray. This tray is removed from the impactor as a single unit, facilitating quick sample turn-around times if multiple trays are used. For accomplishing drug recovery, the user can add up to approximately 40 mL of an appropriate solvent directly to the cups. Another unique feature is a micro-orifice collector (MOC) that captures in a collection cup extremely small particles normally collected on the final filter in other impactors. The particles captured in the MOC cup can be analyzed in the same manner as the particles collected in the other impactor stage cups. The user-friendly features and the aerodynamic design principles together provide an impactor well suited to the needs of the inhaler testing community.

An extension of the archival calibration of the recently developed 30-100-L/min seven-stage impactor, the Next Generation Pharmaceutical Impactor (NGI), has been undertaken at 15 L/min. The NGI stage cut sizes are 0.98-14.1 microm aerodynamic diameter at this flow rate. This 15-L/min calibration was motivated by the desire to sample the entire aerosol produced by a nebulizer when tested in accordance with a new international standard developed by the Comite Européen de Normalisation (CEN), as well as the need to test various types of inhalers at flow rates lower than 30 L/min for pediatric applications. Measurements were undertaken with monodisperse oleic acid droplets in the range of 0.7-22 microm aerodynamic diameter following a procedure established in the original 30-100-L/min calibration study. The NGI was found to be effective for particle size separation at 15 L/min. Users should decide the most applicable configuration that meets their needs, based on the following recommendations: (1) the pre-separator should not normally be used, as its performance is significantly degraded by the influence of gravity, resulting in interference with stage 1; and (2) a filter should be inserted below the micro-orifice collector (MOC), as the size corresponding to 80% collection efficiency of the MOC becomes excessively large with decreasing flow rate, so that this component becomes ineffective as a means of collecting fine particles that penetrate beyond stage 7.

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A particle sampler has been developed, built, and tested. The sampler draws ambient air at approximately 300 L/min and then splits the sampled air into a particle-rich sample stream and a particle-depleted, reject stream.

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Nanosized silica size standards produced with a sol-gel synthesis process were evaluated for particle size, effective density, and refractive index in this study. Particle size and effective density measurements were conducted following protocol from the National Institute of Advanced Industrial Science and Technology (AIST) in Japan. Particle sizes were measured via electrical mobility analysis using a differential mobility analyzer (DMA) at sheath flow rates (Q sh ) of 3.0 and 6.0 L/min and a constant aerosol flow rate (Q a ) of 0.3 L/min. The measured mean and mode diameters agreed well with the labeled sizes in the size range 40-200 nm, with differences ranging from 0.03% to 0.8%, well within the labeled expanded uncertainties (95% confidence intervals) of 1.8%-2.2%. The coefficient of variation (CV) of the size distribution was 0.012-0.027 for 40-200 nm. Particle sizes measured for 20 nm and 30 nm standards showed size differences with respect to the certified sizes of 1.7% and 8.3% at Q sh D 6.0 L/min, but the size distributions were narrow, with CV D 0.047-0.064. The average effective density for the range 40-200 nm measured with an aerosol particle mass analyzer (APM) was 1.9 g/cm 3 . The real component of the refractive index measured with an optical particle counter (OPC) was 1.41 at a wavelength of 633 nm. All properties (size, effective density, and refractive index) were stable and could be measured with good repeatability. From these evaluations, it was found that the nanosized silica size standards have good characteristics for use as size standards and constitute a feasible alternative to PSL particles.

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Current pharmacopeial methods for testing dry powder inhalers (DPIs) require that 4.0 L be drawn through the inhaler to quantify aerodynamic particle size distribution of "inhaled" particles. This volume comfortably exceeds the internal dead volume of the Andersen eight-stage cascade impactor (ACI) and Next Generation pharmaceutical Impactor (NGI) as designated multistage cascade impactors. Two DPIs, the second (DPI-B) having similar resistance than the first (DPI-A) were used to evaluate ACI and NGI performance at 60 L/min following the methodology described in the European and United States Pharmacopeias. At sampling times ≥2 s (equivalent to volumes ≥2.0 L), both impactors provided consistent measures of therapeutically important fine particle mass (FPM) from both DPIs, independent of sample duration. At shorter sample times, FPM decreased substantially with the NGI, indicative of incomplete aerosol bolus transfer through the system whose dead space was 2.025 L. However, the ACI provided consistent measures of both variables across the range of sampled volumes evaluated, even when this volume was less than 50% of its internal dead space of 1.155 L. Such behavior may be indicative of maldistribution of the flow profile from the relatively narrow exit of the induction port to the uppermost stage of the impactor at start-up. An explanation of the ACI anomalous behavior from first principles requires resolution of the rapidly changing unsteady flow and pressure conditions at start up, and is the subject of ongoing research by the European Pharmaceutical Aerosol Group. Meanwhile, these experimental findings are provided to advocate a prudent approach by retaining the current pharmacopeial methodology.