The abbreviated impactor measurement (AIM) concept: part II--Influence of evaporation of a volatile component-evaluation with a "droplet-producing" pressurized metered dose inhaler (pMDI)-based formulation containing ethanol as cosolvent.

The abbreviated impactor measurement (AIM) concept is a potential solution to the labor-intensive full-resolution cascade impactor (CI) methodology for inhaler aerosol aerodynamic particle size measurement. In this validation study, the effect of increasing the internal dead volume on determined mass fractions relating to aerodynamic particle size was explored with two abbreviated impactors both based on the Andersen nonviable cascade impactor (ACI) operating principle (Copley fast screening Andersen impactor [C-FSA] and Trudell fast screening Andersen impactor [T-FSA]). A pressurized metered dose inhaler-delivered aerosol producing liquid ethanol droplets after propellant evaporation was chosen to characterize these systems. Measures of extrafine, fine, and coarse particle mass fractions from the abbreviated systems were compared with corresponding data obtained by a full-resolution ACI. The use of liquid ethanol-sensitive filter paper provided insight by rendering locations visible where partly evaporated droplets were still present when the "droplet-producing" aerosol was sampled. Extrafine particle fractions based on impactor-sized mass were near equivalent in the range 48.6% to 54%, comparing either abbreviated system with the benchmark ACI-measured data. The fine particle fraction of the impactor-sized mass determined by the T-FSA (94.4 +/- 1.7%) was greater than using the C-FSA (90.5 +/- 1.4%) and almost identical with the ACI-measured value (95.3 +/- 0.4%). The improved agreement between T-FSA and ACI is likely the result of increasing the dead space between the entry to the induction port and the uppermost impaction stage, compared with that for the C-FSA. This dead space is needed to provide comparable conditions for ethanol evaporation in the uppermost parts of these impactors.

The abbreviated impactor measurement (AIM) concept: part 1--Influence of particle bounce and re-entrainment-evaluation with a "dry" pressurized metered dose inhaler (pMDI)-based formulation.

The abbreviated impactor measurement concept is a potential improvement to the labor-intensive full-resolution cascade impactor methodology for inhaler aerosol aerodynamic particle size distribution (APSD) measurement by virtue of being simpler and therefore quicker to execute. At the same time, improved measurement precision should be possible by eliminating stages upon which little or no drug mass is collected. Although several designs of abbreviated impactor systems have been developed in recent years, experimental work is lacking to validate the technique with aerosols produced by currently available inhalers. In part 1 of this two-part article that focuses on aerosols produced by pressurized metered dose inhalers (pMDIs), the evaluation of two abbreviated impactor systems (Copley fast screening Andersen impactor and Trudell fast screening Andersen impactor), based on the full-resolution eight-stage Andersen nonviable cascade impactor (ACI) operating principle, is reported with a formulation producing dry particles. The purpose was to investigate the potential for non-ideal collection behavior associated with particle bounce in relation to internal losses to surfaces from which particles containing active pharmaceutical ingredient are not normally recovered. Both abbreviated impactors were found to be substantially equivalent to the full-resolution ACI in terms of extra-fine and fine particle and coarse mass fractions used as metrics to characterize the APSD of these pMDI-produced aerosols when sampled at 28.3 L/min, provided that precautions are taken to coat collection plates to minimize bounce and entrainment.

Hydrofluoroalkane-beclomethasone versus chlorofluorocarbon-beclomethasone delivery in neonatal models.

Dose delivery of hydrofluoroalkane-beclomethasone and chlorofluorocarbon-beclomethasone was compared during in vitro neonatal simulations: mechanical ventilation with 40% and 100% relative humidity + Neonatal Chamber-Ventilator System/endotracheal tube; manual ventilation + Neonatal Chamber/endotracheal tube; "spontaneous breathing" + Neonatal Chamber/face mask without/with manual assistance. The delivery of hydrofluoroalkane-beclomethasone was significantly greater in each simulation.

Time-of-flight aerodynamic particle size analyzers: their use and limitations for the evaluation of medical aerosols.

Time-of-flight (TOF) aerosol analyzers are a class of instruments that measure the aerodynamic diameter of individual particles following a controlled acceleration in a well-defined flow field. Two instruments have been used to analyze the size of medical aerosols: Aerosizer particle size analyzer (TSI Particle Instruments/Amherst, Amherst, MA), Aerodynamic Particle Sizer (APS) aerosol spectrometer (TSI) Both instruments are capable of sizing several thousand particles a second, making it possible to obtain aerodynamic particle size distributions in a few seconds compared with up to 1 hour per measurement using compendial methods that are based on either the multistage liquid impinger or cascade impactor. This rapidity makes TOF analysis attractive for product development, as many different variables can potentially be investigated during a short period of time. The data thus obtained should be used with caution, however. Several issues, most notably the lack of a direct relationship with the mass of drug substance present and the vulnerability of the measurements to coincidence effects when sampling concentrated aerosols, may severely limit the value of data from many aerosol delivery systems, especially pressurized metered dose inhalers (pMDIs). A review of the literature illustrating the issues that are involved and providing guidance on the most appropriate uses of these analyzers is presented.

Size analysis of a pressurized metered dose inhaler-delivered suspension formulation by the API Aerosizer time-of-flight aerodynamic particle size analyzer.

Aerosizer time-of-flight (TOF) aerodynamic particle size analyzers (TSI-Amherst, Amherst, MA) are widely used for the rapid assessment of aerosols from a wide variety of drug delivery devices, including pressurized metered dose inhalers (pMDIs). This technique offers significant advantages in terms of rapid measurement times in comparison with the more time-consuming compendial methods such as the cascade impactor or multistage liquid impinger. Particle size analysis takes place by determining the TOF of individual particles following acceleration to supersonic velocity. No drug assay is performed; thus, the resulting size distribution also includes particles that do not contain any medication such as the excipients and surfactant that are present in most pMDI-based formulations. Illustrative data are presented for one particular formulation (Pulmicort: 200 micrograms of budesonide per dose; Astra Draco; Lund, Sweden) and demonstrate that bias from this source can significantly shift the reported particle distribution to finer sizes compared with impactor-based analysis in which direct assay for drug has taken place. In this case, the mass median aerodynamic diameter (MMAD) determined by an Aerosizer-LD was close to 2.4 microns, but was found to be approximately 4 microns using the cascade impactor-based procedure. Such a shift results in an overestimation of the fine particle fraction of the emitted dose, which may lead to misleading conclusions about the therapeutic benefit of a particular drug delivery system when making use of this formulation. TOF aerosol measurement techniques appear to be vulnerable to this type of bias for any suspension formulation in which the drug content is not homogeneously distributed within all particle sizes.

In vitro performance testing of three small volume-holding chambers under conditions that correspond with use by infants and small children.

The in vitro behavior of three types of small volume-holding chambers intended for use by infants and small children (child AeroChamber, Vent-170 and Space Chamber) has been compared with two pMDI-delivered aerosol formulations (salbutamol: 100 micrograms unit dose and beclomethasone di-propionate (BDP): 50 micrograms unit dose) widely prescribed for this age group of patients. All devices were evaluated using a pediatric breathing simulator that created respiratory conditions likely to be encountered with infants and small children. The filter that collected aerosol delivered from the holding chamber on test was located at approximately the position that the patient's lips would be in the mask, by means of an annular support plate glued into the mask itself. At the lowest tidal volume (50 ml), no salbutamol or BDP was delivered by either the Vent-170 or Space Chamber, whereas the unit doses from the child AeroChamber were 39.7 +/- 1.6 micrograms and 11.8 +/- 1.2 micrograms, respectively. The Vent-170 and Space Chamber delivered measurable doses of both drugs when the tidal volume was increased to 100 ml and again to 200 ml, however, the corresponding doses available from the AeroChamber were always significantly greater. These findings emphasize the importance of designing in vitro tests that mimic use by the patient group for which the device is intended. In vitro measurements made at constant high flow rates in excess of 20 l/min do not reveal these differences in performance that are clinically significant, and may lead the physician to prescribe a device that under certain conditions may not deliver any drug to infants or small children.