Mark Nagel

Cascade Impactors for the Size Characterization of Aerosols from Medical Inhalers: Their Uses and Limitations

Cascade impactors, including the multi-stage liquid impinger, are by far the most widely encountered means for the in vitro determination of the particle size distribution of aerosols from medical inhalers, both in product development, batch release and in applications with add-on devices. This is because they directly measure aerodynamic size, which is the most relevant parameter to describe particle transport within the respiratory tract. At the same time, it is possible to quantify the mass of active pharmaceutical ingredient in different size ranges independent of other non-physiologically active components of the formulation. We begin by providing an overview of the operating principles of impactors and then highlight the various configurations and adaptations that have been adopted to characterize the various classes of inhaler. We continue by examining the limitations of the cascade impaction method, in particular looking at potential sources of measurement bias and discussing both appropriate and inappropriate uses of impactor-generated data. We also present a synopsis of current developments, including the Next Generation Pharmaceutical Impactor, and automation of cascade impactors for routine inhaler performance measurements.

Aerodynamic particle size analysis of aerosols from pressurized metered-dose inhalers: Comparison of andersen 8-stage cascade impactor, next generation pharmaceutical impactor, and model 3321 aerodynamic particle sizer aerosol spectrometer

The purpose of this research was to compare three different methods for the aerodynamic assessment of (1) chloroflurocarbon (CFC)-fluticasone propionate (Flovent), (2) CFC-sodium cromoglycate (Intal), and (3) hydrofluoroalkane (HFA)-beclomethasone dipropionate (Qvar) delivered by pressurized metered dose inhaler. Particle size distributions were compared determining mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD), and fine particle fraction <4.7 μm aerodynamic diameter (FPF<4.7 μm). Next Generation Pharmaceutical Impactor (NGI)-size distributions for Flovent comprised finer particles than determined by Andersen 8-stage impactor (ACI) (MMAD=2.0±0.05 μm [NGI]; 2.8±0.07 μm [ACI]); however FPF<4.7 μm by both impactors was in the narrow range 88% to 93%. Size distribution agreement for Intal was better (MMAD=4.3±0.19 μm (NGI), 4.2±0.13 μm (ACI), with FPF<4.7 μm ranging from 52% to 60%. The Aerodynamic Particle Sizer (APS) undersized aerosols produced with either formulation (MMAD=1.8±0.07 μm and 3.2±0.02 μm for Flovent and Intal, respectively), but values of FPF<4.7 μm from the single-stage impactor (SSI) located at the inlet to the APS (82.9%±2.1% [Flovent], 46.4%±2.4% [Intal]) were fairly close to corresponding data from the multi-stage impactors. APS-measured size distributions for Qvar (MMAD=1.0±0.03 μm; FPF<4.7 μm=96.4% ±2.5%), were in fair agreement with both NGI (MMAD=0.9±0.03 μm; FPF<4.7 μm=96.7%±0.7%), and ACI (MMAD=1.2±0.02 μm, FPF<4.7 μm=98%±0.5%), but FPF<4.7 μm from the SSI (67.1%±4.1%) was lower than expected, based on equivalent data obtained by the other techniques. Particle bounce, incomplete evaporation of volatile constituents and the presence of surfactant particles are factors that may be responsible for discrepancies between the techniques.

Performance of Large- and Small-Volume Valved Holding Chambers with a New Combination Long-Term Bronchodilator/Anti-inflammatory Formulation Delivered by Pressurized Metered Dose Inhaler

The treatment of both the bronchoconstriction and inflammatory aspects of asthma simultaneously by a single pressurized metered dose inhaler (pMDI) represents a significant advance in convenience to the patient. However, a valved holding chamber (VHC) may still be needed to reduce the coarse component of the dose that is likely to deposit in the oropharyngeal region, and a small sized device may offer significant advantages to the patient from the standpoint of compliance with therapy. VHCs representing small (adult AeroChamber Plus with mouthpiece, 149-mL) and large (Volumatic, 750-mL) devices have been compared in an in vitro evaluation with Seretide/Advair (hydro-fluoro alkane [HFA]-formulated fluticasone propionate [FP = 125 microg/dose] and salmeterol xinafoate [SX = 25 microg/dose]) by Andersen Mark-II eight-stage impactor operated at 28.3 L/min following compendial methodology. Fine particle fraction, based on the size range from 1.1 to 4.7 microm aerodynamic diameter, from either large or small VHCs with either component (69-79%) was similar [p > or = 0.08], and significantly greater than that from the pMDI alone (approximately 40%) [p < 0.001]. Fine particle dose emitted by the VHCs for SX (8.2 +/- 0.8 microg for the AeroChamber Plus and 7.7 +/- 0.5 microg for the Volumatic) were comparable, and also similar to the fine particle dose delivered by the pMDI when used without a VHC (7.6 +/- 0.6 microg). Fine particle doses for the FP component delivered by the two VHCs (46.4 +/- 3.4 microg for the AeroChamber Plus and 46.3 +/- 2.7 microg for the Volumatic) were equivalent, but were slightly greater than the corresponding fine particle dose from the pMDI alone (39.1 +/- 2.6 microg). However, this difference (approximately 20%) is close to the limit of resolution based on intermeasurement variability and is unlikely to have clinical significance, given the interpatient variability seen with inhaled drug therapy. It is therefore concluded that either of these VHCs has equivalent in vitro performance with this combination formulation in terms of the portion of the dose emitted from the pMDI that is likely to reach the receptors in the lungs.

Relative Precision of Inhaler Aerodynamic Particle Size Distribution (APSD) Metrics by Full Resolution and Abbreviated Andersen Cascade Impactors (ACIs): Part 1

The purpose of this study was to compare relative precision of two different abbreviated impactor measurement (AIM) systems and a traditional multi-stage cascade impactor (CI). The experimental design was chosen to provide separate estimates of variability for each impactor type. Full-resolution CIs are useful for characterizing the aerosol aerodynamic particle size distribution of orally inhaled products during development but are too cumbersome, time-consuming, and resource-intensive for other applications, such as routine quality control (QC). This article presents a proof-of-concept experiment, where two AIM systems configured to provide metrics pertinent to QC (QC-system) and human respiratory tract (HRT-system) were evaluated using a hydrofluoroalkane-albuterol pressurized metered dose inhaler. The Andersen eight-stage CI (ACI) served as the benchmark apparatus. The statistical design allowed estimation of precision with each CI configuration. Apart from one source of systematic error affecting extra-fine particle fraction from the HRT-system, no other bias was detected with either abbreviated system. The observed bias was shown to be caused by particle bounce following the displacement of surfactant by the shear force of the airflow diverging above the collection plate of the second impaction stage. A procedure was subsequently developed that eliminated this source of error, as described in the second article of this series (submitted to AAPS PharmSciTech). Measurements obtained with both abbreviated impactors were very similar in precision to the ACI for all measures of in vitro performance evaluated. Such abbreviated impactors can therefore be substituted for the ACI in certain situations, such as inhaler QC or add-on device testing.

Relative Precision of Inhaler Aerodynamic Particle Size Distribution (APSD) Metrics by Full Resolution and Abbreviated Andersen Cascade Impactors (ACIs): Part 2—Investigation of Bias in Extra-Fine Mass Fraction with AIM-HRT Impactor

The purpose of this study was to resolve an anomalously high measure of extra-fine particle fraction (EPF) determined by the abbreviated cascade impactor possibly relevant for human respiratory tract (AIM-HRT) in the experiment described in Part 1 of this two-part series, in which the relative precision of abbreviated impactors was evaluated in comparison with a full resolution Andersen eight-stage cascade impactor (ACI). Evidence that the surface coating used to mitigate particle bounce was laterally displaced by the flow emerging from the jets of the lower stage was apparent upon microscopic examination of the associated collection plate of the AIM-HRT impactor whose cut point size defines EPF. A filter soaked in surfactant was floated on top of this collection plate, and further measurements were made using the same pressurized metered-dose inhaler-based formulation and following the same procedure as in Part 1. Measures of EPF, fine particle, and coarse particle fractions were comparable with those obtained with the ACI, indicating that the cause of the bias had been identified and removed. When working with abbreviated impactors, this precaution is advised whenever there is evidence that surface coating displacement has occurred, a task that can be readily accomplished by microscopic inspection of all collection plates after allowing the impactor to sample ambient air for a few minutes.

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.

Size Analysis of a Pressurized Metered Dose Inhaler-Delivered Solution Formulation by an Aerosizer®-LD Time-of-Flight Aerosol Particle Size Spectrometer

In a previous study, an Aerosizer-LD time-of-flight (TOF) aerosol spectrometer was shown to underestimate significantly the aerodynamic size of airborne particles produced following actuation of a suspension-based formulation delivered from a pressurized metered-dose inhaler (pMDI) via a nonelectrostatic valved holding chamber (VHC). It was postulated that the nonspecific nature of the particle detection system in terms of chemical composition was responsible for the inclusion of smaller non-drug-containing excipient particles in the measured size distribution data from this analyzer. This limitation may not apply to certain solution formulations in which the only particles remaining after the evaporation of propellant and volatile excipient (solubilizer) are composed of pure drug substance. Such a formulation (QVAR, HFA-formulated beclomethasone di-propionate [BDP]) has recently become available, and the present investigation was therefore designed to test this hypothesis. Aerosizer-LD measured mass-weighted size distribution data for QVAR had a mass median aerodynamic diameter (MMAD) close to 1.1 microm, very similar to published data for this parameter, based on measurement of the aerosol by cascade impactor followed by drug-specific assay. However, the Aerosizer-LD underestimated the spread of the size distribution significantly. The causes are believed to be a combination of two separate effects: (1) lack of sensitivity of the particle detection system to particles finer than about 0.7 microm aerodynamic diameter and (2) preferential removal of particles larger than the MMAD, either by evaporation of residual solvent (ethanol) or by inertial/gravitational deposition in the sampling arrangement upstream of the measurement zone.

Development and Calibration of a Low-Flow Version of the Marple-Miller Impactor (MMI™)

ABSTRACT Cascade impactor analysis of drugs for inhalation in aerosol form is regarded by both European and U.S. pharmacopoeias as an important method to determine particle size-related information concerning dose that might be delivered to various parts of the respiratory tract. Existing measurements usually are made at flow rates in excess of 25 1/min, which are more representative of peak inspiratory flow rates achieved by adults. There is therefore a need for a low-flow impactor that can be used to evaluate drug delivery devices intended for use by infants or small children, or by those whose disease status prevents the achievement of higher inspiratory flow rates. A new version of the Marple-Miller impactor™ (MMI™) is described that meets this need, operating at either 4.9 or 12 1/min by the substitution of a different uppermost stage jet. A novel feature is the use of external stage collection cups instead of plates, enabling quantitative transfer of drug collecting on each stage for subsequent chem...

Oral inhalation therapy: meeting the challenge of developing more patient- appropriate devices

Although oral inhalers have been mass produced for more than 50 years, there is a large body of literature in which evidence has been provided that patients either misuse their inhalers inadvertently or deliberately, thereby reducing their intended efficacy or, in the worst cases, rendering them altogether ineffective. In general, inhalers are becoming increasingly complicated with the incorporation of add-on devices, miniaturized electronics and ever more complex mechanical systems that aid aerosol delivery to the lower respiratory tract and, at the same time provide user feedback. However, these benefits often come at a significant cost, and there are signs that increasing attention will need to be given to the cost–benefit equation in the future. This review explores the development of pressurized metered-dose inhalers, dry powder inhalers and devices for liquid-droplet dispersal and inhalation from the perspective of the patient, by focusing on aspects that improve user interaction. These include designed-in features, such as breath-enhanced or breath-actuated operation that interact with the breathing pattern of the user, as well as more direct feedback aids that confirm, to the patient or healthcare provider that the dose has been delivered and that the patient has inhaled.

Improved laboratory test methods for orally inhaled products

Existing pharmacopeial methods for the in vitro testing of orally inhaled products (OIPs) are simplified representations of clinical reality, as their objective is to provide metrics that are discriminating of product quality. Attempts to correlate measures such as fine particle fraction <5 µm aerodynamic diameter with in vivo measures of lung deposition have therefore been notoriously difficult to achieve. Although particle imaging-based techniques may be helpful to link in vitro to in vivo data as surrogates for clinical responses, a reappraisal of the purposes for laboratory-based testing of OIPs is required. This article provides guidance on approaches that may be helpful to develop clinically appropriate methods to assess OIP performance in the laboratory, with the ultimate goal of developing robust in vitro-in vivo relationships for the major inhaled drug classes.