Next Generation Pharmaceutical Impactor Research Articles

Role of dispersion enhancer selection in the development of novel tratinterol hydrochloride dry powder inhalation formulations

Tratinterol hydrochloride (TH) is a new long-acting bronchodilator with strong β2 adrenoceptor stimulation activity. The aim of this study was to design a new carrier-based dry powder inhalation (DPI) formulation for TH and to investigate the effect of dispersion enhancers on the aerosol performance of TH in vitro. To this end, coarse lactose was used as a carrier. TH was micronized by using a jet mill and blended with the carrier to obtain a reference DPI formulation. Commercial magnesium stearate (MgSt) as received, micronized MgSt (MgSt-M), and fine lactose (FL) were used as the dispersion enhancers and formulated with the micronized TH (TH-M) and the carrier as DPI formulations. The obtained DPI formulations were characterized using dynamic light scattering (DLS), X-ray powder diffraction (XRPD), thermal analysis, powder rheometer, and Raman microscopy. A next generation pharmaceutical impactor (NGI) was used to evaluate the aerodynamic performance of the dry powders. The results showed that TH-M was in an inhalable particle size range, and based on the XRPD and thermal analysis, the solid form of TH-M did not change compared to the starting materials. The NGI results showed that the fine particle fraction (FPF) of TH could be increased with the addition of MgSt and FL as dispersion enhancers in the reference formulation. In addition, the FPF of TH could be increased with a decrease in the particle size of MgSt or an increase in the amount of FL. A combination of MgSt-M and FL could further improve the aerosol performance of TH. Raman spectroscopic imaging confirmed the spatial location of MgSt and TH at the surface of the carrier. This study demonstrates that TH could be formulated into carrier-based dry powder formulation for inhalation using coarse lactose as the carrier. The dual strategy based on using both MgSt and FL as dispersion enhancers improved the aerosol performance of a novel TH dry powder formulation.

In Vitro Tests for Aerosol Deposition. V: Using Realistic Testing to Estimate Variations in Aerosol Properties at the Trachea.

The dose and aerodynamic particle size distribution (APSD) of drug aerosols' exiting models of the mouth and throat (MT) during a realistic inhalation profile (IP) may be estimated in vitro and designated Total Lung Dose, TLDin vitro, and APSDTLDin vitro, respectively. These aerosol characteristics likely define the drug's regional distribution in the lung. A general method was evaluated to enable the simultaneous determination of TLDin vitro and APSDTLDin vitro for budesonide aerosols' exiting small, medium and large VCU-MT models. Following calibration of the modified next generation pharmaceutical impactor (NGI) at 140 L/min, variations in aerosol dose and size exiting MT were determined from Budelin® Novolizer® across the IPs reported by Newman et al., who assessed drug deposition from this inhaler by scintigraphy. Values for TLDin vitro from the test inhaler determined by the general method were found to be statistically comparable to those using a filter capture method. Using new stage cutoffs determined by calibration of the modified NGI at 140 L/min, APSDTLDin vitro profiles and mass median aerodynamic diameters at the MT exit (MMADTLDin vitro) were determined as functions of MT geometric size across Newman's IPs. The range of mean values (n ≥ 5) for TLDin vitro and MMADTLDin vitro for this inhaler extended from 6.2 to 103.0 μg (3.1%-51.5% of label claim) and from 1.7 to 3.6 μm, respectively. The method enables reliable determination of TLDin vitro and APSDTLDin vitro for aerosols likely to enter the trachea of test subjects in the clinic. By simulating realistic IPs and testing in different MT models, the effects of major variables on TLDin vitro and APSDTLDin vitro may be studied using the general method described in this study.

Aerodynamic particle size distribution and dynamic properties in aerosols from electronic cigarettes

Aerodynamic Particle Size Distribution (APSD) is an important factor governing if aerosols can be inhaled to different parts of a human's respiratory system. To understand the APSD of the aerosol produced from several brands of E-cigarettes, measurements using the Next Generation Pharmaceutical Impactor (NGI) were performed.The NGI impactor was operated at two different temperature conditions, ambient room temperature condition (20–25°C) and in a cold condition (4–8°C). The relative humidity (RH) in the latter case, cooled impactor, was close to 100%, similar to the human's respiratory system. Obtained Mass Median Aerodynamic Diameters (MMAD) for the investigated electronic cigarettes were in the range 0.5–0.9µm. The different NGI temperature conditions had a significant effect on the result and this is probably due to dynamic processes during the aerosol transport in the NGI pass ways.For each NGI measurements performed the nicotine present in both the droplets and in the gaseous phase were measured. This is different from the previously published data using physical aerosol sizing techniques (such as Scanning Mobility Particle Sizer, SMPS), where obtained droplet sizes is a result of all chemical components in the aerosol, not only nicotine. In principle, it could be only excipients in the droplets and all nicotine in gaseous phase. Thus, impactor and a gas trap with nicotine specific quantification is a good complement for more thorough understanding of droplet size distributions of E-cigarette.The APSD in vitro data was used in theoretical modeling using the Multiple-Path Particle Dosimetry Model (MPPD v 2.11), for estimation of the lung deposition. Using the model it was estimated that 75–90% of the nicotine droplets will be exhaled and 10–25% deposited in the respiratory system. However, when an aerosol is inhaled to a human's respiratory system it will be diluted and the evaporation of nicotine will increase. This will lead to overestimation of the fraction of exhaled nicotine using the MPPD model.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 26 Edinburgh International Conference Centre Edinburgh, Scotland, UK December 9-11, 2015.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 26 Edinburgh International Conference Centre Edinburgh, Scotland, UK December 9-11, 2015.

Formulation of a novel fixed dose combination of salmeterol xinafoate and mometasone furoate for inhaled drug delivery

Co-administration of an inhaled corticosteroid and long acting beta agonist for chronic obstructive pulmonary disease has reduced mortality compared to either drug alone. This combination reduces exacerbations, hospitalization, emergency department visits and health care costs. A novel fixed-dose combination of the long acting beta-2 agonist salmeterol xinafoate (SX) and the corticosteroid mometasone furoate (MF) were prepared in a composite particle formulation as brittle matrix powder (BMP) and investigated for suitability as an inhaled combination product. In this study, BMP fixed dose combinations of SX and MF with or without stabilizing excipients (lactose, mannitol, glycine and trehalose) were prepared and characterized with respect to their thermal properties, morphology, aerodynamic performance and physical stability. BMP combination formulations of SX and MF exhibited improved aerodynamic properties when delivered by dry powder inhalation as compared to the micronized blends of the same substances. Aerodynamic evaluation was carried out by next generation pharmaceutical impactor (NGI) with a marketed DPI device. Results demonstrated that co-deposition occurred when SX and MF were formulated together as composite particles in a BMP, while physical blends resulted in inconsistent deposition and dose uniformity. As a result of the bottom-up particle engineering approach, combination BMP formulations allow for dual API composite formulations to be dispersed as aerosolized particles. Aerosolized BMP combination formulations resulted in delivered dose uniformity and co-deposition of each API. Further, an excipient-free formulation, BMP SXMF, delivered approximately 50% of the loaded dose in the respirable range and demonstrated stability at ambient conditions for 6months. Single dose 24-h pharmacokinetic studies in rats demonstrated that lung tissue deposition and blood circulation (AUC0–24h) of two APIs were higher for the BMP combination group exhibiting a significantly higher lung concentration of drugs than for the crystalline physical blend. While high system drug levels are generally undesirable in lung targeted therapies, high blood levels in this rodent study could be indicative of increased pulmonary tissue exposure using BMP formulations.

Investigation of dry powder inhaler (DPI) resistance and aerosol dispersion timing on emitted aerosol aerodynamic particle sizing by multistage cascade impactor when sampled volume is reduced from compendial value of 4 L.

Compendial methods determining dry powder inhaler (DPI)-emitted aerosol aerodynamic particle size distribution (APSD) collect a 4-L air sample containing the aerosol bolus, where the flow, which propagates through the cascade impactor (CI) measurement system from the vacuum source, is used to actuate the inhaler. A previous article described outcomes with two CIs (Andersen eight-stage cascade impactor (ACI) and Next-Generation Pharmaceutical Impactor (NGI)) when the air sample volume was ≤4L with moderate-resistance DPIs. This article extends that work, examining the hypothesis that DPI flow resistance may be a factor in determining outcomes. APSD measurements were made using the same CI systems with inhalers representing low and high flow resistance extremes (Cyclohaler® and HandiHaler® DPIs, respectively). The ratio of sample volume to internal dead space (normalized volume (V*)) was varied from 0.25 to 1.98 (NGI) and from 0.43 to 3.46 (ACI). Inhaler resistance was a contributing factor to the rate of bolus transfer; the higher resistance DPI completing bolus relocation to the NGI pre-separator via the inlet when V* was as small as 0.25, whereas only ca. 50% of the bolus mass was collected at this condition with the Cyclohaler® DPI. Size fractionation of the bolus from either DPI was completed within the ACI at smaller values of V* than within the NGI. Bolus transfer from the Cyclohaler® capsule and from the HandiHaler® to the ACI system were unaffected by the different flow rise time observed in the two different flow controller systems, and the effects the ACI-based on APSD measurements were marginal.

The Effect of Nonideal Cascade Impactor Stage Collection Efficiency Curves on the Interpretation of the Size of Inhaler-Generated Aerosols

Cascade impactors, operating on the principle of inertial size separation in (ideally) laminar flow, are used to determine aerodynamic particle size distributions (APSDs) of orally inhaled product (OIP) aerosols because aerodynamic diameter can be related to respiratory tract deposition. Each stage is assumed typically to be an ideal size fractionator. Thus, all particles larger than a certain size are considered collected and all finer particles are treated as penetrating to the next stage (a step function stage efficiency curve). In reality, the collection efficiency of a stage smoothly increases with particle size as an "S-shaped" curve, from approximately 0% to 100%. Consequently, in some cases substantial overlap occurs between neighboring stages. The potential for bias associated with the step-function assumption has been explored, taking full resolution and two-stage abbreviated forms of the Andersen eight-stage nonviable impactor (ACI) and the next-generation pharmaceutical impactor (NGI) as example apparatuses. The behavior of unimodal, log-normal APSDs typical of OIP-generated aerosols has been investigated, comparing known input values to calculated values of central tendency (mass median aerodynamic diameter) and spread (geometric standard deviation, GSD). These calculations show that the error introduced by the step change assumption is larger for the ACI than for the NGI. However, the error is sufficiently small to be inconsequential unless the APSD in nearly monodisperse (GSD ≤1.2), a condition that is unlikely to occur with realistic OIPs. Account may need to be taken of this source of bias only for the most accurate work with abbreviated ACI systems.

Effect of Sampling Volume on Dry Powder Inhaler (DPI)-Emitted Aerosol Aerodynamic Particle Size Distributions (APSDs) Measured by the Next-Generation Pharmaceutical Impactor (NGI) and the Andersen Eight-Stage Cascade Impactor (ACI)

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.

Preparation and In Vitro Aerosol Performance of Spray-Dried Shuang-Huang-Lian Corrugated Particles in Carrier-Based Dry Powder Inhalers

The development of dry powder inhalation (DPI) products of traditional Chinese medicine (TCM) remains to be a challenge due to chemical complexity and batch-to-batch variations in constituent composition. This study was to investigate the feasibility of using spray-dried corrugated particles to improve the aerodynamic performance of a TCM, Shuang-Huang-Lian (SHL), in carrier-based DPI. Particles with different surface roughness were spray-dried by the addition of leucine and concomitant manipulation of spray-drying parameters. The surface roughness was determined by atomic force microscopy, whilst the aerodynamic performance of drug particle-mannitol/lactose blends was evaluated using a next-generation pharmaceutical impactor through a Cyclohaler. Although the emission efficiency for corrugated particle-based DPI was ~10% lower than that for smooth SHL, the fine particle fractions (FPF(<4.4 μm)) of 32.4-36.8% for the former were significantly higher than those of 14.7-16.2% for the latter. In particular, the FPF and fraction of drug detached from the carrier appeared not to be significantly affected by the variation in constituent composition of SHL. This study demonstrates that the use of corrugated particles in carrier-based DPI improved aerosol performance by facilitating drug detachment from the carrier, independent of variation in constituent composition, and such particles were potentially applicable to the development of SHL DPI products.

Nebulisation of Receptor-Targeted Nanocomplexes for Gene Delivery to the Airway Epithelium

BackgroundGene therapy mediated by synthetic vectors may provide opportunities for new treatments for cystic fibrosis (CF) via aerosolisation. Vectors for CF must transfect the airway epithelium efficiently and not cause inflammation so they are suitable for repeated dosing. The inhaled aerosol should be deposited in the airways since the cystic fibrosis transmembrane conductance regulator gene (CFTR) is expressed predominantly in the epithelium of the submucosal glands and in the surface airway epithelium. The aim of this project was to develop an optimised aerosol delivery approach applicable to treatment of CF lung disease by gene therapy.MethodologyThe vector suspension investigated in this study comprises receptor-targeting peptides, cationic liposomes and plasmid DNA that self-assemble by electrostatic interactions to form a receptor-targeted nanocomplex (RTN) of approximately 150 nm with a cationic surface charge of +50 mV. The aerodynamic properties of aerosolised nanocomplexes produced with three different nebulisers were compared by determining aerosol deposition in the different stages of a Next Generation Pharmaceutical Impactor (NGI). We also investigated the yield of intact plasmid DNA by agarose gel electrophoresis and densitometry, and transfection efficacies in vitro and in vivo.ResultsRTNs nebulised with the AeroEclipse II BAN were the most effective, compared to other nebulisers tested, for gene delivery both in vitro and in vivo. The biophysical properties of the nanocomplexes were unchanged after nebulisation while the deposition of RTNs suggested a range of aerosol aerodynamic sizes between 5.5 µm–1.4 µm cut off (NGI stages 3–6) compatible with deposition in the central and lower airways.ConclusionsRTNs showed their ability at delivering genes via nebulisation, thus suggesting their potential applications for therapeutic interventions of cystic fibrosis and other respiratory disorders.

A Methodology to Study Impactor Particle Reentrainment and a Proposed Stage Coating for the NGI

Mass-weighted aerodynamic particle-size distribution (APSD) is a key attribute for pharmaceutical products developed to deliver drugs to or through the lungs. In development and quality control, APSD is primarily determined using multistage cascade impactors. For impactor techniques, particle reentrainment is critical because it may lead to an overestimation of the respirable fraction. To avoid reentrainment, the collection surfaces need to be coated with a suitable material. In this study a method was developed to test flow dependence of particle reentrainment in the Next Generation Pharmaceutical Impactor (NGI) at flow rates ranging from 20 to 80 L/min, and was used to test three coating materials: glycerol coating, aqueous coating with, and without soaked filter paper. Uncoated cups were also tested. In the experimental setup a Vilnius Aerosol Generator generated a flow-independent dry powder aerosol, consisting of micronized insulin. The glycerol coating was not well suited to reduce particle reentrainment at flows >or=40 L/min. The soaked filter paper coating was found to give nearly the same particle size distributions regardless of flow and was therefore judged to be the best of those tested. Using liquid only, without the filter paper, gave the same particle size distributions as soaked filter paper for flows <or=40 L/min, while at >or=60 L/min particle reentrainment increased with flow. However, for most applications liquid coating reduced particle reentrainment to an extent at which further reduction was irrelevant. Particle reentrainment was prevalent for uncoated cups at all flow rates tested. This study shows the advantage of using a stable and flow-independent aerosol generation method to examine particle reentrainment at various flows through the NGI. For insulin dry powder, the use of an aqueous solution as cup coating, preferably with a filter, reduced particle reentrainment to a minimum. The results were confirmed in a study with a DPI.

Cascade Impactor Practice for a High Dose Dry Powder Inhaler at 90 L/min: NGI Versus Modified 6-Stage and 8-Stage ACI

The compendial methods of particle size distribution (PSD) profile determination for dry powder inhalers (DPIs) were compared between the Next Generation Pharmaceutical Impactor (NGI) and the Andersen Cascade Impactor (ACI). Relenza® Rotadisk® (zanamivir) and Diskhaler® was used as a model DPI and sampled into each impactor via its preseparator (PS), at 90L/min under various protocols. In the NGI, silicone coating was shown to be indispensable to prevent or minimize particle bounce and reentrainment, and to reduce wall losses to the levels acceptable to the compendia (5%). In contrast, the ACI exceeded this 5% limit, regardless of coating, implying different wall loss mechanisms from the NGI. Particle bounce occurred in both impactors, inaccurately undersizing the PSD profiles for Relenza®, unless the collection surfaces were coated or an increased number of doses were employed. Hence, the PSD profile for Relenza® following single dose collection in the stage-coated NGI was the most accurate. In contrast, the use of the ACI and its PS for Relenza® at 90L/min suffered from several problems, even though the poorly designed PS still resulted in consistent impactor dose and PSD profiles, compared to those obtained from the NGI and its PS.

Comparison of Delivery Characteristics from a Combination Metered-Dose Inhaler Using the Andersen Cascade Impactor and the Next Generation Pharmaceutical Impactor

The purpose of this research was to compare two cascade impaction devices for the aerodynamic particle size assessment of a combination metered-dose inhaler (MDI) product, Combivent. Particle size analysis was performed using an Anderson Mark II cascade impactor (ACI) and a Next Generation Pharmaceutical Impactor (NGI), both fitted with a preseparator and either a 1 L glass chamber or USP throat, and operated at various flow rates. Particle size distributions (PSDs) and dose delivery profiles were assessed by means of the mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD), fine particle fraction <5 micron aerodynamic diameter (FPF(<5 microm)), and induction port deposition fraction (IPF). Under their normal operating conditions, the ACI (28.3 L/min) and the NGI (30 L/min) yield similar PSDs and dose delivery profiles. However, this equivalent performance for the ACI and the NGI no longer exists at a higher flow rate of 60 L/min. Furthermore, changes in PSD results may also be obtained between different operators and/or when different induction port designs were employed. Thus, it is strongly recommended that special care be taken to eliminate variation in experimental parameters and/or selection of ancillary devices such as the preseparator, induction port or throat, to insure good repeatability and reproducibility when testing inhalation drugs.

Comparative Analysis of Methods to Measure Aerosols Generated by a Vibrating Mesh Nebulizer

Different approaches have been employed for in vitro assessment of the aerosol particle size generated by inhalation devices. In this study, aerosols from the Omron MicroAir vibrating mesh (VM) nebulizer were measured by cascade impaction (CI) using the MSP Next Generation Pharmaceutical Impactor (NGI), the ThermoAndersen Cascade Impactor (ACI), and by time-of-flight (TOF) analysis with the TSI 3321 Aerodynamic Particle Sizer Spectrometer (APS). The VM nebulizer was evaluated with sodium fluoride (NaF; 2.5%) and with generic albuterol (0.083%). Aerosol particle size (MMAD), respirable fractions (RF < 5 microm), and fine particle fractions (FPF < 3.3 microm) were determined with each method at room temperature (RT) and 4 degrees C using 50% average relative humidity. By NGI at either RT or 4 degrees C, aerosol particle sizes were similar for both NaF and albuterol (4.3-4.5 microm MMAD) with 55-61% RF and 27-43% FPF. With ACI, the distribution of particles at RT was similar except at the extremes of the dispersion and the MMAD was smaller (3.3 microm MMAD; p = 0.03). At 4 degrees C, particle sizes determined by ACI results were similar to the NGI (MMAD 4.1 microm; p > 0.05). TOF analysis by APS with albuterol gave significantly larger calculated MMAD (cMMAD) than either CI method (7.2 microm; p < 0.001). TOF measurements of nebulized albuterol at RT and 4 degrees C were equivalent. In summary, the results of VM nebulized NaF and albuterol were more consistent and generally equivalent when determined by NGI (at RT and 4 degrees C) and ACI analysis (at 4 degrees C). In contrast, aerosol particle sizes measured by TOF in the APS at both RT and 4 degrees C were larger than results obtained by CI. Differences in aerosol particle distribution obtained by different analysis methods should be considered while evaluating the in vitro performance of VM nebulizers.

Next Generation Pharmaceutical Impactor: A New Impactor for Pharmaceutical Inhaler Testing. Part III. Extension of Archival Calibration to 15 L/min

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.

Aerodynamic sizing of metered dose inhalers: An evaluation of the andersen and next generation pharmaceutical impactors and their USP methods

The particle sizing performance of a Next Generation Pharmaceutical Impactor (NGI) was compared to that of an Andersen cascade impactor (ACI). A single lot of Vanceril® MDIs containing beclomethasone dipropionate (BDP) was used throughout. MDIs were sampled into NGI and ACI in accordance with USP recommendations, at 30.0 and 28.3 L/min, respectively, following 1, 2, 6, and 30 actuations with or without a silicone cup or stage coating, to determine the apparent particle size distributions (PSD) of BDP. The mass balance and the statistical comparability of drug deposits were assured on a “per actuation basis” across all experiments, demonstrating “good cascade impactor practices.” Interstage deposition or “wall losses” in NGI were found to be lower than those in ACI, although their determination was laborious in NGI. The PSD profiles for Vanceril® from a single actuation were distinguishable between NGI and ACI, when uncoated collection surfaces were used, most specifically for drug mass <4‐μm aerodynamic diameter (p < 0.05). Silicone coating of collection surfaces and an increased number of actuations were shown to result in PSD profile shifts for both NGI and ACI. Such effects were most pronounced for NGI, although coating the collection surfaces and/or increasing the number of actuations improved drug retention significantly on the upper stages of NGI, and thereby, minimized the effects of particle bounce of BDP from Vanceril® MDIs. PSD profiles from a single actuation could be determined reliably in either of these impactors, provided that coated collection surfaces were employed; also, cumulative % mass undersize profiles were similar between instruments. However, small differences in PSD profiles still existed to support NGI's design claims for reduced “overlap” in its stage collection efficiency curves. © 2004 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1828–1837, 2004

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 microm aerodynamic diameter (FPF(<4.7 microm)). 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 micro m [NGI]; 2.8 +/- 0.07 microm [ACI]); however, FPF(<4.7 microm) by both impactors was in the narrow range 88% to 93%. Size distribution agreement for Intal was better (MMAD = 4.3 +/- 0.19 microm (NGI), 4.2 +/- 0.13 microm (ACI), with FPF(<4.7 microm) ranging from 52% to 60%. The Aerodynamic Particle Sizer (APS) undersized aerosols produced with either formulation (MMAD = 1.8 +/- 0.07 micro m and 3.2 +/- 0.02 micro m for Flovent and Intal, respectively), but values of FPF(<4.7 microm)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 micro m; FPF(<4.7 micro m)= 96.4% +/- 2.5%), were in fair agreement with both NGI (MMAD = 0.9 +/- 0.03 micro m; FPF(<4.7 microm)= 96.7% +/- 0.7%), and ACI (MMAD = 1.2 +/- 0.02 microm, FPF(<4.7 microm)= 98% +/- 0.5%), but FPF(<4.7 microm) 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.

Next Generation Pharmaceutical Impactor (A New Impactor for Pharmaceutical Inhaler Testing). Part I: Design

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.

Next generation pharmaceutical impactor (a new impactor for pharmaceutical inhaler testing). Part II: Archival calibration.

A new seven-stage cascade impactor, the Next Generation Pharmaceutical Impactor (NGI), has been developed for the pharmaceutical industry. A calibration following "good laboratory practice (GLP)" procedures has been performed on a specific archival NGI, deemed to be representative of all NGIs. Thus, this impactor had nozzle dimensions for each stage manufactured close to the middle of the tolerance band for the design specification, and therefore the average nozzle diameter was equal to the nominal value for that stage. An essential feature of the NGI is that it is designed to operate at any flow rate between 30 and 100 L/min. Thus, the calibration was made at inlet flow rates of 30, 60 and 100 L/min representing the lower bound, mid-region and upper bound of the specified range of operation for the impactor. The calibration data were then used to develop equations that predict the particle cut size for all components of the impactor at any flow rate from 30 to 100 L/min.