Effect of Drug Load and Plate Coating on the Particle Size Distribution of a Commercial Albuterol Metered Dose Inhaler (MDI) Determined Using the Andersen and Marple-Miller Cascade Impactors

Purpose. The purpose of this study is to investigate the effect of drug load, the coating of impactor stages, and the design of cascade impactors on albuterol MDIs particle size distribution measurements. The results of the investigation will be used to explain the 'loading effect' recently reported. Methods. Particle size distribution parameters of a commercial albuterol MDI were measured using both Andersen (AI) and Marple-Miller (MMI) Cascade Impactors, where plates were either left uncoated or coated with silicone or glycerin. A previously validated HPLC-EC method was used for the assay of albuterol collected by the impactor and in single spray content determinations. Results. Coating impactor collection plates had an impact on measured MM AD and GSD values for single puff measurements but very little or no effect for the multi puff measurements. Due to particle bounce, the percent of albuterol fine particles deposited in the filter and impactor finer stages (<1.10 m in AI and <1.25 m in MMI) in uncoated single puff experiments was much higher in comparison to either coated single puff or multi-puff (coated and uncoated) measurements. Conclusions. Evaluation of drug load and plate coating are necessary to determine whether observed particle size distributions are representative of the generated aerosol or are the result of particle bounce and reentrainment. In order to minimize particle bounce, especially for single puff determinations, it may be useful to apply a thin layer of a sticky coating agent to the surfaces of impactor plates.     

Formulation and Physical Characterization of Large Porous Particles for Inhalation

Purpose. Relatively large (>5 µm) and porous (mass density < 0.4 g/cm³) particles present advantages for the delivery of drugs to the lungs, e.g., excellent aerosolization properties. The aim of this study was, first, to formulate such particles with excipients that are either FDA-approved for inhalation or endogenous to the lungs; and second, to compare the aerodynamic size and performance of the particles with theoretical estimates based on bulk powder measurements. Methods. Dry powders were made of water-soluble excipients (e.g., lactose, albumin) combined with water-insoluble material (e.g., lung surfactant), using a standard single-step spray-drying process. Aerosolization properties were assessed with a Spinhaler ^TM device in vitro in both an Andersen cascade impactor and an Aerosizer^TM.. Results. By properly choosing excipient concentration and varying the spray drying parameters, a high degree of control was achieved over the physical properties of the dry powders. Mean geometric diameters ranged between 3 and 15 µm, and tap densities between 0.04 and 0.6 g/cm³. Theoretical estimates of mass mean aerodynamic diameter (MMAD) were rationalized and calculated in terms of geometric particle diameters and bulk tap densities. Experimental values of MMAD obtained from the Aerosizer^TM most closely approximated the theoretical estimates, as compared to those obtained from the Andersen cascade impactor. Particles possessing high porosity and large size, with theoretical estimates of MMAD between 1–3 µm, exhibited emitted doses as high as 96% and respirable fractions ranging up to 49% or 92%, depending on measurement technique. Conclusions. Dry powders engineered as large and light particles, and prepared with combinations of GRAS (generally recognized as safe) excipients, may be broadly applicable to inhalation therapy.     

撞击器法测定吸入粉雾剂空气动力学粒径分布颗粒反弹的研究

目的 对撞击器(cascade impactor,CI)法检测吸入粉雾剂空气动力学粒径分布(aerodynamic particle size distributions,APSDs)时颗粒反弹和二次夹带进行研究,为涂层材料的选择提供方法.方法 用甘油、硅油分别对收集杯/盘进行涂层或不涂层处理后,分别在30~90 L·min-1流速下,按照《美国药典》601项下规定进行样品收集并分析检测结果.结果 对收集杯/盘进行涂层处理能明显减少滤膜沉积率;用硅油涂层后,相同流速下质量平均空气动力学粒径(mass median aerodynamic diameter,MMAD)不随收集剂量的变化而变化,APSDs也较稳定.结论 使用撞击器法检测吸入粉雾剂APSDs时,对收集表面进行涂层很大程度上能够消除颗粒反弹和二次夹带;新一代碰撞取样器(next generation impactor,NGI)检测格隆溴铵吸入粉雾剂APSDs时,用硅油对收集杯进行涂层,可使检测结果更准确.     

Effect of inhalation flow rate on the dosing characteristics of dry powder inhaler (DPI) and metered dose inhaler (MDI) products.

Both the dose delivered from the device and the particle size of the medication are important parameters for inhalation products because they influence the amount of drug that is delivered to the patient's lung. The inspiratory flow rate may vary from dose to dose in a given patient and between patients. The Marple-Miller Cascade Impactor, a new multistage inertial impactor that operates at two flow rates (30 and 60 liters/min) with comparable particle size cut-offs, provides a means to study the effect of inhalation flow rate on the particle size distributions of inhalation products. The medication delivery, mass median aerodynamic diameter (MMAD), and fine particle mass were determined, in a randomized fashion, for albuterol, beclomethasone, budesonide, and terbutaline in both metered dose inhaler (MDI) and dry powder inhaler (DPI) products as a function of flow rate. In all cases, independent of drug or device used, the MDI products had a more reproducible respirable dose than the breath-actuated DPI products tested as a function of inhalation flow rate.     

High-Output Generation of Aerosols with Narrow Size Distributions

Abstract

Two aerosol generators–a small particle generator (SPG) and a large particle generator (LPG)–were designed and fabricated to produce water-soluble particles with high mass output and narrow size distributions. The mass median aerodynamic diameter (MMAD) of solid particles produced could be varied by changing operation conditions and using different concentrations of sodium chloride (NaCl) solutions. The aerosol generation rate varied from about 0.2 to 24 mg/min depending upon the particle size produced as the geometric standard deviation (GSD) was maintained below 1.5. The SPG employed a Collison-type nebulizer with multiple nozzles and a solid-plate impactor, which removes generating droplets larger than the cutpoint diameter for the production of submicrometer aerosols with GSD < 1.5. Different combinations of nebulization pressure/cutpoint diameter were selected to produce solid particles with MMAD in the range of 0.13–1.0 μm. The LPG was consisted of a Delavan simplex nozzle installed at the bottom of the generation chamber (about 190 cm in height and 15 cm in diameter) and an improved virtual impactor located at the top of the generation chamber. Gravity was used to remove large droplets and the improved virtual impactor was employed to remove droplets less than the cutpoint diameter. Two sets of acceleration nozzle and collection probe were used to vary the impactor cut size. The size-selective droplets were then evaporated to form solid particles with the MMAD nominally varying from 1 to 10 μm and GSD < 1.5.     

The AERX™ Aerosol Delivery System

Purpose. We describe the AER_X aerosol delivery system, a new, bolus inhalation device that is actuated at preprogrammed values of inspiratory flow rate and inhaled volume. We report on its in vitro characterization using a particular set of conditions used in pharmacokinetic and scintigraphic studies. Methods. Multiple doses of aerosol were delivered from single use collapsible plastic containers containing liquid formulation. The aerosol was generated by forcing the formulation under pressure through an array of 2.5 micron holes. Air was drawn through the device at 70 LPM, and the aerosol was collected onto a filter or Andersen cascade impactor. The emitted dose was quantified from the filter collection data, and the particle size distribution was obtained from the best fit log-normal distribution to the impactor data. Results. 57.0 ± 5.9% of the dose of drug placed as an aqueous solution in the 45 L collapsible container was delivered as an aerosol (n = 40). The best fit size distribution had an MMAD = (2.95 ± 0.06) m and a geometric standard deviation _g = 1.24 ± 0.01 (n = 6). Conclusions. The AER_X aerosol delivery system generates a nearly monodisperse aerosol with the properties required for efficient and repeatable drug delivery to the lung.     

吸入用色甘酸钠溶液雾化特性的体外评价

目的 对吸入用色甘酸钠溶液的雾化质量特性进行评价.方法 分别采用激光衍射法和撞击法测定吸入用色甘酸钠溶液的雾滴粒径及其分布,并考察采用不同厂家雾化器进行雾化时微细粒子空气动力学特性指标的区别;使用呼吸模拟器考察药液递送速率、递送总量,对两家企业的样品进行比较分析.结果 吸入用色甘酸钠溶液雾滴粒径、空气动力学粒径分布、递...     

A Cascade Impactor Entry Port for MDI Sprays with Collection Characteristics Imitating a Physical Model of the Human Throat

Purpose. This work was performed in order to compare and contrast results obtained from cascade impactor measurements on metered dose inhalers (MDIs) using a variety of inlet ports. Methods. The collection characteristics of four cascade impactor ports (a physical model of the human throat, a simplified geometry intended to mimic the physical model, and two currently-used ports) were measured on a variety of MDI formulations. Results. The portion of the MDI spray which collects on the entry port depends in a complicated fashion on the characteristics of the formulation; in these studies the fraction of the total dose which was collected on the port ranged between about 20% and 90% of the total emitted dose. The collection characteristics of the simplified geometry closely corresponded to the physical model. The length of the flow path between the port and the impactor was varied, and found not to have a strong effect on the measured size distribution passing the port. Conclusions. Ranking of various MDI formulations according to performance criteria as measured with a cascade impactor should be expected to depend on the particular inlet port which is used.     

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.     

Flixotide™‐pressurized metered‐dose inhalers loaded with [18F]fluticasone propionate particles for drug deposition studies in humans with PET–formulation and analysis

Fluticasone propionate (FP) is a potent anti‐inflammatory synthetic steroid, used for the treatment of asthma. Flixotide? is a formulated pressurized metered‐dose inhaler (pMDI) that contains small‐micronized FP particles in a blend of CFC propellants. Our objective was to develop a radiotracer method for accurately measuring the regional deposition of FP within the human lung using positron emission tomography (PET), which would be of important clinical interest. Flixotide? pMDIs were used to prepare [¹⁸F]FP pMDIs labeled isotopically with the positron emitter, fluorine‐18 (t_1/2=109.7 min). FP particles from Flixotide? pMDIs were mixed with [¹⁸F]FP formulated into a pMDI and sonicated at room temperature. The drug delivery of [¹⁸F]FP pMDI (250 μg of FP per actuation dose) was assessed for particle size distribution and dose uniformity. The distributions of FP and [¹⁸F]FP across particle size in such preparations were measured with an Andersen cascade impactor. This procedure was shown to provide an emitted dose from a [¹⁸F]FP pMDI of 246±19 μg/per metered dose. The particle size distribution as measured by mass median aerodynamic diameter (MMAD) (The mass median aerodynamic diameter (MMAD) and the geometric standard deviation (GSD) for each distribution were calculated. MMAD is defined as the aerodynamic diameter around which the mass of particles is equally distributed and the GSD is a measure of the dispersion of these particle diameters around the MMAD) from a commercial Flixotide? pMDI was 2.6±0.2 μm and agreed well with that from an [¹⁸F]FP pMDI (2.8±0.1 μm). The MMAD and geometric standard deviation (GSD) of newly formulated [¹⁸F]FP pMDIs were unaffected by the formulation procedure. [¹⁸F]FP was distributed with good uniformity with respect to the mass of FP for particles greater than 0.43 μm. Hence, the radiolabeled pMDI is a suitable source of radiotracer for the regional measurement of lung deposition for inhaled FP in human subjects with PET. Copyright © 2003 John Wiley & Sons, Ltd.     

Cascade impactor data and the lognormal distribution: nonlinear regression for a better fit.

At present, cascade impactors are the instruments of choice for measuring the particle size distribution of aerosol present in the complex discharge from pharmaceutical inhalers. The distribution of drug captured in the cascade impactor may be most usefully represented by the lognormal distribution. Only two parameters must be extracted from the analysis of cascade impactor data in order to describe the distribution. These two parameters are the mass median aerodynamic diameter (MMAD) and the geometric standard deviation (GSD). A cumulative version of the lognormal curve or more frequently, a linearized version of the cumulative curve called a "log probability plot," is used as a surrogate for the lognormal curve. The probability plot has great appeal since a lognormal distribution yields a straight line on log probability paper. One may easily determine the apparent MMAD and GSD from this linear plot. However, when one plots a lognormal curve, using the MMAD and GSD derived from a log probability plot, over a histogram constructed from cascade impactor data, an obvious mismatch is frequently seen. In order to derive parameters that more truly reflect the impactor data, a computer program, which uses nonlinear regression to derive an MMAD and GSD for the lognormal curve, has been written. It is presented here.     

Optimization of the operation conditions of an Andersen-Cascade impactor and the relationship to centrifugal adhesion measurements to aid the development of dry powder inhalations

The standardization of the operation conditions of an Andersen-Cascade impactor (Mark II), based on the physical relationship between adhesion and aerodynamic particle behaviour, has been undertaken using the Serevent® Disk-haler. In this case, the drug (Salmeterol xinafoate) is primarily adhered to a carrier material (lactose monohydrate), and thus the standard operation procedure to use this type of impactor had to be modified. For the modified procedure, operating conditions such as air flow rate, thickness of a silicon coat of the impaction plates and drug loading were optimized, bearing in mind the findings reported in the literature about the relationship between adhesion and impaction on plates. For this particular drug, the optimal thickness of the silicon film was found to be 3.75 μm, and the drug loading should not exceed 400μg. Although any air flow velocity between 20 and 60 1 min ⁻¹ gave a physically correct aerodynamic particle size for this drug and the chosen inhaler device, a maximum amount of drug was released from the device only applying flow rates between 50 and 60 1 min⁻¹. Four different industrially manufactured Serevent® batches were studied under these optimized operation conditions. Using centrifugal adhesion force measurements, the median adhesion force between Salmeterol xinafoate particles and lactose monohydrate carrier particles was established and linked to the aerodynamic behaviour of the drug using the Cascade impactor. The median adhesion force (F_ad) and the mass median aerodynamic diameter (MMAD) were found to be directly proportional. Statistical analysis, however, indicated that the differences in F_ad and MMAD were not significant between the tested batches. The procedure established that the formulation had been produced with high accuracy and reproducibility. The sensitivity of the adhesion force measurements to variability in the manufacturing process would allow an in-process control of the mixture and could help to assure this high standard.     

Predicting the quality of powders for inhalation from surface energy and area

Purpose. To correlate the surface energy of active and carrier components in an aerosol powder to in vitro performance of a passive dry powder inhaler. Methods. Inverse gas chromatography (IGC) was used to assess the surface energy of active (albuterol and ipratropium bromide) and carrier (lactose monohydrate, trehalose dihydrate and mannitol) components of a dry powder inhaler formulation. Blends (1%w/w) of drug and carrier were prepared and evaluated for dry powder inhaler performance by cascade impaction. The formulations were tested with either of two passive dry powder inhalers, Rotahaler^® (GlaxoSmithKline) or Handihaler^® (Boehringer Ingelheim). Results. In vitro performance of the powder blends was strongly correlated to surface energy interaction between active and carrier components. Plotting fine particle fraction vs. surface energy interaction yielded an R² value of 0.9283. Increasing surface energy interaction between drug and carrier resulted in greater fine particle fraction of drug. Conclusions. A convincing relationship, potentially useful for rapid formulation design and screening, was found between the surface energy and area parameters derived from IGC and dry powder inhaler performance.     

Effect of tubing deposition, breathing pattern, and temperature on aerosol mass distribution measured by cascade impactor.

Aerosols produced by nebulizers are often characterized on the bench using cascade impactors. We studied the effects of connecting tubing, breathing pattern, and temperature on mass-weighted aerodynamic particle size aerosol distributions (APSD) measured by cascade impaction. Our experimental setup consisted of a piston ventilator, low-flow (1.0 L/min) cascade impactor, two commercially available nebulizers that produced large and small particles, and two "T"-shaped tubes called "Tconnector(cascade)" and "Tconnector(nebulizer)" placed above the impactor and the nebulizer, respectively. Radiolabeled normal saline was nebulized using an airtank at 50 PSIG; APSD, mass balance, and Tconnector(cascade) deposition were measured with a gamma camera and radioisotope calibrator. Flow through the circuit was defined by the air tank (standing cloud, 10 L/min) with or without a piston pump, which superimposed a sinusoidal flow on the flow from the air tank (tidal volume and frequency of breathing). Experiments were performed at room temperature and in a cooled environment. With increasing tidal volume and frequency, smaller particles entered the cascade impactor (decreasing MMAD; e.g., Misty-Neb, 4.2 +/- 0.9 microm at lowest ventilation and 2.7 +/- 0.1 microm at highest, p = 0.042). These effects were reduced in magnitude for the nebulizer that produced smaller particles (AeroTech II, MMAD 1.8 +/- 0.1 to 1.3 +/- 0.1 microm; p = 0.0044). Deposition on Tconnector(cascade) increased with ventilation but was independent of cascade impactor flow. Imaging of the Tconnector(cascade) revealed a pattern of deposition unaffected by cascade impactor flow. These measurements suggest that changes in MMAD with ventilation were not artifacts of tubing deposition in the Tconnector(cascade). At lower temperatures, APSD distributions were more polydisperse. Our data suggest that, during patient inhalation, changes in particle distribution occur that are related to conditions in the tubing and may reduce the diameters of particles entering the patient. This effect is more significant for nebulizers producing large particles. Changes in ambient temperature did not affect these observations.     

Selecting an accessory device with a metered-dose inhaler: variable influence of accessory devices on fine particle dose, throat deposition, and drug delivery with asynchronous actuation from a metered-dose inhaler.

Accessory devices reduce common problems with metered-dose inhalers (MDIs), namely high oropharyngeal deposition of aerosol and incoordination between actuation and inhalation by the patient. The objective of this study was to systematically compare the performance of various accessory devices in vitro. MDIs were tested alone or in combination with four spacers (Toilet paper roll, Ellipse, Optihaler, Myst Assist) and five holding chambers (Aerochamber, Optichamber, Aerosol Cloud Enhancer, Medispacer, and Inspirease). An Anderson cascade impactor was used to measure aerosol mass median aerodynamic diameter (MMAD) and fine particle dose (MMAD < 4.7 microm). In separate experiments, the influence of asynchronous MDI actuation on drug delivery was determined with a simulated spontaneous breathing model. Compared with the MDI alone, all of the accessory devices reduced aerosol MMAD and increased lung-throat ratio (fine particle dose/throat impaction; p < 0.05 for both parameters). The fine particle dose of albuterol was 40% higher with the Ellipse (p < 0.01), was equivalent with the Toilet Paper Roll, Aerochamber, Optichamber, and Medispacer, and was 33-56% lower with the Optihaler, Myst Assist, Aerosol Cloud Enhancer, and Inspirease (p < 0.03). MDI actuation in synchrony with inspiration produced highest drug delivery; when MDI actuation occurred 1-sec before inspiration or during exhalation, decrease in drug delivery with holding chambers (10-40% reduction) was less than that with spacers (40-90% reduction). Accessory device selection is complicated by variability in performance between devices, and in the performance of each device in different clinical settings. In vitro characterization of a MDI and accessory device could guide appropriate device selection in various clinical settings.     

Optimized Inhalation Aerosols. II. Inertial Testing Methods for Particle Size Analysis of Pressurized Inhalers

Pressurized metered dose inhaler (MDI) output from three different albuterol formulations was characterized using three inertial separation devices. Results were compared for the Delron six-stage cascade impactor (DCI6), the Andersen Mark II eight-stage impactor (ACI8), and Copley's twin-stage liquid impinger (LI). None of the devices tested in this study was ideal in all respects. All devices could differentiate between formulations in terms of respirable doses (albuterol amount with aerodynamic diameters <5.5 through 6.4 µm). Only the high-flow rate LI could differentiate among all three formulations when data were presented in terms of respirable percentage (RP) of drug collected. Values for RP were in excellent agreement for the independently calibrated impactors when the same evaporation chamber was used atop the impactors. The LI appeared to overestimate values for RP in vivo. Results are discussed in light of the debate surrounding the revision of USP aerosol testing requirements. Rigorous specifications for evaporation chambers and methodologies are necessary for meaningful inter- and intra-laboratory comparison of results when any of these devices are used.     

Influence of flow rate on aerosol particle size distributions from pressurized and breath-actuated inhalers.

Particle size distribution of delivered aerosols and the total mass of drug delivered from the inhaler are important determinants of pulmonary deposition and response to inhalation therapy. Inhalation flow rate may vary between patients and from dose to dose. The Andersen Sampler (AS) cascade impactor operated at flow rates of 30 and 55 L/min and the Marple-Miller Impactor (MMI) operated at flow rates of 30, 55, and 80 L/min were used in this study to investigate the influence of airflow rate on the particle size distributions of inhalation products. Total mass of drug delivered from the inhaler, fine particle mass, fine particle fraction, percentage of nonrespirable particles, and amount of formulation retained within the inhaler were determined by ultraviolet spectrophotometry for several commercial bronchodilator products purchased in the marketplace, including a pressurized metered-dose inhaler (pMDI), breath-actuated pressurized inhaler (BAMDI), and three dry powder inhalers (DPIs), two containing salbutamol sulphate and the other containing terbutaline sulphate. Varying the flow rate through the cascade impactor produced no significant change in performance of the pressurized inhalers. Increasing the flow rate produced a greater mass of drug delivered and an increase in respirable particle mass and fraction from all DPIs tested.     

格隆溴铵吸入喷雾剂的雾化特性研究

目的 考察格隆溴铵吸入喷雾剂的雾化特性。方法 采用激光成像系统和新一代撞击器等测定格隆溴铵吸入喷雾剂的喷雾模式、喷雾形态、递送剂量均一性和空气动力学粒径分布。结果 样品的椭圆度均符合美国食品药品管理局指导原则建议，不同样品喷雾模式和喷雾形态同一参数之间RSD值均小于7%，样品的罐间和罐内递送剂量均一性良好。格隆溴铵吸入喷雾剂与雾化吸入溶液的质量中值、几何标准偏差值基本一致，在肺内沉积方面上高于雾化吸入溶液。结论 格隆溴铵吸入喷雾剂具备良好的雾化特性。     

Reducing bounce effects in the Andersen cascade impactor

The collection efficiency of the Andersen cascade impactor (ACI) can be affected by particle bounce, overload and re-entrainment (or blow-off), collectively referred to as bounce effects. Reduction of bounce effects in the ACI operated at 60 LPM was investigated for placebo large porous particles. Aerodynamic particle size distributions (aPSDs) obtained with the ACI and multi-stage liquid impinger (MSLI) were compared by observation of modes and statistical comparisons of the mass median aerodynamic diameter (MMAD) and geometric standard deviation (sigmag). Particle bounce effects were prevalent in the ACI with uncoated plates, i.e., bi-modal distribution with statistically significant differences in MMAD and sigmag (P<0.05). Coating the impaction plates with a thin layer of vacuum grease and decreasing the ACI stage jet velocities reduced, but did not minimize bounce effects. Bounce effects were minimized using 20-microm pore glass fiber filters saturated in water placed on inverted impaction plates, with good agreement obtained between the ACI and MSLI aPSDs, i.e., mono-modal with no statistically significant differences in MMAD and sigmag (P>0.05). Selection of the impaction substrate material and solvent must be evaluated with the drug product and analytical methods to minimize bounce effects and obtain an accurate measure of the aPSD.     

Aerodynamic particle size of metered-dose inhalers determined by the quartz crystal microbalance and the Andersen cascade impactor.

Given the rapid sizing capability and high sensitivity, the quartz crystal microbalance (QCM) cascade impactor has been evaluated for the size determination of metered-dose inhaler (MDI) aerosols. The effects of surfactants present in MDI formulations, crystal coating, particle bounce and crystal overloading on the QCM cascade impactor are investigated. To reduce particle bounce, it is necessary to coat the crystals and use new coated surfaces for each measurement. Mass median aerodynamic diameters (MMADs) obtained from the QCM cascade impactor are compared to those from the commonly used Andersen cascade impactor. For MDI formulations containing little or no surfactants, MMADs obtained from the QCM and Andersen cascade impactors are comparable. For MDI formulations containing a significant amount of surfactant (or any non-volatile excipients), the QCM cascade impactor measures the combined size distribution of the drug and non-volatile excipients. A technique is devised in this study to deduce the drug-only size distribution from the QCM impactor for surfactant-containing MDI formulations and show comparable results to the Andersen cascade impactor except for high drug load Intal. The QCM impactor has proved to be a useful tool for rapid size measurement of MDI formulations.