Effect of design on the performance of a dry powder inhaler using computational fluid dynamics. Part 2: Air inlet size

This study investigates the effect of air inlet size on (i) the flowfield generated in a dry powder inhaler, and (ii) the device-specific resistance, and the subsequent effect on powder deagglomeration. Computational fluid dynamics (CFD) analysis was used to simulate the flowfield generated in an Aerolizer with different air inlet sizes at 30, 45, and 60 l/min. Dispersion performance of the modified inhalers was measured using mannitol powder and a multistage liquid impinger at the same flow rates. The air inlet size had a varying effect on powder dispersion depending on the flow rate. At low flow rates (30 and 45 l/min), reducing the air inlet size increased the inhaler dispersion performance by increasing the flow turbulence and particle impaction velocities above their critical levels for maximal powder dispersion. At 60 l/min, reducing the air inlet size reduced the inhaler dispersion performance by releasing a large amount of powder from the device before the turbulence levels and particle impaction velocities could be fully developed. The results demonstrate that the maximal inhaler dispersion performance can be predicted if details of the device flowfield are known.     

Understanding the Different Effects of Inhaler Design on the Aerosol Performance of Drug-Only and Carrier-Based DPI Formulations. Part 1: Grid Structure

The design of a dry powder inhaler device has significant influence on aerosol performance; however, such influence may be different between the drug-only and carrier-based formulations. The present study aims to examine the potential difference on the dispersion between these distinct types of formulations, using Aerolizer^® as a model inhaler with the original or modified (cross-grid) designs. A coupled CFD-discrete element method analysis was employed to determine the flow characteristics and particle impaction. Micronized salbutamol sulphate as a drug-only formulation and three lactose carrier-based formulations with various drug-to-carrier weight ratios 1:5, 1:10 and 1:100 were used. The in vitro aerosolization performance was assessed by a next-generation impactor operating at 100 L/min. Using the original device, FPF_loaded was reduced from 47.5?±?3.8% for the drug-only formulation to 31.8?±?0.7%, 32.1?±?0.7% and 12.9?±?1.0% for the 1:5, 1:10 and 1:100 formulations, respectively. With the cross-grid design, powder-mouthpiece impaction was increased, which caused not only powder deagglomeration but also significant drug retention (doubling or more) in the mouthpiece, and the net result is a significant decrease in FPF_loaded to 36.8?±?1.2%, 20.9?±?2.6% and 21.9?±?1.5% for the drug-only, 1:5 and 1:10 formulations, respectively. In contrast, the FPF_loaded of the 1:100 formulation remained the same at 12.1?±?1.3%, indicating the increased mouthpiece drug retention was compensated by increased drug detachment from carriers caused by increased powder-mouthpiece impaction. In conclusion, this study has elucidated different effects and the mechanism on the aerosolization of varied dry powder inhaler formulations due to the grid design.     

Development of a High Efficiency Dry Powder Inhaler: Effects of Capsule Chamber Design and Inhaler Surface Modifications

Purpose

The objective of this study was to explore the performance of a high efficiency dry powder inhaler (DPI) intended for excipient enhanced growth (EEG) aerosol delivery based on changes to the capsule orientation and surface modifications of the capsule and device.

Methods

DPIs were constructed by combining newly designed capsule chambers (CC) with a previously developed three-dimensional (3D) rod array for particle deagglomeration and a previously optimized EEG formulation. The new CCs oriented the capsule perpendicular to the incoming airflow and were analyzed for different air inlets at a constant pressure drop across the device. Modifications to the inhaler and capsule surfaces included use of metal dispersion rods and surface coatings. Aerosolization performance of the new DPIs was evaluated and compared with commercial devices.

Results

The proposed capsule orientation and motion pattern increased capsule vibrational frequency and reduced the aerosol MMAD compared with commercial/modified DPIs. The use of metal rods in the 3D array further improved inhaler performance. Coating the inhaler and capsule with PTFE significantly increased emitted dose (ED) from the optimized DPI.

Conclusions

High efficiency performance is achieved for EEG delivery with the optimized DPI device and formulation combination producing an aerosol with MMAD?<?1.5 μm, FPF_<5μm/ED?>?90%, and ED?>?80%.     

Influence of Air Flow on the Performance of a Dry Powder Inhaler Using Computational and Experimental Analyses

Purpose The aims of the study are to analyze the influence of air flow on the overall performance of a dry powder inhaler (Aerolizer^®) and to provide an initial quantification of the flow turbulence levels and particle impaction velocities that maximized the inhaler dispersion performance.Methods Computational fluid dynamics (CFD) analysis of the flowfield in the Aerolizer^®, in conjunction with experimental dispersions of mannitol powder using a multistage liquid impinger, was used to determine how the inhaler dispersion performance varied as the device flow rate was increased.Results Both the powder dispersion and throat deposition were increased with air flow. The capsule retention was decreased with flow, whereas the device retention first increased then decreased with flow. The optimal inhaler performance was found at 65 l min⁻¹ showing a high fine particle fraction (FPF) of 63 wt.% with low throat deposition (9.0 wt.%) and capsule retention (4.3 wt.%). Computational fluid dynamics analysis showed that at the critical flow rate of 65 l min⁻¹, the volume-averaged integral scale strain rate (ISSR) was 5,400 s⁻¹, and the average particle impaction velocities were 12.7 and 19.0 m s⁻¹ at the inhaler base and grid, respectively. Correlations between the device flow rate and (a) the amount of throat deposition and (b) the capsule emptying times were also developed.Conclusions The use of CFD has provided further insight into the effect of air flow on the performance of the Aerolizer^®. The approach of using CFD coupled with powder dispersion is readily applicable to other dry powder inhalers (DPIs) to help better understand their performance optimization.     

Influence of Mouthpiece Geometry on the Aerosol Delivery Performance of a Dry Powder Inhaler

Purpose

To investigate the influence of mouthpiece geometry on the amount of throat deposition and device retention produced using a dry powder inhaler (Aerolizer^®), along with the subsequent effect on the overall inhaler performance.

Materials and Methods

Computational Fluid Dynamics analysis of the flowfield generated in the Aerolizer^® with various modified mouthpiece geometries (including cylindrical, conical and oval designs) was used in conjunction with experimental dispersions of mannitol powder using a multi-stage liquid impinger to determine how the overall inhaler performance varied as the mouthpiece geometry was modified.

Results

Geometry of the inhaler mouthpiece had no effect on device retention or the inhaler dispersion performance. In contrast, the mouthpiece geometry strongly affected the amount of throat deposition by controlling the axial component of the exit air flow velocity. The radial motion of the emitted aerosol jet was found to have little effect on throat deposition in representative mouth–throat models. Despite the reduced throat deposition, there was no difference in the overall inhaler performance.

Conclusions

For cases where low throat deposition is a key design parameter, this study demonstrates that the amount of throat deposition can be reduced by making minor modifications to the inhaler mouthpiece design.

     

Characteristics of a capsule based dry powder inhaler for the delivery of indacaterol

Abstract

Objective:

To report performance characteristics and robustness of the Breezhaler device, a new capsule based dry powder inhaler (DPI) with low resistance (0.07?cm?H₂O^½/L/min) facilitating high inspiratory flow rates. This device was developed to deliver the novel, inhaled once-daily ultra long-acting β₂-agonist indacaterol, formulated as an inhalation powder in a capsule, and other investigational drugs including NVA237 and QVA149.     

Use of Solid Corrugated Particles to Enhance Powder Aerosol Performance

Purpose. To study the dispersion performance of non-porous corrugated particles, with a focus on the effect of particle surface morphology on aerosolization of bovine serum albumin (BSA) powders. Methods. The solid-state characteristics of the spray-dried BSA powders, one consisting of smooth spherical particles and another corrugated particles, were characterized by laser diffraction, X-ray powder diffraction, scanning electron microscopy, confocal microscopy, thermogravimetric analysis, surface area analyzer, and buoyancy method. The powders were dispersed using the Rotahaler® and the Dinkihaler® coupled to a four-stage liquid impinger operating at 30 to 120 L/min. Fine particle fraction (FPF) was expressed as the wt. % of BSA particles of size 5 m collected from the liquid impinger. Results. Apart from the morphology and morphology-related properties (specific surface area, envelope density), the corrugated particles and spherical particles of BSA had very similar solid-state characteristics (particle size distribution, water content, true density, amorphous nature). Using the Dinkihaler®, the FPFs of the corrugated particles were 10-20 wt. % higher than those of the smooth particles. Similar FPF differences were found for the powders dispersed by the Rotahaler®, but the relative changes were larger. In addition, the differences were inversely proportional to the air flows (17.3% at 30 L/min, 25.2% at 60 L/min, 13.8% at 90, 8.5% at 120 L/min). Depending on the inhaler, capsule and device retention and impaction loss at the impinger throat were lower for the corrugated particles. Conclusions. Enhanced aerosol performance of powders can be obtained by surface modification of the particles. The surface asperities of the corrugated particles could lower the true area of contact between the particles, and thus reduce the powder cohesiveness. A distinct advantage of using corrugated particles is that the inhaler choice and air flow become less critical for these particles.     

Effect of design on the performance of a dry powder inhaler using computational fluid dynamics. Part 1: Grid structure and mouthpiece length

This study investigates (1) the effect of modifying the design of a dry powder inhaler on the device performance, and (2) which design features significantly contribute to overall inhaler performance. Computational Fluid Dynamics (CFD) analysis was performed to determine how the flowfield generated in an Aerolizer at 60 l min(-1) varied when the inhaler grid and mouthpiece were modified. The computational models were validated by Laser Doppler Velocimetry (LDV). Dispersion performance of the modified inhalers was measured with a mannitol powder using a multistage liquid impinger at 60 l min(-1). The inhaler grid was found to significantly affect the performance of the Aerolizer. As the grid voidage was increased, the amount of powder retained in the device doubled (due to increased tangential flow of particles in the inhaler mouthpiece) and the FPF(Loaded) was reduced from 57 to 44% (due to increased mouthpiece retention). The length of the mouthpiece played a lesser role on the inhaler performance, having no significant effect on the flowfield generated in the devices. In summary, the performance of a dry powder inhaler can be affected by simple design changes. CFD, coupled with experimental results, provides a rational basis for understanding the performance difference.     

Accessorized DPI: a Shortcut towards Flexibility and Patient Adaptability in Dry Powder Inhalation

Purpose

In this work, a novel powder dispersion add-on device, the AOS (Axial Oscillating Sphere), was studied in conjunction with commercially available DPI devices to improve the powder dispersion.

Methods

An ordered mixture of formoterol fumarate and lactose was selected. We studied in two laboratories located at different altitudes the dispensing and dispersion of the drug at different flow rates, paying particular attention to a number of metrics of Fine Particle Dose (FPD).

Results

Two novel findings emerged from the data collected. First, the aerosol quality, measured as fine particle dose, can be increased by adding the accessory promoting the dispersion and de-aggregation of the formulation. The second finding was that, albeit the emitted dose was independent of altitude, the drug/lactose carrier DPI aerosolizing performance changed with the altitude of testing. In particular, fine particle dose depended on both altitude and device configuration. The RS01 inhaler without the AOS accessory used at higher altitude gave the lowest FPD values. By combining the AOS accessory with the DPI, however, the performance dependence on altitude/atmospheric pressure was essentially removed.

Conclusions

Increasing inhaler performance can be achieved using an add-on accessory that enhances aerosol dispersion and minimizes flow rate dependency.

     

Computer-aided design of dry powder inhalers using computational fluid dynamics to assess performance

Dry powder inhalers (DPIs) are gaining popularity for the delivery of drugs. A cost effective and efficient delivery device is necessary. Developing new DPIs by modifying an existing device may be the simplest way to improve the performance of the devices. The aim of this research was to produce a new DPIs using computational fluid dynamics (CFD). The new DPIs took advantages of the Cyclohaler® and the Rotahaler®. We chose a combination of the capsule chamber of the Cyclohaler® and the mouthpiece and grid of the Rotahaler®. Computer-aided design models of the devices were created and evaluated using CFD. Prototype models were created and tested with the DPI dispersion experiments. The proposed model 3 device had a high turbulence with a good degree of deagglomeration in the CFD and the experiment data. The %fine particle fraction (FPF) was around 50% at 60?L/min. The mass median aerodynamic diameter was around 2.8–4?μm. The FPF were strongly correlated to the CFD-predicted turbulence and the mechanical impaction parameters. The drug retention in the capsule was only 5–7%. In summary, a simple modification of the Cyclohaler® and Rotahaler® could produce a better performing inhaler using the CFD-assisted design.     

Aerosol Dispersion of Respirable Particles in Narrow Size Distributions Using Drug-Alone and Lactose-Blend Formulations

PURPOSE: To examine the effect of formulation type on the aerosolization of respirable particles in narrow size distributions. METHODS: Aerosol dispersion of two formulation types (drug alone and 2% w/w drug-lactose blends) containing micronized or spray-dried fluticasone propionate (FP) particles (d50% = 1.3 to 9.6 microm, GSD = 1.8 to 2.2) were examined using cascade impaction at 60 l/min with low and high resistance inhaler devices: Rotahaler and Inhalator, respectively. RESULTS: The aerosol dispersion of FP particles was significantly affected by the particle size, particle type, inhaler device, and formulation type. Interactions were observed between all factors. Generally, greater powder entrainment was obtained with smaller d50%. Higher emitted doses were obtained from drug-alone formulations of spray-dried FP particles and lactose blends of micronized FP particles. Greater aerosol dispersion of spray-dried FP particles was obtained using lactose-blend formulations with d50% around 4 microm. Greater aerosol dispersion of micronized FP particles was obtained using formulations of drug alone. Larger d50% produced larger mass median aerodynamic diameters. CONCLUSIONS: Small changes in the particle size within the 1-10-microm range exerted a major influence on aerosol dispersion of jet-milled and spray-dried FP particles using drug-alone and lactose-blend formulations.     

Characterisation and functionality of inhalation anhydrous lactose

The relationships between the physicochemical properties and functionality in dry powder inhaler (DPI) performance was investigated for inhalation grade anhydrous lactose and compared to monohydrate grades. The excipients were characterised using a range of techniques including particle size analysis, moisture sorption and powder rheometry. The inhalation anhydrous lactose grades were readily characterisable. The aerosolisation performance of capsule based DPI formulations containing budesonide (200 μg) and different grades of lactose evaluated using inertial impaction measurements produced fine particle doses of budesonide ranging from 24 to 49 μg. There were no apparent relationships between aerosolisation performance and excipient characteristics, such as particle size and powder density. However, formulations containing lactose grades which exhibit higher powder fluidisation energy values resulted in higher fine particle doses of budesonide.     

Adhesion of Powders for Inhalation: An Evaluation of Drug Detachment from Surfaces Following Deposition from Aerosol Streams

Purpose. To evaluate micronized powder retention and detachment from inhaler surfaces following reproducible deposition by impaction, coupled with centrifugal particle detachment (CPD). Methods. Micronized albuterol sulfate (AS) and beclomethasone dipropionate (BDP) were aerosolized as dry powders and deposited by cascade impaction onto different contact surfaces. Drug detachment from the surfaces was characterized using CPD, coupled with HPLC assay and scanning electron microscopy. Results. Drugs which accumulated as aggregates on model surfaces detached with distinctive profiles for % remaining vs. applied centrifugal force; each profile showed reproducible values for the minimum force required to initiate drug detachment, F_yield. While differences occurred in the observed detachment profiles for different drugs and contact surfaces (polyacetal vs. aluminum), the deposited drug particle size had the most significant effect on these profiles, e.g., F_yield for AS (2.1-3.3 m) was 383 12.7 N compared with 18 13.8 N for AS (4.7-5.8 m). Conclusions. A technique was developed which enabled the experimental review, and subsequent data analysis, of the adhesive properties between different DPI construction materials and drug substances deposited from aerosol clouds. The technique appears to be of greater relevance to inhaler design decisions than earlier studies in the literature claiming to show differences in the adhesion of single drug particles to surfaces.     

Correlations between cascade impactor analysis and laser diffraction techniques for the determination of the particle size of aerosolised powder formulations

The purpose of the study was to examine the suitability of the Spraytec laser diffraction technique for measuring the size distribution of aerosol particles generated from dry powder inhalators. A range of formulations with different dispersion properties were produced by spray-drying. The percentage of particles below 5.0 microm of these formulations was measured by laser diffraction (Mastersizer 2000 and Spraytec and inertial impaction (MsLI and NGI) using various inhaler devices and at different flow rates between 30 and 100 l/min. Linear relationships and correlations (R(2)>0.9) existed between the results obtained from, on one hand, the Mastersizer 2000 and the Spraytec, and, on the other hand, the MsLI and the Spraytec regardless of flow rates and inhaler devices. The Spraytec could be a reliable technique for the development, evaluation and quality control of dry powder aerosol formulations.     

Delivery of Nasal Powders of β-Cyclodextrin by Insufflation

Purpose. Delivery of nasal powders of granulated -cyclodextrin by insufflation was studied in order to find the relationship between powder properties and delivery behavior. Methods. Three nasal powder formulations, prepared by granulating -cyclodextrin with different binders, were delivered from a powder insufflation device, in which the dose to be emitted was loaded in a gelatin capsule. The delivery sequence of powder was recorded and characterized using an image analysis program. Results. Particle size was the main parameter affecting nasal powder delivery, both as to the amount of dose sprayed and the aspect of cloud produced. Between 50–150 µm of particle size a substantial change in delivery behavior of powders was observed. Powder of around 100 µm in size showed useful insufflation characteristics for nasal delivery. Bioavailability of nasal formulations of progesterone/-cyclodextrin powders was discussed in term of delivery behavior. Conclusions. The formulation approaches for improving nasal delivery of powders require the use of size optimized carriers. Insufflation of powders over 50 µm can favour the particle deposition by impaction, whereas for powders below 50 µm, deposition by sedimentation is moved. -cyclodextrin is a suitable carrier for achieving high systemic availability following nasal administration of powder formulations.     

Assistance for Predicting Deposition of Tranilast Dry Powder in Pulmonary Airways by Computational Fluid Dynamics

Purpose

Computational fluid dynamics (CFD) simulation was performed to predict deposition behavior of the dry powder inhaler (DPI) formulation in a pulmonary airway model. A synergistic study on CFD simulation and sample preparation with highly branched cyclic dextrin (HBCD) as an excipient matrix for dry powder inhaler formulations of tranilast (TL) were performed.

Methods

The crystal form of TL in spray-dried particles was characterized by powder X-ray diffraction and fluorescence spectroscopy. The aerodynamic performance of DPI formulations was assessed using the Andersen cascade impactor. CFD simulations could simulate the movement of fluids by resolving the mathematic equations governing the movement following Navier-Stokes equations. Particle behavior and deposition from CFD analysis compared with experimental data.

Results

Spray-dried particles (SDPs) of TL/HBCD showed characteristic diffraction peaks differing from untreated TL crystalline in powder X-ray diffraction. The polymorphic transition of TL was also observed in a fluorescence spectrum. Cascade impactor evaluation on SDPs of TL/HBCD at a 40% ethanol ratio demonstrated high inhalation performance with a fine particle fraction of 33%, while SDPs prepared at a 30% ethanol ratio were lower than that of the others. Regarding the cause of this difference, CFD analysis revealed that high inhalation performance was related to the true density and particle size of SDPs. The change in true density of TL associated with polymorphic transition would affect the inhalation performance.

Conclusion

The results on CFD simulations made a prediction about the particle behavior or deposition in pulmonary airways.

     

Effect of Device Design on the Aerosolization of a Carrier-Based Dry Powder Inhaler—a Case Study on Aerolizer® Foradile®

The objective of this study is to investigate the effect of device design of the Aerolizer^® on the aerosolization of a carrier-based dry powder inhaler formulation (Foradile^®). The Aerolizer was modified by reducing the air inlet size and mouthpiece length to 1/3 of the original dimensions, or by increasing the grid voidage. Aerosolization of the powder formulation was assessed on a multi-stage liquid impinger at air flow rates of 30, 60, and 100 L/min. Coupled CFD-DEM simulations were performed to investigate the air flow pattern and particle impaction. There was no significant difference in the aerosolization behavior between the original and 1/3 mouthpiece length devices. Significant increases in FPF total and FPF emitted were demonstrated when the inlet size was reduced, and the results were explained by the increases in air velocity and turbulence from the CFD analysis. No significant differences were shown in FPF total and FPF emitted when the grid voidage was increased, but more drugs were found to deposit in induction port and to a lesser extent, the mouthpiece. This was supported by the CFD-DEM analysis which showed the particle–device collisions mainly occurred in the inhaler chamber, and the cross-grid design increased the particle–device collisions on both mouthpiece and induction port. The air inlet size and grid structure of the Aerolizer^® were found to impact significantly on the aerosolization of the carrier-based powder.     

Influence of Particle Size,Air Flow,and Inhaler Device on the Dispersion of Mannitol Powders as Aerosols

Purpose. To study the effect of particle size, air flow and inhaler type on the dispersion of spray dried mannitol powders into aerosols. Methods. Mannitol powders were prepared by spray drying. The solid state properties of the powders were determined by laser diffraction, X-ray powder diffraction, scanning electron microscopy, freeze fracture, Karl Fischer titration and gas pycnometry. The powders were dispersed using Rotahaler^® and Dinkihaler^®, connected to a multistage liquid impinger at different air flows. Results. Three crystalline mannitol powders with primary particle size (MMD) 2.7, 5.0, 7.3 m and a similar polydispersity were obtained. The particles were spherical with a density of 1.5 g/cm³ and a moisture content of 0.4 wt.%. At an air flow of 30 L/min all the powders were poorly dispersed by both inhalers. With the Rotahaler^® increasing the flow (60–120 L/min) increased the fine particle fraction (FPF) in the aerosols for the 2.7 m powder, and decreased the FPF for the 7.3 m powder; whereas the FPF for 5.0 m powder was unaffected. With the Dinkihaler^®, all the powders were near complete dispersion at 60 L/min. Conclusions. The FPF in the mannitol powder aerosols was determined by an interplay of the particle size, air flow and inhaler design.     

Effect of Device Design on the In Vitro Performance and Comparability for Capsule-Based Dry Powder Inhalers

This study investigated the effect of modifying the design of the Cyclohaler on its aerosolization performance and comparability to the HandiHaler at multiple flow rates. The Cyclohaler and HandiHaler were designated as model test and reference unit-dose, capsule-based dry powder inhalers (DPIs), respectively. The flow field, pressure drop, and carrier particle trajectories within the Cyclohaler and HandiHaler were modeled via computational fluid dynamics (CFD). With the goal of achieving in vitro comparability to the HandiHaler, the CFD results were used to identify key device attributes and to design two modifications of the Cyclohaler (Mod 1 and Mod 2), which matched the specific resistance of the HandiHaler but exhibited different cyclonic flow conditions in the device. Aerosolization performance of the four DPI devices was evaluated by using the reference product''s capsule and formulation (Spiriva capsule) and a multistage cascade impactor. The in vitro data showed that Mod 2 provided a closer match to the HandiHaler than the Cyclohaler and Mod 1 at 20, 39, and 55 l/min. The in vitro and CFD results together suggest that matching the resistance of test and reference DPI devices is not sufficient to attain comparable aerosolization performance, and the improved in vitro comparability of Mod 2 to the HandiHaler may be related to the greater degree of similarities of the flow rate of air through the pierced capsule (Q_c) and the maximum impact velocity of representative carrier particles (V_n) in the Cyclohaler-based device. This investigation illustrates the importance of enhanced product understanding, in this case through the CFD modeling and in vitro characterization of aerosolization performance, to enable identification and modification of key design features of a test DPI device for achieving comparable aerosolization performance to the reference DPI device.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-012-9379-9) contains supplementary material, which is available to authorized users.KEY WORDS: computational fluid dynamics, device design, dry powder inhaler, in vitro comparability, in vitro performance     

Dry powder inhaler device influence on carrier particle performance

Dry powder inhalers (DPIs) are distinguished from one another by their unique device geometries, reflecting their distinct drug detachment mechanisms, which can be broadly classified into either aerodynamic or mechanical-based detachment forces. Accordingly, powder particles experience different aerodynamic and mechanical forces depending on the inhaler. However, the influence of carrier particle physical properties on the performance of DPIs with different dispersion mechanisms remains largely unexplored. Carrier particle trajectories through two commercial DPIs were modeled with computational fluid dynamics (CFD) and the results were compared with in vitro aerosol studies to assess the role of carrier particle size and shape on inhaler performance. Two percent (w/w) binary blends of budesonide with anhydrous and granulated lactose carriers ranging up to 300 μm were dispersed from both an Aerolizer? and Handihaler? through a cascade impactor at 60 L min(-1). For the simulations, carrier particles were modeled as spherical monodisperse populations with small (32 μm), medium (108 μm), and large (275 μm) particle diameters. CFD simulations revealed the average number of carrier particle-inhaler collisions increased with carrier particle size (2.3-4.0) in the Aerolizer?, reflecting the improved performance observed in vitro. Collisions within the Handihaler?, in contrast, were less frequent and generally independent of carrier particle size. The results demonstrate that the aerodynamic behavior of carrier particles varies markedly with both their physical properties and the inhalation device, significantly influencing the performance of a dry powder inhaler formulation.