dry powder inhaler device influence on carrier particle

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RESEARCH ARTICLES

Dry Powder Inhaler Device Influence on Carrier ParticlePerformance

MARTIN J. DONOVAN,1 SIN HYEN KIM,2 VENKATRAMANAN RAMAN,2 HUGH D. SMYTH1

1Division of Pharmaceutics, College of Pharmacy, University of Texas at Austin, Austin, Texas 78712

2Department of Aerospace Engineering and Engineering Mechanics, University of Texas at Austin, Austin, Texas 78712

Received 3 February 2011; revised 27 August 2011; accepted 28 October 2011

Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.22824

ABSTRACT: 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, pow-der particles experience different aerodynamic and mechanical forces depending on the in-

haler. 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 :m were dispersed from both an

Aerolizer R and Handihaler R through a cascade impactor at 60 L min−1. For the simulations, car-

rier particles were modeled as spherical monodisperse populations with small (32 :m), medium

(108 :m), and large (275 :m) 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 R, reflecting the improved performance observed in vitro. Collisions within the

Handihaler R, in contrast, were less frequent and generally independent of carrier particle size.

The results demonstrate that the aerodynamic behavior of carrier particles varies markedlywith both their physical properties and the inhalation device, significantly influencing the per-

formance of a dry powder inhaler formulation. © 2011 Wiley Periodicals, Inc. and the American

Pharmacists Association J Pharm Sci

Keywords: excipients; physical characterization; pulmonary drug delivery; formulation;

morphology; particle size

INTRODUCTION

Dry powder inhaler (DPI) formulations are typicallybinary mixtures comprising micronized active agentblended with a coarse carrier particle population thatconstitutes the bulk of the formulation (>95%, w/w).1

When a patient inhales through a DPI, the energy de-rived from their inspiratory effort fluidizes the pow-dered dose, detaching a fraction of the drug from thelarger carrier particles and depositing it in the deeplung where it exerts its intended therapeutic effect.2

It is well recognized that DPIs possess distinct mecha-nisms of powder dispersion.3 Passive DPIs rely solelyon the patient’s inspiratory effort to fluidize and dis-

Correspondence to: Martin J. Donovan (Telephone: + 512-471-4752; Fax: +512-471-7182; E-mail: [email protected])

Journal of Pharmaceutical Sciences

© 2011 Wiley Periodicals, Inc. and the American Pharmacists Association

perse the powdered formulation, and have evolvedconsiderably from their inception, incorporating a di-

verse array of geometries, including vortex generatorsand cyclones, to induce turbulence and particle–in-haler collisions to maximize the detachment potential

of the available flow stream.4, 5

The use of computational fluid dynamics (CFD) tomodel the inhalation flow stream, pressure profiles,and particle trajectories within therapeutic inhalershas become increasingly prevalent, finding employ-ment in the optimization of device parameters dur-ing development or, ex post facto, to elucidate thedeagglomeration principle of a commercially avail-able inhaler.6–11 By coupling CFD simulations within vitro aerosol performance, information on the rel-ative contributions of device and formulation can beobtained. A notable example of this approach is a se-ries of studies by Coates and colleagues6–10 on the

JOURNAL OF PHARMACEUTICAL SCIENCES 1



2 DONOVAN ET AL.

Aerolizer R (Plastiape S.p.A., Italy) DPI, where the device geometry (e.g., air inlet area, mouthpiece length)and operating parameters (volumetric flow rate, cap-sule size) were varied to assess their influence onin vitro aerosol performance.

Drug detachment from carrier particles is believedto proceed through two primary mechanisms: (1) aero-

dynamic, or fluid-based, detachment arising from thedirect interaction of the flow stream with drug parti-cles located on the carrier surface; and (2) mechani-cal, or impaction-based, detachment due to collisionsbetween carrier particles and the inhaler walls dur-ing particle transit through the device.3,12 Althoughthe diverse internal geometries of inhalers will varythe relative contributions between aerodynamic andmechanical detachment forces, it has been reportedthat the magnitude of impact-based events may ex-ceed those of flow-based events, and could potentiallybe the dominating factor in drug detachment from

carrier particles.

3,13–15

Previous research in our laboratory has demon-strated that large lactose carrier particles (>180 :m)can improve drug deposition in vitro for both an-hydrous and granular lactose populations, althoughthe improvement with carrier particle size was morepronounced in formulations with granulated carrierparticles.16 It is speculated that the surface rough-ness of the granulated particles shifted the drug de-tachment mechanism from flow-based detachment forcarrier particles with minimal surface roughness, toimpaction-based detachment forces as carrier parti-cle size and roughness increased. The aerosol perfor-

mance improvement was thought to result from anincreased incidence of carrier particle–inhaler colli-sions, given the higher inertia of larger carrier par-ticles, which inhibit their ability to travel with theflow stream through the inhaler. However, it is recog-nized that the aerodynamic behavior of carrier par-ticles can vary significantly based on the inhalerthrough which a formulation is dispersed, and im-proved performance may be observed if the carrierparticle design matches the predominant mecha-nism(s) of detachment induced by specific inhalertypes. Accordingly, the specific aim of this study was

to assess the role of the DPI design on aerosol per-formance as the size and shape of the carrier particlepopulation are varied. CFD simulations of carrier par-ticle trajectories were coupled with in vitro drug de-position studies to investigate the combined influenceof device and carrier on formulation performance.

MATERIALS AND METHODS

Materials

Micronized budesonide (EP) was purchased fromSpectrum Chemicals (Gardena, CA) and used as re-

ceived. Analytical grade ethanol was supplied bySigma Chemical Company (St. Louis, MO). Sam-ples of anhydrous (SuperTab R 22AN), and granu-lated (SuperTab R 30GR) lactose were obtained fromDFE Pharma (formerly DMV-Fonterra, Princeton,NJ). Size three gelatin capsules were provided byCapsugel R (Greenwood, SC).

Fractionation of Lactose Carrier Particles

Samples of each lactose batch were fractionated on an Autosiever vibrating sieve shaker (Gilson CompanyInc., Lewic Center, OH) with a sieve intensity, or am-plitude, setting of 40 for 5 min through the following sieves: 300, 250, 212, 180, 150, 125, 90, 75, 63, 45, and32 :m. Following the initial fractionation, the lactosecarriers were again sieved to obtain narrow particlesize distributions.

Preparation of Budesonide/Lactose Binary Blends

Budesonide and lactose were mixed in a ratio of 1:50 (w/w) via geometric dilution to obtain 500 mg of a 2% binary blend. The formulations were blendedwith a Turbula R orbital mixer (Glen Mills, Clifton,New Jersey) for 40min at 46rpm. Samples werestored in a desiccator at least 5 days prior to use.Blend uniformity was determined by randomly se-lecting eight 20-mg samples from each mixture, andassessing the drug content in the powder. Formula-tions were considered well blended and ready for useif the coefficient of variation (% CV) between the sam-ples for a given blend was below 5%.

Scanning Electron MicroscopyThe size and morphology of carrier particles were

visually assessed by scanning electron microscopy(SEM; Supra 40VP, Zeiss, Germany). Prior to SEM,approximately 20 nm of platinum was deposited ontothe particle surfaces via sputter coating.

Surface Area Analysis

Specific surface areas of the lactose carrier parti-cle populations were determined via nitrogen ad-sorption with a single-point BET method using aMonosorb R surface area analyzer (Quantachrome,

Boynton Beach, FL).Density of Lactose Carriers

The true densities of the lactose carrier particles weredetermined with a helium multipycnometer (Quan-tachrome; Boynton Beach, FL).

In Vitro Drug Deposition

About 20 (±1) mg of powder was loaded into size 3gelatin capsules and dispersed through an Aerolizer R

(Plastiape S.p.A.) and Handihaler R (BoehringerIngelheim Inc., Ridgefield, CT) DPI into a next gen-eration cascade impactor (NGI; MSP Corporation,

JOURNAL OF PHARMACEUTICAL SCIENCES DOI 10.1002/jps



DPI INFLUENCE ON CARRIER PARTICLE PERFORMANCE 3

Shoreview, MN) at a volumetric flow rate of 60 Lmin−1 actuated for 4-s intervals. To prevent parti-cle re-entrainment, the NGI stages were precoatedwith a 1% (w/v) solution of silicon oil in hexane. Priorto each actuation, 15 mL of EtOH was added to thepreseparator and collected following powder disper-sion from each capsule. Drug depositing in the cap-

sule, inhaler, mouthpiece adaptor, and induction portwere collected by rinsing each component with 10 mLof EtOH, whereas the NGI stages were each rinsedwith 5 mL. Drug content was assessed via ultraviolet-

visible absorption spectroscopy at 244 nm. The emit-ted fraction (EF) was calculated as the ratio of thedrug mass depositing in the mouthpiece, inductionport, preseparator, and impactor stages over the cu-mulative mass of drug collected following actuation(total drug deposited in the capsule, inhaler, mouth-piece, induction port, preseparator, and stages). Thefine particle fraction (FPF) of each dose was the ra-

tio of the drug mass depositing on stages 3 through 8(corresponding to an aerodynamic diameter less than4.46 :m) of the impactor over the emitted dose. Therespirable fraction (RF) was the ratio of the drug massdeposited on stages 3–8 over the entire dose recoveredfollowing each actuation.

Computational Fluid Dynamics

Computational fluid dynamics analysis was employedto study the flow field and assess carrier particle tra-

jectories within the DPIs during actuation. The geom-etry of the Aerolizer R was generously provided as a

CAD file by the manufacturer (Plastiape S.p.A.); thecomputational mesh consisted of approximately 3.7million unstructured computational volumes. By com-parison, the Handihaler R is composed of relativelysimpler internal geometric features, which were mod-eled from measurements obtained with a caliper. TheHandihaler R geometry was modeled using 3 millionunstructured computational volumes. The computa-tional mesh, in each case, was clustered near the wallsto provide better resolution of the near-wall turbu-lence. For instance, the y+ value, which is a normal-ized distance used to characterize the near-wall reso-

lution with respect to the boundary layer, was roughly15. For both the configurations, the incoming massflow rate was set at 60 L min−1. A size 3 capsule wasplaced in the capsule chamber. The flow inside the in-haler is turbulent, composed of a range of length andtime scales. To ensure computational tractability, thisturbulent flow field is modeled using the Reynolds-averaged Navier Stokes (RANS) approach.17 In thiswork, the commercial solver FLUENT R (ANSYS, Inc.,Canonsburg, Pennsylvania) is used to solve the RANSequations. The turbulence properties of the flow fieldare described using the shear-stress transport- basedk-T model. The turbulence intensity at the inflow was

assumed to be 10% for all the cases. The flow equa-tions were discretized using a first-order numericalscheme. By using a large number of computational

volumes, the dissipative errors associated with a first-order scheme were minimized. Extensive grid conver-gence studies demonstrated that the mesh used hereprovides mesh-converged results. The RANS equa-

tions were solved until a steady state solution wasreached. After this step, discrete particles correspond-ing to the drug carrier particles were introduced inthe flow. The particles were evolved using a Stoke-sian drag law, with nonspherical corrections imposedto account for particle shape effects [Fluent Inc. (2006)Centerra Resource Park, Lebanon, New Hampshire).The flow rate is high enough for gravitational forcesto be negligible. The initial locations of the particleswere different for the two configurations (as shownin Fig. 2). These locations were based on the assump-tion that the capsule was perforated from one side,and the particles leave the capsule with identical ve-locities. Because the mass loading of the particles inrelation to the local fluid mass is very small, the effectof the particles on the flow field is neglected. Threedifferent particle diameters were simulated for eachinhaler. The particles were assumed to be a monodis-perse population of uniform spheres with diametersof 32, 108, and 275 :m. In each simulation, roughly1000 particles were initiated with zero velocity. Be-cause the mass loading is small, collisions amongstthe particles were neglected. The number of colli-sions that each particle experienced with differentsections of the DPIs was tracked as the particles trav-

eled through the inhaler. In order to ensure statisticalconvergence of the results, different particle numberswere considered. It was found that using 500 parti-cles was sufficient to obtain converged statistics forthe average number of collisions that the particlesundergo with the inhaler walls.

Statistics

Statistical significance between performance valueswas determined with one-way analysis of variancewith post hoc tests between groups according to the

Bonferroni method ( P < 0.05).

RESULTS AND DISCUSSION

Physical Characterization of Carrier Particle Populations

The double-sieving technique yielded narrow par-ticle size distributions (Fig. 1). Although "-lactosemonohydrate is typically used as the carrier particlepopulation in binary dry powder formulations, othergrades including anhydrous and granulated lactosehave been studied, affording the opportunity to as-sess the influence of carrier morphology on aerosol

DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES



4 DONOVAN ET AL.

Figure 1. SEM micrographs of uncoated (a) 32–45 :m anhydrous lactose, (b) 90–125 :m

anhydrous lactose, (c) 250–300 :m anhydrous lactose, (d) 32–45 :m granulated lactose,

(e) 90–125 :m granulated lactose, and (f) 250–300 :m granulated lactose sieve fractions. Scale

bars denote 200 :m.

performance.16,18–20 The disparity in surface rough-ness between the anhydrous and granulated lactoseparticles increases with particle size, as evidenced bythe diminishing specific surface areas of the anhy-drous particles relative to their granulated counter-parts with increasing carrier sieve fraction (Table 1).Surface areas of larger granulated lactose did not di-minish appreciably as particle sizes were increased(as would be expected for perfectly smooth sphericalparticles). Instead, the increasing roughness (due togranulation) causes a relatively minimal decline in

surface area as the size of the particles within thepowder is increased. The true densities of all carrierparticle size fractions in both grades of lactose rangedbetween 1.54 and 1.58 g/cm3.

CFD Analysis

Internal geometries of the Handihaler R and Aerolizer R are illustrated in Figure 2. The flowstream enters the Aerolizer R via two tangential in-lets found on opposite sides of the capsule chamber.9

Table 1. Specific Surface Areas (SSA) of Anhydrous and

Granulated Lactose Carrier Particles by Sieve Fraction

Carrier Sieve

Fraction (:m)

Anhydrous

(m2 g −1)

Granulated

(m2 g −1)

<32 0.94 1.87

32–45 0.48 1.71

45–63 0.38 1.62

63–75 0.43 1.64

75–90 0.37 1.52

90–125 0.41 1.56

125–150 0.38 1.81

150–180 0.38 1.73

180–212 0.40 1.44

212–250 0.42 1.67

250–300 0.36 1.46

The resulting turbulent flow field induces the capsuleto rotate and rattle with high frequency during in-halation, assisting in ejecting and dispersing the pow-dered dose through the perforations in the capsulewall.7 It is noted that although the motion of the cap-sule itself is not simulated in this work, it may affectparticle release and transport in the fluid flow, and ithas been speculated that the emitted powder parti-cles may collide with the capsule, though a previousinvestigation concluded that impactions between thepowder particles and the spinning capsule do not sig-

nificantly contribute to dispersion performance in the Aerolizer R.7 However, those studies were performedon pure spray-dried mannitol, and the inclusion of carrier particles may potentially alter this result andis a topic that merits future study.

Figure 2. Schematic views of the Handihaler R (left) and

Aerolizer R dry powder inhalers. The bold arrow denotes the

particle launch location for each inhaler.





A key feature of the internal geometry of the Aerolizer R is a grid dividing the capsule chamber andthe mouthpiece to prevent capsule egress from the de-

vice during inhalation. In addition, it is noted that thegrid has been demonstrated to straighten the flow andsuppress turbulence downstream of its location.6 Onthe contrary, the mechanism of the Handihaler R is

based on the sudden expansion of the inhalation flowstream as it passes from the inlet into the larger cap-sule chamber. The abrupt opening from the smallerinlet chamber to the capsule chamber causes theboundary layer of the flow stream to separate at thecorner of the expansion, creating an annular regionwhere a portion of the flow recirculates, resulting ina pressure loss in this region.21 The incoming flowstream pushes the capsule toward the grid while thelow pressure region simultaneously attracts the cap-sule toward the inlet, causing the capsule to spin and

vibrate in the chamber.11 Similar to the Aerolizer R,the Handihaler R also contains a mesh between thecapsule chamber and the mouthpiece. However, thisgrid is made of thinner wires and its effect on the flowfield is comparably less significant than the grid lo-cated in the Aerolizer R, as the blockage representedby the wires is a very small fraction of the total sur-face area.

Figure 3 depicts the velocity magnitude of theflow stream in the inhalers at 60 L min−1. In theHandihaler R, the maximum flow speed is found up-stream of the capsule with very high shear flowaround the capsule itself. In contrast, the Aerolizer R

exhibits a much more complex flow pattern, as the

incoming flow generates a swirling motion inside thecapsule chamber. The grid between the capsule cham-ber and the mouthpiece constricts the flow, and con-sequently the velocity magnitude is very high whenthe fluid exits the capsule chamber through the gridspacing. The grid also regulates the swirling flow gen-erated by the capsule chamber.6

Carrier particle trajectories were simulatedthrough the DPIs to quantify the frequency of theircollisions with the internal geometry of the inhaler(Table 2). It was expected that the distinct internalgeometries of the inhalers would yield distinct par-

ticle trajectories. As seen in Figure 4, the fluid flowinside the Aerolizer R actively promotes particle colli-sions with the inhaler wall. The tangential air inletsintroduce a swirl component to the flow stream thatis imparted to the powder as they exit the capsule,causing particles to swirl through the mouthpiece.

In contrast to the Aerolizer R, carrier particleswithin the Handihaler R experience markedly fewercollisions with the inhaler (Fig. 5). The wake regiondownstream of the cavity causes the particles to ac-celerate and travel at an angle to the vertical direc-tion, directing the particle trajectory toward the in-haler wall. As the particles have significant inertia

Figure 3. Contour of velocity magnitude inside

Handihaler R (left) and Aerolizer R (right).

(increasing with carrier particle size), once they arelaunched on this trajectory the fluid flow is unable tosignificantly alter the particle trajectory. The initialacceleration around the capsule introduces the colli-sional movement, pushing the particles downstreamtoward the inhaler exit.

Table 2 shows the influence of particle diameter

on the number of collisions with the mouthpiece wallexperienced by the particles. It should be noted thatthe fluid flow corresponds to particles with zero diam-eter, or zero Stokes number. Increasing the particlediameter increases the Stokes number and causes adeparture of the particle trajectory from the fluid tra-

jectory. As the particles become larger, their responseto changes in the fluid flow is slower. Consequently,larger particles can possess ballistic trajectories andundergo more collisions, and increasing the particlediameter increases the number of collisions. It is seenthat the Aerolizer R exhibits greater sensitivity to par-ticle size relative to the Handihaler R. This is primar-ily attributed to the fact that the Handihaler R doesnot introduce a swirling motion inside the mouth-piece, which causes the particles to have a longer res-idence time (or trajectory length) inside the mouth-piece.

In Vitro Aerosol Performance

In vitro drug dispersion profiles for all experimen-tal formulations are presented in Tables 3 and 4.The percentage of the nominal dose emitted fromthe Handihaler R exceeded that emitted from the




6 DONOVAN ET AL.

Table 2. Average Number of Collisions Between a Carrier Particle and the Inhaler As It Exits the

Device During Actuation from the Aerolizer R and Handihaler R at 60 L min−1

Aerolizer R Handihaler R

Carrier Particle Sieve Fraction (:m) 32 (:m) 107.5 (:m) 275 (:m) 32 (:m) 107.5 (:m) 275 (:m)

Inhaler–carrier collisions 2.3 3.6 4.0 1.7 2.2 2.3

Figure 4. Carrier particle trajectory inside the Aerolizer R

at 60 L min−1 (From left, dparticle = 32, 108, and 275 :m).

Aerolizer R, yielding over 75% EF for all carrier parti-cle sizes between both lactose grades. For anhydrouslactose formulations dispersed from the Handihaler R,the enhanced EF did not correspond to improveddrug deposition compared with the Aerolizer R, asRF values were generally comparable between de-

vices across most carrier particle size fractions. The

disparity between EF and RF is reconciled by thehigher FPF values obtained from the Aerolizer R, indi-

Figure 5. Carrier particle trajectory inside the

Handihaler R at 60 L min−1 (From left, dparticle = 32,

108, and 275 :m).

cating that although for anhydrous formulations theHandihaler R is more effective at emitting drug fromthe device, the Aerolizer R demonstrates a greater ten-dency for detaching drug from the carrier particles.In contrast, granulated carrier particle formulationsdispersed from the Handihaler R outperformed thosefrom the Aerolizer R for all but the largest carrier par-ticle size fractions.

From the drug dispersion profiles, it is observedthat the increased number of collisions between thecarrier particles and inhaler does not directly trans-late into improved aerosol performance, as measured

by RF. For a given dry powder formulation, RF val-ues reflect the combined EF and FPF, revealing aninhaler’s potential to both emit the drug from the de-

vice and detach it from the carrier, such that it cantravel to the deep lung.18 By itself, EF is a metricdescribing the inhaler’s ability to emit the drug fromthe device and deliver it to the patient, but revealsnothing as to whether the drug is detached from thecarrier, and drug that remains adhered to the coarsecarrier particles will deposit in the mouth, throat andupper airways. Accordingly, FPF is a better measureof an inhaler’s drug detachment potential, providing

the fraction of detached drug exiting the device rela-tive to the total amount that leaves the inhaler. A highEF coupled with a high FPF will generate excellentRF values, but opposing EF and FPF performance(e.g., high EF and low FPF) will only yield moderaterespirable fractions.

Although significant differences in emitted dosewere observed between the devices, this did notyield a consistent disparity in overall performance,as the relatively high EF from Handihaler R was off-set by the Aerolizer R’s enhanced tendency to emitdrug particles detached from the carriers. To pro-

vide an approximate measure of the relative drug detachment potential of the DPIs, the ratio of FPF

values from the Aerolizer R over the Handihaler R

(FPF Aerolizer /FPFHandihaler ) against the carrier particlesize fraction were plotted (Fig. 6). Values >1 indi-cate the Aerolizer R may be more effective at drug detachment while a ratio less than unity gives theadvantage to the Handihaler R. It must be notedthat detached drug particles may be agglomeratesof primary drug particles, which due to their largesize will deposit in the throat and conducting air-ways. This is especially relevant for the corticosteroidbudesonide, which has been demonstrated to be a





Table 3. Emitted Fraction (EF), Fine Particle Fraction (FPF), and Respirable Fraction (RF) for 2% (w/w) Budesonide Formulations with

Anhydrous Lactose Carrier Particles Characterized In Vitro from the Aerolizer R and Handihaler R Dry Powder Inhalers at 60 L min−1


Carrier Particle Sieve Fraction (:m) EF FPF RF EF FPF RF

<32 63.5 (1.6) 29.1 (1.4) 18.4 (0.7) 86.4 (1.1) 18.5 (0.7) 15.9 (0.4)

32–45 64.5 (1 .8) 21.3 (0.8) 13.7 (0.3) 79.0 (8.0) 15.5 (0.7) 12.2 (1.1)

45–63 63.

1 (2.

2) 23.

1 (1.

8) 14.

6 (1.

4) 76.

3 (1.

2) 17.

1 (1.

2) 13.

0 (0.

9)63–75 68.9 (1 .8) 15.1 (0.4) 10.4 (0.3) 79.2 (2.5) 13.7 (0.3) 10.8 (0.2)

75–90 71.8 (2.4) 15.2 (0.3) 10.9 (0.5) 77.1 (1.3) 14.4 (0.7) 11.1 (0.4)

90–125 62.3 (1.9) 13.7 (0.6) 8.5 (0.4) 80.0 (8.1) 15.9 (0.8) 12.4 (1.2)

125–150 62.7 (2 .1) 15.6 (1.4) 9.8 (1.2) 81.1 (4.7) 9.9 (0.5) 8.0 (0.8)

150–180 62.3 (2 .0) 12.1 (0.8) 7.5 (0.3) 82.3 (1.9) 9.5 (1.6) 7.8 (1.3)

180–212 61.8 (1.9) 14.1 (1.1) 8.7 (0.5) 79.9 (1.8) 10.1 (0.2) 8.1 (0.2)

212–250 63.4 (2.3) 15.5 (0.8) 9.9 (0.6) 82.3 (0.8) 8.7 (1.9) 7.1 (1.5)

250–300 61.6 (1 .7) 15.0 (1.1) 9.3 (0.9) 80.2 (0.4) 9.8 (0.3) 8.1 (0.6)

Values are given as the mean of N = 3 replicates, and values within parentheses represent the standard deviation for N = 3 replicates.

relatively cohesive drug.22,23 However, as the sameformulation was used for each size fraction within

a lactose grade, the extent of drug agglomerationwas presumed constant between samples, with theinhaler as the variable. For the anhydrous carrierformulations, all but a single size fraction (90–125:m) exceeded 1 (Fig. 6), indicating the ability of the Aerolizer R to emit drug particles detached fromthe carrier outperforms the Handihaler R. Conversely,most granulated carriers yielded better drug detach-ment from the Handihaler R (ratios were less than 1).However, at carrier particle sizes greater than 75–90and 90–125:m fractions for the granulated and an-hydrous carriers, respectively, the FPF ratio beganto increase, indicating an improvement in drug de-

tachment potential of the Aerolizer R relative to theHandihaler R for large carrier particle formulations. Itis speculated that the higher frequency of carrier–in-haler collisions within the Aerolizer R as carrier size isincreased may account for the observed improvementin drug detachment. In these larger carrier formu-lations, impaction-based forces may be a significantmechanism of drug detachment as discussed below.

Influence of Device on Performance

Because of the marked variation in the internal ge-

ometries of the two inhalers, differences in aerosolperformance were expected between the Aerolizer R

and Handihaler R. Regarding device resistance, the Aerolizer R and Handihaler R reside on opposing endsof the spectrum, as the Aerolizer R has less than half the resistance [0.072 (cmH2O)0.5 /(L min−1)] of theHandihaler R [0.158 (cmH2O)0.5 /(L min−1)].9,24 Thisincreased resistance of the Handihaler R arises fromthe narrow inlet tube at the base of the capsule cham-ber (Fig. 2).11 It is noted that the flow rate selectedfor this study (60 L min−1) is much higher than thattypically generated through the Handihaler R, but isreadily attainable by > 90% of adult patients throughan Aerolizer R.24–26 The relationship between inhalerresistance ( R), volumetric flow rate (Q), and pressuredrop ( P) across a device is ( P)0.5 = QR.27 For afixed flow rate, a higher resistance device will pro-duce a greater pressure drop, which has been foundto correlate with improved aerosol performance.28–30

In addition, the overall energy passing through aninhaler can be approximated from the product of the

Table 4. Emitted Fraction (EF), Fine Particle Fraction (FPF), and Respirable Fraction (RF) for 2% (w/w) Budesonide Formulations with

Granulated Lactose Carrier Particles Characterized In Vitro from the Aerolizer R and Handihaler R Dry Powder Inhalers at 60 L min−1


Carrier Particle Sieve Fraction (:m) EF FPF RF EF FPF RF

<32 57.0 (1.4) 18.5 (1 .2) 11.1 (1.6) 76.9 (1.6) 17.1 (1.4) 13.1 (0 .8)

32–45 69.1 (3.7) 11.1 (0 .6) 7.7 (0.1) 82.0 (0.5) 15.4 (1.0) 12.6 (0 .8)

45–63 74.4 (4.1) 8.9 (1 .2) 6.6 (0.6) 82.1 (1.9) 12.8 (0.2) 10.5 (0.3)

63–75 73.8 (3.7) 12.6 (1.4) 9.3 (0 .6) 78.4 (2.7) 16.2 (0.7) 12.6 (0.2)

75–90 73.9 (6.6) 9.7 (2 .1) 7.2 (0.8) 78.7 (1.9) 19.4 (2.4) 15.3 (1 .6)

90–125 77.8 (1.8) 11.6 (0 .9) 9.0 (0.5) 86.1 (2.0) 17.9 (0.8) 15.3 (0 .4)

125–150 71.3 (4.2) 18.9 (1 .5) 13.4 (0.3) 84.3 (3.4) 20.5 (2.5) 17.2 (1.7)

150–180 73.8 (2.5) 14.2 (1.3) 10.5 (0 .7) 87.3 (1.4) 15.2 (1.5) 13.3 (1.1)

180–212 72.6 (3.2) 20.8 (1 .1) 15.1 (0.8) 87.1 (1.6) 16.1 (1.4) 14.0 (1 .1)

212–250 68.7 (5.4) 20.2 (1 .5) 13.8 (0.7) 84.3 (1.1) 15.4 (2.8) 13.1 (2 .3)

250–300 68.5 (4.5) 20.1 (1 .5) 14.5 (0.5) 85.5 (0.6) 18.4 (1.0) 15.7 (1.0)

Values are given as the mean of N = 3 replicates, and values within parentheses represent the standard deviation for N = 3 replicates.




8 DONOVAN ET AL.

Figure 6. Ratio of the FPF values obtained from the

Aerolizer R over the Handihaler R for both anhydrous and

granulated lactose formulations.

pressure drop across the device, volumetric flow rate,and actuation time.31 Thus, although the volumetricflow rate is the same through both inhalers (60 Lmin−1), a greater pressure drop, and hence a higherenergy value is calculated for the Handihaler R, whichis predicted to improve performance from this DPI.However, despite the device differences, RF valuesexhibited minimal dependence on the inhaler forthe anhydrous carrier particles, varying instead asa function of carrier particle size, with larger carrierparticle diameters diminishing overall performance(Fig. 7). By comparison, granulated lactose formu-lations showed some device dependency, notably in

the smaller carrier particle size fractions, with bothinhalers demonstrating comparable performance ascarrier size increased.

For anhydrous lactose formulations, the relativelyflat surfaces of the carriers permit direct interac-tion between the drug particles and inhalation flowstream. The overall dispersion performance betweenthe devices is similar across all anhydrous carriersize fractions, indicating the comparable ability of theDPIs to detach drug readily accessible to the air flow.However, in granulated lactose formulations, wheredirect interaction between the drug and flow stream

is inhibited by the surface roughness of the carri-ers, the Handihaler R exhibited higher RF values upto the largest size fractions, when it is speculatedthat increasingly larger mechanical forces allowedthe Aerolizer R to improve its detachment potential(as indicated by the increasing FPF ratio), and attaincomparable RF values. The improved performanceat smaller carrier sizes of granulated lactose in theHandihaler R may be attributed to the greater energyinput through this device (as mentioned above), whichhas been found to correlate positively with disper-sion performance.31 Furthermore, a previous studyon the Handihaler R revealed that a pressure gra-

Figure 7. Respirable fraction (RF) values of (a) anhydrous

and (b) granulated lactose carrier particles dispersed from

the Aerolizer R and Handihaler R at 60 L min−1. Values are

given as the mean of N = 3 replicates, with error bars rep-

resenting the standard deviation for N = 3 replicates.

dient develops across the capsule chamber, pulling drug particles primarily from the lower capsule per-foration located nearest the corner of the flow streamexpansion.11 Accordingly, the relatively high energyinput through this device at the studied flow rate,coupled with the Handihaler R’s mechanism-of-action,may enable drug within the surface asperities of thegranulated particles to be pulled-off of the carriers,allowing performance to be relatively independentof surface roughness, and thus carrier particle size,

given that the surface roughness of granulated carri-ers increased with particle diameter.

Interparticle Collisions

In addition to carrier particles colliding with the in-haler walls, interparticle collisions between carriersduring actuation may provide an additional sourceof mechanical detachment forces. For a fixed massof powder, increasing the diameter of the carrierpopulation diminishes the overall number of carrierparticles in the dose, such that formulations withthe largest lactose sizes contain a fraction of the





number of carrier particles relative to the small-est carrier size ranges. Previous studies have re-ported that lactose fluidizes from capsules via twodistinct mechanisms dependent upon the flowability,and hence the cohesiveness, of the powder.32–34 Pow-ders with good flowability are entrained by way of an“erosion” mechanism, where the powder is fluidized

by layers and exits the inhaler gradually as a contin-uous stream.33,34 By contrast, for poorly flowing pow-ders fluidization occurs by the “fracture” mechanismwhereby the powder fluidizes as multiple agglomer-ates, and in extreme cases may fluidize as a singleaggregated powder plug.

It has been proposed that smaller carrier particlesize fractions, particularly those with a significantconcentration of lactose fines, improve aerosol perfor-mance by coupling the fracture entrainment mecha-nism with an extensive number of carrier particles,thereby generating a high density aerosol cloud thatpromotes collisions between lactose carriers.33,34 Inthe present study, only anhydrous formulations ex-hibited performance consistent with this mechanism,but performance from granulated carriers was incom-patible with this theory, as the<32:m carrier popula-tions did not yield RF values significantly higher thanthe larger carriers. However, variables apart from car-rier particle size can affect the extent to which inter-particle collisions may occur. For instance, the DPIemployed may influence interparticle collisions, asdevices with more complex internal geometries mayenhance the frequency and/or magnitude of interpar-ticle collisions relative to inhalers with simpler inter-

nal geometries. In addition, the cross-sectional areaof the capsule perforation may likewise affect inter-particle collisions, as smaller openings can preventthe powder from exiting the capsule as agglomeratedplugs, thus limiting the density of the aerosol cloud.Thus, it is noted that the inhalers employed in thesestudies may not be ideal for promoting interparticleinteractions, as the swirling particle trajectories inthe capsule chamber of the Aerolizer R may be off-set by the small cross-sectional area of the capsuleperforations, whereas the larger diameter capsuleopenings from the Handihaler R are coupled with an

internal geometry that may not induce extensive in-terparticle collisions relative to the Aerolizer R. Ac-cordingly, although interparticle collisions may influ-ence aerosol performance under certain conditions,this detachment mechanism was not supported bythe data for both lactose grades, and thus CFD sim-ulations capturing carrier–carrier interactions weredeemed beyond the scope of the present study.

Mass Median Aerodynamic Diameter

In contrast to the respirable fraction, the mass me-dian aerodynamic diameter (MMAD) of drug deposit-ing on the stages of the cascade impactor varies

Figure 8. Mass median aerodynamic of budesonide par-

ticles following dispersion of 2% (w/w) formulations with

(a) anhydrous lactose, and (b) granulated lactose car-

rier particles at 60 L min−1 from both the Aerolizer R

and Handihaler R DPIs. Values are given as the mean of

N = 3 replicates, with error bars representing the standard

deviation for N = 3 replicates.

significantly between inhalers for both anhydrousand granulated lactose formulations (Fig. 8). Fur-thermore, although the MMAD from the Aerolizer R

displayed an overall decreasing trend with increas-ing carrier particle size for both lactose populations,MMAD values obtained from the Handihaler R weregenerally independent of the formulation. The dis-parity between the MMAD values for formulationsdispersed through the inhalers were greatest at the

smaller carrier particle formulations, and eventuallyconverged on a mutual value for the largest carriersize fractions. In our previous study, it was postulatedthat the reduction in MMAD obtained from larger car-rier particles dispersed through the Aerolizer R maybe attributed to the increased detachment of smallerdrug particles from the carrier surface.16 As the col-lision force between a particle and inhaler is depen-dent on the mass, and thus the volume, of the carrierparticle, the momentum generated from a collision in-creases with the cube of the carrier particle diameter,assuming a relatively constant particle velocity (as

volume ∝ diameter3).2 Thus, larger carrier particles




10 DONOVAN ET AL.

can generate strong mechanical detachment forces,which can potentially exceed fluid-based forces.3,13,14

These strong mechanical forces may dislodge drug particles resistant to fluid-based detachment, in-cluding small aggregates and primary drug parti-cles located within carrier particle surface asperities,inhibiting their interaction with the flow stream. Ac-

cordingly, the size of drug particles depositing in theimpactor would be expected to decrease with largercarrier particle populations, as observed in both theanhydrous and granulated formulations dispersedfrom the Aerolizer R. Comparing MMAD values ob-tained from the Aerolizer R with the corresponding RF values, the carrier particle size fraction whenthe MMAD markedly declined matched the carriersize when aerosol performance exhibited a local im-provement; this corresponded to the 180–212 :m sizefraction for anhydrous carriers, and 90–125 :m forgranulated lactose ( p < 0.05). Conversely, MMAD

values in the Handihaler R were relatively consis-tent between carriers for both lactose grades, dis-playing no general trend with performance, althoughthe MMAD from formulations dispersed through theHandihaler R was consistently lower than that dis-persed from the Aerolizer R, with the exception of thelargest carrier sizes (>180:m).

In combination with the particle trajectory sim-ulations, the aerosol performance data suggest thepresence of an impaction-based mechanism of drug detachment in the Aerolizer R whereby the relativelynumerous and high energy collisions between largecarriers and the inhaler wall generate a force suf-

ficient in both magnitude and direction to detachsmaller drug particles immune to detachment bythe flow stream. As discussed in detail elsewhere,this favors large carrier particles with extensive sur-face roughness, and accordingly the improvementin aerosol performance with larger carrier popu-lations is more pronounced in granulated lactoseformulations.16 However, it is noted that while thepresent studies were performed at a fixed flow rate,the velocity, and hence momentum, of the carrier par-ticles may significantly affect performance, particu-larly for larger carrier populations. Accordingly, stud-

ies exploring the effectiveness of mechanical detach-ment forces at variable flow rates are presently underinvestigation in our lab.

CONCLUSION

Coupling the CFD particle trajectory simulationswith the in vitro results, it is concluded thatimpaction-based forces are not a significant mecha-nism of detachment in the Handihaler R, as reflectedby both the absence of improved performance at thelarge carrier fractions and the minimal increase insimulated carrier particle–inhaler collisions with car-

rier diameter. In contrast, the internal geometry of the Aerolizer R is capable of generating a highernumber of particle–inhaler collisions, with the fre-quency of the collisions markedly increasing with car-rier diameter. Accordingly, aerosol performance fromthis DPI exhibited a dependence on the carrier par-ticle size fraction, which was not observed in the

HandihalerR

to a similar extent. In addition, per-formance was also significantly influenced by carrierparticle morphology, and although granulated lac-tose is not commonly employed in DPI formulations,the use of this lactose grade afforded greater insightinto distinctions in DPI performance than relativelysmooth surfaced anhydrous lactose. In conclusion, theresults of this study suggest that matching the physi-cal properties of the carrier population to the predom-inant detachment mechanism of the DPI may signifi-cantly influence aerosol performance.

ACKNOWLEDGMENTS

The authors would like to express their gratitude toProf. Hak Kim Chan and Mr. Mauro Citterio for theirassistance in providing the Aerolizer R CAD file. Theauthors also wish to acknowledge Stephen Marek forobtaining the SEM images.

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