evaluation of the malvern spraytec® with inhalation cell for the measurement of particle size...

Evaluation of the Malvern Spraytec1 with Inhalation Cell forthe Measurement of Particle Size Distribution from MeteredDose Inhalers

ALFRED HAYNES,1 MADHU SUDHAN SHAIK,1 HENRIK KRARUP,2 MANDIP SINGH1

1Division of Pharmaceutics, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee,Florida 32307

2Malvern Instruments, Inc., Southborough, Massachusetts 01772

Received 3 January 2003; revised 21 August 2003; accepted 25 August 2003

ABSTRACT: The purpose of this study was to evaluate the Malvern Spraytec1 withinhalation cell attachment as a means of analyzing the particle size distribution ofaerosols from pressurized metered dose inhalers (pMDIs). The aerosol particle sizedistribution of various commercially available, placebo, and experimental pMDI formula-tions was determined using Spraytec1 under various experimental conditions and therelevant data were compared with the Andersen cascade impactor data. The Spraytec1

volume median diameter (Dv 50) values for commercial chlorofluorocarbon- andhydrofluoroalkane (HFA)-based pMDIs were respectively smaller and higher comparedwith their reportedmassmedianaerodynamic diameter values. Itwaspossible to obtainaclose agreement between Spraytec1 Dv 50 and the reported mass median aerodynamicdiameter values for a solution-type pMDI formulation, Qvar 50, by equilibrating thepMDI to 558Cbefore themeasurement andusing a 20-cm throat extension. Incorporationof a nonvolatile solvent propylene glycol (PG) in placebo pMDIs (15% w/w ethanol, 0.5–20.0%w/wPG inHFA134a) showedan increase inDv50with increasing concentration ofPG.Furthermore, itwas possible to obtain a correlation (R2¼ 0.8037) betweenSpraytec1

and Andersen cascade impactor data for the experimental nimesulide-pMDI formula-tions containing 0.1% w/w drug, 0.25–10% w/w PG, and 15% ethanol in HFA 134a.� 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:349–363, 2004

Keywords: laser diffraction; particle size analysis; metered dose inhaler; Spraytec1;inhalation cell

INTRODUCTION

In the area of respiratory drug delivery, particlesize has a paramount role in the delivery anddeposition of the aerosolized drug in the lungs.Therefore, in order to deliver a drug or activecompound to the lungs in an efficacious manner, it

is believed that the optimum particle size fordeposition into the pulmonary system should bebetween 0.5–8 mm.1 The pressurized metereddose inhaler (pMDI) represents the most com-monly used drug delivery device for the deliveryof drugs to the lungs by inhalation.2 Methodsavailable to analyze the particle size distribution(PSD) for pMDIs include microscopy, inertialseparation, laser diffraction, time-of-flight, andphase-Doppler analysis. Currently, the most ac-ceptable technique for the evaluation of PSD ofaerosols generated from pMDIs is the Andersencascade impactor (ACI). This is primarily attrib-uted to the fact that this technique provides direct

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 2, FEBRUARY 2004 349

Correspondence to: Mandip Singh (Telephone: 850-561-2790; Fax: 850-599-3347;E-mail: [email protected])

Journal of Pharmaceutical Sciences, Vol. 93, 349–363 (2004)� 2004 Wiley-Liss, Inc. and the American Pharmacists Association

chemical analysis of drug mass irrespective ofthe excipients contained in the formulation.Additional advantages of the ACI include massbalance, as well as drug quantification as afunction of aerodynamic diameter. However, ACIdeterminations are time consuming in the for-mulation development process while trying toscreen and optimize different formulations. Inrecent years, several instruments have beendeveloped to serve as more independent andefficient methods for particle size analysis.

Laser diffraction represents a well-establishedmethod for determining particle size. Instrumentswithin this family include the Malvern 2600,MalvernMasterSizer E and S,Malvern Spraytec1

(Malvern Instruments, Inc., Southborough, MA),and also the Sympatec (Sympatec Inc., Lawrence-ville, NJ). The Malvern instruments (MasterSizerE, MasterSizer S, and Spraytec1) apply Miescattering, whereas the Sympatec spray analyzerallows for the option of Fraunhofer or Mie appro-ximations to derive the PSD. The Mie scatteringtheory and the Fraunhofer approximation to theMie theory have been described elsewhere.3–5

However, a few remarks on the advantages anddisadvantages of these two theories are brieflypresented herein. The Fraunhofer approximationdoes not make use of any knowledge of the opticalproperties of the material and is recommended forthe particle size measurements of mixtures ofdifferent materials. If the particle size is >50 mm,then the Fraunhofer approximation gives goodresults. For medium-sized particles (1–50 mm)with a ratio of refractive index of the particle tothat of the medium of >1.1, the Fraunhoferapproximation usually gives good results. How-ever, for small particles which have low relativerefractive index, errors occur in the proportion ofvolume subscribed to a given size.6 Annapragadaand Adjei7 noted that Fraunhofer approximationmay give incorrect mass fractions in the presenceof small particles (<1 mm). Mie theory addressesthe interaction of light with a three-dimensionalobject by taking into account the combined effectsof diffraction, refraction, and absorption and offersthe best general solution for particles<50 mm. TheMie theory canalsobeused forparticles for>50mmand is preferred for cases in which the refractiveindex of the particles is close to that of themedium.To exploit the Mie theory to its full potential,optical properties of the system such as complexrefractive index (including both the real andimaginary part of the particle) and the refractiveindex of the suspending medium should be

known.6 It has been reported that widely differentresults could be obtained for a given set of data, ifthe particle refractive index specified in the soft-ware deviates significantly from its real value.Therefore, correct refractive index informationconcerning the particles to be measured is requir-ed to obtain accurate PSD results using Mietheory.8

It must be noted that inertial impactorssuch as ACI measure the aerodynamic diameter(Da), whereas laser diffraction gives geometricparticle dimensions. However, a relationshipbetween these two parameters is given byHickey9

Da ¼ ðr=r0Þ0:5Dv ð1Þ

where r¼density of the particle, r0¼unit density(1.0 g/cm3), andDv¼ equivalent volume diameter.This equation assumes that the particles arespherical and slip-correction factors are insignif-icant.9,10 Laser diffraction-based size determina-tion of the nebulized aerosols has been shown tobe comparable with ACI data.11,12 However, therehave been only few reports specifically evaluatinglaser diffraction as a means of determiningparticle size from pMDIs.1,13

TheMalvern Spraytec1with its inhalation cell,represents the newest diffraction-based deviceintroduced by Malvern Instruments, which hasbeen specifically modified for measuring the PSDgenerated from medicinal aerosols, includingpMDIs, dry powder inhalers, and nebulizers. Thepurpose of our investigation was to evaluateSpraytec1 with inhalation cell attachment forthe measurement of PSD from pMDIs. To addressthe usefulness of this device, various commercialpMDIs (bothCFCandnon-CFCbased)were evalu-ated in comparison to their reported mass medianaerodynamic diameter (MMAD) values. We ob-served that the Spraytec1 data, expressed asvolume median diameter (VMD), underestimatedthe particle size of CFC-based pMDIs and over-estimated the HFA-based products. Becausethe CFC-based products are soon to be phasedout, we focused only on HFA-based pMDIs. There-fore, several experimental pMDI formulationswere prepared and evaluated using Spraytec1

with inhalation cell attachment to understand thepossible reasons for the overestimation of size bystudying the effect of pMDI ingredients such aspropellant (HFA 134a or 227), and cosolvents[ethyl alcohol and propylene glycol (PG)] on theaerosol size distribution. To compare and obtain acorrelation for the particle size data between ACI

350 HAYNES ET AL.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 2, FEBRUARY 2004

and Spraytec1 over a wide particle size range (1–5 mm), we prepared pMDI formulations of nime-sulide (a nonsteroidal antiinflammatory drug) inHFA134awith 0.25–10%w/wof PGand comparedthe particle size data between these two methods.We exploited the aerosol bulking properties of PGto modify the emitted aerosol size by altering itsconcentration and keeping the other formulationingredients constant.

MATERIALS AND METHODS

Materials

Eight commercially available pMDIs (Table 1)were used in the study. Anhydrous ethanol(Absolute 200 Proof; Aldrich), HFA 134a (DuPont, Ingleside, TX), HFA 227 (Solvay FloridesInc., Hanover, Germany), and PG (1,2-propane-diol; Sigma) were obtained and used as supplied.Continuous and noncontinuous valves werekindly provided by 3M Pharmaceuticals (St. Paul,MN).

Methods

Malvern Spraytec1 with Inhalation Cell Attachment

The Malvern Spraytec1 with inhalation cellattachment is shown in Figure 1. It consists ofthe Spraytec1 unit with a USP throat heldin place by the inhalation cell. The unitallows for an optional connection for an ACI ordirectly to a vacuum-driven particle-collectingsource. This entire assembly is a closed systemand allows for a controlled airflow rate in themeasurement zone.

PSD Measurements

A variety of commercially available pMDIs(Table 1) were used in the study. Before eachexperiment, each pMDI can was shaken by handfor 30 s, the first five shots were fired into waste,and one dose was actuated for measurement. Foreach pMDI, the PSD was measured with theinhalation cell attachment on the Spraytec1. ThepMDI was fired into a USP throat under an airflow rate of 28.3 L/min, measured using a Sierra‘‘Top Trac’’ mass flow meter (Sierra Instruments,Inc., Monterey, CA). PSD was measured after oneactuation, and each formulation was tested sixtimes. All measurements were made at roomtemperature (258C) at a relative humidity close to50%. The focal length of the Spraytec1 lens usedwas 100 mm, which has a particle size range of0.5–200 mm. The refractive index and absorptioncoefficient used for these investigations were amedia refractive index of 1.00 þ 0.00i and parti-culate refractive index of 1.33 þ 0.00i. Data werereported as VMD (Dv 50) defined by 50% of thecumulative volumeundersize. The geometric stan-dard deviation (GSD) was calculated by thefollowing equation, obtained from Kwong et al.11:

Dv 50

particle diameter@ 15:87%ð2Þ

Equation (2) is based on the assumption that dataare obtained from a log-normal distribution. Thefine particle fraction (FPF) was obtained from theSpraytec1 software based on the percentage ofparticles having a diameter of <4.7 mm.

Throat Extensions

In an attempt to elucidate the effect of formulationingredients in pMDI on the observed PSD of

Table 1. Commercial pMDIs Used for Investigation

pMDI Active Ingredient Propellant SystemDose per

Actuation (mg)

Aerobid (Forest Pharmaceutical, Inc.) Flunisolide CFC 250Vanceril (Key) Beclomethasone dipropionate CFC 42Proventil (Schering) Albuterol CFC 90Ventolin (Allen and Hanbury) Albuterol CFC 90Combivent (Boehringer Ingelheim) Ipratropium bromide (IB)

and albuterol sulfate (AS)CFC 18 IB and 103 AS

Qvar 50 (3M) Beclomethasone dipropionate HFA-134a 50Qvar 80 (3M) Beclomethasone dipropionate HFA-134a 80Proventil HFA (3M) AS HFA-134a 90

EVALUATION OF THE MALVERN SPRAYTEC1 351


aerosols, additional experiments with throat ex-tensions of 10, 20, and30 cmwereperformed.Thesevertical extensions were applied between the USPthroat and the entrance of the sampling port. Thethroat extensions were intended to provide ad-ditional time for the aerosol cloud to completelyevaporate before it enters themeasurement zone.

Heating pMDI or Heating Throat Extensions

The effect of directly heating the commercialpMDI formulation or heating a throat extensionon particle size was evaluated by using thefollowing experimental methods: (a) equilibratingthe formulations for 8 h at i) 408C and ii) 558C; (b)equilibrating the formulations for 8 h at i) 408Cand ii) 558C with subsequent aerosolization alongwith a 20-cm throat extension; and (c) heating a20-cm throat extension at i) 408C and ii) 558Cwith

subsequent aerosolization of a room-temperatureformulation.

Preparation of Placebo Ethanol andPG pMDI Formulations

Several formulations with HFA 134a and 227were prepared in plastic-coated glass vials with50-mL noncontinuous valves. Placebo formula-tions with anhydrous ethanol (200 proof) wereprepared at concentrations of 0, 5, 10, and 15% w/w in both HFA 134a and 227 and evaluated fortheir PSD using a USP throat or throat with 10- or20-cm extensions. Further, formulations with15% w/w ethanol in HFA 134a with six concentra-tions of PG (0.5 1.0, 2.5, 5.0, 10.0, and 20.0% w/w)were also prepared. These pMDI formulationswere kept at room temperature (258C) and evalu-ated for their PSD using a USP throat or

Figure 1. Spraytec1 unit with inhalation cell assembly used for the particle sizedetermination of various pMDI formulations used in the study. The figure shows that theSpraytec1 laser source (A) and the detector (B) held in a closed system with the use ofinhalationcell(C).TheinhalationcellallowsprovisionsfortheattachmentofUSPthroat(D)above the laserbeamand toavacuumsource (E) belowthe laser beam.Theentireassemblywith the throat, Spraytec1 optics, and the vacuum assembly is a closed unit. The airflowthrough the unit can be controlled by using a vacuum source (2.0 HP) through the voltageregulator (F). The outlet of the inhalation cell is attached to the vacuumthrough the tubing(E). The air flow rate wasmaintained at 28.3 L/min for all the particle sizemeasurements.The focal length of the Spraytec1 lens was 100 mm (0.5–200 mm size range). All themeasurements were made at Spraytec1 settings of 98% transmission (2% obscuration)usingamediarefractiveindexof1.00þ0.00iandparticulaterefractiveindexof1.33þ0.00i.

352 HAYNES ET AL.


throat with 20- and 30-cm extensions. Two otherconditions were also used to determine the PSDfor these placebo-pMDI formulations containingPG. These testing conditions were: (a) particlesize measurements using 20- and 30-cm throatextensions heated to 408C, and (b) heating thepMDI to 408C and then determining the PSDusing a 20-cm extension to the USP throat. All ofthese formulations were evaluated using commer-cially available Proventil HFA actuators.

Preparation of Nimesulide pMDI Formulations

Nimesulide, a nonsteroidal antiinflammatorydrug and a relatively selective cyclooxygenase(COX)-2 inhibitor (COX-1/COX-2 50% inhibitoryconcentration ratio of 17.69) was used in thisinvestigation. Nimesulide-pMDI formulation wasprepared based on its solubility in HFA propel-lants containing ethyl alcohol. The saturatedsolubility of nimesulide in HFA 134a with 16%w/w ethanol was found to be 0.16% w/w.14 There-fore, a solution-type pMDI formulation containing0.1% w/w nimesulide and 15% w/w ethyl alcoholin HFA 134a was prepared for the determinationof aerosol PSD. Briefly, 15 mg of nimesulidewas placed in a clean 15-mL glass vial containing2.25 g of ethyl alcohol (200 proof). The vial wascrimped with a continuous valve followed by theaddition of HFA 134a. The vial was placed on aplatform shaker at 150 rpm and allowed to shakeovernight. The continuous valve was then repla-ced with a 50-mL noncontinuous valve. Further,nimesulide-pMDI formulations (solution type)were also prepared containing 0.1% nimesulide,15% ethyl alcohol, and varying concentrations ofPG (0.25–10% w/w) in HFA 134a in the same wayas described above. The addition of PG (0.25–10%w/w) to the nimesulide-pMDI did not alter anysolution characteristics of the formulation (i.e., noprecipitation). PG was used to modulate the PSDof the aerosol as a bulking agent. The nimesulideformulations were evaluated for their particle sizeusing Spraytec1 with a 20-cm throat extension byusing the pMDI either at room temperature (258C)or equilibrated to 408C. In addition, the vapor pres-sure of the nimesulide pMDIs at room tempera-ture, 408 and 558C were measured using a hand-held vapor pressure gauge (Aero-Tech LaboratoryEquipment Co., NY).

ACI Analysis

The PSD of the nimesulide solution formulations(containing 0.1% w/w drug, 15% w/w ethanol in

HFA 134a with 0.25–10% w/w PG) were alsodetermined using an ACI. Each formulation wasprimed by firing five shots into waste. Then fiveshots (at 10-s intervals) were fired into the ACIunder a flow rate of 28.3 L/min. The depositednimesulide was determined on each stage of theimpactor by transferring each component to indi-vidual polyethylene bags and rinsing with appro-priate volume of methanol. The samples wereanalyzed for chemical analysis of nimesulide con-centration on a spectrophotometer (Beckman DU640) at a wavelength of 320 nm. The impactordata were used to calculate MMAD and GSDvalues using an established software in ourlaboratory.15 The FPF, defined as the percentageof particles with an aerodynamic diameter<4.7 mm, was calculated based on emitted (ex-actuator) dose for ACI analysis.

Statistical Analysis

One-way analysis of variance followed by Tukey’sor Dunnett’s Multiple Comparison Test wasperformed to determine the significance of differ-ences from the size distributions obtained by thevarious experimental procedures. The statisticalanalysis was performed using GraphPad PRISMversion 3.0 software (San Diego, CA) and differ-ences were deemed significant when p< 0.05.

RESULTS

PSD of Commercial pMDIs

Figure 2A and B show a typical time-historyprofile (Fig. 2A) showing the development andconsistency of the plume and the average PSD(Fig. 2B) of a HFA-based pMDI measured usingthe Spraytec1 with the inhalation cell attach-ment. Table 2 summarizes the particle size data(Dv 50, GSD, and FPF) of the various commercialpMDIs as determined using Spraytec1 with inha-lation cell attachment and the reported MMADvalues. Figure 3 shows a comparison of PSD be-tween Proventil CFC and Proventil HFA, both ofwhich deliver a dose of 90 mg (active ingredient)per actuation. From Figure 3, it is clear that theinstrument can discriminate the size distributionbetween these two formulations with differentpropellant-based systems, because the Dv 50values differ significantly (p< 0.05). However, itis also evident from Table 2 that the Dv 50 valuesobtained from the CFC pMDIs were lower incomparison to the reported MMAD. Little differ-ence was found in Dv 50 values among the various



Figure 2. (A) Time-history plot and (B) the PSD measured after one actuation fromProventil HFA-based pMDI.

Table 2. PSD Values of Commercial pMDIs

pMDI

Spraytec1 with Inhalation Cell AttachmentReported ACI Data

(MMAD) (mm)Dv 50 (mm) GSD FPF< 4.7 (mm)

Aerobid 1.64 (0.07) 2.36 (0.10) 92.87 (0.46) 3.6a

Vanceril 1.74 (0.04) 2.45 (0.04) 90.79 (0.45) 2.7a

Proventil 1.71 (0.08) 2.27 (0.20) 92.38 (1.28) 1.77b

Ventolin 1.61 (0.06) 2.45 (0.07) 94.70 (0.34) 2.2c

Combivent 1.61 (0.18) 2.73 (0.16) 93.29 (2.03) —Qvar 50 2.70 (0.08) 2.76 (0.09) 81.70 (1.81) 1.1d,e

Qvar 80 2.62 (0.07) 2.92 (0.11) 81.10 (0.97) 1.1f,g

Proventil HFA 3.10 (0.13) 2.17 (0.17) 79.01 (2.49) 2.23h,i

Data presented as mean (SD), n¼6.aReported by Childers et al.35bReported by Nasr and Allgire.36cReported by Mitchell et al.37dReported by Leach et al.28eExperimentally determined value in our laboratory, 0.9 mm.fReported by Nagel et al.38gExperimentally determined value in our laboratory, 1.1 mm.hReported by Ross and Gabrio27iExperimentally determined value in our laboratory, 2.5 mm.It is evident from the literature that ACI determinations for the commercial products were

performed using an eight-stage Andersen cascade impactor (Mark II, 1ACFM) at a flow rate of28.3 L/min.27,28,35,36,38 The ACI determinations for Qvar 50, Qvar 80, and Proventil HFA productswere performed essentially in the same way as described for nimesulide-pMDI as described in theMethods section.

354 HAYNES ET AL.


CFC pMDIs. All of the CFC pMDIs investigatedwere suspension-based formulations, consistingof micronized drug suspended with a suspendingagent.

The HFA 134a–based pMDIs evaluated con-sisted of solution-based (Qvar 50 andQvar 80) andsuspension-based (Proventil HFA) formulations.The solution formulations contained ethanol as acosolvent, whereas the suspension formulationcontained ethanol along with a suspending aid(oleic acid). It is clear from Figure 4 that theSpraytec1 is able to discriminate thePSDbetweena solution-based (Qvar 50) and suspension-based(Proventil HFA) formulation, and the difference intheDv 50 values for these productswas found to besignificant (p< 0.05). The Spraytec1 consistentlyoversized HFA-based aerosols and undersizedthe CFC-based formulations compared with theirreported MMAD values obtained from ACI(Table 2).

Effect of Throat Extensions on PSDon Commercial pMDIs

The effect of distance on PSD was evaluated byintroducing vertical throat extensions of 10, 20,and 30 cm located between the USP throat andthe sample entrance port. Table 3 summarizes thedata from these pMDIs. Increasing the distanceup to 30 cm had no significant effect on the Dv 50values for the commercial formulations Aerobid,Qvar 50, and Qvar 80 (p> 0.05, comparing noextension with a 30-cm extension). A significantdifference (p< 0.05) in Dv 50 value was observedfor Proventil HFA pMDI with 30-cm throat exten-sion in comparison to no throat extension (Table 3).

Effect of Heating the Commercial pMDIs orHeating the Extension on the PSD

As shown in Table 4, equilibrating the Qvar50 and Proventil HFA pMDIs at the different

Figure 3. Comparison of PSD from Proventil HFA-and Proventil CFC-based formulations. Statistical sig-nificance of the difference in the Dv 50 values: ProventilCFC versus Proventil HFA, p< 0.05.

Figure 4. Comparison of PSD from a solution (Qvar50) and suspension (Proventil HFA) HFA-based for-mulations. Statistical significance of the difference inthe Dv 50 values: Qvar 50 versus Proventil HFA,p< 0.05.

Table 3. Effect of Throat Extensions on the Particle Size (Expressed as Dv 50) of Commercial pMDIs MeasuredUsing Spraytec1 with Inhalation Cell Attachment

pMDI

Dv 50 values (mm)

No Extension 10-cm Extension 20-cm Extension 30-cm Extension

Aerobid 1.64 (0.07) 1.68 (0.08) 1.63 (0.08) 1.59 (0.12)Proventil 1.71 (0.08) 1.72 (0.16) 1.65 (0.13) No responseQvar 50 2.70 (0.08) 2.79 (0.03) 2.81 (0.06) 2.77 (0.14)Qvar 80 2.62 (0.07) 2.62 (0.04) 2.68 (0.05) 2.56 (0.08)Proventil HFA 3.10 (0.13) 3.05 (0.22) 2.97 (0.11) 2.92 (0.08)

Data presented as mean (SD), n � 6.One-wayanalysis of variance onDv50valueswithTukey’smultiple comparison test showeda significant difference (p<0.05)with

theProventilHFApMDIcomparingnoextensionand30-cmextension.All other comparisonsof the effect of throat extensionsonDv50values were not significant (p>0.05) for each pMDI.



temperatures (408 and 558C) resulted in a reduc-tion in Dv 50 values compared with the normal(room temperature) formulations. Figure 5 showsthat all of the various experimental conditionsreduced the particle size, resulting in a shift in thePSD curve to the left for the Qvar 50 pMDI. TheDv 50 values were reduced by 46.3% and 13.9% forQvar 50 and Proventil HFA, respectively, afterequilibration at 558C compared with room tem-perature pMDIs (Table 4). The experimentalmethod of heating the 20-cm throat extensiondid not prove to be comparable with the heated

Qvar 50 formulation (between conditions 3 and7 as shown in Table 4).

Effect of Ethanol Concentration and ThroatExtensions on PSD of Placebo HFA 134aand 227 Formulations

Ethanol placebo formulations with HFA 134a and227 were evaluated with different throat exten-sions to ensure that complete droplet evaporationof the aerosol cloud takes place before passing thelaser beam in the measurement zone. Placeboformulations in HFA 134a with 0% and 5% w/wethanol gave no signal response with the USPthroat alone (indicating complete droplet eva-poration occurred). Further, placebo HFA 134aformulations containing 10% and 15% w/w etha-nol showed Dv 50 values of 2.81� 0.2 and3.64� 0.12 mm, respectively, using a USP throat.However, a 20-cm extension to the USP throatresulted in no instrument response in placeboHFA 134a formulations containing 10% and 15%w/w ethanol, thus indicating the complete eva-poration of the aerosol before it enters the laserbeam. Interestingly, all the placebo formulationscontaining ethanol concentrations ranging from0 to 15% w/w in HFA 227, did not give a signalresponse with the USP throat alone. Therefore, nothroat extension was needed with the HFA 227–based formulations despite the concentration ofethanol (up to 15% w/w).

Table 4. Effect of Various Experimental Conditions on Dv 50 (mm) of Two CommercialpMDIs Determined Using Spraytec1 with Inhalation Cell Attachment

Condition Qvar 50Proventil

HFA

1. pMDI at RT 2.70 (0.08) 3.10 (0.13)2. pMDI heated to 408C 1.62 (0.09) 2.67 (0.19)3. pMDI heated to 558C 1.45 (0.13) 2.67 (0.18)4. pMDI heated to 408C with 20-cm throat extension at RT 1.61 (0.04)5. pMDI heated to 558C with 20-cm throat extension at RT 1.38 (0.06)6. pMDI at RT with 20-cm throat extension at 408C 1.97 (0.08)7. pMDI at RT with 20-cm throat extension at 558C 1.85 (0.05)

Data presented as mean (SD), n � 6.RT, room temperature (258C); NS, not significant.One-wayanalysis of varianceonDv50valueswithTukey’smultiple comparison test onQvar50: 1

and 2: significant (p< 0.05); 1 and 3: significant (p<0.05); 1 and 4: significant (p< 0.05); 1 and 5:significant (p< 0.05); 1 and 6: significant ( p< 0.05); 1 and 7: significant (p< 0.05); 2 and 3:significant (p<0.05); 2 and 4: NS (p>0.05); 2 and 5: significant ( p< 0.05); 2 and 6: significant(p<0.05); 2 and 7: significant ( p< 0.05); 3 and 4: significant (p<0.05); 3 and 5: NS (p>0.05); 3 and6: significant (p<0.05); 3 and 7: significant (p<0.05); 6 and 7: NS (p> 0.05); 6 and 4: significant(p<0.05); 6 and5: significant (p< 0.05); 7and4: significant (p< 0.05); 7and5: significant (p<0.05);4 and 5: significant (p<0.05).

One-wayanalysis of variance onDv50 valueswithTukey’smultiple comparison test onProventilHFA: 1 and 2: significant ( p< 0.05); 1 and 3: significant (p< 0.05); 2 and 3: NS (p>0.05).

Figure 5. Effect of various experimental conditionson the PSD from Qvar 50 pMDI. Measurement condi-tions—normal [room temperature (RT)]: Qvar 50 pMDIat RT (258C); pMDI at 408C: Qvar 50 pMDI heated to408C; pMDI at 558C: Qvar 50 pMDI heated to 558C;heated 20 cm ext 408Cw/RTpMDI: Qvar 50 pMDI at RT(258C) with heated 20-cm throat extension at 408C;heated 20 cm ext 558Cw/RT pMDI: Qvar 50 pMDI at RT(258C) with heated 20-cm throat extension at 558C.

356 HAYNES ET AL.


Effect of the Concentration of a NonvolatileCosolvent in Placebo HFA Formulations on PSD

The effect of the concentration of a nonvolatilecosolvent, such as PG, on PSD was evaluated.Ethanol was incorporated in the formulation as acosolvent to ensure the complete solubility of PGat all concentrations investigated. It is evidentfrom Table 5 that increasing the nonvolatile cosol-vent PG concentration from 0.5 to 20% resulted inan increase in the Dv 50 value from 2.44� 0.1 to4.41� 0.19 mm, when measured with USP throatalone. It is also evident from Table 5 that the useof vertical throat extensions or heated throatextensions resulted in lower Dv 50 values com-pared with the data obtained without throatextension. There was a 3.7–13.4% reduction inDv 50 values by using a 30-cm throat extensioncompared with no throat extension over the entirerange of PG concentrations studied (Table 5).Similarly, there was a 6.5–15.8% reduction in Dv

50 values by using a heated 30-cm throat exten-sion in comparison with Dv 50 values measuredusing no throat extension. The maximum reduc-tion (10.2–28.3%) in Dv 50 values was observed inplacebo pMDIs heated to 408C and analyzed usinga 20-cm throat extension. In all the measuringconditions, there was an increase in the Dv 50values by increasing the PG concentration from0.5% to 20% w/w in pMDI. This trend was alsoevident in placebo pMDI formulations containingethanol (15% w/w) and PG (0.5–20% w/w) in HFA227, as increasing concentrations of PG alsoshifted the PSD curve to the right (data not shown).

Comparison of the Spraytec1 with the ACI

A direct comparison of particle size was madebetween the ACI and Spraytec1 for the variousexperimental nimesulide pMDI formulations(Table 6) using experimental nimesulide-pMDI

Table 5. Effect of PG Concentration in Placebo pMDIs (HFA 134a with 15% Ethanol) on Dv 50 Values (mm)Determined Using Spraytec1 with Inhalation Cell Attachment

PG concentration(% w/w) A B C D E F

0.5 2.44 (0.10) 2.35 (0.06) 2.33 (0.10) 2.13a (0.08) 2.13a (0.20) 1.92a (0.13)1.0 2.47 (0.07) 2.21a (0.06) 2.14a (0.05) 2.17a (0.07) 2.11a (0.04) 1.77a (0.15)2.5 2.53 (0.09) 2.41a (0.05) 2.43 (0.07) 2.23a (0.07) 2.13a (0.08) 2.05a (0.06)5.0 2.75 (0.05) 2.51a (0.04) 2.62a (0.10) 2.71 (0.05) 2.57a (0.10) 2.47a (0.09)10.0 3.52 (0.06) 3.33a (0.09) 3.39a (0.09) 3.29a (0.04) 3.19a (0.09) 2.95a (0.10)20.0 4.41 (0.19) 4.30 (0.24) 3.93a (0.10) 4.19 (0.04) 3.92a (0.12) 3.31a (0.11)

Data presented as mean (SD), n¼6.A: no throat extension (USP throat alone); B: 20-cm throat extension; C: 30-cm throat extension; D: heated 20-cm throat extension

at 408C; E: heated 30-cm throat extension at 408C; F: heated pMDI at 408C with 20-cm throat extension at room temperature (258C).Statistical analysis was performed using one-way analysis of variance on Dv 50 values with Dunnett’s multiple comparison test.aSignificant difference (p< 0.05) in comparison to condition A (no throat extension) for each pMDI formulation.

Table 6. Comparison of the ACI and Spraytec1 Data for ExperimentalNimesulide pMDIs

PG Concentration (% w/w)Spraytec1

Condition 1Spraytec1

Condition 2 ACI

0.25 1.95 (0.06) 1.66 (0.09) 0.88 (0.10)0.5 1.94 (0.08) 1.52 (0.07) 1.08 (0.17)2.5 2.04 (0.08) 1.82 (0.03) 2.78 (0.08)5 2.50 (0.06) 2.32 (0.06) 3.82 (0.09)10 3.23 (0.07) 2.91 (0.05) 4.77 (0.12)

Data presented as mean (SD), n¼6. Spraytec1 data given as Dv 50 values (mm). ACI dataexpressed as MMAD (mm).

Condition 1: pMDI at RT (258C) with 20-cm throat extension at room temperature (258C);condition 2: pMDI heated to 408C with 20-cm throat extension at room temperature (258C).

Data as shown above for nimesulide-pMDIs containing 0.5, 2.5, and 10% PG (measured usingSpraytec1 condition 1 as given in Table 6) were also reanalyzed at various refractive indices such asat 1.18 (representing only propellant), 1.36 (representing nimesulide in ethanol), and 1.47(representing nimesulide in PG) and we found that there was no significant difference in the Dv50 in the range of refractive index values studied (1.18–1.47). The refractive index values of 0.1%nimesulide in ethanol andPGweredetermined at room temperatureusingAbbe-type refractometer.



formulations. The PSD of experimental pMDIformulations either at room temperature (condi-tion 1) or heated to 408C (condition 2) along with a20-cm throat extension was determined usingSpraytec1 and compared with ACI data. MMADobtained from the ACI data ranged from 0.88 to4.77 mm, whereas Spraytec1 Dv 50 values variedbetween 1.95–3.23 mm and 1.66–2.91 mm forconditions 1 and 2, respectively, for the variousformulations studied (Table 6). However, therewas a correlation between Spraytec1Dv 50 valuesand the MMAD values from the ACI data and theR2 values were found to be 0.8037 and 0.8853 forconditions 1 and 2, respectively (Fig. 6).

Effect of Temperature on Vapor Pressure of pMDI

Table 7 presents the vapor pressure data of thevarious experimental nimesulide-pMDI formula-tions (as described above) as a function of tem-perature. The vapor pressure from the pMDIformulations was found to increase with tempera-ture at all the concentrations of PG (0–10% w/w).For example, the vapor pressure of nimesulide-pMDIs prepared with 0% and 10% PG wasincreased by 39% and 33% at 408C in comparisonto the corresponding pMDIs at room temperature(258C), respectively (Table 7).

DISCUSSION

Aerosols generated by pMDIs represent a complexsystem in which the generated plume continu-ously changes in its flight.1 Therefore, accurate

characterization of the plume is vital to determinethe aerodynamic particle size, which in turnallows the prediction of the deposition and deli-very of the aerosolized drug in the lungs. Laserdiffraction-based instruments have been shown toprovide real time measurement of the plumeparticle size during its propagation.1 The aim ofthis work was to evaluate a new device, theMalvern Spraytec1 with inhalation cell attach-ment, for the measurement of particle size frompMDIs. Evaluating various commercial pMDIsprovided vital information in evaluating thisdevice.

In general, the Spraytec1 with inhalation cellattachment was found to underestimate the PSDfrom the CFC-based pMDIs, whereas it oversizedthe PSD from the HFA-based pMDIs. The lowDv50 values obtained from theCFC-based pMDIs,compared with their reported MMAD data, couldbe related to several factors, including highdeposition in the USP throat, low vapor pressure,and the presence of non-drug-containing excipientparticles produced upon aerosolization of the for-mulation. Ding et al.13 evaluated PSD fromvarious commercial CFC-based pMDIs using theMalvern Mastersizer, comparing the effects ofspacer, USP induction port, and distance betweenthe pMDI’s actuator and the laser beam on themass median diameter. Their findings showed areduced particle size with a USP induction port(compared to without) and a decrease in massmedian diameter as a function of distance, 5 cmcompared with 25 cm (likely because of dropletevaporation). Underestimation of aerosol sizefor CFC-based products has been reported usingSpraytec116 and Aerosizer-time-of-flight aerody-namic particle size analyzer.17

In comparing the HFA-based pMDIs, thedevice was able to discriminate between the typeof formulation, solution, or suspension (Figs. 3and 4). However, the Dv 50 values obtained were

Figure 6. The correlation of Dv 50 (mm) and MMAD(mm) values from the Spraytec1with inhalation cell andACI, respectively. Spraytec1 conditions evaluated con-sisted of: (1) pMDI at RT (258C) with 20-cm throatextension at RT (258C), and (2) pMDI heated to 408Cwith 20-cm throat extension at RT (258C).

Table 7. Vapor Pressure (psia) of ExperimentalNimesulide-pMDI Formulations at Various Temperatures

% PG (w/w) RT (258C) 408C 558C

0 70.0 (1.0) 97.3 (2.2) 107.3 (4.0)0.5 71.0 (1.0) 94.5 (3.0) 103.7 (2.5)5 69.3 (0.6) 94.0 (2.3) 103.7 (2.5)10 71.7 (1.5) 95.5 (3.4) 104.0 (4.0)

Data presented as mean (SD), n¼3.All formulations contain 0.1% w/w nimesulide, 15% w/w

ethanol in HFA 134a.

358 HAYNES ET AL.


significantly larger than reported MMADs for thepMDIs, which may be due to the presence ofpropellant and/or excipient droplets in the aerosolcloud during diffractionmeasurement. It has beenreported that aerosol size measurement usingSpraytec1 with inhalation cell occurs withinmillisecondsof theaerosol release,16whereassubs-tantial evaporation of aerosol constituent such asethanol could take place within 2 s of actuation aspredicted by Hickey and Evans.18 Factors thatinfluence the rate of evaporation and PSD ofaerosol cloud include the type of propellant andformulation factors such as concentrations of ethylalcohol, surfactant, and drug (active ingredient) inthe formulation. The commercial pMDI formula-tions used in this study contain HFA 134a as thepropellant, which has different physical andchemical properties compared with the CFCs.19

Because of the phase out of the CFCs, additionalemphasiswasplaced onevaluating theHFA-basedformulations in order to determine optimal experi-mental conditions in which the measurementscould be more comparable to the reported valuesobtained from the ACI.

The larger Dv 50 values obtained from thecommercial HFA-based pMDIs compared with thereported ACI data imply that the instrument ismeasuring droplets that have not fully evaporatedbefore reachingthemeasurementzone.Thisobser-vation has been noted with other instruments,such as time-of-flight analyzers, when evaluatingpMDIs. Methods used to aid in the evaporation ofdroplets emitted from the pMDI with theseinstruments include the AerobreatherTM,20,21

Aerosampler,22 and vertical throat extensions.23

The latter method used by Stein et al.23 wasstudied in our experiments. However, our datashowed that increasing the throat extension up to30 cm had no significant effect on the PSD for fourof the five commercial pMDIs (Table 3). Possibly,increasing the distance of the throat extensionbeyond 30 cm could further aid in the evaporationof the droplets. Gupta et al.24 have consideredthroat extensions of 40 cm for their studies withthe aerodynamic particle sizer.

In an effort to rapidly evaporate the volatilecomponents in the aerosol cloud before it reachesthe measurement zone of the Spraytec1 unit, weconsidered heating the pMDI formulation (at 408and 558C) for 8 h, before measurement. In fact,these equilibrated formulations showed smallerDv 50 values compared with the formulationsevaluated at room temperature.Additional experi-ments conducted with heating the solution for-

mulation Qvar 50 (at 408 and 558C) showed atemperature-dependent reduction in Dv 50. Thisobservation can be expected because heating theformulation will increase the vapor pressure(as described in Table 7 for our experimentalpMDIs),25 which increases the rate of atomizationof the emitted droplets from the pMDI with agreater initial forward velocity.2,26 This results ina finer aerosol and contributes to the lower particlesize of the emitted aerosol.27,28 The data from thisexperimental method were compared with a simi-lar method reported from communications withPaul Kippax (Malvern Instruments, UK, personalcommunications) in which he noted better agree-ment of results reported from the Spraytec1 withinhalation cell and the ACI for HFA-based pMDIaerosols when the temperature during the aerosolpassage through a heated throat extension wasraised to 558C. In our laboratory, we found thatheating a 20-cm throat extension (at 408 and 558C)also reduced the Dv 50 values from the Qvar50 pMDI (compared with pMDI at room tempera-ture). However, the reduction in Dv 50 was low incomparison to the method of directly heating thepMDI formulation (Table 4).

HFA 134a is a poor solvent for the commonlyused surfactants such as sorbitan trioleate, oleicacid, and lecithin, and ethanol is commonlyused inHFA-based formulations as a cosolvent to aid inthe solubilization of excipients (such as surfac-tants) or to dissolve the active ingredient itself.29

Varying the concentration of ethanol can drama-tically affect not only the formulation but also itsperformance. Ethanol has been shown to lower thevapor pressure of pMDI.25 As a result, ethanol canreduce the rate of evaporation and energies foratomization when incorporated with the HFAs.30

This directly contributes to the larger PSD ob-tained from the Spraytec1, or any laser diffrac-tion–based instrument, because of the largerdroplets that have not fully evaporated. Our datasupports this foundation by evaluating the dataobtained from formulations with various concen-trations of ethanol in HFA 134a. Placebo pMDIformulations containing<5% w/w ethanol in 134awere not detected by Spraytec1. However, a 20-cmthroat extension was required to provide enoughtime for the ethanol droplets to evaporate (nodetection) from formulations containing higherethanol concentrations (10% and 15% w/w). Thus,it is possible to ensure complete evaporation ofaerosol from placebo-pMDI containing HFA 134awith ethanol for up to 15% w/w by using a 20-cmvertical extension under the conditions used in



this study. Subsequently, we tested the usefulnessof Spraytec1 with inhalation cell attachment indistinguishing the PSD of solution-type pMDIformulations containing either HFA 134a or 227,ethanol (15% w/w), and varying concentrations ofPG (0.5–20% w/w). PG is a hydrophilic cosolventthat can be used as a bulking agent for aerosols. Ithas been shown that nonvolatile solvents such asglycerin, polyethylene glycol in HFA solutionformulations can increase the aerosol particlesize.31 It is evident from the data shown inTable 5 that Spraytec1 could differentiate thePSD of these pMDI formulations.

Instruments based on different measurementmethods and assumptions are likely to reportdifferent results. However, an attempt to find acorrelation between the ACI and Spraytec1 withinhalation cell attachment was made. For thisinvestigation, homogeneous solution pMDIs withvarying concentrations of PG (0.25–10%w/w) andethanol (15% w/w) were studied. Nimesulide wasincorporated at a concentration of 0.1% w/w intothe solution formulations to aid in chemical analy-sis of the generated aerosol droplets. Holmeset al.16 showed that simultaneous measurementsof particle size using the Spraytec1 with inhala-tion cell attachment coupled with the ACI arepossible without any alterations in ACI measure-ments. For this study, particle size measurementswere obtained independently with each instru-ment. Spraytec1measurementswere takenwitha20-cm throat extension using the pMDI at roomtemperature (condition 1) or heated to 408C(condition 2). The Spraytec1 Dv 50 values werefound to be greater than MMAD values at PGconcentrations between 0.25–0.5%w/w and lesserthan MMAD at PG concentrations 2.5–10% w/w(Table 6). However, there was an increasing trendin Dv 50 values (for both conditions of Spraytec1

measurements) as MMAD values increased withincreasing PG concentrations. This resulted ina correlation between Spraytec1 and ACI data(Fig. 6). The difference between theSpraytec1 andACI data for each concentration of PG used inpMDImight be attributable to the difference in theaerosol measurement techniques and the effect ofPG concentration on aerosol characteristics. Cor-rection of VMD data in Table 6 to aerodynamicdiameter using eq. (1) resulted in only slightchange as the estimated density of the nonvolatilecomponents of the formulation are closer to unitywith the conversion factor (r/r0)

0.5 varying be-tween 0.93 and 1.01. Tiwari et al.1 compared theparticle size of albuterol-pMDI formulations by

laser diffraction (Malvern 2600) and Aerosizertime-of-flight analyzer and found that laser dif-fraction gave higher particle size in comparison tothe Aerosizer. This was attributed to the measur-ing technique used with theMalvern laser diffrac-tion unit as the particle size was measured, whilethe plume is still evaporating, whereas the pMDIwas fired into a large induction port (4-L volume)and then introduced into the sensor unit of theAerosizer. In addition, the authors have reportedthat cascade impactor analysis gave the largestparticle size. This indicates that data obtainedby different particle sizing techniques may notalways be comparable to one another because it isinfluenced by the measurement method. Dinget al.13 have shown a good correlation betweenMMAD (determined by ACI) and VMD (de-termined by Malvern Mastersizer X) for theirexperimental formulations aerosolized using theprinciple of electrohydrodynamic atomization.

We observed a decrease in Dv 50 values byheating the pMDI to 408C in comparison to pMDIat room temperature for both commercial (Table 4)and experimental pMDI formulations (Table 5).This decrease in particle size due to increasedtemperature may be explained by the increase invapor pressure of the formulation. As shown inTable 7, the vapor pressure was increased withincreasing temperature (408 and 558C) in compar-ison to room temperature, irrespective of PGconcentration used in nimesulide-pMDI formula-tions. Therefore, an increase in vapor pressuremight have facilitated a rapid atomization of theaerosol cloud, which resulted in a smaller size. Itmust be noted that the method of heating thepMDI was attempted to provide rapid evaporationof the propellant and any volatile constituent suchas ethanol in the formulation in the short timeavailable (milliseconds) between pMDI actuationand the entrance of aerosol in the laser beam. Thiswas used to highlight the importance of fasterevaporation of aerosol cloud before it enters thelaser beam to obtain particle size data contributedby only nonvolatile components of the formulation.In the absence of any supporting data, such asthe effect of heating the pMDI on the stability,medication delivery, and other formulation char-acteristics, this method may not be a practicalapproach for the pMDI aerosol particle sizedetermination by laser diffraction.

It may be noted that accurate size determina-tion can be obtained by laser diffraction using Mietheory if the refractive index values are known,and several approaches to determine the refractive

360 HAYNES ET AL.


index have been recently described.8 Some ofthe measurement errors that occur during theparticle size measurement using laser diffractioninclude beam steering and the presence of irregu-lar-shaped particles. Beam steering refers to theshift in the laser beam caused by alteration in therefractive index of the dispersing medium (gas orliquid) due to temperature fluctuations generatedby, for example, evaporation of the dispersingliquid.6 Further, the presence of nonsphericalparticles may show deviating scattering patterns,which may result in a systematic error in theapparent PSD.32 Novel techniques are emergingnow to account for the determination of both sizeand shape by using laser diffraction devices modi-fied with appropriate detectors.33,34

Despite certain limitations, our results suggestthat the PSD of different pMDI formulations canbedistinguishedbyusing theSpraytec1unit (withits software) along with inhalation cell assembly.Our study indicates that the agreement betweenSpraytec1 and ACI data for a pMDI productdepends on the concentration of formulationingredients such as ethanol and the method usedto determine the PSD using Spraytec1. Further,our data show that if faster evaporation of propel-lant and ethanol can bemade in a short duration oftime, before the aerosol cloud enters the measur-ing zone, a close agreement to ACI data can beobtained. Currently, there are no manufacturersuggested add-on devices, which can aid in theevaporation of propellant and ethanol, before theaerosol enters the measuring zone for Spraytec1.Definitely, further device improvements areneeded to the existing setup of Spraytec1 withinhalation cell attachment so as to obtain a closeagreement between Spraytec1 and ACI for HFA-based pMDIs containing volatile ingredients suchas ethanol in the formulation.

CONCLUSIONS

The particle size of pMDI-based aerosols at theexit of USP throat region using Spraytec1 withinhalation cell is influenced by the type ofpropellants (CFC or HFA), ethanol concentration,and other formulation ingredients such as surfac-tants and nonvolatile solvents and their concen-tration. It may be possible to account for thecontribution to the observed particle size due tothe presence of high concentrations of ethanol insolution-based HFA formulations by using throatextensions. Incorporation of a nonvolatile solvent

such as PG in placebo and experimental nimesu-lide pMDI formulations increases the particle sizein a concentration-dependent manner. It is possi-ble to obtain a correlation in the particle size databetween Spraytec1 and ACI under a given set ofexperimental conditions. In the current setup ofSpraytec1 with inhalation cell assembly, it maybe necessary to develop appropriate methods forparticle size determination for each pMDI depen-ding on its formulation ingredients so as to obtaina close agreement to ACI data. Furthermore,device modifications to the existing Spraytec1

unit are needed to achieve this objective.

ACKNOWLEDGMENTS

The authors acknowledge the financial supportprovided by RCMI award, G12RR03020 from theNational Institutes of Health. The authors alsoacknowledge Mr. Stephen Stein (3M Drug Deliv-ery Systems Division, Inhalation Drug DeliveryLaboratory, Saint Paul, MN) for his assistance inthe cascade impactor experiments.

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evaluation of the malvern spraytec® with inhalation cell for the measurement of particle size...

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