Aerosol Synthesis of Inhalation Particles viaa Droplet-to-Particle Method

A. LAHDEJ. RAULAE. I. KAUPPINEN

Center for New Materials, Helsinki University of Technology, Finland

W. WATANABEP. P. AHONEN

Aerosol Technology Group, VTT Processes Espoo, Finland

D. P. BROWN

StreamWise, St. Petersburg, Florida, USA

Inhalation powders with consistent particle properties, including particle size, sizedistribution, and shape were produced with an aerosol synthesis method. Comparedto conventional spray drying, the aerosol method provides better control of thethermal history and residence time of each droplet and product particle due to thelaminar flow in the heated zone of the reactor where the droplet drying and particleformation take place. A corticosteroid, beclomethasone dipropionate, generally usedfor asthma treatment was chosen as a representative material to demonstrate theprocess. Spherical particles were produced with a droplet-to-particle method froman ethanolic precursor solution. The droplets produced with an ultrasonic nebulizerwere carried to a heated zone of the reactor at 50–150�C where the solvent wasevaporated and dry particles formed. The mass mean diameter of the particles werewell within the respirable size range (approximately 2 lm). The geometric standarddeviation (GSD) of produced particles was approximately 2. The particle surfacestructure varied from smooth to rough depending on the degree of particle crystal-linity and was affected by the thermal history of the particle. Amorphous particleswith smooth surface were most likely obtained due to the rapid evaporation of thesolvent from the droplet combined with the slow diffusion of the beclomethasonedipropionate molecule. The amorphous particles were transformed slowly to crystal-line particles in the open atmosphere. In addition, the particle surface structurechanged from smooth to rough during storage. The process was accelerated by ther-mal post-annealing. However, additional heating also increased particle sintering.By optimizing the reactor parameters, and thus increasing the molecular diffusion,stable, crystalline particles were produced at 150�C.

Keywords inhalation particle, formation, crystallization, aerosol method

Address correspondence to Esko I. Kauppinen, Center for New Materials, HelsinkiUniversity of Technology, Finland. E-mail: esko.kauppinen@vtt.fi

Particulate Science and Technology, 24: 71–84, 2006Copyright # Taylor & Francis LLCISSN: 0272-6351 print/1548-0046 onlineDOI: 10.1080/02726350500403199

71

Introduction

In a dry powder inhaler (DPI), a mixture of active particles (1–5 mm) and coarsecarrier particles such as lactose (60–90 mm, mentioned by Zeng et al. (2001)) is usedto obtain an effective drug particle discharge as discussed by Hickey et al. (1994),Byron (1993), and Staniforth (1995). In this kind of system the interaction betweendrug-to-drug and drug-to-carrier particles and particle-to-wall are of great impor-tance for successful drug delivery to the deep lung. The interaction between particlesis determined by adhesion forces such as van der Waals, capillary, and coulombicforces. The strength of these forces is affected by the particle size, shape, andmorphology, as studied by Podczeck (1999). Spherical particles with a rough surfaceare considered best for pulmonary drug delivery due to their small contact area andincreased separation distance between particles. Large separation distance decreasesthe attachment forces and improves the powder dispersion, as stated by Tsukadaet al. (2004). Particle engineering for the optimum drug particles together withDPI device engineering are essential for efficient drug delivery via the lungs.

Two common techniques to produce fine particles for DPIs are mechanicalmicronization and spray drying, as has been described by Zeng et al. (2001) andHickey (1996). A high-energy milling operation generates particles that are highlycharged and thus very cohesive, as mentioned by Zeng et al. (2001). To decreasecohesiveness, surfactants are used, for example, in wet milling. The milling processalso introduces surface and crystallographic damage that affects powder stability.The produced particles often contain irregular fragments that can form strong aggre-gates. In addition, multistep processing may cause significant losses of materialsduring powder production and variability of the product properties from batch tobatch. Unlike milling, the spray-drying technique is a one-step continuous processthat can directly produce pharmaceutical particles with a desired size as describedby Hickey (1996), Chan et al. (1997), Chew and Chan (2001), and Chawla et al.(1994). No surfactants or other solubilizing agents are needed in the process. How-ever, the thermal history and drying rate of each particle is difficult to control due tothe high flow rates needed in the process and limited controllable parameters. Conse-quently, the produced particles are usually amorphous and thus sensitive to tempera-ture and humidity variations that may cause structural changes and sintering of theparticles during storage of the powder.

This article presents a simple and efficient method to produce pharmaceuticalpowders with consistent particle properties including particle size distribution, shape,and chemical purity. The aerosol synthesis method is a one-step continuous process,that is able to produce particles within respirable size range (1–5 mm) and providesgood control of the particle size distribution. The precursor solution is first atomizedto droplets with an ultrasonic nebulizer. Unlike in the commonly used spray-dryingmethod, where droplets are sprayed in the hot gaseous medium, in the aerosolmethod the produced droplets are transferred with a carrier gas to a well-controlledheated reactor where the solvent is evaporated and dry particles formed, as describedby Watanabe et al. (2002). The flow is fully laminar and largely noncirculating withthe flow Reynolds number (Ref) around 53 at 150�C, whereas in spray drying theflow is typically recirculating and turbulent. The laminar flow field provides goodcontrol over residence time of each particle in the heated zone of the reactor. Inaddition, the heating rate, and thus the thermal history of the particles, can be easilyvaried depending on the material properties and requirements. These are important

72 A. Lahde et al.

parameters, since they affect the crystallization of the particles. The aerosol methodis well known in the production of oxide, non-oxide, and metal powders, describedby Che et al. (1998) and by Kodas and Hampden-Smith (1999), but it has not beenused in the production of pharmaceutical particles that consist of organic molecules.Organic molecules are often heat sensitive and the reactor temperature range isusually limited. In addition, the diffusion of large and bulky molecules is relativelyslow and thus tends to behave very differently from inorganic materials.

Materials and Methods

Precursor Solutions

Two beclomethasone dipropionate (BDP) precursor solutions were prepared by dis-solving 5 and 25g of BDP powder in one liter of ethanol (Alko Ltd., Finland;99.5%) at room temperature. A slurry solution was prepared by adding 50g of BDPin one liter of ethanol at room temperature. The solution was stirred vigorously for1 h before use.

Particle Production

Laboratory-Scale ExperimentsThe setup for laboratory-scale experiments is shown Figure 1 and the parameters ofthe studies are given in Table 1. The precursor solution was atomized with an ultra-sonic nebulizer (RBI Pyrosol 7901) that produces droplets in a suitable size range.The average consumption rate of the precursor solution was around 0.09mL=min.The produced droplets were suspended into a carrier gas (N2) at the flow rate of1.5 L=min (t ¼ 22�C, p ¼ 101.3 kPa). The carrier gas was saturated with ethanolprior to entering the nebulizer to prevent any concentration changes in the precursorsolution during aerosolization. The produced droplets were then carried in a tubewith an inner diameter of 30mm and length of 800mm placed in the furnace thatwas kept at constant temperature between 50 and 150�C. The flow Reynolds numberin the heated zone was 64 at 50�C and 53 at 150�C. The residence time in the heatedzone varied between 16 and 21 s depending on the temperature. The solvent evapo-rated in the reactor and dry particles were produced. A porous tube diluter wasplaced after the heated zone of the reactor to prevent the recondensation of thesolvent and the agglomeration of the produced dry particles. The dilution gas(N2, 22

�C) was heated between 50 and 100�C depending on the reactor temperature,and the flow rate varied from 10 to 75L=min (t ¼ 22�C, p ¼ 101.325 kPa). Theparticles were collected either with an electrostatic precipitator (ESP) or a cyclone,depending on the total flow rate. The cyclone was designed based on the work ofZhu and Lee (1999). The collection method did not affect the properties of the pro-duced particles.

Large-Scale ExperimentsTo increase the production rate of particles, the reactor was scaled up and five tubesinstead of one were placed in the furnace symmetrically to ensure uniform flowprofile in all tubes. The parameters used in the experiments are given in Table 1.The particles were produced from either a clear or slurry solution. The precursor sol-ution was atomized with an ultrasonic nebulizer (RBI Pyrosol 7901) with a high

Aerosol Synthesis of Inhalation Particles 73

production rate. The average consumption rate of the precursor solution was around1.6mL=min (approximately 18 times higher than in the small-scale experiments).The ultrasonic nebulizer used in the droplet production also mixed the slurry precur-sor solution, thus keeping it homogeneous during the experiment. The produceddroplets were suspended in the carrier gas (N2, 22

�C) with a flow rate of 10L=min(t ¼ 22�C, p ¼ 101.325 kPa). This gives a flow rate of 2L=min through each tubedue to the symmetric reactor design. The carrier gas was not saturated. Since theduration of each experiment was short, the change in the precursor solution concen-tration was negligible during atomization. The set temperature in the heated zone ofthe reactor was kept at 100�C. The length of the heated zone was 1200mm, whichgives a residence time (20 s) similar to that in the small-scale experiments. The flowReynolds number was 77. A porous tube diluter was used to dilute the produced dryparticles with 75L=min (t ¼ 22�C, p ¼ 101.3 kPa) of nitrogen. The dilution gastemperature was 70�C. The powder was collected with a cyclone.

Figure 1. Experimental setup of laboratory-scale production of inhalation particles via aerosolprocess. Similar setup with five heated tubes was used in the large-scale experiments.

74 A. Lahde et al.

Instrumentation and Characterization

The size distribution of the particles in the gas phase was monitored on-line every 1 sduring the production with an electrical low-pressure impactor (ELPI, Dekati Ltd.).In addition, the mass size distribution was determined gravimetrically with an ELPIor Berner low-pressure impactor (BLPI) during particle production before theparticles were collected. The design of the BLPI is described by Hillamo and Kaup-pinen (1991). The morphology of collected particles was imaged using a field emis-sion low-voltage scanning electron microscope (FE-SEM, Leo Gemini DSM982)operated at 2 kV acceleration voltage. The powder sample for SEM was taken afterthe particle collection and placed on the carbon-coated copper grid. Crystallinity andpolymorphism of the powder were determined with X-ray analysis (DiffractometerD500, Siemens GmbH). A copper target X-ray tube (wavelength 0.1541 nm) wasoperated with power of 40 kV� 40mA. The stability tests were carried out byobserving moisture adsorption profiles of the powder when exposed to different rela-tive humidity values for 2 h and then when kept at 80% relative humidity for 24 h.The chemical composition of the powder was verified with a high performance liquidchromatograph (HPLC) (Hewlett-Packard HP 1090 Liquid Chromatograph,equipped with a diode array detector). The eluents were water (solvent A) and acet-onitrile (solvent B) with a gradient elution of 65% B for 2min followed by 100% B in5min, and with a flow rate of 0.4mL=min. The oven temperature was set to 40�C.

Reactor Conditions

Computational fluid dynamics (CFD) calculations were used to study the effects ofthe flow development and heat transfer on the particle trajectories through the

Table 1. Parameters of laboratory- and large-scale experiments

ParameterLaboratory-scale

experimentsLarge-scaleexperiments

Number of tubes inthe heated zone

1 5

Precursor solutionconcentration [g=L]

5–25 25–50

Average solution consumptionrate [mL=min]

0.09 1.6

Carrier and dilution gas N2 N2

Length of the heated zone [mm] 800 1200Temperatures in the

heated zone [�C]50–150 100

Flow rate=tube [L=min] 1.5 2.0Ref in the heated zone 64–53 77Residence time in the heated zone 21–16 20Dilution gas temperature [�C] 50–100 70Dilution gas flow rate [L=min] 10–75 75Collection method ESP or cyclone CycloneCollection temperature [�C] 40–100 60

Aerosol Synthesis of Inhalation Particles 75

heated zone of the reactor used in the experiments with set wall temperature between50 and 150�C. The calculations were done with the commercial StreamWise CFDprogram (StreamWise, St. Petersburg, Fla., USA) that simultaneously solvesequations for conservation of mass, momentum, and energy. The Navier-Stokesequations, continuity equation, and total enthalpy equations were discretized usinga staggered grid finite difference method. Since only a single gas phase species wasmodeled, no individual species equations were solved. In addition, since particleloadings were small and temperatures low, multiphase and radiative heat transfereffects were neglected in the computations. Details of the governing equations andsolution procedure are described by Rubin and Tannehill (1992). The boundary con-ditions for the calculations were defined by measuring the reactor tube inner walltemperatures every 5 cm along the reactor tube with a K-type thermocouple with1 and 2.5 L=min (t ¼ 22�C, p ¼ 101.325 kPa) vertical nitrogen flow. The fluctuationof measured temperature was �1�C.

Results and Discussion

Reactor Conditions

The results of CFD calculations of the flow and temperature field in the heated zoneof the reactor at 150�C with N2 flow of 1.5 L=min are shown in Figure 2. The reactorinlet is at X ¼ 0 and the end of the heated zone at X ¼ 0.8. Similar results were alsoobtained at 50�C and 100�C, though the size of the inflow recirculation region wassmaller at the lower set wall temperatures. The temperature contours and velocityvectors are shown in the upper and lower figures respectively. The calculation wasaxisymmetric with gravity pointing opposite to the flow direction. The aerosol was

Figure 2. CFD results showing temperature contours and velocity vectors in the heated zoneof the reactor at 150�C with the flow rate 1.5 L=min. The inlet of the heated zone is at X ¼ 0mand the outlet at X ¼ 0.8m. Each contour represents a 10�C change in gas temperature.

76 A. Lahde et al.

found to reach the maximum reactor temperature within 25 cm of the reactor inlet,and the temperature and velocity fields were fully developed by approximately 30 cmuntil the beginning of the porous tube diluter at the domain outlet.

Due to the uniform temperature field and laminar flow in the heated zone, themajority of produced particles have similar thermal histories and thus similarproperties, as discussed later. The vertical flow against gravity minimizes thebuoyancy effects and related losses due to recirculation as compared to a horizontalconfiguration as discussed in Ahonen et al. (2001), thus providing a more uniformsynthesis conditions in the hot zone of the reactor.

Particle Size

Particle production from either the clear or slurry solution involves atomizing the sol-ution with an ultrasonic nebulizer, which enables stable production of droplets with ahigh production rate. The initial droplet diameter is affected by both the nebulizerparameters (e.g., frequency and orifice size) and the precursor solvent properties(e.g., surface tension and density), as mentioned by Kodas and Hampden-Smith(1999). The diameter of the produced droplets is in the range of micrometers. Inthe heated zone of the reactor the solvent evaporates, which leads to shrinkage ofthe droplet.

The final particle size is also affected by the precursor solution concentration.Two different concentrations (5 and 25 g=L) were used to study the size of theparticles with the small-scale reactor at 150�C. The number size distributions weremonitored on-line with ELPI during the experiment to ensure the stability of theproduction conditions. The mass size distributions were determined during particleproduction before the particles were collected. The particle mass size distributionsnormalized with the total mass (dM=MdlogDp) are shown in Figure 3. Thegeometric standard deviation (GSD) of particles produced from 5 g=L and 25 g=Lwas approximately 1.8 and 2.0, respectively. The particles produced from 5 g=L weresmaller, with mass mean diameter (dm ¼ Rmidi=Mtot, given by Hinds (1999)) of1.4 mm as compared to the particles produced from 25 g=L, which had a dm of2.2 mm. The larger particle size from the higher concentration is due to larger totalvolume of the solute. Temperature also affected the particle size distribution, andslightly bigger particles, with a dm of 2.5 mm and a GSD of approximately 2.0, wereobtained at 50�C from the 25 g=L precursor solution. The lower temperature (50�C)reduced the molecular diffusion of BDP and decreased intraparticle sintering, thuscausing the formation of bigger particles with a less organized molecular structurethan those produced at 150�C.

The particles produced with the large-scale reactor from the 25 g=L solution at100�C had a dm of 1.7 mm (Figure 3) but the GSD remained approximately 2.0. Theslightly smaller dm is due to the higher flow rate (10L=min) through the nebulizerchamber in the droplet production phase with the large-scale reactor compared tothe 1.5 L=min laboratory-scale reactor. With the higher flow rate, the droplets aremore rapidly carried to the heated zone of the reactor, resulting in fewer interparticlecollisions and smaller particle sizes. When the concentration was increased over thesolubility limit (50 g=L), forming a slurry solution, the particle size increased to2.1 mm and GSD was approximately 2.1. The existing crystal seeds in the precursorsolution are likely to affect the atomization of the solution by changing the precursorsolvent properties (e.g., surface tension and effective viscosity). Thus, the size of the

Aerosol Synthesis of Inhalation Particles 77

produced droplets may change. In addition, the droplets contain crystalline seeds,and once the droplet begins to dry only the size of the surface layer around thecrystals decreases.

Particle Shape and Crystallinity

Particles Produced from the Clear SolutionFigure 4(a) shows an SEM image of particles produced at 50�C from the clearsolution. The produced particles were spherical and smooth. The surface structureof the particles was not stable, and it changed with time from smooth to rough asshown in Figure 4(b)–(d). This indicates that particles were amorphous andpost-crystallize only after production. The rate of change was dependent on theparameters of the droplet production and also on the storage conditions. Whenthe droplet production rate was decreased about 30%, the produced particlesremained smooth even after a two-month storage period, while all particles producedwith the higher production rate changed to a rough morphology in two days at roomtemperature. In this work the amount of ethanol vapor in the reactor was affectedboth by pre-saturation of the carrier gas in the small-scale experiments and by thedroplet concentration. The higher droplet concentration increased the amount ofethanol vapor in the reactor. The high saturation ratio (S) of ethanol in the gas phasedecreases the evaporation rate from the droplets during the drying phase. Thus, theBDP molecules have more time to diffuse within the liquid medium and to organizein clusters and further crystals inside the droplet. However, at a high S and a slowevaporation rate, particle formation is very sensitive even to small variations inthe conditions, according to Leong (1987). Nucleation and further crystallization

Figure 3. The mass size distribution of the particles produced from 5 g=L and 25 g=L at 150�Cwith the small-scale reactor, and at 100�C from 25 g=L and 50 g=L with a large-scale reactor.

78 A. Lahde et al.

may be even inhibited if the S is too high. Therefore, the droplet production rate isalso an important parameter in controlling particle crystallization. The storage tem-perature also affected the particle surface structure. All particles became rough in 2 hwhen the particles were placed in a furnace heated to 40�C.

The reactor temperature was increased to 100�C in order to improve particlecrystallization. The higher reactor temperature also increased the temperature inthe collection. Only rough but slightly sintered particles (Figure 5(a)) were observedafter 30min of collection, indicating that particle crystallization was not completedin the reactor heated zone but continued during the collection in the cyclone. Theexperiments were repeated with the large-scale reactor, which allows a fast pro-duction of a high amount of particles in less than 10min. All obtained particles werespherical and smooth (Figure 5(b)). The X-ray diffraction (XRD) analysis showedthat the particles were originally amorphous. However, a fast change in the surfacestructure from smooth to rough was observed when the powder was stored at roomtemperature. The thermal history of the particles affected the rate of change, and itwas more rapid than observed with the particles produced at 50�C.

The diffusion rate of the BDP molecules in the amorphous solid state isdependent on the glass transition temperature (Tg), and the overall rate of crystalli-zation is at its maximum at the mid-temperature between the Tg and the melting

Figure 4. SEM images of particles prepared from the ethanolic solution at 50�C (a)immediately after 30min collection, (b) after one day at room temperature and 0% relativehumidity produced with the high production rate, (c) after two months produced with the lowerproduction rate at room temperature and 0% relative humidity, and (d) after 3 h at 40�C.

Aerosol Synthesis of Inhalation Particles 79

point (Tm), as discussed by Hancock and Zografi (1997). Tg can be roughly estimatedby the relation of Tg ¼ 2=3�Tm (Tm ¼ 483K, given by Eerikainen and Kauppinen(2003)) where Tg and Tm are in degrees Kelvin, as expressed by Hickey (1996).According to this relation, the approximated Tg of BDP is 49�C and the fastest crys-tallization rate is obtained at 130�C. Therefore, crystallization of particles producedat 100�C was much faster than that of particles produced at 50�C and the rough sur-face structure appeared more rapidly.

To further accelerate crystallization, the reactor temperature was raised to150�C. At 150�C the particles were rough and spherical as shown in Figure 6, indicat-ing that the particles were crystalline. The surface structure was also stable and didnot change with time. However, the structure and sintering of the particles varieddepending on the temperature and duration of the collection. The particles collectedfor a long time at a temperature of approximately 100�C were usually sintered. Thelower collection temperature (between 40 and 60�C) decreased the sintering, but thesurface structure was not as well defined as at the higher collection temperature.

The crystallinity and polymorphism of the particles produced at 150�C werestudied with X-ray powder diffraction, as shown in Figure 7. The polymorphic formof the powder was determined by comparing the diffraction pattern of the produced

Figure 6. SEM images of particles produced at 150�C.

Figure 5. SEM images of particles produced at 100�C (a) with the small-scale reactor and(b) with the large-scale reactor.

80 A. Lahde et al.

powder to the reference powder (ORION Corporation, Finland) with the knownpolymorphic form (Figure 7). The position of the peaks is the same in both samplesand there are no additional peaks. Therefore, the produced powder was classified asthe previously known crystal form class I. The relative degree of crystallinity was100%. Due to the high crystallinity, the powder was also very stable. The maximumweight increase was only 0.02%, even when the powder was exposed to 80% relativehumidity for 24 h. The HPLC analysis results showed that the chemical compositionof the produced powder was not changed during the drug particle engineering com-pared to the reference powder.

Particles Produced from the Slurry SolutionA slurry solution with existing crystal seeds was used in the attempt to accelerate theparticle crystallization. Crystal seeding is an effective way to control crystallizationoutcomes because of the potential of the crystal surfaces to promote heterogeneousnucleation and direct the crystal growth, as described by Rodrıguez-Hornedo andMurphy (1999). The particles produced from the slurry solution at 100�C with thelarge-scale reactor were spherical with a smooth surface structure (Figure 8(a)).However, the X-ray studies showed crystallinity of the powder, as seen in the datainserted in Figure 8(a), whereas the powder produced from the clear solution in simi-lar conditions was amorphous. The degree of crystallinity was further increasedwhen the particles were kept for 1 h at 60�C as the intensity of the peaks increased.The heat treatment also changed the surface structure of the particles (Figure 8(b))and increased interparticle sintering (not seen in Figure 8(b)). The nondissolved frac-tion of the drug in the slurry solution formed a crystalline core, while the surface

Figure 7. XRDpattern of the BDP particles produced at 150�C and of the BDP reference sample.

Aerosol Synthesis of Inhalation Particles 81

layer of the particle was smooth and most likely amorphous. This further indicatesthat the diffusion of BDP molecules is relatively slow and the solvent evaporationtime too short for obtaining crystalline particles without seeds in these conditions.

Particle Formation and CrystallizationParticle crystallization is believed to occur in two phases, as stated by Leong (1981),where the rate of crystallization within each droplet or particle is limited accordingto processes presented by Che et al. (1998). The first phase covers the evaporation ofthe solvent until the onset of crystallization. Here, the evaporation rate can be con-trolled with the temperature in the heated zone and the concentration of solvent inthe reactor, which together control the local saturation ratio. The process is depen-dent on the diffusion of the solvent vapors to the gas phase and the solute diffusioninside the droplet. According to this description, it had been expected thatcrystallization would most likely begin on the droplet surface, where the solute con-centration is highest due to solvent evaporation. This, however, was not observed inthis work. Instead, the particle surface was found to be smooth and amorphous at alltemperatures studied.

Our proposed mechanisms for particle formation and crystallization from clearand slurry solutions based on the obtained results are shown in Figure 9. Rapid evap-oration of the ethanol from the droplet is likely to produce amorphous particles, sincethe molecules do not have time to organize into clusters and crystals. The solid-statediffusion of BDP molecules is slow below Tg, and, as expected, amorphous particleswith a smooth surface structure were obtained at 50 and 100�C. These particles trans-formed slowly into rough crystalline particles when exposed at room temperature toan open atmosphere. Thermal post-annealing accelerated the transformation but alsoincreased interparticle sintering. By optimizing the reactor and collection conditions(e.g., temperature, residence time, and saturation level) sintering could be avoided.Based on the results, the temperature during particle collection is important forproducing individual particles, if the particles are initially amorphous.

Raising the reactor temperature increases the evaporation rate of the solvent.Glass or amorphous solids are often formed due to the rapid evaporation of thesolvent and low diffusion rate of the molecules, according to Hickey (1996) andRodrıguez-Hornedo and Murphy (1999). On the other hand, at high temperatures,the diffusion of the molecules in the solid is increased, which, in contrast, favors

Figure 8. SEM images of particles produced from the slurry solution at 100�C (a) immediatelyafter collection and (b) after post-crystallization for 1 h at 60�C.

82 A. Lahde et al.

crystallization. Crystalline particles with a rough surface were obtained when thereactor set temperature was raised to 150�C. Even though the increased temperatureincreased the rate of solvent evaporation, it also accelerated the solid-state diffusionof BDP molecules. Due to higher molecular diffusion, the molecules were able toorganize, thus increasing the crystallinity of the particles, and a fraction of crystallineparticles was observed.

A slurry solution with the existing seeds was used to further improve particlecrystallization. Particles with a crystalline core and amorphous surface layer witha smooth structure were obtained. With post-annealing, the degree of particlecrystallinity was increased and the surface structure changed from smooth to rough.

Conclusions

BDP drug particles with the mass mean diameter of approximately 2 mm wereproduced with an aerosol reactor starting from either clear or slurry solutions.Under all studied conditions, spherical particles with a narrow size distribution(GSD of approximately 2) were observed. The aerosol method gave good controlover the thermal history and residence time of the particles due to the laminar flowand uniform temperature field in the reactor. We were able to somewhat control theparticle surface structure from smooth to rough by varying the temperature in theheated zone of the reactor during particle production.

It was not possible to prepare a large fraction of crystalline particles directlyfrom the reactor. However, the study provided understanding about molecularmobility at different drying and annealing conditions. Heat treating the collectedparticles provided energy sufficient for the molecules to organize and crystallize. Thiswas particularly pronounced with those particles produced at high temperature;however, post-crystallization lead to the formation of crystalline bridges betweencontacting particles.

Future study will focus on the crystallization of drug molecules within dropletscontaining different solvents as well as solvent mixtures containing an anti-solventfor the drug.

Figure 9. Schematics of particle formation from clear or slurry solution.

Aerosol Synthesis of Inhalation Particles 83

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