Surface & Coatings Technology 205 (2011) S597–S600

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Surface & Coatings Technology

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Plasma surface modification of powders for pharmaceutical applications

Christian Roth, Zaira Künsch, Axel Sonnenfeld, Philipp Rudolf von Rohr ⁎ETH Zurich, Institute of Process Engineering, Sonneggstrasse 3, 8092 Zurich, Switzerland

⁎ Corresponding author. Tel.: +41 44 632 67 90; fax:E-mail addresses: roth@ipe.mavt.ethz.ch (C. Roth), z

(Z. Künsch), sonnenfeld@ipe.mavt.ethz.ch (A. Sonnenfe(P. Rudolf von Rohr).

0257-8972/$ – see front matter © 2010 Elsevier B.V. Aldoi:10.1016/j.surfcoat.2010.10.046

a b s t r a c t

a r t i c l e i n f o

Available online 28 October 2010

Keywords:Plasma enhanced chemical vapor depositionDusty plasmaPlasma downstream reactorParticle treatmentFlowabilityParticle size distribution

The surfaces of lactose particles are coated with SiOx nanostructures in a plasma downstream reactor toincrease the surface roughness and thus, to reduce the prevailing van der Waals forces between the substrateparticles. As a consequence of the smaller interparticle friction, both the bulk density and the flowability ofplasma modified powders are increased. In this study different powder fractions with mean particle sizesbetween 5 and 40 μm are processed separately to investigate the influence of the particle size on the process.The measured bulk densities and flow factors become larger with increasing mean particle size for bothuntreated and plasma treated powders. The bulk density of all powder fractions is increased by 40 to 50% andall originally cohesive powders reach an easy flowing regime through the short low-temperature plasmatreatment. Scanning electronmicroscope images are presented to appraise the particle size and distribution ofthe deposited spacer structures on the lactose surface. This estimation leads to the conclusion that the spacerstructures have typical diameters between 15 and 60 nm and cover the surface with approximately 5 to 15%.Comparative studies investigating the influence of admixed glidants on the powder flowability show that thisrange is desirable for a maximal reduction of attractive van der Waals forces.

+41 632 13 25.kuensch@student.ethz.chld), vonrohr@ipe.mavt.ethz.ch

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© 2010 Elsevier B.V. All rights reserved.

1. Introduction

The poor flow behavior of fine and cohesive powders causesproblems throughout the chemical, pharmaceutical and food industry.Basic processing steps such as conveying, dosing or mixing becomea challenge as soon as the particles are small and cohesive. But formany applications a high specific surface area of powder materials isnecessary and therefore, small particles cannot be avoided. Hence,methods to improve the powder flowability are required, to processalso very fine powder fractions.

The flow behavior of a particle collective is mainly dependent onthe ratio between the gravitational force and the attractive interpar-ticle forces [1]. For dry particles in the micrometer range the van derWaals interaction FVdW is identified as the dominant attractive force.The force between two spherical particles with diameter R calculatesaccording to the Hamaker law [2] as given in Eq. (1). A is the Hamakerconstant and a material property and H is the interparticle distance.

FVdW =A⋅R

12⋅H2 : ð1Þ

The van der Waals interaction is a short-range force. This explainswhy the number of interparticle contacts and thus, the size and shape

of particles are of major importance for the flow behavior of a powder[3]. Since the gravitational force for a spherical particle is proportionalto the third power of the radius, the ratio between the van der Waalsinteraction and the gravitation is proportional to 1/R2. For mostorganic powders the van der Waals forces exceed the gravitationbelow a mean particle diameter of approximately 30 μm [4], which isthe main reason for the poor flowability of very fine powders.

A common technique to improve the flow behavior of suchcohesive powders is the admixture of SiO2 nanoparticles, which act asspacer material between the larger substrate particles [1,5]. Theresultant increase of the interparticle distance H is responsible for areduction of the attractive van derWaals force and the achieved betterflowability of the powder [4].

Unfortunately the achieved flowablities depend strongly on thedistribution [5], amount [4], size [4] and shape [6] of the admixedglidants and thus, on the mixing time [4,7]. Furthermore, complexnanoparticle handling is required to avoid nanoparticle agglomera-tion and particle segregation.

Several years ago, Spillmann et al. started developing and inves-tigating a plasma process to directly deposit such spacer structureson substrate particles by means of plasma enhanced chemical vapordeposition (PECVD) [8]. This allows combining nanoparticle pro-duction, nanoparticle handling and mixing of nanoparticles into thesubstrate powder in one single process step. For this, SiOx nanopar-ticles are directly formed in the plasma chamber out of the monomerhexamethyldisiloxane (HMDSO) and deposited on the substrate par-ticle surfaces. A reactor concept which allows a homogeneous and fast(b0.1 s) treatment of the particles is the plasma downstream reactor

S598 C. Roth et al. / Surface & Coatings Technology 205 (2011) S597–S600

(PDR) [9]. The good dispersion of the negatively charged substrateparticles in this type of plasma reactor guarantees a uniform dis-tribution of the emerging spacer structures on the particle surface,which is necessary for good flow behavior [5]. In recent years, wesignificantly improved the flowability of lactose powder [8] with thePDR concept which implies as well an increase in bulk density [10].

So far, the effectiveness of the process for powders with variousparticle size distributions has not been studied in detail. Thereforelactose powder is sieved into different fractions and processedseparately. For each powder fraction the particle size distribution,the flow factor and the bulk density are measured and scanningelectron microscope (SEM) images of the untreated and modifiedpowder particles are taken in order to reason the huge differences inflowability and bulk density.

2. Experimental

Since the first deposition experiments with the PDR [8] the reactorsetup was further improved to increase the deposition rate, reactorcooling and the separation efficiency of the treated particles from thegas stream. The process scheme of the used PDR and a sketch of thedowner section are shown in Fig. 1. The plasma chamber (1) consistsof a 1.5 m long double wall glass reactor with an inner diameter of40 mm. The gap between inner and outer tube is filled with deionizedwater (2) to ensure a constant reactor temperature at 20 °C. Thedischarge is driven by an inductively coupled plasma (ICP) sourcewhich operates at a radio frequency (RF) of 13.56 MHz and a forwardpower of 300 W. The RF-generator (3) is connected over a matchingnetwork (4) with the water cooled copper coil (5) on the outside ofthe cooling jacket. The flow rates of the gases oxygen (750 sccm,purity N99.5%), argon (700 sccm, purity N99.999%) and the organo-

Fig. 1. Plasma downstream reactor for particle surface modification;

silicon monomer HMDSO (50 sccm, purity N98%) are adjusted by flowcontrollers and the monomer is evaporated in a controlled evapora-tion mixing device (6). The lactose powder (GranuLac 200, Meggle,Germany, purity N99%) is fed from the storage container (7) over ametering screw (8) with 2 kg/h to the downer pipe and mixed withthe process gases in a nozzle (9). Below the plasma zone the particlesare separated from the gas stream by a downcomer (10), cyclone (11)and filter unit (12) and collected in the solid collection vessels (13). Aconstant pressure of 200 Pa in the reactor is maintained during theprocess by a butterfly control valve (14) in front of the two stage rootsand rotary vane vacuum pump (15).

Three lactose fractions are produced with a sieving machine(Retsch, AS Control 200, Germany) and sieves with a mesh width of63 and 80 μm respectively. As the lactose is cohesive before theplasma treatment, no sharp separation can be obtained and it isnearly impossible to produce a powder fraction with a mean diametersmaller than approximately 20 μm. Therefore, an additional fourthand even smaller fraction is produced by milling.

The particle size distributions of the four different powder frac-tions are measured by laser diffraction method (Sympatec, HELOSand RODOS, Germany). The powder is fed over a vibrating chute anddispersed in an air stream while passing the laser beam. The bulkdensity ρb of the powder fractions is determined by pouring 20.0 gpowder in a graduated cylinder and reading the respective volume. Anaccepted measure for the flow behavior of a powder is the so calledflow factor ffc, which is defined as the ratio between the consolidationstress σ1 and the unconfined yield strength σc.

ffc =σ1

σcð2Þ

PIC: pressure indicator controller, FIC: flow indicator controller.

0 10 20 30 40

Flo

w fa

ctor

ffc

[-]

0

2

4

6

8

10

plasma treateduntreated

Median particle size x50 [μm]

Fig. 3. Flow factor of untreated and plasma treated lactose as a function of the meanparticle diameter.

S599C. Roth et al. / Surface & Coatings Technology 205 (2011) S597–S600

The flow behavior is classified according to [11] as not flowingfor ffcb1, very cohesive for 1b ffcb2, cohesive for 2b ffcb4, easyflowing for 4b ffcb10 and as free-flowing for 10b ffc. The flow factor ismeasured with a ring shear tester (RST-XS, Schulze Schüttguttechnik,Germany) and a shear cell volume of 30 ml. The preshear stress wasset to 5000 Pa and shear stresses of 1000, 2500 and 4000 Pa wereapplied to determine the yield locus and thus, the value of the flowfactor. Details about the ring shear tester, the method and theconnected theory are well described in [12]. The measurements ofbulk density and flow factor are performed three times and the errorbars in Figs. 2 and 3 indicate the 95% confidence interval.

The SEM images are taken with a Zeiss Gemini 1530 microscopeoperated at an acceleration voltage of 2.0 kV and using the secondaryelectron detector (SE2). The powder samples are fixed to conductivestickers (polycarbonate with admixed graphite) and coated with a2 nm thick platinum layer before the SEM analysis to reduce chargeaccumulation on the sample surface.

3. Results and discussion

Particle size measurements of the four powder fractions prior tothe plasma treatment resulted in mean particle diameters (x50) of 5.3,20.4, 24.0 and 39.7 μm respectively. After the treatment in the PDRthe collected powders from the downcomer, cyclone and filter cham-ber are mixed together and stored for at least 4 days to exclude anyshort-term aging effects. A second particle size measurement afterthe treatment and storage showed equal or slightly higher meandiameters of 5.5, 22.3, 25.5 and 39.5 μm respectively, which could bedue to minor agglomeration of the powder during storage or losses ofvery fine particles during handling of samples.

Themeasured bulk densities of the untreated and plasmamodifiedpowder fractions are shown in Fig. 2 as a function of the mean particlediameter. Compared to the particle density of lactose monohydrate(approximately 1520 kg/m3) the bulk densities of the untreatedfractions are between three and five times smaller, meaning that theporosity of the finest powder sample is about 80%. This very finefraction does not compact more under its own weight due to theprevailing interparticle forces. For larger particles the influence ofgravity compared to the van der Waals forces increases and thus,higher bulk densities are evident.

After the plasma treatment in the PDR the bulk densities areincreased by 40 to 50% compared to the untreated powder fractions.The highest relative increase is reached for the finest powder. As in anearlier study [10] we assume that the created additional surfaceroughness on the substrate particles is responsible for the reduction ofthe prevailing van der Waals forces and therefore, the powders are

0 10 20 30 400

200

400

600

800

1000

plasma treateduntreated

Bul

k de

nsity

ρb

[kg/

m3 ]

Median particle size x50 [μm]

Fig. 2. Bulk density of untreated and plasma treated lactose as a function of the meanparticle diameter.

compacted more under the influence of gravity only. The influence ofmass and volume gain by the SiOx deposition on the bulk density canbe neglected, since the mass fraction of SiOx is below 0.8% (whichwould correspond to a total conversion of HMDSO to SiO2).

The decrease of interparticle forces by the applied plasma surfacemodification becomes even more apparent by flow factor ffc mea-surements of the bulk powders. The flow factors of both untreated andplasma treated fractions are shown in Fig. 3. All untreated powdersare classified as cohesive or even as very cohesive. By the depositionof SiOx nanostructures on the substrate particle surface all powdersreach flow factors which are generally classified as easy flowing,meaning that no problems due to insufficient flow behavior shouldarise in the downstream processing. The fact, that larger particlesgenerally exhibit a better flow behavior [13,14] is also valid for theplasma treated powders and the flow factors correlate well with themeasured bulk densities in Fig. 2.

The finest investigated powder fraction (x50=5.5 μm) is verysimilar to a fine-grained powder studied in [8]. Spillmann et al. wereable to increase the flow factor from about 1.5 to 3 with their PDR. Aflow factor of 3 was as well the benchmark reached by nanoparticleadmixture (Aerosil 300, 0.7 wt.%) after a mixing time of 8 h. Since nochange on the surface could be detected in a SEM analysis, the authorsassumed that the emerging nanostructures responsible for theincrease in flow factor have typical diameters below 3 nm. Based ona theoretical model of the attractive interparticle forces, Spillmannet al. additionally assumed that the produced nanoparticles are belowthe optimal spacer size, required for a maximal reduction of the vander Waals force.

The powders investigated in this study are analyzed by SEM aswell. Micrographs of an untreated a) and plasma treated b) powdersurface (x50=25 μm) are shown in Fig. 4. The large particles (~0.2–2 μm in diameter) present on both surfaces in image a) and b) arefine-grained lactose. In image b) the emerging nanostructures areclearly visible and therefore certainly larger than 3 nm in diameterwith the chosen process parameters. Based on the SEM micrographs,the particle size of the produced spacers is estimated to be betweenapproximately 15 and 60 nm with a typical surface coverage of 5 to15%.

Investigations to find the optimal size and distribution of admixedglidants for flowability improvement can be found in pharmaceuticalstudies [4,5,15]. One of the most commonly used glidant [1] isAerosil 200 with a primary particle diameter of approximately 12 nm.Since such nanomaterials are highly aggregated and agglomeratedto particles with diameters of several 100 nm or more, intense mixingis necessary to break up the agglomerates and to distribute theaggregates on the powder surface. Zimmermann et al. [1] found that

Fig. 4. SEM images of: a) the untreated surface of a lactose particle from the fractionwith x50=25 μm and b) a corresponding surface of the same powder fraction after thesurface modification in the PDR.

S600 C. Roth et al. / Surface & Coatings Technology 205 (2011) S597–S600

the optimal size of glidants for starch particles with a mean diameterof 22 μm is in the range between approximately 50 and 85 nm at asurface coverage of 5 to 6%. Their theoretical approach lead to theconclusion that glidants with diameters between 7 and 100 nmgenerally lead to a decrease of the prevailing van derWaals forces andthus, to an improvement of the flowability.

The fact that the structures deposited in the presented experi-ments aremuch larger than the ones in previous studies [8,10] explaintherefore the measured higher flow factors and bulk densities. Withthe applied process conditions the plasma polymerized SiOx struc-tures may even be close to the optimal size in terms of maximalreduction of interparticle forces.

4. Conclusions

Four different powder fractions of lactose with different particlesize distributions have been coated with SiOx nanostructures in aplasma downstream reactor. The deposited structures act as spacersand increase the interparticle distance. As a consequence the pre-vailing van der Waals force between the lactose particles is reducedand thus, higher bulk densities and flow factors of the powders aremeasured after the surface modification. The flowability of all inves-tigated powder fractions is considerably increased, such that originallycohesive or very cohesive powders become easy flowing after theplasma treatment. At the same time the bulk density is increased by40 to 50% compared to the untreated powder.

It is shown, that the presented plasma process is well suited totreat very fine powders in the lowmicrometer range.With the appliedprocess conditions it was possible to increase the flowability and bulkdensity during the very short residence time of only 0.1 s to values,which are up to our best knowledge not reached by conventionalmethods such as nanoparticle admixture.

SEM analysis of the coated surfaces revealed a surface coveragebetween 5 and 15% with nanoparticle like structures in the size rangeof 15 to 60 nm. Comparable studies investigating the nanoparticleadmixture to improve the powder flow behavior suggest that ourdeposited structures lie near the optimum for a maximal reduction ofvan der Waals interactions of fine particles.

Acknowledgements

The authors gratefully acknowledge support of the ElectronMicroscopy Centre EMEZ of the Swiss Federal Institute of TechnologyETHZ and financial support by the Claude & Giuliana Foundation(Switzerland).

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