Surface & Coatings Technology 206 (2012) 3832–3838

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Surface & Coatings Technology

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Adjusting dissolution time and flowability of salicylic acid powder in a two stageplasma process

Christian Roth, Lukas Keller, Philipp Rudolf von Rohr ⁎ETH Zurich, Institute of Process Engineering Sonneggstrasse 3, 8092 Zurich, Switzerland

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

(L. Keller), vonrohr@ipe.mavt.ethz.ch (P. Rudolf von Ro

0257-8972/$ – see front matter © 2012 Elsevier B.V. Alldoi:10.1016/j.surfcoat.2012.01.046

a b s t r a c t

a r t i c l e i n f o

Article history:Received 20 December 2011Accepted in revised form 24 January 2012Available online 2 February 2012

Keywords:Particle surface modificationDissolution timeFlowabilitySalicylic acidPlasma downstream reactorPlasma enhanced chemical vapor deposition

Many industrial products and intermediates in powder form suffer from low flowability and poor dissolutionbehavior. Current techniques to overcome such problems often include time-consuming admixture of addi-tives or wet-chemical processes that are harmful to the environment. Therefore, the objective of this workwas to develop a continuous non-equilibrium plasma process to modify the flowability and dissolution be-havior of fine-grained, cohesive and temperature sensitive powders. As test substance salicylic acid wasused due to its low melting point, cohesive nature and similarity to many pharmaceutical products.In the proposed process the powders were passed through a low-pressure discharge to modify the single par-ticle surfaces. In a first process step SiOx nanostructures and thin films were formed in the plasma and depos-ited on the salicylic acid particles. The created nanostructures acted as spacers and reduced the prevailinginterparticle van der Waals forces. Hence, the flowability of the dry powder was improved from the cohesiveto the easy-flowing regime. The flowability was higher the more nanoparticles were deposited per surfacearea. On the other hand, the deposition of nanostructures retarded the dissolution, which was attributed tothe partial coverage of the particle surfaces. Therefore, these already coated powders were surface activatedin a second plasma-assisted process step in the same reactor. The particle surfaces were enriched with polargroups, which increased the surface free energy. This improved the powder wettability and the dissolutiontime was reduced even below the measured value of uncoated powder.Hence, with the introduced process both the flowability and dissolution time of the cohesive, temperature-sensitive and fine-grained test substance salicylic acid could be adjusted within a very short process timein the order of 1 s.

© 2012 Elsevier B.V. All rights reserved.

1. Introduction

Many products and intermediates in powder form suffer from lowflowability and poor dissolution behavior. Low powder flowabilitycauses clogging of equipment, poor dosing, mixing, and sieving per-formance. In a tablet press cohesive drugs can result in non-uniformtablet weight, which is not tolerated by the approval authorities.Therefore, flow agents such as silica nanoparticles are often admixedto overcome flowability problems [1,2]. The admixed nanoparticlesact as spacers between the much larger substrate particles and there-by diminish the interparticle van der Waals forces [1]. This reducesthe friction between the particles and leads to an improved flowabil-ity. Nevertheless, the amount of admixed glidants and the requiredmixing time are highly empirical. Even more adequate mixing cantake hours in case of very fine substrate powders and the mixturehas to be handled with care to avoid segregation.

: +41 44 632 13 25.ukaskeller@student.ethz.chhr).

rights reserved.

On the other hand, the dissolution time of a powdery drug has adirect influence on the speed of release and can be the rate-limitingstep in the whole absorption process [3]. A fast dissolution is essentialfor many drugs such as analgetics, while a slow dissolution is of inter-est for highly active drugs or in the field of controlled release.

Both, the dissolution time and flowability of a powder dependrather on surface than on bulk properties of the particles. Hence,these macroscopic powder properties can be improved by a functio-nalization of the particle surfaces. Even though non-equilibrium plas-ma systems are seldom used for surface modification of particles, theyfacilitate the effective tuning of particle surfaces without changingthe bulk product. Entering a discharge, the agglomerated substratematerial is charged negatively due to the electron impact. This nega-tive surface charge leads to a repulsive force between the singleparticles and helps to disperse them in the gas and to break up soft-agglomerates. In such a well-mixed system consisting of solid partic-ulates, free electrons, neutral, exited, and ionized gas particles, whichis also known as “dusty plasma”, non-equilibrium reactions on thesolid particle surface are possible [4]. This enables chemical reactionsat low temperatures, which would require temperatures above themelting point of the substrate material under equilibrium chemistry

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conditions. Depending on the used gas mixtures and process condi-tions different surface modifications or coatings can be obtained.

As illustrated in Fig. 1, the oxygen molecule can be dissociated,ionized or activated in the discharge. By this means, polar groupssuch as hydroxyl or carboxyl are formed on the surface of thesubstrate particle. These functional groups increase the surface freeenergy of the powder and thus, enable low contact angles even withpolar liquids such as water. The plasma-assisted wettability improve-ment of powders has extensively been studied for polymers e.g. in [5].The wettability of a substance is also directly linked with the intrinsicdissolution rate [6]. Thus, the dissolution behavior of a powder can betuned in a certain range by only creating some functional groups onthe particle surface.

If precursor monomers are additionally introduced to the dis-charge, they will be partially charged and split into fragments aswell. Under appropriate plasma conditions such precursor fragmentscan grow to nanoparticles forming spacer structures [7,8] or even co-herent films [9] on the surface of the substrate particles. These spacerstructures are deposited to increase the surface roughness of thepowder as sketched in Fig. 2. The increased surface roughness reducesthe interparticle friction and leads to an improved flowability [7,8]and compactibility [8,10] of the powder, exactly as in the case ofnanoparticle admixture.

The dissolution time does not only depend on the wettability, butalso on the available surface. Susut and Timmons encapsulated acet-ylsalicylic acid crystals within a thin polymeric film by plasmaenhanced chemical vapor deposition (PECVD) and were able to in-crease the dissolution time by several orders of magnitude [11]. Wetherefore expected that the dissolution time increases as well byany deposition of spacer structures due to the partial coverage ofthe particle surface.

Several reactor concepts for the plasma-assisted particle surfacemodification at reduced pressure are compared in [12]. Besides fluid-ized bed, circulating fluidized bed, and downstream reactors also ro-tating drum and so-called plasma batch reactors were used in thepast. In addition, a system using a remote plasma [13] and a spiralconveyor type of reactor using a hollow cathode glow discharge[14] are known. Among them the patented plasma downstream reac-tor concept was chosen for this study [15]. It features a confined plas-ma zone in a long glass tube, low wall temperatures [16], short anddefined residence times, and a good dispersion of the powder in thegas stream. An overview of both processes (surface activation andspacer deposition) in a plasma downstream reactor (PDR) is pre-sented in [17]. The single processes to increase either the wettabilityor flowability are fairly well understood. Nevertheless, the influenceof plasma deposited flow agents on the dissolution behavior hasnever been studied in detail.

The first goal of this study was therefore to investigate the influ-ence of the spacer deposition on the flowability and dissolutiontime for a test substance relevant to industry. In a second phase we

Fig. 1. Principal sketch of the wettability improvem

investigated a novel two-step process in which spacer structureswere deposited in a first step and surface activated in a second stepto yield powders with both, enhanced flow and dissolution behavior.

2. Materials and methods

2.1. Test substance salicylic acid

Salicylic acid (SA) was chosen as test substance due to its lowflowability, moderate dissolution behavior and its similarity tomany pharmaceutical products. The fine-grained powder with a puri-ty of >99% was supplied by Acros Organics (Belgium).

2.2. Size and morphology characterization

The SA particle size distribution was measured by laser diffraction(HELOS BR, Sympatec, Germany) in connection with a dry dispersionunit (RODOS/M, Sympatec, Germany) at a dispersion pressure of2.0 bar. The particle size distribution was measured three times andaveraged.

Scanning electron microscope (SEM) images were taken with aZeiss Gemini 1530 microscope operated at an acceleration voltageof 2.0 kV and using both, secondary electron and in-lens detector.The powder samples were fixed to conductive stickers (polycarbon-ate with admixed graphite) and coated with an approximately 2 nmthick platinum layer before the SEM analysis to reduce charge accu-mulation on the sample surfaces.

2.3. Plasma downstream reactor

A process scheme of the PDR was published in a previous study [8]and a sketch of the downcomer section is shown in Fig. 3. The plasmachamber consists of a 1.5 m long double wall glass reactor with aninner diameter of 40 mm. The gap between inner and outer tubewas filled with deionized water to ensure a constant reactor temper-ature of 20 °C.

The discharge was driven by an inductively coupled plasma (ICP)source which operates at a radio frequency (RF) of 13.56 MHz. TheRF-generator was connected to the copper coil on the outside of thecooling jacket via a matching network. The flow rates of the gasesoxygen (PanGas, Switzerland, purity>99.999%), argon (PanGas,Switzerland, purity>99.999%) and the organosilicon monomerHMDSO (purity>98%, Sigma-Aldrich, USA) were adjusted by flowcontrollers and the monomer was evaporated prior feeding. Thetotal flow rate was kept constant within all series at 1500 sccm. Toavoid powder accumulation in the reactor 10 wt.% of glass beads(SiLibeads Type S, 0.4–0.6 mm, Sigmund Linder GmbH, Germany)were admixed to the SA before the plasma treatment. This mixturewas fed from a storage container into in a dispersing nozzle by ametering screw and mixed with the process gases before entering

ent by the plasma-assisted surface activation.

Fig. 2. Principal sketch of the flowability improvement by the plasma-assisted formation and attachment of spacer structures.

Fig. 3. Principal sketch of the downcomer section.

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the downstream pipe. The particle–gas mixture passed the dischargein approximately 0.1 s. Within this short period of time the differentplasma-physical processes and surface reactions took place. Belowthe plasma zone the particles were separated from the gas streamby a downcomer, cyclone, and filter unit. A constant low pressure of200 Pa in the reactor was maintained by a control valve in front ofthe vacuum pump. After the treatment the glass beads were removedfrom the SA by sieving the product with a mesh width of 355 μm.

2.4. Dissolution testing

The electric conductivity of a solution of salicylic acid in water is afunction of the SA concentration and the self-ionization of water mol-ecules. Since the contribution of the self-ionization is very small com-pared to the contribution of the dissolved SA [18], a simple and fastmethod to observe the dissolution at a high temporal resolution isan electrical conductivity measurement.

Our dissolution testing apparatus consisted of a double-wall glassvessel with an inner diameter of 80 mm. It was filled with 500 mldeionized water, heated to 37 °C, and stirred with a magnetic sir barat 1000 rpm. A conductivity cell (Willi Möller AG, Switzerland) waspositioned 1 mm from the outer wall. The calibration curve of theelectric conductivity as a function of the dissolved salicylic acid isshown in Fig. 4 for concentrations between 0 and 0.4 g/l. The line rep-resents the fourth degree polynomial used for the transformation ofthe measured electrical conductivity of the solution to the respectiveSA concentration.

The conductivity was measured with a resolution of 1 Hz after theSA was added. The transient conductivity measurement was fitted bya fourth degree polynomial function and the time when the concen-tration reached 80% of the steady state value was taken as compara-tive dissolution time t80. For each powder three dissolutionexperiments were performed and the error bars of the t80 values indi-cate the 95% confidence interval.

2.5. Flowability testing

The flowability was assessed with a ring shear tester (RST-XS,Schulze Schüttguttechnik, Germany). The flow function coefficientffc was used as comparative value to describe the flow behavior andis defined as the ratio between the consolidation stress σ1 and theunconfined yield strength σc, as outlined in Eq. (1).

f f c ¼σ1

σ c: ð1Þ

The flow behavior is classified according to [19] as not flowing forffcb1, very cohesive for 1b ffcb2, cohesive for 2b ffcb4, easy-flowing

for 4b ffcb10, and as free-flowing for 10b ffc. A shear cell with a vol-ume of 30 ml was used. The preshear stress was set to 5000 Pa andshear stresses of 1000, 2500, and 4000 Pa were applied to determinethe yield locus and thus, the value of the flow function coefficient. Themeasurements were performed three times and the error bars in

Fig. 4. Conductivity calibration of salicylic acid in deionized water at 37 °C.

Fig. 5. SEM image of untreated salicylic acid at a nominal magnification of 2000, ac-quired with the secondary electron detector.

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figures with flowability measurements indicate the 95% confidenceinterval.

3. Results

The measurements were performed in two independent series.First, the influence of the pure spacer deposition on the flowabilityand the dissolution time was determined. In this series, four differentpowder feed rates were explored at a constant plasma power of200 W. Hence, the specific amount of SiOx deposited per substrateparticle surface area was varied and its influence could be assessed.

In the second series, the powder was passed through the plasmareactor twice and at a higher plasma power of 300 W. In the firstrun (step A), the monomer HMDSO was added to the discharge inorder to form SiOx spacer structures and to increase the roughnessof the particle surfaces. During the second plasma treatment (stepB), the collected powder was fed to the reactor again but withoutmonomer admixture. In this way, we aimed at enriching the surfacewith oxygen containing polar groups to improve the wettability anddissolution behavior of the product. During the surface activationstep the oxygen concentration of the process gas was varied tostudy its influence. The plasma power was increased from 200 W inthe first series to 300 W in all experiments of the second series inorder to intensify the effect of the surface functionalization. At elevat-ed power more energy is available for monomer fragmentation andnucleation of spacer structures. The process conditions of all experi-ments and the main results are listed in Table 1.

3.1. Properties of untreated salicylic acid

A SEM image of an uncoated SA particle is shown in Fig. 5. The sur-face roughness in the micrometer range is relatively high. Different

Table 1Process conditions and results of the performed measurements.

Parameter 1st series

Plasma power [W] 200System pressure [Pa] 200Monomer flow rate [sccm] 50Oxygen flow rate [sccm] 500Argon flow rate [sccm] 950Powder feed rate [kg/h] 1.54 2.96 4.50 6.07Flowability [–] 8.9 7.3 6.6 6.2Dissolution time t80 [s] 130.1 119.6 110.9 107.8

investigated particles showed a broad variation in particle size andmorphology. The cumulative particle size distribution measured bylaser diffraction is shown in Fig. 6. The mean particle size x50 of the in-vestigated SA powder batch was 31.8 μm, while the x10 and x90 valueswere determined to 6.8 and 69.4 μm respectively.

The dissolution time t80 of untreated SA lasted 88 s at the beforementioned conditions in the stirred vessel. The flowability ffc ofuntreated SA was determined to 2.4 which corresponds to the cohesiveregime according to the classification of [19]. The untreated powdertends to build up larger blocks and soft agglomerates during storage,an effect which is known as time consolidation or caking.

3.2. Influence of spacer deposition on the dissolution time

The effect of the spacer deposition on the dissolution time t80 wasassessed in the first series of experiments at a plasma power of200 W. The formation of SiOx structures on the particle surfacesslows down the dissolution process, as shown in Fig. 7. The t80 risesfrom 88 s (untreated SA) to values between 107.8 and 130.1 s,depending on the powder feed rate. The less powder was fed pertime, the longer was the dissolution time. On the other hand, iflarge amounts of powder were fed to the reactor and treated underthe same plasma conditions, the dissolution time approached thevalue of untreated SA powder.

3.3. Influence of spacer deposition on the flowability

The flowability of the powders after the plasma-assisted deposi-tion of spacer structures is shown in Fig. 8 as a function of the powderfeed rate. The flowability of all coated powder samples was drasticallyincreased up to values which are classified as easy-flowing. In addi-tion, all coated powders showed no time consolidation any more.With increasing powder feed rate the effect of the surface modifica-tion became smaller since less nanostructured SiOx was deposited

2nd series step A 2nd series step B

300 300200 20050 0500 500 750 1000 1250950 1000 750 500 2501.83 2.63 2.61 2.61 2.628.1 6.8 8.2 7.8 8.3153.1 73.1 75.8 75.9 73.6

Fig. 6. Cumulative particle size distribution function of the investigated salicylic acidpowder batch.

Fig. 8. Flowability as a function of the powder feed rate.

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per specific surface area. As a consequence, the highest flowabilitywas reached at the lowest powder feed rate.

3.4. Influence of the two step process on the dissolution time andthe flowability

After the deposition of spacer structures (step A) a flowability of8.1 was reached at a powder feed rate of 1.83 kg/h. At the sametime the dissolution was retarded and 80% of the SA was dissolvedafter 153 s. Different types of coatings were observed during theSEM analysis of this sample. Several particle surfaces showed thecharacteristic coating with nanoparticles, as already found for lactosein a previous study [8]. Furthermore, porous layers were found onparticle surfaces, which seem to cover up to approximately 90% ofthe particle surfaces. These porous layers often incorporated nano-sized structures as exemplarily shown in Fig. 9. These spacer struc-tures featured sizes up to approximately 40 nm and were well dis-persed over the substrate particle surface.

After the subsequent surface activation (step B) the dissolutiontime t80, shown in Fig. 10, was strongly decreased even below thevalue of untreated SA. Nearly independent on the oxygen concentra-tion in the process gas t80 values between 73 and 76 s were measured.

On the other hand, the flowability remained above 6 also after thesurface activation step, as shown in Fig. 11. For oxygen contents of

Fig. 7. Dissolution time t80 as a function of the powder feed rate.

50% and more nearly the same flowability as directly after step Awas measured.

4. Discussion

According to our current understanding of the process the precur-sor molecules are partially dissociated, ionized and activated due toelectron and ion impact, as soon as they enter the discharge. Theresulting monomer fragments and radicals contribute then either tothe nucleation of nanoparticles [20] or to the growth of a SiOx-film[9] on the substrate particle surface. Most of the growing nanoparti-cles attach to the substrate particles in a stochastic process, drivenby both electrostatic interaction and fluid dynamic mixing. Which de-position process (nanoparticle formation or surface growth) domi-nates, depends on many process parameters like pressure, gascomposition, residence time, or plasma power such as on substrateparticle properties like size, electric conductivity, or temperature.

By variation of the substrate powder feed rate, the available SAsurface in the discharge zone was changed. Assuming that approxi-mately the same amount of spacer structures and monomer frag-ments was produced, the specific coverage and thus, the resultingsurface roughness was influenced by a variation of the powder feedrate. At low powder feed rates approximately the same amount ofnanostructures was distributed on a smaller surface, resulting in ahigher coverage and more pronounced increase of the surface

Fig. 9. SEM image of surface coated SA after step A of the two stage treatment at a nom-inal magnification of 100,000, acquired with the in-lens detector.

Fig. 10. Dissolution time t80 after the surface activation for various oxygen contents inthe process gas.

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roughness. The stronger increase of flowability and dissolution timefor lower powder feed rates is therefore comprehensible.

In an earlier study the amount of nanoparticles produced at theseprocess conditions without the addition of substrate powder wasassessed and is in the range between approximately 2.2 and 2.6 g/h[20]. Hence, the weight ratio between coating and substrate particleswas in the order of 1:1000. If more substrate powder was fed to thereactor, the coverage diminished and thus, the dissolution time andflowability approached the value of uncoated SA for high powderfeed rates.

In the second series a higher plasma power was applied and moreenergy was available to split the precursor molecules into fragments.We suppose that the nucleation and attachment of spacer structureson the substrate particles as well as the surface growth of SiOx filmswere enhanced under these conditions. The higher abundance of pre-cursor fragments and a resulting higher surface coverage could ex-plain the increased dissolution time compared to the first series.The coverage of lactose particles at similar process conditions and apowder feed rate of around 2 kg/h in the same plasma reactor rangedfrom about 5 to 15% in an earlier study [8]. Compared to lactose, thecoverage of SA particles after step A in the second series seems

Fig. 11. Flowability after the surface activation for various oxygen contents in the pro-cess gas.

much higher. In the SEM image shown in Fig. 9 a nearly pinhole-free coating could be observed, with only one large defect at theupper right corner of the micrograph. Hence, the SEM investigationsupports the hypothesis of a combined treatment by both pro-nounced film growth and attachment of nanoparticles in the case ofsalicylic acid. Again, we relate the high flowability after step A inthe second series primarily to the increased surface roughness. Spill-mann et al. investigated the concomitant change in surface free ener-gy by the deposition process and attributed the reduction ofinterparticle forces mostly to the increased surface roughness, sincethe surface energy changed only slightly [21].

On the other hand, the surface free energy of a powder is signifi-cantly increased by a treatment in a low-temperature argon–oxygendischarge, as shown in the past for polymer powders [5]. Functionalgroups are formed, which favor the wetting with polar liquids likewater and thus, increase as well the dissolution rate [6].

Our hypothesis for step B in the second series is therefore as fol-lows: The surface roughness created during step A, responsible forthe improved flowability, is mostly preserved during the precedingsurface activation step. The simultaneous etching of the surface insuch an argon–oxygen discharge may create more defects in the po-rous layers, but cannot considerably diminish the deposits. More es-sential was most probably that both, the spacer structures and theuncoated SA surface were enriched with polar groups which en-hanced the wettability of the powder. Particles featuring a high sur-face roughness and at the same time a high surface free energy, leadthen most probably to the observed very good dispersion in water.The coated and surface activated powders showed no lump formationduring the dissolution test providing a very large solid–liquid inter-face, contrary to the untreated SA powder which had a strong tenden-cy to form lumps when added into water. We therefore believe thatthe synergetic effect of coating and functionalization resulting in ahigh dispersion concomitant with a high surface free energy was re-sponsible for the fact that the dissolution time t80 decreased evenbelow the value of untreated SA.

A significant influence of the different applied oxygen concentra-tions between 33 and 83% during the surface activation step wasnot found. A better method to adjust the degree of surface activationwould probably be to adjust the powder feed rate as shown in thefirst series.

5. Conclusions

A plasma process to change both the dissolution time and theflowability of fine-grained powders was investigated. The simulta-neous formation and deposition of SiOx-like nanoparticles and thinfilms on the surface of the test substance salicylic acid increased theflowability from the cohesive to the easy-flowing regime. Due to thepartial surface coverage of the substrate particles with the depositednanostructures the dissolution time t80 also increased from 88 toover 150 s.

By means of a two stage process, in which the SA surface was coat-ed in a first step and enriched with polar groups by a subsequent sur-face activation, powders were obtained which featured bothenhanced flow and dissolution behavior. On the one hand, these pow-der properties facilitate the handling of the dry powder and on theother hand, they provide a rapid dissolution favoring for instancefast uptake of a drug in its final dosage form.

The presented process is much faster compared to conventionaltechniques aiming at increased flowability for instance by admixingSiO2 nanoparticles. The residence time in the PDR is about 0.1 s,while adequate mixing can take several minutes or even hours inthe case of cohesive and fine-grained powders. In addition, no segre-gation can occur if the nanostructures are directly bond to the sub-strate material. The implementation of the subsequent surfaceactivation increases the number of potential applications in industry

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since also products with poor wetting or dissolution characteristics(vitamins, pigments, pharmaceuticals, nutraceuticals, or food addi-tives) could profit from the process in this form. Nevertheless, clinicstudies must be performed before this technique can be used in thefood or pharmaceutical sector. Based on the nearly stoichiometric na-ture of the deposited SiOx [20], similar risks as in the case of SiO2

nanoparticle admixture are expected. Since the deposits correspondto only approximately 0.1wt.% of the product this new process caneven be seen as advantageous, since mostly higher flow agent toproduct ratios are required using the standard mixing technology toreach similar flowabilities.

The throughput being limited to several kilograms per hour in ourpilot facility could be further increased by enlarging the reactor crosssection or installing multiple reactor tubes in parallel. Even more, theadvantageous two stage process can be realized in one reactor withtwo plasma zones in the future. This would enable to adjust the flow-ability and dissolution time in one unit operation within a very shortprocess time in the order of 1 s.

Acknowledgements

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

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