Online Control of Particle Size during Fluidised Bed ... · Chemistry, Bundesstr. 45, 20146 Hamburg (Germany), e-mail: [email protected] Key words Particle

Reprint Originale pharmind

1. IntroductionIn the pharmaceutical industry, the tablet still remainsthe most widespread of all drug forms. However, veryfew active ingredients can be tabletted directly. For thisreason, in an initial production stage often a granulatesuited for tabletting is produced. An important granu-late parameter − in addition to factors such as moisture

Online Control of Particle Size duringFluidised Bed GranulationExamination of a new type of laser probe for better control of particle size growthin fluidised bed granulation

Sebastian Schmidt-Lehr1, Hans-Ulrich Moritz1, and Kai C. Jürgens2

Hamburg University, Institute for Technical and Macromolecular Chemistry1, Hamburg (Germany),and Schering AG2, Berlin (Germany)

Correspondence: Dipl.-Chem. Sebastian Schmidt-Lehr, Hamburg University, Institute for Technical and MacromolecularChemistry, Bundesstr. 45, 20146 Hamburg (Germany), e-mail: [email protected]

Key words

� Particle size, size measure-ment, online control, growth

� Fluidised bed granulation

Pharm. Ind. 69, Nr. 4, 478−484(2007)

Zusammenfassung

Online-Kontrolle der Partikelgröße wäh-rend einer Wirbelschichtgranulation /Untersuchung einer neuartigen Laser-sonde zur besseren Kontrolle des Parti-kelgrößenwachstums in der Wirbel-schichtgranulation

Die Kontrolle der Partikelgrößenvertei-lung während des Granulierprozessesführt zu gut verarbeitbaren Pressmassen.Eine Online-Methode zur schnellen Be-stimmung der Partikelgröße kann Zeitund Ressourcen sparen, indem sie pro-zessbegleitend die Qualität des Produktessicherstellt und die Möglichkeit eröffnet,rechtzeitig einzugreifen, sollten währenddes Prozesses Abweichungen auftreten.

Summary

Online-control of the Particle Size duringFluid-bed Granulation / Evaluation of anovel Laser probe for better control ofparticle size in fluid-bed granulation

Good control over the particle size dis-tribution during granulation is useful toobtain material that exhibits good com-pressability and hence good tabletingproperties. Time and resources can be sa-ved using an on-line method capable ofdetermining the particle size in real timethus ensuring the quality of the productand enabling the operator to react to de-viations during the manufacturing pro-

and active ingredient concentration − is the particle sizeas it influences many physical properties [1−3].

The median particle size x50 provides an indicationof the quality of the granulate − particularly its suitabi-lity for tabletting. Consequently the particle size is asignificant parameter for the control of granulation pro-cesses.

cess. Such a method based a novel laserprobe will be introduced. It will be dem-onstrated in this article that the granularsize up can be followed with high resolu-tion and in real time. Based on the re-sults obtained with the new probe it waspossible to establish a model describingthe correlation between the fluid-bedparameters like inlet air temperature, in-let air flow and spray rate and the finalparticle size in the granulation. With thismodel it is possible to calculate the para-meters settings necessary to obtain a tar-get particle size.

Eine solche Methode, basierend auf einerneuartigen Lasersonde, wird vorgestellt.Es wird gezeigt, dass die Verfolgung desPartikelaufbaus anhand der Partikel-größe mit sehr hoher zeitlicher Auflö-sung und Geschwindigkeit möglich ist.Basierend auf den mit der Sonde erhalte-nen Ergebnissen war es möglich, ein Mo-dell zu erstellen, das den Zusammen-hang zwischen Parametern des Wirbel-schichtprozesses wie Zulufttemperatur,Zuluftstrom und Sprührate der Granulier-flüssigkeit sowie der erzielten Partikel-größe im Granulat beschreibt. Mit die-sem Modell können die für das Erreicheneiner bestimmten Partikelgröße nötigenParametereinstellungen berechnet werden.

Pharm. Ind. 69, Nr. 4, 478−484 (2007) ECV · Editio Cantor Verlag, Aulendorf (Germany) Schmidt-Lehr et al. − Wirbelschichtgranulation 1

Wissenschaft und Technik: Originale

2. PATPAT is an initiative to develop and implement processanalytical technology [4−8). The basic idea behind thePAT initiative is for the pharmaceutical industry to com-pletely understand the processes used in the manufac-ture of drugs. Critical process variables are monitoredonline and the process is controlled in feed-back loopso the result is always a product conforming to specifi-cation. This enables the method of parametric releasewithout end product control. In contrast to the conven-tional validation strategy, which considers the success-ful production of three consecutive batches to be proofof a reproducible process, a PAT based approach maybe based on the continuous analysis of the process ena-bling the product to be released as soon as the processends. The release is dependent on compliance with thedefined process parameter limits. At the same time, newknowledge is generated about the process from the dataenabling the process to be continually optimised.

3. Particle size measurement with spatialfilter velocimetryThere are numerous methods for determining particlesize. However, very few meet the requirements deman-ded of an online measuring technique. Two methodshad been given particular consideration: NIR spectros-copy and new inline particle probes based on lasertechniques. As complicated chemometric models haveto be used in NIR methods and these often lack flexibi-lity, a laser probe from the Parsum Company (Chem-nitz, Germany) is used for this work [9].

The measurement principle is based on an extendedspatial filter which can convert light obscuration signalsfrom individual particles into size information for ana-lysis. In addition, the individual speeds and flight timesof the particles are measured by a fibre optic array. Atthe same time, the movement of the particles is projec-ted on the light collector, the spatial frequency filter(Fig. 1).

The fibre optic array is formed from a series of pho-todetectors. A particle passing these detectors producesa set of time-limited impulses: light obscuration data.Each photodetector produces an impulse whose lengthdepends on the blockage time, which is correlated tothe particle size, particle speed and flight path of theparticle through the measurement cell. Summarizingthe signals of the photodetectors in groups of the evenand uneven detector numbers and subsequently sub-tracting these two sums, yields over time a characteri-stic frequency, f0, for the analysed particle (Fig. 1). Theparticle speed, v, can be determined from this fre-quency:

ν = f0 · g

g is the spatial filter interval corresponding to the di-stance between two laser light barriers in the samegroup. If the particle speed, ν, is known then by analy-

Fibre optic spatial filter

Individual particle

Illumination

Vp – direction of movement

Fig. 1: Principle of the spatial filter to determine particle speed.

Optical pulse channel

Individual particle

Illumination

Vp – direction of movement

Fig. 2: Principle of a single optical channel to determine particleflight time.

sing one single additional channel (Fig. 2), the particlesize, x, can be determined as a chord length from thelength of the impulse, t:

x = ν · t − d

d is the diameter of the optical fibre.Due to the unknown flight path of the analysed parti-

cle, the chord length can be any line of intersectionthrough the 2D projection surface of the particle. Thesize statistics determined are, therefore, based on theparticle chord length. The measurement method is sui-table for particle sizes from 50 to 2500 µm.

The measurement cell itself is equipped with sap-phire windows kept free from fine dust or sticky parti-cles by a permanent purge air flow. The laser light re-quired for analysis is directed to the measurement cellby special fibre optics. The measurement volume illu-minated by laser light in this way is placed directly inthe particle flow.

Pharm. Ind. 69, Nr. 4, 478−484 (2007) ECV · Editio Cantor Verlag, Aulendorf (Germany)2 Schmidt-Lehr et al. − Wirbelschichtgranulation


By installing a disperser unit into the measurementcell, the probe can also be used in systems with a highparticle concentration. The disperser unit continuouslysupplies the measurement cell with an air flow of 10 to20 l/min, which firstly disperses the particles − i.e. di-lute to a measurable range − and secondly optimizesthe flight path into the centre of the measurement celland into the exact measuring direction. This enablesmeasurements to be taken even in the case of irregularparticle movement, e.g. as in the case of a fluidised bed.Well-directed dispersing makes it much easier to recordindividual particles. At the same time, the measuringconditions are strongly improved by adjusting the va-rious flight paths and flight speeds of the individualparticles to an optimized flight path for the measure-ment.

The individual particles are recorded at a measure-ment rate of up to several thousand particles per se-cond. The raw data is transferred from the probe to acomputer where the particle size is calculated. The re-sult is presented in the form of a particle size distribu-tion or a discrete particle size, e.g. x50. Different calcula-tion models such as q0 or q3 distribution can be obtai-ned. x50 indicates an average value for the particle sizeand means the 50th percentile or in other words: 50 %of the values are smaller. x10 (only 10 % of all particlesare smaller) or x90 (only 10 % are bigger) can also beindicated accordingly. The total number of graded par-ticles is permanently held in a circular buffer providinga sliding, constantly updated particle size distribution.In contrast to laser light scattering or the NIR method,no mathematical particle model is used as a basis, in-stead each particle is characterised immediately by me-ans of its chord length.

4. Subject under examinationThe granulation process examined in this article is flui-dised bed granulation. The experiments were perfor-med on a fluidised bed granulator from the Glatt Com-pany (Binzen, Germany) with a capacity of 5 kg. Laserlight scattering was chosen as reference method to becompared against particle size determination using theParsum probe due to its widespread use and its accep-tance as the standard method [10, 11].

5. Installing the probeIn a first set of experiments the general operational ca-pability of the probe was tested in the fluidised bed. Asa result the basic parameters could be fixed. A measu-ring interval of five seconds is required for online obser-vation. Furthermore, the internal buffer of the measu-ring instrument was adapted to the measuring intervalwith 5000 to 10 000 particles to ensure the values provi-ded were up to date.

In order to find the optimum measuring position forthe probe, tests were performed for the vertical installa-

tion height in the fluidised bed, for the horizontal im-mersion depth in the fluidised bed and for the angulardependence of the probe.

The influence of the immersion depth and adjust-ment angle were examined in two tests with a spraydried granulate which was largely stable in the fluid bedas far as particle size was concerned.

The installation height of the probe in the directionof the air flow depends on how high the minimum par-ticle concentration has to be for a representative me-asurement and how high the maximum particle con-centration can be so the probe is not overloaded. Thepossible variations for the vertical installation heightwere predetermined, in this case, by the number ofavailable installation ports.

The horizontal immersion depth was chosen so that,on the one hand, a relatively high particle concentra-tion on the edge of the fluid bed was avoided and, onthe other, direct contact of the probe with the granula-ting fluid sprayed on the fluidised bed was prevented.The measured results were consistent within these li-mits.

As the probe has a defined measuring direction, theangle of the probe can also be varied in relation to thedirection of the air flow in the fluidised bed. Adjustmentangle here means the rotation around the longitudinalaxis of the probe rod. In the tests for angle dependency,a strong dependency of the measured results was de-monstrated at angles over approx. 90°. For this reason,these large angles were avoided and the probe was al-ways operated at an adjustment angle of 0° relative tothe preferred direction of flow.

6. Test planThe fluidised bed granulation process is affected by se-veral factors and it is necessary to determine which ofthese have a significant influence on the process. Thefollowing parameters are examined: inlet air tempera-ture, inlet air flow and the spray rate of the granulationfluid. The formulation is kept the same for all tests sothat it was not an influencing factor. The particle sizemeasured by the probe is stipulated as the target size.

Using the Design-Expert software of Stat-Ease Com-pany (Minneapolis, USA), a D-optimal test plan is cre-ated for the above mentioned parameters, i.e. inlet airtemperature, inlet air flow and spray rate of the granula-ting fluid.

The test plan is composed of ten experiments to de-termine relationships, four experiments to test the mo-del and one experiment to document reproducibility −i.e. a total of 15 sets of parameters (Table 1). For thetest environment, the limiting ranges are defined: sprayrate: 30 to 50 g/min, air flow: 120 to 200 m3/h and tem-perature: 60 to 70 °C, within which all test points are lo-cated.



Table 1: Statistical test plan. CentEdge: test point at thecentre of an edge; PlaneCent: test point at the centre of aplane; Vertex: test point at a corner; Interior: test point atthe centre of the cubic test environment.

Random- Temper-SprayStandard Design Air flowised atureratesequence points (m3/h)(g/min)sequence (°C)

10 1 CentEdge 40 200 706 2 PlaneCent 50 160 658 3 Vertex 30 200 607 4 PlaneCent 40 160 60

12 5 Vertex 30 120 7015 6 Vertex 50 120 70

2 7 Vertex 30 120 601 8 Vertex 50 200 60

11 9 Interior 35 180 659 A CentEdge 30 160 703 B Vertex 50 120 60

13 C Vertex 30 200 7014 D Vertex 50 200 70

4 E Vertex 50 120 705 F PlaneCent 40 120 65

7. Materials and methodsIn the tests, a placebo mixture is granulated. The mix-ture consists of:

− 3200 g lactose monohydrate− 900 g maize starch− 600 g starch 1500− 50 g magnesium stearate

The granulating solution consists of:

− 250 g polyvinylpyrrolidon− 1312.5 g water

Taking into account a production factor of 1.25, 312.5 gPVP is slowly stirred and dissolved into 1640.6 g waterat approx. 700 rpm.

The fluidised bed granulator is loaded with exci-pients and prepared for granulation. Just before star-ting, the probe measurement record is started.

The interval between tests was every two minutes −after ten minutes the tests were performed every fiveminutes − the air flow, air temperature and the quantityof the already sprayed PVP solution are noted.

When the spray quantity planned for the test wasreached, the spraying was ended and the product wasdried until the product temperature had increased by0.5 °C. Immediately after this, samples are taken to me-asure particle size using the reference method and theproduct moisture is determined by means of a rodprobe.

Finally a lubricant (magnesium stearate) is added.The magnesium stearate is blended with the granulatefor a period of 45 seconds.

8. Results and discussionIn the tests, the system gave an unexpectedly detailedpicture of the granulation. Instead of the expected li-near growth of the particles over the total duration ofthe spray phrase, an initiation phase could be noted

Part

icle

siz

e (

µm

)

Normalised time

Fig. 3: Comparison between the expected course of granulation(blue) and the detected (black, red) I = Initiation phase; II = Phaseof particle size growth; III = Disagglomeration process. I and II:Spray phase; III: Drying phase.

and its length and course under test conditions wereindependent of the fluidised bed parameters (Fig. 3,Phase I). This was followed by the phase of particle sizegrowth which was heavily dependent on the fluidisedbed parameters (Fig. 3, Phase II). Finally, as a thirdphase after spraying ended, the drying phase was iden-tified, in which a granule disagglomeration process oc-curred (Fig. 3, Phase III).

Moreover, periodic fluctuations in the particle size(“waves”) were observed in the curves which could becorrelated with the periodic shaking of the fine dust fil-ters. Against initial considerations, it could be shownthat the shaking parameters had a pronounced effecton the granulation process by continuously extractingthe fine fraction from the fluidised bed and then perio-dically releasing this into the fluidised bed again.

As seen in Fig. 3, various particle sizes distributionscan be produced with the same substance simply byvarying the fluidised bed parameters. The analysis ofthe statistical test plan showed that the air flow, sprayrate of the granulating fluid and the temperature canbe used to control the particle size (x50) in a linear rela-tionship over a wide range (Fig. 4 and 5).

The model relationship found for the test granula-tion in the range tested is given by:

x50 = −26.1 + 3.0 · (spray rate in g/min) + 1.2 · (air flowin m3/h) − 0.8 · (temperature in °C)

The influence of the individual parameters on the targetsize (x50), therefore, differs significantly. The effects ofthe parameters obtained from the statistical test planprovide information on this. The spray rate and air flowwere found to have a great influence. The influence ofthe temperature is, in contrast, rather small and its si-gnificance is also much less. This may possibly be dueto the very small temperature range examined (rangingonly from 60 to 70 °C). Further tests are required to de-monstrate the validity of a linear relationship, especiallybeyond the current set limits of the test environment



X1 = A: spray rateX2 = C: temperature

Actual FactorB: air flow = 200.00

Fig. 5: Parsum x50 air flow 200 m3/h.

(spray rate of 30 to 50 g/min and air flow of 120 to 200m3/h).

9. Comparison with laser diffractiondataTo compare the values measured by the probe with va-lues measured by laser diffraction, the fluidised bed wasbriefly switched off during granulation a total of threetimes at 1300, 2000 and 2700 seconds to take samples.In addition, the finished product was examined andcompared with the last value from the granulation re-cord of the probe.

A tendential consistency with the values measuredby laser light scattering can be observed (Fig. 6). The 1st

sample at 1300 seconds could not, however, be exami-ned as agglomerates had formed which could not bedisintegrated by the disperser unit of the laser diffracto-meter. The 2nd and 3rd samples examined by laser lightscattering are approx. 8 % over the value measured bythe probe. The last sample examined demonstrates with

X1 = A: spray rateX2 = C: temperature

Actual FactorB: air flow = 120.00

Fig. 4: Parsum x50 air flow 120 m3/h. Time [s]

Pa

rtic

le s

ize

[µ

m]

Fig. 6: Comparison of laser diffraction measurements (Helos) andParsum x50.

a greater negative deviation of more than 10 %. It is as-sumed that this is reasoned in the composition of thesample, as it is inhomogeneous, The reason is that afterthe spray phase ends, there is a short pause in which50 g magnesium stearate is added to the fluidised bedcontainer. Then the fluidised bed is switched on againfor 45 seconds. This time is too short for the probe toproduce a stable measurement (Fig. 6) as the circularbuffer cannot be completely filled. Therefore, the finis-hed granulate including the magnesium stearate frac-tion can be analysed by laser diffraction without anyproblems whereas the probe gives the last measure-ment for analysis as the value at the end of granulationwithout the addition of magnesium stearate.

10. Further testsIn addition to the statistical test plan, some further testswere performed to respond to specific questions con-cerning probe use. Firstly, these include testing repro-ducibility and the use of the probe in a second fluidisedbed granulator. Moreover, tests were performed to inc-rease understanding of the process and to examine theprobe’s reaction to failures and malfunctions during thegranulation process.

11. ReproducibilityAt the same time as the tests to examine the reproduci-bility of the measurement results, the reliability of theprobe was ensured during the granulation of a mixturecontaining active ingredients. Placebo mixtures are ge-nerally easy to granulate. However, mixtures containingactive ingredients are often poorly suited to granulationand can only be granulated with a great deal of expe-rience due to the high proportion of active ingredients.

For the test, a formulation comprising 40 % of a mic-ronised active ingredient was granulated twice under



identical conditions. The results of both tests show highsimilarity. The difference between the measured PSDcurves is on average 5 to 8 µm (Fig. 7). In the case ofx10, the difference is a maximum of 10 %, in the case ofx90, only a maximum of 3 %, referring in each case tothe smallest value assumed by x10 and x90 in the courseof the tests. It can, therefore, be deduced that the me-asurement results are reproducible.

12. TransferabilityTo examine transferability to other fluidised bed granu-lators, in addition to the tests on WSG 5, four tests wereperformed on a WSG 15. As with WSG 5, this is a fluidi-sed bed granulator from Glatt featuring a capacity of 15kg. As the first two tests were required to establish theminimum immersion depth − 10 instead of 6 cm withWSG 5 − the next two tests could record the granulationprocess. The different stages of granulation can be cle-arly seen (Fig. 8).

At the start, an air flow of 400 m3/h is used. Here theparticle size growth is 9.7 µm/min in the range from 50to 350 seconds (Phase I). When the air flow was chan-ged to 500 m3/h at time point 450 seconds, the particlesize growth decreased to 0.3 µm/min in the range from600 to 1200 seconds (Phase II). For this reason, at time-point 1250 seconds, the spray rate was adjusted from140 to 145 g/min. The particle size growth then changedto 1.3 µm/min in the range from 1300 to 2800 seconds(Phase III). After 2900 seconds, spraying ended. Subse-quent drying in the range from 2900 to 3000 secondsled to a partial disagglomeration and a resultant reduc-tion in the average particle size by --5.5 µm/min (PhaseIV). Any change to an influencing factor is, therefore,directly reflected in the granulation process shown bythe probe. Consequently, the transfer of the methodfrom WSG 5 to WSG 15 was successful.

Pa

rtic

le s

ize

[µ

m]

Time [s]

Fig. 7: Comparison of two identical tests on particle sizes x10, x25,x50, x75and x90 (Parsum).

13. Reactions to anomalies in the processDuring another test, several process failures and systemmalfunctions were simulated during granulation to testtheir influence on the measurement (Fig. 9). After star-ting the granulation under standard conditions, at 750seconds, the spray rate was changed. Subsequently anincrease in the particle growth rate could clearly beseen. The particle size growth rate increased from 3.6µm/min to 12.9 µm/min. After 1335 seconds, the ex-haust air filter failed. However, within the next 160 se-conds, the fine fraction was still being continuously ta-ken from the fluidised bed and collected in the filterbags. After 160 seconds, at 1495 seconds, the exhaustair filter restarted again and shook the fine fraction backinto the fluidised bed. Whilst shaking was interrupted,the growth of the particles in the fluidised bed accelera-ted to 21.6 µm/min, due to the continuous withdrawalof the fine fraction. By restarting the shaking process,within 30 seconds, the complete fine fraction collected

Time [s]

Part

icle

siz

e [

µm

]

Fig. 8: Test on the WSG 15 with four distinguishable stages ofgranulation (Phase I to IV).

Part

icle

siz

e [

µm

]

Time [s]

Change in spray rate

Failure of exhaust air filter, 1335th second

Exhaust air filter restarted, 1495th second

Fig. 9: Particle size development (x50) with probe reactions tofaults in the granulation process.



in the filters over the last 160 seconds was returned tothe fluidised bed leading to a strong reduction in theaverage particle size which was in clear contrast to thefluctuations in the granulation process to that point.

However, the failure of the exhaust air filters revealedadditional aspects. Both before and after the failure, thefluctuations in the granulation process are much moreevident than during the 160-second pause. This provesthe fluctuations to be caused by the filters shaking.These fluctuations can be observed in all tests and al-ways with an interval of 20 seconds, as this is the defaultinterval for the shaking sequence.

Fig. 10 shows an enlarged section from the develop-ment of particle size during granulation.

14. ConclusionWithin the scope of this work, a detailed insight intothe granulation process could be provided by the me-asuring system into particle size growth during fluidisedbed granulation. By performing the tests, initially theoptimum installation parameters could be determinedand the software settings could be adjusted. The firstanalyses of the recorded granulation processes provideda conclusive picture. A surprising observation was thatthe shaking intervals led to an oscillation in the courseof particle growth. Just as unexpected was the initial lagphase at the start of granulation, during which, in spiteof spraying binder solution, no particle size growthcould be recorded.

Using a statistically based design of experiment ap-proach containing the variation of the factors sprayrate, temperature and air flow, the granulation beha-viour could be examined closely, using the probe undervarious conditions. The model derived from the testsshowed statistical significance and made precise pre-dictions about the properties of granulates to be produ-ced.

In further tests, both the transferability of the measu-ring method to another unit and the reproducibility ofthe measurement results could be ensured. The compa-rison of the probe data with the results from laser lightscattering reference method was successful.

In conclusion, the probe has proven to be a suitableinstrument for the online control of particle size. Addi-tionally, it features easy handling − both with regard toinstallation in the unit and software. Moreover, it is ro-bust, easy to clean and shows demonstrably no in-fluence on the process.

Part

icle

siz

e [µ

m]

Time [s]

Fig. 10: Influence of the shake timing on the particle sizes (x10,x25, x50, x75and x90).

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Online Control of Particle Size during Fluidised Bed ... · Chemistry, Bundesstr. 45, 20146 Hamburg (Germany), e-mail: [email protected] Key words Particle