In-line measurement of layer thickness, agglomerate ...

In-line measurement of layerthickness, agglomerate fractionand spray drying during pelletcoating in the fluidized bedUse of an in-line particle probe as PAT instrument for real-time monitoring

Dieter Petrak1, Günter Eckardt2, Stefan Dietrich2, Michael Köhler2, Dimitri Wiegel3,Bertram Wolf3, Florian Priese4, Michael Jacob5

1Chemnitz University of Technology, Chemnitz, 2Parsum GmbH, Chemnitz, 3An-halt University of Applied Sciences, Bernburg, 4AEROPHARM GmbH, Rudolstadt,5Glatt Ingenieurtechnik GmbH, Weimar

Correspondence: Stefan Dietrich, Parsum GmbH, Reichenhainer Str. 34–36, 09126 Chem-nitz, Germany; email: [email protected]

n ABSTRACT

The layer thickness in the fluidized bed pellet coating processrepresents an important process variable for the plantoperator. The measurement in real time may be applied tomonitor the influence of spray drying, layer thickness growthduring the process time and to determine the end of theprocess. In-line measurements of the film thickness by aParsum particle probe IPP 70-S are presented in this work.Directions for use of percentiles x50,3 and x90,0 to thedetermination of film thickness are given by application ofmodel calculations and coating runs in fluidized bed Wurstercoaters GPCG 1.1 and GF3. Undesirable generation ofagglomerates in the coating process becomes visible by meansof the cumulative distribution by volume Q3(x) and thedensity distribution by volume q3(x). The formation of fineparticles by spray drying and abrasion is visible by means ofthe percentile x10,0.

n ZUSAMMENFASSUNG

Inline-Messung von Schichtdicke, Agglomeratanteil undSprühtrocknung beim Pelletcoating in der Wirbelschicht:Einsatz einer Inline-Partikelsonde als PAT-Instrumentzur Echtzeit-ÜberwachungDie Schichtdicke im Wirbelschicht-Pellet-Coatingprozess stelltfür den Anlagenbediener eine wichtige Prozessgröße dar.Anhand ihrer Messung in Echtzeit kann der Einfluss desProzessparameters Sprührate während des Coatingprozessesüberwacht, das Wachstum der Schichtdicke verfolgt und dasEnde des Coatingprozesses festgestellt werden. Im vorliegen-den Beitrag werden Inline-Messungen der Schichtdicke miteiner Parsum-Partikelsonde IPP 70-S vorgestellt. Ausgehendvon Modellrechnungen werden anhand von Coatingversuchenin den Wirbelschichtapparaten GPCG 1.1 bzw. GF3 mitWurster-Einsatz Hinweise zur Verwendung der Feinheits-merkmale x50,3 und x90,0 bei der Schichtdickenbestimmungangegeben. Unerwünschte Agglomeratbildung während derCoatingprozesse wird mit Volumensummen- und Dichtever-teilungen Q3(x), q3(x) dargestellt ebenso wie die Entstehungvon Feinkorn infolge von Sprühtrocknung und Abrieb mitdem Feinheitsmerkmal x10,0.

1. Introduction

With the Process Analytical Technology (PAT) Initiativeof the United States FDA [1] and the Quality by Design(QbD) approach of the ICH [2, 3], new process applica-tions are increasingly being integrated into pharmaceut-ical manufacturing processes, e.g. drug layering pro-cesses in coating. The coating of pellets is an importantpharmaceutical-technological process in which the

n KEY WORDS

• Fluidized bed pellet coat-ing

• Wurster coating• In-line particle probe• Layer thickness• Agglomeration• Spray drying• PAT• Particle measurement

Pharm. Ind. 80, Nr. 2, 262–270 (2018)

English reprint of the German original publication

Wissenschaft und Technik

Originale

Pharm. Ind. 80, Nr. 2, 262–270 (2018)© ECV • Editio Cantor Verlag, Aulendorf (Germany) Petrak et al. • In-line measurement 1

Zur Verwendung mit freundlicher Genehm

igung des Verlages / For use with permission of the publisher

product properties can be specifically adjusted by modi-fying the pellet surface. During coating in the fluidizedbed and in the blasting bed as a batch or continuous sys-tem, the coating fluid is sprayed onto the pellets anddried off. For the system operator, the coating thicknessin the coating process is an important parameter forprocess control. Measuring the coating thickness in realtime makes it possible to monitor the influence of theprocess parameter spray rate during the coating processand detect malfunctions (e.g. irregularly nozzle spraying,spray rate too high, nozzle failure) in time. The dynamicmeasurement of the coating thickness allows the systemoperator to finish the coating process when the desiredcoating thickness is achieved.

Different PAT instruments have been investigatedwith respect to their suitability for determining the aver-age film layer thickness and the uniformity of the filmapplication. These include the sophisticated Raman andNIR spectroscopy [4] as well as the less complex dy-namic image analysis and the fibre-optical spatial filter-ing method. For a fluidized bed pellet coating process,Folttmann et al. [6] determined the pellet size from in-line measurement with an in-line particle probe IPP 70-S(Parsum GmbH, Chemnitz). For comparison, at-linemeasurement of the minimum chord length (xcmin) wasmade with the dynamic image analysis system Camsi-zer®XT (Retsch Technology GmbH, Haan). The layerthickness was determined from the differences of thefineness characteristics x50,3 or xcmin,50,3 respectively. Onaverage, absolute layer thickness deviations of 4 µm (ap-prox. 12 %) were found between the two measuringmethods [6]. Investigations by Hudovornik et al. [7] re-sulted in a satisfactory correspondence of layer thick-nesses from measurements with the in-line particleprobe and a NIR probe.

During the coating of the pellets in the fluidized bedwith functional polymers, if the moisture content is toohigh, larger agglomerates can be formed during the pro-cess because of the stickiness of the polymer coating so-lution in particular; this leads to defects in the layer aswell as undesirable changes in the release behaviour ofthe active ingredients. As it is often not possible to com-pletely prevent the formation of agglomerates, it isnecessary to specify the agglomerate content in real timeduring the running process. By change of the processstate variables, the coating process can be adjusted insuch a way that only small tolerable agglomerate frac-tions occur. During the process, spray drying occurs be-cause of excessively high gas temperature and spraypressure. The fine dust resulting from the dried atom-ised coating fluid can lead to clogging of the filters, re-sulting in reduced cleaning intervals and, in extremecases, process interruption. In functional coating, someof the fine dust is integrated into the film layer leadingto altered porosity and impaired release behaviour. Thereal time detection of fine grains with the aid of a suit-

able PAT instrument is necessary in order to be able toinfluence the course of the process in acceptable time.

The aim of this work was to investigate the PAT in-strument fibre-optical spatial filter with regard to thesuitability of different fineness characteristics for deter-mining the layer thickness and for determining the ag-glomerate and fines fractions during pellet fluidized bedcoating. The use of the in-line particle probe as a PATinstrument allows the particle size to be measured sim-ultaneously with the process in real time. The measuringprinciple consists of a fibre-optical spatial filter for mea-suring the particle velocity and a fibre-optical spot scan-ning for measuring the particle size [8, 9]. In spot scan-ning, a chord length is determined as a measure of theparticle size. An overview of the applications of the spa-tial filter technology is presented in Dietrich and Petrak[10].

2. Materials and Methods

The aim of the model calculations is to find suitable fineness par-ameters for determining the layer thickness with as little uncertaintyas possible. For this purpose, spherical pellets with a modal particlesize distribution are assumed in approximation to real coating pro-cesses. The pellets have the same layer thickness at the end of the coat-ing process regardless of the pellet size and agglomeration is ignored.

With the spot scanning in the vertical direction, the result is achord for which the length x1 depends on the random local position ofthe pellet and the spatially fixed point sensor, where y1 is the verticaldistance of the chord to a line parallel to the chord through the spheri-cal centre.

The chord length distribution at a random pellet position can thenbe calculated from

P indicates the probability that the chord length according to fig. 1lies between the chord lengths x1 and x2 in the case of a random cut.

Figure 1: Circle with radius rand two chord lengths x1 andx2 in the scanning direction(source of all figures: theauthors).


Originale

2 Petrak et al. • In-line measurementPharm. Ind. 80, Nr. 2, 262–270 (2018)

© ECV • Editio Cantor Verlag, Aulendorf (Germany)

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The number distributions for the density q0 and the sum Q0 areobtained from P for given values of x1 and x2, and the volume distribu-tions q3 and Q3 are obtained by conversion.

First, the corresponding start chord length distribution in the formq0(xm), Q0(xo), q3(xm) and Q3(xo) is calculated for the present pellet startdistribution using equation (2) (xm = interval centre, xo = interval uppersize). The same procedure is performed at the end of the coating pro-cess. To avoid the time-consuming process of comparing the start andend distribution of chord lengths, variables derived from the cumula-tive distributions, e.g. the fineness characteristics x50,0, x90,0, x50,3 andx90,3, are determined. These values are used to determine the coatingthickness and thus to control the coating process and the characterisa-tion of product quality. Figure 2 shows an example for the coating of apellet batch (spherical fraction 250–450 µm) with modal start distribu-tion. The uniform layer thickness is 10 µm.

The calculation of the layer thickness from the half differences ofthe characteristic values from the cumulative distributions Q0(xo) andQ3(xo) yields acceptable results with low uncertainty for the character-istic values x90,0, x50,3 and x90,3 (Table 1). Higher uncertainties arise forsmall fineness parameters.

For relatively narrow pellet size distributions found in standardcommercial pellet grades such as Cellets® (made of microcrystallinecellulose) and homogeneous coating processes, the fineness param-

eters x90,0 and x90,3 with an uncertainty < 1 % can be used for determin-ing the layer thickness.

The aim of further investigations was to check the results of themodel calculations using real coating processes, whereby the use ofdifferent fineness characteristics as well as the influence of agglomer-ation and fine grain formation from spray drying and abrasion wereclarified.

3. Results and Discussion

The coating tests were carried out in a GPCG 1.1 fluid-ized bed apparatus (Glatt GmbH, Binzen) with Wursterinsert. Cellets®200 (median 300 µm) were coated with anaqueous solution of sodium benzoate (30 %m/m) andpolyvinylpyrrolidone (1.5 %m/m). An IPP 70-S particleprobe with disperser D23 was used for the in-line meas-urement of particle size ( fig. 3). The measuring point ofthe probe is located in the process vessel above theproduct layer in the downbed zone.

0

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a) b)Figure 2: a) modal start distribution of the pellets, b) calculated chord length distributions Q0(xo) of the start distribution (blue line)and the coated start distribution (red line) at the end of the process.

n Table 1

Uncertainty of the layer thickness determination from thecharacteristic values x50,0, x90,0, x50,3 and x90,3 of the chordcumulative distributions Q0 and Q3 for a modal start distribution ofthe pellets.

Uncertainty of thelayer thicknessfrom x50,0 [%]

Uncertainty of thelayer thickness

from x90,0[%]

Uncertainty of thelayer thickness from

x50,3[%]

Uncertainty from thelayer thickness from

x90,3[%]

10.9 1.8 5.3 3.7




The relationship between spray rate ( fig. 4, black line),fineness characteristics, layer thickness, and processtime was investigated for the coating of Cellets®200 withsodium benzoate/polyvinylpyrrolidone using the IPP 70-S in-line particle probe. After 10 min of process time( fig. 4), the spraying phase was started and after 30 minthe spray rate was gradually increased and ended after50 min. With constant spray rate, the fineness character-istics increase continuously (spray phase 10–30 min pro-cess time). With an increase in the spray rate, super-hu-midification and increasing agglomerate formation oc-cur in the process chamber; in particular, x50,3 and x90,3

increase disproportionately. A corresponding increase isobserved for the layer thickness. At the end of the pro-cess the layer thickness was determined (45 µm) fromthe xcmin,50,3 values with the Camsizer. Correspondencewith the result of the particle probe (48 µm) is foundhere.

The time interval of the evaluated measuring pointswas selected such that the circular buffer (2000) wascompletely rewritten in each case. For process times be-tween 0 and 40 min, the respective layer thicknesses aswell as the agglomerate and fines fractions were deter-mined. In the density distributions by volume, the heightof the product peak at 300 µm decreases with increasingprocess time ( fig. 5). Peaks above 600 µm also occur in-dicating agglomeration.

The total cumulative distribution by volume ( fig. 6)remains practically unchanged for particle size below200 µm. With increasing process time, it is shifted tohigher particle size intervals because of agglomeration.

According to the authors’ theoretical investigationsfor a polydisperse modal particle size distribution(spheres), the coating thickness can be determined fromhalf the difference of the investigated fineness character-istics of final and starting cumulative distribution withaccuracy of 2–10 %. The fineness characteristics deter-mined tend to produce an increase in layer thicknesswith increasing process time ( fig. 7), whereas the cumu-lative distribution by volume (curve x90,3) increasingly

Figure 3: GPCG 1.1 with Wurster insert and in-line particleprobe IPP 70-S.

Figure 4 Fineness characteristics x10,3, x50,3, and x90,3, spray rate, and layer thickness versus process time forcoating of Cellets200 in laboratory apparatus GPCG 1.1, coating with aqueous solution of sodium benzoate(30 %) and polyvinyl pyrrolidone (1.5 %), spray start after 10 min, incremental increase in spray rate between20 and 40 min spray time.


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Figure 5: Density distribution by volume q3(xm) with increasing process times.

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Figure 6: Cumulative distribution by volume Q3(xo) with increasing process times.




produces a layer thickness that appears larger than itreally is due to the strong weighting of single large parti-cles (agglomerates) after 30 min process time. The values

of the layer thickness using x90,0 and x50,3 correspond re-latively well.

The fineness characteristic x10,0 is significantly re-duced after the start of the spray phase ( fig. 8, from aprocess time of 15 min) indicating the formation of finegrains from spray drying. The induced increase in sprayrate after 30 min counteracts spray drying with the in-creased supply of liquid, whereby x10,0 increases again.This trend also affects the fineness characteristic x50,0,albeit to a lesser extent. The formation of fines at pro-

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Mean from x90,0+x50,3

Figure 7: Curve of the layer thickness s as a function of theprocess time (parameter: fineness characteristics).

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Process time

Figure 8: Fineness characteristic x10,0 versus process time.

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Figure 9: Density distribution by number q0 (xm) with increasing process times.


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cess times of 23.5 min and 31.5 min can also be clearlyseen in the density distribution by number q0 ( fig. 9, in-crease in the quantity proportions for pellets below100 µm), while the fines below 100 µm in the density dis-tribution by volume q3 in fig. 5 become rather small inquantity because of the conversion. Another characteris-tic for the formation of fines is the increase in the pelletrate, which represents the number of pellets measuredper unit of time.

The formation of agglomerates becomes visible by asignificant increase of the x50,3 fineness characteristicagainst the process time [11]. It makes sense to usethe cumulative distributions by volume when deter-mining the mass fraction of agglomerates. It can be as-sumed that the agglomerate fraction will only becomeeffective starting from a certain pellet size because ofthe volume fractions. This threshold value should bedetermined by considering the respective layer thick-

Agg

lom

erat

e m

ass

frac

tion

Process timeFigure 10 Agglomerate mass fraction versus process time,experiment fig. 4.

Figure 11: Fluid bed unit GF3 with Wurster insert and particleprobe IPP 70-S.

Figure 12: Fineness characteristics, spray rates and layer thickness versus process time for coating Cellets® 1000 with sodiumbenzoate solution (25%) in the GF3 fluidized bed apparatus.




ness and the form of the density distribution by vol-ume. With the beginning of the spraying phase after10 min, few agglomerates are formed which are disinte-grated soon. A clear formation of agglomerates startsafter a process time of 25 min with the increase of thespray rate as provoked process disturbance in the ex-periment ( fig. 4–6). From the position of the median ofthe pellet size distribution at 300 µm and the positionof the agglomeration peaks at 600–800 µm and1,000 µm in the density distribution by volume ( fig. 5),it becomes clear that as the process time progresses,the coated pellets predominantly combine into doubleand triple agglomerates.

The agglomerate mass fraction shown as a percent-age in fig. 10 can be determined from the associatedtotal cumulative distribution by volume ( fig. 6).

Another example for in-line layer thickness measure-ment concerns batch processes for coating in a fluidizedbed apparatus GF3 (Glatt Ingenieurtechnik GmbH, Wei-mar; fig. 11). Cellets®1000 were coated with an aqueoussolution of sodium benzoate (25 %). All process para-meters were kept constant. The measuring point of theprobe was again located in the process vessel in thedownbed zone. The relation between spray rate, finenesscharacteristics and layer thickness and the process timeis shown in fig. 12. With the end of the spraying phaseand the beginning of drying, the growth of the layerthickness comes to a standstill. At the end of the pro-cess, for comparison, the xcmin,50,3 value was measuredwith the Camsizer. It agrees well with the x50,3 value ofthe in-line measurement (340 µm).

Using the IPP 70-S particle probe installed in-line as aPAT instrument for a pellet coating process made it pos-sible to achieve a more uniform layer thickness thanwith gravimetric adjustment and to avoid inter-batchfluctuations.

Conclusion

The inline particle probe IPP 70/80 can be successfullyused as a PAT instrument for in-line measurement oflayer thickness as well as agglomerate and spray dryingformation during pellet coating in the fluidized bed. Themonitoring and control of the coating process madepossible by the probe leads to a significant improvementin the quality of pharmaceutical products as well as anincrease in the effectiveness of the processes.

n LITERATURE[1] FDA. Guidance for industry: PAT – A framework for innovative

pharmaceutical development, manufacturing and quality assur-ance, 2004.

[2] ICH. Guidance for industry – Pharmaceutical development (Q8),2005.

[3] ICH. Guidance for industry – Quality risk management (Q9),2005.

[4] Wirges M, Pein M, Knop K, Kleinebudde P, Boeggering A, FunkeA, et al. Raman vs. NIR – Echtzeit-Überwachung von ProzessenzumWirkstoffüberzug auf Tabletten in der pharmazeutischenIndustrie, TechnoPharm. 2013 Apr;(3):98–107.

[5] Plitzko M, Dietrich S. Optimale Prozessführung im Wurster-Coat-ing, CAV Chemie, Anlagen+Verfahren. 2010 Mai;5:16–18.

[6] Folttmann F, Knop K, Kleinebudde P, Pein M. In-line spatialfiltering velocimetry for particle size and film thickness deter-mination in fluidized-bed pellet coating processes, Eur. J. Pharm.Biopharm. 2014 Nov;88(3):931–938.

[7] Hudovornik G, Korasa K, Vrečer F. A study on the applicability ofin-line measurements in the monitoring of the pellet coating pro-cess, Eur. J. Pharm. Sci. 2015 Jul 30;75:160–168.

[8] Stöckel P, Dietrich S, Petrak D. Inline Partikelmessung in der Wir-belschicht, Pharm. Ind. 2013 Nov;75(11):1824–1832.

[9] Petrak D. Simultaneous Measurement of Particle Size and Par-ticle Velocity by the Spatial Filtering Technique, Particle & Par-ticle Systems Characterization, 2002 Dec;19(6):391–400.

[10] Dietrich S, Petrak D. In-Line Particle Size Characterization ofMultiparticulate Systems. In: Rajabi-Siahboomi AR, editor. Multi-particulate Drug Delivery, Formulation, Processing and Manufac-turing. New York: Springer-Verlag; 2017. p. 301–332.

[11] Wiegel D, Eckardt G, Priese F, Wolf B. In-line particle size meas-urement and agglomeration detection of pellet fluidized bedcoating by Spatial Filter Velocimetry, Powder Technol. 2016Nov;301:261–267.


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