0

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20

30

40

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1.5 3.0 5.0 1.5 3.0 5.0 1.5 3.0 5.0

PVP K25 PVP K90 PVA-PEG

Binder / binder content [%]

Fine

/ fr

iabi

lity

[%]

Fine Friability

Figure 6: Fines and friability after 15 minutes testing time as function of polymer content and type of binder

0.0

0.2

0.4

0.6

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1 5 3 0 5.0 1.5 3.0 5.0 1.5 3.0 5.0

PVP K25 PVP K90 PVA-PEG

Polymer / polymer content [%]Pa

rtic

le s

ize

dist

ribut

ion

[-]

<125µm 125-355µm >355µm

. .

Figure 7: Classifi ed particle size distribution as function of polymer content and type of binder

The amount of binder infl uenced the hardness of the agglomerates as well as the tensile strength of the tablets. In this investigation, it could be shown that higher binder contents led to harder tablets, whereas this effect was more pronounced for PVA-PEG (Figure 8).

0

2

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8

1 5 3 0 5 0 1 5 3 0 5 0 1 5 3 5 0

PVP K25 PVP K90 PVA-PEG

Tens

ile s

tren

gth

[N/m

m²]

. . . . . . . .0 .

Figure 8: Tensile strength of tablets

ConclusionPVP K90 was found to be the strongest binder in the test, es-pecially when used in high concentrations such as 5 %. Yet, depending on the application, the high viscosity of the poly-mer solutions could limit its use.PVA-PEG graft copolymer was found to be an interesting al-ternative, because it offered a moderate viscosity. The result-ing granulation process was very robust leading to constant particle size distributions and strong agglomerates inde-pendent of the amount of binder used. These granules result-ed in tablets yielding very high hardness.The peroxide free PVA-PEG copolymer is an effi cient binder combining low viscosity of the polymer solution and strength of the fi nal agglomerates which in turn led to high tablets hardness.

References[1] Kolter, K.; Binding properties of the new polymer Kollicoat® IR;

AAPS Annual Meeting and Exposition; Nov. 10–14, 2002; Toronto, Canada

[2] Bühler, V.; Kollidon® Polyvinylpyrrolidone excipients for the phar-maceutical industry; 9th edition; 2008; BASF SE, Ludwigshafen, Germany

[3] Agnese, T.; Mittwollen, J.-P.; Kolter, K.; Herting, M. G.; An Innova-tive Method to Determine the Strength of Granules; AAPS An-nual Meeting and Exposition; Nov. 16–20, 2008; Atlanta, Georgia, U.S.A.

PurposePVA-PEG graft copolymer is originally intended for instant release fi lm coating applications. However, the polymer offers excellent wet bind-ing properties as well. Since this synthetic polymer is peroxide-free, it can be considered as binder for actives being vulnerable to oxidation [1].To evaluate the wet granulation properties of PVA-PEG, the fi ndings were compared to those of polyvinylpyrrolidone (PVP) which can be considered as standard binding agent. Different grades are available, varying in molecular weight, viscosity and K-value respectively. Typi-cal wet binders are PVP K25, K30 and K90. With regard to most of their properties, K25 and K30 were found to be almost equal, whereas K90 differs distinctively in regard to binding capabilities and viscosity of its aqueous solutions [2].The aim of this work was to compare the wet binding properties of PVA-PEG graft copolymer and the PVP grades K25 and K90 in a high shear granulation process.

Materials and MethodsMaterialsAs wet binders, the PVP grades K25 (Kollidon® 25), K90 (Kollidon® 90F) and PVA-PEG graft copolymer (Kollicoat® IR) were tested. All three products are supplied by BASF SE, Ludwigshafen, Germany. As fi lling material, a special lactose grade for wet granulation (GranuLac® 200, Molkerei Meggle GmbH & Co. KG, Wasserburg, Germany) was used.

MethodsThe granulation process was performed according to the schema shown in Table 1.

Batch sizeImpeller speedChopper speedProcess timeScreening

Drying time (fl uid bed)

400 g200 rpm2,200 rpm15 min1.6 mm (wet)0.8 mm (dry)30 min

Table 1: Schema of the trial set-up in high shear granulator

In all trials, the binders were applied as aqueous solutions, whereas the amount of polymer dissolved in 50 g of water was chosen to lead to a fi nal binder content of 1.5, 3.0 or 5.0 % in the resulting granules. Of all granules, particle size distribution and friability were determined. All granules were compressed into tablets applying a compression force of 15 kN.

ViscosityIn order to test the rheological investigations on dynamic viscosity, the Thermo Scientifi c HAAKE RotoVisco 1 rotational rheometer (Thermo Fisher Scientifi c, Karlsruhe, Germany) with liquid temperature control for concentric cylinder measuring geometries was used.

GranulationAs high shear granulator, the P1-6 (Diosna GmbH, Osnabrück, Ger-many) assembled with 2 L product bowl was used (Table 1).

Particle size distributionThe test was performed with a sieve tower Retsch AS 200 (Retsch GmbH, Haan, Germany) by using sieves in the range of 38–500 µm (according to Ph. Eur.). The results were categorised into three differ-ent particle size classes: coarse (> 355 µm), mean (125–355 µm) and fi ne (< 125 µm) particles.

FriabilityAn air jet sieve LPS 200 (Rhewum GmbH, Remscheid, Germany) as-sembled with a 125 µm sieve was used to determine both residual fi nes (remaining un-agglomerated particles) and friability of the gran-ules [3].

CompressionThe single punch press XP 1 (Korsch GmbH, Berlin, Germany) equipped with a set of fl at punches (diameter 8 mm) was used for compression.

Tensile strengthThe crushing force of the tablets (n = 20) was determined by using a multi-tester HT-TMB-CI-12 FS (Kraemer Elektronik GmbH, Darmstadt, Germany). Based on these results, tensile strength was calculated ac-cording to equation given in Figure 1.

Figure 1: �: tensile strength [N/mm²]; Fc: crushing force [N]; h: tablet height [mm]; d: diameter [mm]

� =2 · Fc

� · h · d

Results and DiscussionViscosity of the polymer solution plays a decisive role in high shear wet granulation processes, since it is responsible for the time needed to incorporate the binder into the powder components. Additionally, the way of administering a binder solution is also determined by vis-cosity.The dynamic viscosity of the aqueous polymer solutions showed the typical dependency on polymer content (Figure 2). As a consequence of a difference in molecular weight, PVP K90 resulted in much higher viscosity than PVP K25. The values of PVA-PEG were between those of both PVP grades.

Comparing the Wet Granulation Properties of PVA-PEG Graft Copolymer and different PVP Grades in High Shear Granulation Processes using various Binder ConcentrationsT. Agnese1, T. Cech1, V. Geiselhart2

1 European Pharma Application Lab, E-mail: thorsten.cech@basf.com, BASF SE, 67056 Ludwigshafen, Germany 2 Pharma Ingredients & Services Europe, BASF SE, 67056 Ludwigshafen, Germany

1.0E+00

1.0E+01

1.0E+02

1.0E+03

1.0E+04

1.0E+05

0 5 10 15 20 25 30 35

Polymer concentration [%]

Log.

dyn

amic

vis

cosi

ty [m

Pas]

PVP K25 PVP K90 PVA-PEG copolymer

Figure 2: Dynamic viscosity of aqueous polymer solutions at 25 °C as function of polymer concentration

The visual appearance of the fi nal granules was similar for the different binders (Figure 3 – Figure 5).

Figure 3: SEM picture of lactose agglomerates, using PVP K25 as binder

Figure 4: SEM picture of lactose agglomerates, using PVP K90 as binder

Figure 5: SEM picture of lactose agglomerates, using PVA-PEG as binder

Strength of the particles is one of the most important parameters, in regard to the quality of an agglomerated product. Friability data indicate that the strength did clearly depend on the binder content. In general, the lowest friability values could be found for those granules holding binder contents of 5 % (Figure 6). For lower binder contents such as 1.5 and 3.0 %, PVA-PEG gave the best results. The effect of binder content on fi nes is markedly low (blue bars). Almost every trial resulted in un-agglomerated particles with a quantity of 10 to 15 %.

The same result in regard to fi nes could be seen in the particle size distribution, where almost the same amount of un-agglomerated par-ticles could be found for all granules tested (Figure 7). Interestingly, for PVA-PEG the fraction of mean and coarse particles was quite inde-pendent from the amount of applied binder. This leads to the assump-tion that the process should be quite robust.

2nd Conference Innovation in Drug Delivery; October 3–6, 2010;Aix-en-Provence, France; G-EMP/MD302

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