PurposePVA-PEG graft copolymer is originally intended for instant release fi lm coating applications. However, the polymer offers excellent wet binding 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 polyvinyl-pyrrolidone (PVP) which can be considered as standard binding agent. Different grades are available, vary-ing in molecular weight, viscosity and K-value respectively. Typical 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 high shear granulation (HSG) and fl uid bed granulation (FBG) processes.

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 and Table 2.In all trials, the binders were applied as aqueous solutions leading to a binder content of 5.0 % in the fi nal granules. Of all granules, particle size distribution and friability were determined. Finally, the granules were compressed into tablets by applying a compression force of 15 kN.

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

Batch sizeInlet air quantityInlet air temperatureProcess timeSpray rate

1,150 g85–110 m³/h60 °C45 min21 g/min

Table 2: Schema of the trial set-up in fl uid bed granulator

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 con-centric cylinder measuring geometries was used.

Granulation equipmentAs high shear granulator the P1-6 (Diosna GmbH, Osnabrück, Germany) assembled with 2 L product bowl was used for the trials. As fl uid bed granulator the GPCG 3 (Glatt GmbH, Binzen, Germany) assembled with 5 L product container and top spray nozzle (d = 0.8 mm) was used.

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 different 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) assembled with a 125 µm sieve was used to determine both residual fi nes (remaining un-agglomerated particles) and friability of the granules [3].

CompressionThe single punch press XP 1 (Korsch GmbH, Berlin, Germany) assembled with a set of plane punches (di-ameter 8 mm) was used for compression.

Tensile strengthThe crushing force of the tablets was determined by using a multi-tester HT-TMB-CI-12 FS (Kraemer Elek-tronik GmbH, Darmstadt, Germany). Based on these results, tensile strength was calculated according 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 DiscussionIn wet granulation processes, dynamic viscosity is one of the most important physical characteristics of a binder solution. The fl ow characteristics of the liquid are responsible for both the spreading on the particle surface (time needed to incorporate binder solution into the powder components) and the processability (e.g. application via spray nozzle).The aqueous solutions of the wet binders tested showed the typical dependency of dynamic viscosity on polymer content (Figure 2). As a consequence of the 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 two technologies FBG and HSG distinctively different quantities of water were necessary to conduct a proper process. In FBG the binder was dissolved in an amount of water equal to 75 % of the mass of the fi nal batch size, whereas in HSG the maximum mass of water that could be used corresponded to just 10 % of the mass of the fi nally dried granules. Therefore, much higher concentrated binder solutions resulting in higher viscosities had to be used for HSG processes.

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

0

20

40

60

80

100

HSG FBG HSG FBG HSG FBG

PVP K25 PVP K90 PVA-PEG

Binder / technology

Fine

/ fr

iabi

lity

[%]

Fine Friability

Figure 3: Fines and friability after 3 minutes testing time as function of technology and binder

Whereas, the visual appearance of the agglomerates produced with the same technology hardly show any difference between the binders tested (Figure 6 – Figure 11), the particles could clearly be distinguished ac-cording to the technology in which they were processed.

Comparing the Wet Granulation Properties of PVA-PEG Graft Copolymer and different PVP Grades in High Shear and Fluid Bed Granulation ProcessesT. Agnese1, T. Cech1, V. Geiselhart2

1 European Pharma Application Lab, E-mail: thorsten.cech@basf.com, BASF SE, 67056 Ludwigshafen, Germany2 Pharma Ingredients & Services Europe, BASF SE, 67056 Ludwigshafen, Germany

The higher mechanical stress applied in HSG led to solidifi cation (Figure 6 – Figure 8), whereas in a FBG process, the particles were glued together and ended up with a high porosity and a different particle shape (Figure 9 – Figure 11).The HSG process led to agglomerates with just about 10 % residual fi nes and very low friability. In FBG processes, the differences in binding properties are much more pronounced (Figure 3). This huge difference between the two technologies was mainly caused by the additional binding effect deriving from the water soluble fi ller lactose. However, independent of the technology, the use of PVA-PEG as binder led to ag-glomerates with properties in-between the two PVP grades.The same could be found for the particle size distribution. Coarser agglomerates with fewer fi nes could be produced in HSG, whereas, especially for PVP K25 and PVA-PEG the PSD was much more homogeneous in FBG (Figure 4).Despite the fact that the agglomerates of HSG were found to be much stronger than the ones deriving from FBG process, the tablets based on FBG agglomerates yielded in higher tensile strengths (Figure 5).

0.0

0.2

0.4

0.8

1.0

HSG FBG HSG FBG HSG FBG

PVP K25 PVP K90 PVA-PEG

Binder / technology

Part

icle

siz

e di

sstr

ibut

ion

[-]

<125µm 125-355µm >355µm

0.6

Figure 4: Particle size distribution as function of technology and binder

0

2

4

6

8

HSG FBG HSG FBG HSG FBG

PVP K25 PVP K90 PVA-PEG

Binder / technology

Tens

ile s

tren

gth

[N/m

m²]

Figure 5: Tensile strength of tablets as function of granules produced with different technologies and binders

Figure 6: SEM picture of lactose agglomerates produced in a high shear granulator, using PVP K25 as binder

Figure 9: SEM picture of lactose agglomerates produced in a fl uid bed granulator, using PVP K25 as binder

Figure 7: SEM picture of lactose agglomerates produced in a high shear granulator, using PVP K90 as binder

Figure 10: SEM picture of lactose agglomerates produced in a fl uid bed granulator, using PVP K90 as binder

Figure 8: SEM picture of lactose agglomerates produced in a high shear granulator, using PVA-PEG as binder

Figure 11: SEM picture of lactose agglomerates produced in a fl uid bed granulator, using PVA-PEG as binder

ConclusionIndependent of the technique applied, viscosity of the polymer solution plays a distinctive role in wet granulation processes. It infl uences wetting behaviour and drying time and therefore deter-mines the properties of the fi nal granules.The peroxide-free PVA-PEG copolymer was found to be an effi cient and easy-to-use binder in both high shear and fl uid bed granulation. The obtained granules offered excellent compression properties leading to tablets of high hardness.In regard to both binding strength and viscosity PVA-PEG copolymer is closing the gap between PVA K25 and K90, thereby leading to tablet strength comparable to PVP K90.

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 pharmaceutical industry; 9th edition; 2008;

BASF SE, Ludwigshafen, Germany[3] Agnese, T.; Mittwollen, J.-P.; Kolter, K.; Herting, M. G.; An Innovative Method to Determine the Strength

of Granules; AAPS Annual Meeting and Exposition; Nov. 16–20, 2008; Atlanta, Georgia, U.S.A.

2nd Conference Innovation in Drug Delivery; October 3–6, 2010; Aix-en-Provence, France; G-EMP/MD306

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