Continuous High Shear Granulation for “difficult” pharmaceutical raw materialsP. Chao, K.-J. SteffensDepartment of Pharmaceutical Technology, University of Bonn, Gerhard-Domagk-Str. 3, D-53121 Bonn, Germany

Tablet Tech TM , FMC BioPolymer , Brussels , Belgium , 25th – 26th October 2007

Introduction

Results & Discussion

Fig.4. X-ray diffractogram of Magnesia 449

Tab.1. Properties of Magnesia 449

1,75 %Humidity

4,17 μmParticle Size d50%

1,91 m2/gSpecific surface area

1,06 g/mlTamped Density

Calcite, rhombohedralCrystal structure

Fig.3. Crystal structure of Magnesia 449

Conclusion

Acknowledgment

References

We thank L.B. Bohle GmbH, Germany

[1] D.A.Skoog, J.J. Leary; Instrumentelle Analytik; Springer-Verlag Berlin Heidelberg 1996, 423-433[2] W.A. Ritschel, A. Bauer-Brandl; Die Tablette; Editio Cantor Verlag; 2. Edition

Fig.7. Magnesia 449, BM-Granules

Fig.6. Magnesia 449, BC-Granules

Methods

Fig.1. Bohle Continuous Granulator

Fig.2. Bohle Mini Granulator

Tablets were made at six compression pressure levels between 60 and 400 MPa. Magnesium stearate was used as external lubricant. Ten samples of each level were taken for analysis. The height, weight, diameter and crushing strength of the tablets were measured 24 hours after compression. The tensile strength (TS) of the tablets was calculated from crushing strength and tablet dimensions.

The aim of this study is to characterize the granulation and tableting behaviour of “difficult” raw materials by using different granulation methods.

A new Continuous High Shear Granulator (Bohle-Continuous-Granulator) was also part of this study. The principle is based on a small high-shear-granulator with continuous material flow. The chopper is used for the continuous discharge of the wet granules. The target of this new development is to perform wet granulation in a perfectly controlled steady state, which leads to superior and more constant granule properties, compared to batch processes. Additionally, the continuous process reduces the production cost.Calcium carbonate, a “difficult” raw material for granulation and tableting was chosen for this study. It exists in many polymorphs and has physicochemical properties differing in a wide range.

Granulation Methods

Calcium carbonate was mixed with 3 % Povidon 25 (Fagron, Germany) in a VMA70 mixer (L.B. Bohle, Germany) or Turbula T2C mixer (Bachofen, Switzerland) for 3 minutes. Water was used as granulation liquid. The mixture was directly granulated by using two different wet granulation methods:• Bohle-Continuous-Granulator (BCG) is a small high shear granulator with a continuous process. A screw conveyor

with two screws transports the mixture (3 kg/h). Granulating liquid is supplied continuously (0,6 kg/h). The speed of impeller/chopper is 300 rpm/500 rpm. [Fig.1]

• Bohle-Mini-Granulator (BMG) is a small high shear granulator running in batch process. The speed of impeller/chopper is 300 rpm/500 rpm. The granulation time is 5 min. Water is dropped slowly into the pot. [Fig.2]

Analytic Methods

• Round flat-faced tablets (punch diameter 10,0 mm) were compressed by an instrumented pneumo-hydraulic press (FlexitabTM, Roeltgen, Germany).

• Crushing strength of tablets was tested with TBH210 (Erweka, Germany).• Scanning Electron Microscopy (SEM) pictures were obtained with Hitachi S-2460N, Germany. [1]• X-ray Powder diffractogram was gained by an X’Pert Pro MPD system (Panalytical, Almelo, The Netherlands). The

scanning range was from 10° to 45° 2θ, step size of 0.0170° 2θ. The generator settings were 35 kV/30 mA.• Laser diffraction spectrometry was used to measure the particle size distribution. (Helos KA/LA&Rodos SR,

Sympatec, Germany).• Specific surface area was determined by the BET-Method (Quantasorb®, Quantachrome, USA).• Water content was measured with Moisture Analyzer 40 (Sartorius, Germany).

Calcium carbonate differ in many chemical and physical characteristics like polymorphism, density, particle size, specific surface area and humidity. Some properties of Magnesia449 (Magnesia, Germany), a heavy calcium carbonate, are shown in Tab.1 and Fig.3,4.

Figure 5 shows that BC-granules have reached a higher tensile strength than the BM-granules.

The Calcium carbonate Magnesia 449 consists of crystals with small particle size and relatively low water content. It belongs to those excipients, which are regarded to be “difficult” in granulation and tableting.

SEM micrographs of BC-granules show that they are more uniform in shape than the BM-granules. The BC-granules have an approx. particle size of 150 µm and seem to be more dense.

The higher tensile strength determined for BC-granules confirms their better properties in comparison to BM-granules.

The SEM micrographs (Fig. 6, 7) show the different appearance of the granules. The BC-granules seem to be more dense and more uniform in shape.

Tableting behaviour of Magnesia 449

0,00,51,01,52,02,53,03,5

0 100 200 300 400 500

Compression Pressure [MPa]

Tens

ile S

tren

gth

[N/m

m2 ]

BC-Granules BM-Granules

Fig.5. Tableting behaviour of Magnesia 449