Session 1: Granulation - The Big Picture


Agglomeration at the Sharp End - Industrial Practice and Needs

D. York (Proctor and Gamble, UK)

The last decade has seen an impressive growth in the research and mechanistic understanding of the agglomeration process, along with attempts to model the process. There have even been a few papers on controlling the process. However, industry is still heavily dependent on empirical process development based on available process equipment and some experientially gained mechanistic insights.

The aim of this presentation will be to provide some of the everyday challenges to process development engineers and manufacturing operators in designing and operating these processes, especially when the binder is a key active ingredient. The aim being to guide future research projects and hopefully equipment design to have a greater impact on the overall application of agglomeration.

Manufacturing Pharmaceutical Granules: Is the Granulation End Point a Myth?

H. Leuenberger (Institute for Innovation in Industrial Pharmacy, Switzerland)

The conventional moist agglomeration process can be subdivided into three unit operations:

1) dry mixing of the powder particles,
2) moistening of the powder particles by adding the correct amount of granulating liquid,
3) massing of the moistened powder bed until the "end-point".

This procedure is as old as Homo habilis using flour and water to prepare bread inspiring Homo faber to mass clay for manufacturing ceramics. For a good quality of the product, it was important to stop the massing at the "end-point" of the granulation process. The correct amount of granulating liquid was determined by "trial and error" experiments. The "end-point" was felt in the fingertips during massing. This empirical knowledge was transmitted from generation to generation.

For a small-scale production of pharmaceutical granules in a lab, the pharmacy student is still taught to add to the powder mass an adequate amount of granulating liquid in order to obtain after massing a "snow-ball"-consistency of the moistened powder bed. There is nothing wrong about empirical knowledge: remarkably, the Nobel Laureates Müller and Bednorz, who discovered the high temperature superconductive, ceramic materials, compared their search with the galenical science of a pharmacist preparing the optimal formulation.

In fact, there is still no generally recognised rigorous theory, which explains the phenomenon of high temperature superconductivity! In general, empirical knowledge prevails the theory. Only in the 1950's the elements for a scientific framework for the moist agglomeration process was developed by Rumpf in Germany and Conway – Jones in the UK. In the mean time, the moist agglomeration process has been described by population models but there is still no process model available, which can be used to identify the "end-point" of the granulation process.

Thus taking into account FDA´s PAT (Process Analytical Technology)- Initiative [1] it is important for Homo sapiens to develop tools for a better understanding of the moist agglomeration process. It is proposed to add to the powder particles at a constant and relatively slow rate the granulating liquid in order to obtain the specific power consumption pattern of the formulation. It is important to know to interpret this pattern and to identify an "early signal" before the "end-point". Thus, it is possible to control the granulation process and to obtain a more homogeneous batch-to-batch quality.

Reference: [1] Pharmaceutical Powder Technology - From Art to Science: The Challenge of FDA's PAT Initiative, Leuenberger Hans, Lanz Michael. Advanced Powder Technol. 16 (1), 2005, 3-25.

Solid Lipid Extrusion for the Production of Sustained Release Pellets

P. Kleinebudde and C. Reitz (Heinrich-Heine-University Duesseldorf, Germany)

In solid lipid extrusion pure lipids or pharmaceutical formulations based on solid lipids are extruded at temperatures of 5-15°C below their melting ranges. The solid fat index is > 80% at these temperatures. An axial twin screw extruder with dies of 1 mm diameter and 2.5 mm length was used for extrusion. The extrusion process is robust and smooth.

Depending on the fraction and the composition of the lipid the dissolution profile can be varied in a broad range. The drugs are released according to a matrix dissolution mechanism. Drugs can be incorporated up to approximately 70% (w/w) depending on the lipid. The solid composition is also important with respect to physical changes after the solid lipid extrusion. The aging of the lipids can influence the dissolution profile. Lipids with similar melting ranges but different compositions were compared with respect to physical changes during storage. Lipids with a narow chain length distribution of the constituing fatty acids are superior for solid lipid extrusion. For these pellets the dissolution profile during storage is stable.

Usually the extrudates are cut into small cylinders or milled in order to achieve a suitable solid dosage form. However, it is also possible to pelletise the extrudates in a spheroniser. The spheroniser must be heated to a suitable temperature. The spheronisation is facilitated by using a combination of two lipids with different melting ranges. The ratio of these lipids has to be optimised for spheronisation purposes. It is possible to achieve pellets with an aspect ratio of <1.2 and a diameter of approx. 1.5 mm. However, the spheronisation process is sensitive to variations in process variables and has to be controlled carefully.

Wet Granule Breakage in a Breakage Only Granulator: Effect of Formulation Properties on Breakage Behaviour

L.X. Liu, R. Smith and J. D. Litster (University of Queensland, Australia)

Wet granule breakage can occur in the granulation process, particularly in granulators with high agitation forces, such as high shear mixers. In this paper, the granule breakage is studied in a breakage only high shear mixer.

Granule pellets made from different formulations with precisely controlled porosity and binder saturation were placed in a higher shear mixer in which the bulk medium is a non-granulating cohesive sand mixture. After subjecting the pellets to different mixing time in the granulator, the numbers of whole pellets without breakage are counted and taken as a measure of granule breakage.

The experimental results showed that the primary powder size, binder viscosity and surface tension as well as binder saturation have significant influence on granule breakage behaviour. The effect of these parameters on granule breakage is presented. The use of different measures of the granule mechanical strength as predictors of breakage behaviour is discussed.

Compression and Compaction of Binary Mixtures of Granules

G. Frenning, J. Hellström and G. Alderborn (Uppsala University, Sweden)

The response of granular materials to confined compression in terms of structural evolution and mechanical strength of compacts is of great interest in a number of disciplines. The possibility to predict compression behaviour from single granule mechanics as well as the modelling of the compression and compaction process are current problems of interest in this context.

From a pharmaceutical formulation perspective, different components are normally mixed before farbrication of tablets and the compression and compaction of binary mixtures and how such relationships can be predicted are currently discussed [1,2]. However, the literature on the use of binary mixtures of granules, which have a more complex response to the compression pressure than solid particles [3], is meagre. In order to systematically build up knowledge of the properties of granule mixtures, there is a need to initially use simple model systems in terms of the particulate and mechanical characteristics of the granules.

In this paper, examples of the compression properties as well as of the compactability of binary mixtures of granules of well described model systems will be presented. In the study, granules formed from common pharmaceutical excipients were used, chosen to represent different combinations of compression properties, for example granules of similar deformation propensity but different compressibility. All granules were nearly spherical and of similar size and they were expected to respond to the applied compression pressure by deformation and densification and not by fragmentation. The compression behaviour of the granule powders and their binary mixtures was analysed in terms of the Kawakita parameters [4], often denoted 'a' and 'b'. It is hypothesized that these parameters reflect different compression properties of the granules, i.e. the Kawakita parameter a represents the total compressibility while the parameter 'b-1' represents the deformation propensity or failure strength of the granules [5]. The compaction properties were described as the relationship between tensile strength of the tablets and the applied compression pressure.

It is concluded that for the model granule systems used, compression properties of the mixture, in terms of the Kawakita parameters, and the compactability could be predicted as additive properties, assuming ideal mixing between the two components. The study will continue with more complex mixtures of granules.

[1] Busignies, V., Leclerc, B., Porion, P., Evesque, P., Couarraze, G., and Tchoreloff, P. Compaction behaviour and new predictive approach to the compressibility of binary mixtures of pharmaceutical excipients. Eur. J. Pharm. Biopharm. 64:66 (2006).
[2] Van Veen, B., Maarschalk, K., Bolhuis, G.K., and Frijlink, H.W. Predicting mechanical properties of compacts containing two components. Powder Technol. 139:156 (2004).
[3] Tunón, Å. and Alderborn, G. Granule deformation and densification during compression of binary mixtures of granules. Int. J. Pharm. 222:65 (2001).
[4] Lüdde, K.H., and Kawakita, K. Die Pulverkompression. Pharmazie. 21:393 (1966).
[5] Adams, M.J., Mullier, M.A., and Seville. J.P.K. Agglomerate strength measurement using a uniaxial confined compression test. Powder Technol. 78:5 (1994).

Comparison of Fibre Optical Measurements and Discrete Element Simulations for the Study of Granulation in a Spout Fluidised Bed

J.M. Link (1), W. Godlieb (1), P. Tripp (2), N.G. Deen (1), S. Heinrich (3), J.A.M. Kuipers (1), M. Schönherr (4) and M. Peglow (3)
University of Twente, The Netherlands
Vibra Maschinenfabrik Schultheis GmbH, Germany
Otto-von-Guericke-University Magdeburg,Germany
BASF AG Ludwigshafen, Germany

Spout fluidized beds are frequently used for the production of granules or particles through granulation. The products find application in a large variety of applications, for example detergents, fertilizers, pharmaceuticals and food. Spout fluidized beds have a number of advantageous properties, such as a high mobility of the particles, which prevents undesired agglomeration and yields excellent heat transfer properties.

The particle growth mechanism in a spout fluidized bed as function of particle-droplet interaction has a profound influence on the particle morphology and thus on the product quality. Nevertheless, little is known about the details of the granulation process. This is mainly due to the fact that the granulation process is not visually accessible. In this work we use fundamental, deterministic models to enable the detailed investigation of granulation behaviour in a spout fluidized bed.

A discrete element model is used describing the dynamics of the continuous gas-phase and the discrete droplets and particles. For each element momentum balances are solved. The momentum transfer among each of the three phases is described in detail at the level of individual elements.

The results from the discrete element model simulations are compared with local measurements of particle volume fractions as well as particle velocities by using a novel fibre optical probe in a fluidized bed of 400 mm I.D. Simulations and experiments were carried for three different cases using Geldart B type aluminium oxide particles: a freely bubbling fluidized bed; a spout fluidized bed without the presence of droplets and a spout fluidized bed with the presence of droplets. It is demonstrated how the discrete element model can be used to obtain information about the interaction of the discrete phases, i.e. the growth zone in a spout fluidized bed (viz. Fig. 1). Eventually this kind of information can be used to obtain closure information required in more coarse grained models.

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