Research Paper The Relation Between Granule Size, Granule Stickiness, and Torque in the High-Shear Granulation Process A. M. Bouwman, 1,4 M. J. Henstra, 1 J. J. M. E. Hegge, 1 Z. Zhang, 2 A. Ingram, 2,3 J. P. K. Seville, 2 and H. W. Frijlink 1 Received May 31, 2004; accepted October 21, 2004 Purpose. To investigate the background of the observed relationship between measured torque and granule size in high-shear granulation processes. Methods. Torque was measured during the granulation process; the behavior of individual wet granules during compaction was investigated using micromanipulation. Surface properties of wet granules were manipulated by coating them with talc. Results. The torque-granule size relationship could not be explained by the rise in mass of the individual granules; it occurs rather through an increase in stickiness of the granules when the moisture content is increased. Obviously, the increased stickiness that causes the granules to grow also increases the torque. Increased stickiness was shown to be the result of an increased deformability of the granules at higher moisture contents, in combination with a change in surface properties. The elastic-plastic behavior (ratio of elastic to plastic deformation) was found to change at increasing moisture contents. Conclusions. Our results imply that changes in the stickiness of the granular material that may be caused by changes in composition shift the torque-size relationship. This may be of particular importance when, for example, granulation results from placebo batches are used to predict the granule size of drug- containing batches. KEY WORDS: elastic-plastic deformation; granule size; stickiness; torque; wet granulation. INTRODUCTION In high-shear granulation, powder particles are swept through the bowl due to impacts of a fast-rotating impeller. Liquid is added and will be distributed over the powder par- ticles. Particles stick together to form nuclei, which will be consolidated by the impacts with the impeller and the wall. This densification of the nuclei pushes water to the outer surface of the granule, which can result in growth. Next to the impeller, a chopper may be present to chop large lumps into smaller pieces. Granule growth stops when the equilibrium between growth and breakage (caused by impacts of particles, impeller, or wall) is reached (1). The granulation process can be monitored by torque or power consumption measurement. Torque is a measure of the amount of energy needed to rotate the impeller. Therefore, torque depends on the resistance of the mass against rotation of the impeller (2–4). In the wet mixing process, changes in torque occur as the result of a change in the cohesive force of the granules in the wet powder bed. Leuenberger (5) de- scribed five stages in the wet granulation process on the basis of power consumption, shown in Fig. 1. In stage I, the powder is moistened. However, an increase in torque is not observed and no noticeable agglomeration has occurred. In stage II, a rapid increase in torque is observed, caused by agglomera- tion. The agglomerates formed in this stage are very weak and break upon drying. In stage III, a plateau region is reached, where the volumes of liquid bridges are increased without significant changes in the cohesive force. Stage IV is reached when pore spaces begin to fill completely with liquid. This results in a fluctuating torque value. Finally in stage V, when too much liquid is added, a slurry is formed, which leads to a decrease in torque. However, during a normal granulation process, the above described procedure is not fully completed; in general the aim is to add such an amount of liquid that the process stops in stage III. This provides the most robust and repro- ducible process. A torque curve obtained from such a normal granulation process is shown in Fig. 2. During the first 30 s liquid is added, which gives a sharp rise in torque. When all particles are moving, torque drops a little bit, to rise again when growth occurs. Finally, a steady-state torque is reached, during which particle size was found not to change anymore. We refer to torque at this stage as equilibrium torque. The value of the equilibrium torque changes when process param- eters are changed. During the past decades, many people tried to identify the parameters by which torque was changed. 1 Department of Pharmaceutical Technology and Biopharmacy, Groningen University Institute for Drug Exploration (GUIDE), Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands. 2 Department of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham, B15 2TT UK. 3 Positron Imaging Centre, School of Physics and Astronomy, Uni- versity of Birmingham, Edgbaston, Birmingham, B15 2TT UK. 4 To whom correspondence should be addressed. (e-mail: a.bouwman@ farm.rug.nl) Pharmaceutical Research, Vol. 22, No. 2, February 2005 (© 2005) DOI: 10.1007/s11095-004-1194-2 270 0724-8741/05/0200-0270/0 © 2005 Springer Science+Business Media, Inc.