Wet granulation is a process used for the particle size enlargement of primary powders. The mixing of a liquid with the powder glues the primary particles together, which results in the formation of the granules. The mixing action can be performed in many ways, like tumbling (drum granulation), fluidizing (fluid bed granulation) and high-intensity mixing (high shear granulation). In the pharmaceutical industry granulation is commonly used for the production of solid formulations (e.g. tablet or capsules). A problem that is regularly observed during high shear granulation is that the drug substance is poorly distributed over the granules. This means that there is a granule size-dependent variation in composition of the granules. In this thesis the granulation mechanisms that are involved in the formation of non-homogeneous granules in a high shear mixer are elucidated. The relevance of the investigation of these mechanisms is emphasised by the current initiative of the authorities concerning quality assurance. This initiative is focused on quality testing throughout the process, which implies that testing at the final stage is inadequate. High shear granulation is commonly used as an intermediate step in the production process of a solid formulation. Consequently, quality control of high shear granulation with respect to granule uniformity is essential. Unfortunately, there is limited information about the mechanisms underlying the inhomogeneity of the granules. This means that the control is often based on trial-and-error experiments instead of science. This thesis provides new scientific insights into these mechanisms, namely;

Granule breakage behaviour, which results in a continuous exchange of primary particles, has a positive influence on granule homogeneity. In contrast, absence of granule breakage means that heterogeneous granules can be formed.

During layering small primary particles have a higher affinity for growth than large particles. This mechanism, called preferential growth, is responsible for the inhomogeneity.

Penetration of binder liquid into the porous powder bed results in the immediate formation of granules already in the early seconds of the granulation process. If these freshly formed granules are strong enough to withstand the shear forces, these granules can function as kernels for preferential growth. Consequently, this nucleation mechanism can induce the granule inhomogeneity.