(439c) A Mechanistic Analysis on the Effect of Mixing Dynamics on Granule Microstructure

Granule microstructure is an important critical quality attribute. It encumbers many individual properties like porosity, surface morphology, component content uniformity, pore size distribution and, open to closed pore ratio. All these properties combined not only affect the flow, strength, content uniformity, and stability of granules [1, 2] but also affect the critical quality attributes of downstream products such as tablets and capsules [3, 4].

Twin-screw granulation (TSG) is a widely used continuous wet granulation technique. In the twin-screw granulator, the granulation regimes are physically separated along the length of the screws [5]. Moreover, given the lack of space available for the granules to grow in a twin-screw granulator, the stresses per unit time applied on the granules are higher compared to high shear and fluid bed granulators [6]. As a result of these factors, the granule formation physics in a TSG are significantly different compared to other types of granulation techniques [5].

Since the physics involved in twin-screw granulation is different from other types of granulation techniques, the factors affecting the granulation rate mechanisms and thence the critical quality attributes of granules are quite different. Studies focusing on explaining the relationship between the input factor, granulation rate mechanism, and granule quality attribute are few, especially for granule microstructure.

Mixing dynamics control the distribution and interaction of particles inside the granulator, which in turn govern the granulation rate mechanisms and ultimately the critical quality attributes of the granule [7]. In an earlier study by the authors, a quantitative relationship between input process & design parameters and mixing dynamics has been established [8]. The objective of this study is to identify and study in detail the different relationships between mixing dynamics, granulation rate mechanisms, and granule microstructure in a twin-screw granulator. In particular, the focus will be on studying the component distribution within the granule, porosity of the granule and the pore network distribution within the granule. All these properties will be studied quantitatively.

In this study, the fundamental factors affecting the granule microstructure are hypothesized. Appropriate experimentation and analysis are underway, and the results of this analysis will be used to accept or reject the hypotheses. Four different hypotheses, linking the mixing dynamics to granulation rate mechanism and ultimately to granule microstructure, are proposed as part of this study.

Hypothesis 1 (Fill level): The powder fill level in the granulator controls the amount of powder in the granulator which affects the number and frequency of collisions of powder particles in the granulator. This collision frequency influences the strength of the shear and compaction forces on the powders and alters the granule microstructure. Granules become denser with an increase in shear forces inside the granulator until a critical force. Shear forces higher than the critical force result in the breakage of granules. The fill level in the granulator will be varied by carefully manipulating the screw speed, throughput, and screw design.

Hypothesis 2 (Liquid Bridges): Liquid bridges are formed when two saturated granules form a bigger granule through successful collision. The collision is deemed successful when the viscous dissipation force between the granules(due to the liquid bridge) is greater than the collision kinetic energy. Liquid bridge strength between granules affects the density and strength of the granule microstructure. These bridges are affected by the solid-liquid distribution and viscosity of the liquid binder. The effect of liquid bridges will be varied by varying the liquid to solid ratio and viscosity of the binder.

Hypothesis 3 (Particle/Agglomerate mixing): Particle/agglomerate mixing affects the component uniformity across different granule size fractions and also within a single granule. The type of colliding-granules also affects the density of the resultant larger granule being formed due to the shape and state of saturation of the colliding granules. The state of mixing also affects the growth mechanism. Particle/agglomerate mixing is a direct consequence of mixing dynamics and will be varied carefully by varying the screw speed, throughput, and screw design.

Hypothesis 4 (Powder Wettability): Mixing dynamics present in the granulator affect the type of particles present in the vicinity of the incoming droplet. This affects the nucleation mechanism, especially in a multi-component blend consisting of both hydrophilic and hydrophobic powders. It was observed in the literature that, hydrophilic material forms smaller, denser nuclei via immersion nucleation and hydrophobic nuclei form larger, hollow nuclei via the solid-spreading mechanism [9]. The kind of nuclei will in turn affect the granulation rate mechanism and the microstructure of the granule formed [7].

By quantitatively studying the component distribution and pore network distribution, this study aims to further the mechanistic understanding of the effect of various process, design, and material parameters on the granule microstructure. Moreover, this study will help in establishing the fundamental correlation between mixing dynamics, granulation rate mechanisms, and granule microstructure.

Figure 1: Map summarizing the effect of mixing dynamics on the granule microstructure.

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