Effects of powder cohesion and segregation on pharmaceutical mixing and granulation
Creators: name: Oka, Sarang
Publisher: name: No Publisher Supplied
Year: 2016

description: This work is a collection of three distinct powder mixing problems, generally applicable to the manufacturing of pharmaceutical solid oral dose products. The first problem investigates scaling up of dispersive transport of poorly flowing powders in a rotating cylinder setup. The rate of self-dispersion of a material along the axis of a rotating cylinder is quantified by tracking the rate of axial transport of a dyed tracer. The dispersion is found to follow Fick’s second law and the rate constant term of the equation, called the axial dispersion coefficient, provides a measure of the rate of the axial dispersion. The effects of flow properties of the material, the scale of the system and rotation speed of the cylinder on the axial dispersion coefficient were investigated. It was observed that the rate of axial dispersion increases with increasing powder cohesion. Poorly flowing materials tend to form aggregates during operation, which break when they collide with the free surface of the powder bed, leading to enhanced dispersion. The dispersion coefficient was also found to increase with the scale of the system. The powder experiences a greater consolidation stress at larger scales leading to formation of bigger aggregates which contribute to greater dispersion. Lastly, the dispersion coefficient also depends on the rotation speed of the cylinder, and in conjunction, the regime of operation. The dispersion coefficient was observed to increase with increasing rotation speed, as the material transitioned from the cascading to the cataracting regime, but decreased as the material began to centrifuge at even higher speeds.    The possibility of efficiently mixing highly segregating ingredients using continuous blenders was examined. It was found that continuous blenders are superior compared to batch blenders in their ability to mix disparate ingredients. Five mixtures with variable segregation tendencies were tested. Continuous blenders operate by forced convection where mixing occurs due to the action of the rotating blades. The dependence of mixing performance on the properties of the material was thus found to be minimal, facilitating mixing of disparate materials. This is in contrast to traditional batch blenders, in which powder ingredients are blended by the virtue of their tumbling motion. In such systems, the particles are allowed to tread their independent paths and accumulate in separate regions. They were thus found to separate, since unlike particles traversed different paths. The finding that continuous mixers prevent segregation opens the door to manufacture by direct compaction formulations that are currently granulated or reformulated due to segregation concerns. Relationships were found between the bulk properties of the ingredients, namely their median particle size and bulk density, and the segregation index of their mixtures. Relationships between the segregation index of mixtures and their mixing performance in batch systems were also obtained.   The roles of powder mixing and ingredient wetting properties on the content uniformity of granules made by a high shear wet granulation process were investigated. Content non-uniformity in granulated product manifests itself as non-uniform distribution of the active ingredient across granule size classes.  It was observed that a non-uniform initial mixture and a large difference in wettability of the ingredients can both contribute towards the content non-uniformity in the granules. Furthermore, a soluble ingredient can also dissolve in the binder fluid during granulation. The active ingredient recrystallizes during drying and appears as fines leading to further non-uniformity. The impact of process parameters on granule properties and granules microstructure was examined. Furthermore, the role of granule microstructure on performance attributes, such as the rate of release of the active ingredient in various dissolution media, was investigated. It was found that the rate of release is dictated by the internal pore structure – higher porosity facilitates dissolution. Rate of release was also found to be proportional to the square of the granule diameter. Content non-uniformity across granule size classes, however, undermines the ability to model and predict such performance attributes. Relationships between process parameters and the resulting product microstructure on the one hand, and between the product microstructure and its end-use properties such as dissolution on the other hand, were established.