Mechanistic understanding of mixing dynamics and its effect on granule quality attributes
Creators: name: Kotamarthy, Lalith
Publisher: name: No Publisher Supplied
Year: 2022

description: Wet granulation is a size enlargement process in which fine powders are agglomerated into a larger, stronger, and a relatively permanent structure called granules. The agglomeration process takes place in presence of a nontoxic liquid binder. Over the past decade, there has been an increase in focus on continuous powder manufacturing. The reason behind this paradigm shift was in part due to the introduction of process analytical technology (PAT) guidance by the Food and Drug Administration (FDA) in 2004. Twin-screw granulation (TSG) is a popular continuous wet granulation technique. It has been widely accepted that twin-screw granulation, on the account of continuous manufacturing capabilities and modular design, provides numerous advantages. Despite that it has not been widely applied in the manufacturing industries, especially the pharmaceutical industry has shown maximum reluctance. The primary reason for this reluctance is the poor mechanistic understanding of this process. In a wet granulation process, dry powders and the liquid binder are rigorously mixed to form the granules with the desired critical quality attributes. So, it is very important to understand the influence of mixing during granulation, especially for a continuous process such as TSG, where average granule formation times are in the order of seconds. In recent years studies have shown that mixing affects the granule quality attributes but no deliberate quantification and analysis of the effect of mixing on granule quality attributes was performed. Therefore, this study aims to improve the mechanistic understanding of the TSG process via a physics-based understanding of the effect of mixing dynamics on the granule quality attributes. To achieve this first the effect of important process parameters, screw parameters, and material properties on mixing in TSG has been mechanistically understood in this study. Then this understanding was applied to link the effect of the input process, screw, and material properties to final granule quality attributes via a physics-based process map development. As a part of this study, a new quantitative metric (axial dispersion coefficient) to analyze mixing in a TSG was introduced, and an experimental method to determine this metric from the residence time distribution (RTD) curve was also developed. This metric helped improve the mechanistic understanding of the effect of process and screw parameters on mixing dynamics in TSG. A physics-based model to predict the axial dispersion based on turbulent mixing principles was developed, this model was validated using the historical data present in the literature. This validated model further helped in the development of the first-ever end-to-end mechanistic model for the prediction of complete RTD curves, which was also validated against experimental data. Extensive material characterization was performed to isolate the material properties affecting wetting and nucleation (powder hydrophobicity, binder viscosity, and liquid to solid ratio) and their effect on mixing dynamics was mechanistically elucidated using axial dispersion coefficient obtained from RTD experiments. This analysis also helped in mechanistic understanding of the granule growth mechanism a particle undergoes as a function of material properties and mixing dynamics. This added the understanding of additional complexity (material properties) to the already achieved knowledge in terms of understanding the process and screw parameters. This understanding was used to analyze the effect of mixing dynamics on the granule quality attributes. This was achieved by identifying physically relevant intermediate parameters that affect mixing and the effect of input parameters on these intermediate parameters was also recognized. Then the effect of identified intermediate parameters on granule quality attributes through a mechanistic understanding of their effect on mixing and granulation rate mechanisms was investigated. Based on this a mechanistic process map was developed to depict the effect of mixing on the time and space evolution of materials inside the TSG from liquid addition to granule formation.