Characteristics of residence time distribution in a continuous high shear mixer granulation using scraper rotation.

Characteristics of residence time distribution (RTD) in a continuous high shear mixer granulation were investigated to promote the development of a continuous manufacturing process in the pharmaceutical industry. A continuous granulator with an impeller and a scraper was utilized. The tracer behavior in the continuous wet granulation was verified in impulse-response experiments with acetaminophen. The RTD of acetaminophen changed depending on the scraper speed (15-50 rpm), and the mean residence time could be adjusted by the scraper speed in the wet granulation. The impact of changes in the liquid-to-solid ratio (0.10-0.20) and the addition of binder were also examined, and the variance of RTD was influenced by both. The degree of axial mixing was quantitatively evaluated with a dimensionless index, the Peclet number (Pe). Higher scraper speed was found to suppress fluctuations of the axial mixing that occurred with changes in the liquid feed. Moreover, the transition of granule size distribution with the change in liquid feed reached a steady state more quickly under the higher scraper speed. These results show that scraper rotation can help to adjust the RTD and the axial mixing, leading to a more robust continuous granulation.

Detection of component segregation in granules manufactured by high shear granulation with over-granulation conditions using near-infrared chemical imaging.

The objective of this study was to evaluate the high shear granulation process using near-infrared (NIR) chemical imaging technique and to make the findings available for pharmaceutical development. We prepared granules and tablets made under appropriate- and over-granulation conditions with high shear granulation and observed these granules and tablets using NIR chemical imaging system. We found an interesting phenomenon: lactose agglomeration and segregation of ingredients occurred in experimental tablets when over-granulation conditions, including greater impeller rotation speeds and longer granulation times, were employed. Granules prepared using over-granulation conditions were larger and had progressed to the consolidation stage; segregation between ethenzamide and lactose occurred within larger granules. The segregation observed here is not detectable using conventional analytical technologies such as high pressure liquid chromatography (HPLC) because the content of the granules remained uniform despite the segregation. Therefore, granule visualization using NIR chemical imaging is an effective method for investigating and evaluating the granulation process.

Optimization of operating conditions in a high-shear mixer using dem model: determination of optimal fill level.

For the purpose of evaluating optimal fill level of starting materials in a high-shear mixer, discrete element method (DEM) simulation was conducted to visualize kinetic status between particles. The simulation results obtained by changing fill levels were used to determine solid fraction of particles, particle velocity, particle velocity vector, and kinetic energy and discuss the flow pattern. Optimal fill level was obtained from the information on these matters. It was pointed out that understanding the kinetic energy between particles in an agitating vessel was effective in determining the optimal fill level. Granulation experiment was conducted to validate the optimal fill level obtained by the simulation, confirming the good agreement between these two results. It was pointed out that determination of kinetic energy between particles through the simulation was effective in obtaining an index of the kinetic status of particles. Further, it was confirmed that the simulation could provide more information than conventional granulation experiments could provide and also helpful in optimizing the operating conditions.