(572c) Comparison of Continuous High Shear Granulation Processes with Twin-Screw Wet Granulation Process

Wet granulation (WG) is an extremely prevalent unit operation in the manufacturing of drug product due to its numerous advantages. As particle size is enlarged in the process, WG can improve the handling and flow properties of powders, content uniformity and compression characteristics; and it alsocan minimize dust and ingredient segregation. These advantages could realize better drug release rate and tablets physical appearance. Currently, substantial attention has been attracted by continuous manufacturing (CM) because it can provide significant technical and business advantages relative to the conventional batch processes. CM methods have been demonstrated to be more robust and controllable, which can improve product quality and process efficiency. Furthermore, scale-up challenges can be overcome in CM by running the operation for a longer time, indicating the reduction of technique transfer risk and capital-intensive equipment requirement. In recent years, several continuous WG techniques have been developed.Most commercial continuous granulators are twin-screw extruders followed by fluid bed driers. In comparison, there have been very few studies so far on continuous high shear granulation, which resembles the batch high shear granulation in terms of dry powder mixing, binder addition and wet massing. In general, the granules produced by continuous fluid bed granulators or twin-screw extruders are different than those from high shear granulation due to the different shear and compressive forces that the material experiences in these systems.

The focus of the study is to quantify performance metrics (particle size distribution (PSD), bulk density, porosity, active concentration in granule, particle shape) of granules as a function of critical process parameters (throughput, impeller rotation speed and liquid to solid (L/S) ratio) for each formulation and granulator. Residence time distribution (RTD) studies are performed to understand the mixing dynamics which can aid in further understanding the relationship between input parameters, mixing and shear and the output granule properties. 

Two continuous high shear granulators, namely Lödige CoriMix CM5 and Glatt GCG70, and Thermo twin-screw granulator/extruder (EuroLab 16-mm, 25:1 L/D) were examined. Two dosages formulations were used for experimentation, i.e., a high-dose drug formulation (15% -lactose monohydrate, 15% Microcrystalline cellulose and 70% semi-fine Acetaminophen) and a low-dose drug formulation (46% -lactose monohydrate, 46% Microcrystalline cellulose and 8% semi-fine Acetaminophen). Purified water served as the binder. A Design of Experiments (DoE) had been performed on each granulator with three levels of L/S ratio, rotation speed and throughput. Eyecon (InnoPharma) offline particle size analysis were used to quantify the median particle size and span of the output granules. Bulk density was measured from calculations involving the mass of the sample and the volume of particles (solid + liquid + pores). Scanning Electron Microscope images of the samples were taken to quantify porosity, active concentration and the shape of the granule. RTD studies, conducted by injecting colored tracer active particles and implementing a Near-infrared spectrometer, were used to evaluate the concentration of dye that was further correlated to the active concentration in the sample collected. The results allow for a quantitative understanding of the design space regarding the process parameters mentioned above, which can be used to identify an optimal operation condition to a specific formulation.