Dry Powder Mixing Is Feasible in Continuous Twin Screw Extruder: Towards Lean Extrusion Process for Oral Solid Dosage Manufacturing.

Using discrete element method (DEM) modeling and near-infrared (NIR) spectroscopy, the feasibility of powder mixing in the initial pre-melting zones of a twin screw extruder using two independent feeders was studied. Previous work in the pharmaceutical and food industry has focused on mixing when materials are melted or on material homogeneity at the extruder's output. Depending on the formulation, ensuring a fully blended formulation prior to melting may be desired. Experiments were conducted using a Coperion ZSK-18 extruder to evaluate if blend uniformity can be achieved by exploring screw configuration, screw speed, and powder feed rate. As powder exited the extruder and deposited on a conveyor belt, an in-line NIR spectrophotometer measured spectra of material. Chemometric-based models predicted unknown concentrations to evaluate if blend uniformity was achieved. Using the EDEM software, Hertz-Mindlin contact model, and dimensions of the extruder, DEM simulations complemented the experimental work. The DEM computational models provided understanding of mixing patterns inside the extruder at particle scale and helped select the screw configuration before doing experimentation. The simulations showed good axial mixing for all the screw configurations studied, while good cross (radial) mixing was only observed for the screw configuration with 90-degree kneading elements. Therefore, the screw configuration with two 90-degree kneading elements was chosen for the experimental study. The RTD profiles when using a screw configuration with only conveying screw elements are comparable to a plug flow reactor (PFR), while the profiles when using kneading elements are more comparable to an ideal continuous stirred tank reactor (CSTR). For the screw configuration with 90 degrees kneading elements, the mean residence time (MRT) decreases with an increase in the screw speed. Experimental NIR spectra showed that concentrations can be predicted with an error of 2%. It was demonstrated that the twin screw extruder can provide proper dry powder mixing of two powder feed streams based on a unit dose scale, enabling continuous powder mixing prior to the melting zone in the extruder for the formulation studied with a cohesive API. This setup may also work for other types of formulations. These studies can help in developing lean hot melt as well as wet extrusion/granulation processes using twin screw extruders for the continuous manufacturing of oral solid dosage products.

A Semi-Mechanistic Prediction of Residence Time Metrics in Twin Screw Granulation.

This work is concerned with the semi-mechanistic prediction of residence time metrics using historical data from mono-component twin screw wet granulation processes. From the data, several key parameters such as powder throughput rate, shafts rotation speed, liquid binder feed ratio, number of kneading elements in the shafts and the stagger angle between the kneading elements were identified and physical factors were developed to translate those varying parameters into expressions affecting the key intermediate phenomena in the equipment, holdup, flow and mixing. The developed relations were then tested across datasets to evaluate the performance of the model, applying a k-fold optimization technique. The semi-mechanistic predictions were evaluated both qualitatively through the main effects plots and quantitatively through the parity plots and correlations between the tuning constants across datasets. The root mean square error (RMSE) was used as a metric to compare the degree of goodness of fit for different datasets using the developed semi-mechanistic relations. In summary this paper presents a new approach at estimating both the residence time metrics in twin screw wet granulation, mean residence time (MRT) and variance through semi-mechanistic relations, the validity of which have been tested for different datasets.