Assessment of Abrasion-Induced Visual Defects in Twin Screw Wet Granulation Using Wall Friction Measurements.

Starting point of the presented study were abrasion effects occurring during a twin screw wet granulation (TSG) process of a new chemical entity (NCE) formulation, resulting in gray spots on the final tablets. Several actions and systematic changes of equipment and process parameter settings of TSG process were conducted which reduced the visual defect rate of the tablets, i.e., gray spots on the surface, below the specification limit. To understand the rationale and mechanism behind these improvements, correlations of defect rates and wall friction measurements using a Schulze ring shear tester were evaluated. To check the suitability of the method, a broad range of wall materials as well as powder formulations at various moisture levels were investigated with regard to their wall friction angle. As differences in wall friction angle could be detected, further experiments were conducted using wall material samples made out of different screw materials for TSG. Evaluation of these screw wall material samples gave first hints, which screw materials should be preferred in regard of friction for TSG process. In the finally presented case study, wall friction measurements were performed using the above mentioned NCE formulation with known abrasion issues at TSG processing. The results confirmed that changes which led to a reduced visual defect rate of tablets correlated with a decreased wall friction angle. The results suggest wall friction measurements as a potent tool for equipment selection and establishment of a suitable process window prior to conducting TSG experiments.

Continuous twin screw granulation and fluid bed drying: A mechanistic scaling approach focusing optimal tablet properties.

This study provides the results of investigation on scaling approaches for three differently-sized continuous granulation lines, each consisting of a twin screw wet granulation process and a continuous fluid bed drying process. To check the initial scaling approach with regard to granule and tablet properties, a process parameter Design of experiment (DoE) was performed on each of the three equipment scales. The processed formulation did not contain cellulose to allow a high overall flowrate through the directly connected granulation and drying sections. Enhanced scaling aspects showed the influence of Froude number [-] at different twin screw granulator scales and screw speeds on the overgranulated particle fraction [% (V/V] as well as on the scale-dependent drying performance of the continuous fluid bed dryers. Scale-independent, specification limits of the two granule material attributes particle fine fraction [%] and residual water content [%] could be defined, resulting in high tableting performance in terms of tabletability and compressibility. Based on these specification limits and the statistical evaluation of the process parameter DoE, a process design space for the continuous granulation and drying process for each scale was calculated. It came up, that this process design space was decreasing in range with increasing equipment scale. The applicability of the presented scaling approach in terms of granule and tablet properties could successfully be demonstrated by three control experiments performed on the different equipment scales. In sum, this work delivers a basis for a smooth transition of scales within process development on the investigated continuous twin screw granulation and drying lines.

Prediction of solid fraction from powder mixtures based on single component compression analysis.

The aim of this study was to provide a systematic evaluation of various compression models (Percolation, Kawakita, Exponential model) in respect to predict tablet́s solid fraction for direct compression mixtures, based on single component compression analysis. Four mixtures were compressed over a wide pressure range at various fractions of microcrystalline cellulose (MCC) and pre-agglomerated lactose monohydrate (LAC) to compare an adjusted Percolation, Kawakita and a simple Exponential model. Based on single compression analysis of the pure excipients and application of these models, it was possible to predict the solid fraction of all mixtures. The Kawakita model showed overall superior prediction accuracy, whereas the Percolation model resulted in the best fit for mixtures containing microcrystalline cellulose in a range of 72%-48%. Both models were in good agreement at residuals below 3%.