The use of rheology to elucidate the granulation mechanisms of a miscible and immiscible system during continuous twin-screw melt granulation.

Twin-screw hot melt granulation (TS HMG) is a valuable, but still unexplored alternative to granulate temperature and moisture sensitive drugs in a continuous way. Recently, the material behavior of an immiscible drug-binder blend during TS HMG was unraveled by using a rheometer and differential scanning calorimetry (DSC). Additionally, vibrational spectroscopic techniques proved the link between TS HMG and rheology since equal interactions at molecular level did occur in both processes. This allowed to use a rheometer to gain knowledge of the material behavior during hot melt processing of an immiscible drug-binder blend. However, miscibility of a drug-binder formulation and drug-binder interactions appear to influence the rheological properties and, hence conceivably also the granulation mechanism. The aim of this research was to examine if the TS HMG process of a miscible formulation system is comparable with the mechanism of an immiscible system and to evaluate whether rheology still serves as a useful tool to understand and optimize the hot melt granulation (HMG) process. The executed research (thermal analysis, rheological parameters and spectroscopic data) demonstrated the occurrence of a high and broad tan(δ) curve without a loss peak during the rheological temperature ramp which implies a higher material deformability without movement of the softened single polymer chains. Spectroscopic analysis revealed drug-polymer interactions which constrain the polymer to flow independently. As a result, the binder distribution step, which generally follows the immersion step, was hindered. This insight assisted the understanding of the granule properties. Inhomogeneous granules were produced due to large initial nuclei or adhesion of multiple smaller nuclei. Consequently, a higher granulation temperature was required in order to get the binder more homogeneously distributed within the granules.

The use of Rheology Combined with Differential Scanning Calorimetry to Elucidate the Granulation Mechanism of an Immiscible Formulation During Continuous Twin-Screw Melt Granulation.

PURPOSE: Twin screw hot melt granulation (TS HMG) is a valuable, but still unexplored alternative to continuous granulation of moisture sensitive drugs. However, knowledge of the material behavior during TS HMG is crucial to optimize the formulation, process and resulting granule properties. The aim of this study was to evaluate the agglomeration mechanism during TS HMG using a rheometer in combination with differential scanning calorimetry (DSC). METHODS: An immiscible drug-binder formulation (caffeine-Soluplus(®)) was granulated via TS HMG in combination with thermal and rheological analysis (conventional and Rheoscope), granule characterization and Near Infrared chemical imaging (NIR-CI). RESULTS: A thin binder layer with restricted mobility was formed on the surface of the drug particles during granulation and is covered by a second layer with improved mobility when the Soluplus(®) concentration exceeded 15% (w/w). The formation of this second layer was facilitated at elevated granulation temperatures and resulted in smaller and more spherical granules. CONCLUSION: The combination of thermal and rheological analysis and NIR-CI images was advantageous to develop in-depth understanding of the agglomeration mechanism during continuous TS HMG and provided insight in the granule properties as function of process temperature and binder concentration.

Vibrational spectroscopy to support the link between rheology and continuous twin-screw melt granulation on molecular level: A case study.

Twin screw hot melt granulation (TSHMG) is an innovative and continuous drug formulation process allowing granulation of moisture sensitive drugs. However, due to the lack of experience and in-depth process understanding, this technique is not yet widely used. During the TSHMG process, the microstructure of the granules is generated and modified and strongly depends on the flow behavior of the material. Hence, rheology might be a suitable tool to simulate and examine this process. However, chemical interactions of the material are influencing the physical properties leading to the microstructure. In this research project it is spectroscopically investigated whether the heat applied in a rheometer induces the same molecular effects as these occurring during TSHMG of the model formulation caffeine anhydrous/Soluplus®. Hence, it is evaluated whether rheology can be used as a simulation tool to improve the understanding of the material behavior at molecular level during continuous melt granulation. Therefore, in-line Raman spectroscopy is executed during TSHMG and in situ Fourier Transform Infra-red (FTIR) during oscillatory rheological experiments. The results from the in-line Raman monitoring revealed polymorph transition of caffeine anhydrous during twin screw melt granulation with Soluplus® which is stimulated depending on the binder concentration and/or granulation temperature. A correlation was seen between the FTIR spectra obtained during the rheological temperature ramp and the in-line collected Raman spectra during the melt granulation runs. The polymorphic conversion of caffeine anhydrous could be detected in the same temperature range with both techniques, proving the comparability of plate-plate rheometry and hot melt granulation (HMG) for this case with the used parameter settings. Process simulation using rheology combined with in situ FTIR seems a promising approach to increase process understanding and to facilitate binder and parameter selection for TSHMG.