Optimisation of an in-line Raman spectroscopic method for continuous API quantification during twin-screw wet granulation and its application for process characterisation.

In a previous publication, the development of an in-line Raman spectroscopic method for continuous API quantification during twin-screw wet granulation was presented. An in-line method was developed successfully and the developed method showed an acceptable prediction error. A disadvantage of the developed method was that a measurement was only possible in the dark since light influenced the Raman spectra and made a data interpretation impossible. Therefore, the measurement setup for the implementation of the Raman probe was optimised in the present study to allow a measurement in interior light and to further improve the predictive performance. With the optimised setup, two different calibration models were developed and compared. For the first calibration model, spectra were collected in the dark as before and for the second in interior light. The dark calibration model was able to predict the API content with an RMSEP of 0.31% and the light model with an RMSEP of 0.29%. Thus, both PLS models showed prediction errors in the same order. Consequently, it was possible to evaluate Raman spectra which were collected in interior light. Further, the previous prediction error of 0.60% could be clearly decreased. The optimised Raman method was applicable to evaluate the mixing efficiency of the twin-screw granulator during a split feeding process. The quality of the mixture was monitored behind different barrel sections by Raman spectroscopy and the corresponding API concentrations were predicted by the developed calibration model. For a screw length of 40 D and a screw configuration with two kneading blocks a good mixing ability was observed. For a screw length of 20 D and one kneading block the mixing efficiency was largely acceptable whereas a broad scattering of the API content was observed when no kneading blocks were used. In a second part, an experimental design was performed for each screw configuration to evaluate the influence of the barrel-fill level and screw speed on the mixing efficiency. The quality of the mixture using the entire barrel length was minimally influenced by the fill-level. For the other two positions, the screw speed influenced the quality of the mixture slightly. Thus, for an appropriate mixing, a certain barrel length and a screw configuration with two kneading blocks were necessary.

Impact of Different Dry and Wet Granulation Techniques on Granule and Tablet Properties: A Comparative Study.

Four granulation techniques were compared evaluating their impact on granule properties and the tablet tensile strength. A common formulation was chosen to be processed with both wet and dry granulation techniques: roll compaction/dry granulation, high-shear granulation, twin-screw granulation, and fluidized-bed granulation. The produced granules were characterized in terms of granule size distribution, X-ray powder diffraction, scanning electron microscopy, porosity, and strength. Granules were tableted, and the tablets were evaluated in terms of tensile strength and mass variation. A particular focus was given to granule strength measurements. Granule strength showed to be strongly affected by the used granulation technique. Moreover, a nonlinear inverse correlation was identified between granule strength and tablet tensile strength. High-shear granulation produced the densest and strongest granules, which presented the lowest tablet tensile strength. Granules manufactured by roll compaction/dry granulation showed no loss in tabletability with the used formulation even for the more compacted and strong granules. Tablets produced by the fluidized-bed granulation showed the best properties in terms of tensile strength and mass variation. However, twin-screw granulation presented comparable results for the specific formulation evaluated in the study, thus revealing a great potential of this technique.

Development of an in-line Raman spectroscopic method for continuous API quantification during twin-screw wet granulation.

Raman spectroscopy was evaluated as a process analytical technology (PAT) tool for continuous API quantification during twin-screw wet granulation. Therefore, a Raman probe was implemented in front of the granulator barrel. This setup enabled the collection of Raman spectra upon a constant granule flow. To develop an in-line PLS calibration model, eight binary mixtures of the API and lactose monohydrate with API contents between 5 and 50% were pre-blended and granulated in a twin-screw granulator with a screw speed of 150 rpm and a powder feed rate of 40 g/min. Water was used as a granulation liquid with different liquid to solid ratios depending on the API content. Ibuprofen and diclofenac sodium were chosen as model drugs and separated PLS models were built for each API. The predictive performance of the developed PLS models was determined by granulating and monitoring new test samples containing different API concentrations. This evaluation showed that the models were able to predict the API concentration with an RMSEP of 0.59% for ibuprofen and 1.5% for diclofenac sodium. In a second part, the developed in-line Raman spectroscopic method was used to determine the API concentration during a split feeding process. Therefore, the API and lactose monohydrate were added by two independently adjustable feeders into the twin-screw granulator barrel. The in-line spectroscopy analysis which was verified by UV-analysis indicated that the mixing ability of the twin-screw granulator was good for the used settings and all adjusted API concentrations.