Granulation is one of the most crucial processes for the pharmaceutical industry. It allows to improve the tabletability and the flowing properties of the powdered formulations. Moreover granules production reduces the dust presence in the working environment improving the operator safety. Several granulation techniques exist and are divided in two main groups: dry and wet granulation processes. Among these, high-shear mixer is one of the most employed wet granulation techniques in the pharmaceutical industries. Despite its wide application, the complete control of the process is far to be achieved. This is mainly due to the several variables which affect the resulting product; in fact high-shear wet granulation presents several process parameters which need to be controlled and most of them are formulation dependent. For this reason the process development is particularly difficult with this technique, with the risk for high-shear mixers to become the last choice when a new formulation needs to be granulated. However, the characteristics of granules produced in a high-shear mixer are strongly affected by the rheology of the wet mass which is processed; thus, it could be a useful tool to obtain preliminary indications about the evolution of the high-shear wet granulation process (HSWG). Several works in literature studied the application of the on-line and off-line wet mass rheology for process control, end-point determination and scale-up. Despite those studies, it is still not possible to employ wet mass rheology unambiguously to predict the granulation process. The possibility to predict several aspects of the granulation process, such as: the amount of liquid binder which need to be employed, the granules growth regimes and the parameters which have a important impact on the granules characteristics, would be of dramatic importance for process development and in particular from a Quality-by-Design (QbD) perspective. The aim of the present work is to investigate the possibility of employing a mixer torque rheometer to predict: the amount of liquid for the process, the granules growth mechanisms and the critical process parameters using different formulations. Results obtained in the first phase of the project have shown that an easy and fast prediction of the optimal liquid amount, required to produce granules with acceptable technological properties, could be carried out by a rheological characterization using a mixer torque rheometer. Moreover the application of the second derivative to the torque profile have permitted to develop a reliable method to identify the optimal value of L/S, following confirmed by granulation experiments.
In the second phase, evaluation of the wet granules strength (expressed as consistency) has permitted to highlight a relationship between wet granule cohesion and the granules growth regimes. In particular, the value of wet mass consistency showed to be indicative of the growth mechanism followed by the granules during the process. In order to predict, and not only to describe, the granule growth mechanism, the torque evolution of wet masses was registered along time and it was used to evaluate the maximum value of the wet mass cohesion, corresponding to the Torque peak. Torque peak showed to be directly related to the final consistency of the granules produced with the same formulation and thus it could be used for the granules growth regimes prediction.
Finally in the last phase of the project was also investigated the possibility to predict the critical process parameters of the HSWG process through rheological measurements. Results highlighted that Torque peak could represent a potential tool for critical process parameters assessments.
Moreover it seems able to give important indications about the granule growth kinetic for those formulations which presented a steady growth regime. In particular, torque peak seemed to be a feasible tool for the prediction of the parameters which had the most significant impact on the mean diameter of the granules. In fact, the data acquired with the mixer torque rheometer in terms of Torque peak showed good accordance with the results obtained from granulation experiments. In conclusion, the results achieved with this study demonstrated the possibility of employing the wet mass rheology to predict several aspects of the high-shear wet granulation process and gain the necessary knowledge to improve the process development phase.