Continuous granulation and drying

Abstract

This thesis investigated a complete integrated continuous granulation and drying line including the process units continuous dosing, continuous twin screw wet granulation and continuous fluid bed drying, considering also the quality of resulting tablets.<br /> In the first part of the thesis (chapters 4, 5 and 6), a process understanding for the integrated continuous line was built investigating all three process units. <br /> Powder characterisation of starting materials of a broad range of different excipients and binary mixtures using volumetric dosing mode proved the importance of the hopper fill level for an accurate dosing rate. Furthermore, it could be shown, that both material attributes bulk density and flowability of the excipient or binary mixture are of high importance and therefore critical for the resulting dosing rate and accuracy of dosing rate over time.<br /> Regarding the continuous twin screw wet granulation, two different formulations were investigated and compared in terms of their granulation behaviour. Both formulations were therefore granulated and dried using the integrated continuous granulation and drying line. One formulation included cellulose, the other formulation explicitly did not. For both investigated formulations granulation moisture level was identified to be a critical process parameter and to have a high impact on the particle size distribution of the produced granules. Interestingly the other two investigated granulation-related process parameters powder feed rate and barrel fill level appeared to be of minor importance for resulting granules material attributes and tablet quality attributes. Characteristics of the two formulations and their granulation behaviour were thoroughly investigated and significant differences could be identified and described. Non beneficial granulation behaviour could be overcome and resulting tablets showed improved tabletability as expected.<br /> As the third unit in the process-chain, the continuous fluid bed dryer was evaluated using the same formulations as being used for the investigation of twin screw wet granulation process. The drying performance was investigated by evaluation of the effect of three main process parameters on granule material attributes and tablet quality attributes. Particle fine fraction and residual water content of the dried granules could be identified to be critical material attributes with regard to tabletability and compressibility. It could also be shown that independent of the used formulation both mentioned material attributes could directly and systematically be controlled by the investigated process parameters.<br /> Within development of a new pharmaceutical product scale-up is an important aspect to be considered in addition to the process understanding presented in the first part of the thesis. Therefore, in the second part of the thesis (chapter 7), a scale up approach for three continuous granulation and drying lines was investigated. For twin screw wet granulation process, enhanced scaling aspects were analysed showing e.g. the influence of Froude number on formation of coarse particle fraction. Within systematic evaluation of the applied scaling approach the drying capacity parameter DCP could be established which can further be utilized to adjust the drying capacity across different scales of continuous fluid bed driers. Statistical evaluation of the DoEs per scale enabled to calculate process design spaces for each scale; targeting on identified critical material attributes of the granules that result in good tabletability and compressibility performance. Overall, it could be shown that scaling of the three different continuous granulation and drying lines was successful using the presented scaling approach.<br /> A special feature of continuous manufacturing compared to traditional batch processing is the consideration of time-dependent effects. Out of that reason, the third part of the thesis (chapter 8) deals with long-term effects evaluated during long-term runs using the integrated continuous granulation and drying line. For the continuous dosing unit a fast, more frequent refilling of the hopper was identified to be key for an accurate dosing rate. With regard to the twin screw wet granulation process, it was found that an efficient temperature control is essential to avoid high shear and friction energies inside the granulator. Parameters were identified indicating the stability and healthiness of the granulation system. Abrasion and friction effects are special, mechanical risks of the twin screw wet granulation process. In the last part of the thesis (chapter 9) that process risk was considered by applying wall friction measurements with a Schulze ring shear tester. Deducted from the evaluation of wall friction angle of different formulations a case study made it possible to link the measured wall friction angles to the calculated specific mechanical energy during twin screw granulation and to the observed visual defect rate of tablets occurring due to abrasion effects during granulation. Thus, wall friction measurements could serve as useful tool to assess abrasion effects inside the twin screw granulator.