PEPT visualisation of continuous twin screw granulation

[摘要] Wet granulation is one of the key processes in the manufacture of pharmaceutical tablets. Traditionally this has been carried out as a batch process, however the need to improve the manufacturability, flexibility and control of products has seen a move toward continuous processing. Of the existing technologies Twin Screw Granulation has emerged as one of the most promising candidates for continuous wet granulation. Implementation of a new technology in a QbD manner requires robust process understanding and there is a need for characterisation of the fundamentals of this new process. This thesis seeks to bridge this gap by building process understanding of the equipment and mechanisms of granulation. A robust and complete review of the current literature is included in order to compile current knowledge and highlight gaps. This includes a review of the different components of twin screw granulators, particularly the role of the available screw elements and how these form granules. The current work to explore the mixing and residence time is presented as this represents one of the key areas of consideration when moving from a batch to continuous process. Liquid to solid ratio is crucial in the formation of granules in wet granulation and is discussed in detail, including the demonstrated wider applicable range compared to high shear granulation and the attempts at quantification through granulation regime maps. The interaction between screw speed and material feed rate is examined with particular focus on the resultant fill level during granulation. This review highlights gaps in the current research and proposes areas of interest worthy of further investigation, particularly around screw configuration and modelling of the granulation system. Twin screw granulators are adapted from twin screw extruders and used to process materials of very different physical properties with different target results. The differences in material properties and equipment operation lead to differences in flow within the granulator. These differences in flow and the impact on granulation are explored. The starve fed nature of the granulator leads to preferential loading of one screw in conveying zones. It is believed this results in poor mixing during nucleation and results in the measured uneven distribution of liquid within final granules. Considerable improvement in liquid distribution can be made by increasing the overall fill level within the granulator. This highlights the importance of fill level during scale up in ensuring good mixing of during granulation and minimising variance in product. The formation mechanism of 60°F kneading blocks is proposed to be primarily breakage of agglomerates formed during nucleation and the need to correlate screw configuration with granule formation is highlighted. The role of temperature during granulation is explored and in particular highlights the significantly lower mechanical power requirements to granulate at elevated temperature. The physical properties of the formulation materials are explored in detail and it is proposed that the change in solubility with temperature causes the lower power requirement. The impact of temperature highlights the need for good temperature control within granulation systems. It is demonstrated that heat generated through mechanical work can lead to considerable time for the system to reach steady state. The changes in the resultant granule properties with temperature are described demonstrating that variability in temperature can have considerable impact over granule consistency. Flow of material, residence time distribution and mixing are explored in detail through PEPT. Particular emphasis is made to understand the behaviour of screw configuration. It is demonstrated for the first time how torque and residence time increase proportionally with kneading block length. Increasing homogeneity in the sizes in the granule population suggest a predictable relationship between kneading block length and the degree of mixing. The impact of the angle of kneading block is explored and forwarding geometries are shown to have much higher conveying capacities than neutral. Direct comparison of the residence time distributions of 60°F and 90° kneading blocks are made and highlight the comparatively low levels of axial mixing in 60°F blocks. The arrangement of screw configuration is shown to impact the flow of material in the granulator and the properties of granules formed. Results suggest that positioning a mixing zone close to the nucleation site is advantageous in producing more uniform granules. Changes in fill level along the axial length of the granulator are measured through PEPT showing consecutively longer residence time and show the potential to link granule properties to mixing zone intensity as part of process design. The impact of kneading element width is explored and highlights how wide elements produce very dense, similar in size granules for the same length of kneading block. As a result it is proposed that exploration of novel geometries tailored to granulation would be valuable. A novel proof of concept for determining distribution of water throughout the intragranular structure through X-ray Micro-Tomography is presented. The potential to scale the technique to the intergranular level and to quantify the degree of distribution is discussed.

[发布机构] University:University of Birmingham;Department:School of Chemical Engineering

[关键词] R Medicine;RS Pharmacy and materia medica