Continuous twin-screw melt granulation of poorly compressible and thermal labile drug




Kittikunakorn, Nada

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Continuous twin-screw melt granulation (TSMG) has been widely used for the last 50 years in various industrial processes. For pharmaceutical manufacturing, TSMG offers many advantages over continuous twin-screw wet granulation and roller compaction. However, TSMG is still limited since there is still a lack of understanding and familiarity by pharmaceutical scientists for the continuous manufacturing of tablets. Therefore, this dissertation aims to facilitate the broader adoption of TSMG by mechanistic understanding of the granulation behavior and the challenges that need to be concerned during the process. In Chapter 1, the processes, challenges, and the future of twin-screw granulation (wet and melt granulation) for manufacturing oral tablets and capsules are reviewed. Four aspects of twin-screw granulation, including (1) granule formation mechanisms, (2) benefit over conventional batch process, (3) process control and monitoring, and (4) history, recent progress, and the future will be highlighted in this chapter. In Chapter 2, the recent progress of twin-screw melt granulation (TSMG) will be reviewed. As TSMG is a solvent-free process, it is a preferable granulation method for a moisture-sensitive drug as compared to twin-screw wet granulation (TSWG). Therefore, this chapter focuses on the understanding of how the formulation and process impact the granule properties as well as the challenges of TSMG that is needed to be considered. In Chapter 3, the effect of thermal binders (PEG, HPC, and Compritol), molecular weight, and binder particle size on the physicochemical properties of gabapentin (GABA), a thermally labile drug, in granules prepared using TSMG was investigated. It was found that higher degradation and crystal size reduction of GABA were observed in HPC-based formulation. Smaller particle size and lower molecular weight of HPC led to faster granule growth. The tabletability of granules was insensitive to the variations in particle size and molecular weight of HPC. In Chapter 4, the effect of screw profile and processing conditions on the process-induced transformation and chemical degradation of gabapentin was studied. It was found that both the granules size and gabapentin degradant level correlated positively with the specific rate, the ratio between feed rate and screw speed. At the higher specific rate, the barrel was filled to a greater extent, enhancing the compressive forces. This resulted in more interaction between the powder particles, facilitating the granule growth as well as generating the crystal size reduction which led to more degradation. In Chapter 5, the difference of granulation behavior in two sizes of twin-screw extruder (Nano-16 and Micro-18) was investigated. It was observed that due to the difference in extruder geometries between the two extruders, correlations between granule properties and processing parameters are different. For Nano-16, DF was a critical parameter, where higher DF led to higher degradant levels and more compressible granules. For granules prepared using the Micro-18, SME was a critical parameter, where a higher SME led to higher degradant level and more compressible granules.


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