In-depth investigation of the effects of powder properties on nucleation and continuous granulation

To modernise manufacturing practices and standards, the pharmaceutical industry is undergoing an evolutionary shift from batch processes to a continuous end-to-end operation. Twin screw granulation (TSG) has gained a lot of attention as a viable continuous alternative to traditional high shear mixing for wet granulation. Additionally, regulatory guidelines have advocated the adoption of Quality by Design principles to develop a more versatile operation to consistently deliver quality products. This includes dynamically adjusting operational parameters within an established design space to accommodate variability of input materials and yield a uniform output. The variability of raw materials poses a threat to the Quality Target Product Profile of solid dosages produced via continuous wet granulation. This work sought to assess particle size as a Critical Material Attribute and barrel fill as a Critical Process Parameter by investigating their effects on the Critical Quality Attributes of an immediate release tablet produced via continuous wet granulation using TSG. A Quality by Design approach was taken to characterise and document the progression of the variable raw materials from powders to nuclei (in vitro and in vivo), from nuclei to granules, and from granules to tablets. Each step sought to link the properties, performance and sensitivity of the material output to the initial raw materials to determine criticality. A novel method of engineering three distinct grades of commonly used excipients was used to evaluate the effect of particle size variability. Single drop penetration tests on bimodal formulation blends were analysed to discern the effect of particle size and packing on powder wetting and granule formation. The engineered grades were then used to assess the effect of variability on granule properties and tablet performance resulting from TSG. Whilst the drastic particle size variability manifested differences between the granules formed from the single drop tests, the tablets produced following TSG were all of acceptable quality. Therefore, for the typical blend used, twin screw granulation proved to be robust enough to mitigate input variability. However, a consistently high proportion of fines and oversized granules highlighted a substantial yield inefficiency across all conditions. Powder material residence time distribution was also characterised to explore the channel fill within the barrel. The analysis demonstrated that by maintaining barrel conditions via the material feed rate and screw speed, granule properties can be preserved whilst increasing throughput as a method of scaling output. This study highlighted that whilst material attributes and process parameters can be adjusted to manipulate material output, fundamental features of the TSG design, such as short residence time and liquid addition, limit production efficiency.To modernise manufacturing practices and standards, the pharmaceutical industry is undergoing an evolutionary shift from batch processes to a continuous end-to-end operation. Twin screw granulation (TSG) has gained a lot of attention as a viable continuous alternative to traditional high shear mixing for wet granulation. Additionally, regulatory guidelines have advocated the adoption of Quality by Design principles to develop a more versatile operation to consistently deliver quality products. This includes dynamically adjusting operational parameters within an established design space to accommodate variability of input materials and yield a uniform output. The variability of raw materials poses a threat to the Quality Target Product Profile of solid dosages produced via continuous wet granulation. This work sought to assess particle size as a Critical Material Attribute and barrel fill as a Critical Process Parameter by investigating their effects on the Critical Quality Attributes of an immediate release tablet produced via continuous wet granulation using TSG. A Quality by Design approach was taken to characterise and document the progression of the variable raw materials from powders to nuclei (in vitro and in vivo), from nuclei to granules, and from granules to tablets. Each step sought to link the properties, performance and sensitivity of the material output to the initial raw materials to determine criticality. A novel method of engineering three distinct grades of commonly used excipients was used to evaluate the effect of particle size variability. Single drop penetration tests on bimodal formulation blends were analysed to discern the effect of particle size and packing on powder wetting and granule formation. The engineered grades were then used to assess the effect of variability on granule properties and tablet performance resulting from TSG. Whilst the drastic particle size variability manifested differences between the granules formed from the single drop tests, the tablets produced following TSG were all of acceptable quality. Therefore, for the typical blend used, twin screw granulation proved to be robust enough to mitigate input variability. However, a consistently high proportion of fines and oversized granules highlighted a substantial yield inefficiency across all conditions. Powder material residence time distribution was also characterised to explore the channel fill within the barrel. The analysis demonstrated that by maintaining barrel conditions via the material feed rate and screw speed, granule properties can be preserved whilst increasing throughput as a method of scaling output. This study highlighted that whilst material attributes and process parameters can be adjusted to manipulate material output, fundamental features of the TSG design, such as short residence time and liquid addition, limit production efficiency