Electronic Thesis and Dissertation Repository


Doctor of Philosophy


Chemical and Biochemical Engineering


Dr. Lauren Briens


High-shear wet granulation is a size enlargement process commonly used by the pharmaceutical industry to improve powder properties for downstream processes, such as tabletting. Granule growth however, is difficult to predict because the final product is sensitive to raw material properties and processing conditions. Development of process analytical technologies (PATs) is recommended by regulators to improve process understanding and monitor quality online.

This work investigates the robustness of AAEs as PAT for high-shear granulation. Condenser microphones suspended in the air exhaust were used to collect AAEs from granulation. Applying power spectral density (PSD) analysis, trends related to wetting and end-point were identified between 20 and 250 Hz. A consistent decrease in PSD was observed with end-point, independent of formulation, material properties and process parameters. A design of experiment (DOE) showed the decrease results from increases in granule size and density, two critical quality attributes. Multivariate analysis confirmed AAEs could be used to monitor changes in size and density online. AAEs were also sensitive to changes in impeller speed, spray rate and total binder volume, suggesting these parameters could be used to adjust processes in real-time and achieve desired product attributes. The source of granulation AAEs was investigated by rotating spheres and wet granules of known size in stainless steel beakers. The results confirmed a relationship to particle size, and revealed AAEs are generated by particle-particle interactions. Overall, the research supports adoption of AAEs as a PAT for high-shear granulation to increase process knowledge and improve product quality.