(159b) Characterization and Filterability Studies for Tamiflu (Oseltamivir Phosphate) at Roche Carolina, Inc

In the API step for production of Tamiflu (Oseltamivir Phosphate), isolation of product from the process slurry through centrifugation proves to be the process bottleneck. To gain a better understanding of changes in solid-state characteristics of the API and to determine their effect on product isolation with the aim of improving filtration rates, a methodology was developed to assess changes in filterability during batch hold times: FBRM techniques were used in conjunction with universal constant-pressure filtration models to evaluate changes in chord length distributions and corresponding specific cake resistances. Additional solid-state characteristics were monitored throughout crystallization, isolation, and drying of the API with BET specific surface area measurements and Scanning Electron Microscopy. Combined data from these techniques indicate a number of conclusions that impact production rates and final product properties of the API. During batch hold times, shifts in chord-length distributions occur towards lower particle sizes, most likely due to crystal breakage from slurry tank recirculation. Although these changes translate to an increase in specific cake resistance during filtration, they apparently do not impact centrifugation cycle time significantly. Appreciable changes were observed in crystal morphology during the drying, which indicates that critical API properties such as bulk density and average crystal size are a strong function of variables in the drying stage.