(169d) Process Development of a Media Milling Process for a Nanoparticle Drug Formulation

Stirred media milling technology using polymeric media and polymeric stabilizer is utilized to reduce the particle size of a poorly water-soluble active pharmaceutical ingredient (API) to enhance bioavailability and minimize food effect. The process consists of milling the slurry of API particles in an aqueous solution of stabilizers from micron to nanometer size range. Process development activities focussed on developing a robust and an efficient media milling process. The design objectives included minimizing media milling time, limiting the colloidal dispersion in the media mill to less than 38 ºC to eliminate the polymeric stabilizer from precipitating, and operating away from hydraulic packing at which the media mill action is significantly reduced due to the packing of the media at the exit of the media mill. The incorporation and optimization of an initial API particle size reduction step using a high shear rotor-stator mixer prior to the media milling step to enhance the robustness of the media milling process will be presented. The inter-relationship between various operating variables and the above design criteria will be presented. The use of media mill heat transfer characteristics, power law correlation, and operating range for hydraulic packing to find the optimal operating parameters will be discussed. The differences in the power law correlation of the pilot-scale and commercial-scale media mills and its impact on the media mill performance will be presented. Finally, the criteria implemented to scale up from the pilot-scale to the commercial-scale media mill will be presented.