Scaleup of a high-shear granulation process using a normalized impeller work parameter.

Abstract

A method was evaluated to accurately identify the granulation end points of microcrystalline cellulose formulations by monitoring impeller work during high-shear processing. Impeller watt meters were calibrated in situ to a common standard to enable direct comparison of power values between equipment. Integration of the impeller power (watts) versus time (seconds) profile provides an energy parameter (watt seconds) or "work of granulation" for correlation with physical changes in tablet properties and performance. Granulation end points were accurately predicted for 25-, 65-, and 150-liter manufacturing scales on the basis of development work run on 5.0- and 10-liter equipment using work values normalized for the weight of dry powders in the granulator (watt sec/g). The ability to arrive at functionally equivalent granulation end points, in different equipment and at different impeller speeds, was established through comparison of cohesion indexes (slopes of the tablet breaking strength versus compression force profiles) and granulation size distributions determined by sieve analysis. Work measured at the impeller correlated quantitatively with changes in the granulation bulk and tapped densities, average particle size of the finished powders, and cohesion index, independent of granulator make or model. The observed changes in granulation properties, however, did not correlate with individual process variables such as impeller power (watts) or process time.