Development and verification of a novel design space and improved scale-up procedure for fluid bed granulation using a mechanistic model

A mechanistic model has been developed for scale-up of batch fluid bed (top spray) granulation, leading to a design space which was verified against experimental data at pilot-plant and commercial scales. Current published models fail to give reliable scale-up. The process is very sensitive to operating conditions, and intermittent spray and air flow during filter bag shaking is shown to substantially affect moisture content and the final granule properties. Three parameters (inlet air temperature, flow rate and humidity) are consolidated into a composite parameter Q(air) which, in combination with solution spray rate m(sol), gives a two-dimensional design space which is typically trapezoidal. Peak moisture content influences final granule attributes and depends on the ratio (Q(air)/m(sol). Scale-up and product transfer between different equipment are predicted. The model has been applied to an actual pharmaceutical product, achieving robust product quality at commercial scale, and incorporated into a successful regulatory filing submission. (C) 2019 Elsevier B.V. All rights reserved.