(199e) Experimental and Theoretical Study of Simultaneous Agglomeration and Drying in Fluidized Bed Granulator

In the present pharmaceutical drug product process, fluid bed granulation is used to co-granulate two APIs (active pharmaceutical ingredients) at high drug loading using a binder solution spray.  This granulation was studied in a twelve batch, half-fractional, D-optimal Design of Experiments (DOE) with factors of superficial air velocity, spray flowrate/air flowrate ratio (S/Q) , inlet air temperature, and solid components ratio.  The D-optimal design allowed interrogation of large ranges for spray rate, inlet air flowrate, and inlet temperature while controlling process moisture within a proven acceptable range.

Mathematical models of increasing complexity were used to analyze the experimental data as follows:

1. Total heat and mass balance model was employed to evaluate the model’s adjustable parameters (heat loss coefficient and evaporation rate coefficient) by fitting to experimental bed temperature and granule moisture (Loss on Drying = LOD). Decreasing external surface area of growing granules was calculated from experimentally measured particle size distributions (PSDs) and used as a model input. An average heat loss coefficient was evaluated before the correlation between the evaporation rate coefficient, S/Q ratio and inlet temperature was calculated (Correlation 1).
2. A population balance model was employed for the evaluation of agglomeration kernel parameters by fitting to experimental PSDs. A correlation between the experimental granule LOD and granule growth kinetics (agglomeration kernel) was observed and evaluated (Correlation 2).
3. A model combining total balances with population balances was developed and used for direct prediction of granule growth at different process conditions. The heat losses coefficient and Correlation 1 were used for "a priori" calculation of the evaporation coefficient and the granule LOD. Correlation 2 was used for calculation of agglomeration kernel and granule growth.

The combined model can be used to simulate the fluid bed granulation process of the particular formulation at the given scale. The main challenges that remain for process transfer and scalability are the physical meaning of the evaporation rate coefficient, its scalability, and relation to the granulator design (i.e. the control volume of the granule bed).