(553d) Controlling The Key Response Variables Through Scaling Rules During The Scale-Up Of A Fluidized Bed Granulation Process

Bilgili, E., Merck & Co., Inc.
Ko, J., Merck & Co., Inc.
Chen, A., Merck & Co., Inc.
Smith, E., Merck & Co.
Rajniak, P., Merck & Co., Inc.
Fliszar, K., Merck & Co., Inc.
Wong, G., Merck & Co., Inc.
Rosen, L., Merck & Co, Inc
Grubb, D., University of Kentucky
Bika, D., Merck & Co., Inc.

This paper presents recent work to develop a fluidized bed process for co-granulation of two highly water-soluble active pharmaceutical ingredients (APIs). The granulations were produced at three scales corresponding to batch sizes of 2 kg, 13 kg, and 130 kg. The effects of binder concentration, binder addition rate, and inlet air temperature were investigated at the 2 kg scale. Based on the process knowledge generated at this scale, four granulations were produced at the 13 kg scale to determine the effects of binder addition rate and moisture level on the process, while using the same superficial air velocity. A Malvern Insitec RTSizer was used to determine the droplet size distribution of binder solutions, which was then used as a guide in our scale-up procedure. The scale up from 13 kg to 130 kg was based on maintaining similar excess air velocity, moisture level, and droplet size distribution. The above-produced granulations were subjected to various analyses: particle size distribution, porosity, SEM imaging, sieve assay of the APIs, bulk and tap density.

The granule growth was monotonic, and the granule size distributions exhibited self-similar character. A simple one-parameter population balance model explained the growth behavior. In general, the granules were very porous, relatively fragile, and free-flowing. Downstream processing of the granules in compression led to acceptable tablet attributes. At higher moisture levels, a drop in granulation yield was observed due to an increased loss into the filters and column surfaces. This, along with other process observations, points to an optimum moisture level for fluid bed granulation.

The paper will highlight both the practical issues faced during the development and the applicability of various proposed scaling rules. Excess air velocity, moisture level in the powder bed, and the droplet size distribution appear to be the key response variables, which are governed by various equipment, process, and formulation parameters. The presentation demonstrates the success of scaling rules for maintaining the key response variables, and thus the granule size distribution upon scale-up.