(36a) An Experimental Analysis of Fluid Bed Co-Granulation of Two Active Pharmaceutical Ingredients

Authors: 
Bilgili, E., Merck & Co., Inc.
Ko, J. S., Merck & Co., Inc.
Chen, A., Merck & Co., Inc.
Smith, E. J., Merck & Co.
Kamali, A., Merck & Co., Inc.
Tijerina, M., Merck & Co., Inc.
Fliszar, K., Merck & Co., Inc.
Wong, G., Merck and Co. Inc.
Rosen, L., Merck & Co, Inc
Ghosh, S., Merck & Co., Inc.


Fluid bed granulation is a widely used wet granulation process in the pharmaceutical industry. The ability to achieve relatively narrow granule size distribution as well as the use of single equipment for both granulation and drying steps offer significant advantages. This paper presents our efforts toward the development of a fluid bed process for co-granulation of two highly soluble active pharmaceutical ingredients (APIs). The granulations were produced at three scales using Glatt GPCG3 (2 kg), GPCG15 (13 kg), and GPCG120 (130 kg) columns. The effects of binder (Povidone) concentration, binder addition rate, and inlet air temperature were investigated at the GPCG3 scale. Based on the process knowledge generated at the GPCG3 scale, four different granulations were produced at the GPCG15 scale to determine the effects of binder addition rate and moisture level (LOD value) in the powder bed for a given superficial air velocity. 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. Similarities in term of superficial air velocity, drying capacity of air, and droplet size distribution were sought in the scale up from GPCG15 to GPCG120 scale.

The above-produced granulations were subjected to various analyses: particle size distribution, porosity, SEM imaging, X-ray microtomography, sieve assay of the APIs, bulk and tap density, attrition propensity, etc. The droplet size distribution of Povidone solutions depended on binder viscosity, atomization pressure, and solution flow rate. We have demonstrated that for a given Povidone solution, the droplet size distribution could be kept similar by adjusting the atomization pressure when different solution flow rates were considered. Moisture level in the powder bed and the droplet size distribution appear to be the major parameters, which are governed by various operating variables and material properties.

In general, the granules were very porous, relatively fragile, and free-flowing. For a given superficial air velocity profile and droplet size distribution, an increase in binder addition rate resulted in a wetter bed, which in turn led to coarser granule size distributions. The attrition propensity of the granules decreased with an increase in the moisture content of the powder bed during granulation. At higher moisture levels, a drop in yield was observed due to an increased loss into the filters and column surfaces. This along with other process observations point to an optimum moisture level. The paper will also discuss both the practical issues faced during the development and the applicability of some of the simple scale-up rules.

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