(384g) End-Point Determination and Scale-up/Scale-Down of High Shear Wet Granulation Process Using an in-Line Di-Electric Probe

Authors: 
Kheiripour Langroudi, M., Merck & Co., Inc.
Sun, J., Merck & Co., Inc.
Eickhoff, W. M., Merck & Co., Inc.
The main goal of this study is to demonstrate anovel in-line process analytical technology (PAT) for detecting end-point of granulation in a high shear wet granulation (HSWG) process. This technique enabled us to monitor liquid distribution and granule densification across different scales. While many reports in the literature have focused on indirect techniques such as power consumption or torque (which are scale and geometry dependent), in this method a physical property (dielectric permittivity of medium) dependent on the liquid amount and granule porosity (or density) is monitored directly during the course of granulation.

A di-electric probe was modified for recording complex dielectric permittivity of wet mass. The output of the probe was monitored and recorded during liquid addition and wet massing, and samples were taken at corresponding time intervals to correlate the final property of granules to the instrument output. Dependence of the real part of the effective dielectric permittivity on solid fraction of moist powder was suggested by Louge et. al. (1997) for non-spherical particles (snow). We adopted this model for high shear wet granulation process and monitored (in-line) density of wet mass during granulation.

Use of this in-line characterization tool enabled us to successfully transfer a 50% drug load API to a 600 L top-driven granulator without the need for any development batch by monitoring granulation end-point based on physical properties of wet mass. Specifically, we could understand the impact of changing process parameters (impeller speed, spray time and wet massing) and API properties (particle size /density) on final granule attributes and tablet CQAâ??s which was consistent during scale-up/down to geometrically similar or non-similar granulators.

M.Y. Louge, R. Steiner, S.C. Keast, R. Decker, J. Dent, and M. Schneebeli, "Application of capacitance instrumentation to the measurement of density and velocity of flowing snow", Cold Regions Sci. & Tech., 25, 47-63 (1997).