(448m) Process Analytical Technology for High Shear Wet Granulation: Wet Mass Consistency Reported By in-Line Drag Flow Force Sensor Is Consistent with Powder Rheology Measured By at-Line FT4 Powder Rheometer

Authors: 
Freeman, T., Freeman Technology
Narang, A., Bristol-Myers Squibb
Sheverev, V., Lenterra, Inc.
Both, D., Bristol-Myers Squibb
Stapaniuk, V., Lenterra, Inc.
Macias, K., Bristol-Myers Squibb
Subramanian, G., Bristol-Myers Squibb
Delancy, M., Freeman Technology Inc.
High shear wet granulation (HSWG) is commonly used in the pharmaceutical industry to tailor the powder properties to the requirements of tableting. The effect of changes in the equipment, scale, or formulation are typically assessed on the attributes of dried granules or compressed tablets. Consequently, quality-by-design drug product development paradigms rely primarily on end product critical quality attributes (CQAs), with limited information on in-process material attributes that can be measured in-line and real-time using appropriate process analytical technologies (PATs) that can enable proactive and flexible control of unit operations.

Optimization of wet granulation process parameters is usually an empirical process that relies on statistical design-of-experiment studies to correlate critical process parameters with CQAs. Development of high (temporal) resolution in-line PATs that correlate well with end product CQAs is crucial to improve process understanding and monitor quality in-line. The primary technologies investigated for HSWG monitoring include power consumption, near-infrared spectroscopy, Raman spectroscopy, capacitance measurements, microwave measurements, imaging, focused beam reflectance measurements, spatial filter velocimetry, stress and vibration measurements, as well as acoustic emissions. All these technologies show promise, but have specific considerations that hinder their widespread acceptance.

The application of a drag flow force (DFF) sensor as a monitoring tool, which overcomes the limitations of other HSWG PATs while providing high frequency and high (temporal) resolution in-line granule densification data that correlates well with granule densification and tablet dissolution, was recently reported. The DFF sensor provides robust, high sensitivity, and high (temporal) resolution in-line measurement of local flow forces within the granulator. The DFF sensor is a thin, hollow cylindrical pin, whose deflection in the flow is measured by 2 optical strain gauges affixed at the inner surface of the pin. The sensor is calibrated to measure the DFF that is related to fundamental parameters of the material such as density and shear viscosity. In addition to force, the DFF sensor outputs temperature. The DFF sensor was shown to be sensitive to changes in formulation composition and process parameters using both a placebo and a brivanib alaninate formulation. In this study, the in-line response of the DFF sensor is correlated with at-line measurements of flow properties of the wet granules collected at different time points during processing and measured using an FT4 Powder Rheometer®. This correlation allows better understanding of the DFF sensor response as representing fundamental properties of the granules which are known to directly impact tablet CQAs.

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