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Dissertation/Thesis Abstract

A Study of Various Process Factors in the Scale Up of a High Shear Granulated Product
by Pappa, David M., Ph.D., University of Cincinnati, 2002, 172; 10857173
Abstract (Summary)

The effects of water level, granulation endpoint, atomization spray, and drug bulk density on granulation / tablet characteristics were studied in a 25L Gral, a 600L Diosna, and 1250L Diosna mixer using a poorly compressible drug substance.

For the 25L lots, increases in granulation water level resulted in a decreased granulation blend bulk density, increased tablet hardness, and slightly decreased tablet dissolution. Increases in granulation endpoint (measured by mixer torque) resulted in increases in granulation blend bulk density and particle size, but did not significantly impact tablet properties. Use of atomization spray at 25L had a small effect on tablet friability weight loss.

For the 1250L lots, increases in water levels resulted in decreased granulation blend bulk density, decreased mean particle size for higher torque levels, higher tablet friability, and lower tablet dissolution. Increases in granulation endpoint (Diosna probe %K) led to increases in granulation blend particle size, increased tablet hardness, and reduced friability Variation of drug bulk density at 1250L only affected granulation blend bulk density.

In comparison to the 600L and 1250L Diosna scales, similar granulation particle size and density as well as tablet hardness and dissolution could be achieved at 25L for similar water levels (21.5-23%) and proper choice of granulation endpoint (140-160 in lbs of torque). Tablet friability for 600L and 1250L scales was not well predicted at 25L.

In comparison to the 600L scale, slightly larger and denser granulation blends were observed at 1250L with lower hardness tablets. While tablet dissolution was equivalent to 600L, tablet friability, particularly capping during friability, was worse in the 1250L system. Increases in granulation endpoint and decreases in water level were necessary to provide similar tablet friability while maximizing dissolution rate.

Despite the differences in scale and equipment (Diosna vs. Gral), water level scaled directly with scale of the mixer. It was possible to empirically determine suitable granulation endpoints to achieve similar product characteristics for all characteristics except tablet friability at 25L.

Indexing (document details)
Advisor: Sakr, A.
School: University of Cincinnati
Department: Pharmaceutical Sciences
School Location: United States -- Ohio
Source: DAI-B 79/10(E), Dissertation Abstracts International
Subjects: Pharmaceutical sciences
Keywords: Granulation, High shear, Scale up
Publication Number: 10857173
ISBN: 978-0-438-02287-4
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