(677c) Defining Scaling Criteria in High Shear Granulation

Pharmaceutical development requires understanding of scale up behaviors of the manufacturing processes. Scale-up of high shear granulation, which is commonly used in the pharmaceutical industry, has been accomplished in a number of ways [1-7]. Typically, impeller tip speeds were kept constant as a scale-up parameter (kinematically similar criterion). Froude number was also suggested a scale-up parameter (as a for dynamic similarity criterion) even for geometrically dissimilar granulators [4].

In this study, the scale up criteria of a typical pharmaceutical high shear granulation process was examined. The high-shear wet granulation process was studied from laboratory to pilot/production scale by (1) keeping the granulation solution to powder mass ratio, the bowl loading, granulation time and the Froude number constant and (2) using the optimal granulation conditions collected at a bench-top scale using a face-centered-central composite design. Pharmaceutically significant attributes of dried granules, and tablets were evaluated. The granulation endpoint for a mixture of microcrystalline cellulose/lactose/Povidone (77:20:3) was studied by correlation to the power consumption profile, manual tactile evaluation, and target properties of granules and tablets. Scale up was examined from a 1L (Key KG5) , 10L (PMA 1) and a 65L (PMA 65) high shear granulator The wet granules were dried in a fluid bed dryer, blended with disintegrant and lubricant, and compressed on a rotatory press (3mm tooling).

Product attributes such as bulk density (0.543± 0.017 g/mL), tapped density (0.691±0.026 g/mL), and flowability (FlowDex =16) of the dried granules and the weight uniformity (RSD 1.55±0.07%) of tablets are comparable across the scales under the scale-up criterion. The particle size distribution of the fluid bed dried granules from equipment of identical design configuration (PMA 1 and 65) are similar (D50 = 80 and 83 μm), but different from that of the KG 5 granulator (D50 = 69 μm). The granule sizes also correlate with the impeller speed and granulator scale. Since the D50 values for the dried granules are similar to that of the input dry blend and larger wet granulation sizes were observed by optical microscopy, the results suggest significant agglomerate attrition during fluid bed drying. The poor granule integrity on down stream processing may be related the a priori determined granulation conditions and/or non optimal dimensionless spray with the binder solution added too fast relative to the powder flux rate. The mean crushing strengths of tablets by wet granulation (1.46-3.08 kP) were somewhat variable and lower than those obtained from direct compression blend (6.32 kP). This is related to the hydration and drying of a typical direct compression ingredient such as microcrystalline cellulose. Discrete power consumption endpoint cannot be determined using the existing formulation and processing parameter.

This study demonstrates that critical process parameters of a typical wet granulation can be mapped using DOE. When the Froude number and key processing parameters are kept constant, the granulation can be scaled-up more successfully with equipment of similar design and configuration. The results also show that the compression behavior of the granules is not only related to the processing conditions alone but also associated with the input material properties. Hence, both the pharmaceutical formulation and process should be addressed when making scale up decisions.

Acknowledgement: The financial support to A. Yan from NSERC is acknowledged.

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