(11c) A Quantitative Assessment of the Effect of Primary Particle Size Distribution On Granule Inhomogeneity: Modelling and Experiments

Inter-granular heterogeneity within a product batch is one of the major issues in granulation processes [1]. Inhomogeneous (or undesired) distribution of binder, active ingredients and primary particles in different size fractions of granule may influence the uniformity of the final dosage form and hence the application performance [2-5]. The distribution of all the above mentioned components among different size class of granules is profoundly affected by both process/design parameters and operating conditions. For instance, the impeller speed in high shear mixers, droplet size of liquid binder in fluid bed process, binder viscosity and its solidification/drying rate and the corresponding process temperature all play important role in uniform (or otherwise) distribution of the binder in the final granulated particles. Similarly the method of addition of active ingredient and its relative size are among the many factors that control its radial arrangement in the final product [6]. .

The phenomenon of preferential growth of smaller particles and their segregation towards the larger granules has been observed by several workers [1,2]. . Their work provided useful insights into inter-granule heterogeneity and suggested possible ways to control it. Their studies were mostly empirical and involved experiments with particles distributions with different median sizes. Furthermore, these studies were empirically based and do not account for the decoupled effect of particle size distribution on granule inhomogeneity, which can be quantified by fixing the mean diameter and varying the size distribution. In this work we present a systematic approach combining both experimental and computational tools to quantitatively assess the effect of size distribution width on granule inhomogeneity among different size classes. Results obtained are encouraging toward the use of model-based feedback control of granule properties (e.g. porosity, composition) using primary particle size distribution as a control handle.

References

1. Schæfer T., Johnsen D., Johansen A. 2004. Effects of powder particle size and binder viscosity on intergranular and intragranular particle size heterogeneity during high shear granulation. European Journal of Pharmaceutical Sciences 21, 525-531.

2. Scott A.C., Hounslow M.J., Instone T. 2000. Direct evidence of heterogeneity during high-shear granulation. Powder Technology 113, 205-213.

3. Iveson S.M., Litster J.D., Hapgood K., Ennis B.J. 2001. Nucleation, growth and breakage phenomena in agitated wet granulation processes: a review. Powder Technology 117, 3-39.

4. Knight P.C. 2001. Structuring agglomerated products for improved performance. Powder Technology 119, 14-25.

5. Stepanek F. 2004. Computer-aided product design: granule dissolution. Chemical Engineering Research and Design, 82(A11), 1458-1466.

6. Ansari M.A., Stepanek F. 2006. Formation of hollow core granules by fluid bed in situ melt granulation: Modelling and experiments. International Journal of Pharmaceuticals, 321, 108-116.