(320e) Combining Formulation and Process Aspects for Optimizing the High-Shear Wet Granulation of Common Drugs

Cavinato, M., University of Padua
Andreato, E., University of Padua
Bresciani, M., GlaxoSmithKline
Pignatone, I., GlaxoSmithKline
Bellazzi, G., GlaxoSmithKline
Franceschinis, E., University of Padua
Realdon, N., University of Padua
Canu, P., University of Padua
Santomaso, A. C., University of Padua

The high-shear wet granulation is a very complex process which involves several competing physical phenomena occurring in the granulation vessel [1]. Granules are thus the result of the complex combination of processing parameters and formulation properties. This study represents the summarizing chapter of a detailed research which has been carried out in order to develop a more quantitative and reliable method for the prediction of the granule growth kinetics in high-shear wet granulation [2, 3]. A mixture of some commonly-used pharmaceutical powders, which are amorphous and crystalline in nature, was processed using a small-scale high-shear wet granulator. Three common active pharmaceutical ingredients (paracetamol, caffeine and acetil salicylic acid) were used within the initial formulation in various concentrations. The dimensionless spray flux concept was used in order to vary and optimize the liquid distribution, in accordance with one of the most accepted theories developed by Litster, Hapgood and co-workers [4]. The influence of the drug properties (e.g. primary particle size, hygroscopicity and crystalline degree) on the granule growth kinetics was deeply analysed. The resistance of the wet mass to mixing was measured using the impeller torque monitoring, which is a widely-used technique for the granulation process monitoring and control [2]. Particle size distribution (PSD) was therefore monitored during the entire process through sieve analysis and laser diffraction methods. The drug distribution in the final product was also evaluated measuring the content uniformity. Finally, the estimation of the granule growth onset was performed considering the glass transition concept [2], which takes into account the changes in the mechanical properties of the amorphous material. As can be appreciated from the final results, a finer primary PSD of the drug leads to a slower and more gradual granule growth. Moreover, the final drug distribution is affected by the difference between the primary drug PSD and the excipients PSDs as well as the liquid distribution.

[1] J.D. Litster, B. Ennis, The science and engineering of granulation processes, Kluwer Academic Publisher, 2004. [2] M. Cavinato, M. Bresciani, M. Machin, G. Bellazzi, P. Canu, A.C. Santomaso, Formulation design for optimal high-shear wet granulation using on-line torque measurements, International Journal of Pharmaceutics 387 (2010) 48-55. [3] M. Cavinato, E. Franceschinis, S. Cavallari, N. Realdon, A.C. Santomaso, Technological properties of granule obtained using diphasic binders in high-shear wet granulation, World Congress on Particle Technology, Nuremberg 25-29 April 2010. [4] J.D. Litster, K.P. Hapgood, J.N. Michaels, A. Sims, M. Roberts, S.K. Kameneni, T. Hsu, Liquid distribution in wet granulation: dimensionless spray flux, Powder Technology 114 (2001) 32?39.