(51c) Scale-up of High Shear Wet Granulation of Active Formulations Using a Dimensional Analysis Approach

Wet granulation is a key process in the pharmaceutical industry in which a liquid binder is distributed into a powder blend to achieve better powder blend characteristics such as flowability and content uniformity. The wet granulation parameters required to obtain the desirable powder characteristics are first determined in small scale and are then scaled for manufacturing purposes. Since the wet granulation process is inherently complex, a significant amount of time is spent on adapting the process for larger scales. It is thus desirable to shorten this scaling-up procedure by using the knowledge obtained at smaller scales and developing dimensionless relationships that can then predict the behavior at larger scales with minimal or no adjustments. In our study, we use the scale-up methodology based on the dimensional analysis model developed by Anne Faure et al. (Faure, A., et al (1999) ?Applicability of a scale-up methodology for wet granulation processes in Collette Gral high shear mixer-granulators?, European Journal of Pharmaceutical Sciences, 8 (1999), 85-93), in which the coefficients ?a' and ?b' of the model characterize the scaling model for that particular formulation. It is assumed that the net power consumption is a good indicator of the stage in the granulation process, and hence is used to predict the wet granulation end point.

Wet Granulation Scale-Up Model: log Np = a ∙ log(ΨRe ∙ Fr ∙ fill ratio) + b

Np (Power number), ΨRe (Pseudo-Reynolds number), Fr (Froude number), fill ratio are the dimensionless groups derived from the parameters that govern the wet granulation process.

Experiments were conducted in a 10-L Collette Gral to develop scale-up correlations for five formulations ? two placebo formulations, and three active formulations. It was found that the model was a good representation of the wet granulation process for all five formulations. The slopes of the active formulations were not statistically different from one another, but were different from the placebo formulations (which shared similar slopes). The intercepts were statistically distinct for all formulations except for two active formulations. The differences in model coefficients for the different formulations reaffirm the belief that wet granulation parameters are formulation specific and that scale-up correlations are also formulation specific. Additionally, these differences could be an indication that the effects of factors affecting wet granulation (i.e. powder particle size distribution) manifest themselves in the dimensionless groups. Experiments were then conducted to validate the correlations: the net power consumption needed to attain the granulation end point for a placebo formulation run at an impeller speed of 450rpm was calculated from the model, and used as an end point. The granule properties of the validation experiments were found to be in spec. Finally, experiments were conducted in a 25-L Collette Gral. After accounting for the different surface area to volume ratios of the bowls, the experiments were found to be in good agreement with the model developed at the 10-L scale. Thus, once a model has been developed for a particular formulation and operating procedure, it can be used to predict the granulation end point across all scales.