Scale-up of a melt granulation process in high shear mixers.

Melt granulation technique is a process by which pharmaceutical powders can be agglomerated using a substance which melts at relatively low temperature; after melting, the substance acts like a liquid binding, thus the melt granulation does not require the use of solvents (organic or aqueous). In recent years, the interest in melt granulation has increased justified by the advantages of this technique over traditional wet granulation: melt granulation is less consuming in terms of time and energy and no risk originating from residuals solvents are present. In perspective of pharmaceutical industry, the scale-up of any process is a critical step leading to additional costs. Several works have been performed concerning the scale up of wet granulation process, however, no paper dealing with the scale up of melt granulation has been yet published. Therefore, the aims of this study were to investigate the scale-up feasibility of melt granulation process in high shear mixers and to establish one approach able to lead constant characteristics of the granules. A series of four high shear mixers, manufactured by Romaco Zanchetta (Lucca, Italy), have been examined. The equipments range from small scale (2.8 liters) up to the production scale (600 liters). A placebo formulation, containing a-lactose monohydrate as diluent and polyethylene glycol 4000 (PEG 4000) as meltable binder, was employed. In total, 91 batches of granules were produced and characterized by morphology (SEM), size distribution analysis and Carr index. The granulation process is scaled up having as target spherical granules, good flowability, gaussian distribution size and median diameter of 750 micron. The results show that the introduction of a corrective factor for the calculation of the batch size allows to overcome the absence of geometric similitude between the high shear mixers. Moreover, employing costant tip speed and swept volume values and using both power consumption and temperature measurements to establish the correct end-point of kneading, it was possible to produce in the four equipments granules having reproducible size distribution, flowability and morphology. In conclusion, the scale up of a melt granulation process in a series of four high shear mixer was successfully performed and a guideline usefull for the scale up of others formulations has been drafted.