The overall objectives of the project are to model and experimentally verify fundamental aspects of the mechanically acjtated granulation processes usivg binders, with focus directed to surface free energy approaches coupled with the experimental technique of mixer torque rheometry (MTR). Further general aims, building on the surface interaction and hlTR knowledge, are to develop predictive relationships which can be applied to address scale up in high shear mixer--Granulators and dry granule characteristics. In all sections of the project, MTR is regarded as a pivotal experimental method.
The surface free energy model utilism, spreading coefficents and interaction paramaters between substrate and binder components has been shown in previous reported project (J and spreading phenomena during granulation by mechanical agitation. Both model and a range of representative substrates with selected binders have been evaluated and predictions verified expel-imentally using mean torque granulation profiles from MTR. This knowledge enables formulation components to be selected in a more rational manner than is current practice, based on sound, physicochemical principles. A key requirement, however, is to link the wet mass torque (rheology) with dry granule properties.
Results of studies probing such relationships are presented. A testing method has been developed which defines a friability index, a measure of the relative ease with which dry granules fragment and fracture in a standardised procedure. For three representative granule formulations, similar trends between mean torque and friability index were observed, indicating that data from MTR for wet massed samples provide an indicator of mechanical characteristics of dry granules prepared from the wet mass. These observations have clear practical and industrial relevance, since, together with selection criteria for formulation components mentioned above, procedures which accommodate both granulation component properties and final granule characteristics are being work to explain wettin, 7 to couple other practically important dry granule properties to wet mass rheology and material properties is indicated.
In considering scale up issues it was considered critically important to test developed relationships at realistic industrial levels and capacity. This has been achieved through extensive collaboration and liaison with mixer-granulator equipment manufacturers as well as by the gnerous supply of large quantities of experimental materials by Zeneca Pharmaceuticals. Based on a dimensionless number principle linking power number with three other dimensionless groups (Reynolds number, Froude number, and a fill ratio term for the miser-granulator-- bowl) a scale up function was developed. This enables a master curve for a specifted formulation to be genet-ated when granulated in geometrically similar equipment, Consistency of wet mass density and rheological 3 characteristics from are key pai-ameters in providing linkage between laboratory, pilot and large scale processes.
These studies, combined with those reported previously, show that in a series of fixed bowl high shear mixer-granulators where geometric similarity is respected, scale up to a selected end point can be predicted over the range 25- 1800 litre bowl capacity. This is the first time a predictive scale up strategy has been successfuly demonstrated to hold over this full range of capacity range for such mixer-granulators.
In a practical situation for scale up prediction, the sequence of events would be to define the formulation master curve (i.e. power number correlation) using a small scale mixer- granulator, identify the optimal density and rhcological consistency for dry granule properties and performance, use these values and lnixel--gl-aliulator variables to calculate power requirements on large scale equipment, run the process at defined setting, and check product for density and consistency.
This report also details further scale up studies on high shear removeable bowl and low shear planetary mixer-ganulators. In the former, geometric similarity was not respected in bowl dimensions for the 75L and 600L equipment and, as expected, parallel power number correlations curves were not found. However, for two bowl sizes of a planetary mixer granulator, although limited in scale up factor, the relationship was verified. Further studies are indicated to probe the breadth of application of these rules, considering additional terms for non-geometric similarity and material and formulation factors.