Modelling of pharmaceutical granule size reduction in a conical screen mill

Conical screen mills, such as the Comil, are ubiquitous in the secondary manufacture of solid oral dosage forms in the pharmaceutical industry. These mills are used for purposes ranging from coarse delumping to fine control of granule size. Control of granule size is important, in particular with respect to manufacturability (flow) and product quality (weight uniformity, dissolution). Population balance models are ideally suited to mechanistically modelling the change in the granule size distribution as the result of granule breakage. Use of a population balance model for granule breakage requires identifying a suitable breakage rate constant and a breakage function (or fragment distribution). A method is presented whereby assuming limited hold-up time in the mill a classification kernel can be used to model the size reduction process. This classification kernel essentially makes the population balance equation insensitive to the breakage rate, leaving only the fragment distribution to be determined. A general purpose fragment distribution is proposed that captures both the localised disintegration and multiple fragmentation modes of agglomerate impact breakage. The model accurately describes the milled granule size distribution. Additionally, the model exhibits characteristic features of dry granule size reduction in a conical screen mill, including the size reduction paradox, whereby coarser input material results in increased generation of fines.