(233i) Population Balance Modeling Applied to the Milling of Hot-Melt Extrudates

Hot-melt extrusion has become a common process in the pharmaceutical industry to improve the solubility and bioavailability of low solubility drugs. Milling following the extrusion process is a necessary unit operation so that the extrudate can be blended with excipients for production of capsules and tablets. Despite the importance of milling processes, as in the production of drug products utilizing extrudate, they are still poorly understood and difficult to control. Population balance modeling (PBM) has traditionally been applied to milling processes for control, optimization, simulation, and scale-up. The PBM is composed of the selection function, which describes the propensity for a material to undergo breakage, and the distribution function, which describes the progeny of particles created once a particle is broken. The parameters of these functions depend on the milling conditions (e.g. impeller speed, screen size, feed rate, etc.) and the properties of the material to be milled (e.g. hardness, facture toughness, etc.). Once the parameters of these functions are determined, the PBM can readily predict the particle size distribution (PSD) for any material and any milling condition.

In this work, the so-called time-discrete event-based breakage PBM is applied to model the size reduction of copovidone extrudate using an impact-type mill (Fitz mill). The impeller speed and the screen size of the Fitz mill were varied to determine the dependence of the PBM model parameters to milling conditions. Material properties and process parameters are successfully separated in the PBM which allows for accurate prediction of PSD. The PBM was extended to predict the PSD using a using a pilot-scale mill and found to be useful for scale-up Accordingly, the application of PBM should greatly reduce the effort related to milling development.

All authors are employees of AbbVie. The design, study conduct, and financial support for this research was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.