Process and scaling parameters for wet media milling in early phase drug development: A knowledge based approach

Abstract

Wet media milling is a well-established unit operation for the manufacturing of suspension formulations during early phase pharmaceutical development. However, knowledge about the kinetics of particle breakage is limited, although the impact of hydro-mechanical process parameters on the mean particle size of finished suspensions has been thoroughly investigated. We performed in this work milling trials with two different compounds on two milling devices with different mechanical design and volume scale. We analyzed our data in terms of a kinetic milling model where we included the milling speed as an explicit process parameter in addition to the process duration. We show, that the milling kinetics can be fairly well predicted for a wide range of these operating parameters. The proposed milling model may therefore be useful for rational process planning and scale-up considerations in the industrial setting.

Keywords: Atorvastatin calcium trihydrate; Ball mill; Grinding limit; Micro- and nanoparticles; Milling kinetics; Pharmaceutical suspensions; Physical pharmacy and pharmaceutical technology; Suspensions; Wet media milling.