Exploring the relationship between bulk Young ' s Modulus of materials and milling efficiency during wet bead milling of pharmaceutical compounds

Wet bead milling (WBM) is one of the main approaches for manufacturing long acting injectable (LAI) suspensions, wherein the particle size of an Active Pharmaceutical Ingredient (API) is reduced in a liquid vehicle via grinding. A common challenge observed during WBM is long milling time to achieve target particle size, resulting in poor milling efficiency. The objective of this work was to identify potential API attributes predictive of milling efficiency during WBM. In this study, physical and mechanical properties of nine APIs were characterized. Formulations with these APIs were manufactured using WBM. Bulk Young 's Modulus was identified to have a significant influence on the rate of particle attrition. The rank order of Young 's Moduli of the APIs was consistent with that of milling efficiency, estimated by an empirical function defined in this study called Milling Resistance ( phi), representing the holistic impact of milling time, tip speed, bead loading, and batch to chamber volume ratio. The identification of such intrinsic material properties, which provide an early evaluation of potential manufacturing risks, is beneficial to product development, as these assessments can be performed with limited quantities of materials and help identify and design out scale-up challenges.