Comparison of wet milling and dry milling routes for ibuprofen pharmaceutical crystals and their impact on pharmaceutical and biopharmaceutical properties

Abstract

Understanding the differences between wet milling (WM) and the dry milling (DM) is crucial in selecting the methodology used in pharmaceutical milling processes. This research examined WM and DM processes for ibuprofen (IBU), a Biopharmaceutics Classification System (BCS) class II drug (low solubility, high permeability). A design of experiment (DOE) was performed for each route of milling using the Comil, with rotor speed, sieve size, milling time and rotor shape selected as variables. Solid state characterization was performed on pre- and post-milled samples by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and powder X-ray diffraction (PXRD). Screen size and speed were observed to be the most important factors in terms of milled particle size, where lower screen size and high speed resulted in smaller particle size. WM resulted in smaller size and larger specific surface area (SSA) compared to DM, when the same milling parameters were used for both processes. It was observed that rotor shape had a negligible impact on particle size. It was observed that the wet-milled samples demonstrated better flow and faster dissolution for the same run (same milling parameters) in the DOE (statistically significant p < 0.05). Differences in measured surface energy values were consistent with differences in the dissolution rates observed. The development of electrostatic charge and/or differences in surface energy as a result of DM probably resulted in particle agglomeration, which resulted in a larger particle size, poor flow performance, and poor dissolution performance. This hypothesis is supported by differences in the dispersive energy component calculated from contact angle measurements (statistically significant p < 0.05). These results indicate that, for IBU, WM would be a better option than DM to facilitate particle size reduction with subsequent improvement in the powder dissolution behaviour and flow properties. The findings presented in this study may be applicable to BCS class II molecules which have poor flow properties due to electrostatic charging on dry milling.