Evaluation of Milling Method on the Surface Energetics of Molecular Crystals Using Inverse Gas Chromatography

The objective of this study was to determine whether high shear wet milling (HSWM) has an impact on the surface properties of model pharmaceutical compounds compared to dry milling (DM, impact milling). The bulk and surface properties of milled samples were characterized by solid-state methods (XRPD, TGA, DSC, microscopy) and inverse gas chromatography (IGC). The bulk properties of both model compounds (succinic acid and sucrose) were unaffected by milling method. For succinic acid, the solvents methyl <i>tert</i>-butyl ether (MTBE) and isopropyl acetate resulted in small changes in surface properties of the powders relative to the DM material. In HSWM, the dispersive surface free energy of sucrose depended on the solvent polarity, changing from 55 to 71 to 90 mJ/m², for hexane, MTBE, and ethanol, respectively, whereas the DM material had a value of 44 mJ/m². The surface free energy difference between DM and HSWM was not attributable to specific solvent adsorption and was shown to be caused by a combination of attrition in the presence of solvent. Analysis of the slip planes and σ surfaces for the compounds supported the nature of particle attrition and its impact on surface energics. Assessment of surface energetics may be used to establish consistency of drug substance surface characteristics when previously established milling processes are modified