Melt Milling as Manufacturing Method for Solid Crystalline Suspensions

Production of submicron particles (0.1-1 µm) has been identified by the pharmaceutical industry as a key technology to enhance the bioavailability of poorly water-soluble drugs. However, nanosuspensions derived from commonly applied wet milling suffer from long-term stability issues, making further downstream processing necessary. In previous works, the formulation as a long–term stable solid crystalline suspension (SCS) was introduced, for which the crystalline drug is ground in a (molten) hydrophilic carrier matrix. The model formulation of the antimycotic Griseofulvin and the sugar alcohol Xylitol was reused for comparative purposes. Due to process limitations regarding the degree of comminution, the present work demonstrates the application of fine grinding in the framework of SCS manufacturing. A custom-built mill with annular gap geometry successfully yielded particles in the targeted submicron range. A process optimization study lead to improved energy utilization during grinding, which reduced the necessary grinding time and, thereby, the thermal exposition of the drug. Investigation of solid-state properties of the SCS, via differential scanning calorimetry and x-ray powder diffraction, showed no alteration even for extended grinding times. In dissolution experiments, the melt-milled SCS outperformed its predecessors, although mostly agglomerates were found by SEM imaging in the solidified product. In conclusion, melt milling is a valuable tool to overcome low aqueous solubility.