Is roller milling – the low energy wet bead media milling – a reproducible and robust milling method for formulation investigation of aqueous suspensions?

Long-acting injectables have shown to offer a prolonged release of a drug compound up to several months, providing the opportunity to increase patient compliance for treatment of long-term and chronic conditions. Different formulation technologies have already been utilized for long-acting injectables, and especially aqueous suspensions with crystalline drug particles in the sub-micron range have sparked an interest for future development of long-acting injectables. Wet bead milling is a common top-down process used to prepare nano- and microsuspensions of crystalline drug particles with the addition of surfactants in the dispersion medium, which are working as stabilizers to prevent agglomeration or crystal growth that ultimately may influence the physical stability of nano- and microsuspensions. To examine the reproducibility of the suspensions manufactured and the behavior of their physical stability, i.e., changes in particle sizes over time, low-energy roller mill was utilized for the manufacturing of nano- and microsuspensions in the present study. Investigated formulation parameters was stabilizer type and concentration and milling parameters varied in bead size and duration of milling. The obtained results demonstrated that the physical stability of suspensions containing the two model compounds, cinnarizine and indomethacin, was highly affected by the constitution of surfactant and processing. Various size classes were obtained and accompanied by high variations between the individual samples that indicated uneven and unpredictable milling by the low-energy roller mill, limiting the possibility to prepare reproducible and physical stable suspensions. Short-term stability studies revealed clear tendencies towards reversed Ostwald ripening of suspensions stabilized with poloxamer 188 that contained cinnarizine as the drug compound, and to a smaller extent suspensions containing indomethacin. Furthermore, X-ray Powder Diffraction confirmed no alteration of the drug compounds crystal structure after roller milling for multiple days.