Wet bead milling by dual centrifugation - An approach to obtain reproducible and differentiable suspensions

Aqueous nano- and microsuspensions containing poorly water-soluble, crystalline drug particles have in the recent years sparked an interest for the preparation of long-acting injectables (LAIs), which increase patient compliance for patients treated for long-term or chronic conditions. Nano- and microsuspensions are often prepared by top-down methods, such as wet bead milling, with the addition of stabilizers in the dispersion media, such as surfactants, which influence the particle sizes and physical stability of the suspension. To improve the efficacy of formulation screening for nano- and microsuspensions, dual centrifugation was utilized in this study whereby 40 samples could be manufactured simultaneously to support the formulation definition. Hence, the type and concentration of stabilizer as well as bead size and milling speed was investigated throughout the presented study, but also the ability of the method to produce consistent data was investigated. The obtained results demonstrated that the particle profile obtained after milling was very consistent from run to run and so was the observed stability data, i.e., running n = 1 experiment per combination could clearly be justified as a predictable approach for the formulation screening. The data also showed that the stabilizer, as well as its concentration highly influenced the physical stability of suspensions containing both the two investigated model compounds, i.e., both cinnarizine and indomethacin, where the biggest increase in particle sizes was observed within the first week. For short-term studies, polysorbate 20 was found to be a suitable stabilizer for suspensions of cinnarizine, whereas sodium dodecyl sulphate was more suitable for indomethacin suspensions immediately after the milling even with 1% (w/v) stabilizer solution, but not sufficient for short-term stability due to an insufficient stabilizer concentration. Smaller particles sizes could be achieved by milling the suspensions with the smallest bead sizes and at the highest speed of 1500 rpm without disrupting the crystal structure of the active pharmaceutical ingredient (API), which was confirmed by X-ray Powder Diffraction.