Long-term versus short-term stress physical stability assessment of pharmaceutical nano- and microsuspensions.

The physical stability of nano- and microsuspensions is a crucial factor to consider during formulation investigation and optimization. Short-term stress studies are often used as predictive studies to evaluate the long-term physical stability of pharmaceutical suspensions. The short-term stress stability of cinnarizine suspensions prepared with dual centrifugation (1 mL scale) was therefore compared to the long-term storage stability, i.e., 18 months of cinnarizine suspensions milled with an agitator bead mill in up-scale. Storage temperature was the main factor impacting the particle size profiles of cinnarizine suspensions stabilized with polysorbate 20 in both short-term stress studies and long-term stability assessment. During short-term stress studies, only minor changes in sizes of particles were seen for suspensions subjected to mechanical stress factors such as rotation or shaking for 72 h where the increase in particle sizes was mainly attributed to the adjustment of storage temperature. Thermal cycling resulted in destabilization of cinnarizine suspensions with minor improvement of the particle size profiles with the addition of mannitol when subjected to heating and freezing. Early indications in the short-term assessment also showed that 1 % (w/v) polysorbate was sufficient for the apparent short-term physical stability when stored at different storage temperatures. Smaller sizes of cinnarizine particles were obtained with a higher concentration of polysorbate 20 during thermal cycling, similar to the improvement in the long-term stability of cinnarizine suspensions stabilized with higher stabilization concentration, indicating that higher percentage of polysorbate 20 as the stabilizer was necessary at long versus short term stability. Storage at 5.0 °C resulted in somehow physical stable suspensions with time, whereas long term storage at 25 °C and 40 °C resulted in increased particle sizes with time, especially in the case of suspensions that were stabilized with the lowest concentration of polysorbate 20 (1 % w/v), where the majority of the prepared suspensions were unmeasurable after 78 weeks of storage.