Zulbeari Nadina, Holm René
Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark.
Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark.
Int J Pharm. 2025 May 30;677:125646. doi: 10.1016/j.ijpharm.2025.125646. Epub 2025 Apr 26.
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.
纳米和微米混悬液的物理稳定性是制剂研究与优化过程中需要考虑的关键因素。短期应力研究常被用作预测性研究，以评估药物混悬液的长期物理稳定性。因此，将采用双重离心法（1 mL规模）制备的桂利嗪混悬液的短期应力稳定性与长期储存稳定性进行了比较，即对经搅拌珠磨机放大研磨的桂利嗪混悬液进行18个月的长期储存稳定性研究。在短期应力研究和长期稳定性评估中，储存温度都是影响用聚山梨酯20稳定的桂利嗪混悬液粒径分布的主要因素。在短期应力研究中，对于经受72小时旋转或振荡等机械应力因素的混悬液，仅观察到颗粒尺寸有微小变化，颗粒尺寸的增加主要归因于储存温度的调整。热循环导致桂利嗪混悬液不稳定，在加热和冷冻时添加甘露醇可使粒径分布略有改善。短期评估的早期迹象还表明，当在不同储存温度下储存时，1%（w/v）的聚山梨酯足以保证明显的短期物理稳定性。在热循环过程中，使用较高浓度的聚山梨酯20可获得较小尺寸的桂利嗪颗粒，这与用较高稳定浓度稳定的桂利嗪混悬液长期稳定性的改善情况相似，表明在长期稳定性方面，需要更高比例的聚山梨酯20作为稳定剂。在5.0℃储存会使混悬液随时间推移在一定程度上保持物理稳定，而在25℃和40℃长期储存会导致颗粒尺寸随时间增加，尤其是在用最低浓度聚山梨酯20（1% w/v）稳定的混悬液中，大多数制备的混悬液在储存78周后无法测量。
