Faculty of Pharmacy, Department of Pharmaceutical Technology, Gazi University, Etiler-Yenimahalle, Ankara, Turkey.
Pharm Res. 2020 May 31;37(6):111. doi: 10.1007/s11095-020-02815-x.
Etodolac (ETD) is one of the non-steroidal anti-inflammatory drugs which has low aqueous solubility issues. The objective of this study was to develop ETD nanosuspensions to improve its poor aqueous solubility properties while investigating formulation and process parameters of wet media milling method via design of experiment (DoE) approach.
The critical formulation parameters (CFP) were selected as ETD amount, stabilizer type and ratio as well as critical process parameters (CPP) which were bead size, milling time and milling speed. The two-factorial-2 and The Box-Benkhen Designs were generated to evaluate CFP and CPP, respectively. Particle size (PS), polydispersity index (PDI) and zeta potential (ZP) were analyzed as dependent variables. Characterization, physical stability and solubility studies were performed.
Optimum nanosuspensions stabilized by PVP K30 and Poloxamer 188 showed 188.5 ± 1.6 and 279.3 ± 6.1 nm of PS, 0.161 ± 0.049 and 0.345 ± 0.007 PDI, 14.8 ± 0.3 and 16.5 ± 0.4 mV of ZP values, respectively. The thermal properties of ETD did not change after milling and lyophilization process regarding to DSC analysis. Also, the crystalline state of ETD was preserved. The morphology of particle was smooth and spherical on SEM. The dry-nanosuspensions stayed physically stable for six months at room temperature. The solubility of nanosuspensions increased up to 13.0-fold in comparison with micronized ETD.
In conclusion, it is found that the poor solubility issue of ETD can be solved by nanosuspension. DoE approach provided benefits such as reducing number of experiments, saving time and improving final product quality by using wet media milling.
依托度酸（ETD）是一种非甾体抗炎药，其水溶性问题较低。本研究的目的是制备 ETD 纳米混悬剂以改善其较差的水溶性性质，同时通过实验设计（DoE）方法研究制剂和工艺参数。
选择关键制剂参数（CFP）为 ETD 用量、稳定剂类型和比例以及关键工艺参数（CPP）为珠粒大小、研磨时间和研磨速度。采用两因素两水平和 Box-Benkhen 设计分别评估 CFP 和 CPP。以粒径（PS）、多分散指数（PDI）和 Zeta 电位（ZP）为因变量进行分析。进行了表征、物理稳定性和溶解度研究。
由 PVP K30 和 Poloxamer 188 稳定的最佳纳米混悬剂的 PS 分别为 188.5±1.6 和 279.3±6.1nm，PDI 分别为 0.161±0.049 和 0.345±0.007，ZP 值分别为 14.8±0.3 和 16.5±0.4mV。DSC 分析表明，研磨和冻干过程后 ETD 的热性能没有变化。此外，ETD 的结晶状态得以保留。SEM 显示粒子形态光滑、呈球形。干纳米混悬剂在室温下放置六个月仍保持物理稳定。与微米化 ETD 相比，纳米混悬剂的溶解度增加了 13.0 倍。
总之，研究发现纳米混悬剂可解决 ETD 的溶解度问题。DoE 方法通过湿磨法提供了许多益处，例如减少实验次数、节省时间和提高最终产品质量。
