Division of Pharmaceutics Sciences, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, The Long Island University, Brooklyn, New York, 11201, USA.
Blueprint Medicines, Cambridge, Massachusetts, 02139, USA.
AAPS PharmSciTech. 2023 Jun 8;24(5):133. doi: 10.1208/s12249-023-02589-6.
The present study adopted a Quality by Design (QbD) approach to spray dry indomethacin nanosuspension (IMC-NS) consisting of HPC-SL, poloxamer 407, and lactose monohydrate. The Box-Behnken Design was used to systematically evaluate the effects of inlet temperature, aspiration rate, and feed rate on the critical quality attributes (CQAs) [redispersibility index (RDI; minimize), % yield (maximize), and % release at 15 min (maximize)] of the indomethacin spray dried nanosuspension (IMC-SD-NS). To identify significant main and quadratic effects, two-way interactions, and create a predictive model for the spray drying process, regression analysis and ANOVA were utilized. Following optimization, the IMC-SD-NS was analyzed for its physicochemical properties using X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FTIR), and in vitro dissolution studies. Statistical analysis revealed significant independent variables, including inlet temperature, feed rate, and aspiration rate, that critically impacted the solidified end product's RDI, % yield, and % release at 15 min. The models developed for critical quality attributes (CQAs) were significant at a p-value of 0.05. The crystalline state of IMC was maintained in the solidified product, as confirmed by XRPD, and no interactions were observed between IMC and the excipients as evaluated by FTIR. In vitro dissolution studies showed improved dissolution rate for the IMC-SD-NS (3.82-fold increase in overall drug release), which may be attributed to the readily redispersible nanosized drug particles. The implementation of a well-designed study, utilizing Design of Experiments (DoE) methodology, played a crucial role in the development of a highly effective spray drying process.
本研究采用质量源于设计（QbD）方法制备包含 HPC-SL、泊洛沙姆 407 和乳糖一水合物的吲哚美辛纳米混悬剂（IMC-NS）。采用 Box-Behnken 设计系统地评估入口温度、吸气率和进料速率对吲哚美辛喷雾干燥纳米混悬剂（IMC-SD-NS）的关键质量属性（CQAs）[再分散指数（RDI；最小化）、产率（最大化）和 15 分钟时的释放百分比（最大化）]的影响。为了识别显著的主效应和二次效应、双向相互作用，并为喷雾干燥过程创建预测模型，使用回归分析和 ANOVA 进行分析。优化后，使用 X 射线粉末衍射（XRPD）、傅里叶变换红外光谱（FTIR）和体外溶出度研究对 IMC-SD-NS 的理化性质进行分析。统计分析显示，入口温度、进料速率和吸气速率等独立变量对固化终产物的 RDI、产率和 15 分钟时的释放百分比有显著影响。关键质量属性（CQAs）的模型在 p 值为 0.05 时具有统计学意义。XRPD 证实 IMC 的结晶状态在固化产物中得以维持，FTIR 评估表明 IMC 与赋形剂之间未观察到相互作用。体外溶出度研究表明 IMC-SD-NS 的溶出速率得到了改善（总药物释放增加 3.82 倍），这可能归因于易于再分散的纳米级药物颗粒。通过实施设计良好的研究，利用实验设计（DoE）方法，在开发高效喷雾干燥工艺方面发挥了关键作用。
