Abdul-Fattah Ahmad M, Truong-Le Vu, Yee Luisa, Nguyen Lauren, Kalonia Devendra S, Cicerone Marcus T, Pikal Michael J
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269, USA.
J Pharm Sci. 2007 Aug;96(8):1983-2008. doi: 10.1002/jps.20859.
The present study was conducted to investigate the impact of drying method and formulation on the storage stability of IgG1. Formulations of IgG1 with varying levels of sucrose with and without surfactant were dried by different methods, namely freeze drying, spray drying, and foam drying. Dried powders were characterized by thermal analysis, scanning electron microscopy, specific surface area (SSA) analysis, electron spectroscopy for chemical analysis (ESCA), solid state FTIR, and molecular mobility measurements by both isothermal calorimetry and incoherent elastic neutron scattering. Dried formulations were subjected to storage stability studies at 40 degrees C and 50 degrees C (aggregate levels were measured by size exclusion chromatography initially and at different time points). Both drying method and formulation had a significant impact on the properties of IgG1 powders, including storage stability. Among the drying methods, SSA was highest and perturbations in secondary structure were lowest with the spray-dried preparations. Sucrose-rich foams had the lowest SSA and the lowest protein surface accumulation. Also, sucrose-rich foams had the lowest molecular mobility (both fast dynamics and global motions). Stability studies showed a log-linear dependence of physical stability on composition. Preparations manufactured by "Foam Drying" were the most stable, regardless of the stabilizer level. In protein-rich formulations, freeze-dried powders showed the poorest storage stability and the stability differences were correlated to differences in secondary structure. In stabilizer-rich formulations, stability differences were best correlated to differences in molecular mobility (fast dynamics) and total protein surface accumulation.
本研究旨在探讨干燥方法和配方对IgG1储存稳定性的影响。将含有不同水平蔗糖且添加或不添加表面活性剂的IgG1配方通过不同方法进行干燥，即冷冻干燥、喷雾干燥和泡沫干燥。通过热分析、扫描电子显微镜、比表面积（SSA）分析、化学分析电子能谱（ESCA）、固态傅里叶变换红外光谱（FTIR）以及等温量热法和非相干弹性中子散射进行分子流动性测量，对干燥粉末进行表征。将干燥后的配方在40℃和50℃下进行储存稳定性研究（最初及在不同时间点通过尺寸排阻色谱法测量聚集体水平）。干燥方法和配方均对IgG1粉末的性质有显著影响，包括储存稳定性。在干燥方法中，喷雾干燥制剂的SSA最高，二级结构的扰动最低。富含蔗糖的泡沫具有最低的SSA和最低的蛋白质表面积累。此外，富含蔗糖的泡沫具有最低的分子流动性（快速动力学和整体运动）。稳定性研究表明物理稳定性对组成呈对数线性依赖关系。无论稳定剂水平如何，通过“泡沫干燥”制备的制剂最稳定。在富含蛋白质的配方中，冷冻干燥粉末的储存稳定性最差，稳定性差异与二级结构差异相关。在富含稳定剂的配方中，稳定性差异与分子流动性（快速动力学）和总蛋白质表面积累差异相关性最佳。
