Food and Drug Administration, Center for Drug Evaluation and Research Office of Testing and Research, Division of Product Quality Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993, United States.
Food and Drug Administration, Center for Drug Evaluation and Research Office of Generic Drugs, 7500 Standish Place, Rockville, MD 20855, United States.
Int J Pharm. 2014 Apr 10;464(1-2):46-52. doi: 10.1016/j.ijpharm.2014.01.008. Epub 2014 Jan 17.
The study objective was to evaluate the thermodynamic stability of iron sucrose complexes as determined by molecular weight (m.w.) changes. The first part of the study focused on the effect of thermal stress, pH, electrolyte or excipient dilution on the stability of a colloidal iron drug product. Part two focused on the physical and chemical evaluation of the colloidal nature of iron sucrose using a series of characterization experiments: ultracentrifugation, dialysis, particle size, zeta potential, and osmotic pressure analysis. A validated Taguchi-optimized high performance gel permeation chromatography method was used for m.w. determinations. Results indicate m.w. of the iron sucrose complex remained unchanged after excipient dilution, ultracentrifugation, dialysis, and electrolyte dilution. Electrolyte dilution studies indicated the lyophilic nature of the iron sucrose colloid with a particle size of 10nm and zeta potential of 0 mV. The complex deformed at low pH and reformed back at the formulation pH. The complex is stable under mild-to-moderate temperature <50°C but aggregates following prolonged exposure to high temperatures >70°C. In conclusion, the resistance of the complex to breakdown by electrolytic conditions, excipient dilution, ultracentrifugation and the reversible complexation after alteration of formulation pH suggest iron sucrose is a lyophilic colloid in nature and lyophilic colloidals are thermodynamically stable.
研究目的是评估铁蔗糖复合物的热力学稳定性，方法是通过分子量（m.w.）变化来确定。研究的第一部分侧重于热应力、pH 值、电解质或赋形剂稀释对胶体铁药物产品稳定性的影响。第二部分侧重于使用一系列特性实验（超速离心、透析、粒径、Zeta 电位和渗透压分析）对铁蔗糖的胶体性质进行物理化学评估。采用经过验证的 Taguchi 优化高效凝胶渗透色谱法进行 m.w. 测定。结果表明，赋形剂稀释、超速离心、透析和电解质稀释后铁蔗糖复合物的 m.w. 保持不变。电解质稀释研究表明，铁蔗糖胶体具有亲水性，粒径为 10nm，Zeta 电位为 0mV。该复合物在低 pH 值下变形，并在制剂 pH 值下重新形成。该复合物在温和至中等温度（<50°C）下稳定，但在长时间暴露于高温（>70°C）后会聚集。总之，复合物对电解质条件、赋形剂稀释、超速离心以及制剂 pH 值改变后的可逆络合的抵抗力表明，铁蔗糖本质上是一种亲水性胶体，亲水性胶体在热力学上是稳定的。
