Wyttenbach Nicole, Birringer Christian, Alsenz Jochem, Kuentz Martin
F. Hoffmann-La Roche Ltd., Pharmaceutical and Analytical R & D, Basel, Switzerland.
Pharm Dev Technol. 2005;10(4):499-505. doi: 10.1080/10837450500299875.
The aim of our research was to develop a miniaturized high throughput drug-excipient compatibility test. Experiments were planned and evaluated using statistical experimental design. Binary mixtures of a drug, acetylsalicylic acid, or fluoxetine hydrochloride, and of excipients commonly used in solid dosage forms were prepared at a ratio of approximately 1:100 in 96-well microtiter plates. Samples were exposed to different temperature (40 degrees C/ 50 degrees C) and humidity (10%/75%) for different time (1 week/4 weeks), and chemical drug degradation was analyzed using a fast gradient high pressure liquid chromatography (HPLC). Categorical statistical design was applied to identify the effects and interactions of time, temperature, humidity, and excipient on drug degradation. Acetylsalicylic acid was least stable in the presence of magnesium stearate, dibasic calcium phosphate, or sodium starch glycolate. Fluoxetine hydrochloride exhibited a marked degradation only with lactose. Factor-interaction plots revealed that the relative humidity had the strongest effect on the drug excipient blends tested. In conclusion, the developed technique enables fast drug-excipient compatibility testing and identification of interactions. Since only 0.1 mg of drug is needed per data point, fast rational preselection of the pharmaceutical additives can be performed early in solid dosage form development.
我们研究的目的是开发一种小型化的高通量药物-辅料相容性测试方法。实验采用统计实验设计进行规划和评估。在96孔微量滴定板中，以大约1:100的比例制备药物（乙酰水杨酸或盐酸氟西汀）与固体剂型常用辅料的二元混合物。将样品在不同温度（40℃/50℃）和湿度（10%/75%）下暴露不同时间（1周/4周），并使用快速梯度高压液相色谱（HPLC）分析化学药物降解情况。应用分类统计设计来确定时间、温度、湿度和辅料对药物降解的影响及相互作用。乙酰水杨酸在硬脂酸镁、磷酸氢钙或淀粉乙醇酸钠存在时最不稳定。盐酸氟西汀仅与乳糖一起时表现出明显降解。因素相互作用图显示，相对湿度对所测试的药物-辅料混合物影响最强。总之，所开发的技术能够实现快速的药物-辅料相容性测试和相互作用的识别。由于每个数据点仅需要0.1毫克药物，因此可以在固体剂型开发的早期对药物添加剂进行快速合理的预选。
