Analytical and Quality Evaluation Research Laboratories, Daiichi Sankyo Co., Ltd.
Quality Assurance Department, Daiichi Sankyo Co., Ltd.
Chem Pharm Bull (Tokyo). 2020;68(11):1049-1054. doi: 10.1248/cpb.c20-00443.
To accelerate drug development, the pharmaceutical industry is working to shorten and improve studies on stability. The Accelerated Stability Assessment Program (ASAP) incorporating the humidity-corrected Arrhenius equation as an accelerated methodology has been proposed for both drug substances and drug products. In this study, the effect of magnesium stearate (MgSt) content on the chemical stability of acetylsalicylic acid was evaluated as a model system of drug-excipient compatibility studies using ASAP. In the acetylsalicylic acid powder blends, temperature and humidity showed a first-order linear response to the natural logarithm of the reaction rate constant, and MgSt content also showed a first-order linear response. A polynomial model was built in which temperature, humidity, and MgSt content were independent each other. The fitting index of the model, the coefficient of determination, was 0.9567, which was a good fit. In the long-term stability study (25 °C/60% relative humidity, 6 months), there was good agreement in total between measured values and model-predicted values. Using this model, we inferred that the degradation rates were depended on MgSt content at the fixed temperature and humidity because the micro-environmental pH of the excipient was catalytically affected. Applying this model equation can significantly reduce the duration of formulation design and stability studies and save time and costs in drug development.
为了加速药物开发，制药行业正在努力缩短和改进稳定性研究。已经提出了将湿度校正的阿伦尼乌斯方程作为加速方法纳入加速稳定性评估计划（ASAP），用于药物物质和药物产品。在这项研究中，作为药物-赋形剂相容性研究的模型系统，使用 ASAP 评估硬脂酸镁（MgSt）含量对乙酰水杨酸化学稳定性的影响。在乙酰水杨酸粉末混合物中，温度和湿度对反应速率常数的自然对数呈一级线性响应，并且 MgSt 含量也呈一级线性响应。建立了一个多项式模型，其中温度、湿度和 MgSt 含量相互独立。模型的拟合指数，即决定系数为 0.9567，拟合效果良好。在长期稳定性研究（25°C/60%相对湿度，6 个月）中，实测值与模型预测值之间存在良好的总体一致性。使用该模型，我们推断降解速率取决于固定温度和湿度下的 MgSt 含量，因为赋形剂的微环境 pH 受到催化影响。应用该模型方程可以显著缩短配方设计和稳定性研究的时间，并在药物开发中节省时间和成本。
