Oliva Alexis, Llabrés Matías, Fariña José B
Departamento Ingeniería Química y Tecnología Farmacéutica, Facultad de Farmacia, Universidad de La Laguna, 38200 La Laguna, Tenerife, Spain.
Pharm Res. 2006 Nov;23(11):2595-602. doi: 10.1007/s11095-006-9096-0. Epub 2006 Sep 13.
Kinetic modelling was applied to predict the stability of cholecystokinin fragment CCK-4 in aqueous solution, which was analyzed by isothermal and nonisothermal methods using a validated stability indicating HPLC method.
The isothermal studies were performed in the temperature range 40 to 80 degrees C at pH 12 and ionic strength 0.01 M as constants, whereas nonisothermal stability studies were performed using a linear increasing temperature program, heating rate 0.25 degrees C/h and a temperature interval 40-82 degrees C. The isothermal studies require two-step linear regression to estimate the parameters, resulting in a well-defined confidence interval. Nonisothermal kinetic studies require nonlinear or linear regression by previous transformation of data to estimate the parameters. In this case, the two most popular approaches, derivative and integral, were used and compared.
Under isothermal conditions, an apparent first-order degradation process was observed at all temperatures. The linear Arrhenius plot suggested that the CCK-4 degradation mechanism was the same within the studied temperature range, with quite large uncertainties due to the small number of degrees of freedom based only on the scatter in the plot, and giving an estimated shelf life at 25 degrees C of 35.2 days. The derivative approach yields high variability in the Arrhenius parameters, since they are dependent on the number of polynomial terms chosen, so several statistical criteria were applied to select the best model. The integral approach allows activation parameters to be calculated directly from experimental data, and provides results in good agreement with those of the traditional method, but have the advantage that the uncertainty in the final result directly reflects the goodness of fit of the experimental data to the chosen kinetic model. The application of the bootstrap technique to estimating confidence limits for the Arrhenius parameters and shelf life is also illustrated, and shows there is no difference between the asymptotic and bootstrap confidence intervals.
Nonisothermal studies give us fast and valuable information about drug stability, although their potential for predicting isothermal behaviour is conditioned by the data analysis method applied.
应用动力学建模预测胆囊收缩素片段CCK - 4在水溶液中的稳定性，采用经验证的稳定性指示高效液相色谱法通过等温法和非等温法对其进行分析。
等温研究在40至80摄氏度、pH值为12且离子强度为0.01 M的条件下进行，这些条件作为常数；而非等温稳定性研究则采用线性升温程序，升温速率为0.25摄氏度/小时，温度区间为40 - 82摄氏度。等温研究需要两步线性回归来估计参数，从而得到明确的置信区间。非等温动力学研究需要通过对数据进行先前的变换，采用非线性或线性回归来估计参数。在这种情况下，使用并比较了两种最常用的方法，即导数法和积分法。
在等温条件下，在所有温度下均观察到明显的一级降解过程。线性阿伦尼乌斯图表明，在研究的温度范围内，CCK - 4的降解机制相同，但由于仅基于图中的散点的自由度数量较少，存在相当大的不确定性，并给出在25摄氏度下的估计保质期为35.2天。导数法在阿伦尼乌斯参数方面产生高度变异性，因为它们取决于所选多项式项的数量，因此应用了几种统计标准来选择最佳模型。积分法允许直接从实验数据计算活化参数，并提供与传统方法结果良好一致的结果，但具有最终结果的不确定性直接反映实验数据与所选动力学模型拟合优度的优点。还说明了应用自举技术来估计阿伦尼乌斯参数和保质期的置信限，并且表明渐近置信区间和自举置信区间之间没有差异。
非等温研究为我们提供了关于药物稳定性的快速且有价值的信息，尽管它们预测等温行为的潜力受所应用的数据分析方法的制约。
