The non-isothermal method for prediction of chemical stability of pharmaceuticals has been discussed in the literature for almost half a century but it has not yet been systematically evaluated. The purpose of this study was to carry out a comprehensive experimental evaluation of the non-isothermal method against the conventional isothermal method for a fast preformulation stability screening. The chemical stabilities of 20 pharmaceutical compounds in aqueous based solution were investigated. Degradation rate constants (k), activation energies (E a), t 90% and t 98% (times for 10 and 2% loss of potency, respectively) were determined by applying the Arrhenius equation to stability data generated by both non-isothermal and isothermal methods. A comparison of the results indicated that the ‘1 week’ non-isothermal experiment is as accurate as the ‘8 weeks’ isothermal experiment for placing compounds (15 out of 16 cases) into the same binning categories based on t 90% and t98% values. The absolute values of k, t 90% and t98% at 25 °C determined by the non-isothermal method for compounds with first order (or pseudo-first order) degradation kinetics were within a factor of two compared to those determined by the isothermal method. The non-isothermal method proved to be not applicable for accurate prediction of the shelf-lives of pharmaceuticals, however, when used to bin discovery compounds based on likely issues related to chemical instability, the non-isothermal method can be carefully implemented as a cost effective, fast, and relatively ‘high-throughput’ method to support drug stability screening at the discovery and development interface.

中文翻译：

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线性加热的非等温稳定性：在发现和开发界面进行药物制剂前稳定性筛选的快速方法

文献已经讨论了预测药物化学稳定性的非等温方法近半个世纪，但尚未对其进行系统评价。这项研究的目的是对非等温方法与常规等温方法进行全面的实验评估，以进行快速的预成型稳定性筛选。研究了20种药物化合物在水溶液中的化学稳定性。降解速率常数（k），活化能（E a），t 90％和t 98％（分别为失去效力10％和2％的时间）是通过将Arrhenius方程应用于非等温生成的稳定性数据而确定的和等温方法。结果比较表明，“ 1周”非等温实验与“ 8周”等温实验一样准确，该实验将基于t 90％和t98％的化合物（16个案例中的15个）放入相同的装箱类别价值观。用非等温方法测定的具有一级（或拟一级）降解动力学的化合物在25°C下的k，t 90％和t98％的绝对值与等温测定的绝对值相比，在两倍之内方法。事实证明，非等温方法不适用于准确预测药物的保质期，但是，当用于基于与化学不稳定性相关的可能问题对发现化合物进行分类时，可以将非等温方法作为成本进行认真实施。有效，快速，