Stability prediction of amorphous benzodiazepines by calculation of the mean relaxation time constant using the Williams-Watts decay function.
Stability prediction of amorphous benzodiazepines by calculation of the mean relaxation time constant using the Williams-Watts decay function.
复制标题
通过使用 Williams-Watts 衰减函数计算平均弛豫时间常数来预测无定形苯二氮卓类药物的稳定性。
DOI：
10.1016/s0939-6411(99)00013-2
复制
发表时间：
1999
期刊：
影响因子：
--
通讯作者：
R. Kinget
中科院分区：
文献类型：
--
作者：
G. Van den Mooter;P. Augustijns;R. Kinget
本文用差示扫描量热法研究了地西泮、替马西泮和三唑仑三种无定形苯二氮卓类药物在低于玻璃化转变温度的老化温度和长达16 h的老化时间下的弛豫行为。实验测定的松弛焓和热容量的变化，都伴随着玻璃化转变，使我们能够计算在特定的老化条件下的无定形药物的松弛程度。将弛豫函数拟合为Williams-Watts双参数衰减函数，计算了平均弛豫时间常数τ和分子弛豫时间分布参数β。三种药物的平均弛豫时间常数从玻璃化转变温度下的约10小时增加到低于玻璃化转变温度66 K时的8个数量级以上。结果发现，苯二氮卓类药物在低于玻璃化转变温度约50 K时表现出显著的分子迁移率;低于该温度时，分子迁移率对有效期稳定性不重要。因此，所提出的程序为配方科学家提供了一种工具来设置无定形药物和玻璃状药物产品的储存条件。
The enthalpic relaxation of three amorphous benzodiazepines, diazepam, temazepam and triazolam was studied using differential scanning calorimetry for ageing temperatures which were below the glass transition temperature, and ageing times up to 16 h. Experimental determination of the relaxation enthalpy and the heat capacity change, both accompanying the glass transition, enabled us to calculate the extent of relaxation of the amorphous drugs at specific ageing conditions. Fitting of the relaxation function to the Williams–Watts two parameter decay function led to calculation of the mean relaxation time constant τ and the molecular relaxation time distribution parameter β. The mean relaxation time constants for the three drugs increased from approximately ten h at the glass transition temperature with more than eight orders of magnitude at 66 K below the glass transition temperature. It was found that the benzodiazepines exhibited significant molecular mobility until approximately 50 K below the glass transition temperature; below this temperature molecular mobility becomes unimportant with respect to the shelf life stability. Hence the presented procedure provides the formulation scientist with a tool to set storage conditions for amorphous drugs and glassy pharmaceutical products.