Stability of Diazepam Solution for Injection Following Long-Term Storage in an Ambient Temperature of the Mediterranean Climate,Pharmaceutical Research

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Stability of Diazepam Solution for Injection Following Long-Term Storage in an Ambient Temperature of the Mediterranean Climate
Pharmaceutical Research ( IF 3.5 ) Pub Date : 2021-01-06 , DOI: 10.1007/s11095-020-02984-9
Constantin Itin ₁ , Maor Liani ₁ , Meital Zur ₁ , Pavel Gorenbein ₁

Affiliation

Purpose

Diazepam is utilized as a convulsion antidote following nerve gas attacks. As an emergency medicine, it requires storage at ambient temperatures which often doesn’t meet manufacturers’ requirements, leading to an early invalidation of the product. Current work investigated this issue.

Methods

Long-term stability of diazepam ampoules for injection stored in an ambient temperature of the Mediterranean climate for ~10 years vs storage at room temperature was studied.

Results

Diazepam assay and pH remained within pharmacopeial specifications irrespective of storage conditions. A major degradation product 2-methylamino-5-chlorobenzophenone (MACB) showed a clear trend of accumulation as a function of storage time, exceeding the permitted limit at ~2 years, irrespective of storage conditions. A strong correlation between the discoloration of the solutions and the concentration of MACB was obtained. Intravenous administration of MACB to rats at doses ~2200-fold higher than permissible specification levels caused neither mortality nor any toxicological nor post-mortem findings.

Conclusions

Regarding the parameters tested: diazepam assay, MACB assay, and pH, storing ampoules of diazepam solution for injection in field conditions of high temperatures of the Mediterranean climate did not cause accelerated degradation as compared to room temperature. These findings open an option for the usage of expired ampoules in special scenarios.

Graphical abstract

中文翻译：

在地中海气候的环境温度下长期储存后注射用地西泮溶液的稳定性

目的

地西泮被用作神经毒气发作后的惊厥解毒剂。作为一种急救药品，它需要在常温下储存，这往往不符合制造商的要求，导致产品过早失效。目前的工作调查了这个问题。

方法

研究了在地中海气候环境温度下储存约 10 年的注射用地西泮安瓿与在室温下储存的长期稳定性。

结果

无论储存条件如何，地西泮测定和 pH 值均保持在药典规范范围内。主要降解产物 2-甲氨基-5-氯二苯甲酮 (MACB) 显示出明显的积累趋势，作为储存时间的函数，无论储存条件如何，都超过了约 2 年的允许限值。获得了溶液变色与 MACB 浓度之间的强相关性。以比允许的规格水平高约 2200 倍的剂量向大鼠静脉注射 MACB，既不会导致死亡，也不会导致任何毒理学或验尸结果。