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

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Abstract

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.

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Abbreviations

MACB:

2-methylamino-5-chlorobenzophenone

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Acknowledgments

Dr. David Stepenski is acknowledged for his constructive comments.

Funding

No funding was received for conducting this study. The authors have no relevant financial or non-financial interests to disclose.

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Authors and Affiliations

  1. Pharmacy, Biomedical Engineering & Medical Supplies Branch, Israel Defense Forces (IDF) Medical Corps, Ramat Gan, Israel

    Constantin Itin, Maor Liani, Meital Zur & Pavel Gorenbein

Authors
  1. Constantin Itin
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  2. Maor Liani
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  3. Meital Zur
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  4. Pavel Gorenbein
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Contributions

Constantin Itin: Conceptualization, Data curation, Formal analysis, Investigation, Writing original draft, Writing – review and editing.

Maor Liani: Investigation, Writing – review and editing.

Meital Zur: Supervision, Writing – review and editing.

Pavel Gorenbein: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Writing – review and editing.

Corresponding author

Correspondence to Constantin Itin.

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Supplementary Information

Supplementary Figure S1

Representative HPLC chromatogram of diazepam ampoule. (DOCX 151 kb)

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Itin, C., Liani, M., Zur, M. et al. Stability of Diazepam Solution for Injection Following Long-Term Storage in an Ambient Temperature of the Mediterranean Climate. Pharm Res 38, 361–367 (2021). https://doi.org/10.1007/s11095-020-02984-9

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  • DOI: https://doi.org/10.1007/s11095-020-02984-9

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