Tracing Hydrazine in Pharmaceuticals: Toxicological Concerns, Extraction Approaches, and Analytical Method Development.
- 1Faculty of Pharmacy University Padjadjaran Jl. Raya Bandung Sumedang KM 21 Sumedang 45363 West Java Indonesia.
- 2Department of Pharmaceutical Analysis and Medicinal Chemistry Faculty of Pharmacy University Padjadjaran Jl. Raya Bandung Sumedang KM 21 Sumedang 45363 West Java Indonesia.
Abstract
Hydrazine (N₂H₄) is a synthetic reagent that is used in the manufacturing of various active pharmaceutical ingredients (APIs) such as isoniazid, hydralazine, and carbidopa. The major concerns associated with its presence in medications as a residual reagent or degradation product arise because of its ability to damage the genetic material, cause mutations, and potentially trigger cancer. It has been classified under Class 2 genotoxic impurity (GTI), based on the ICH M7 guideline. Its multitissue toxicities including hepatotoxicity, neurotoxicity, and hematotoxicity have led to tight regulatory limits with the EMA threshold of toxicological concern (TTC) at 1.5 µg/day. Detecting hydrazine in trace concentrations is challenging because of its low molecular weight, high polarity, absence of chromophores, and chemical instability. In order to provide a unified framework for impurity profiling, we combine hydrazine's toxicological profiles, formation pathways, and analytical advancements. Recent advances on the extraction, derivatization, and analytical determination of hydrazine to improve its stability and detectability in pharmaceutical matrices ranging from 2020 to 2025 were collected. Comparative evaluation of the methodologies reveals that combining chemical derivatization with hyphenated techniques delivers the highest sensitivity. GC-MS/MS stands out as the gold standard, providing exceptionally low detection limits at the sub-ppm level with high precision and reliability, while UHPLC-fluorescence serves as an alternative with considerable sensitivity for detecting hydrazine. Gaps in method harmonization, reference standard availability, and validation for complex formulations still remain therefore future work should focus more on standardized analytical methods, development of greener methods of derivatization, as well as use of high-resolution detection systems.
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BibTeX
@article{donga2026tracing,
title = {{Tracing Hydrazine in Pharmaceuticals: Toxicological Concerns, Extraction Approaches, and Analytical Method Development.}},
author = {Buhlebenkosi Mercy Donga and Rimadani Pratiwi and Aliya Nur Hasanah},
journal = {Journal of analytical methods in chemistry},
year = {2026},
month = oct,
doi = {10.1155/jamc/9609425},
url = {https://europepmc.org/article/MED/42898726},
note = {CC BY},
}
RIS
TY - JOUR
TI - Tracing Hydrazine in Pharmaceuticals: Toxicological Concerns, Extraction Approaches, and Analytical Method Development.
AU - Buhlebenkosi Mercy Donga
AU - Rimadani Pratiwi
AU - Aliya Nur Hasanah
PY - 2026
DA - 2026/10/19
JO - Journal of analytical methods in chemistry
DO - 10.1155/jamc/9609425
UR - https://europepmc.org/article/MED/42898726
AB - Hydrazine (N₂H₄) is a synthetic reagent that is used in the manufacturing of various active pharmaceutical ingredients (APIs) such as isoniazid, hydralazine, and carbidopa. The major concerns associated with its presence in medications as a residual reagent or degradation product arise because of its ability to damage the genetic material, cause mutations, and potentially trigger cancer. It has been classified under Class 2 genotoxic impurity (GTI), based on the ICH M7 guideline. Its multitissue toxicities including hepatotoxicity, neurotoxicity, and hematotoxicity have led to tight regulatory limits with the EMA threshold of toxicological concern (TTC) at 1.5 µg/day. Detecting hydrazine in trace concentrations is challenging because of its low molecular weight, high polarity, absence of chromophores, and chemical instability. In order to provide a unified framework for impurity profiling, we combine hydrazine's toxicological profiles, formation pathways, and analytical advancements. Recent advances on the extraction, derivatization, and analytical determination of hydrazine to improve its stability and detectability in pharmaceutical matrices ranging from 2020 to 2025 were collected. Comparative evaluation of the methodologies reveals that combining chemical derivatization with hyphenated techniques delivers the highest sensitivity. GC-MS/MS stands out as the gold standard, providing exceptionally low detection limits at the sub-ppm level with high precision and reliability, while UHPLC-fluorescence serves as an alternative with considerable sensitivity for detecting hydrazine. Gaps in method harmonization, reference standard availability, and validation for complex formulations still remain therefore future work should focus more on standardized analytical methods, development of greener methods of derivatization, as well as use of high-resolution detection systems.
SN - 2090-8865
SN - 2090-8873
ER -