<i>N</i>-Nitrosodimethylamine (NDMA) Formation from Ranitidine Impurities: Possible Root Causes of the Presence of NDMA in Ranitidine Hydrochloride
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- Yokoo Hidetomo
- National Institute of Health Sciences Medical Chemistry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
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- Yamamoto Eiichi
- National Institute of Health Sciences
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- Masada Sayaka
- National Institute of Health Sciences
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- Uchiyama Nahoko
- National Institute of Health Sciences
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- Tsuji Genichiro
- National Institute of Health Sciences
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- Hakamatsuka Takashi
- National Institute of Health Sciences
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- Demizu Yosuke
- National Institute of Health Sciences
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- Izutsu Ken-ichi
- National Institute of Health Sciences
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- Goda Yukihiro
- National Institute of Health Sciences
Bibliographic Information
- Other Title
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- N-Nitrosodimethylamine (NDMA) Formation from Ranitidine Impurities : Possible Root Causes of the Presence of NDMA in Ranitidine Hydrochloride
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Abstract
<p>N-Nitrosodimethylamine (NDMA) is a probable human carcinogen. This study investigated the root cause of the presence of NDMA in ranitidine hydrochloride. Forced thermal degradation studies of ranitidine hydrochloride and its inherent impurities (Imps. A, B, C, D, E, F, G, H, I, J, and K) listed in the European and United States Pharmacopeias revealed that in addition to ranitidine, Imps. A, C, D, E, H, and I produce NDMA at different rates in a solid or an oily liquid state. The rate of NDMA formation from amorphous Imps. A, C, and E was 100 times higher than that from crystalline ranitidine hydrochloride under forced degradation at 110 °C for 1 h. Surprisingly, crystalline Imp. H, bearing neither the N,N-dialkyl-2-nitroethene-1,1-diamine moiety nor a dimethylamino group, also generated NDMA in the solid state, while Imp. I, as an oily liquid, favorably produced NDMA at moderate temperatures (e.g., 50 °C). Therefore, strict control of the aforementioned specific impurities in ranitidine hydrochloride during manufacturing and storage allows appropriate control of NDMA in ranitidine and its pharmaceutical products. Understanding the pathways of the stability related NDMA formation enables improved control of the pharmaceuticals to mitigate this risk.</p>
Journal
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- Chemical and Pharmaceutical Bulletin
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Chemical and Pharmaceutical Bulletin 69 (9), 872-876, 2021-09-01
The Pharmaceutical Society of Japan
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Details 詳細情報について
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- CRID
- 1390852182141538944
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- NII Article ID
- 130008081978
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- NII Book ID
- AA00602100
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- ISSN
- 13475223
- 00092363
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- NDL BIB ID
- 031643151
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- PubMed
- 34470951
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- Text Lang
- en
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- Data Source
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- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
- KAKEN
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- Abstract License Flag
- Disallowed