Investigation of Nitrosamine Impurities in Pharmaceutical Preparations Containing Metformin and Sitagliptin Active Ingredients

Şana Sungur; Cansel Demetgül

TR EN

Metformin ve Sitagliptin Etkin Maddelerini İçeren İlaçlardaki Nitrozamin Safsızlıklarının Araştırılması

Öz

Amaç: Bu çalışmada, aktif farmasötik bileşen olarak metformin ve sitagliptin içeren ilaçlardaki N-nitrosodimetilamin (NDMA) ve N-nitrosodietilamin (NDEA) içeriklerinin belirlenmesi amaçlanmıştır. Yöntem: Metformin ve sitagliptin içeren farmasötik ürünler yerel eczanelerden temin edilmiştir. Bu ilaçlardaki NDMA ve NDEA düzeyleri, headspace gaz kromatografisi-kütle spektrometrisi (HS-GC-MS) kullanılarak analiz edilmiştir. Bulgular: NDMA konsantrasyonları 0.920 ile 1.571 mg kg-1 arasında, NDEA konsantrasyonları ise 1.241 ile 2.908 mg kg-1 arasında saptanmıştır. Her bir tabletteki NDMA miktarları 4.59.10-4 – 1.65.10-3 mg arasında ve NDEA miktarları da 7.94.10-4 – 3.54.10-3 mg arasında tespit edilmiştir. Sonuç: Elde edilen değerler kabul edilebilir alım limitlerinin (NDMA için 96 ng/gün ve NDEA için 26.5 ng/gün) üzerinde bulunmuştur.

Anahtar Kelimeler

İlaç, headspace GC-MS, N-nitrosodietil amin (NDEA), N-nitrosodimetil amin (NDMA)

Destekleyen Kurum

Hatay Mustafa Kemal Üniversitesi

Proje Numarası

24.YL.006

Etik Beyan

Etik kurul belgesi gerekli değildir.

Teşekkür

Bu araştırma (24.YL.006), Hatay Mustafa Kemal Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Birimi tarafından desteklenmiştir. Yazarlar, mali desteklerinden dolayı Hatay Mustafa Kemal Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Birimi'ne teşekkür ederler.

Investigation of Nitrosamine Impurities in Pharmaceutical Preparations Containing Metformin and Sitagliptin Active Ingredients

Öz

Aim: In this study, the determination of N-nitrosodimethyl amine (NDMA) and N-nitrosodiethyl amine (NDEA) contents in medicines containing metformin and sitagliptin as active pharmaceutical ingredients was aimed. Methods: Pharmaceutical products containing metformin and sitagliptin were obtained from local pharmacies. The levels of NDMA and NDEA in these medicines were analyzed using headspace gas chromatography–mass spectrometry (HS-GC-MS). Results: NDMA concentrations were found to range between 0.920 and 1.571 mg kg-1, while NDEA levels ranged from 1.241 to 2.908 mg kg-1. On a per-tablet basis, the detected NDMA amounts were between 4.59.10-4 and 1.65.10-3 mg, and NDEA amounts were between 7.94.10-4 and 3.54.10-3 mg. Conclusion: The values obtained were found to be above the acceptable intake limits (96 ng/day for NDMA and 26.5 ng/day for NDEA).

Anahtar Kelimeler

Drug, headspace GC-MS, N-nitrosodiethyl amine (NDEA), N-nitrosodimethyl amine (NDMA)

Destekleyen Kurum

Hatay Mustafa Kemal University

Proje Numarası

24.YL.006

Etik Beyan

The authors declare that the ethics committee approval is not required for this study.

Teşekkür

This research (24.YL.006) was supported by the Scientific Research Projects Coordination Unit of Hatay Mustafa Kemal University. The authors would like to thank the Scientific Research Projects Coordination Unit of Hatay Mustafa Kemal University for financial support.

Kaynakça

1. Chourasiya SS, Ranbhan KJ. Nitrosamine impurities in APIs: A comprehensive review. Int J Pharm Biol Sci. 2022;12(1):145– 157.
2. Özbay S. Investigation of the formation of volatile N-nitrosamines in sausage production [PhD thesis]. Ankara: Ankara University; 2020.
3. Horsch AM. The effect of pH and nitrite concentration on the antimicrobial impact of celery juice compared with sodium nitrite on Listeria monocytogenes [Master’s thesis]. Iowa: Iowa State University; 2013.
4. Mirvish SS. Effects of vitamins C and E on N-nitroso compound formation, carcinogenesis, and cancer. Cancer. 1986;58(S8):1842–1850. https://doi.org/10.1002/1097- 0142(19861015)58:8+<1842::AIDCNCR2820581410> 3.0. CO;2
5. International Agency for Research on Cancer (IARC). N-methyl-N′-nitro-N-nitrosoguanidine (MNNG). In: Overall evaluations of carcinogenicity. IARC Monogr Suppl 7. Lyon: IARC; 1987. p. 248–250.
6. Rojas LBA, Gomes MB. Metformin: An old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr. 2013;5:6. https://doi.org/10.1186/1758-5996-5-6
7. Jires J, Kalasek S, Gibala P, Rudovski J, Dousa M, Kubelka T, et al. Insight into the formation of N-nitrosodimethylamine in metformin products. J Pharm Biomed Anal. 2021;195:113877. https://doi.org/10.1016/j.jpba.2020.113877
8. Bessa-Jambrina S, Marlés-Torres A, Galán-Rodríguez C. Ultra-high-performance liquid chromatography–tandem mass spectrometry analytical method for the determination of nitrosamine drug substance-related impurity in sitagliptin base and salts. Sep Sci Plus. 2024;7(4). https://doi.org/10.1002/ sscp.202400003
9. Pepakayala S, Ratnakaram VN, Zunjarrao Y. Green and sustainable LC-APCI-MS/MS method for simultaneous quantification of genotoxic nitrosamines in antidiabetic medication: sitagliptin. BMC Chem. 2025;19:135. https://doi. org/10.1186/s13065-025-01503-4
10. Akyüz G, Kadıoğlu ELA. Farmasötik ürünler ve ham maddelerde N-nitrozaminlerin oluşum mekanizması ve toksisitesi: Geleneksel derleme. Literatür Eczacılık Bilimleri Dergisi. 2023;12(2):171–182. https://doi.org/10.5336/ pharmsci.2022-94271

11. European Medicines Agency (EMA). CHMP assessment report: Nitrosamine impurities in human medicinal products. Procedure under Article 5(3) of Regulation (EC) No 726/2004. London: EMA; 2020.
12. U.S. Food and Drug Administration (FDA). Control of nitrosamine impurities in human drugs: Guidance for industry. Silver Spring (MD): FDA; 2021.
13. International Council for Harmonisation (ICH). ICH guideline M7: Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk. Geneva: ICH; 2015.
14. Tsutsumi T, Akiyama H, Demizu Y, Uchiyama N, Masada S, Tsuji G, et al. Analysis of an impurity, N-nitrosodimethylamine, in valsartan drug substances and associated products using GC- MS. Biol Pharm Bull. 2019;42:547–551. https://doi.org/10.1248/ bpb.b19-00006
15. Abe Y, Yamamoto E, Yoshida H, Usui A, Tomita N, Kanno H, et al. Temperature-dependent formation of N-nitrosodimethylamine during the storage of ranitidine reagent powders and tablets. Chem Pharm Bull (Tokyo). 2020;68:1008– 1012. https://doi.org/10.1248/cpb.c20-00431
16. Zmysłowski A, Książek I, Szterk A. N-nitrosodimethylamine contamination in metformin finished products. Molecules. 2020;25(22):5304. https://doi.org/10.3390/molecules25225304
17. Lim HH, Oh YS, Shin HS. Determination of N-nitrosodimethylamine and N-nitrosomethylethylamine in drug substances and products of sartans, metformin and ranitidine by precipitation and solid phase extraction and gas chromatography–tandem mass spectrometry. J Pharm Biomed Anal. 2020;189:113460. https://doi.org/10.1016/j. jpba.2020.113460
18. Chang SH, Chang CC, Wang LJ, Chen WC, Fan SY, Zang CZ, et al. A multi-analyte LC-MS/MS method for screening and quantification of nitrosamines in sartans. J Food Drug Anal. 2020;28(2):292–301. https://doi.org/10.38212/2224-6614.1063
19. Liu J, Zhao Z, Yang X, Jin Y, Liu X, Wang C, et al. Determination of N-nitrosodimethylamine in ranitidine dosage forms by ESI-LC-MS/MS: Applications for routine laboratory testing. Iran J Pharm Res. 2021;20(4):255.
20. Campillo N, Vinas P, Martínez-Castillo N, Hernández- Córdoba M. Determination of volatile nitrosamines in meat products by microwave-assisted extraction and dispersive liquid–liquid microextraction coupled to gas chromatography– mass spectrometry. J Chromatogr A. 2011;1218(14):1815–1821. https://doi.org/10.1016/j.chroma.2011.02.010
21. Keire DA, Bream R, Wollein U, Schmaler-Ripcke J, Burchardt A, Conti M, et al. International regulatory collaboration on the analysis of nitrosamines in metformin-containing medicines. AAPS J. 2022;24(3):56. https://doi.org/10.1208/s12248-022- 00702-4
22. Vogel M, Norwig J. Analysis of genotoxic N-nitrosamines in active pharmaceutical ingredients and market authorized products in low abundance by means of liquid chromatography–tandem mass spectrometry. J Pharm Biomed Anal. 2022;219:114910. https://doi.org/10.1016/j.jpba.2022.114910
23. Tay KSJ, Breadmore MC, Soh ES, See HH. Development of dispersive inclusion complex microextraction for the analysis of nitrosamines in medicinal products. J Chromatogr A. 2022;1685:463605. https://doi.org/10.1016/j. chroma.2022.463605
24. Tarawneh IN, Shmeis RA, Alfuqaha SM, Al Omari MM. Determination of N-nitrosodimethylamine impurity in valsartan by HPLC and LC-MS/MS methods. Chin J Anal Chem. 2022;50(11):100150. https://doi.org/10.1016/j. cjac.2022.100150
25. Zhang J, Selaya SD, Shakleya D, Mohammad A, Faustino PJ. Rapid quantitation of four nitrosamine impurities in angiotensin receptor blocker drug substances. J Pharm Sci. 2023;112(5):1246– 1254. https://doi.org/10.1016/j.xphs.2022.12.005
26. U.S. Food and Drug Administration (FDA). Combined N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) impurities. Silver Spring (MD): FDA; 2019.
27. Sungur S, Aljoubasi M, Aydın Z. Determination of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) in medicines containing sartan and its derivatives. J Fac Pharm Ankara Univ. 2024;48(3):1118–1127. https://doi. org/10.33483/jfpau.1436182
28. Chung BY, Choi SM, Roh TH, Lim DS, Ahn MY, Kim YJ, et al. Risk assessment of phthalates in pharmaceuticals. J Toxicol Environ Health A. 2019;82(5):351–360. https://doi.org/10.1080 /15287394.2019.1598053

Ayrıntılar

Birincil Dil

İngilizce

Konular

Hasta Güvenliği

Bölüm

Araştırma Makalesi

Yazarlar

Şana Sungur ^*
0000-0001-7370-8972
Türkiye

Cansel Demetgül
0009-0008-9220-169X
Türkiye

Yayımlanma Tarihi

29 Temmuz 2026

Gönderilme Tarihi

25 Nisan 2026

Kabul Tarihi

5 Temmuz 2026

Yayımlandığı Sayı

Yıl 2026 Cilt: 7 Sayı: 3

IZ

https://izlik.org/JA32ZW83NN

APA

Sungur, Ş., & Demetgül, C. (2026). Investigation of Nitrosamine Impurities in Pharmaceutical Preparations Containing Metformin and Sitagliptin Active Ingredients. Yeni Yüzyıl Journal of Medical Sciences, 7(3), 119-128. https://izlik.org/JA32ZW83NN

AMA

1.Sungur Ş, Demetgül C. Investigation of Nitrosamine Impurities in Pharmaceutical Preparations Containing Metformin and Sitagliptin Active Ingredients. JMS. 2026;7(3):119-128. https://izlik.org/JA32ZW83NN

Chicago

Sungur, Şana, ve Cansel Demetgül. 2026. “Investigation of Nitrosamine Impurities in Pharmaceutical Preparations Containing Metformin and Sitagliptin Active Ingredients”. Yeni Yüzyıl Journal of Medical Sciences 7 (3): 119-28. https://izlik.org/JA32ZW83NN.

EndNote

Sungur Ş, Demetgül C (01 Temmuz 2026) Investigation of Nitrosamine Impurities in Pharmaceutical Preparations Containing Metformin and Sitagliptin Active Ingredients. Yeni Yüzyıl Journal of Medical Sciences 7 3 119–128.

IEEE

[1]Ş. Sungur ve C. Demetgül, “Investigation of Nitrosamine Impurities in Pharmaceutical Preparations Containing Metformin and Sitagliptin Active Ingredients”, JMS, c. 7, sy 3, ss. 119–128, Tem. 2026, [çevrimiçi]. Erişim adresi: https://izlik.org/JA32ZW83NN

ISNAD

Sungur, Şana - Demetgül, Cansel. “Investigation of Nitrosamine Impurities in Pharmaceutical Preparations Containing Metformin and Sitagliptin Active Ingredients”. Yeni Yüzyıl Journal of Medical Sciences 7/3 (01 Temmuz 2026): 119-128. https://izlik.org/JA32ZW83NN.

JAMA

1.Sungur Ş, Demetgül C. Investigation of Nitrosamine Impurities in Pharmaceutical Preparations Containing Metformin and Sitagliptin Active Ingredients. JMS. 2026;7:119–128.

MLA

Sungur, Şana, ve Cansel Demetgül. “Investigation of Nitrosamine Impurities in Pharmaceutical Preparations Containing Metformin and Sitagliptin Active Ingredients”. Yeni Yüzyıl Journal of Medical Sciences, c. 7, sy 3, Temmuz 2026, ss. 119-28, https://izlik.org/JA32ZW83NN.

Vancouver

1.Şana Sungur, Cansel Demetgül. Investigation of Nitrosamine Impurities in Pharmaceutical Preparations Containing Metformin and Sitagliptin Active Ingredients. JMS [Internet]. 01 Temmuz 2026;7(3):119-28. Erişim adresi: https://izlik.org/JA32ZW83NN

Metformin ve Sitagliptin Etkin Maddelerini İçeren İlaçlardaki Nitrozamin Safsızlıklarının Araştırılması

Öz

Anahtar Kelimeler

Destekleyen Kurum

Proje Numarası

Etik Beyan

Teşekkür

Investigation of Nitrosamine Impurities in Pharmaceutical Preparations Containing Metformin and Sitagliptin Active Ingredients

Öz

Anahtar Kelimeler

Destekleyen Kurum

Proje Numarası

Etik Beyan

Teşekkür

Kaynakça

Ayrıntılar

Birincil Dil

Konular

Bölüm

Yazarlar

Yayımlanma Tarihi

Gönderilme Tarihi

Kabul Tarihi

Yayımlandığı Sayı

IZ

Kaynak Göster