Insight into Analytical Techniques for the Detection of Nitrosamine Impurities: A Review

 

Karishma P. Fuse1, Vinod H. Jadhav2

1Department of Pharmaceutical Quality Assurance, Dadasaheb Balpande College of Pharmacy, Nagpur, Maharashtra, India.

2Quest Medpharma Consultants, Nagpur, Maharashtra, India.

*Corresponding Author E-mail: vj47422@gmail.com

 

ABSTRACT:

Nitrosamine impurities in pharmaceutical products have increased attention for safety in the direction of the use of various drugs. Nitrosamines are the class of compounds which represents nitroso group attached to an amine (R1N(-R2)-N=0). Nitrosamines are molecules that have a nitroso group connected to an amine (R1N(-R2)-N=0). Controlling cancer-causing contaminants in pharmaceutical products is critical for predicting and avoiding the carcinogenic risk of medicine in people. According to recent findings, nitrosamine impurities have increased the medicinal product's carcinogenic risk. The literature search was accomplished using PubMed, Google scholar, and the Cochrane library to identify relevant scientific articles using various sensitive techniques and analytical instruments for the detection of nitrosamine impurities from the years 1981 to 2022. The search terms included nitrosamine detection techniques, formation of nitrosamine, HPLC technique for nitrosamine detection, GC-MS/MS, GC-MS/MS, GC-MS-Head space, and GC-QTOF technique for nitrosamine detection, LC-MS/MS technique for nitrosamine detection, The literature search included 29 scientific articles from the English lamnguage, including original research and standard guidelines intended to review all the sensitive techniques for detection of nitrosamine impurities in pharmaceutical products. The current review aims to discuss the highly sensitive, cost effective, accurate and precise methods for the detection of various nitrosamine contaminations in the pharmaceutical products.

 

KEYWORDS: Nitrosamine impurities, Pharmaceutical products, Analytical techniques, Nitrosamine detection techniques, HPLC, GC-MS/MS, LC-MS/MS.

 

 


INTRODUCTION:

Nitrosamine impurities in pharmaceutical products have increased attention to safety in the direction of the use of various drugs, not only sartans and tetrazole- bearing angiotensin II receptor antagonist but also metformin, ranitidine, and other pharmaceutical products, many among these needed recall and likely to shortage.

 

These impurities may present at any stage of drug synthesis and throughout the products lifetime, these impurities may develop if amine reacts with a nitrosating agent.1 Nitrosamines are the class of compounds which represents nitroso group attached to an amine (R1N(-R2)-N=0) (fig 1)2 The control of cancer-causing impurities in pharmaceutical products is of utmost importance to predict and avoid the carcinogenic risk of medication in humans. The recent findings suggest that nitrosamine impurities have amplified the carcinogenic risk of the pharmaceutical product.3

 

The modern findings of intoxicating cancer-causing nitrosamine impurities in numerous medicines have created a need for product reminiscences and interrupted the supply of life-threatening medication for a huge number of patients, suggesting a need for improving nitrosamine detection in pharmaceutical products.4 The latest discovery of nitrosamine impurities in Ranitidine, Metformin, Nizatidine, and angiotensin II receptor blockers (ARB) has clearly suggested the need for assessment strategies for nitrosamine in pharmaceutical products.2 

 

Fig. 1: N-nitrosamine (Rotamer structures)5

 

Sources and major reasons for the Occurrence of nitrosamine contamination in active pharmaceutical ingredients:

The nitrosamine formation was first detected in EU licenced Angiotensin-II-receptor blockers, representing a tetrazole ring (valsartan, losartan, olmesartan, irbesartan and candesartan), represents tetrazole rings during synthesis step of all sartans results in formation of nitrosamines. In all sartans, solvents like dimethylformamide (DMF), N-methylpyrrolidone (NMP) and triethylamine (TEA) reveal cradles of amines like dimethylamine (DMA), methylbutylamine (MBA) and diethylamine (DEA), which represent major role in nitrosamine formation. Additionally the solvent TEA have a capability for N-DEA formation by nitrosative dealkylation.6

 

Nitrosamine formation may take place in the presence of secondary, tertiary, or quaternary amines and nitrite salts in an acidic environment. In this environment, nitrite salts may form nitrous acid, which react with an amine, leading to the formation of nitrosamine. Nitrates are utilized a reagent which reacts with amines, leading to the generation of nitrosamine contamination. (fig 2)

 

Figure 2. Reaction representing formation of N- nitrosamine impurities.7

 

The current review aims to discuss the highly sensitive, cost effective, accurate and precise methods for the detection of various nitrosamine impurities in the pharmaceutical products.

 

Methods:

The literature search was accomplished using PubMed, Google scholar, and the Cochrane library to identify relevant scientific articles using various sensitive techniques and analytical instruments for the detection of nitrosamine impurities from the years 1981 to 2022. The search terms included nitrosamine detectiontechniques, formation of nitrosamine, HPLC technique for nitrosamine detection, GC-MS/MS, GC-MS/MS, GC-MS-Head space, and GC-QTOF technique for nitrosamine detection, LC-MS/MS technique for nitrosamine detection, The literature search included 29 scientific articles, including original research and standard guidelines intended to review all the sensitive techniques for detection of nitrosamine impurities in pharmaceutical products.

 

Analytical techniques for the detection of nitrosamine impurities:

HPLC (high-pressure liquid chromatography):

Liquid chromatography is an important separation method with a marked impact in the area of pharmaceuticals. Previous discoveries reported by National Agency for Medicines and Health Products Safety and official Medicines Control Laboratories (OMCL), French, with the help of UV detector at 228 nm NDMA impurities were successfully detected in Valsartan. Moreover reproducible detection of nitrosamine with the help of HPLC could be accomplished through post-column photolysis and chemiluminiscence detector (LC-PR-CLD).8 Li et al initially utilized diode array detectors (DAD) in the HPLC to detect NDMA impurities in the wavelength range of 230–233nm.9

 

Ho je et al. came up with a method development for detection of N-nitrosodiethanolamine (NDELA) in cosmetic products. The NDELA fractions were separated from cosmetic products and the isolated fractions of NDELA were analyzed using HPLC coupled with a thermal energy analyzer (TEA). The LOD of NDELA by TEA reported to be 2-3 ng, which is nearly contrast to 20-30 ppb in the cosmetic product. The emulsion cream and hair grooming gel were analysed for the NDELA detection.10 Masada et al developed an HPLC method for quantitative analysis of NDMA impurities in Valsartan. The reported LOD and LOQ was 0.0085 μg/mL and 0.0285μg/mL correspondingly. The method could accomplish required linearity, accuracy and preciseness to analyse NDMA impurity in the Valsartan. The method rapidly screened and detected NDMA contamination in Valsartan.11

 

LC-MS/MS (liquid chromatography-tandem mass spectrometry):

LC-MS/MS is a sensitive technique that splits and detects the constituents of a complex mixture with the help of a mass spectrometer.12 LC-MS/MS is an ideal technique in the case of NDMA impurities due to thermal degradation of drugs to form NDMA. The USFDA developed two NDMA detection methods that revealed 0.033ppm LOQ for ranitidine API and products. The U.S. FDA presented an NDMA detection technique for ranitidine API and products that reported the LOQ range at 0.033 ppm; using LC-HRMS (QTRAP).13 Cheng S et al. developed a more realistic and sensitive LC-MS/MS capable of quantifying multiple samples. A total of 12 nitrosamines in sartans were detected in the API and final product. The LOD and LOQ for 12 nitrosamines were 20ng/g and 50 ng/g, respectively. The major nitrosamines quantified included NDEA, NDMA, N-nitroso-N-methyl-4aminobutyric acid, N-nitrosomorpholine (NMOPh) and N-nitrosopiperidine, were quantified from 557 samples.14 The LC-MS technique was established with an LOQ or below the standard limit of all engaged reversed-phase LC attached to a high-resolution mass spectrometer (HRMS) or MS/MS. The Major mass detector was the quadrapole-ion trap (QTRAP) or a triple quadrapole (QQQ) were the mass analyser fit with either electrospray ionization. NDMA and NDEA were quantified with the lowest LOQ.15

 

Baksam V et al. invented a sensitive and simple ultra-high -performance liquid chromatography (UPLC) coupled with an LC-MS/MS technique for the quantification of N-nitrosamine contamination, N-(2-hydroxyethyl)-N-phenylnitrous amide in the pharmaceutical product, Rivaroxaban in the nanogram range. The length and diameters of column used was (150mm × 4.6mm, 3μm). The LOD and LOQ of the N-nitrosamine contamination was 0.045 ng ML-1 and 0.15 ng mL−1, the precision and accuracy of the technique were reported well within the quantified range. The established method could detect N-nitrosamine contamination in large-scale sample of Rivaroxaban.16 Wohlfart J detected 4-methyl-1-nitrosopiperazine (MeNP) in rifampicin by, using Liquid chromatography coupled to mass spectrometry (LC-MS- high resolution mass spectrometry (LC-HRMS), a standard technique reported by FDA. The outcome of the analysis reported significant MeNP impurities (0.7 to 5.1 ppm) in all samples and found 32 fold exceedance of the limit suggested by the FDA.17

 

Chidella K established an ultra-sensitive LC-MS/MS technique for quantifying six genotoxic nitrosamine contamination namely NDMA, NDEA, N-nitrosoethylIsopropylamine (NEIPA), N-Nitroso-N-methyl-4-amiinobutyric acid (NMBA), N-nitrosodibutyl amine (NDBA) and N-nitrosodiisopropylamino (NDIPA). The LOQ detected range was 0.004 ppm, column used for chromatographic separation was Zorbax SB C18 150 × 3.0mm, 3.5μ. The LOQ and quantification were found with a virtuous linearity range of 0.002 - 2 ppm and a regression coefficient of > 0.99 reported for all the six contaminations of nitrosamine. The technique can be utilized regularly for the quantification of nitrosamine impurities in Telmisartan concentrations of 1.5ng/ml.18 Wu Q identified isotopes of N, N-dimethylformamide (DMF) interfered while detecting NDMA, which is detected by using an LC-MS instrument. The sensitive method developed was LC-HRMS by which the NDMA from DMF was separated in metformin to remove the interference.19

 

GC-MS (Gas chromatography-mass spectrometry):

GC-MS is a critical and tough ionisation technique for both quantitative and qualitative detection of volatile organic APIs. Although GC with various detectors will be helpful in the detection of nitrosamine, though nitrogen chemiluminescence detector (NCD) and nitrogen-phosphorous detector (NPD) are the most appropriate.20 Zheng J et al. used full evaporation static headspace GC with nitrogen phosphorous detection (FE-SHSGC-NPD) and reported the presence of NDMA impurities in the pharmaceutical product. The method was revealed to be sensitive, accurate, specific and precise, along with having the potential to be considered as a collective method for quantification of semi-volatile nitrosamines through numerous drug products. This method is considered a major advancement over traditional LC-MS methods, due to its potential to eliminate detrimental headspace-liquid partition and a quantification limit of 0.25 ppb accomplished for NDMA. The outcome reported that the in situ nitrosation generally found in GC methods for nitrosamine detection was purely restricted by adding up a small proportions of pyrogallol, isopropanol, and phosphoric.21 Wichitnithad W et al. developed a high-throughput method based on headspace Gas Chromatography-Mass Spectrometry (HS-GC-MS) for the real-time quantification of four nitrosamines N-Nitrosadimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N- nitrosoethylisopropylamine (NEPA), and N-nitrosodiisopropylamine (NDIA) in Losartan potassium API. The levels were detected with the help of aa single quadrapole mass spectrometer, electron impact followed by validated rendering to Q2 (R1) ICH guidelines. The accuracy of the method was found to be 7.04%–7.25% and the precision % CV was found to be ≤11.5.22

 

Another recent development and validation for the quantification of nine nitrosamines in ranitidine samples includes NDMA, NDEA, nitrosopyrrolidine (NPYR), N-nitrosodi-n-propylamine (NDnPA), N-nitrosopiperidine (NPIP), N-nitrosodi-n-butylamine (NDBA), and N-nitrosodiphenylamine (NDPhA). The quantification was achieved by an arrangement of microextraction and GC-MS. The detection limits were observed in the range of 0.21-21ng g -1, matching the lower limit for NDPhA and the greater for NDMA. The standard deviation was less than 12%. The method successfully revealed no nitrosamine impurities in seven pharmaceutical samples of ranitidine.23 Likewise, Liu J et al established  a profound and steady GC-MS/MS method linked with a number of reaction detector modes for real-time quantification of four nitrosamines, namely NDMA, NDEA, NDBA and N-nitrosodiisopropylamine (NDIPA) from the sartan drug samples. The LOD of N-nitrosamines in the sartan samples vacillated from 0.002 to 0.150ppm and the corresponding LOQ were in ranges from 0.008-0.500 ppm which met the sensitivity limits set by the Food and Drug Administration of the United States (US-FDA). The linearity of regression coefficient was over 0.99 which revealed the internal standard curve for N-nitrosamine, with less than 9.15% standard deviation; the outcome revealed the good sensitivity, accuracy and precision and a reckless quantification speed.24

 

Dawson and Lawrence observed 21 out of 34 samples to present 12µg/kg NDMA impurities. The limit of detection (LOD) and LOQ were quantified at LOD= 0.1 µg/kg, LOQ found 0.3 µg/kg. The technique used was GC-Thermal energy analyser (GC-TEA) with packed column at isothermal settings. The outcome revealed no rise in NDMA level in the prepared sample.25 Lim H et al established isotope dilution, clean-up technique and GC-MS for real-time quantification of NDMA and NDEA impurities in metformin, sartans, and ranitidine. Additionally the precipitation and activated charcoal cartridges were used in the method. The lower limit of detection range reported 0.07-0.3μg/kg, the range for LOC reported 0.3-0.9μg/kg. However the precision ranges found to differ 0.4-2.7% for NDMA and for NDEA range 0.4–4.2% were reported, additionally ranges for accuracy testified were reported  95.0–105 % for NDMA and 93.6–104% for NDEA.26 Chang SH et al developed a viable GC–tandem mass spectrometry (GC–MS/MS) technique for concurrent detection of 13 nitrosamines. The LODs and LOQs were reported to be 15-250ng/g and 50-250ng/g for all 13 nitrosamine. Additionally at intra-day and inter-day accuracies were reported to be 91.4-104.8% which satisfied validation criteria. However NDEA, NDPhA, N-nitrosomorpholine, N-nitrosopiperidine, N-nitrosodimethylamine, were presented the LOD concentration above the limit. 27 Alsheri Y et al established a more sensitive technique which is an add up technique to GC-MS. The solid-phase microextractiom (SPME) utilised as technique of extraction with GC (SPME-GC-MS). As compared to LC-MS/MS greater level of NDMA were detected when headspace (HS) and liquid injection mode used in GC for quantification of NDMA in ranitidine. Alsheri Y et al reported benefit of HS-SPME-GC-MS that avoided the high temperature which presented in liquid injection and HS mode. Furthermore the outcome gained using HS-SPME-GC-MS offered the comparable outcomes that achieved by LC-MS/MS.28

 

Supercritical fluid chromatography (SFC):

The SFC has ability to distinguish and quantify the broad range very polar and nonpolar impurities within 20 minutes. It can be considered for testing of adopted nitrosamines. Schmidtsdorff S et al developed the SFC method for quantification of nitrosamine impurities in pharmaceutical API. The column used in the method (C18, Diol, Fluorophenyl, BEH-pure silica) exhibited appropriate separation and retention characteristics for valsartan, losartan, and NDMA. Additional findings displayed both NDMA and NDEA quantified in single batch of losartan. NDEA was identified roughly at the LOD and NDMA twofold beyond the LOD. The method was found as sensitive as LC and GC-MS/MS.29


 

Table no. 1 various sensitive techniques with LOD and LOQ

Authors

Technique

LOD

LOQ

References

Ho je et al

HPLC coupled with a thermal energy analyzer (TEA)

2-3 ng

-

10

Masada et al

HPLC

0.0085 μg/mL

0.0285 μg/mL

11

Cheng S

LC-MS/MS

20 ng/g

50 ng/g,

14

Baksam V et al

UPLC- LC-MS/MS

0.045 ng ML-1

0.15 ng mL−1

16

Chidella K

LC-MS/MS

-

0.004 ppm

18

Zheng J et al

FE-SHSGC-NPD

 

0.25 ppb

21

Liu J et al

GC-MS/MS

0.002 to 0.150 ppm

0.008-0.500 ppm

24

Dawson and Lawrence

GC-TEA

0.1 µg/kg

0.3 µg/kg

25

Lim H et al

GC-MS

0.07-0.3 μg/kg

0.3-0.9 μg/kg

26

Chang SH et al

GC–MS/MS

15-250 ng/g

50-250 ng/g

27

 


CONCLUSION:

The current review discusses the newer and older sensitive techniques in for the quantification of the nitrosamine contamination in the pharmaceutical products. The detection and low-level quantification of nitrosamine impurities in potentially exaggerated resources a challenging and demands the need for highly sensitive analytical methods.

 

ACKNOWLEDGEMENT:

Authors and co-authors acknowledge Mr.VinodJadhav, scientific writer, QuestMedpharma Consultants, Nagpur for his assistance in the review.

 

CONFLICTS OF INTEREST:

Authors declares no conflicts of interest

 

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19.   Wu Q, Kvitko E, et al. A Broadly Accessible Liquid Chromatography Method for Quantification of Six Nitrosamine Compounds and N, N-Dimethylformamide in Metformin Drug Products Using High Resolution Mass Spectrometry. 10.26434/chemrxiv.13202849.v1

20.   Shaik KM, Sarmah B, et al. Regulatory updates and analytical methodologies for nitrosamine impurities detection in sartans, ranitidine, nizatidine, and metformin along with sample preparation techniques. Critical reviews in analytical chemistry. 2022 Jan 2;52(1):53-71. DOI: 10.1080/10408347.2020.1788375

21.   Zheng J, Kirkpatrick CL, et al. A Full Evaporation Static Headspace Gas Chromatography Method with Nitrogen Phosphorous Detection for Ultrasensitive Analysis of Semi-volatile Nitrosamines in Pharmaceutical Products. The AAPS Journal. 2022 Feb;24(1):1-8. DOI: 10.1208/s12248-021-00669-8

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24.   Liu J, Xie B, et al. Development of a sensitive and stable GC-MS/MS method for simultaneous determination of four N-nitrosamine genotoxic impurities in sartan substances. Journal of Analytical Science and Technology. 2021 Dec;12(1):1-8. DOI

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26.   Lim HH, Oh YS, et al. 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. Journal of pharmaceutical and biomedical analysis. 2020 Sep 10;189:113460. DOI: 10.1016/j.jpba.2020.113460

27.   Chang SH, Ho HY, et al. Screening of Nitrosamine Impurities in Sartan Pharmaceuticals by GC-MS/MS. Mass Spectrometry Letters. 2021;12(2):31-40.https://doi.org/10.5478/MSL.2021.12.2.31

28.   Alshehri YM, Alghamdi TS, et al. HS-SPME-GC-MS as an alternative method for NDMA analysis in ranitidine products. Journal of pharmaceutical and biomedical analysis. 2020 Nov 30;191:113582. DOI: 10.1016/j.jpba.2020.113582

29.   Schmidtsdorff S, Schmidt AH. Simultaneous detection of nitrosamines and other sartan-related impurities in active pharmaceutical ingredients by supercritical fluid chromatography. Journal of pharmaceutical and biomedical analysis. 2019 Sep 10;174:151-60. DOI: 10.1016/j.jpba.2019.04.049

 

 

 

 

Received on 17.04.2022       Modified on 19.10.2022

Accepted on 25.01.2023   ©Asian Pharma Press All Right Reserved

Asian J. Pharm. Ana. 2023; 13(1):30-34.

DOI: 10.52711/2231-5675.2023.00005