Nitrosamine impurities in medications: test methods

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Test method for sartans or angiotensin II receptor blockers (ARBs)

Determination of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) by GC-MS/MS (direct injection) in sartan finished products and drug substances

1. Principle and Scope

The present method has been developed to detect and quantify the nitrosamine impurities N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) in valsartan, irbesartan and losartan finished products. The method is performed by gas chromatography-tandem mass spectrometry (GC-MS/MS) using direct injection.

The method can also be used to detect and quantify NDMA and NDEA in candesartan and olmesartan finished products, and in sartan drug substances (e.g., valsartan, irbesartan, losartan, candesartan and olmesartan). However, if interferences are observed, further validation may be required.

2. Reagents and Reference Standards

3. Instrument/Equipment

4. Preparation of Solutions

Standard solutions
Reference standard stock solutions (as purchased)
  • NDMA standard solution in methanol (5000 ppm)
  • NDEA standard solution in methanol (100 ppm)
Internal reference standard stock solution (as purchased)
  • NDMA-d6 standard solution in methanol (1000 ppm)
Diluted standard solutions
NDMA standard solution (200 ppm):
Transfer 800 μL of NDMA reference solution (5000 ppm) into a 20 mL volumetric flask, dilute to volume with methanol.
Diluted standard solution (NDMA: 40 ppm, NDEA: 20 ppm):
Transfer 800 μL of NDMA standard solution (200 ppm) and 800 μL of NDEA reference solution (100 ppm) into a 4 mL volumetric flask, dilute to volume with methanol.
Internal standard solution-1 (20 ppm):
Transfer 500 μL of NDMA-d6 standard solution (1000 ppm) into a 25 mL volumetric flask, dilute to volume with methanol.
Internal standard solution-2 (0.2 ppm):
Transfer 5 mL of internal standard solution-1 (20 ppm) into a 500 mL volumetric flask, dilute to volume with methanol.

Calibration solutions

STD-12:
Transfer 500 μL of diluted standard solution (NDMA: 40 ppm, NDEA: 20 ppm) and 50 μL of internal standard solution-1 (20 ppm) into a 5 mL volumetric flask, dilute to volume with methanol. Mix well.
STD-7:
Transfer 1000 μL of STD-12 into a 20 mL volumetric flask, dilute to volume with internal standard solution-2 (0.2 ppm). Mix well. This solution will be used for the system suitability test and system drift check.
STD-11:
1:1 dilution of STD-12 with internal standard solution-2
STD-10:
1:1 dilution of STD-11 with internal standard solution-2
STD-9:
1:1 dilution of STD-10 with internal standard solution-2
STD-8:
3:2 dilution of STD-9 with internal standard solution-2
STD-6:
1:1 dilution of STD-7 with internal standard solution-2
STD-5:
1:1 dilution of STD-6 with internal standard solution-2
STD-4:
2:3 dilution of STD-5 with internal standard solution-2
STD-3:
1:1 dilution of STD-4 with internal standard solution-2
STD-2:
1:1 dilution of STD-3 with internal standard solution-2
STD-1:
2:3 dilution of STD-2 with internal standard solution-2
Concentration of calibration solutions:
Description NDMA concentration (µg/mL) NDEA concentration (µg/mL) NDMA-d6 concentration (µg/mL)
STD-1 0.002 0.001 0.2
STD-2 0.005 0.0025 0.2
STD-3 0.01 0.005 0.2
STD-4 0.02 0.01 0.2
STD-5 0.05 0.025 0.2
STD-6 0.1 0.05 0.2
STD-7 0.2 0.1 0.2
STD-8 0.3 0.15 0.2
STD-9 0.5 0.25 0.2
STD-10 1 0.5 0.2
STD-11 2 1 0.2
STD-12 4 2 0.2

For NDMA, STD-1 to STD-6 are used as working range from 0.002 - 0.1 µg/mL, and STD-6 to STD-12 are used as working range from 0.1 - 4.0 µg/mL.

For NDEA, STD-1 to STD-5 are used as working range from 0.001 - 0.025 µg/mL, and STD-5 to STD-11 are used as working range from 0.025 - 1.0 µg/mL.

The working ranges of NDMA and NDEA can be adjusted as needed.

Sample Preparation

For finished product:

Weigh NLT 20 tablets and calculate average tablet weight. Carefully grind NLT 20 tablets into fine powder using a mortar and pestle.

Prepare triplicate samples for each product. Accurately weigh an amount equivalent to 250 mg of drug substance of the homogenized sample powder into a screw cap round bottom glass tube.

Using an automatic pipette, add 5 mL of NDMA-d6 internal standard solution-2 to each sample tube. Tightly cap the tubes, sonicate for 5 minutes, and then vortex the rack of tubes on the multi-tube vortex mixer at 2000 rpm for five minutes.

Centrifuge the tubes for at least 5 minutes at 1500 rpm. Carefully remove the tubes from the centrifuge. Use a Pasteur pipette to transfer an aliquot from each tube to a 2 mL GC vial and cap.

Note: Method accuracy was assessed by recovery studies. Valsartan, irbesartan and losartan finished products were spiked with reference standard solution in the following way:

For samples with NDMA above 0.3 ppm and/or NDEA above 0.08 ppm:
Spike sample solution with the reference standard solution at concentration level close to sample concentration and calculate recovery.
For samples with NDMA below 0.3 ppm and/or NDEA below 0.08 ppm:
Spike sample solution with STD-3 (1:1) to get solution containing 0.05 ppm of NDMA and 0.025 ppm of NDEA. Check S/N and calculate the LOD and LOQ.

For drug substance:

Prepare triplicate samples for each substance. Accurately weigh 250 mg of the homogenized sample powder into a screw cap round bottom glass tube.

Continue as per the instructions above for finished product. Spiking to determine method accuracy is recommended.

5. Instrument Operating Parameters:

Suggested GC parameters:

Injector Settings:

Injector mode:
Pulsed Splitless
Injector temperature:
240°C
Flow rate:
1.8 mL/min
Septum purge flow:
3 mL/min
Purge Flow:
50 mL/min after 0.75 minutes
Injection volume:
2.0 µL
Oven program:
Initial Temp: 60°C
Hold: 2 minutes
Table 1. oven program
Ramp # Rate (°C/min) Final Temp (°C) Hold Time (min)
1 5 130 0
2 40 240 5
Total run time: 24 minutes

Suggested MS settings

MS transfer line (aux. temp):
250°C
Ion source:
EI
Source temperature:
250 °C
Solvent delay:
6 minutes
Stop time:
15 minutes
Quench gas:
Helium at 2.25 mL/min
Collision gas:
Nitrogen at 1.5 mL/min
Table 2. MS/MS parameters
Analyte Retention time (min) Segment Retention time window (min) Precursor ion (m/z) Product ion (m/z) CE
(V)
Resolution Dwell (ms)
NDMA-d6 (ISTD) 7.8 1 7.5-8.1 80 50 5 wide/wide 100
NDMA 7.8 1 7.5-8.1 74 42 15 wide/wide 100
74 44 4 100
NDEA 12.7 2 12.4-13.0 102 44 12 wide/wide 150
102 85 2 150

6. System Suitability

The coefficient of determination (R2) for each calibration curve is NLT 0.995.

The signal-to-noise of the STD-1 (NDMA = 0.002 µg/mL; NDEA = 0.001 µg/mL) solution should be NLT 10.

7. Calculation

Construct calibration curves for NDMA and NDEA by plotting the ratio of response factor (NDMA or NDEA peak area divided by internal standard peak area) against standard concentration (µg/mL). Using the slopes and intercepts of the calibration curves, determine the content of NDMA and NDEA in each sample using the following equations.

For finished product:

The results, in ppm relative to the declared amount of sartan drug substance in the product, are given by:

Equation 1

equation 1

Where,

y =
ratio of peak area of NDMA or NDEA to peak area of NDMA-d6
b =
intercept of the linear curve
m =
slope of the linear curve
Wtspl =
sample weight (g)
AVGwt =
average tablet weight (g)
LC =
label claim of sample (g)
V =
5 mL (volume)
Text description

Parts per million equals y minus b over m, which is the difference between the ratio of the peak area of the impurity to peak area of internal standard minus the intercept of the linear curve over the slope of the linear curve. This value is multiplied by average tablet weight, then multiplied by the volume, divided by the sample weight and then divided by the label claim of the sample.

For drug substance:

The results, in ppm relative to the drug substance being tested, are given by:

Equation 2

equation 2

Where,

y =
Ratio of Peak Area of NDMA or NDEA to Peak Area of NDMA-d6
b =
intercept of the linear curve
m =
slope of the linear curve
Wtspl =
sample weight (g)
V =
5 mL (volume)
Text Description

Parts per million equals y minus b over m, which is the difference between the ratio of the peak area of the impurity to peak area of internal standard minus the intercept of the linear curve over the slope of the linear curve. This value is multiplied by the volume and then divided by the weight of the sample.

8. LOD and LOQ results

LOD/LOQ can be calculated using the S/N of the spiked sample solution (spiked with STD-3 at 1:1).

Theoretical LOD/LOQ:

If no spiked results are available, the theoretical LODs and LOQs can be calculated by using the S/N of STD-1 (NDMA: 0.002 µg/mL; NDEA 0.001 µg/mL).

For reference, the theoretical LOD/LOQ results at Health Canada are as follows:

Table 3. S/N of NDMA and NDEA of STD-1
Drug substance conc. µg/mL NDMA NDEA
µg/mL S/N LOD (calc.) ppm LOQ (calc.) ppm µg/mL S/N LOD (calc.) ppm LOQ (calc.) ppm
50 0.002 74 0.002 0.0054 0.001 55 0.002 0.0073

9. Sample Chromatograms

Figure 1

Figure 1

Text description

The figure shows chromatograms of a sample showing typical peaks for NDMA and NDEA. The chromatograms are arranged in 4 rows.

  • The first row shows the Total Ion Current chromatogram from 6.0 to 15.0 minutes. There is a large peak at 8.5 minutes (labelled "matrix") and smaller peaks at 7.7 minutes (NDMA, NDMA-d6) and 12.6 minutes (NDEA).
  • The second row shows a Multiple Reaction Monitoring chromatogram (m/z 80.0 → 50.0) with a single peak at 7.735 minutes for the NDMA-d6 internal standard.
  • The third row shows two Multiple Reaction Monitoring chromatograms (m/z 74.0 → 44.0 and m/z 74.0 → 42.0) each with a single peak at 7.787 minutes for NDMA.
  • The fourth row shows two Multiple Reaction Monitoring chromatograms (m/z 102.0 → 85.0 and m/z 102.0 → 44.0) each with a single peak at 12.561 minutes for NDEA.

Figure 2. Chromatogram of STD-1

Figure 2

Text description

The figure shows chromatograms of the STD-1 standard solution. The chromatograms are arranged in 4 rows.

  • The first row shows the Total Ion Current chromatogram from 6.0 to 15.0 minutes. There is a large peak at 7.7 minutes (NDMA, NDMA-d6) and a small peak at 8.5 minutes (labelled "matrix").
  • The second row shows a Multiple Reaction Monitoring chromatogram (m/z 80.0 → 50.0) with a single peak at 7.715 minutes for the NDMA-d6 internal standard.
  • The third row shows two Multiple Reaction Monitoring chromatograms (m/z 74.0 → 44.0 and m/z 74.0 → 42.0) each with a single peak at 7.767 minutes for NDMA.
  • The fourth row shows two Multiple Reaction Monitoring chromatograms (m/z 102.0 → 85.0 and m/z 102.0 → 44.0) each with a single peak at 12.515 minutes for NDEA.

Test method for ranitidine products

Determination of N-nitrosodimethylamine (NDMA) in ranitidine products by UPLC-MS/MS

1. Principle and Scope

The present method has been developed to detect and quantify N-nitrosodimethylamine
(NDMA) in ranitidine products by UPLC-tandem mass spectrometer (UPLC-MS/MS).

2. Reagents and Reference Standards

3. Instrument/Equipment

4. Preparation of Solutions

Storage

Calibration and sample solutions are stored in refrigerator.

Mobile Phase Preparation

Diluent Preparation

Standard Solutions

Reference standard stock solutions (as purchased)
NDMA standard solution in methanol (200 ppm)

Calibration standard solutions

STD-1:
Transfer 50 µL of NDMA reference standard stock solution (200 ppm) into a 50 mL volumetric flask, dilute to volume with diluent. Mix well. This solution will be used as system suitability test and system drift check.
STD-2:
1:1 dilution of STD-1 with diluent. Mix well.
STD-3:
1:1 dilution of STD-2 with diluent. Mix well.
STD-4:  
1:1 dilution of STD-3 with diluent. Mix well.
STD-5:  
2:3 dilution of STD-4 with diluent. Mix well.
STD-6: 
1:1 dilution of STD-5 with diluent. Mix well.
STD-7: 
1:1 dilution of STD-6 with diluent. Mix well.
STD-8: 
2:3 dilution of STD-7 with diluent. Mix well.
STD-9: 
3:1 dilution of STD-8 with diluent. Mix well (LOD).
Table 1. Concentration of calibration solutions
Calibration Standard Solution NDMA Concentration (ng/mL)
STD-1 200
STD-2 100
STD-3 50
STD-4 25
STD-5 10
STD-6 5
STD-7 2.5
STD-8 1
STD-9 0.75

R2 for calibration curve should be NLT 0.99.

Sample Preparation

Suggested sample preparation:

The concentration of samples (weight and/or volume) may be modified as required.

Suggested Recovery Spiking:

Spike samples: Spike sample solutions with reference standard solution in triplicate and check recoveries.

5. Instrument Operating Parameters

Suggested UPLC Parameters:

Flow rate:
0.4 mL/min
Injection volume:
10.0 µL
Run time:
12.5 minutes
Table 2. Gradients
Time (min) Mobile Phase A% Mobile Phase B%
0 95 5
5 95 5
7 0 100
10 0 100
10.1 95 5
12.5 95 5

Suggested MS Parameters:

APCI probe temperature:
450°C
Source temperature:
150°C
Corona:
4.0 kV
Type:
MRM
Ion mode:
Positive
Span (Da):
0.3
Start time:
3.3 minutes
End time:
5.0 minutes

Run events:

Event 1:
0.00 min flow state: Waste
Event 2:
3.30 min flow state: LC
Event 3:
5.00 min flow state: Waste

Note: Flow state setting may be adjusted as necessary depending on the system to divert ranitidine to waste.

MRM Parameters:

Table 2. MRM parameters
Name Parent Ion (m/z) Daughter Ion (m/z Dwell (s) Cone (V) Collision Cell (eV)
NDMA 75.1 42.9 0.3 22 10
NDMA 75.1 58.1 0.3 22 10

Note: Transition 75.1→58.1 is used for quantification; transition 75.1→42.9 usually has a higher background. It is possible to quantify by using another parent ion/daughter ion pair transition.

6. Calculation

The results, in ppm relative to the declared amount of drug substance in the product, are given by:

NDMA (ppm) = [(y-b)/m] x AVGwt x V ÷ Wtspl ÷ LC

Where,

y =
peak area of NDMA
b =
intercept of the calibration curve
m =
slope of the calibration curve
Wtspl  =
sample weight (mg)
AVGwt  =
average tablet weight (mg)
LC =
label claim of sample (mg)
V =
5 mL (volume)
Equation - Text Description

NDMA in parts per million equals y minus b over m, which is the difference between the peak area of the impurity minus the intercept of the linear curve over the slope of the linear curve. This value is multiplied by average tablet weight, then multiplied by the volume, divided by the sample weight and then divided by the label claim of the sample.

7. Range, limit of detection (LOD), and limit of quantification (LOQ)

Table 3. Range, LOD and LOQ
  NDMA (ng/mL) NDMA (ppm)Table 3 Footnote *
LOQ 1 0.033
LOD 0.75 0.025
Range 1 – 200 0.03 – 6.7
Table 3 Footnote *

ppm relative to the declared amount of drug substance in the product

Table 3 Return to footnote * referrer

8. Example of Calibration Curve and Chromatograms

Figure 1. Calibration curve

Figure 1

Text description

The figure shows a calibration curve with concentration of the NDMA standard solutions on the x axis and response (in arbitrary units) on the y axis. There is a data point for each of the nine standard solutions listed in the method, connected by a straight line. The correlation coefficient is r2 = 0.999761, and the calibration curve equation is y = 257.934 x – 15.8397.

Figure 2. Chromatograms of 200 ppb standard: MRM and UV

Figure 2

Text description

The figure includes two panels. The panel on the left shows two Multiple Reaction Monitoring chromatograms (m/z 75.1 → 58.1 and m/z 75.1 → 42.9) of the STD-1 standard solution, each with a single peak at 4.05 minutes for NDMA. The panel on the right shows the UV chromatogram of the STD-1 standard solution. The portion of the chromatogram between 3.3 and 5.0 minutes (corresponding to the period when flow is routed to the MS detector) is relatively flat, while the rest of the chromatogram contains multiple peaks and baseline shifts.

Figure 3. Chromatogram of sample: MRM and UV

Figure 3

Text description

The figure includes two panels. The panel on the left shows two Multiple Reaction Monitoring chromatograms (m/z 75.1 → 58.1 and m/z 75.1 → 42.9) of a typical sample solution, each with a single peak at 4.01 minutes for NDMA. The panel on the right shows the UV chromatogram of a typical sample solution. The portion of the chromatogram between 3.3 and 5.0 minutes (corresponding to the period when flow is routed to the MS detector) is relatively flat, while the rest of the chromatogram contains multiple peaks and baseline shifts.

Test Method for metformin products

Determination of Nitrosamine Impurities in metformin Products by UPLC-MS/MS

1. Principle and Scope

The present method has been developed to detect and quantify the following nitrosamine impurities in Metformin products by UPLC with tandem mass spectrometer (UPLC-MS/MS): N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (NDIPA), N-ethyl-N-nitroso-isopropylamine (NEIPA), N-nitroso-di-N-butylamine (NDBA) and N-Nitroso-N-methyl-4-aminobutyric acid (NMBA).

2. Reagents and Reference Standards

3. Instrument/Equipment

4. Preparation of Solutions

4.1 Storage

Calibration and sample solutions are stored in refrigerator.

4.2 Mobile Phase Preparation

4.3 Diluent Preparation

4.4 Standard Solutions

Reference Standard Stock Solutions (as purchased)

Suggested NMBA Stock Standard Solution (100 ppm) preparation

Accurately weigh 2.0 mg of NMBA to 20 mL volumetric flask. Dissolve and dilute to volume with methanol.

Note: The concentration of NMBA stock standard solution can be varied. The dilution for the preparation of the Intermediate Stock Standard Solution -1 and -2 can be calculated and adjusted accordingly to make the final concentration close to 200 ppb and 5 ppb.

Intermediate Stock Standard Solution-1 (200 ppb) preparation

Transfer 100 µL of NDMA reference standard stock solution (200 ppm), 200 µL of the other Nitrosamine reference standard stock solutions (100 ppm) and 200 µL of NMBA Stock Standard Solution (100 ppm) into a 100 mL volumetric flask, dilute to volume with diluent. Mix well. 

Intermediate Stock Standard Solution-2 (5 ppb) preparation (STD-4)

Transfer 500 µL of Intermediate Stock Standard Solution-1 (200 ppb) into a 20 mL volumetric flask, dilute to volume with diluent. Mix well. 

Suggested Calibration Standard Solutions
STD Solution Working solution Working solution Conc. (ppb) Volume of Working Solution (mL) Total Vol. (mL) Nitrosamine STD Conc. (ppb)
LOD Intermediate Stock Standard Solution-2 5 0.5 5 0.5
LOQ Intermediate Stock Standard Solution-2 5 0.75 5 0.75
STD-1 Intermediate Stock Standard Solution-2 5 1 5 1
STD-2 Intermediate Stock Standard Solution-2 5 2 5 2
STD-3 Intermediate Stock Standard Solution-2 5 3 5 3
STD-4 Intermediate Stock Standard Solution-2 5     5
STD-5 Intermediate Stock Standard Solution-1 200 0.25 5 10
STD-6 Intermediate Stock Standard Solution-1 200 0.375 5 15
STD-7 Intermediate Stock Standard Solution-1 200 0.5 5 20
STD-8 Intermediate Stock Standard Solution-1 200 0.625 5 25
STD-9 Intermediate Stock Standard Solution-1 200 1.25 5 50

R2 for calibration curve should be NLT 0.995.

STD-9 will be used for system suitability and system drift.

4.5 Sample Preparation

Suggested Sample Preparation:

The concentration (weight and/or volume) of samples may be modified as required.

4.6 Suggested Recovery Spiking:

5. Instrument Operating Parameters

5.1 Suggested UPLC Parameters:

Flow Rate:
0.4 mL/min
Injection Volume:
10.0 µL
Run Time:
30 min
Gradient Table:
Time (min) Mobile Phase A % Mobile Phase B %
0 95 5
5 95 5
22 0 100
27 0 100
28 95 5
30 95 5

5.2 Suggested MS Parameters:

APCI probe Temp:
400°C
Source Temperature:
150°C  
Corona:
4.0 kV
Type:
MRM
Ion mode:
Positive
Span (Da):
0
Start time:
3.5 min
End time:
21 min

Run Events:

Event 1: 0.00 min
Flow State: Waste
Event 2: 3.5 min
Flow State: LC
Event 3: 21 min
Flow State: Waste

Note: Flow state setting may be adjusted as necessary depending on the system to divert metformin to waste.

5.3 MRM Parameters:

Name Time period (min) Parent Ion (m/z) Daughter Ion (m/z) Dwell (s) Cone (V) Collision Cell (eV)
NDMA 3.5 – 6.0 75.0 43.1 0.1 30 10
75.0 58.0Table 11 Footnote * 0.1 30 8
NMBA 6.0 –  10.0 146.9 44.0 0.1 22 12
146.9 117.0Table 11 Footnote * 0.1 22 4
NDEA 10.0 – 13.0 103.0 47.1 0.1 30 12
103.0 75.0Table 11 Footnote * 0.1 30 10
NEIPA 12.8 – 15.0 117.0 47.0 0.1 26 14
117.0 75.0Table 11 Footnote * 0.1 26 10
NDIPA 14.6 – 17.0 131.0 43.1 0.1 26 10
131.0 89.0Table 11 Footnote * 0.1 26 6
NDBA 17.0 – 21.0 159.0 57.1 0.1 32 12
159.0 103.0Table 11 Footnote * 0.1 32 10
Table 11 Footnote *

Target ions used for calculation.

Table 11 Return to footnote * referrer

6. Calculation

The results, in ppm relative to the declared amount of drug substance in the product, are given by:
Nitrosamine impurity (ppm) = [(y-b)/m] × AVGwt × V ÷ Wtspl ÷ LC

Where: Nitrosamine impurity refers to NDMA, NDEA, NEIPA, NDIPA NDBA or NMBA

y =
Peak Area of the nitrosamine impurity
b =
Intercept of the Linear Curve
m =
Slope of the Linear Curve
Wtspl  =
Sample Weight (mg)
AVGwt  =
Average Tablet Weight (mg)
LC =
Label claim of Sample (mg)
V =
10 mL (volume)
Equation - Text Description

Nitrosamine impurity in parts per million (ppm) equals y minus b over m, which is the difference between the peak area minus the intercept of the calibration curve over the slope of the calibration curve. This value is multiplied by average tablet weight, then multiplied by the volume, divided by the sample weight and then divided by the label claim of the sample.

7. Range, limit of detection (LOD) and limit of quantification (LOQ)

Comp. Name Conc. (ng/mL) Conc. (ppmTable 12 Footnote *)
LOD LOQ Range LOD LOQ Range
NDMA 0.5 0.75 0.75 – 50 0.010 0.015 0.015 – 1.0
NDEA 0.1 0.5 0.5 – 50 0.002 0.010 0.010 – 1.0
NEIPA 0.1 0.5 0.5 – 50 0.002 0.010 0.010 – 1.0
NDIPA 0.1 0.5 0.5 – 50 0.002 0.010 0.010 – 1.0
NDBA 0.1 0.5 0.5 – 50 0.002 0.010 0.010 – 1.0
NMBA 0.25 0.5 0.5 – 50 0.005 0.010 0.010 – 1.0
Table 12 Note de bas de page *

ppm (ng/g) relative to the declared amount of Metformin in the product

Table 12 Retour à la référence de la note de bas de page *

8. Example Chromatograms

Figure 1. MRM Chromatogram of 5 ppb standard - NDMA

figure 1

Text Description

The figure includes two rows. The top row shows an MRM chromatogram (m/z 75.0 → 58.0) of the 5 ppb NDMA standard while the bottom row shows an MRM chromatogram (m/z 75.0 → 43.1) of the 5 ppb NDMA standard. Each chromatogram displays a single peak at approximately 4.03 minutes.

Figure 2. MRM Chromatogram of 5 ppb standard - NMBA

figure 2

Text Description

The figure includes two rows. The top row shows an MRM chromatogram (m/z 146.9 → 117.0) of the 5 ppb NMBA standard while the bottom row shows an MRM chromatogram (m/z 146.9 → 44.0) of the 5 ppb NMBA standard.  Each chromatograph displays a large peak at approximately 8.5 minutes and two smaller peaks at approximately 8.6 and 8.7 minutes.  The presence of these extra peaks are likely due to the asymmetric structure of NMBA.

Figure 3. MRM Chromatogram of 5ppb standard - NDEA

figure 3

Text Description

The figure includes two rows. The top row shows an MRM chromatogram (m/z 103.0 → 75.0) of the 5 ppb NDEA standard while the bottom row shows an MRM chromatogram (m/z 103.0 → 47.1) of the 5 ppb NDEA standard. Each chromatogram displays a single peak at approximately 11.7 minutes.

Figure 4. MRM Chromatogram of 5 ppb standard – NEIPA

figure 4

Text Description

The figure includes two rows. The top row shows an MRM chromatogram (m/z 117.0.0 → 75.0) of the 5 ppb NEIPA standard while the bottom row shows an MRM chromatogram (m/z 117.0 → 47.0) of the 5 ppb NEIPA standard.  Each chromatograph displays a large peak at approximately 13.8 minutes and a smaller shoulder peak at approximately 14.0 minutes.  The presence of the shoulder is likely due to the asymmetric structure of NEIPA.

Figure 5. MRM Chromatogram of 5 ppb standard - NDIPA

figure 5

Text Description

The figure includes two rows. The top row shows an MRM chromatogram (m/z 131.0 → 89.0) of the 5 ppb NDIPA standard while the bottom row shows an MRM chromatogram (m/z 131.0 → 43.1) of the 5 ppb NDIPA standard.  Each chromatograph displays a single peak at approximately 15.6 minutes.

Figure 6. MRM Chromatogram of 5 ppb standard - NDBA

figure 6

Text Description

The figure includes two rows. The top row shows an MRM chromatogram (m/z 159.0 → 103.0) of the 5 ppb NDBA standard while the bottom row shows an MRM chromatogram (m/z 159.0 → 57.1) of the 5 ppb NDBA standard.  Each chromatograph displays a single peak at approximately 19.2 minutes.

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