Method for detecting residues of NDMA, NMBA, NDEA, NDIPA and NDBA in tea diphenhydramine

Abstract

The invention belongs to the technical field of chemical component detection, and particularly relates to a method for detecting residues of NDMA, NMBA, NDEA, NDIPA and NDBA in tea diphenhydramine, which comprises the following steps: (1) preparing a tea diphenhydramine test solution; and (2) determining the tea diphenhydramine test solution by using a liquid chromatography-mass spectrometry method, and liquid chromatography conditions are as follows: a chromatographic column takes phenyl-hexyl bonded silica gel as a filler, an aqueous solution containing trifluoroacetic acid and ammonium formate as a mobile phase A, and a methanol-acetonitrile mixed solution containing trifluoroacetic acid as a mobile phase B, gradient elution is performed, and the content of the tea diphenhydramine is determined. The residual contents of NDMA, NMBA, NDEA, NDIPA and NDBA in a tea diphenhydramine test sample are calculated by adopting an external standard method. The method provided by the invention plays an important role in formulating and improving quality standards of tea diphenhydramine bulk drugs and preparations.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of chemical component detection, and particularly relates to a detection method for NDMA, NMBA, NDEA, NDIPA and NDBA residues in dimenhydrinate. BACKGROUND

[0002] Dimenhydrinate is a complex of diphenhydramine and 8-aminotheophylline, has antihistamine effect, can inhibit vascular exudation, reduce tissue edema, and has sedative and antiemetic effects, is suitable for allergic reactions of skin and mucosa, such as urticaria, allergic dermatitis, allergic rhinitis, angioedema, hay fever and pruritus, can effectively control symptoms, is used for allergic diseases such as serum sickness and allergic conjunctivitis, has less curative effect, can be used for preventing motion sickness, is often used with hyoscine, and can also be used for treating pregnancy vomiting and radioactive vomiting.

[0003] In the production process of dimenhydrinate raw material, nitrosamine impurities may be generated: NDMA (N-nitrosodi-methylamine), NMBA (N-nitroso-N-methyl-4-aminobutyric acid), NDEA (N-nitrosodiethylamine), NDIPA (N-nitrosodiisopropylamine) and NDBA (N-nitros-n-butylamine), the nitrosamine impurities have high carcinogenicity under extremely low exposure, belong to the “focus group” substances mentioned in the ICH M7(R1) (Evaluation and Control of DNA-reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk) guide, and therefore it is of great significance to detect the nitrosamine impurities in dimenhydrinate.

[0004] Sheng Ting et al. disclosed “determination of dimethyl ethanolamine in dimenhydrinate by liquid-liquid extraction-ion chromatography” in Chinese Journal of Pharmaceuticals, established a liquid-liquid extraction-ion chromatography (IC) method for determining dimethyl ethanolamine in dimenhydrinate. Dimenhydrinate is dissolved with chloroform, extracted with pure water (25℃ water bath oscillation for 30 min), an IonPac CS17 type cation exchange column is used, 6 mmol / L methanesulfonic acid (MSA) solution is used as eluent, and suppressive conductivity detection is used, and the column temperature is 30℃. The dimethyl ethanolamine has good linear relationship in the range of 0.75-7.5 µg / mL, the average recovery rate is 98.2%, the RSD is 4.81%, and the detection limit is 70.7 ng / mL; however, the detection limit concentration of the scheme is high, and micro-impurities cannot be detected; and the technical scheme cannot simultaneously detect NDMA, NMBA, NDEA, NDIPA and NDBA residues.

[0005] The detection methods of nitrosamine impurities in drugs in the prior art mostly use chromatography-mass spectrometry combined technology for detection, such as LC-MS, LC-MS / MS, GC-MS, GC-MS / MS, etc. For example, a detection method of nitrosamine impurities in drugs is disclosed in Chinese Patent No. CN 113899834 B, which uses high performance liquid chromatography-triple quadrupole tandem mass spectrometer for detection, and uses external standard method to calculate the content of nitrosamine impurities in the drug test sample. The technical scheme can simultaneously detect eight kinds of nitrosamine impurities, the signal-to-noise ratio of the eight kinds of nitrosamine impurities is greater than 10, and the separation degree of N-nitrosodiisopropylamine and its isomer N-nitrosodi-n-propylamine is greater than 1.5. The method has the advantages of high sensitivity, strong specificity, rapid analysis, and strong anti-interference, and is especially suitable for the detection of metformin hydrochloride nitrosamine impurities; however, due to the different synthesis processes or prescription compositions of different drugs, the existing detection method has poor universality, and the detection time of the above technical scheme is long. SUMMARY

[0006] The present application aims to solve one or more technical problems existing in the prior art, and at least provide a beneficial alternative. Specifically, the present application provides a detection method of NDMA, NMBA, NDEA, NDIPA and NDBA residues in dimenhydrinate, which can quickly and accurately detect five kinds of nitrosamine impurities in dimenhydrinate.

[0007] To achieve the above-mentioned purpose, the present application adopts the following technical scheme: A detection method of NDMA, NMBA, NDEA, NDIPA and NDBA residues in dimenhydrinate, comprising the following steps: (1) preparing a dimenhydrinate test sample solution; (2) using liquid chromatography-mass spectrometry combined method to determine the dimenhydrinate test sample solution, the liquid chromatography conditions include: using phenyl-hexyl bonded silica gel as the filler, using a solution containing trifluoroacetic acid and ammonium formate as the mobile phase A, using a solution containing trifluoroacetic acid in methanol-acetonitrile mixed solution as the mobile phase B, performing gradient elution, and using external standard method to calculate the residual content of NDMA, NMBA, NDEA, NDIPA and NDBA in the dimenhydrinate test sample.

[0008] Further, the dimenhydrinate test sample includes dimenhydrinate raw material and / or preparation.

[0009] Further, the preparation method of the dimenhydrinate test sample solution is: mixing the dimenhydrinate test sample and purified water, vortexing, ultrasonicating, centrifuging, and taking the supernatant to obtain the dimenhydrinate test sample solution.

[0010] Further, the ultrasonic time is 5-15 min. Further, the centrifugal speed is 8000-12000 r / min, and the time is 3-5 min. Further, the concentration of the dimenhydrinate sample solution is 50 mg / mL.

[0011] Further, step (1) further comprises preparing NDMA control solution, NMBA control solution, NDEA control solution, NDIPA control solution and NDBA control solution.

[0012] Further, the preparation method of the NDMA control solution is that the NDMA control is diluted with purified water to 12 ng / mL. Further, the preparation method of the NMBA control solution is that the NMBA control is diluted with purified water to 12 ng / mL. Further, the preparation method of the NDEA control solution is that the NDEA control is diluted with purified water to 3.3 ng / mL. Further, the preparation method of the NDIPA control solution is that the NDIPA control is diluted with purified water to 3.3 ng / mL. Further, the preparation method of the NDBA control solution is that the NDBA control is diluted with purified water to 3.3 ng / mL.

[0013] Further, the column of the liquid chromatography is InfinityLab Poroshell 120 Phenyl-Hexyl, 2.7 μm, 3.0*150 mm.

[0014] Further, the column temperature of the liquid chromatography is 35-40 ℃; the injection volume is 5-10 μL; the sample tray temperature is 3-8 ℃; and the flow rate is 0.4-0.6 mL / min. Still further, the column temperature of the liquid chromatography is 40 ℃; the injection volume is 10 μL; the sample tray temperature is 5 ℃; and the flow rate is 0.5 mL / min.

[0015] Further, the concentration of trifluoroacetic acid in the mobile phase A is 0.02-0.05%, and the concentration of ammonium formate is 1-10 mM. Still further, the concentration of trifluoroacetic acid in the mobile phase A is 0.03%, and the concentration of ammonium formate is 5 mM.

[0016] Further, the concentration of trifluoroacetic acid in the mobile phase B is 0.02-0.05%. Still further, the concentration of trifluoroacetic acid in the mobile phase B is 0.03%.

[0017] Further, the volume ratio of methanol to acetonitrile in the methanol-acetonitrile mixed solution is 70-90:10-30.

[0018] Still further, the volume ratio of methanol to acetonitrile in the methanol-acetonitrile mixed solution is 80:20.

[0019] Further, the conditions of the gradient elution are as follows: .

[0020] Further, the conditions of the gradient elution are as follows: .

[0021] Further, the mass spectrometry conditions comprise: detection by a triple quadrupole tandem mass spectrometer, ion source is APCI, scanning mode is positive ion mode, and scanning mode is multiple reaction monitoring.

[0022] Further, the mass spectrometry conditions further comprise: gas curtain gas is 30 psi, collision gas is 9 psi, temperature is 350 DEG C, ionization current is 3 A, and spray gas is 65 psi.

[0023] Further, the parameters of the multiple reaction monitoring are as follows: .

[0024] Compared with the prior art, the present application has the following beneficial effects: 1、The present application selects phenyl-hexyl bonded silica gel as the filler, uses an aqueous solution containing trifluoroacetic acid and ammonium formate as mobile phase A, uses a methanol-acetonitrile mixed solution containing trifluoroacetic acid as mobile phase B, adopts a specific gradient elution program and combines optimized mass spectrometry conditions, so that NDMA, NMBA, NDEA, NDIPA and NDBA in dimenhydrinate can be effectively separated, peak shape is improved, NDMA, NMBA, NDEA, NDIPA and NDBA residues in dimenhydrinate can be effectively detected at the same time, and the present application has an important role for formulating and improving the quality standards of dimenhydrinate bulk drug and preparations.

[0025] 2、The detection method provided by the present application has good specificity, high sensitivity, short detection time, the detection limit of NDMA is 0.024 ppm, the quantitative limit is 0.048 ppm; the detection limit of NMBA is 0.024 ppm, the quantitative limit is 0.048 ppm; the detection limit of NDEA is 0.0066 ppm, the quantitative limit is 0.0132 ppm; the detection limit of NDIPA is 0.0066 ppm, the quantitative limit is 0.0132 ppm; the detection limit of NDBA is 0.0066 ppm, the quantitative limit is 0.0132 ppm, and the detection can be completed in only 14 minutes.

[0026] 3、The detection method provided by the present application has good linear relationship in the range of 6.15 ng / mL-18.45 ng / mL for NDMA, 6.00 ng / mL-18.00 ng / mL for NMBA, 1.65 ng / mL-4.95 ng / mL for NDEA, 1.64 ng / mL-4.91 ng / mL for NDIPA, and 1.65 ng / mL-4.95 ng / mL for NDBA; 4、The detection method provided by the present application has high accuracy, and the average spiked recovery rates of NDMA at 50%, 100% and 150% levels are 99%, 101% and 100% respectively, and the RSD of the average spiked recovery rate is 2.1%; the average spiked recovery rates of NMBA at 50%, 100% and 150% levels are 95%, 95% and 95% respectively, and the RSD of the average spiked recovery rate is 0.8%; the average spiked recovery rates of NDEA at 50%, 100% and 150% levels are 98%, 100% and 101% respectively, and the RSD of the average spiked recovery rate is 2.0%; the average spiked recovery rates of NDIPA at 50%, 100% and 150% levels are 94%, 99% and 99% respectively, and the RSD of the average spiked recovery rate is 3.5%; the average spiked recovery rates of NDBA at 50%, 100% and 150% levels are 96%, 96% and 97% respectively, and the RSD of the average spiked recovery rate is 2.0%; 5、The detection method provided by the present application also has the advantages of good repeatability, high intermediate precision, good durability and good solution stability. BRIEF DESCRIPTION OF DRAWINGS

[0027] Figure 1 The chromatogram of NDMA 100% spiked-2 solution; Figure 2 The chromatogram of NMBA 100% spiked-2 solution; Figure 3 The chromatogram of NDEA 100% spiked-2 solution; Figure 4 The chromatogram of NDIPA 100% spiked-2 solution Figure 5 The chromatogram of NDBA 100% spiked-2 solution; Figure 6 The linear graph of NDMA; Figure 7 The linear graph of NMBA; Figure 8 The linear graph of NDEA; Figure 9is a linear plot of NDIPA; Figure 10 is a linear plot of NDBA; Figure 11 is a chromatogram of the spiked sample solution at the 100% limit level of NDIPA in Comparative Example 1-1; Figure 12 is a chromatogram of the spiked sample solution at the 100% limit level of NDIPA in Comparative Example 1-2; Figure 13 is a chromatogram of the spiked sample solution at the 100% limit level of NDBA in Comparative Example 1-3; Figure 14 is a chromatogram of the spiked sample solution at the 100% limit level of NDBA in Comparative Example 1-4; Figure 15 is a chromatogram of the spiked sample solution at the 100% limit level of NDMA in Comparative Example 1-5; Figure 16 is a chromatogram of the spiked sample solution at the 100% limit level of NMBA in Comparative Example 2-1; Figure 17 is a chromatogram of the spiked sample solution at the 100% limit level of NDMA in Comparative Example 2-2; Figure 18 is a chromatogram of the spiked sample solution at the 100% limit level of NMBA in Comparative Example 2-2; Figure 19 is a chromatogram of the spiked sample solution at the 100% limit level of NDEA in Comparative Example 2-2; Figure 20 is a chromatogram of the spiked sample solution at the 100% limit level of NDIPA in Comparative Example 2-2; Figure 21 is a chromatogram of the spiked sample solution at the 100% limit level of NDBA in Comparative Example 2-2. DETAILED DESCRIPTION

[0028] In order to make the objects, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be described clearly and completely below. If specific conditions are not indicated in the embodiments, conventional conditions or the conditions suggested by the manufacturers are adopted. If the reagents or instruments used are not indicated by the manufacturers, they are all conventional products that can be purchased in the market.

[0029] In the examples and comparative examples of the present application: the NDMA control sample was from ANPEL, batch number E0620065; the NMBA control sample was from BePure, batch number 17753-024; the NDEA control sample was from BePure, batch number C0006777; the NDIPA control sample was from BePure, batch number C0008411; and the NDBA control sample was from LGC, batch number H1066503ME.

[0030] Example 1: A method for detecting NDMA, NMBA, NDEA, NDIPA and NDBA residues in dimenhydrinate, comprising the following steps: (1) Dimenhydrinate sample solution: 500 mg of dimenhydrinate sample was mixed with 10 mL of purified water, vortexed, ultrasonically treated for 10 min, centrifuged at 10,000 r / min for 5 min, and the supernatant was taken to obtain a 50 mg / mL dimenhydrinate sample solution; NDMA control sample solution: The NDMA control sample was diluted with purified water to 12 ng / mL.

[0031] NMBA control sample solution: The NMBA control sample was diluted with purified water to 12 ng / mL.

[0032] NDEA control sample solution: The NDEA control sample was diluted with purified water to 3.3 ng / mL.

[0033] NDIPA control sample solution: The NDIPA control sample was diluted with purified water to 3.3 ng / mL.

[0034] NDBA control sample solution: The NDBA control sample was diluted with purified water to 3.3 ng / mL.

[0035] (2) The dimenhydrinate sample solution was determined by liquid chromatography-mass spectrometry, and the conditions are shown in Table 1: Table 1 .

[0036] The dimenhydrinate sample was dimenhydrinate raw material from Shanghai Wanyang Pharmaceutical Co., Ltd., and there were three batches with batch numbers 2402022, 2402023 and 2402024. The detection results of the above three batches are shown in Table 2: Table 2 .

[0037] Example 2: Validation test: In order to verify the specificity and accuracy of the detection method of the present application, the methodological validation test including specificity test, limit of quantification and limit of detection test, linearity and range test, stability test, precision test, accuracy test and durability test was carried out, and the test process and results are as follows: 2.1 Specificity test (1) The dimenhydrate sample solution, NDMA control solution, NMBA control solution, NDEA control solution, NDIPA control solution, NDBA control solution were prepared according to the preparation method of Example 1; the NDMA blank solution, NMBA blank solution, NDEA blank solution, NDIPA blank solution, NDBA blank solution were water; The detection was carried out according to the method of Example 1, and the results are as follows in Table 3: Table 3 .

[0038] Conclusion: The blank solution and sample solution do not interfere with the detection, and the specificity of the present application is high.

[0039] 2.2 Limit of detection: 1 part of 10% limit control solution was prepared as LOD solution (NDMA concentration was 1.23 ng / mL, the relative content in the sample was 0.024 ppm; NMBA concentration was 1.20 ng / mL, the relative content in the sample was 0.024 ppm; NDEA concentration was 0.33 ng / mL, the relative content in the sample was 0.0066 ppm; NDIPA concentration was 0.33 ng / mL, the relative content in the sample was 0.0066 pm; NDBA concentration was 0.33 ng / mL, the relative content in the sample was 0.0066 pm), and the signal-to-noise ratio test results are as follows in Table 4: Table 4 .

[0040] 2.3 Limit of quantification: 1 part of 20% limit control solution was prepared as LOQ solution (NDMA concentration was 2.46 ng / mL, the relative content in the sample was 0.048 ppm; NMBA concentration was 2.40 ng / mL, the relative content in the sample was 0.048 ppm; NDEA concentration was 0.66 ng / mL, the relative content in the sample was 0.0132 ppm; NDIPA concentration was 0.65 ng / mL, the relative content in the sample was 0.0132 pm; NDBA concentration was 0.66 ng / mL, the relative content in the sample was 0.0132 pm), and the test results are as follows in Table 5: Table 5 .

[0041] Conclusion: The signal-to-noise ratios of the detection limit test results of NDMA, NMBA, NDEA, NDIPA and NDBA were all greater than 3, and the signal-to-noise ratios of the quantitative limit test results were all greater than 10, and the sensitivity met the requirements.

[0042] 2.4 Linearity and range: A series of linear test solutions were prepared from LOQ to 200% limit concentration (20%, 50%, 100%, 150%, 200%), each solution was analyzed by injection once, and the equation and regression coefficient (r) were calculated, and the results are shown in Table 6, The linear graph of NDMA is shown in Figure 6 ; the linear graph of NMBA is shown in Figure 7 ; the linear graph of NDEA is shown in Figure 8 ; the linear graph of NDIPA is shown in Figure 9 ; and the linear graph of NDBA is shown in Figure 10 .

[0043] Table 6 .

[0044] Conclusion: The linear relationship of each component is good.

[0045] 2.5 Accuracy: Three spiked sample solutions at 50%, 100% and 150% limit levels were prepared, and two sample solutions were prepared, each solution was analyzed by injection once, and the results are shown in Tables 7-11, the chromatogram of NDMA 100% spiked-2 solution is shown in Figure 1 , the chromatogram of NMBA 100% spiked-2 solution is shown in Figure 2 , the chromatogram of NDEA 100% spiked-2 solution is shown in Figure 3 , the chromatogram of NDIPA 100% spiked-2 solution is shown in Figure 4 , and the chromatogram of NDBA 100% spiked-2 solution is shown in Figure 5 .

[0046] Table 7 .

[0047] Table 8 .

[0048] Table 9 .

[0049] Table 10 .

[0050] Table 11 .

[0051] Conclusion: The method of the present application has high accuracy.

[0052] 2.6 Reproducibility: Six 100% limit level spiked sample solutions were prepared and analyzed in one injection each, and the results are shown in Tables 12-16.

[0053] Table 12 .

[0054] Table 13 .

[0055] Table 14 .

[0056] Table 15 .

[0057] Table 16 .

[0058] Conclusion: The method of the present application has good reproducibility.

[0059] 2.7 Intermediate precision: Six 100% limit level spiked sample solutions were prepared by another analyst at different times, and the results are shown in Tables 17-21.

[0060] Table 17 .

[0061] Table 18 .

[0062] Table 19 .

[0063] Table 20 .

[0064] Table 21 .

[0065] Conclusion: The method of the present application has good intermediate precision.

[0066] 2.8 Solution stability: One 100% limit level control solution and one 100% limit level spiked sample solution were prepared, respectively, and these solutions were analyzed at 24 hours or other time periods and compared with freshly prepared solutions, and the results are shown in Table 22.

[0067] Table 22 .

[0068] Conclusion: The solution of the method has good stability.

[0069] 2.9 Robustness: Change the proportion of the starting organic phase, column temperature, flow rate, respectively, prepare 100% control solution in two portions, inject once under each condition, and the results are shown in Table 23.

[0070] Table 23 .

[0071] Conclusion: The method has good robustness.

[0072] Impurity detection and separation under different mobile phase conditions of Comparative Example 1 Comparative Example 1-1: The only difference from Example 1 is that the mobile phase A is 0.1% formic acid aqueous solution; the mobile phase B is 0.1% formic acid methanol solution; the rest are the same; the above conditions are used to detect NDMA 100% limit level spiked sample solution, NMBA 100% limit level spiked sample solution, NDEA 100% limit level spiked sample solution, NDIPA 100% limit level spiked sample solution and NDBA 100% limit level spiked sample solution. Results: NDIPA peak shape is poor, and tailing phenomenon occurs, as shown in Figure 11 .

[0073] Comparative Example 1-2: The only difference from Example 1 is that the mobile phase A is 0.03% trifluoroacetic acid + 5mM ammonium formate aqueous solution; the mobile phase B is a methanol-acetonitrile mixed solution (methanol: acetonitrile = 80:20); the rest are the same. The above conditions are used to detect NDMA 100% limit level spiked sample solution, NMBA 100% limit level spiked sample solution, NDEA 100% limit level spiked sample solution, NDIPA 100% limit level spiked sample solution and NDBA 100% limit level spiked sample solution. Results: NDIPA tailing phenomenon is improved, but the peak shape is poor, as shown in Figure 12 .

[0074] Comparative Example 1-3: The only difference from Example 1 is that the mobile phase A is 0.1% trifluoroacetic acid aqueous solution; the mobile phase B is methanol; the rest are the same. The above conditions are used to detect NDMA 100% limit level spiked sample solution, NMBA 100% limit level spiked sample solution, NDEA 100% limit level spiked sample solution, NDIPA 100% limit level spiked sample solution and NDBA 100% limit level spiked sample solution. Results: NDBA peak shape is poor, as shown in Figure 13 .

[0075] Comparative Example 1-4: The only difference from Example 1 is that the gradient elution is replaced by isocratic elution, the ratio of mobile phase A and mobile phase B is 90:10; the rest is the same. The above conditions are used to detect NDMA 100% limit level spiked sample solution, NMBA 100% limit level spiked sample solution, NDEA 100% limit level spiked sample solution, NDIPA 100% limit level spiked sample solution and NDBA 100% limit level spiked sample solution. Results: NDBA peak shape is poor, as shown in Figure 14 .

[0076] Comparative Example 1-5: The only difference from Example 1 is that the gradient elution is as follows: Table 24 ; the rest is the same.

[0077] The above conditions are used to detect NDMA 100% limit level spiked sample solution, NMBA 100% limit level spiked sample solution, NDEA 100% limit level spiked sample solution, NDIPA 100% limit level spiked sample solution and NDBA 100% limit level spiked sample solution. Results: NDMA peaks too early, its retention time is earlier than 2 min, as shown in Figure 15 .

[0078] Comparative Example 2-1: The only difference from Example 1 is that the chromatographic column is InfinityLab Poroshell 120 SB-Aq, 3,0 x 150 mm, 2.7 µm; the rest is the same. The above conditions are used to detect NDMA 100% limit level spiked sample solution, NMBA 100% limit level spiked sample solution, NDEA 100% limit level spiked sample solution, NDIPA 100% limit level spiked sample solution and NDBA 100% limit level spiked sample solution. Results: NMBA cannot be separated, as shown in Figure 16 .

[0079] Comparative Example 2-2: The only difference from Example 1 is that the chromatographic column is Agilent Poroshell 120 PFP 2.7μm 3.0*150mm; the rest is the same. The above conditions are used to detect NDMA 100% limit level spiked sample solution, NMBA 100% limit level spiked sample solution, NDEA 100% limit level spiked sample solution, NDIPA 100% limit level spiked sample solution and NDBA 100% limit level spiked sample solution. Results: NDMA and NMBA peak too late, NDEA, NDIPA and NDBA do not peak, as shown in Figures 17-21 .

[0080] ​Finally, it should be noted that the above is only to illustrate the technical solutions of the present application, and is not a limitation on the scope of protection of the present application, and simple modifications or equivalent replacements of the technical solutions of the present application by those skilled in the art do not deviate from the essence and scope of the technical solutions of the present application.

Claims

1. A method for detecting NDMA, NMBA, NDEA, NDIPA, and NDBA residues in dimenhydrinate, characterized in that: The following steps are involved: (1) Prepare dimenhydrinate test solution; (2) The dimenhydrinate test solution was determined by liquid chromatography-mass spectrometry. The liquid chromatography conditions included: the chromatographic column was filled with phenyl-hexyl bonded silica gel, the mobile phase A was an aqueous solution containing trifluoroacetic acid and ammonium formate, and the mobile phase B was a methanol-acetonitrile mixed solution containing trifluoroacetic acid. Gradient elution was performed, and the external standard method was used to calculate the residual contents of NDMA, NMBA, NDEA, NDIPA, and NDBA in the dimenhydrinate test sample.

2. The method for detecting NDMA, NMBA, NDEA, NDIPA and NDBA residues in dimenhydrinate according to claim 1, wherein: The liquid chromatography column is InfinityLab Poroshell 120 Phenyl-Hexyl, 2.7 μm, 3.0*150 mm.

3. The method for detecting NDMA, NMBA, NDEA, NDIPA and NDBA residues in dimenhydrinate according to claim 2, wherein: The column temperature of the liquid chromatography is 35-40° C.; the injection volume is 5-10 μL; the sample plate temperature is 3-8° C.; and the flow rate is 0.4-0.6 mL / min.

4. The method for detecting NDMA, NMBA, NDEA, NDIPA and NDBA residues in dimenhydrinate according to claim 3, wherein: The concentration of trifluoroacetic acid in the mobile phase A is 0.02-0.05%; the concentration of ammonium formate is 1-10 mM.

5. The method for detecting NDMA, NMBA, NDEA, NDIPA and NDBA residues in dimenhydrinate according to claim 4, wherein: The concentration of trifluoroacetic acid in the mobile phase B is 0.02-0.05%.

6. The method for detecting NDMA, NMBA, NDEA, NDIPA and NDBA residues in dimenhydrinate according to claim 5, wherein: The volume ratio of methanol to acetonitrile in the methanol-acetonitrile mixed solution is 70-90:10-30.

7. The method for detecting NDMA, NMBA, NDEA, NDIPA and NDBA residues in dimenhydrinate according to claim 6, wherein: The conditions of the gradient elution are as follows: 。 8. The method for detecting NDMA, NMBA, NDEA, NDIPA and NDBA residues in dimenhydrinate according to claim 7, wherein: The mass spectrometry conditions include: detection by a triple quadrupole tandem mass spectrometer, APCI as the ion source, a positive ion mode, and a multiple reaction monitoring scan mode.

9. The method for detecting NDMA, NMBA, NDEA, NDIPA and NDBA residues in dimenhydrinate according to claim 8, wherein: The mass spectrometry conditions also include: curtain gas of 30 psi, collision gas of 9 psi, temperature of 350° C., ionization current of 3 A, and spray gas of 65 psi.

10. The method for detecting NDMA, NMBA, NDEA, NDIPA and NDBA residues in dimenhydrinate according to claim 9, wherein: The parameters of the multiple reaction monitoring are as follows: 。

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