Method for identifying impurity structure in meropenem bulk drug

Abstract

The invention relates to the technical field of pharmaceutical analysis, and provides a method for identifying the structure of an impurity in a meropenem bulk drug, which is used for identifying the structure of the impurity in the meropenem bulk drug by liquid chromatography-mass spectrometry. In the chromatographic conditions of the liquid chromatography-mass spectrometry, a mobile phase comprises a mobile phase A and a mobile phase B, and the mobile phase A is a formic acid aqueous solution with the mass fraction of 0.1%-0.3%; and the mobile phase B is an acetonitrile solution containing formic acid with the mass fraction of 0.1-0.3%. By means of the technical scheme, the problems that in the related technology, the variety of structure identification of impurities of meropenem raw material medicine is few, and the accuracy and the like are not high when an existing detection method is used for identification are solved.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical analysis, and specifically, to a method for identifying the structures of impurities in meropenem bulk drugs. Background Art

[0002] Meropenem belongs to carbapenem antibiotics, is stable to β-lactamase and renal dehydropeptidase, does not need to be used in combination with dehydropeptidase inhibitors, has a broad antibacterial effect on Gram-positive and Gram-negative aerobic and anaerobic bacteria, and is used for the treatment of complicated urinary tract infections and other severe bacterial infections, including hospital-acquired pneumonia and ventilator-associated pneumonia.

[0003] The impurities in meropenem bulk drugs include by-products in the synthesis process, unreacted raw materials, degradation products, or impurities generated during storage. According to the literature by Hu Changqin. Formation and development of control strategies for polymer impurities in β-lactam antibiotics [J]. Chinese Journal of New Drugs, 2020, 29(11): 1231-1244., these impurities have a significant impact on the quality, safety and effectiveness of the bulk drug, and may cause serious problems especially in terms of pharmacological activity, toxicity and stability. Molecular polymerization reactions may occur during the production, storage and clinical use of meropenem. Its polymers have the following characteristics and risks: there are two types of polymerization reactions, including the N-type reaction that does not involve the side chain and only the parent ring participates, and the L-type reaction that involves the side chain. The polymers produced by meropenem are tautomers, which are difficult to separate. For example, the dimer of meropenem forms polymers that undergo ring-opening degradation reactions to varying degrees, and the polymers also have sensitization, so strict control of their content is required.

[0004] The 2020 edition of the Chinese Pharmacopoeia, the 2024 edition of the United States Pharmacopoeia, and the 10.0 edition of the European Pharmacopoeia all include meropenem bulk drugs and their preparations. The establishment and verification of the related substances analysis methods for this variety have also been reported in the literature, but there has been no in-depth study on the structure identification of meropenem impurities, and there are also problems such as fewer types of identified impurities and low precision in the existing detection methods for identification. Summary of the Invention

[0005] The present invention proposes a method for identifying the structures of impurities in meropenem bulk drugs, which solves the problems of fewer types of structure identification of impurities in meropenem bulk drugs and low precision in the existing detection methods for identification in the related art.

[0006] The technical solution of the present invention is as follows: The present invention provides a method for identifying the structures of impurities in meropenem bulk drugs, and the liquid chromatography-mass spectrometry (LC-MS) method is used to identify the structures of impurities in meropenem bulk drugs; in the chromatographic conditions of the LC-MS method, the mobile phase includes mobile phase A and mobile phase B, and mobile phase A is an aqueous formic acid solution with a mass fraction of 0.1% - 0.3%; mobile phase B is an acetonitrile solution containing formic acid with a mass fraction of 0.1% - 0.3%.

[0007] As a further technical solution, in the chromatographic conditions of the LC-MS method, gradient elution is carried out using the following procedure: from 0 to 15 min, 6% of mobile phase B; from 15 to 20 min, 6% of mobile phase B → 95% of mobile phase B; from 20 to 23 min, 95% of mobile phase B; from 23 to 23.1 min, 95% of mobile phase B → 6% of mobile phase B; from 23.1 to 30 min, 6% of mobile phase B.

[0008] As a further technical solution, in the chromatographic conditions of the LC-MS method, the flow rate is 0.2 - 0.4 mL / min, the injection volume is 1 - 5 μL, and the column temperature is 25 - 35 °C.

[0009] As a further technical solution, in the chromatographic conditions of the LC-MS method, the chromatographic column includes an ACQUITY UPLC CSH C18 chromatographic column or an Agilent Poroshell 120 PFP chromatographic column.

[0010] As a further technical solution, in the mass spectrometry conditions of the LC-MS method, the ion source is a HESI ion source, the spray voltage is 3.5 - 3.8 KV, and the scanning range is M / Z 100 - 1500.

[0011] As a further technical solution, in the mass spectrometry conditions of the LC-MS method, the positive ion scanning mode is adopted, the ion transfer tube temperature is 325 °C, the sheath gas flow rate is 50 min / L, the auxiliary gas flow rate is 10 min / L, the acquisition mode is the Full MS / dd-MS2 mode, the Full MS scanning resolution is 120000, the scanning range is M / Z 100 - 1500, and the dd-MS2 scanning resolution is 15000 FWHM.

[0012] As a further technical solution, after the structure identification, five types of impurities are identified in the meropenem bulk drug, including synthetic intermediates, decarboxylated products, lactam ring-opened degradation products, polymerization products, and amide degradation products.

[0013] As a further technical solution, the synthetic intermediate includes related substance 7 and related substance 8; the decarboxylated product includes related substance 11; the lactam ring-opening degradation products include related substance 1, related substance 2, related substance 3, related substance 5, related substance 6, related substance 9, and related substance 15; the polymerization products include related substance 4, related substance 10, related substance 12, related substance 13, related substance 14, related substance 16, related substance 18, and related substance 19; the amide degradation products include related substance 17.

[0014] As a further technical solution, the following steps are included: S1. Preparation of the test solution: After dissolving the meropenem bulk drug, a test solution is obtained; S2. Preparation of the reference solution: After dissolving the ring-opened product of meropenem, a reference solution of meropenem impurity A is obtained; after dissolving the dimer of meropenem, a reference solution of meropenem impurity B is obtained; S3. Identification: The impurities in the meropenem bulk drug are structurally identified for the test solution and the reference solution respectively by liquid chromatography-mass spectrometry.

[0015] As a further technical solution, the mass concentration of the test solution is 0.1 - 1 mg / mL.

[0016] As a further technical solution, the mass concentration of the reference solution of meropenem impurity A and the reference solution of meropenem impurity B are each independently 0.01 - 0.1 μg / mL.

[0017] The working principle and beneficial effects of the present invention are as follows: In the present invention, liquid chromatography-mass spectrometry is used to structurally identify the impurities in the meropenem bulk drug. Among them, the mobile phase includes mobile phase A and mobile phase B. Mobile phase A is an aqueous formic acid solution with a mass fraction of 0.1% - 0.3%, and mobile phase B is an acetonitrile solution containing 0.1% - 0.3% formic acid by mass fraction. Structurally identifying the impurities in the meropenem bulk drug has the characteristics of high detection sensitivity, high accuracy, strong specificity, excellent system adaptability, and good durability. Description of the Drawings

[0018] The present invention will be further described in detail below with reference to the drawings and specific embodiments.

[0019] Figure 1 It is the chromatogram of the test solution in Example 1 of the present invention; Figure 2 It is the chromatogram of the meropenem reference solution in Example 1 of the present invention; Figure 3Chromatogram of meropenem impurity A reference solution for Example 1 of the present invention; Figure 4 Chromatogram of meropenem impurity B reference solution for Example 1 of the present invention; Figure 5 EIC diagram of meropenem and related substances 1-7 for Example 1 of the present invention; Figure 6 EIC diagram of related substances 8-19 for Example 1 of the present invention; Figure 7 Structural formula and secondary mass spectrum of meropenem for Example 1 of the present invention; Figure 8 Structural formula and secondary mass spectrum of related substance 1 for Example 1 of the present invention; Figure 9 Structural formula and secondary mass spectrum of related substance 2 for Example 1 of the present invention; Figure 10 Structural formula and secondary mass spectrum of related substance 3 for Example 1 of the present invention; Figure 11 Structural formula and secondary mass spectrum of related substance 4 for Example 1 of the present invention; Figure 12 Structural formula and secondary mass spectrum of related substance 5 for Example 1 of the present invention; Figure 13 Structural formula and secondary mass spectrum of related substance 6 for Example 1 of the present invention; Figure 14 Structural formula and secondary mass spectrum of related substance 7 for Example 1 of the present invention; Figure 15 Structural formula and secondary mass spectrum of related substance 8 for Example 1 of the present invention; Figure 16 Structural formula and secondary mass spectrum of related substance 9 for Example 1 of the present invention; Figure 17 Structural formula and secondary mass spectrum of related substance 10 for Example 1 of the present invention; Figure 18 Structural formula and secondary mass spectrum of related substance 11 for Example 1 of the present invention; Figure 19 Structural formula and secondary mass spectrum of related substance 12 for Example 1 of the present invention; Figure 20 Structural formula and secondary mass spectrum of related substance 13 for Example 1 of the present invention; Figure 21 Structural formula and secondary mass spectrum of related substance 14 for Example 1 of the present invention; Figure 22 Structural formula and secondary mass spectrum of related substance 15 for Example 1 of the present invention; Figure 23 The structural formula and secondary mass spectrum of related substance 16 in Example 1 of the present invention; Figure 24 The structural formula and secondary mass spectrum of related substance 17 in Example 1 of the present invention; Figure 25 The structural formula and secondary mass spectrum of related substance 18 in Example 1 of the present invention; Figure 26 The structural formula and secondary mass spectrum of related substance 19 in Example 1 of the present invention. Detailed implementation manners

[0020] Next, in combination with the embodiments of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts fall within the scope of protection of the present invention.

[0021] Example 1 1. Instruments and reagents Meropenem impurity A (meropenem ring-opened product): Batch number: 202405140001, source: Guangzhou Jiantu Technology Co., Ltd.; Meropenem impurity B (meropenem dimer): Batch number: 202403260068, source: Guangzhou Jiantu Technology Co., Ltd.; Instrument: Vanquish-Orbtirap Exploris 120 liquid chromatography-mass spectrometry combined system, source: Thermo Fisher Scientific (China) Co., Ltd.

[0022] 2. Chromatographic conditions Chromatographic column: ACQUITY UPLC CSH C18 (150mm×3.0mm, 1.7µm); Mobile phase: Mobile phase A is an aqueous solution of formic acid with a mass fraction of 0.1%, and mobile phase B is an acetonitrile solution containing formic acid with a mass fraction of 0.1%; Gradient elution program: 0 - 15 min, 6% mobile phase B; 15 - 20 min, 6% mobile phase B → 95% mobile phase B; 20 - 23 min, 95% mobile phase B; 23 - 23.1 min, 95% mobile phase B → 6% mobile phase B; 23.1 - 30 min, 6% mobile phase B; flow rate is 0.3 mL / min, injection volume is 3 µL, and column temperature is 30°C.

[0023] 3. Mass spectrometry conditions Detection mode: positive ion scanning mode; Ion source: HESI ion source; Spray voltage: 3.8 kV; Ion transfer tube temperature: 325 °C; Sheath gas flow rate: 50 min / L; Auxiliary gas flow rate: 10 min / L; Acquisition mode: Full MS / dd-MS2 mode, Full MS scan resolution 120,000; Scan range: m / z 100 - 1500; dd-MS2 scan resolution 15,000 FWHM; Collision energy gradient is 20 eV, 25 eV, 30 eV.

[0024] 4. Determination Test solution: Take 10 mg of meropenem raw material, weigh accurately, place it in a 10 mL volumetric flask, dissolve it with water, dilute to the mark, shake well, filter through a 0.45 µm organic filter membrane, and take the subsequent filtrate to obtain a test solution with a mass concentration of 1 mg / mL.

[0025] Reference solution: Weigh accurately meropenem impurity A (ring-opened product of meropenem), dissolve it with water, and dilute to prepare a solution with a mass concentration of 0.1 µg / mL as the reference solution for meropenem impurity A; Weigh accurately meropenem impurity B (dimer of meropenem), dissolve it with water, and dilute to prepare a solution with a mass concentration of 0.1 µg / mL as the reference solution for meropenem impurity B; Weigh accurately meropenem, dissolve it with water, and dilute to prepare a solution with a mass concentration of 0.1 µg / mL as the reference solution for meropenem.

[0026] Inject the test solution and the reference solution into the detection system respectively, and record the chromatogram; The chromatogram of the test solution is as Figure 1 shown; The chromatogram of the reference solution is as Figures 2 - 4 shown; Determination results: For the raw material of meropenem and its forced degradation solution, separation analysis and structure identification of related substances were carried out. A total of 19 related substances' mass spectra and structural formulas were found. Combining the first-order and second-order mass spectrometry data, fragment cleavage rules and synthesis process, the possible chemical structures of 19 related substances were identified, and their sources were attributed. They are mainly divided into 5 categories: Related substances 7 and 8 are synthesis intermediates; Related substance 11 is a decarboxylated product; Related substances 1, 2, 3, 5, 6, 9, 15 are lactam ring-opened degradation products; Related substances 4, 10, 12, 13, 14, 16, 18, 19 are polymerization products; Related substance 17 is an amide degradation product; The EIC diagrams of meropenem and related substances 1 - 7 are as Figure 5 shown, and the EIC diagrams of related substances 8 - 19 are as Figure 6 shown; The structural formulas and secondary mass spectrometry diagrams of meropenem and related substances 1 to 19 are respectively as follows Figures 7 - 26 shown

[0027] Example 2 The difference between this example and Example 1 lies only in the chromatographic conditions: the flow rate is 0.3 mL / min, the injection volume is 3 μL, and the column temperature is 30 °C; in the mass spectrometry conditions: the spray voltage is 3.5 kV; the mass concentration of the test solution is 0.1 mg / mL; the mass concentration of the reference solution of meropenem impurity A is 0.01 μg / mL; the mass concentration of the reference solution of meropenem impurity B is 0.01 μg / mL; Determination result: the same as that of Example 1

[0028] Example 3 The difference between this example and Example 1 lies only in the chromatographic conditions: mobile phase: mobile phase A is an aqueous solution of formic acid with a mass fraction of 0.3%, and mobile phase B is an acetonitrile solution containing formic acid with a mass fraction of 0.3%; the flow rate is 0.4 mL / min, the injection volume is 5 μL, and the column temperature is 35 °C

[0029] Determination result: the same as that of Example 1

[0030] Experimental example Methodological verification 1. Specificity experiment Take 10 mg of meropenem raw material, accurately weigh it, and take a total of 8 portions, which are respectively placed in 8 10-mL volumetric flasks, and degradation experiments are carried out under the following conditions

[0031] A: Undamaged B: Acid destruction, add 2 mL of 0.1 mol / L hydrochloric acid solution, let it stand for 20 min, add 2 mL of 0.1 mol / L sodium hydroxide solution, and adjust the pH to 7.0 ± 0.5 C: Alkali destruction, add 1 mL of 0.1 mol / L sodium hydroxide solution, let it stand for 10 min, add 1 mL of 0.1 mol / L hydrochloric acid solution, and adjust the pH to 7.0 ± 0.5 D: Oxidation destruction, add 1 mL of 35% hydrogen peroxide solution by mass fraction, let it stand for 5 min E: High-temperature dry destruction, place it in an oven at 105 °C for 2 h F: High-temperature wet destruction, add 1 mL of water and place it in a water bath at 90 °C for 2 h H: Light dry destruction, place it in a light box at 4500 LX for 7 d I: Photochemical degradation in solution. Add 1 mL of water and place the sample in a 4500 LX light box for 7 days. After cooling (neutralize the acid-base treatment solution first), add an appropriate amount of water, shake to dissolve meropenem, and dilute to the mark with water. Filter through a 0.45 µm organic filter membrane, and take the subsequent filtrate as the forced degradation solution with a meropenem concentration of approximately 100 ng / mL.

[0032] The results of the specificity experiment showed that: the peak shape was good, and the blank solvent had no influence on the detection of each impurity.

[0033] 2. System suitability test Chromatographic conditions: same as in Example 1; Preparation of solution: Weigh accurately 10 mg of meropenem raw material, mix with 1 mL of 0.1 mol / L sodium hydroxide solution, let stand for 10 min, add 1 mL of 0.1 mol / L hydrochloric acid solution, and adjust the pH to 7.0 ± 0.5. Add water respectively, shake to dissolve meropenem, and dilute to the mark with water. Filter through a 0.45 µm organic filter membrane, and take the subsequent filtrate as the alkaline degradation solution with a meropenem concentration of approximately 100 ng / mL.

[0034] Determination: Accurately measure the alkaline degradation solution and inject it for detection.

[0035] The results showed that: the tailing factors of each impurity peak were less than 1.5, and the system suitability of the identification method of the present invention was excellent.

[0036] 3. Detection limit and quantification limit experiment Chromatographic conditions: same as in Example 1; Results of detection limit and quantification limit experiment: The detection limits of related substances 4, 5, 10, and 12 were: 0.001 µg / L, 0.001 µg / L, 0.004 µg / L, 0.005 µg / L; The quantification limits of related substances 4, 5, 10, and 12 were: 0.003 µg / L, 0.003 µg / L, 0.013 µg / L, 0.017 µg / L.

[0037] 4. Precision experiment Chromatographic conditions: same as in Example 1.

[0038] Preparation of solution: Weigh accurately 10 mg of meropenem raw material, mix with 1 mL of 0.1 mol / L sodium hydroxide solution, let stand for 10 min, add 1 mL of 0.1 mol / L hydrochloric acid solution, and adjust the pH to 7.0 ± 0.5. Add water respectively, shake to dissolve meropenem, and dilute to the mark with water. Filter through a 0.45 µm organic filter membrane, and take the subsequent filtrate as the alkaline degradation solution with a meropenem concentration of approximately 100 ng / mL.

[0039] Determination: Inject the alkaline degradation solution continuously for 6 times, and the RSD values of the relative retention times of the related substances are shown in Table 1.

[0040] Table 1

[0041] The results show that the RSD values of the relative retention times of related substances 4, 5, 10, and 12 are ≤ 0.6%, indicating good system precision of this identification method.

[0042] 5. Precision Experiment Chromatographic conditions: The same as in Example 1.

[0043] Preparation of solution: Weigh accurately 10 mg of meropenem raw material drug, mix it with 1 mL of 0.1 mol / L sodium hydroxide solution, let it stand for 10 min, add 1 mL of 0.1 mol / L hydrochloric acid solution, and adjust the pH to 7.0 ± 0.5. Add water respectively, shake to dissolve meropenem, dilute it to the scale line with water, filter through a 0.45 µm organic filter membrane, and take the subsequent filtrate as the alkaline degradation solution with a mass concentration of about 100 ng / mL of meropenem.

[0044] Determination: Accurately measure the above alkaline degradation solution and inject it for detection.

[0045] Result: The types of related substances remain unchanged.

[0046] 6. Robustness Experiment 6.1 Changing Chromatographic Conditions Chromatographic conditions are the same as in Example 1, and the rest of the experimental content is the same as in Example 1. The results are shown in Table 2.

[0047] Table 2

[0048] Mobile phase A in the chromatographic conditions is an aqueous solution of formic acid with a mass fraction of 0.1%, mobile phase B is an acetonitrile solution containing formic acid with a mass fraction of 0.1%, the flow rate is 0.2 mL / min, the column temperature is 30 °C, the chromatographic column is an ACQUITY UPLC CSH C18 chromatographic column (150 mm × 3.0 mm, 1.7 µm), and the rest of the experimental content is the same as in Example 1. The results are shown in Table 3.

[0049] Table 3

[0050] Mobile phase A in the chromatographic conditions was an aqueous solution of formic acid with a mass fraction of 0.3%, mobile phase B was an acetonitrile solution containing formic acid with a mass fraction of 0.3%, the flow rate was 0.3 mL / min, the column temperature was 30 °C, the chromatographic column was an ACQUITY UPLC CSH C18 chromatographic column (150 mm × 3.0 mm, 1.7 µm), and the rest of the experimental content was the same as in Example 1. The results are shown in Table 4.

[0051] Table 4

[0052] Mobile phase A in the chromatographic conditions was an aqueous solution of formic acid with a mass fraction of 0.1%, mobile phase B was an acetonitrile solution containing formic acid with a mass fraction of 0.1%, the flow rate was 0.3 mL / min, the column temperature was 35 °C, the chromatographic column was an ACQUITY UPLC CSH C18 chromatographic column (150 mm × 3.0 mm, 1.7 µm), and the rest of the experimental content was the same as in Example 1. The results are shown in Table 5.

[0053] Table 5

[0054] Mobile phase A in the chromatographic conditions was an aqueous solution of formic acid with a mass fraction of 0.1%, mobile phase B was an acetonitrile solution containing formic acid with a mass fraction of 0.1%, the flow rate was 0.3 mL / min, the column temperature was 30 °C, the chromatographic column was an Agilent Poroshell 120 PFP (100 mm × 3 mm, 2.7 µm), and the rest of the experimental content was the same as in Example 1. The results are shown in Table 6.

[0055] Table 6

[0056] The durability experiment showed that: by changing the flow rate of the mobile phase, the column temperature, and the chromatographic column, there was no significant difference in the measured amounts of 19 impurities, and the durability was good.

[0057] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for identifying the structure of impurities in meropenem raw materials, characterized in that: Liquid chromatography-mass spectrometry (LC-MS) was used to structurally identify the impurities in the meropenem raw material. In the chromatographic conditions of the LC-MS method, the mobile phase included mobile phase A and mobile phase B, the mobile phase A was an aqueous formic acid solution with a mass fraction of 0.1% to 0.3%, and the mobile phase B was an acetonitrile solution containing a mass fraction of 0.1% to 0.3% formic acid.

2. The method for structural identification of impurities in meropenem bulk drug according to claim 1, characterized in that: In the chromatographic conditions of the LC-MS method, the gradient elution adopts the following procedure: 0-15 min, 6% mobile phase B; 15-20 min, 6% mobile phase B→95% mobile phase B; 20-23 min, 95% mobile phase B; 23-23.1 min, 95% mobile phase B→6% mobile phase B; 23.1-30 min, 6% mobile phase B.

3. The method for structural identification of impurities in meropenem bulk drug according to claim 1, characterized in that: The chromatographic conditions of the LC-MS method include a flow rate of 0.2-0.4 mL / min, an injection volume of 1-5 µL, and a column temperature of 25-35 °C.

4. The method for structural identification of impurities in a meropenem bulk drug according to claim 1, characterized in that: In the chromatographic conditions of the LC-MS method, the chromatographic column includes an ACQUITY UPLC CSH C18 chromatographic column or an Agilent Poroshell 120 PFP chromatographic column.

5. The method for structural identification of impurities in meropenem bulk drug according to claim 1, characterized in that: In the mass spectrometry conditions of the LC-MS method, the ion source is a HESI ion source, the spray voltage is 3.5-3.8 kV, and the scanning range is M / Z 100-1500.

6. The method for structural identification of impurities in meropenem bulk drug according to claim 1, characterized in that: After the structural identification, five types of impurities were identified in the meropenem raw material, including synthetic intermediates, decarboxylation products, lactam ring opening degradation products, polymerization products, and amide degradation products.

7. The method for structural identification of impurities in meropenem bulk drug according to claim 1, characterized in that: The synthetic intermediates include related substance 7 and related substance 8; The decarboxylation product includes related substance 11; The lactam ring opening degradation products include related substance 1, related substance 2, related substance 3, related substance 5, related substance 6, related substance 9, and related substance 15; The polymerization product includes related substance 4, related substance 10, related substance 12, related substance 13, related substance 14, related substance 16, related substance 18, and related substance 19; The amide degradation products include related substances 17; The structural formula of the related substance 1 is: ； The structural formula of the related substance 2 is: ； The structural formula of the related substance 3 is: ； The structural formula of the related substance 4 is: ； The structural formula of the related substance 5 is: ； The structural formula of the related substance 6 is: ； The structural formula of the related substance 7 is: ； The structural formula of the related substance 8 is: ； The structural formula of the related substance 9 is: ； The structural formula of the related substance 10 is: ； The structural formula of the related substance 11 is: ； The structural formula of the related substance 12 is: ； The structural formula of the related substance 13 is: ； The structural formula of the related substance 14 is: ； The structural formula of the related substance 15 is: ； The structural formula of the related substance 16 is: ； The structural formula of the related substance 17 is: ； The structural formula of the related substance 18 is: ； The structural formula of the related substance 19 is: 。 8. The method for structural identification of impurities in meropenem bulk drug according to claim 1, characterized in that: The following steps are involved: S1. Preparation of test solution: dissolving the meropenem API to obtain a test solution; S2. Preparation of reference solution: dissolving the meropenem ring-opened product to obtain a meropenem impurity A reference solution; After dissolving the meropenem dimer, a meropenem impurity B reference substance solution is obtained; S3. Identification: The structure of the impurities in the meropenem raw material is identified by liquid chromatography-mass spectrometry on the test solution and the reference solution respectively.

9. The method for structural identification of impurities in meropenem bulk drug according to claim 8, characterized in that: The mass concentration of the test solution is 0.1~1 mg / mL.

10. The method for structural identification of impurities in meropenem bulk drug according to claim 8, characterized in that: The mass concentrations of the meropenem impurity A reference solution and the meropenem impurity B reference solution are each independently 0.01 to 0.1 µg / mL.

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