A method for detecting related substances of faropenem sodium preparation

Abstract

The present application relates to the technical field of pharmaceutical analysis, and specifically discloses a detection method of faropenem sodium preparation related substances.The detection method of faropenem sodium preparation related substances provided by the present application uses acetate buffer as mobile phase A and acetate buffer-methanol as mobile phase B, and realizes effective separation of faropenem and seven impurities or degradation products including impurity A-impurity G by high performance liquid chromatography, and has the advantages of strong specificity, good accuracy, high precision, good repeatability, high stability, high sensitivity, suitable peak time, low detection cost and the like, and meets the technical requirements of the pharmaceutical quality research standard, and can be used for quality control of faropenem sodium preparation.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical analysis technology, and in particular to a method for detecting related substances in faropenem sodium preparations. Background Technology

[0002] Faropenem is an atypical β-lactam antibiotic, belonging to the penicillin class, and is available via both oral and injectable routes. This drug has a broad antibacterial spectrum, with particularly significant antibacterial activity against anaerobic bacteria, superior to carbapenems. It also exhibits significant inhibitory effects against Gram-positive bacteria such as Staphylococcus and Streptococcus, as well as various Gram-negative bacteria such as Haemophilus influenzae, Neisseria gonorrhoeae, and Lancashireella, demonstrating outstanding biological activity.

[0003] Faropenem was developed by Suntory Pharmaceutical Co., Ltd. of Japan and patented in Japan in 1986. In 1990 and 1992, Yamanouchi Pharmaceutical Co., Ltd. of Japan and Wyeth-Ayerst Pharmaceutical Co., Ltd. of the United States respectively obtained clinical trial approvals for the drug and jointly conducted clinical research. Finally, in 1997, the tablet dosage form was first approved for marketing in Japan under the brand name Farom. Pediatric faropenem sodium granules were launched in Japan in 1999, and this dosage form was first approved for import into China in 2018. Currently, faropenem sodium formulations available in China include tablets, capsules, and granules.

[0004] Both the Chinese Pharmacopoeia and the Japanese Pharmacopoeia include methods for detecting related substances of faropenem sodium. However, given that faropenem sodium is an atypical β-lactam antibiotic with relatively poor stability, it is prone to the formation of various impurities during storage, and existing pharmacopoeia detection methods have significant limitations in their control scope. Specifically, the Chinese Pharmacopoeia's detection method only controls diastereomers, unknown single impurities, and total impurities; the Japanese Pharmacopoeia's method for detecting related substances in pediatric faropenem sodium granules only controls decomposition derivatives and total impurities. Furthermore, faropenem sodium may degrade under conditions such as high temperature and light exposure, and current pharmacopoeia methods cannot separate related substances and degradation impurities, leading to inaccurate detection. Therefore, there is an urgent need to develop a more suitable method for detecting faropenem sodium and its related substances. Summary of the Invention

[0005] To address the shortcomings of existing detection methods that cannot effectively separate faropenem sodium from related impurities and degradation products, this invention provides a method for detecting related substances in faropenem sodium preparations. This method can effectively separate faropenem sodium from seven impurities or degradation products introduced during production and storage, and has advantages such as good separation, high specificity, high sensitivity, high accuracy, and low cost. It can effectively ensure the quality of faropenem sodium preparations and thus improve the safety of clinical use.

[0006] To solve the above-mentioned technical problems, the technical solution provided by the present invention is as follows: This invention provides a method for detecting related substances in faropenem sodium preparations. The related substances include impurities A, B, C, D, E, F, and G, and are detected using high-performance liquid chromatography (HPLC). The chromatographic conditions include: Chromatographic column: Octadecylsilane-bonded silica gel column; Mobile phase: Acetate buffer is used as mobile phase A, and acetate buffer-methanol is used as mobile phase B; The elution process is gradient elution; The gradient elution procedure is as follows:

[0007] Based on the original review report of pediatric faropenem sodium granules and related studies, the impurities studied in this invention are identified as impurity A (epomer), impurity B, impurity C, impurity D (decomposition derivative), impurity E, impurity F, and impurity G. The structures and sources of each impurity are shown in Table 1 below.

[0008] Table 1 Impurity Information Table

[0009] This invention utilizes high-performance liquid chromatography (HPLC) to effectively separate and quantitatively detect faropenem from seven impurities or their degradation products introduced during production or storage, thereby improving the sensitivity and accuracy of faropenem sodium and related substances detection. The detection method provided by this invention offers advantages such as high specificity, high accuracy, high precision, good repeatability, suitable peak time, high sensitivity, and low cost. It meets the technical requirements of drug quality research standards and can be used for the quality control and comprehensive evaluation of faropenem sodium preparations.

[0010] As a first limitation of the detection method for related substances in the above-mentioned faropenem sodium preparation, the acetate buffer is a mixed solution of acetate and tetraalkyl quaternary ammonium salt with a pH of 5.6-6.0.

[0011] As a further limitation of the first limitation of the detection method for related substances of the above-mentioned faropenem sodium preparation, the acetate buffer contains ammonium acetate; the tetraalkyl quaternary ammonium salt contains tetrabutylammonium bromide; and the pH of the acetate buffer is adjusted to 5.6-6.0 using acetic acid.

[0012] As a further limitation of the first limitation of the detection method for related substances of the above-mentioned faropenem sodium preparation, the concentration of ammonium acetate in the acetate buffer is 3.6 g / L-4.0 g / L and the concentration of tetrabutylammonium bromide is 1.4 g / L-1.8 g / L.

[0013] As a second limitation of the detection method for related substances in the above-mentioned faropenem sodium preparation, the volume ratio of acetate buffer to methanol in the mobile phase B is 2-3:7-8.

[0014] Compared to the detection methods in the Chinese Pharmacopoeia or the Japanese Pharmacopoeia, this invention, by optimizing parameters such as elution conditions and mobile phase types, can achieve a higher degree of separation between faropenem sodium and various impurities, ensuring the effective detection of impurities and thus achieving the goal of effectively, accurately, and efficiently controlling the content of related substances in faropenem sodium preparations.

[0015] As a third limitation of the detection method for related substances in the above-mentioned faropenem sodium preparation, the chromatographic conditions are as follows: flow rate is 0.8 mL / min-1.2 mL / min; column temperature is 38℃-42℃; detection wavelength is 238 nm-242 nm; and injection volume is 20 μL-60 μL.

[0016] For example, the injection temperature of the high performance liquid chromatograph is 5°C.

[0017] As a further limitation of the third limitation on the detection method of related substances in the above-mentioned faropenem sodium preparation, the chromatographic conditions are as follows: flow rate is 1.0 mL / min; column temperature is 40 °C; detection wavelength is 240 nm; and injection volume is 50 μL.

[0018] As a fourth limitation of the detection method for related substances in the above-mentioned faropenem sodium preparation, the octadecylsilane-bonded silica gel column is an XBridge C18 column with dimensions of 4.6 mm × 250 mm and 5 μm.

[0019] The optimal chromatographic column can provide excellent peak shape, resolution, and detection sensitivity for each component, with minimal baseline interference. This facilitates the effective separation of the raw material from various impurities in faropenem sodium, resulting in accurate, reliable, and reproducible results.

[0020] As a fifth limitation of the detection method for related substances in the above-mentioned faropenem sodium preparation, the faropenem sodium preparation includes at least one of faropenem sodium tablets, faropenem sodium capsules, or faropenem sodium granules.

[0021] As a further limitation of the fifth limitation of the detection method for related substances in the above-mentioned faropenem sodium preparation, the faropenem sodium granules include pediatric faropenem sodium granules.

[0022] For example, this invention provides a method for detecting related substances in faropenem sodium preparations, using pediatric faropenem sodium granules as an example. This method can also achieve comparable technical results when detecting related samples such as faropenem sodium tablets, faropenem sodium capsules, or faropenem sodium granules. The detection method specifically includes the following steps: (1) Solution preparation Preparation of test solution: Accurately weigh the pediatric faropenem sodium granules, place them in a brown volumetric flask, add water to dissolve and dilute to the mark, shake well, filter, and take the filtrate to obtain the test solution; Preparation of impurity reference stock solutions: Accurately weigh the reference standards of impurities A, B, C, D, E, F and G and place them in different volumetric flasks. Add methanol to each flask to obtain impurity reference stock solutions with concentrations of approximately 75 μg / mL, 50 μg / mL, 50 μg / mL, 250 μg / mL, 50 μg / mL, 50 μg / mL and 50 μg / mL, respectively. Preparation of system suitability solution: Weigh approximately 25 mg of faropenem reference standard accurately and place it in a 50 mL brown volumetric flask. Dissolve the solution in an appropriate amount of water. Accurately measure 1 mL of each impurity reference standard stock solution and place them in the same brown volumetric flask. Dilute to the mark with water and shake well to obtain the system suitability solution. (2) Detection Take the test solution, impurity reference stock solution and system suitability solution, inject them into the high performance liquid chromatograph, record the chromatogram, and calculate the content of faropenem sodium and its related substances.

[0023] Based on a clear understanding of the types of impurities, this invention employs pharmacopoeia-recorded detection methods to detect related substances in faropenem sodium. The results showed that none of these methods could achieve efficient and effective separation between the faropenem sodium chromatographic peak and the chromatographic peaks of specific impurities. Therefore, this invention optimizes key detection parameters such as mobile phase type and elution conditions to develop a method for detecting related substances suitable for faropenem sodium formulations, particularly for pediatric faropenem sodium granules. This method combines excellent separation, high specificity, high sensitivity, high accuracy, high efficiency, speed, and low cost. Attached Figure Description

[0024] Figure 1 The liquid chromatogram of the system suitability solution under the detection method for related substances in faropenem sodium preparations provided in Example 1 of the present invention; Figure 2 The liquid chromatogram of the test sample solution after accelerated testing under the method for detecting related substances in faropenem sodium preparations provided in Example 1 of the present invention; Figure 3 The liquid chromatogram of the system suitability solution for the detection method of related substances in faropenem sodium preparations provided in Comparative Example 1 of the present invention; Figure 4 The liquid chromatogram of the system suitability solution for the detection method of related substances in faropenem sodium preparations provided in Comparative Example 2 of the present invention; Figure 5 The liquid chromatogram of the system suitability solution for the detection method of related substances in faropenem sodium preparations provided in Comparative Example 3 of the present invention; Figure 6 The liquid chromatogram of the system suitability solution for the detection method of related substances in faropenem sodium preparations provided in Comparative Example 4 of the present invention; Figure 7 The liquid chromatogram of the system suitability solution for the detection method of related substances in faropenem sodium preparations provided in Comparative Example 5 of the present invention; Figure 8 The liquid chromatogram is a system suitability solution for the detection method of related substances in faropenem sodium preparations provided in Comparative Example 6 of this invention. Detailed Implementation

[0025] The technical solution of the present invention will be clearly and completely described below. It should be understood that the specific embodiments described herein can enable those skilled in the art to have a more comprehensive understanding of the present invention, but do not limit the present invention to the scope of the embodiments described.

[0026] The faropenem sodium preparation used in this invention is pediatric faropenem sodium granules produced by Bozhi Anjian (Hebei) Pharmaceutical Co., Ltd., with production batch number X250301, 0.05g / bag.

[0027] Reference standards for impurities B, C, D, E, F, and G were all purchased from Shenzhen Zhuoyue Biomedical Technology Co., Ltd., while reference standards for impurity A and faropenem were purchased from the National Institutes for Food and Drug Control. Specific information about the reference standards is shown in Table 2.

[0028] Table 2. Statistical table of relevant information for reference standards

[0029] Example 1 This invention provides a method for detecting related substances in faropenem sodium preparations, taking pediatric faropenem sodium granules as an example, and validates the method.

[0030] 1. The method for detecting related substances in faropenem sodium preparations provided in this embodiment of the invention includes the following steps: (1) Solution preparation Test solution: Accurately weigh an appropriate amount of pediatric faropenem sodium granules (equivalent to about 25 mg of faropenem), place them in a 50 mL brown volumetric flask, add water to dissolve and dilute to the mark, shake well, filter, and take the filtrate to prepare a solution containing about 0.5 mg of faropenem per mL, thus obtaining the test solution.

[0031] Control solution: Accurately measure 1 mL of the test solution and place it in a 100 mL brown volumetric flask. Dilute with water to the mark and shake well to obtain the control solution.

[0032] Sensitivity solution: Accurately measure an appropriate amount of the control solution and dilute it quantitatively with water to prepare a solution containing approximately 0.25 μg of faropenem per 1 mL.

[0033] Accelerated test solution: The pediatric faropenem sodium granules used in this invention are packaged in a paper / aluminum / polyethylene pharmaceutical composite film bag + cardboard box; storage temperature: 40±2℃; storage humidity: 75±5%; storage time: 6 months. Following the method described in the "Test Solution" section above, an appropriate amount of the sample after 6 months of accelerated testing storage was taken to prepare the accelerated test solution.

[0034] Impurity reference stock solutions: Accurately weigh the reference standards of impurities A, B, C, D, E, F, and G and place them in different volumetric flasks. Add methanol to each flask to obtain impurity reference stock solutions with concentrations of approximately 75 μg / mL, 50 μg / mL, 50 μg / mL, 250 μg / mL, 50 μg / mL, 50 μg / mL, and 50 μg / mL, respectively. System suitability solution: Weigh approximately 25 mg of faropenem reference standard accurately and place it in a 50 mL brown volumetric flask. Dissolve the flask in an appropriate amount of water. Accurately measure 1 mL of each impurity reference standard stock solution and place them in the same brown volumetric flask. Dilute to the mark with water and shake well to obtain the system suitability solution. Blank excipients: Weigh 12.68g of fine sucrose powder, 4.80g of mannitol, 25mg of sodium edetate, 20mg of aspartame, and 20mg of orange flavoring, and mix them evenly.

[0035] Blank excipient solution: Take an appropriate amount of blank excipient, dissolve and dilute it with water to prepare a solution containing approximately 4.5 mg of excipient per 1 mL.

[0036] For each impurity positioning solution: Take 1 mL of the above-mentioned impurity reference standard stock solution, place it in a 50 mL brown volumetric flask, dilute with water to the mark, and shake well to obtain the solution.

[0037] (2) Detection Take 50 μL each of the above-mentioned test solution, blank excipient solution, impurity localization solution and system suitability solution, inject them into the high performance liquid chromatograph, record the chromatograms, and calculate the content of faropenem and its related substances.

[0038] The specific conditions for high-performance liquid chromatography are as follows: Chromatographic column: XBridge C18 column (250mm × 4.6mm, 5μm); Mobile phase A: Acetate buffer, specifically prepared as follows: take 3.65g of ammonium acetate and 1.6g of tetrabutylammonium bromide, dissolve in 990mL of water, adjust the pH to 5.8 with glacial acetic acid, and bring the volume to 1000mL. Mobile phase B: Prepare 300 mL of acetate buffer according to the preparation method of mobile phase A; mix the acetate buffer and methanol at a volume ratio of 30:70 to obtain mobile phase B; Flow rate: 1.0 mL / min; Detection wavelength: 240nm; Column temperature: 40℃; Injection volume: 50 μL; Injection temperature: 5℃.

[0039] The elution program is gradient elution, as shown in Table 3.

[0040] Table 3 Gradient Elution of Mobile Phase

[0041] 2. Methodological Validation (1) Specificity examination Accurately measure 50 μL each of the blank excipient solution, sensitivity solution, impurity localization solution, system suitability solution, control solution, and test solution, and inject them into the high-performance liquid chromatograph (HPLC). Perform the determination under the chromatographic conditions described above and record the chromatograms. The HPLC chromatogram of the system suitability solution under the method for detecting related substances in faropenem sodium preparations provided in this embodiment of the invention is shown below. Figure 1 As shown in Table 4, the results of the specificity test are as follows.

[0042] Table 4 Results of specificity test

[0043] Depend on Figure 1 As shown in Table 4, the baseline of the detection method for related substances in faropenem sodium preparations provided in this embodiment is stable and interference-free. The blank excipient solution does not interfere with the detection of impurities and the main component. The resolution between the main component and adjacent impurities is greater than 7.0, and the resolution between each component and each impurity is greater than 2.5. There is no interference between impurities, and the resolution between each component meets the requirements, making it suitable for the detection of related substances. Therefore, the detection method provided by this invention has good specificity.

[0044] The liquid chromatogram of the test solution after accelerated testing is shown below. Figure 2 As shown. By Figure 2It can be seen that after the pediatric faropenem sodium granules are stored at a specific temperature and humidity for a period of time, impurities A and G are indeed present in the product. The detection method provided in this embodiment can effectively separate faropenem from its related substances.

[0045] (2) Repeatability and intermediate precision test Following the method described above for preparing the system suitability solution, two technicians prepared six parallel spiked test solutions and six control solutions. 50 μL of each test and control solution was accurately injected into the high-performance liquid chromatograph (HPLC), and the chromatograms were recorded. The RSDs of all relevant substances in the six test solutions were calculated using the principal component external standard method with correction factors. The results of repeatability and intermediate precision tests are shown in Table 5 below.

[0046] Table 5 Results of Repeatability and Intermediate Precision Tests

[0047] As shown in the table above, the RSD of each impurity content is less than 5.0%, indicating that the detection method for related substances in faropenem sodium preparations provided in this embodiment has good repeatability and intermediate precision.

[0048] (3) Investigation of limit of quantitation and limit of detection Take appropriate amounts of faropenem sodium and its impurity reference standards and prepare a series of solutions. Solutions with a S / N ≥ 10 are used as the limit of quantitation (LOQ) solutions; solutions with an S / N ≥ 3 are used as the limit of detection (LOD) solutions. The LQ and LOD results for faropenem sodium and its impurities are shown in Table 6.

[0049] Table 6 Results of Limit of Quantitation and Limit of Detection

[0050] As shown in the table above, the signal-to-noise ratio of the detection limit for faropenem main component and impurities is greater than 3:1, and the signal-to-noise ratio of the quantitation limit is greater than 10:1. The detection limits for impurities A-G and faropenem are in the range of 0.011-0.096 μg / mL, and the quantitation limits are in the range of 0.011-0.191 μg / mL. This indicates that the sensitivity of the main component and each impurity in the detection method of faropenem sodium preparations provided by this invention meets the detection requirements.

[0051] (4) Linear examination The above-mentioned impurity reference standard stock solutions were used to prepare linear solutions at the limits of quantitation (LOQ), 10%, 20%, 50%, 80%, 100%, and 120% of the limit concentration, respectively. The limits for different related substances are listed in Table 1. 50 μL of each linear solution was accurately injected into the high-performance liquid chromatograph (HPLC), and the chromatograms were recorded. The linear correlation coefficient was calculated. The results showed that faropenem sodium and its impurities exhibited good linearity within the linear range. The linearity test results are shown in Table 7.

[0052] Table 7 Linearity Results

[0053] The above results indicate that, within the scope of this invention, the method for detecting related substances in faropenem sodium preparations provided by this invention exhibits a good linear relationship between the concentration and peak area of ​​faropenem and various impurities.

[0054] (5) Accuracy assessment Prepare a recovery stock solution of the above-mentioned impurity reference standard stock solution to obtain a mixed impurity recovery rate at 400% limit concentration. Then, accurately weigh approximately 100 mg of pediatric faropenem sodium granules (approximately equivalent to 10 mg of faropenem) and place it in a 20 mL amber volumetric flask. Accurately add 4 mL, 5 mL, and 6 mL of the recovery stock solution, dissolve and dilute to the mark with diluent, and mix well. Prepare three parallel aliquots for each concentration. Accurately inject 50 μL of each recovery solution into the high-performance liquid chromatograph (HPLC) and record the chromatogram. The recovery rate results for different impurities are shown in Tables 8-1 to 8-7.

[0055] Table 8-1 Results of Impurity A Recovery Rate Test

[0056] Table 8-2 Results of Impurity B Recovery Rate Test

[0057] Table 8-3 Results of Impurity C Recovery Rate Test

[0058] Table 8-4 Results of Impurity D Recovery Rate Test

[0059] Table 8-5 Results of Impurity E Recovery Rate Test

[0060] Table 8-6 Results of Impurity F Recovery Rate Test

[0061] Table 8-7 Results of Impurity G Recovery Rate Test

[0062] As shown in the table above, the recovery rates of each impurity are all in the range of 85% to 115%, and the RSD of the recovery rates of each impurity in the nine recovery solutions of different impurities is less than 10%.

[0063] (6) Durability test The durability test was conducted according to the test conditions shown in Table 8. The results of the system adaptability solution under different initial mobile phase ratios, column temperatures, flow rates, and detection wavelengths are shown in Tables 9-12.

[0064] Table 9 Durability Test Conditions

[0065] Table 10. Experimental results with different initial proportions of mobile phase.

[0066] Table 11 Test results at different column temperatures

[0067] Table 12 Test results at different flow rates

[0068] Different detection wavelengths did not appear to affect the separation degree of different components.

[0069] The above experiments show that, within the experimental range, changing the initial ratio of the mobile phase, column temperature, flow rate, and detection wavelength did not significantly change the separation degree of faropenem and its various impurities, indicating that the detection method provided by this invention has good durability.

[0070] (7) Solution stability study Solution stability is the determination of the stability of a test solution over a period of time.

[0071] Detection solution: Take appropriate amounts of system suitability solution and test solution, and inject them at 0h, 2h, 4h, 9h, and 16h respectively for determination. Detect according to the chromatographic conditions and methods provided in Part (2) of this embodiment. Calculate the relative standard deviation based on the peak area. The results are shown in Table 13. After study, the peak area RSD is between 0.06% and 1.16%, and the test solution is relatively stable.

[0072] Table 13 Results of solution stability test

[0073] The data in the table above show that the mixed sample of related substances is stable within 16 hours.

[0074] In summary, the detection method for related substances in faropenem sodium preparations provided in this embodiment of the invention has advantages such as high specificity, high accuracy, high precision, good repeatability, high sensitivity, strong stability, and low detection cost. It meets the technical requirements of drug quality research standards, and the results are stable and reliable.

[0075] Example 2 This invention provides a method for detecting related substances in faropenem sodium preparations. This method is basically the same as that in Example 1, except that the preparation method of the mobile phase is different, while all other parameters are the same. In this example: mobile phase A is acetate buffer, which is prepared as follows: take 3.8g of ammonium acetate and 1.5g of tetrabutylammonium bromide, dissolve them in 990mL of water, adjust the pH to 5.9 with glacial acetic acid, and bring the volume to 1000mL; mobile phase B: prepare 280mL of acetate buffer according to the preparation method of mobile phase A; mix the acetate buffer and methanol at a volume ratio of 28:72 to obtain mobile phase B.

[0076] The method for detecting related substances in faropenem sodium preparations provided in this embodiment has been validated, and the results show that the method performs well and meets the relevant technical specifications for drug quality research.

[0077] Example 3 This invention provides a method for detecting related substances in faropenem sodium preparations. This method is basically the same as that in Example 1, except that the preparation method of the mobile phase is different, while all other parameters are the same. In this example: mobile phase A is acetate buffer, which is prepared as follows: take 4.0 g of ammonium acetate and 1.8 g of tetrabutylammonium bromide, dissolve them in 990 mL of water, adjust the pH to 6.0 with glacial acetic acid, and bring the volume to 1000 mL; mobile phase B: prepare 200 mL of acetate buffer according to the preparation method of mobile phase A; mix the acetate buffer and methanol at a volume ratio of 20:80 to obtain mobile phase B.

[0078] The method for detecting related substances in faropenem sodium preparations provided in this embodiment has been validated, and the results show that the method performs well and meets the relevant technical specifications for drug quality research.

[0079] Comparative Example 1 This comparative example, referencing the relevant methods in the Chinese Pharmacopoeia, provides a method for the detection of related substances in faropenem sodium preparations. The specific chromatographic conditions are as follows: Chromatographic column: XBridge C18 250mm × 4.6mm, 5μm; Mobile phase A: Phosphate buffer, prepared as follows: Take 6.12 g of potassium dihydrogen phosphate, 1.79 g of disodium hydrogen phosphate and 1.61 g of tetrabutylammonium bromide, dissolve in water and bring the volume to 1000 mL; Mobile phase B: prepared by mixing phosphate buffer and acetonitrile at a volume ratio of 50:50; The flow rate was 1.0 mL / min; the column temperature was 40 °C; the detection wavelength was 240 nm; the injection temperature was 5 °C; and the injection volume was 50 μL. Gradient elution was performed according to Table 14 below.

[0080] Table 14 Gradient Elution Table

[0081] Prepare 50 μL of the system suitability solution according to the method provided in Example 1, inject it into a high-performance liquid chromatograph (HPLC), and record the chromatogram. The HPLC chromatogram of the system suitability solution under the related substances detection method for faropenem sodium preparations provided in this comparative example is shown below. Figure 3 As shown.

[0082] Depend on Figure 3 The results show that impurities A and F in the system suitability solution cannot be completely separated, and the separation degree between impurity A and the main peak cannot meet the requirements.

[0083] Comparative Example 2 This comparative example, referencing the relevant methods in the Japanese Pharmacopoeia, provides a method for detecting related substances in faropenem sodium preparations. The specific chromatographic conditions are as follows: Chromatographic column: XBridge C18 250mm × 4.6mm, 5μm; Mobile phase A: Phosphate buffer, prepared as follows: Take 6.12 g of potassium dihydrogen phosphate, 1.79 g of disodium hydrogen phosphate and 1.61 g of tetrabutylammonium bromide, dissolve in water and bring the volume to 1000 mL; Mobile phase B: prepared by mixing phosphate buffer and acetonitrile at a volume ratio of 50:50; The flow rate was 1.0 mL / min; the column temperature was 40 °C; the detection wavelength was 240 nm; the injection temperature was 5 °C; and the injection volume was 50 μL. Gradient elution was performed according to Table 15 below.

[0084] Table 15 Gradient Elution Table

[0085] Prepare 50 μL of the system suitability solution according to the method provided in Example 1, inject it into a high-performance liquid chromatograph (HPLC), and record the chromatogram. The HPLC chromatogram of the system suitability solution under the related substances detection method for faropenem sodium preparations provided in this comparative example is shown below. Figure 4 As shown. By Figure 4It can be seen that the peaks of impurity A and impurity F cannot be completely separated, and the separation degree between impurity A and the main peak cannot meet the requirements.

[0086] Comparative Example 3 This comparative example provides a method for detecting related substances in faropenem sodium preparations. This method is basically the same as that of comparative example 1, except that the gradient elution procedure is different. This comparative example performs gradient elution according to Table 16 below.

[0087] Table 16 Gradient Elution Table

[0088] Under the method for detecting related substances in faropenem sodium preparations provided in this comparative example, the liquid chromatogram of the system suitability solution is as follows: Figure 5 As shown.

[0089] Depend on Figure 5 It can be seen that even after adjusting the elution program, impurity A and impurity F still could not be completely separated, and the separation effect of impurity A from the main peak was not improved.

[0090] Comparative Example 4 This comparative example provides a method for detecting related substances in faropenem sodium preparations. This method is basically the same as that of comparative example 1, except that the gradient elution procedure is different. This comparative example performs gradient elution according to Table 17 below.

[0091] Table 17 Gradient Elution Table

[0092] Under the method for detecting related substances in faropenem sodium preparations provided in this comparative example, the liquid chromatogram of the system suitability solution is as follows: Figure 6 As shown.

[0093] Depend on Figure 6 It can be seen that even after adjusting the elution program, impurity A and impurity F still could not be completely separated, and the separation effect of impurity A from the main peak was not improved.

[0094] Comparative Example 5 This comparative example provides a method for detecting related substances in faropenem sodium preparations. This method is basically the same as that of comparative example 1, except that the mobile phase B is different from that of comparative example 1. The preparation method of mobile phase B in this comparative example is as follows: phosphate buffer (prepared in comparative example 1), methanol and acetonitrile are mixed evenly in a volume ratio of 50:25:25.

[0095] Inject 50 μL of the system suitability solution into the high-performance liquid chromatograph (HPLC) and record the chromatogram. The HPLC chromatogram of the system suitability solution under the related substances detection method for faropenem sodium preparations provided in this comparative example is shown below. Figure 7As shown. By Figure 7 It can be seen that impurities A and F, and impurity A can be effectively separated from the main peak. However, the peak elution time of faropenem is 41.962 min, which is relatively late. There is a risk that some impurities cannot be eluted during the gradient operation time.

[0096] Comparative Example 6 This comparative example provides a method for detecting related substances in faropenem sodium preparations. This method is basically the same as that of comparative example 1, except that the mobile phase B is different from that of comparative example 1. The preparation method of mobile phase B in this comparative example is as follows: phosphate buffer (prepared in comparative example 1) and methanol are mixed evenly at a volume ratio of 40:60.

[0097] Inject 50 μL of the system suitability solution into the high-performance liquid chromatograph (HPLC) and record the chromatogram. The HPLC chromatogram of the system suitability solution under the related substances detection method for faropenem sodium preparations provided in this comparative example is shown below. Figure 8 As shown. By Figure 8 It can be seen that impurities A and F, and impurity A can be effectively separated from the main peak. However, the peak elution time of faropenem is 43.187 min, which is relatively late. There is a risk that some impurities will not be eluted during the gradient operation time.

[0098] As can be seen from the results of the above embodiments and comparative examples, the detection method for related substances in faropenem sodium preparations provided by the embodiments of the present invention can effectively separate impurity peaks and impurity peaks from the main peak, and the elution time of the main peak is appropriate. It has advantages such as high specificity, good accuracy, high precision, good repeatability, strong stability, high sensitivity, and low detection cost, which can effectively ensure the quality of faropenem sodium preparations and thus improve the safety of clinical drug use.

[0099] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for detecting related substances in faropenem sodium preparations, characterized in that, The related substances of the faropenem sodium include impurities A, B, C, D, E, F, and G, which are detected by high-performance liquid chromatography (HPLC) under the following chromatographic conditions: Chromatographic column: Octadecylsilane-bonded silica gel column; Mobile phase: Mobile phase A is acetate buffer, and mobile phase B is acetate buffer-methanol; The elution process is gradient elution; The gradient elution procedure is as follows:

2. The method for detecting related substances in faropenem sodium preparations as described in claim 1, characterized in that, The acetate buffer solution is a mixed solution of acetate and tetraalkyl quaternary ammonium salt with a pH of 5.6-6.

0.

3. The method for detecting related substances in faropenem sodium preparations as described in claim 2, characterized in that, In the acetate buffer solution, the acetate includes ammonium acetate; and / or The tetraalkyl quaternary ammonium salt includes tetrabutylammonium bromide; and / or The pH of the acetate buffer solution was adjusted to 5.6-6.0 using acetic acid.

4. The method for detecting related substances in faropenem sodium preparations as described in claim 3, characterized in that, In the acetate buffer solution, the concentration of ammonium acetate is 3.6 g / L-4.0 g / L, and the concentration of tetrabutylammonium bromide is 1.4 g / L-1.8 g / L.

5. The method for detecting related substances in faropenem sodium preparations as described in claim 1, characterized in that, The volume ratio of acetate buffer to methanol in the mobile phase B is 2-3:7-8.

6. The method for detecting related substances in faropenem sodium preparations as described in claim 1, characterized in that, The chromatographic conditions are as follows: flow rate is 0.8 mL / min-1.2 mL / min; column temperature is 38℃-42℃; detection wavelength is 238 nm-242 nm; and injection volume is 20 μL-60 μL.

7. The method for detecting related substances in faropenem sodium preparations as described in claim 6, characterized in that, The chromatographic conditions were as follows: flow rate 1.0 mL / min; column temperature 40 °C; detection wavelength 240 nm; injection volume 50 μL.

8. The method for detecting related substances in faropenem sodium preparations as described in claim 1, characterized in that, The octadecylsilane-bonded silica gel column is an XBridge C18 column with dimensions of 4.6 mm × 250 mm and a diameter of 5 μm.

9. The method for detecting related substances in faropenem sodium preparations as described in any one of claims 1-8, characterized in that, The faropenem sodium formulation includes at least one of faropenem sodium tablets, faropenem sodium capsules, or faropenem sodium granules.

10. The method for detecting related substances in faropenem sodium preparations as described in claim 9, characterized in that, The faropenem sodium granules include pediatric faropenem sodium granules.

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