Method for detecting related substances in eldoxaban tosylate medicine
By employing high-performance liquid chromatography and gradient elution technology, the problem of isomer separation of edoxaban tosylate was solved, achieving high-resolution and sensitive detection, ensuring drug quality and safety, and meeting regulatory requirements.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-08-29
- Publication Date
- 2026-03-10
AI Technical Summary
Existing detection methods are insufficient to effectively separate and identify the various isomers of edoxaban tosylate, failing to meet the requirements of drug quality control and regulatory oversight, and posing a potential risk of reduced efficacy or enhanced side effects.
High-performance liquid chromatography (HPLC) was employed, using dipotassium hydrogen phosphate solution-acetonitrile as the mobile phase with gradient elution. An octadecylsilane-bonded silica column was used, and the flow rate, column temperature, and detection wavelength were optimized. Specific detection steps and procedures were designed to achieve effective separation and identification of isomers.
This study achieved high-resolution separation and sensitive detection of isomers in edoxaban tosylate, improving the stability and reproducibility of analytical results, meeting drug quality control and regulatory requirements, and ensuring the safety and efficacy of the drug.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application belongs to the field of chemical drug analysis, and specifically relates to a detection method for related substances in edoxaban tosylate drug. BACKGROUND
[0002] Edoxaban tosylate is an oral anticoagulant drug, and different isomers may have differences in activity, stability and bioavailability. The current detection method is difficult to separate each impurity of edoxaban tosylate. Therefore, it is crucial to develop and implement an effective and accurate detection technology for each isomer in edoxaban tosylate drug, which helps to ensure that the drug meets the predetermined quality standards and efficacy requirements, reduces the risk of potential adverse reactions, and is beneficial to quality control during drug production and meets regulatory requirements.
[0003] The technical background behind the development of the detection method for isomers of edoxaban tosylate drug mainly includes the following aspects: 1. Differences in properties of drug isomers: Many drug molecules exist in multiple stereoisomer forms, such as enantiomers of chiral drugs and spatial isomers of achiral drugs. Different isomers may exhibit significantly different biological activity, pharmacokinetic properties (absorption, distribution, metabolism, excretion) and toxicity. The activity and safety of isomers of edoxaban, an important anticoagulant drug, are particularly critical.
[0004] 2. Regulatory requirements: International drug regulatory agencies such as the US FDA and the European EMA require strict stereoselective synthesis and quality control for drugs containing chiral centers to ensure that only the isomer with the desired therapeutic effect or a specific ratio of isomer combination is present in the marketed drug.
[0005] 3. Production process monitoring: During drug research and development and production, it is necessary to monitor the reaction progress to ensure the purity of the final product, i.e. high purity of the target isomer and low content of impurity isomers. Therefore, an effective isomer detection method needs to be established to monitor and optimize the production process.
[0006] 4. Drug efficacy and safety: Due to the performance differences between isomers, which may lead to reduced efficacy or increased side effects, precise detection methods must be developed to accurately assess drug quality and safety, thereby ensuring patient safety and treatment efficacy.
[0007] In summary, the development of a detection method for isomers of edoxaban tosylate drug is based on the need for strict control of drug quality, and also follows global drug regulatory requirements to ensure scientific, standardized and standardized production and use of drugs. SUMMARY
[0008] The application aims to develop a detection method for related substances in edoxaban tosylate, which comprehensively covers impurity types, has good stability and reproducibility, and can effectively separate related substances in edoxaban tosylate.
[0009] To achieve the above-mentioned application purposes, the detection method for related substances in edoxaban tosylate, specific embodiments are as follows: The detection method for related substances in edoxaban tosylate is a high-performance liquid chromatography method, potassium phosphate dibasic solution-acetonitrile is used as mobile phase A, acetonitrile is used as mobile phase B, gradient elution is performed, and the gradient elution conditions are as follows:
[0010] The detection method has the following gradient elution conditions:
[0011] The detection method has the following gradient elution conditions:
[0012] The detection method has the following gradient elution conditions:
[0013] The detection method has the following gradient elution conditions:
[0014] The detection method has the following gradient elution conditions:
[0015] The detection method has the following gradient elution conditions: 1) Preparation of stock solution: precisely weigh edoxaban tosylate, impurity SM3, impurity API-F, impurity API-J, and impurity SM3-D reference substances, and respectively place them in 20 ml volumetric flasks, dissolve and dilute to the scale with a solvent, and shake well for standby use; 2) Preparation of positioning solution: respectively take the edoxaban tosylate, impurity SM3, impurity API-F, impurity API-J, and impurity SM3-D stock solutions prepared in step 1) and place them in 10 ml volumetric flasks, dilute to the scale with a solvent; 3) Preparation of system suitability solution: take edoxaban tosylate medicine, place it in a 100 ml volumetric flask, add impurity SM3, impurity API-F, impurity API-J, and impurity SM3-D stock solutions, dissolve and dilute to the scale with a solvent, shake well, and obtain the system suitability solution; 4) Preparation of the reference solution: Take the edoxaba mesylate stock solution and place it in a 100ml volumetric flask. Dilute to the mark with solvent and shake well to obtain the solution. 5) Preparation of the test solution: Take the edoxaba mesylate drug and place it in a 10ml volumetric flask. Dissolve and dilute to the mark with solvent and shake well to obtain the solution. 6) Test by high performance liquid chromatography and record the chromatogram.
[0016] The detection method of the application is characterized in that the injection program of the detection method is:
[0017] Advantage analysis of the detection method of the application: High resolution and sensitivity: Through careful design of chromatographic conditions, especially selection of high-efficiency octadecylsilane-bonded silica gel packing as the stationary phase, and use of a gradient elution system of buffer and organic solvent under suitable pH conditions, edoxaba mesylate and its various potential related impurities can be effectively separated, the resolution of the detection is improved, and trace impurities can also be accurately identified and quantified.
[0018] Optimized gradient elution scheme: The application adopts a dynamic gradient elution mode, which can realize good separation of the target compound and other impurities in a short time, reduces the analysis time, and improves the laboratory work efficiency.
[0019] Stability and reproducibility: The set flow rate, column temperature and detection wavelength are the best conditions for the characteristics of edoxaba mesylate, which helps to improve the stability of the analysis results and ensures the consistency and reproducibility of the tests between different batches.
[0020] Comprehensive coverage of impurity types: This method can cover various possible related substances in edoxaba mesylate bulk drug and preparations, meet the strict requirements of drug quality control, and is conducive to ensuring the safety and effectiveness of drugs.
[0021] Widely applicable: The method is not only suitable for the quality control of edoxaba mesylate, but also easy to be applied to the detection of related substances of similar drugs, showing good universality. BRIEF DESCRIPTION OF DRAWINGS
[0022] Figure 1 The detection chromatogram and results of the application are shown. DETAILED DESCRIPTION
[0023] The following examples are only for further illustrating the scope of the application, and do not limit the scope of the application in any form. EXAMPLE
[0024] Edoxaban tosylate stock solution: About 2 mg of edoxaban tosylate reference substance was precisely weighed into a 20-ml volumetric flask, dissolved and diluted to the mark with solvent, and shaken well.
[0025] Impurity SM3 stock solution: About 2.4 mg of impurity SM3 reference substance was precisely weighed into a 20-ml volumetric flask, dissolved and diluted to the mark with solvent, and shaken well.
[0026] Impurity API-F stock solution: About 2 mg of impurity API-F reference substance was precisely weighed into a 20-ml volumetric flask, dissolved and diluted to the mark with solvent, and shaken well.
[0027] Impurity API-J stock solution: About 2 mg of impurity API-J reference substance was precisely weighed into a 20-ml volumetric flask, dissolved and diluted to the mark with solvent, and shaken well.
[0028] Impurity SM3-D stock solution: About 2 mg of impurity SM3-D reference substance was precisely weighed into a 20-ml volumetric flask, dissolved and diluted to the mark with solvent, and shaken well.
[0029] SM3 positioning solution: 1 ml of the SM3 stock solution was taken and placed in a 10-ml volumetric flask, diluted to the mark with solvent.
[0030] SM3-D positioning solution: 1 ml of the SM3-D stock solution was taken and placed in a 10-ml volumetric flask, diluted to the mark with solvent.
[0031] API-J positioning solution: 1 ml of the API-J stock solution was taken and placed in a 10-ml volumetric flask, diluted to the mark with solvent.
[0032] API-F positioning solution: 1 ml of the API-F stock solution was taken and placed in a 10-ml volumetric flask, diluted to the mark with solvent.
[0033] System suitability solution: About 100 mg of the product was precisely weighed into a 100-ml volumetric flask, 1 ml of each of the impurity SM3 stock solution, impurity API-F stock solution, impurity API-J stock solution, and impurity SM3-D stock solution was added, dissolved and diluted to the mark with solvent, and shaken well.
[0034] Reference solution: 1 ml of the edoxaban tosylate stock solution was precisely measured into a 100-ml volumetric flask, diluted to the mark with solvent, and shaken well.
[0035] Test solution: About 10 mg of the product was precisely weighed into a 10-ml volumetric flask, dissolved and diluted to the mark with solvent, and shaken well.
[0036] Chromatographic conditions: Column: octadecylsilane-bonded silica gel as the filler (Inertsil ODS-3, 250 mm x 4.6 mm, 5 μm or a column of equivalent performance); 0.02 mol / L potassium phosphate dibasic solution (adjust pH to 8.0 with phosphoric acid)-acetonitrile (90:10) as the mobile phase A, acetonitrile as the mobile phase B, gradient elution according to the following table; flow rate: 1.0 ml / min; column temperature: 30°C; detection wavelength: 260 nm; injection volume: 20 μl. Determination: after obtaining a stable baseline, sample analysis was carried out in the following order, and the chromatogram was recorded.
[0037] Sample procedure: Number Name Injection times Remarks 1 Blank solvent ≥1 2 System suitability solution 1 3 Reference solution 2 4 Test solution 1 5 SM3 positioning solution 1 6 SM3-D positioning solution 1 7 API-J positioning solution 1 8 API-F positioning solution 1 The detection spectrum is shown in Figure 1 .
Claims
1. A method for detecting related substances in a medicament of edoxaban tosylate, characterized by, The detection method is high performance liquid chromatography, using dipotassium hydrogen phosphate solution-acetonitrile as mobile phase A, acetonitrile as mobile phase B, gradient elution, and the gradient elution conditions are:
2. The method of claim 1, wherein, The gradient elution conditions of the detection method are:
3. The detection method according to claim 1, characterized in that, The detection method is described as follows The substance is:
4. The method of claim 1, wherein, The concentration of the dipotassium hydrogen phosphate solution is 0.02 mol / L, and the pH value is 8.0-9.
0.
5. The detection method according to claim 1, characterized in that, The ratio of the mobile phase A dipotassium hydrogen phosphate solution-acetonitrile is 85-95:5-15.
6. The method of claim 1, wherein, The high performance liquid chromatography uses octadecylsilane bonded silica gel as the filling agent of the chromatographic column, the flow rate is 1.0 ml per minute; the column temperature is 30 DEG C; the detection wavelength is 260 nm; and the injection volume is 20 ul.
7. The method of detection according to any one of claims 1 to 6, wherein, The detection method specifically includes the following steps: 1) 1) Preparation of stock solution: accurately weigh edoxaban tosylate, impurity SM3, impurity API-F, impurity API-J and impurity SM3-D reference substances, and respectively place them in 20 ml volumetric flasks, dissolve and dilute to the mark with solvent, and shake well for standby use; 2) 2) Preparation of positioning solution: respectively take edoxaban tosylate, impurity SM3, impurity API-F, impurity API-J and impurity SM3-D stock solution prepared in step 1) and place them in 10 ml volumetric flasks, dilute to the mark with solvent; 3) 3) Preparation of system suitability solution: take edoxaban tosylate drug, place it in a 100 ml volumetric flask, add impurity SM3, impurity API-F, impurity API-J and impurity SM3-D stock solution, dissolve and dilute to the mark with solvent, shake well, and obtain; 4) 4) Preparation of reference solution: take edoxaban tosylate stock solution, place it in a 100 ml volumetric flask, dilute to the mark with solvent, shake well, and obtain; 5) 5) Test sample solution: take edoxaban tosylate drug and place it in a 10 ml volumetric flask, dissolve and dilute to the mark with solvent, shake well, and obtain; 6) 6) Test by high performance liquid chromatography, and record the chromatogram.
8. The detection method according to claim 7, characterized in that, The injection program of the detection method is: 。