Preparation method and application of epalrestat dimer
By reacting the pulverized epalstat under light conditions, and combining solvent and drying steps, a high-purity epalstat dimer was prepared, which solved the problem of difficulty in controlling the content and properties of epalstat dimer in the prior art, and achieved drug quality control and stability monitoring.
Patent Information
- Application Number
- CN202510120389.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-25
- Publication Date
- 2025-05-06
AI Technical Summary
The lack of methods for preparing ipastat dimers in the prior art makes it difficult to control the content and properties of ipastat drugs during the production process, affecting the safety and effectiveness of the drugs.
The pulverized epalstat was reacted under light conditions, and stirred, filtered and crystallized using the first solvent and the second solvent, and finally, a high purity epalstat dimer was obtained by vacuum drying.
The efficient preparation of ipastat dimer is achieved, and a high-purity reference product is provided for quality control and stability monitoring of ipastat drugs to ensure the safety and effectiveness of the drugs.
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Figure CN119930539A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of drug synthesis, and in particular to a preparation method of an epalrestat dimer and application thereof. Background Art
[0002] In clinical practice, epalrestat is often used to treat diabetic patients' neuropathy symptoms, such as numbness, pain, and paresthesia in the hands and feet. In addition, it helps to improve the nerve conduction velocity of diabetic patients and improve their quality of life. The preparation of its impurities has important applications in drug quality control, impurity limit research, and drug safety evaluation.
[0003] As an impurity reference substance, epalrestat dimer can be used to study and control epalrestat dimer in epalrestat bulk drug and pharmaceutical composition. By using epalrestat dimer reference substance, researchers can understand the existence state, source and properties of epalrestat dimer, so as to take corresponding measures to control the production and content of epalrestat dimer. This helps to ensure the safety and effectiveness of the drug; as an impurity reference substance, it can be used to determine the stability and composition of epalrestat drug to determine the maximum feasible limit of epalrestat drug. In addition, epalrestat dimer as a reference substance can also be used to describe the process characteristics of epalrestat ingredients and evaluate the changing trend of inactive ingredients in drugs.
[0004] In the production process of epalrestat, epalrestat dimer can be used as a reference substance to monitor the stability of the epalrestat production process and product quality. By comparing the properties and content of epalrestat dimer with samples in actual production, problems in the process can be discovered in a timely manner, and corresponding measures can be taken to adjust and optimize. This helps to improve the production efficiency and product quality of drugs.
[0005] In view of the high medicinal value of epalrestat and the fact that epalrestat dimers are easily produced under light conditions, it is necessary to conduct quality research on epalrestat dimers for epalrestat APIs and their pharmaceutical compositions. When conducting quality research on epalrestat APIs or their pharmaceutical compositions, high-purity epalrestat dimers are required as reference substances. Epalrestat dimers are one of the main degradation impurities of epalrestat, and the JP (Japanese Pharmacopoeia) stipulates that their limit should not exceed 0.1%. Moreover, epalrestat dimers will increase significantly under accelerated conditions during the stability placement of epalrestat, exceeding the prescribed limit, posing certain safety risks to the human body.
[0006] Currently, there are no literature reports or patent claims on the preparation of epalrestat dimer; therefore, it is of great significance to conduct research on the preparation method of epalrestat dimer. Summary of the invention
[0007] The present invention provides a method for preparing epalrestat and an epalrestat dimer in a pharmaceutical composition thereof.
[0008] The technical solutions adopted to achieve the above objectives are: The present invention provides a method for preparing an epalrestat dimer, comprising the following steps: (1) crushing epalrestat and reacting it under light conditions, adding a first solvent to the reaction substrate, stirring and dissolving it, and then filtering it. After concentrating the filtrate, crystallizing it, filtering it with suction, and vacuum drying the filter cake to obtain a crude product of epalrestat dimer; (2) Adding the crude epalrestat dimer to the second solvent, heating, stirring, filtering while hot, crystallizing the filtrate, filtering and vacuum drying to obtain the epalrestat dimer.
[0009] Preferably, in step (1), the particle size after pulverization is 1-1000 μm, preferably 100-200 μm.
[0010] Preferably, in step (1), the reaction is carried out at a light intensity of more than 100 Lx, preferably 5000-50000 Lx.
[0011] Preferably, in step (1), the reaction time is 24 h to 336 h.
[0012] Preferably, in step (1), the total illumination received by the reaction substrate is not less than 1.2*10 6 Lx, preferably (3~5)*10 6 Lx*h.
[0013] Preferably, in step (1), the mass ratio of the reaction substrate to the first solvent is 1:1-20; preferably, the mass ratio is 1:3; and the crystallization time is 1-5 hours. 7. The preparation method according to any one of claims 1-6, characterized in that the first solvent is a mixture of one or more solvents selected from methanol, ethanol, dichloromethane, chloroform, tetrahydrofuran and isopropanol; preferably, the first solvent is ethanol or methanol.
[0014] Preferably, the second solvent is one or a mixture of several solvents including DMF, tetrahydrofuran, methanol, ethanol, acetone, dichloromethane and chloroform; preferably, the second solvent is methanol or ethanol.
[0015] Preferably, in step (2), the mass ratio of the crude epalrestat dimer to the second solvent is 1:1-20; preferably, the mass ratio is 1:1.5; the stirring time is 1-5 hours; the crystallization temperature is 0°C-50°C; preferably, the crystallization temperature is 20-30°C.
[0016] The present invention also provides the use of the epalrestat dimer prepared by the preparation method as an impurity reference substance in the quality control of the epalrestat raw material.
[0017] The preparation method provided by the present invention has the following reaction process: The present invention provides an application of a dimer in quality control of an epalrestat bulk drug, wherein the dimer is used as an impurity reference substance of the epalrestat bulk drug; the specific structure of the dimer is: The present invention further provides a method for determining a dimer of epalrestat bulk drug, the method comprising: Provide test products, self-reference products and dimer standards of epalrestat API; The presence and amount of dimer in epalrestat drug substance were determined by chromatographic analysis of test, reference and standard substances.
[0018] In a preferred embodiment of the present invention, the method for determining the dimer of the epalrestat bulk drug comprises: Provide standard products of epalrestat API; Provide dimer controls; Analyze the dimer standard by HPLC to determine the retention time of the dimer; The test sample of the epalrestat drug substance is analyzed by HPLC to determine whether the test sample contains a substance whose retention time is substantially consistent with the retention time of the dimer, thereby determining the presence of the dimer in the epalrestat drug substance.
[0019] The preparation method of the epalrestat dimer of the present invention has the beneficial effects that the epalrestat dimer provided by the present invention can be used for the detection and control of the dimer content generated during the preparation or storage process of the epalrestat raw material and its pharmaceutical composition, and the content of related impurities in the epalrestat raw material and its pharmaceutical composition is controlled to meet the required standards, and also provides a reference for process condition control and storage condition control. The method is simple and feasible, does not require the preparation of liquid phase, and a high-purity epalrestat dimer reference substance can be obtained through a simple crystallization process. BRIEF DESCRIPTION OF THE DRAWINGS
[0020] Figure 1 This is the HPLC determination chart of epalrestat dimer in epalrestat raw material. DETAILED DESCRIPTION
[0021] The present application is further described in detail below in conjunction with specific examples, which are not intended to limit the present invention. The examples described are only some embodiments of the present invention, rather than all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0022] Example 1 Preparation of dimer (1) Take 50g of epalrestat, add it to a mortar, pass it through a 100-mesh sieve, and evenly spread the sieved epalrestat on a surface dish. Then place the surface dish in a light box and illuminate it for 200 hours, turning the material over every day. The solid after the reaction was sent to liquid chromatography for analysis and detection, and the central control purity was 16.38%. The solid after the reaction was added to 150ml of ethanol and stirred to dissolve. After 2 hours, it was filtered and the filter cake was vacuum dried at 45°C for 1 hour to obtain 10.07g of epalrestat dimer crude product, which was sent to liquid chromatography for analysis and detection. The purity of the dimer crude product was 84.50%. (2) 10.07 g of crude epalrestat dimer was added to 15 ml of methanol solution, heated to 40°C, stirred for 1 h and filtered while hot. The filtrate was cooled to 20°C for crystallization. After 2 h, 5.61 g of yellow epalrestat dimer was obtained by suction filtration. The target compound was analyzed by liquid chromatography, and the purity was 99.66%.
[0023] 1 H-NMR (600MHz, DMSO-d6, 25℃): δ:1.800(s,3H),1.938(s,3H),3.976(s,1H),4.568~4.644(m,2H),5.209(s,1H),6.653(s,1H) ,7.216~7.364(m,10H) ,7.657(s,1H),13.458(s,2H) 13 C-NMR (600MHz, DMSO-d6, 25℃): δ: 19.589, 21.176, 45.440, 45.562, 45.890 ,56.623,62.946,66.204,124.550,127.448,127.715,128.058,128.783, 128.936,129.225,133.085,133.711,135.099,136.991,146.114,165.992,167.663,167.724,176.336,193.666,199.036.
[0024] LC-MS (m / z) : 639.1 [M+H] + .
[0025] HPLC purity(99.66)%.
[0026] Example 2 Preparation of dimer (1) Take 50g of epalrestat, add it to a mortar, pass it through a 100-mesh sieve, and evenly spread the sieved epalrestat on a surface dish. Then place the surface dish in a light box for 168 hours, turning the material over every day. The solid after the reaction was sent to liquid chromatography for analysis and detection, and the central control purity was 14.26%. The solid after the reaction was added to 150ml of ethanol and stirred to dissolve. After 2 hours, it was filtered and the filter cake was vacuum dried at 45°C for 1 hour to obtain 8.82g of epalrestat dimer crude product, which was sent to liquid chromatography for analysis and detection. The purity of the dimer crude product was 80.33%. (2) 8.82 g of crude epalrestat II was added to 13 ml of ethanol solution, heated to 40°C, stirred for 1 h and filtered while hot. The filtrate was cooled to 20°C for crystallization. After 2 h, 4.25 g of yellow epalrestat dimer was obtained by suction filtration. The target compound was analyzed by liquid chromatography, and the purity was 98.73%.
[0027] Example 3 (1) Take 50g of epalrestat, add it to a mortar, pass it through a 100-mesh sieve, and evenly spread the sieved epalrestat on a watch glass. Then place the watch glass in a light box and illuminate it for 168 hours, turning the material over every day. The solid after the reaction was sent to liquid chromatography for analysis and detection, and the central control purity was 11.26%. The solid after the reaction was added to 150ml of ethanol and stirred to dissolve. After 2 hours, it was filtered and the filter cake was vacuum dried at 45°C for 1 hour to obtain 6.42g of crude epalrestat dimer, which was sent to liquid chromatography for analysis and detection. The purity of the crude dimer was 78.33%. (2) 6.42 g of crude epalrestat II was added to 15 ml of tetrahydrofuran solution, heated to 40°C, stirred for 1 h and filtered while hot. The filtrate was cooled to 20°C for crystallization. After 2 h, 0.25 g of yellow epalrestat dimer was obtained by suction filtration. The target compound was analyzed by liquid chromatography, and the purity was 88.73%.
[0028] Effect Example 1 HPLC Determination of Epalrestat Dimer in Epalrestat API Weigh 5 mg of epalrestat API accurately, place it in a 100 ml volumetric flask, dilute to the mark with mobile phase A, shake well, and place in the dark for 1 hour as the test solution. Take an appropriate amount of epalrestat dimer reference substance, accurately weigh it, add mobile phase A to a 50 ml volumetric flask, dissolve it, and quantitatively dilute it to make a solution containing about 50 µg of epalrestat dimer per 1 ml as the impurity stock solution; accurately weigh an appropriate amount of epalrestat reference substance, add the impurity stock solution, and dilute it with mobile phase A to make a solution containing about 0.5 mg of epalrestat and 1 µg of epalrestat dimer per 1 ml as the system suitability solution. Determine according to the high performance liquid chromatography method (General Rules 0512 of Part IV of the 2020 edition of the Chinese Pharmacopoeia). Octadecylsilane bonded silica gel was used as filler (Waters Symmetry C18 250mm×4.6mm, 5cm or chromatographic column of equivalent performance); phosphate buffer (0.06mol / L potassium dihydrogen phosphate solution adjusted to pH 7.6 with 0.06mol / L disodium hydrogen phosphate solution)-acetonitrile (3:1) was used as mobile phase A; phosphate buffer (0.06mol / L potassium dihydrogen phosphate solution adjusted to pH 7.6 with 0.06mol / L disodium hydrogen phosphate solution)-acetonitrile (2:8) was used as mobile phase B; gradient elution was performed according to Table 1; the flow rate was 1.0ml per minute; the detection wavelength was 280nm; and the column temperature was 25℃.
[0029] Table 1 Take 20μl of the system suitability solution and inject it into the liquid chromatograph, record the chromatogram, epalrestat dimer, epalrestat peak once, the separation between the peaks should meet the requirements, the theoretical plate number calculated based on the epalrestat peak should not be less than 5000. Accurately measure 20μl of the test solution, inject it into the liquid chromatograph, record the chromatogram, see Figure 1 .
[0030] Content calculation: The mass percentage of epalrestat dimer in the epalrestat bulk drug substance test sample was calculated according to the area normalization method. The collective experimental results are shown in Table 2: Table 2 Content of epalrestat dimer in epalrestat bulk drug It can be seen from the results of the above-mentioned Effect Example 3 that the epalrestat dimer provided by the present invention can be used as an impurity reference substance for the epalrestat bulk drug and can be used for its quality control, which plays a very important role in the quality monitoring of epalrestat or its drug combination.
[0031] The various technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the various technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these features, they should be considered to be within the scope of this specification.
[0032] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the scope of the present invention shall be based on the attached claims, and the description can be used to interpret the content of the claims.
Claims
1. A method for preparing an epalrestat dimer, characterized in that: The following steps are involved: (1) crushing epalrestat and reacting it under light conditions, adding a first solvent to the reaction substrate, stirring and dissolving it, and then filtering it. After concentrating the filtrate, crystallizing it, filtering it with suction, and vacuum drying the filter cake to obtain a crude product of epalrestat dimer; (2) Adding the crude epalrestat dimer to the second solvent, heating, stirring, filtering while hot, crystallizing the filtrate, filtering and vacuum drying to obtain the epalrestat dimer.
2. The preparation method according to claim 1, characterized in that: In step (1), the particle size after pulverization is 1-1000 μm, preferably 100-200 μm.
3. The preparation method according to claim 1, characterized in that: In step (1), the reaction is carried out at a light intensity of 100 Lx or more, preferably 5000-50000 Lx.
4. The preparation method according to claim 1 or 3, characterized in that: In step (1), the reaction time is 24h~336h.
5. The preparation method according to claim 4, characterized in that: The total illumination received by the reaction substrate is not less than 1.2*10 6 Lx, preferably (3~5)*10 6 Lx*h.
6. The preparation method according to any one of claims 1 to 5, characterized in that: In step (1), the mass ratio of the reaction substrate to the first solvent is 1:1-20; preferably, the mass ratio is 1:3; and the crystallization time is 1-5 hours.
7. The preparation method according to any one of claims 1 to 6, characterized in that: The first solvent is one or a mixture of several solvents selected from methanol, ethanol, dichloromethane, chloroform, tetrahydrofuran and isopropanol; preferably, the first solvent is ethanol or methanol.
8. The preparation method according to claim 1, characterized in that: The second solvent is one or a mixture of several solvents including DMF, tetrahydrofuran, methanol, ethanol, acetone, dichloromethane and chloroform; preferably, the second solvent is methanol or ethanol.
9. The preparation method according to claim 8, characterized in that: In step (2), the mass ratio of the crude epalrestat dimer to the second solvent is 1:1-20; preferably, the mass ratio is 1:1.5; the stirring time is 1-5 hours; the crystallization temperature is 0°C-50°C; preferably, the crystallization temperature is 20-30°C.
10. Use of the epalrestat dimer prepared by the preparation method according to any one of claims 1 to 9 as an impurity reference substance in the quality control of epalrestat bulk drug.