CN109580821B - Method for detecting impurity succinic acid in S-benzylsuccinic acid - Google Patents
Method for detecting impurity succinic acid in S-benzylsuccinic acid Download PDFInfo
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- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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Abstract
The invention discloses a method for detecting impurity succinic acid in S-benzylsuccinic acid. According to the method, Agilent SB-CN is used as a chromatographic column, an HPLC detection method is adopted to perform qualitative and quantitative detection on succinic acid in S-benzylsuccinic acid, and methodological verification is performed. The invention establishes a qualitative and quantitative method for the impurity succinic acid in the S-benzylsuccinic acid for the first time, and is convenient to control the quality of the S-benzylsuccinic acid, thereby improving the medication safety of the active ingredient taking the S-benzylsuccinic acid as an intermediate.
Description
Technical Field
The invention relates to a method for detecting impurity-succinic acid in S-benzylsuccinic acid, belonging to the technical field of medicines.
Background
S-Benzylsuccinic acid ((S) -2-Benzylsuccinic acid) is an important medical intermediate and is mainly used for producing mitiglinide calcium. Mitiglinide calcium is an ATP-dependent potassium ion channel blocker developed by Kissei PHARMACEUTICAL, a crude drug product of Japanese orange, which is first marketed in Japan in 2004-4, marketed in Korea in 2006, and a primary product of the republic of 2010, which is approved to be marketed in China, and is currently produced by a plurality of drug manufacturers in China. The mitiglinide calcium is clinically used for treating type II diabetes, has an action mechanism similar to sulfonylurea, but has higher effect taking speed and short half-life, is beneficial to reducing the postprandial blood sugar of a diabetic patient, can avoid the hypoglycemia caused by continuous blood sugar reduction, has obvious advantages compared with other traditional hypoglycemic drugs, can be used as a first-line diabetes treatment drug, and therefore has wide market prospect as an important intermediate of S-benzylsuccinic acid.
The succinic acid is a reaction material of the S-benzylsuccinic acid, so a detection method of the succinic acid in the S-benzylsuccinic acid is formulated to control the quality of the S-benzylsuccinic acid. However, no report about the content detection method of succinic acid in S-benzylsuccinic acid exists at present after retrieval.
Succinic acid, english name: succinic acid, molecular formula: c4H6O4(ii) a Molecular weight: 118.09, the structural formula is shown below:
disclosure of Invention
Aiming at the problems, the invention provides a method for detecting impurity succinic acid in S-benzylsuccinic acid for the first time. The method adopts an HPLC detection method to perform qualitative and quantitative detection on succinic acid in S-benzylsuccinic acid, and performs methodology verification. Experiments prove that the method has the advantages of strong specificity, rapidness, sensitivity, accuracy and the like, and can reliably carry out qualitative and quantitative analysis on the succinic acid serving as the impurity in the S-benzylsuccinic acid.
The technical scheme of the invention is as follows: a method for detecting impurity succinic acid in S-benzylsuccinic acid is characterized in that an S-benzylsuccinic acid sample is dissolved and then is directly injected to perform qualitative and quantitative analysis on succinic acid in S-benzylsuccinic acid by an HPLC detection method.
Wherein, the chromatographic conditions are as follows:
a chromatographic column: agilent SB-CN (4.6X 250mm, 5 μm) or Kromasil 60-5CN (4.6X 150mm, 5 μm), flow rate: 0.8-1.2 ml/min, column temperature: 33-37 ℃, sample injection amount: 40 μ l, detection wavelength: 212nm, mobile phase A: methanol-water (containing 0.1% phosphoric acid) ═ 3:97 to 7:93, mobile phase B: methanol-water (containing 0.1% phosphoric acid) ═ 43: 57-47: 53, solvent: methanol-water ratio is 3:97 to 7: 93.
Preferred chromatographic conditions are as follows: a chromatographic column: agilent SB-CN (4.6X 250mm, 5 μm), flow rate: 1.0ml/min, column temperature: 35 ℃, sample introduction: 40 μ l, detection wavelength: 212nm, mobile phase A: methanol-water (containing 0.1% phosphoric acid) 5:95, mobile phase B: methanol-water (containing 0.1% phosphoric acid) 45:55, solvent: methanol-water ═ 5: 95.
The gradient elution conditions are shown in table 1.
TABLE 1 gradient elution Table
Furthermore, the method firstly establishes a standard curve of a reference substance (succinic acid), and adopts an external standard method to measure the impurity succinic acid in the S-benzylsuccinic acid.
Further, under the detection condition of the invention, the succinic acid peak RT is 3.8 +/-0.1 min; s-benzylsuccinic acid peak RT was 15.48 ± 0.1min, and the standard curve established was y-1317586.7 x-0.5, r-0.9999.
In a preferred embodiment of the present invention, the detection method is specifically as follows:
1) dissolving S-benzylsuccinic acid by using a solvent, fixing the volume, and preparing 1ml of solution containing 3mg of S-benzylsuccinic acid as a test solution;
2) dissolving succinic acid with solvent, and diluting to constant volume to obtain 1ml solution containing 0.003mg succinic acid as reference solution;
3) carrying out HPLC detection on the test solution prepared in the step 1) and the reference solution prepared in the step 2), and recording a chromatogram;
3) according to an external standard method, calculating the content of impurity succinic acid in S-benzylsuccinic acid by peak area.
The invention has the advantages that:
1. succinic acid is the reaction material for S-benzylsuccinic acid. The invention establishes a method for detecting impurity succinic acid in S-benzylsuccinic acid for the first time, and is convenient for controlling the quality of S-benzylsuccinic acid, thereby improving the medication safety of the active ingredient taking S-benzylsuccinic acid as an intermediate.
2. Good separation effect
The invention establishes the HPLC method for measuring the content of the succinic acid in the S-benzylsuccinic acid for the first time, and optimizes the method, so that the two components can be well separated. As can be seen from fig. 3: succinic acid peak RT of 3.803 min; the peak RT of the S-benzylsuccinic acid is 15.483min, and the separation effect of the S-benzylsuccinic acid and the S-benzylsuccinic acid is good.
3. The method has strong specificity, and is rapid, sensitive and accurate
Experiments prove that the method has the advantages of strong specificity (specially aiming at succinic acid), rapidness, sensitivity (the detection limit is 9.3ng, the quantitative limit is 37.4ng), accuracy (97.3-101.6%) and the like, and can reliably carry out qualitative and quantitative analysis on the content of the succinic acid in the S-benzylsuccinic acid.
Drawings
FIG. 1 is a succinic acid solution chromatogram with a succinic acid peak RT of 3.805;
FIG. 2 is a chromatogram of a test solution, with a peak RT of S-benzylsuccinic acid of 15.482 min;
FIG. 3 is a mixed solution chromatogram; succinic acid peak RT of 3.803 min; the S-benzylsuccinic acid peak RT is 15.483 min;
FIG. 4 succinic acid linear curve.
Detailed Description
Example 1
1 instruments and materials
1.1 Instrument: waters Arc 2489 high performance liquid chromatography (Waters, usa);
1.2 reagent: methanol (chromatographic grade), phosphoric acid (chromatographic grade) and water as ultrapure water.
2 methods and results
2.1 chromatographic conditions
A chromatographic column: agilent ZORBAX SB-CN column (4.6X 250mm, 5 μm), column temperature: 35 ℃, sample introduction: 40 mu l of the solution;
mobile phase A: methanol-water (containing 0.1% phosphoric acid) 5:95, mobile phase B: methanol-water (containing 0.1% phosphoric acid) 45:55, solvent: methanol-water 5: 95; flow rate: 1.0ml/min, and the gradient elution conditions are shown in Table 1.
A detector: waters 2489 ultraviolet detector, detection wavelength: 212 nm.
2.2 preparation of the solution
2.21 preparation of the specialty solutions
Accurately weighing 31.15mg of succinic acid reference substance, placing in a 100ml measuring flask, adding a solvent to dissolve, and diluting to scale to obtain a solution a, namely a reference substance solution.
Accurately weighing 30.21mg of diethyl succinate, placing the diethyl succinate in a 100ml measuring flask, diluting the diethyl succinate to a scale with a solvent, accurately weighing 1.0ml of diethyl succinate, placing the diethyl succinate in a 10ml measuring flask, and diluting the diethyl succinate to the scale with the solvent to obtain a solution b.
Precisely weighing 30.65mg of benzaldehyde, placing the benzaldehyde in a 100ml measuring flask, diluting the benzaldehyde to a scale with a solvent, precisely weighing 1.0ml of benzaldehyde, placing the benzaldehyde in a 10ml measuring flask, and diluting the benzaldehyde to the scale with the solvent to obtain a solution c.
Weighing 3.10mg of benzoic acid, placing the benzoic acid in a 100ml measuring flask, adding a solvent to dissolve the benzoic acid and diluting the benzoic acid to a scale mark to obtain a solution d.
Weighing 3.06mg of benzylidene succinic acid, placing the benzylidene succinic acid in a 100ml measuring flask, adding a solvent, ultrasonically dissolving, and diluting to a scale mark to obtain a solution e.
Accurately weighing 30.36mg of alpha-phenylethylamine, placing the alpha-phenylethylamine in a 100ml measuring flask, diluting the alpha-phenylethylamine to a scale with a solvent, accurately weighing 1.0ml of alpha-phenylethylamine in a 10ml measuring flask, and diluting the alpha-phenylethylamine to the scale with the solvent to obtain a solution f.
Weighing 3.12mg of (S) -benzylsuccinic acid (R) -alpha-phenethylamine salt, placing the weighed solution in a 100ml measuring flask, adding a solvent to dissolve the solution and diluting the solution to a scale mark to obtain a solution g.
Precisely measuring 1.0ml of the solution a, placing the solution a into a 100ml measuring flask, and diluting the solution a to the scale with a solvent to obtain a control solution with the concentration of 0.003115 mg/ml.
Accurately weighing 300.23mg of S-benzylsuccinic acid, placing in a 100ml measuring flask, adding solvent, ultrasonically dissolving, and diluting to scale to obtain sample solution.
Precisely weighing 30.26mg of S-benzylsuccinic acid, placing the S-benzylsuccinic acid into a 10ml measuring flask, respectively weighing 0.1ml of solution a and 1.0ml of solutions b to f, placing the solutions into the same 10ml measuring flask, adding a solvent to dissolve and dilute the solutions to a scale, and obtaining a mixed solution.
2.22 preparation of Linear solution
Precisely weighing 31.15mg of succinic acid reference substance, placing the reference substance in a 100ml measuring flask, dissolving the reference substance by using a solvent and diluting the reference substance to a scale, precisely weighing 1.0ml of succinic acid, placing the reference substance in the 100ml measuring flask, and diluting the reference substance by using the solvent to the scale to obtain a reference substance solution with the concentration of 0.003115 mg/ml. Samples of control solutions 15. mu.l, 20. mu.l, 30. mu.l, 40. mu.l and 50. mu.l were injected to give linear solutions with concentrations of 0.001168mg/ml, 0.001558mg/ml, 0.002336mg/ml, 0.003115mg/ml and 0.003894mg/ml, respectively.
2.23 preparation of solutions for spiked test samples
Weighing six S-benzylsuccinic acid samples (300 mg (accurate to 0.01 mg)) in six parts, respectively placing the six parts in a 100ml measuring flask, adding solution a1.0ml, adding a solvent for dissolving, diluting to a scale, using the scale as a labeling test sample solution, and calculating the repeatability of the method. The same sample was measured on different days and the intermediate precision of the method was calculated.
Preparing standard sample solutions added with succinic acid reference substance solutions with different concentrations, and calculating the accuracy of the method.
2.24 detection
Precisely measuring 40 μ l of each of 2.21 reference solution, sample solution and mixed solution, directly (respectively) injecting sample, performing HPLC detection according to 2.1 chromatography conditions, and recording chromatogram. The chromatograms of the three solutions are shown in FIGS. 1-3, respectively. As can be seen from fig. 3: succinic acid peak RT of 3.803 min; the RT of the S-benzylsuccinic acid peak is 15.483min, the chromatographic peaks of the S-benzylsuccinic acid peak and the S-benzylsuccinic acid peak can be well separated, and other impurities do not interfere the determination of succinic acid. And detecting the linear solution, drawing a linear standard curve by taking the concentration of the succinic acid as an abscissa and the peak area as an ordinate, and calculating the content of impurity succinic acid in the S-benzylsuccinic acid by the peak area through an external standard method.
3 validation of analytical methods
3.1 specificity
Taking a reference substance solution for continuous sample injection for six times to carry out HPLC detection, wherein the obtained succinic acid peak area RSD is 0.93%, and the retention time RSD is 0.01%.
The separation degree of the succinic acid and an adjacent peak in the mixed solution is 4.88, other impurities and samples do not interfere with the determination of the succinic acid, and the specificity meets the requirement.
3.2 Linear relationship
And (3) performing HPLC (high performance liquid chromatography) determination on the linear solution, and drawing a standard working curve by taking the concentration of the succinic acid as a horizontal coordinate and the peak area as a vertical coordinate. The linear equation is y-1317586.7 x-0.5 and r-0.9999 (see fig. 4).
3.3 repeatability and intermediate precision
Six solutions prepared from the same S-benzylsuccinic acid sample were used for the repeatability tests, and the results are shown in Table 2.
TABLE 2 repeatability results
Six solutions prepared from the same S-benzylsuccinic acid sample in repeated tests on different dates were used for repeated tests, and the results are shown in Table 3.
TABLE 3 intermediate precision results
3.4 accuracy
Preparing a sample solution to be tested by adding succinic acid reference substance solutions with different concentrations, and calculating the accuracy of the method. The results are shown in Table 4.
TABLE 4 accuracy results
3.5 durability: taking a reference substance solution under the specificity term, repeatedly injecting samples within 32 hours, wherein the relative standard deviation of the peak area of the reference substance is 1.04%; and (3) repeatedly injecting an S-benzylsuccinic acid sample solution under the specificity term within 8 hours, wherein succinic acid in the sample solution is not detected.
3.6 detection limit: the detection Limit (LOD) of the method is the sample injection concentration of the succinic acid when the signal-to-noise ratio S/N is more than 3 times, and the sample injection concentration is 9.3ng by calculation, and the percentage concentration is 0.0075%.
3.7 quantitation limit: the quantitative Limit (LOQ) of the method is that the sample injection concentration of the succinic acid when the signal-to-noise ratio S/N is more than 10 times is calculated to be 37.4ng, and the percentage concentration is 0.03 percent.
Discussion 4
An HPLC detection method for measuring the content of succinic acid in S-benzylsuccinic acid is established and optimized, so that the two components can be well separated (as shown in figure 3). Experiments prove that the method has the advantages of strong specificity, rapidness, sensitivity, accuracy and the like, and can reliably carry out qualitative and quantitative analysis on the content of the succinic acid in the S-benzylsuccinic acid.
The succinic acid has no genotoxicity warning structure, and specific toxicity data are not found, and the control limit is defined to be less than or equal to 0.10 percent according to the requirement of unknown impurities in the ICHQ 3A.
Example 2: detection of actual samples
1) Dissolving S-benzylsuccinic acid by using a solvent, fixing the volume, and preparing 1ml of solution containing 3mg of S-benzylsuccinic acid as a test solution;
2) dissolving succinic acid with solvent, and diluting to constant volume to obtain 1ml solution containing 0.003mg succinic acid as reference solution;
3) directly (respectively) sampling 40 μ l of each of the sample solution prepared in step 1) and the reference solution prepared in step 2), performing HPLC detection by using the same instrument and reagent as in example 1 under the chromatographic conditions shown in 2.1, and recording the chromatogram;
3) according to an external standard method, calculating the content of impurity succinic acid in S-benzylsuccinic acid by peak area.
Three batches of samples were tested using the method described above, and the results are shown in table 5:
TABLE 5 succinic acid content in three batches of product
| Sample batch number | 1 | 2 | 3 |
| Content of succinic acid% | Not detected out | Not detected out | Not detected out |
。
Claims (7)
1. A detection method of impurity succinic acid in S-benzylsuccinic acid is characterized in that an S-benzylsuccinic acid sample is dissolved and then is directly injected to perform qualitative and quantitative analysis on succinic acid in S-benzylsuccinic acid by an HPLC detection method; the HPLC chromatographic conditions of the HPLC detection method are as follows:
a chromatographic column: agilent SB-CN chromatographic column or Kromasil 60-5CN chromatographic column; flow rate: 0.8-1.2 ml/min; column temperature: 33-37 ℃; detection wavelength: 212 nm; mobile phase A: methanol-water with 0.1% phosphoric acid 3:97 to 7: 93; mobile phase B: methanol-water with 0.1% phosphoric acid-43: 57-47: 53;
the gradient elution conditions were as follows:
2. the method for detecting the impurity succinic acid in S-benzylsuccinic acid as claimed in claim 1, wherein the chromatographic conditions are as follows:
a chromatographic column: agilent SB-CN chromatographic column, 4.6X 250mm, 5 μm; flow rate: 1.0 ml/min; column temperature: 35 ℃; sample introduction amount: 40 mu l of the solution; detection wavelength: 212 nm; mobile phase A: methanol-water with 0.1% phosphoric acid 5:95, mobile phase B: methanol-water with 0.1% phosphoric acid-45: 55.
3. The method for detecting the impurity succinic acid in S-benzylsuccinic acid as claimed in claim 1 or 2, wherein the solvents adopted for dissolving S-benzylsuccinic acid and succinic acid are: the volume ratio of methanol to water is 5: 95.
4. The method for detecting the impurity succinic acid in S-benzylsuccinic acid as claimed in claim 3, wherein a standard curve of succinic acid is established, and the content of the impurity succinic acid in S-benzylsuccinic acid is determined by an external standard method.
5. The method as claimed in claim 4, wherein the established standard curve is y-1317586.7 x-0.5, and r-0.9999.
6. The method for detecting the impurity succinic acid in S-benzylsuccinic acid as claimed in claim 3, wherein in the HPLC detection method, the succinic acid peak RT is 3.8 ± 0.1 min; s-benzylsuccinic acid peak RT was 15.48. + -. 0.1 min.
7. The method for detecting impurity succinic acid in S-benzylsuccinic acid as claimed in claim 4, wherein the detection method comprises the following steps:
1) dissolving S-benzylsuccinic acid by using a solvent, fixing the volume, and preparing 1ml of solution containing 3mg of S-benzylsuccinic acid as a test solution;
2) dissolving succinic acid with solvent, and diluting to constant volume to obtain 1ml solution containing 0.003mg succinic acid as reference solution;
3) carrying out HPLC detection on the test solution prepared in the step 1) and the reference solution prepared in the step 2), and recording a chromatogram;
4) according to an external standard method, calculating the content of impurity succinic acid in S-benzylsuccinic acid by peak area.
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| CN110568100B (en) * | 2019-09-12 | 2022-05-31 | 江西金水宝制药有限公司 | Mitiglinide calcium R-isomer detection method |
| CN110850003B (en) * | 2019-12-16 | 2023-03-24 | 湖南九典制药股份有限公司 | Method for separating impurity succinic acid from ferrous succinate |
| CN112557566A (en) * | 2020-12-12 | 2021-03-26 | 江西济民可信药业有限公司 | Method for detecting corresponding isomer of mitiglinide calcium intermediate S-benzylsuccinic acid |
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