CN115266965A - High performance liquid chromatography method for detecting specific impurities of oseltamivir phosphate key intermediate - Google Patents

High performance liquid chromatography method for detecting specific impurities of oseltamivir phosphate key intermediate Download PDF

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CN115266965A
CN115266965A CN202210774104.2A CN202210774104A CN115266965A CN 115266965 A CN115266965 A CN 115266965A CN 202210774104 A CN202210774104 A CN 202210774104A CN 115266965 A CN115266965 A CN 115266965A
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祁芳芳
王鲜
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Suzhou Boyan Pharmaceutical Technology Co ltd
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Abstract

The invention relates to a high performance liquid chromatography method for detecting specific impurities of an oseltamivir phosphate key intermediate, wherein oseltamivir phosphate is a specific drug for treating influenza, and (3R, 4R, 5S) -4, 5-epoxy-3- (1-ethyl propoxy) -1-cyclohexene-1-ethyl formate is a key intermediate in the oseltamivir phosphate synthesis process. The invention relates to a high performance liquid chromatography method for detecting specific impurities of an oseltamivir phosphate key intermediate. The method adopts an octadecyl bonded silica gel column, can simultaneously separate and detect (3R, 4R, 5S) -4, 5-epoxy-3- (1-ethyl propoxy) -1-cyclohexene-1-ethyl formate related process impurities and isomers, has the advantages of high accuracy, good reproducibility, simple and convenient operation and the like, and has very important significance for improving the quality control of the medicine.

Description

High performance liquid chromatography method for detecting specific impurities of oseltamivir phosphate key intermediate
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, in particular to a high performance liquid chromatography method for detecting specific impurities of an oseltamivir phosphate key intermediate.
Background
Oseltamivir phosphate (Oseltamivir phosphate) is a neuraminidase specific inhibitor jointly developed by Gilidaceae (Gilead Sciences) and Switzerland pharmacy, and acts on influenza virus neuraminidase to inhibit mature influenza virus from separating from host cells, so that the propagation of the influenza virus in the body is inhibited, and the effect of preventing and treating influenza is achieved. The (3R, 4R, 5S) -4, 5-epoxy-3- (1-ethyl propoxy) -1-cyclohexene-1-ethyl formate is a key raw material and an intermediate for synthesizing oseltamivir, and the structural formula is as follows:
Figure BDA0003725855750000011
multiple chiral centers and impurities of oseltamivir are all introduced by ethyl (3R, 4R, 5S) -4, 5-epoxy-3- (1-ethyl propoxy) -1-cyclohexene-1-carboxylate, and the control of the impurities and isomers of the ethyl (3R, 4R, 5S) -4, 5-epoxy-3- (1-ethyl propoxy) -1-cyclohexene-1-carboxylate is of great significance for controlling the quality of oseltamivir phosphate.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a simple and accurate method capable of effectively controlling (3R, 4R, 5S) -4, 5-epoxy-3- (1-ethyl propoxy) -1-cyclohexene related impurities, which comprises the following steps:
the technical scheme is as follows: the detection method comprises the following steps:
(1) Preparing a test solution: a test sample solution with a concentration of 0.8 to 1.2mg/ml was prepared by dissolving and diluting a suitable amount of ethyl (3R, 4R, 5S) -4, 5-epoxy-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylate with a solvent [ acetonitrile-water (20.
(2) Preparation of self-control solutions: the test solution is diluted with solvent to obtain the self-control solution with the concentration of 0.8-1.2 mug/ml.
(3) The stationary phase of the chromatographic column is octadecyl bonded silica gel; adopting an ultraviolet detector; the mobile phase A is phosphoric acid aqueous solution, and the mobile phase B is acetonitrile; the elution mode is gradient elution.
(4) Detecting by high performance liquid chromatography, and gradient eluting.
(5) The contents of each single impurity and the total impurity are calculated according to the main component self-comparison method.
Preferably, in the step (3), the concentration of the phosphoric acid solution is 0.05-0.15%.
Preferably, in step (3), the specification of the chromatographic column: the inner diameter is 3.0-5.0 mm, the length is 100-250 mm, and the grain diameter of the filler is 3-5 mu m. Further, the specification of the chromatographic column: the inner diameter was 4.6mm, the length was 250mm, and the filler particle size was 5 μm.
Further, the chromatographic column was Shimadzu GL Sciences C18 Superb.
Preferably, the column temperature of the chromatographic column is 20 to 50 ℃, and further, the column temperature of the chromatographic column is 35 ℃.
Preferably, in the step (3), the concentration of the phosphoric acid solution is 0.05% to 0.15%, and more preferably 0.1%.
Preferably, in the step (4), the amount of the sample is 5 to 100. Mu.l, and more preferably 10. Mu.l. Further, the flow rate is 0.9 to 1.1ml/min, preferably 1.0ml/min.
Preferably, the wavelength of the ultraviolet detector is 202nm, 207nm or 212nm, preferably 207nm.
Further, the concentration ratio of the gradient elution mobile phase is shown in table 1:
table 1 concentration ratios of gradient elution mobile phases:
Figure BDA0003725855750000021
has the advantages that: at present, reports of a detection method of related impurities of (3R, 4R, 5S) -4, 5-epoxy-3- (1-ethyl propoxy) -1-cyclohexene-1-ethyl formate are not reported temporarily, and the invention provides an accurate and simple detection method, which has the remarkable advantages that: the method has the advantages of capability of separating 12 potential impurities in the sample, simple and convenient operation, accurate and stable result, high sensitivity and capability of more accurately controlling the impurity level of the oseltamivir intermediate, thereby improving the controllability of the medicine quality.
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FIG. 1 is an HPLC chromatogram of a blank solvent of the present invention;
FIG. 2 is an HPLC chromatogram of a mixed solution of a sample and various impurities according to the present invention;
FIG. 3 is an HPLC chromatogram of a test solution of the present invention;
FIG. 4 is an HPLC chromatogram of a self-control solution of the present invention.
Detailed Description
The technical scheme of the invention is further explained by combining the attached drawings.
1. Instruments and reagents.
Agilent 1260Infinity type II high performance liquid chromatograph, setolis BSA224S-CW type electronic balance.
Phosphoric acid (chromatographic grade), acetonitrile (chromatographic grade), purified water.
Example 1: and (4) performing specificity tests.
Solvent: acetonitrile-water (20.
Impurity stock solution: weighing about 5mg of an impurity 004S1S1 reference substance, an impurity 004S1M2 reference substance, an impurity 004S1M3 reference substance, an impurity 004S1M4-Z1 reference substance, an impurity 004S1M4-Z2 reference substance, an impurity 004S1-Z1 reference substance, an impurity 004S1-Z2 reference substance, an impurity 004S1-Z6 reference substance, an impurity 004S1-Z8 reference substance and an impurity 004S1-Z9 reference substance respectively, placing the reference substances into different 50ml measuring bottles respectively, adding a solvent to dissolve and dilute the reference substances to the scales, and shaking up (the concentrations are all 0.1 mg/ml).
Impurity localization solution: transferring 1ml of each impurity stock solution, placing into different 10ml measuring flasks, dissolving with solvent, diluting to scale, and shaking (concentration is 0.01 mg/ml).
Test solution: about 20mg of (3R, 4R, 5S) -4, 5-epoxy-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid ethyl ester sample is weighed, precisely weighed, placed in a 20ml measuring flask, dissolved and diluted to the scale by adding a solvent, and shaken up (the concentration is 1 mg/ml).
Self-control solution: precisely measuring 1ml of test solution, placing the test solution in a 100ml measuring flask, adding a solvent to dilute the test solution to a scale, and shaking up; precisely measuring 1ml of the above solution, placing in a 10ml measuring flask, adding solvent to dilute to the scale, and shaking up (concentration is 1 μ g/ml).
Mixing the solution: about 20mg of (3R, 4R, 5S) -4, 5-epoxy-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid ethyl ester sample is weighed and precisely weighed, placed in a 20ml measuring flask, respectively added with 0.2ml of each impurity preparation solution, dissolved by a solvent and diluted to the scale (the concentration of the sample is 1mg/ml, and the concentration of each impurity is 1 mug/ml).
TABLE 2 specificity test
Figure BDA0003725855750000031
Figure BDA0003725855750000041
Precisely measuring blank solution, sample solution, self-contrast solution, mixed solution and impurity locating solutions respectively in an amount of 10 μ l according to the above chromatographic conditions, injecting into a liquid chromatograph, and recording chromatogram.
The test results are shown in Table 3 and FIGS. 1 to 4.
TABLE 3 results of the specificity test
Name of impurity Positioning solution RT (min) Mixed solution RT (min) RRT Degree of separation
004S1S1 3.486 3.498 0.09 /
004S1M1 14.079 14.147 0.38 69.9
004S1-Z1 18.741 18.817 0.50 26.3
004S1M4-Z2 21.006 21.058 0.56 13.2
004S1-Z8 28.147 28.226 0.75 39.8
004S1-Z9 30.992 31.068 0.83 5.1
004S1M2 31.769 31.815 0.85 3.6
004S1-Z2 34.533 34.601 0.92 13.3
004S1M4-Z1 35.192 35.200 0.94 2.9
004S1M4 36.082 36.085 0.96 4.4
Main peak 37.514 37.515 1.00 6.9
004S1M3 38.137 38.170 1.02 3.1
004S1-Z6 38.633 38.701 1.03 2.5
As can be seen from Table 3 and FIGS. 1 to 4, the blank solvent has no interference to the detection of the impurities in the test sample; the separation degrees of the impurities and the main components are all larger than 1.5, which indicates that the specificity of the detection method meets the requirement.
Example 2: sensitivity test
Impurity quantitative limiting solution: precisely measuring 1ml of each positioning solution of 004S1S1, 004S1M2, 004S1M4-Z2, 004S1-Z1, 004S1-Z2, 004S1-Z8 and 004S1-Z9, 2ml of each positioning solution of 004S1M3, 004S1M4 and 004S1M4-Z1 and 3ml of each positioning solution of 004S1-Z6 under the term of 'special property', placing the positioning solutions in the same 100ml measuring flask, diluting the positioning solutions to scales by using a solvent, and shaking up. Impurity detection limiting solution: precisely measuring 5ml of the quantitative limiting solution, adding the quantitative limiting solution into 10ml of solvent, and shaking up.
Respectively and precisely measuring 10 μ l of the solution, injecting into a liquid chromatograph, continuously injecting the quantitative limiting solution into a sample 6 needles, injecting the detection limiting solution into a sample one needle, and recording the chromatogram, wherein the results are shown in tables 4 and 5.
TABLE 4 quantitative limit results
Figure BDA0003725855750000051
TABLE 5 detection Limit results
Name (R) Peak area S/N ratio
004S1S1 1.48 7
004S1M1 1.18 4
004S1-Z1 1.32 5
004S1M4-Z2 0.92 3
004S1-Z8 1.13 3
004S1-Z9 1.18 3
004S1M2 1.04 3
004S1-Z2 1.08 3
004S1M4-Z1 1.20 4
004S1M4 1.32 4
004S1 1.22 3
004S1M3 1.63 5
004S1-Z6 1.75 4
Example 3: linear experiment linear solution: the stock solutions of the main component and each impurity control were measured in different volumes under the "specificity" term to prepare linear solutions of LOQ, 50% (about 0.5. Mu.g/ml for each component), 100% (about 1.0. Mu.g/ml for each component), 150% (about 1.5. Mu.g/ml for each component), and 200% (about 2.0. Mu.g/ml for each component) at the limit concentration level.
Precisely measuring 10 μ l of each linear solution, injecting into a liquid chromatograph, and recording chromatogram, wherein the test result is shown in 6.
TABLE 6 Linear results
Components Linear equation of equations Coefficient of correlation r
004S1 y＝21.9068x+0.2102 1.0000
004S1S1 y＝28.5271x+0.0549 1.0000
004S1M1 y＝24.3225x-0.0171 1.0000
004S1M2 y＝19.3480x-0.0413 1.0000
004S1M3 y＝16.2965x+0.1149 0.9999
004S1M4 y＝15.1751x-0.1960 0.9999
004S1M4-Z1 y＝13.2609x-0.0021 1.0000
004S1M4-Z2 y＝19.2929x-0.0425 1.0000
004S1-Z1 y＝30.6280x-0.3432 0.9999
004S1-Z2 y＝22.4565x+0.0213 1.0000
004S1-Z6 y＝11.5202x+0.0985 0.9999
004S1-Z8 y＝24.1715x-0.0744 1.0000
004S1-Z9 y＝24.2269x+0.2396 0.9999
As is clear from Table 6, the linearity of each impurity was good in the range of LOQ to 150% of the limiting concentration, indicating that the analytical method was good.
Example 4: repeatability test
Adding a standard test solution: taking about 20mg of a sample, placing the sample in a 20ml measuring flask, precisely adding 0.2ml of each impurity stock solution, adding a solvent to dissolve and dilute the sample to a scale, and shaking up.
Self control solution (1. Mu.g/ml): precisely measuring 1ml of a sample solution added with a label, placing the sample solution in a 100ml measuring flask, adding a solvent to dilute the sample solution to a scale, and shaking up; precisely measuring 1ml of the solution, placing the solution in a 10ml measuring flask, adding a solvent to dilute the solution to the scale, and shaking up.
Preparing 6 parts of standard sample solution and self-contrast solution in parallel, injecting the solution into a chromatograph, recording the chromatogram, and calculating the content of each impurity and the total impurity, wherein the result is shown in table 7.
TABLE 7 repeatability test results
Labeled test article 1 2 3 4 5 6
004S1S1(％) 0.10 0.10 0.11 0.10 0.10 0.11
004S1M1(％) 0.11 0.12 0.12 0.12 0.12 0.12
004S1-Z1(％) 0.10 0.10 0.10 0.10 0.10 0.01
004S1M4-Z2(％) 0.10 0.10 0.10 0.10 0.10 0.10
004S1-Z8(％) 0.11 0.11 0.12 0.11 0.11 0.12
RRT0.800(％) 0.06 0.06 0.06 0.06 0.06 0.06
004S1-Z9(％) 0.11 0.11 0.12 0.11 0.11 0.12
004S1M2(％) 0.10 0.11 0.11 0.11 0.11 0.11
004S1-Z2(％) 0.10 0.10 0.10 0.10 0.10 0.10
004S1M4-Z1(％) 0.10 0.10 0.10 0.10 0.10 0.10
004S1M4(％) 0.10 0.10 0.10 0.10 0.10 0.10
004S1M3(％) 0.10 0.10 0.10 0.10 0.10 0.10
004S1-Z6(％) 0.09 0.09 0.10 0.09 0.09 0.10
As can be seen from Table 7, the fluctuation of the impurity content of each of the 6 solutions prepared in parallel was within. + -. 0.01%, indicating that the reproducibility of the method was good.

Claims (6)

1. A high performance liquid chromatography method for detecting specific impurities of an oseltamivir phosphate key intermediate is characterized by comprising the following steps: the method comprises the following steps;
(1) Preparing a test solution; taking a proper amount of (3R, 4R, 5S) -4, 5-epoxy-3- (1-ethyl propoxy) -1-cyclohexene-1-ethyl formate, adding 20% acetonitrile for dissolving and diluting to obtain a test solution with the concentration of 0.8-1.2 mg/ml;
(2) Preparation of self-control solutions: taking a test solution, and diluting the test solution by using 20% acetonitrile to obtain a self control solution with the concentration of 0.8-1.2 mu g/ml;
(3) The chromatographic column stationary phase is octadecyl bonded silica gel, the mobile phase A is phosphoric acid water solution, the mobile phase B is acetonitrile, and the detector is an ultraviolet detector;
(4) Sampling a test solution and a self-contrast solution, carrying out gradient elution, and calculating the content of impurities according to a main component self-contrast method; the specific impurity structure is as follows:
Figure FDA0003725855740000011
2. the detection method according to claim 1, wherein the concentration of the phosphoric acid solution in the mobile phase A in the step (4) is 0.05-0.15%.
3. The detection method according to claim 1, wherein the column temperature of the chromatography in the step (4) is 30 to 40 ℃.
4. The detection method according to claim 1, wherein the ultraviolet detector wavelength of step (4) is one of 202nm, 207nm or 212 nm.
5. The detection method according to claim 1, wherein the sample is introduced in the step (5) in an amount of 5 to 50 μ l.
6. The detection method according to claim 1, wherein the concentration ratio of the gradient elution mobile phase in the step (5) is as follows:
Figure FDA0003725855740000021
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117214369A (en) * 2023-11-09 2023-12-12 山东百诺医药股份有限公司 Liquid chromatography method for detecting related substances of oseltamium phosphate Wei Ganhun suspension
CN117214369B (en) * 2023-11-09 2024-02-02 山东百诺医药股份有限公司 Liquid chromatography method for detecting related substances of oseltamium phosphate Wei Ganhun suspension

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