CN117871705A - Analysis method of estradiol valerate tablet related substances - Google Patents
Analysis method of estradiol valerate tablet related substances Download PDFInfo
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- CN117871705A CN117871705A CN202311731871.6A CN202311731871A CN117871705A CN 117871705 A CN117871705 A CN 117871705A CN 202311731871 A CN202311731871 A CN 202311731871A CN 117871705 A CN117871705 A CN 117871705A
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- 229960004766 estradiol valerate Drugs 0.000 title claims abstract description 51
- RSEPBGGWRJCQGY-RBRWEJTLSA-N Estradiol valerate Chemical compound C1CC2=CC(O)=CC=C2[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCC)[C@@]1(C)CC2 RSEPBGGWRJCQGY-RBRWEJTLSA-N 0.000 title claims abstract description 50
- 238000004458 analytical method Methods 0.000 title claims abstract description 28
- 239000000126 substance Substances 0.000 title claims abstract description 21
- 239000012535 impurity Substances 0.000 claims abstract description 56
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000012488 sample solution Substances 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 239000012046 mixed solvent Substances 0.000 claims abstract description 13
- 238000010828 elution Methods 0.000 claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000741 silica gel Substances 0.000 claims abstract description 4
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 4
- 239000000945 filler Substances 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- 238000001514 detection method Methods 0.000 claims description 13
- 239000000523 sample Substances 0.000 claims description 12
- 238000002347 injection Methods 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 6
- 150000002825 nitriles Chemical group 0.000 claims description 4
- 238000010812 external standard method Methods 0.000 claims description 2
- 230000015556 catabolic process Effects 0.000 abstract description 4
- 238000006731 degradation reaction Methods 0.000 abstract description 4
- 230000035945 sensitivity Effects 0.000 abstract description 2
- 125000002560 nitrile group Chemical group 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 26
- 239000003085 diluting agent Substances 0.000 description 19
- 230000000052 comparative effect Effects 0.000 description 11
- 239000013558 reference substance Substances 0.000 description 11
- 239000003814 drug Substances 0.000 description 6
- 238000007865 diluting Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- -1 polytetrafluoroethylene Polymers 0.000 description 4
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 4
- 239000004810 polytetrafluoroethylene Substances 0.000 description 4
- 238000009210 therapy by ultrasound Methods 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000012937 correction Methods 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000004807 localization Effects 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- RQFMPXMLRRPOJH-ORADRBJOSA-N (8r,9s,10r,13s,14s,17r)-13-ethyl-17-ethynyl-17-hydroxy-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-3-one;(8r,9s,13s,14s,17s)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1.O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 RQFMPXMLRRPOJH-ORADRBJOSA-N 0.000 description 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- 206010003439 Artificial menopause Diseases 0.000 description 1
- 206010030247 Oestrogen deficiency Diseases 0.000 description 1
- FQZLTMNDOCEKNR-JVRACWEPSA-N [C@@H]12C(CC(O)[C@@]1(C)CC[C@@H]1C3=C(CC[C@@H]21)C=C(O)C=C3)CCCCC(=O)OC3=CC2=C([C@H]1CC[C@@]4(C(CC[C@H]4[C@@H]1CC2)OC(CCCC)=O)C)C=C3 Chemical compound [C@@H]12C(CC(O)[C@@]1(C)CC[C@@H]1C3=C(CC[C@@H]21)C=C(O)C=C3)CCCCC(=O)OC3=CC2=C([C@H]1CC[C@@]4(C(CC[C@H]4[C@@H]1CC2)OC(CCCC)=O)C)C=C3 FQZLTMNDOCEKNR-JVRACWEPSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000012490 blank solution Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 238000012495 forced degradation study Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000027758 ovulation cycle Effects 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
Abstract
The invention discloses an analysis method of estradiol valerate tablet related substances. The method comprises the following steps: detecting the sample solution by adopting a high performance liquid chromatography; the sample solution contains estradiol valerate and impurities; the impurities comprise one or more of impurities A, G, K, L, C, D and E; the chromatographic column adopted by the high performance liquid chromatography is a column taking phenyl bonded silica gel with the granularity of 3 mu m as a filler; the high performance liquid chromatography adopts a mobile phase A and a mobile phase B; wherein the mobile phase A is a mixed solvent formed by water and an alcohol solvent, and the volume ratio of the water to the alcohol solvent is 50:50-80:20; the mobile phase B is a nitrile solvent; the high performance liquid chromatography adopts gradient elution. The method can effectively separate the process and the degradation impurities of the estradiol valerate tablet, is simple to operate, can effectively detect a plurality of impurities of the estradiol valerate tablet, and has high sensitivity and strong specificity.
Description
Technical Field
The invention relates to the field of medicine analysis and detection, in particular to an analysis method of estradiol valerate tablet related substances.
Background
Estradiol valerate (Estradiol Valerate), chemical name: 1,3,5 (10) -estratriene-3, 17 beta-diol-17-pentanoate, chemical structure:
estradiol valerate is an estrogen that is used in combination with progestins to establish an artificial menstrual cycle for the supplementation of estrogen deficiency primarily associated with natural or artificial menopause.
Since the estradiol valerate tablet possibly remains the starting materials, intermediates, reaction byproducts and the like in the process from the synthesis of the raw materials to the preparation, degradation products can be generated in the storage process. Therefore, an effective analysis method for the relevant substances of the estradiol valerate tablet is established, the determination of the relevant substances of the estradiol valerate tablet is rapidly and accurately realized, and the method has important practical significance in the aspects of synthesis and quality control in the preparation process.
4 related substances of estradiol valerate tablet are disclosed in the imported drug registration standard JX20100066 of the food and drug administration (NMPA), as shown in table 1 below:
table 1: related substances have been disclosed
However, after forced degradation studies on estradiol valerate tablets we found that they were slightly less stable in high temperature environments, the main degradation product was 1 larger unknown impurity, combined with drug substance impurity profile, and after locating them we determined that this unknown impurity was impurity C in table 2 below (loaded in EP). In addition, the above method is cumbersome to operate and takes a long time, specifically, a double wavelength (242/280 nm), a double external standard (levonorgestrel/estradiol valerate) is adopted, the running time is 90min, and the problem of poor separation of impurity G, impurity C from the main peak is present (see comparative examples 1 and 2). Therefore, the detection conditions need to be explored and improved, and a set of rapid, simple, effective and reliable finished product reaction monitoring and related substance analysis methods are established.
Table 2: other degradation/process impurities that may be contained in the estradiol valerate tablet
Disclosure of Invention
Aiming at the problems of complicated operation, long time consumption and poor separation effect of the existing analysis method, the invention provides the analysis method for the substances related to the estradiol valerate tablet, which can effectively separate the process and degradation impurities of the estradiol valerate tablet, has simple operation, can effectively detect a plurality of impurities of the estradiol valerate tablet, and has high sensitivity and strong specificity.
The invention provides an analysis method of estradiol valerate tablet related substances, which comprises the following steps:
detecting the sample solution by adopting a high performance liquid chromatography; the sample solution contains estradiol valerate and impurities; the impurities comprise one or more of impurities A, G, K, L, C, D and E;
the chromatographic column adopted by the high performance liquid chromatography is a column taking phenyl bonded silica gel with the granularity of 3 mu m as a filler;
the high performance liquid chromatography adopts a mobile phase A and a mobile phase B; wherein the mobile phase A is a mixed solvent formed by water and an alcohol solvent (the volume ratio is 50:50 to 80:20);
the mobile phase B is a nitrile solvent;
the high performance liquid chromatography adopts gradient elution;
the gradient elution conditions were:
(wherein the% is by volume).
In some embodiments, the chromatography column is a 250mm x 4.6mm,3 μm phenyl-bonded silica gel chromatography column.
In some embodiments, the chromatography column is a chrom core Phenyl,250mm x 4.6mm,3 μm chromatography column.
In some embodiments, the mobile phase a is a mixed solvent of water and methanol, preferably a mixed solvent of water and methanol in a volume ratio of 50:50.
In some embodiments, the mobile phase B is acetonitrile.
In some embodiments, the high performance liquid chromatography employs a detection wavelength of 220nm or 280nm; preferably 220nm.
In some embodiments, the high performance liquid chromatography employs a flow rate of: 0.5-1.0ml/min; preferably 0.6ml/min.
In some embodiments, the high performance liquid chromatography employs a column temperature of 35-45 ℃; preferably 40 ℃.
In some embodiments, the high performance liquid chromatography employs a sample volume of 40-80 μl; preferably 50 μl.
In some embodiments, in the sample solution, the solvent is a mixed solvent formed by a nitrile solvent, an alcohol solvent and water, preferably a mixed solvent formed by acetonitrile, methanol and water; more preferably a mixed solvent of acetonitrile, methanol and water in a volume ratio of 60:10:30.
In some embodiments, the main component external standard method is used to determine the content of estradiol valerate and impurities in the test solution.
In some embodiments, the high performance liquid chromatography uses a column of chrom core Phenyl,250mm x 4.6mm,3 μm as a chromatographic column, uses acetonitrile and a mixed solvent formed by water and methanol with a volume ratio of 50:50 as a mobile phase, performs gradient elution, and uses a detector which is an ultraviolet detector, the detection wavelength is 220nm, the flow rate is 0.6ml/min, the column temperature is 40 ℃, and the sample injection volume is 50 μl.
On the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the invention.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the method is suitable for separating and measuring the estradiol valerate and related impurities, can be used for independently detecting a certain substance, and can also be used for simultaneously separating and detecting the estradiol valerate and related impurities. Compared with the prior art, the detection method provided by the invention is convenient to measure, the requirement can be met by using a single wavelength and a main component external standard, more estradiol valerate tablet related substances (including 7 process impurities and degradation impurities) can be detected, and estradiol valerate and other inactive substances can be well separated.
Detailed Description
The sources of the samples and controls related to the examples and comparative examples are as follows:
table 3: information table of sample and reference substance
The experimental apparatus used in the following examples or comparative examples was either Shimadzu or Siemens' high performance liquid chromatograph (UV detector).
In examples 1-3 below, the chromatographic conditions are as follows:
the chromatographic column is as follows: a chromatographic column of chromCore Phenyl,250mm 4.6mm,3 μm;
mobile phase A is water-methanol (volume ratio 50:50);
mobile phase B is acetonitrile;
the gradient elution procedure was:
column temperature is 40 ℃; the sample injection amount is 50 μl; the detection wavelength was 220nm and the flow rate was 0.6ml/min.
The diluents added in the following examples and comparative examples were a mixed solution of acetonitrile, methanol and water (volume ratio: 60:10:30).
EXAMPLE 1 determination-specificity of estradiol valerate tablet related substance
The apparatus and chromatographic conditions are as described above, test steps:
impurity localization solution: taking 25mg of each impurity, respectively placing into different 25ml measuring flasks, adding a diluent, dissolving and uniformly mixing to obtain the product.
Mixed solution 1: taking 10 pieces of estradiol valerate, placing the 10 pieces into a 10ml measuring flask, adding 8ml of diluent, heating and shaking in a water bath at 50 ℃ for 10 minutes to disintegrate, then carrying out ultrasonic treatment for 15 minutes to dissolve the estradiol valerate, cooling, adding 50 mu l of impurity positioning solution respectively, diluting to a scale with the diluent, shaking uniformly, filtering with a polytetrafluoroethylene microporous filter membrane with the thickness of 0.22 mu m, and taking a subsequent filtrate to obtain the estradiol valerate.
Estradiol valerate blank solution: taking 1 blank estradiol valerate tablet (without API), placing into a 10ml measuring flask, adding 8ml diluent, heating and shaking in a water bath at 50 ℃ for 10 minutes to disintegrate, then carrying out ultrasonic treatment for 15 minutes, cooling, diluting to scale with the diluent, shaking uniformly, filtering with a polytetrafluoroethylene microporous filter membrane with the thickness of 0.22 mu m, and taking a subsequent filtrate.
The diluent and the solutions are taken and analyzed according to the chromatographic conditions, the specific results of different solution retention times are shown in the following table 4, the high performance liquid chromatography results of the mixed solution 1 are shown in the following table 5, and the results show that the impurities are well separated, the air assist is free from interference, and the method specificity is good.
TABLE 4 results of analysis of different solution retention times
TABLE 5 analysis of the chromatographic results of the mixed solution 1
EXAMPLE 2 determination of estradiol valerate drug substance 1
Test article solution 1: about 10mg of estradiol valerate raw material medicine is taken and added with a diluent to be dissolved to prepare a sample solution with the concentration of 1.0 mg/ml.
Control solution 1: and diluting the estradiol valerate reference substance with a proper amount of diluent to prepare a reference substance solution with the concentration of 0.01 mg/ml.
And taking the diluent and the solution, analyzing the diluent and the solution by sample injection according to the chromatographic conditions, and calculating the content of estradiol valerate and related impurities in the sample solution 1.
The impurity content calculation formula is as follows:
total impurity = Σindividualimpurity content
Wherein:
A 1 peak area of estradiol valerate for control solution 1;
A 2 is a test samplePeak areas of the components of solution 1;
p is the purity of the reference substance,%;
V 1 is the volume of the reference substance solution, ml;
V 2 the volume of the sample solution 1 is ml;
m is the sample weighing amount of the reference substance, mg;
s1 is the sample weighing amount of the raw material medicine, and mg;
f is a correction factor of impurities, and is specifically as follows:
the results of the detection are shown in Table 6 below, and the chromatographic results of the sample solution 1 and the control solution 1 are shown in tables 7 and 8 below, respectively:
TABLE 6 detection results of substances related to crude drugs
| Component name | Content (%) |
| Estradiol valerate | 99.83 |
| Impurity A | 0.04 |
| Impurity C | 0.08 |
| Impurity E | 0.01 |
| Sum of unknown impurities | 0.04 |
| Total impurities | 0.17 |
TABLE 7 analysis of sample solution 1 chromatographic results
TABLE 8 analysis of control solution 1 chromatographic results
EXAMPLE 3 estradiol valerate tablet related substance determination 2
High temperature test solution 2: taking 20 estradiol valerate tablets (140 mg in weight), placing in a 60 ℃ oven for 10d, taking out, cooling, grinding into powder, precisely weighing 1400mg (about 10mg corresponding to main component) of the powder, placing in a 10ml volumetric flask, adding 8ml of diluent, heating and shaking in a 50 ℃ water bath for 10min to dissolve, then carrying out ultrasonic treatment for 15min to dissolve the estradiol valerate, shaking uniformly, fixing the volume with the diluent, shaking uniformly, and filtering with a 0.22 mu m polytetrafluoroethylene filter membrane to obtain the product.
Control solution 2: and diluting the estradiol valerate reference substance with a proper amount of diluent to prepare a reference substance solution with the concentration of 0.01 mg/ml.
And taking the diluent and the solution, analyzing the diluent and the solution by sample injection according to the chromatographic conditions, and calculating the content of estradiol valerate and related impurities in the high-temperature sample solution 2.
The impurity content calculation formula is as follows:
total impurity = Σindividualimpurity content
Wherein:
A 1 peak area of estradiol valerate for control solution 2;
A 2 peak areas of the components of the sample solution 2;
p is the purity of the reference substance,%;
V 1 is the volume of the reference substance solution, ml;
V 2 is the volume of the sample solution 2, ml;
m is the sample weighing amount of the reference substance, mg;
s is the specification of estradiol valerate tablets, mg/tablet;
f is a correction factor of impurities, and is specifically as follows:
n is the number of samples, sheets.
The results of detection of the substances are shown in the following table 9, and the chromatographic results of the high temperature sample solution 2 and the control solution 2 are shown in tables 10 and 11, respectively:
TABLE 9 detection results of estradiol due to high Wen Wu acid
| Component name | Content (%) |
| Estradiol valerate | 98.72 |
| Impurity K | 0.14 |
| Impurity L | 0.09 |
| Impurity G | 0.01 |
| Impurity C | 0.34 |
| Sum of unknown impurities | 0.70 |
| Total impurities | 1.28 |
TABLE 10 analysis of high temperature sample solution 2 chromatography results
TABLE 11 analysis of control solution 2 chromatographic results
Comparative examples 1 to 5
The test steps are as follows:
impurity localization solution: and respectively placing 25mg of impurity A, impurity K, impurity L and impurity G into different 25ml measuring flasks, and adding a diluent to dissolve the mixture to a certain volume to obtain an impurity positioning solution.
Test solution: taking 10 pieces of estradiol valerate, placing the 10 pieces into a 10ml measuring flask, adding 8ml of diluent, heating and shaking in a water bath at 50 ℃ for 10 minutes to disintegrate, then carrying out ultrasonic treatment for 15 minutes to dissolve the estradiol valerate, cooling, adding 50 mu l of impurity positioning solution respectively, diluting to a scale with the diluent, shaking uniformly, filtering with a polytetrafluoroethylene microporous filter membrane with the thickness of 0.22 mu m, and taking a subsequent filtrate to obtain the estradiol valerate.
The comparative test results are shown in the following table:
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table 12 comparative example 1 chromatographic results analysis
TABLE 13 analysis of comparative example 2 chromatographic results
Table 14 comparative example 3 chromatographic results analysis
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TABLE 15 comparative example 4 chromatographic results analysis
TABLE 16 comparative example 5 chromatographic results analysis
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Claims (10)
1. An analysis method of estradiol valerate tablet related substances comprises the following steps:
detecting the sample solution by adopting a high performance liquid chromatography; the sample solution contains estradiol valerate and impurities; the impurities comprise one or more of impurities A, G, K, L, C, D and E;
the chromatographic column adopted by the high performance liquid chromatography is a column taking phenyl bonded silica gel with the granularity of 3 mu m as a filler;
the high performance liquid chromatography adopts a mobile phase A and a mobile phase B; wherein the mobile phase A is a mixed solvent formed by water and an alcohol solvent, and the volume ratio of the water to the alcohol solvent is 50:50-80:20; the mobile phase B is a nitrile solvent;
the high performance liquid chromatography adopts gradient elution; the gradient elution conditions were:
2. the analytical method according to claim 1, wherein the chromatographic column is a 250mm x 4.6mm,3 μm phenyl-bonded silica gel chromatographic column; preferably a chromatographic column of chromCore Phenyl,250mm x 4.6mm,3 μm.
3. The analytical method according to claim 1, wherein the mobile phase a is a mixed solvent of water and methanol;
and/or, the mobile phase B is acetonitrile.
4. The analytical method according to claim 3, wherein the mobile phase A is a mixed solvent of water and methanol in a volume ratio of 50:50.
5. The analytical method according to claim 1, characterized in that it fulfils one or more of the following conditions:
(1) The detection wavelength adopted by the high performance liquid chromatography is 220nm or 280nm;
(2) The flow rate adopted by the high performance liquid chromatography is 0.5-1.0ml/min;
(3) The column temperature adopted by the high performance liquid chromatography is 35-45 ℃;
and (4) the high performance liquid chromatography adopts a sample injection volume of 40-80 μl.
6. The analytical method according to claim 1, characterized in that it fulfils one or more of the following conditions:
(1) The detection wavelength adopted by the high performance liquid chromatography is 220nm;
(2) The flow rate adopted by the high performance liquid chromatography is 0.6ml/min;
(3) The column temperature adopted by the high performance liquid chromatography is 40 ℃;
and (4) the high performance liquid chromatography employs a sample volume of 50 μl.
7. The method according to claim 1, wherein the solvent in the sample solution is a mixed solvent of a nitrile solvent, an alcohol solvent and water, preferably acetonitrile, methanol and water.
8. The method according to claim 7, wherein the solvent in the sample solution is 60:10:30, methanol and water.
9. The method according to claim 1, wherein the main component external standard method is used to measure the content of estradiol valerate and impurities in the sample solution.
10. The analytical method according to claim 1, wherein the high performance liquid chromatography uses a column of chromacore Phenyl,250mm by 4.6mm,3 μm as a chromatographic column, uses acetonitrile and a mixed solvent of water and methanol in a volume ratio of 50:50 as a mobile phase, performs gradient elution, and uses a detector of ultraviolet detector, wherein the detection wavelength is 220nm, the flow rate is 0.6ml/min, the column temperature is 40 ℃, and the sample injection volume is 50 μl.
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