CN113063881A - Related substance analysis method of entecavir oral solution - Google Patents
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- CN113063881A CN113063881A CN202110404607.6A CN202110404607A CN113063881A CN 113063881 A CN113063881 A CN 113063881A CN 202110404607 A CN202110404607 A CN 202110404607A CN 113063881 A CN113063881 A CN 113063881A
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- 239000000126 substance Substances 0.000 title claims abstract description 41
- 229940070923 entecavir oral solution Drugs 0.000 title claims abstract description 30
- 238000004458 analytical method Methods 0.000 title claims abstract description 8
- 229960000980 entecavir Drugs 0.000 claims abstract description 38
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 claims abstract description 38
- 239000012535 impurity Substances 0.000 claims abstract description 31
- 238000001514 detection method Methods 0.000 claims abstract description 16
- 239000007853 buffer solution Substances 0.000 claims abstract description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000010828 elution Methods 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 239000000945 filler Substances 0.000 claims abstract description 4
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 4
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 63
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 22
- 239000001509 sodium citrate Substances 0.000 claims description 18
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 18
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 claims description 6
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 claims description 6
- RTGDFNSFWBGLEC-TVPGTPATSA-N 2-morpholin-4-ylethyl (z)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1h-2-benzofuran-5-yl)-4-methylhex-4-enoate Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(\C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-TVPGTPATSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 238000000926 separation method Methods 0.000 abstract description 6
- 239000000463 material Substances 0.000 abstract description 5
- 238000003908 quality control method Methods 0.000 abstract description 3
- 230000035945 sensitivity Effects 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 8
- 239000000523 sample Substances 0.000 description 7
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- 238000007865 diluting Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000012085 test solution Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- DEHZIARQYIUCOF-GUBZILKMSA-N 2-amino-9-[(1s,3r,4s)-4-[hydroxy(dimethyl)silyl]-3-(hydroxymethyl)-2-methylidenecyclopentyl]-3h-purin-6-one Chemical compound C=C1[C@H](CO)[C@@H]([Si](C)(O)C)C[C@@H]1N1C(NC(N)=NC2=O)=C2N=C1 DEHZIARQYIUCOF-GUBZILKMSA-N 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 238000009658 destructive testing Methods 0.000 description 2
- -1 guanine nucleoside Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 2
- 239000000845 maltitol Substances 0.000 description 2
- 229940035436 maltitol Drugs 0.000 description 2
- 235000010449 maltitol Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 229960003415 propylparaben Drugs 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- QNKNWNRZJDYAPK-DWQAGKKUSA-N 2-amino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylcyclopentyl]-1H-purin-6-one Chemical compound NC=1NC(C=2N=CN(C=2N=1)[C@@H]1C([C@@H]([C@H](C1)O)CO)C)=O QNKNWNRZJDYAPK-DWQAGKKUSA-N 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
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- 230000001066 destructive effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000000122 inhibitory effect on hepatitis Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
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- 231100000331 toxic Toxicity 0.000 description 1
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Images
Classifications
-
- G—PHYSICS
- 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
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- G—PHYSICS
- 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
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
Abstract
The invention discloses an entecavir oral solution related substance analysis method, which adopts high performance liquid chromatography, takes octadecylsilane chemically bonded silica as a chromatographic column filler, adopts an ultraviolet detector, selects a proper organic solvent and a buffer solution as a mobile phase, and performs gradient elution to effectively complete the separation of entecavir and related impurities thereof and ensure the effective detection of the impurities. The invention has good specificity, can effectively separate the existing degraded impurities, residual intermediates and auxiliary materials absorbed by ultraviolet from the main component, has high sensitivity, and can be applied to the quality control of entecavir oral solution.
Description
Technical Field
The invention relates to the technical field of determination of related substances of medicines, in particular to an analysis method of related substances of an entecavir oral solution.
Background
The related substances are closely related to the quality, safety and curative effect of the medicine, and the existence of the related substances may reduce the curative effect of the medicine and even cause toxic and side effects, so the types and the contents of the related substances in the medicine must be controlled by a proper detection and analysis method to ensure the quality of the medicine.
Entecavir is a guanine nucleoside analog, has inhibitory effect on Hepatitis B Virus (HBV) polymerase, and has the chemical name: 2-amino-9- ((1S,3R,4S) -4-hydroxy-3- (hydroxymethyl) -2-methylcyclopentyl) -3H-purin-6 (9H) -one |9- (4-hydroxy-3-hydroxymethyl-2-methylenecyclopent-1-yl) guanine.
The entecavir oral solution belongs to 3 kinds of new drugs, namely drugs which are sold in the market abroad and are not sold in the market at home. However, no related substance detection method of the entecavir is reported at home and abroad at present, and by inquiring the original research specification, the entecavir oral solution prescription contains various auxiliary materials with ultraviolet absorption, such as maltitol, methyl hydroxybenzoate, propyl hydroxybenzoate and the like, so that the difficulty in developing related substance analysis methods is increased.
Therefore, a method for analyzing related substances in the entecavir oral solution, which has high sensitivity and good specificity, is urgently needed to be developed so as to realize quality control of the related substances in the entecavir oral solution.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a method for analyzing related substances of an entecavir oral solution.
The invention provides an entecavir oral solution related substance analysis method, wherein the related substances are 10 as follows: EP impurity A, EP impurity B, EP impurity C, EP impurity D, EP impurity E, EP impurity F, guanine, furan entecavir, entecavir N2 analog, and 4-dimethylsilane entecavir. The method adopts high performance liquid chromatography, takes octadecylsilane chemically bonded silica as chromatographic column filler, adopts an ultraviolet detector, selects proper organic solvent and buffer solution as mobile phase, and performs gradient elution to effectively complete the separation of entecavir and related impurities, thereby ensuring the effective detection of the impurities.
Among them, EP impurity A, EP impurity B, EP impurity C, EP impurity D, EP impurity E, EP impurity F, guanine, furan entecavir, entecavir N2 analogue, 4-dimethylsilane entecavir. The chemical formulas are respectively as follows:
preferably, the organic solvent is acetonitrile, the buffer solution is a sodium citrate aqueous solution, the concentration of the sodium citrate is 0.04-0.06% by volume ratio, and the pH value is adjusted to 6.0-8.0 by triethylamine.
Preferably, the gradient elution procedure in the method is: 0-3 min, wherein the proportion of acetonitrile is 2%; 3-40 min, wherein the proportion of acetonitrile is changed from 2% to 10%; 40-50 min, wherein the proportion of acetonitrile is changed from 10% to 20%; changing the proportion of acetonitrile from 20% to 70% in 50-75 min; 75-85 min, wherein the proportion of acetonitrile is 70%; 85-88 min, wherein the acetonitrile proportion is changed from 70% to 2%.
Further, the detection conditions are: the detection wavelength is 249nm to 259 nm; the flow rate is 0.9-1.1 ml/min; the sample injection amount is 10-50 mu l; the concentration of the sodium citrate in the buffer solution is 0.04-0.06% by volume ratio, and the pH value is 6.0-8.0.
Preferably, the detection wavelength is 254 nm; the flow rate is 1.0 ml/min; the sample amount is 20 mul; the concentration of sodium citrate in the buffer solution is 0.05 percent by volume, and the pH value is 7.0.
Further, the sample configuration method comprises the following steps: precisely measuring a proper amount of entecavir oral solution, adjusting the pH value of acetonitrile-0.05% sodium citrate solution to 7.00 by using triethylamine, and adjusting the pH value of the adjusted acetonitrile-0.05% sodium citrate solution according to the weight ratio of 2: 98 portions of the entecavir oral solution are diluted to prepare the solution with the concentration of 0.020-0.030 mg/ml.
Preferably, the concentration of the solution containing entecavir is 0.025 mg/ml.
The invention has the beneficial effects that: 1. the method has good specificity, can effectively separate the existing degradable impurities, residual intermediates and auxiliary materials absorbed by ultraviolet from the main component, has high sensitivity, and can be applied to the quality control of the entecavir oral solution.
Drawings
FIG. 1 is a comparison chromatogram of the specificity of entecavir related impurities in example 1.
In the chromatogram: the curve is respectively impurity A, impurity B, impurity C, impurity D, impurity E, impurity F, guanine, furan entecavir, entecavir N2 analogue, 4-dimethyl silane entecavir, maltitol, methyl hydroxybenzoate, propyl hydroxybenzoate, essence and solvent from top to bottom.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings and specific embodiments. The embodiments of the present invention have been presented for purposes of illustration and description, and are not intended to be exhaustive or limited to the invention in the form disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art. The embodiment was chosen and described in order to best explain the principles of the invention and the practical application, and to enable others of ordinary skill in the art to understand the invention for various embodiments with various modifications as are suited to the particular use contemplated.
Example 1:
this example illustrates a solution containing entecavir, as verified using the methodology of the chromatographic method.
1. Test for locating related substances
Preparing an entecavir sample solution, a relevant substance control solution and an auxiliary material solution, respectively injecting into a liquid chromatograph, and recording a chromatogram. The results are shown in Table 1 and the spectra are shown in FIG. 1.
TABLE 1 results of entecavir separation parameters from various impurities
| Name of impurity | Sample retention time | Relative retention time | Degree of separation from prepeak |
| Guanine and its preparing process | 5.232 | 0.22 | Greater than 2.0 |
| Entecavir furan | 15.52 | 0.66 | Greater than 2.0 |
| EP impurity A | 21.187 | 0.90 | Greater than 2.0 |
| EP impurity B | 22.002 | 0.94 | Greater than 2.0 |
| Entecavir | 23.415 | 1.00 | Greater than 2.0 |
| Entecavir N2 analogs | 24.235 | 1.04 | Greater than 2.0 |
| EP impurity C | 24.973 | 1.07 | Greater than 2.0 |
| EP impurity D | 26.315 | 1.12 | Greater than 2.0 |
| EP impurity E | 34.38 | 1.47 | Greater than 2.0 |
| 4-dimethylsilyl entecavir | 53.402 | 2.28 | Greater than 2.0 |
| EP impurity F | 78.53 | 3.35 | Greater than 2.0 |
The results show that: good separation can be achieved between entecavir related substances.
2. Limit of detection, limit of quantification test
The detection limit and the quantitative limit of the entecavir and all related substances thereof are determined by a signal-to-noise ratio method. Respectively preparing stock solutions of entecavir and relevant substances thereof, diluting to a certain concentration, injecting, calculating the ratio of peak height to noise (signal-to-noise ratio), wherein the sample detection amount with the signal-to-noise ratio (S/N) of about 10 is the quantitative limit, the sample detection amount with the signal-to-noise ratio (S/N) of about 3 is the detection limit, and the result is shown in table 2.
TABLE 2 quantitative limit and detection limit test results
The results show that: the method has high response to various related substances and can accurately control the content of the various related substances.
3. Standard curve
Entecavir and 10 related substances are precisely weighed, diluted with acetonitrile-0.05% sodium citrate solution (pH value is adjusted to 7.00 by triethylamine) (2: 98), and prepared into 7 parts of solutions with different concentrations. And (3) respectively injecting samples and recording chromatograms, and obtaining a linear regression equation of the entecavir and all related substances thereof by taking the concentration as a horizontal coordinate and the peak area as a vertical coordinate, wherein the result is shown in a table 3.
TABLE 3 results of the standard curve experiment
The results show that: under the method, the entecavir and 10 related substances thereof can show good linearity within a certain concentration range.
4. Accuracy of
Precisely measuring a proper amount of entecavir oral solution, diluting with acetonitrile-0.05% sodium citrate solution (pH value is adjusted to 7.00 by triethylamine) (2: 98), preparing 9 parts of solution with entecavir concentration of 0.025mg/ml, wherein three parts are a group, and respectively adding a proper amount of related substances into each group, so that the concentrations of the related substances in the three groups of solutions are respectively the quantitative limit concentration, 50% of the relative limit and 100% of the relative limit. And (5) injecting and recording a chromatogram, and calculating the recovery rate, wherein the result is shown in a table 4.
TABLE 4 accuracy test results
The results show that: the method has good accuracy.
5. Destructive testing
Precisely measuring a proper amount of entecavir oral solution, respectively carrying out a destruction test on the entecavir oral solution under the conditions of strong acid, strong base, high temperature, illumination, oxidation and the like, carrying out sample introduction and chromatogram recording, and counting the destroyed impurity conditions, wherein the results are shown in Table 5.
TABLE 5 destructive testing results
The results show that: the method can well detect the degradation product generated by entecavir destructive test, the material balance rate is between 90% and 110%, the separation degree of the degradation impurity and the main peak meets the requirement, and the spectral purity of the main peak also meets the requirement. Therefore, the related substances and degradation products thereof in the entecavir oral solution can be measured by adopting the chromatographic system.
Example 2
In this example, 2 batches of entecavir oral solution original drug (manufactured by Baishimeisha Guibao Co., Ltd.) were used as an example, and the measurement of the relevant substances was carried out.
Precisely measuring 1ml of each of 2 batches of entecavir oral solutions, respectively placing the entecavir oral solutions into 2ml measuring flasks, diluting the entecavir oral solutions with an acetonitrile-0.05% sodium citrate solution (pH value is adjusted to 7.00 by triethylamine) (2: 98), and shaking up to obtain a test solution; precisely measuring 1ml of the test solution, placing the test solution into a 100ml measuring flask, diluting the test solution to a scale with acetonitrile-0.05% sodium citrate solution (pH value is adjusted to 7.00 by triethylamine) (2: 98), and shaking up to obtain a control solution.
The method adopts high performance liquid chromatography, uses octadecylsilane chemically bonded silica as chromatographic column filler, adopts an ultraviolet detector, selects proper organic solvent and buffer solution as mobile phase, and performs gradient elution.
The organic solvent is acetonitrile, the buffer solution is a sodium citrate aqueous solution, the concentration of the sodium citrate is 0.04-0.06% by volume ratio, the pH value is adjusted to 6.0-8.0 by triethylamine, and the gradient elution procedure is as follows: 0-3 min, wherein the acetonitrile proportion is 2% and 3-40 min, the acetonitrile proportion is changed from 2% to 10% and 40-50 min, the acetonitrile proportion is changed from 10% to 20% and 50-75 min, the acetonitrile proportion is changed from 20% to 70% and 75-85 min, the acetonitrile proportion is 70% and 85-88 min, and the acetonitrile proportion is changed from 70% to 2%.
Precisely measuring 20 μ l of each of the reference solution and the sample solution, respectively injecting into a liquid chromatograph, injecting and recording chromatogram, and calculating the content of each related substance by using a self-reference method, wherein the result is shown in Table 6.
TABLE 6 comparison of results of the measurement of two batches of entecavir oral solution in the original drug
| Impurities/batch number | 3E76102 | HL0319 |
| Guanine and its preparing process | 0.013 | 0.010 |
| Entecavir furan | Not detected out | 0.012 |
| Impurity A | Not detected out | Not detected out |
| Impurity B | Not detected out | Not detected out |
| Entecavir N2 analogs | Not detected out | Not detected out |
| Impurity C | Not detected out | Not detected out |
| Impurity D | 0.047 | 0.046 |
| Impurity E | Not detected out | Not detected out |
| 4-dimethylsilyl entecavir | Not detected out | Not detected out |
| Impurity F | Not detected out | Not detected out |
| Other maximum single hetero | 0.118 | 0.116 |
| Total miscellaneous | 0.538 | 0.578 |
It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments. All other embodiments, which can be derived by one of ordinary skill in the art and related arts based on the embodiments of the present invention without any creative effort, shall fall within the protection scope of the present invention. It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments. All other embodiments, which can be derived by one of ordinary skill in the art and related arts based on the embodiments of the present invention without any creative effort, shall fall within the protection scope of the present invention.
Claims (8)
1. An analysis method of related substances of an entecavir oral solution is characterized in that: the method adopts high performance liquid chromatography, uses octadecylsilane chemically bonded silica as chromatographic column filler, adopts an ultraviolet detector, selects proper organic solvent and buffer solution as mobile phase, and performs gradient elution.
2. The method for analyzing related substances in entecavir oral solution according to claim 1, wherein: the organic solvent is acetonitrile, the buffer solution is a sodium citrate aqueous solution, the concentration of the sodium citrate is 0.04-0.06% by volume ratio, and triethylamine is used for adjusting the pH value to 6.0-8.0.
3. The method for analyzing related substances in entecavir oral solution according to claim 2, wherein: the gradient elution procedure used was: 0-3 min, wherein the proportion of acetonitrile is 2%; 3-40 min, wherein the proportion of acetonitrile is changed from 2% to 10%; 40-50 min, wherein the proportion of acetonitrile is changed from 10% to 20%; changing the proportion of acetonitrile from 20% to 70% in 50-75 min; 75-85 min, wherein the proportion of acetonitrile is 70%; 85-88 min, wherein the acetonitrile proportion is changed from 70% to 2%.
4. The method for analyzing related substances in entecavir oral solution according to claim 2, wherein: detection conditions are as follows: the detection wavelength is 249nm to 259 nm; the flow rate is 0.9-1.1 ml/min; the sample injection amount is 10-50 mu l; the concentration of the sodium citrate in the buffer solution is 0.04-0.06% by volume ratio, and the pH value is 6.0-8.0.
5. The method for analyzing related substances in entecavir oral solution according to claim 4, wherein: the detection wavelength is 254 nm; the flow rate is 1.0 ml/min; the sample injection amount is 20 mu l; the concentration of the sodium citrate in the buffer solution is 0.05 percent by volume, and the pH value is 7.0.
6. The method for analyzing related substances in entecavir oral solution according to claim 2, wherein: the sample configuration method comprises the following steps: precisely measuring a proper amount of entecavir oral solution, adjusting the pH value of acetonitrile-0.05% sodium citrate solution to 7.00 by using triethylamine, and adjusting the pH value of the adjusted acetonitrile-0.05% sodium citrate solution according to the weight ratio of 2: 98 portions of the entecavir oral solution are diluted to prepare the solution with the concentration of 0.020-0.030 mg/ml.
7. The method for analyzing related substances in entecavir oral solution according to claim 6, wherein: the concentration of the solution containing the entecavir is 0.025 mg/ml.
8. The method for analyzing entecavir oral solution related substances according to any one of claims 1 to 7, wherein: the related substances are EP A, EP impurity B, EP impurity C, EP impurity D, EP impurity E, EP impurity F, guanine, furan entecavir, entecavir N2 analogue and 4-dimethyl silane entecavir.
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