CN114264745A - Imatinib mesylate related substance and detection method of preparation related substance thereof - Google Patents
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Abstract
The invention belongs to the technical field of drug analysis and detection, and particularly relates to a method for detecting imatinib mesylate related substances and preparation related substances thereof. The method adopts a high performance liquid chromatography, uses an octadecyl bonded silica gel chromatographic column, uses a buffer solution containing 0.08-0.12% of sodium hexane sulfonate and 0.6-0.8% of monopotassium phosphate as a mobile phase A, uses a buffer solution containing 0.25-0.35% of sodium hexane sulfonate and 0.6-0.8% of monopotassium phosphate as a mobile phase B, has a flow rate of 1.0-1.5 ml/min, a column temperature of 30-50 ℃, a detection wavelength of 230-240 nm, and gradient elution, can simultaneously realize effective separation of imatinib mesylate and 8 impurities in a liquid chromatographic system, and particularly can simultaneously separate impurities I, J, G and E with very similar structural properties for the first time, and has the advantages of strong durability, accuracy, reliability and high sensitivity, and can be used for quality control of imatinib mesylate.
Description
Technical Field
The invention belongs to the technical field of drug analysis and detection, and particularly relates to a method for detecting imatinib mesylate related substances and preparation related substances thereof.
Background
Imatinib mesylate (imatinib mesylate), shown in formula 1, is the first small molecule tyrosine kinase inhibitor introduced by Novartis Pharmaceuticals in the beginning of the 21 st century, attenuates protein phosphorylation involved in cell signal transduction by inhibiting the interaction between tyrosine kinase and adenosine triphosphate, inhibits the proliferation of tumor cells, is mainly clinically used for treating chronic myelocytic leukemia, gastrointestinal stromal tumor, myelodysplasia caused by PDGFR gene recombination, chronic eosinophilic leukemia caused by FIP1L1-PDGFRa rearrangement, and the like,
in recent years, imatinib mesylate continuously enters medical insurance catalogs of provinces and cities, the production and sales volume in China is rapidly increased, the quality standard of imatinib mesylate is formulated by research, and the quality of raw materials and preparations thereof is more and more important to control. According to the relevant production process and stability data, 8 impurities exist in imatinib mesylate produced by Chinese manufacturers, and the structure is shown as a formula 2-9. The existing data are researched to find that the separation difficulty of the impurity G and the impurity E is very high, the structures of the impurity I and the impurity J are only different by one methyl group and basically produce peaks simultaneously, and a detection method capable of simultaneously and effectively separating the 8 impurities and the imatinib mesylate is not reported, so that the research on a method capable of simultaneously separating the 9 substances has important significance for controlling the quality of the imatinib mesylate and improving the production efficiency.
Disclosure of Invention
The invention provides a method for detecting imatinib mesylate related substances. The method can simultaneously realize the effective separation of the imatinib mesylate and 8 impurities in one liquid chromatography system, particularly can simultaneously separate the impurity I, the impurity J, the impurity G and the impurity E with extremely similar structural properties for the first time, has strong durability, high accuracy and reliability and high sensitivity, and can be used for the quality control of the imatinib mesylate.
The invention provides a method for detecting imatinib mesylate related substances, which adopts a high performance liquid chromatography, uses an octadecyl bonded silica gel chromatographic column, uses a buffer solution containing 0.08-0.12% of sodium hexane sulfonate and 0.6-0.8% of potassium dihydrogen phosphate as a mobile phase A, uses a buffer solution acetonitrile mixed solution containing 0.25-0.35% of sodium hexane sulfonate and 0.6-0.8% of potassium dihydrogen phosphate as a mobile phase B, has a flow rate of 1.0-1.5 ml/min, a column temperature of 30-50 ℃, a detection wavelength of 230-240 nm, and performs gradient elution according to a procedure in a table 1,
TABLE 1 gradient elution schedule
The invention provides a detection method of imatinib mesylate related substances, wherein an octadecyl bonded silica gel chromatographic column is Waters Sunfire C18A chromatographic column; preferably, the octadecyl bonded silica gel chromatographic column is Waters Sunfire C18Chromatography column (250 mm. times.4.6 mm, 5 μm).
According to the detection method of imatinib mesylate related substances, provided by the invention, the mobile phase A is a buffer solution containing 0.09-0.11% of sodium hexanesulfonate and 0.65-0.75% of monopotassium phosphate; preferably, the preparation method of the mobile phase A comprises the steps of firstly preparing a buffer solution containing 0.11-0.14% of sodium hexanesulfonate and 0.81-0.94% of monopotassium phosphate, then adjusting the pH value to 2.5 +/-0.5 by using phosphoric acid, and finally diluting the buffer solution into the buffer solution containing 0.09-0.11% of sodium hexanesulfonate and 0.65-0.75% of monopotassium phosphate by using water; further preferably, the preparation method of the mobile phase a is to prepare a buffer solution containing 0.125% sodium hexanesulfonate and 0.85% potassium dihydrogen phosphate, then adjust the pH value to 2.5 ± 0.5 with phosphoric acid, and finally dilute the buffer solution containing 0.1% sodium hexanesulfonate and 0.68% potassium dihydrogen phosphate with water.
The invention provides a detection method of imatinib mesylate related substances, wherein a mobile phase B is a buffer solution containing 0.28-0.32% of sodium hexanesulfonate and 0.65-0.75% of potassium dihydrogen phosphate, and the mobile phase B and acetonitrile are mixed according to a volume ratio of 25-40: 75-60 of mixed solution; preferably, the preparation method of the mobile phase B comprises the steps of firstly preparing a buffer solution containing 0.35-0.40% of sodium hexane sulfonate and 0.81-0.94% of potassium dihydrogen phosphate, then adjusting the pH value to 2.5 +/-0.5 by using phosphoric acid, then diluting the buffer solution into a buffer solution containing 0.28-0.32% of sodium hexane sulfonate and 0.65-0.75% of potassium dihydrogen phosphate by using water, and finally mixing the buffer solution with acetonitrile according to a volume ratio of 30-35: 70-65 of mixed solution; further preferably, the preparation method of the mobile phase B is to prepare a buffer solution containing 0.375% sodium hexane sulfonate and 0.85% potassium dihydrogen phosphate, then adjust the pH value to 2.5 ± 0.5 with phosphoric acid, dilute the buffer solution with water to a buffer solution containing 0.3% sodium hexane sulfonate and 0.68% potassium dihydrogen phosphate, and finally mix the buffer solution with acetonitrile in a volume ratio of 33: 67 mixed solution.
The flow rate of the detection method for the imatinib mesylate related substances provided by the invention is 1.5 ml/min.
According to the detection method of imatinib mesylate related substances, provided by the invention, the column temperature is 30-40 ℃; preferably, the column temperature is 35 ℃.
The detection wavelength of the detection method for imatinib mesylate related substances provided by the invention is 230 nm.
The invention provides a method for detecting imatinib mesylate and related substances of a preparation thereof, which comprises the following steps:
(1) taking a proper amount of imatinib or an imatinib preparation sample, and adding a hydrochloric acid methanol solution to dissolve to prepare a sample solution;
(2) performing high performance liquid chromatography by using an octadecyl bonded silica gel chromatographic column, taking a buffer solution containing 0.08-0.12% of sodium hexane sulfonate and 0.6-0.8% of monopotassium phosphate as a mobile phase A, taking a buffer solution containing 0.25-0.35% of sodium hexane sulfonate and 0.6-0.8% of monopotassium phosphate as a mobile phase B, performing gradient elution according to the procedure shown in Table 1 at the flow rate of 1.0-1.5 ml/min and the column temperature of 30-50 ℃, wherein the detection wavelength is 230-240 nm, and obtaining a high performance liquid chromatography analysis chart.
In the invention, the impurities I and J are too similar in properties and are extremely difficult to completely separate when an analysis method is established. The inventor inspects the impurity separation condition according to the methods of imatinib mesylate standards YBH03852014, YBH01712017 and related substances of EP9.0, and finds that under the liquid phase conditions of the three methods, the impurity I and the impurity J all peak at the same position and cannot be separated, and meanwhile, the situations of unsatisfactory separation effects of the impurity H and the impurity F, the main peak and the impurity A and the like exist, and the result is shown in the attached figures 1-3.
The inventor finds that the separation degree of related substances is greatly influenced by the type of mobile phase, and attempts to separate the 9 substances by multiple mobile phases are not effective, and the inventor surprisingly finds that a buffer solution containing 0.08-0.12% of sodium hexane sulfonate and 0.6-0.8% of potassium dihydrogen phosphate is taken as a mobile phase A, a buffer solution containing 0.25-0.35% of sodium hexane sulfonate and 0.6-0.8% of potassium dihydrogen phosphate is taken as a mobile phase B, the gradient elution degree is adjusted, the main peak and the separation degree of each impurity are good while the peaks of imatinib and each impurity are sharp, and particularly the impurities I and J begin to be separated; the inventor finds that the mobile phase proportion is further optimized, and the preparation of the mobile phase A is as follows: firstly, preparing a buffer solution containing 0.11-0.14% of sodium hexanesulfonate and 0.81-0.94% of monopotassium phosphate, then adjusting the pH value to 2.5 +/-0.5 by using phosphoric acid, finally diluting the buffer solution into the buffer solution containing 0.09-0.11% of sodium hexanesulfonate and 0.65-0.75% of monopotassium phosphate by using water, and preparing a mobile phase B as follows: firstly, preparing a buffer solution containing 0.35-0.40% of sodium hexanesulfonate and 0.81-0.94% of potassium dihydrogen phosphate, then adjusting the pH value to 2.5 +/-0.5 by using phosphoric acid, diluting the buffer solution into a buffer solution containing 0.28-0.32% of sodium hexanesulfonate and 0.65-0.75% of potassium dihydrogen phosphate by using water, and finally mixing the buffer solution with acetonitrile according to a volume ratio of 30-35: 70-65, adjusting the gradient elution degree to obtain the separation effects of complete separation of imatinib main peak and impurities, symmetrical peak shape of each peak and small tailing factor; the inventor finally finds that a buffer solution containing 0.125% of sodium hexanesulfonate and 0.85% of potassium dihydrogen phosphate is prepared, then the pH value is adjusted to 2.5 +/-0.5 by using phosphoric acid, and finally the buffer solution is diluted by using water to form a buffer solution containing 0.1% of sodium hexanesulfonate and 0.68% of potassium dihydrogen phosphate to serve as a mobile phase A; preparing a buffer solution containing 0.375% of sodium hexane sulfonate and 0.85% of potassium dihydrogen phosphate, adjusting the pH value to 2.5 +/-0.5 by using phosphoric acid, diluting the buffer solution into a buffer solution containing 0.3% of sodium hexane sulfonate and 0.68% of potassium dihydrogen phosphate by using water, and mixing the prepared buffer solution and acetonitrile according to a volume ratio of 33: 67 the mixed solution was used as mobile phase B, and eluted according to the gradient elution procedure of Table 1, to obtain the liquid chromatogram for separating imatinib and impurities shown in FIG. 4.
The inventors have also found that the pH of the mobile phase has a greater influence on the degree of separation of impurities. The inventor finds that the separation degree of the impurities G, E, H, imatinib and J is optimal and the service life of a chromatographic column is long when the pH is 2.5 +/-0.5.
The inventor finds that chromatographic columns of different brands have certain influence on the separation effect, when the Waters Sunfire chromatographic column is selected, the column effect is the best, and the difference of the new chromatographic column and the old chromatographic column is not obvious in investigation result.
Interpretation of terms
The "%" in the present invention refers to volume ratio (ml/ml) in the gradient elution table, and refers to that 100ml of the solution contains several grams of solute (g/ml) in the preparation of the mobile phase.
Drawings
FIG. 1 is a high performance liquid chromatogram of imatinib mesylate and various impurities under the liquid chromatography conditions of imatinib mesylate standard YBH03852014, wherein impurity I and impurity J peak at almost the same position, and impurity H and impurity F peak at the same position;
FIG. 2 is a high performance liquid chromatogram of imatinib mesylate and various impurities under the liquid chromatography conditions of imatinib mesylate standard YBH01712017 related substances, wherein the impurity I and the impurity J peak at the same position, and the separation degree of a main peak and the impurity A is poor;
FIG. 3 is a high performance liquid chromatogram of imatinib and various impurities under the condition of liquid chromatography of imatinib mesylate EP9.0 related substances, wherein impurities I and J peak at the same position, and impurities H and F have poor separation degree;
FIG. 4 is a high performance liquid chromatogram of imatinib and various impurities under the conditions of liquid chromatography provided by the present invention, wherein 1 is impurity C; 2 is impurity A; 3 is impurity G; 4 is impurity E; 5 is impurity H; 6 is imatinib mesylate; 7 is an impurity F; 8 is impurity I; 9 is impurity J.
Detailed Description
The instrument comprises the following steps: water 2695 high performance liquid chromatograph (Waters corporation, usa, equipped with PDA detector); mettler Toledo XPE205 electronic analytical balance (Mettler, Switzerland).
Drugs and reagents: imatinib mesylate control (Zhengda Nintenbang pharmaceutical industry, batch number: 2016001, purity 99.9%); impurity A (Zhengda Ningqing pharmaceutical industry, batch number: 20180106, purity: 99.3%); impurity C (Nanjing Warren technologies, Inc., lot number 20160310, purity 99.9%); impurity E (Zhengda Ningqing pharmaceutical industry, lot number: 20180115, purity: 99.5%); impurity F (Zhengda Ningqing pharmaceutical industry, lot number: 20180115, purity: 99.6%); impurity G (Zhengda Ningqing pharmaceutical industry, lot number: 20180115, purity: 99.3%); impurity H (Zhengda Ningqing pharmaceutical industry, lot number: 20170112, purity: 98.9%); impurity I (toronto research chemicals inc, batch number: 3-MRS-77-3, purity: 100%); impurity J (Shenzhen St & Deerzification technology Co., Ltd., batch No. 1567517I-HB-08, purity: 98.5%); imatinib mesylate bulk drug (Shiyao Europe, lot No. 695171257, 695180104, 695180203); sodium hexanesulfonate and anhydrous potassium dihydrogen phosphate are analytically pure; acetonitrile is chromatographically pure, and ultrapure water is prepared by self.
Chromatographic conditions are as follows: with Waters Sunfire C18Chromatography column (250 mm. times.4.6 mm, 5 μm); mobile phase: phosphate buffer (6.8 g of monopotassium phosphate and 1.0g of sodium hexanesulfonate are taken, 800mL of water is added for dissolution, then the pH value is adjusted to 2.5 by phosphoric acid, and 1000mL of water is added for dissolution) is taken as a mobile phase A, phosphate buffer (6.8 g of monopotassium phosphate and 3.0g of sodium hexanesulfonate are taken, 800mL of water is added for dissolution, then the pH value is adjusted to 2.5 by phosphoric acid, and 1000mL of water is added) is taken as a mobile phase B; the flow rate is 1.5 ml/min; the column temperature is 35 ℃; the sample volume is 20 mu L; detection wavelength: 230 nm; the gradient elution procedure is shown in table 1.
Solution preparation: preparing a reference solution, precisely weighing appropriate amount of imatinib mesylate and each impurity reference, dissolving with hydrochloric acid methanol [0.1mol/L hydrochloric acid solution-methanol (6:4) ] and diluting to prepare a reference stock solution containing about 100 μ g of each component per 1 mL; 1mL of the solution was measured precisely, and the solution was placed in a 100mL measuring flask and diluted with methanol hydrochloride to give a control solution containing about 1. mu.g of each component per 1 mL. And hydrochloric acid methanol is used as a blank solution.
Preparation of test solution an appropriate amount of imatinib mesylate is precisely weighed, dissolved in methanol hydrochloride and diluted to prepare a test solution containing 0.5mg of imatinib mesylate per 1 mL.
Example 1 specificity test
Precisely weighing appropriate amounts of A, C, E, F, G, H, I, J imatinib mesylate reference substances, adding 0.1mol/L hydrochloric acid solution-methanol (4: 6) to prepare a mixed reference substance solution containing about 10 mug per 1ml, respectively taking a blank solution (hydrochloric acid solution-methanol (4: 6)), the mixed reference substance solution and a single-component reference substance solution, injecting into a liquid chromatogram, and measuring according to the chromatographic conditions, wherein the result is shown in figure 4, imatinib, impurity A, impurity C, impurity E, impurity F, impurity G, impurity H, impurity I and impurity J can be well separated, retention time is respectively 31.04, 19.186, 6.04, 27.96, 32.53, 27.48, 29.92, 49.20 and 49.71min, and blank solvent does not interfere with measurement.
Weighing about 20mg of imatinib mesylate respectively, and treating according to the following method: (1) adding 1 mol--1HCl solution 2mL dissolved, standing for 2 hours, adding 1 mol. L-12ml NaOH solution is neutralized and diluted by solvent to be used as acid dropSample solution; (2) adding 1 mol-- 1NaOH solution 2mL and standing for 2 hours, adding 1 mol. L-1Neutralizing with 2ml of HCl solution, diluting with a solvent, and taking the solution as an alkali degradation sample; (3) adding 3mL of 30% hydrogen peroxide solution, heating in a water bath at 80 ℃ for 20 minutes, and adding a solvent for dilution to serve as an oxidative degradation sample; (4) adding 10mL of solvent for dissolving, heating in a water bath for 2 hours, and diluting with the solvent to obtain a high-temperature degradation sample; (5) adding 10mL of solvent for dissolving, irradiating for 48 hours under an ultraviolet 254nm lamp, adding the solvent for diluting, and using as light to destroy and degrade the sample. The results show that: the imatinib mesylate can be degraded in acid, alkali, high temperature and illumination, more degradation products are especially degraded under the oxidation condition, and the separation degree of each degradation product is good under the chromatographic condition of the invention.
Example 2 precision investigation test
And (3) taking a reference substance solution, carrying out continuous sample injection for 6 times, and evaluating according to relative standard deviations of peak areas of imatinib, impurity A, impurity C, impurity E, impurity F, impurity G, impurity H, impurity I and impurity J, wherein results meet the requirements, and are shown in Table 2.
TABLE 2
Example 3 Linear Range examination
0.1, 0.25, 0.5, 1, 1.5 and 2mL of the control stock solution were precisely measured out, and each of the solutions was diluted with a solvent to a concentration of 0.1. mu.g, 0.3. mu.g, 1.0. mu.g, 1.5. mu.g and 2.0. mu.g in each 1mL of the standard solution, and the solutions were shaken to prepare a linear series of solutions. The peak area y was linearly regressed with the mass concentration x and the results are shown in Table 2.
Example 4 correction factor investigation test
And calculating correction factors according to the ratio of the slope of the linear equation of the imatinib mesylate to the slope of the linear equation of the impurity, wherein the correction factors of the impurity A, the impurity C, the impurity E, the impurity F, the impurity G, the impurity H, the impurity I and the impurity J are 1.20, 1.11, 0.94, 1.00, 0.94, 0.87, 0.97 and 1.07 in sequence (the correction factor of the imatinib mesylate is calculated according to 1.0).
Example 5 detection and quantitation limits
A20. mu.L portion of the mixed control solution having a concentration of about 0.1. mu.g/mL was measured precisely and injected into a liquid chromatograph. The detection limits of imatinib mesylate, impurity A, impurity C, impurity E, impurity F, impurity G, impurity H, impurity I and impurity J are respectively 0.004, 0.009, 0.011, 0.008, 0.011, 0.009, 0.005, 0.021 and 0.026 mu G, and are respectively equal to mL-1(S/N ═ 3) with quantitation limits of 0.014, 0.032, 0.037, 0.027, 0.035, 0.029, 0.018, 0.069, 0.088 μ g/mL-1(S/N＝10)。
Example 6 recovery test
A solvent is used for preparing a test sample diluent containing 0.5mg per 1mL of imatinib mesylate raw material medicine. Taking about 0.8 mL, 1mL and 1.2mL of impurity reference substance stock solution, placing in a 100mL measuring flask, diluting to scale with test substance diluent, measuring 20 μ L precisely, injecting into liquid chromatogram, recording chromatogram, and finding the result meeting the requirement, see Table 2.
Example 7 stability test
Sample introduction is carried out on the test sample solution and the reference sample solution at room temperature for 0H,3H and 6H respectively, chromatogram is recorded, and evaluation is carried out according to the relative standard deviation of peak areas, so that imatinib, impurity A, impurity C, impurity E, impurity F, impurity G, impurity H, impurity I and impurity J are stable within 6H, and the results are shown in Table 2.
EXAMPLE 8 durability test
Taking a mixed reference solution under the special item, and investigating the flowing phase proportion, the column temperature, the flow rate, the chromatographic column and the like. The results show that the column temperature (+ -5 ℃) and the flow rate (+ -0.2 ml) have little influence on the separation degree of each component, and when the concentration of the sodium hexanesulfonate and the proportion of the acetonitrile in the mobile phase are changed by less than 10%, the separation degree among the components is still more than 5, and the peak area is basically unchanged.
Example 9 sample determination
According to the method, 3 batches of imatinib mesylate raw material medicines are detected, and the result shows that all batches of samples accord with the specification, and the result is shown in table 3.
TABLE 3 sample-related substance measurement results table (%)
Claims (10)
1. A detection method of imatinib mesylate related substances is characterized by comprising the following steps: performing high performance liquid chromatography by using an octadecyl bonded silica gel chromatographic column, taking a buffer solution containing 0.08-0.12% of sodium hexane sulfonate and 0.6-0.8% of potassium dihydrogen phosphate as a mobile phase A, taking a buffer solution containing 0.25-0.35% of sodium hexane sulfonate and 0.6-0.8% of potassium dihydrogen phosphate as a mobile phase B, performing gradient elution according to the procedure shown in Table 1 at a flow rate of 1.0-1.5 ml/min and a column temperature of 30-50 ℃, wherein the detection wavelength is 230-240 nm,
TABLE 1 gradient elution schedule
2. The detection method according to claim 1, characterized in that: the octadecyl bonded silica gel chromatographic column is Waters Sunfire C18A chromatographic column.
3. The detection method according to claim 1, characterized in that: the preparation method of the mobile phase A comprises the steps of firstly preparing a buffer solution containing 0.11-0.14% of sodium hexanesulfonate and 0.81-0.94% of monopotassium phosphate, then adjusting the pH value to 2.5 +/-0.5 by using phosphoric acid, and finally diluting the buffer solution into the buffer solution containing 0.09-0.11% of sodium hexanesulfonate and 0.65-0.75% of monopotassium phosphate by using water.
4. The detection method according to claim 1, characterized in that: the preparation method of the mobile phase A comprises the steps of firstly preparing a buffer solution containing 0.125% of sodium hexanesulfonate and 0.85% of monopotassium phosphate, then adjusting the pH value to 2.5 +/-0.5 by using phosphoric acid, and finally diluting the buffer solution into the buffer solution containing 0.1% of sodium hexanesulfonate and 0.68% of monopotassium phosphate by using water.
5. The detection method according to claim 1, characterized in that: the preparation method of the mobile phase B comprises the steps of firstly preparing a buffer solution containing 0.35-0.40% of sodium hexane sulfonate and 0.81-0.94% of potassium dihydrogen phosphate, then adjusting the pH value to 2.5 +/-0.5 by using phosphoric acid, diluting the buffer solution into a buffer solution containing 0.28-0.32% of sodium hexane sulfonate and 0.65-0.75% of potassium dihydrogen phosphate by using water, and finally mixing the buffer solution with acetonitrile according to a volume ratio of 30-35: 70-65 of mixed solution.
6. The detection method according to claim 1, characterized in that: the preparation method of the mobile phase B comprises the steps of firstly preparing a buffer solution containing 0.375% of sodium hexane sulfonate and 0.85% of potassium dihydrogen phosphate, then adjusting the pH value to 2.5 +/-0.5 by using phosphoric acid, then diluting the buffer solution into the buffer solution containing 0.3% of sodium hexane sulfonate and 0.68% of potassium dihydrogen phosphate by using water, and finally mixing the buffer solution with acetonitrile according to the volume ratio of 33: 67 mixed solution.
7. The detection method according to claim 1, characterized in that: the flow rate was 1.5 ml/min.
8. The detection method according to claim 1, characterized in that: the column temperature was 35 ℃.
9. The detection method according to claim 1, characterized in that: the detection wavelength is 230 nm.
10. A detection method for imatinib mesylate and related substances of a preparation thereof is characterized in that: the method comprises the following steps:
(1) taking a proper amount of imatinib or an imatinib preparation sample, and adding a hydrochloric acid methanol solution to dissolve to prepare a sample solution;
(2) performing high performance liquid chromatography by using an octadecyl bonded silica gel chromatographic column, taking a buffer solution containing 0.08-0.12% of sodium hexane sulfonate and 0.6-0.8% of monopotassium phosphate as a mobile phase A, taking a buffer solution containing 0.25-0.35% of sodium hexane sulfonate and 0.6-0.8% of monopotassium phosphate as a mobile phase B, performing gradient elution according to the procedure shown in Table 1 at a flow rate of 1.0-1.5 ml/min and a column temperature of 30-50 ℃, wherein the detection wavelength is 230-240 nm, obtaining a high performance liquid chromatography analysis chart,
TABLE 1
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