CN112924612A - Method for determining content of impurity C in gliquidone - Google Patents
Method for determining content of impurity C in gliquidone Download PDFInfo
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- CN112924612A CN112924612A CN201911239423.8A CN201911239423A CN112924612A CN 112924612 A CN112924612 A CN 112924612A CN 201911239423 A CN201911239423 A CN 201911239423A CN 112924612 A CN112924612 A CN 112924612A
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- 239000012535 impurity Substances 0.000 title claims abstract description 94
- LLJFMFZYVVLQKT-UHFFFAOYSA-N 1-cyclohexyl-3-[4-[2-(7-methoxy-4,4-dimethyl-1,3-dioxo-2-isoquinolinyl)ethyl]phenyl]sulfonylurea Chemical compound C=1C(OC)=CC=C(C(C2=O)(C)C)C=1C(=O)N2CCC(C=C1)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 LLJFMFZYVVLQKT-UHFFFAOYSA-N 0.000 title claims abstract description 71
- 229960003468 gliquidone Drugs 0.000 title claims abstract description 71
- 238000000034 method Methods 0.000 title claims abstract description 19
- 238000001514 detection method Methods 0.000 claims abstract description 28
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 123
- 239000000243 solution Substances 0.000 claims description 114
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 19
- 239000000523 sample Substances 0.000 claims description 18
- 239000012071 phase Substances 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 229910019142 PO4 Inorganic materials 0.000 claims description 12
- 239000010452 phosphate Substances 0.000 claims description 12
- 239000000945 filler Substances 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 239000008346 aqueous phase Substances 0.000 claims description 5
- 238000010828 elution Methods 0.000 claims description 5
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- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 238000007865 diluting Methods 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 239000012088 reference solution Substances 0.000 claims description 3
- 239000012488 sample solution Substances 0.000 claims description 3
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 238000010812 external standard method Methods 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 238000005303 weighing Methods 0.000 claims description 2
- 239000013558 reference substance Substances 0.000 claims 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims 1
- 239000012085 test solution Substances 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 230000035945 sensitivity Effects 0.000 abstract description 3
- 238000011084 recovery Methods 0.000 description 32
- 238000012360 testing method Methods 0.000 description 13
- 238000002474 experimental method Methods 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 11
- 238000004587 chromatography analysis Methods 0.000 description 10
- 230000004807 localization Effects 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 2
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 description 2
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 2
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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 235000019837 monoammonium phosphate Nutrition 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- KQWGXHWJMSMDJJ-UHFFFAOYSA-N cyclohexyl isocyanate Chemical compound O=C=NC1CCCCC1 KQWGXHWJMSMDJJ-UHFFFAOYSA-N 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 229940126904 hypoglycaemic agent Drugs 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
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- 230000004048 modification Effects 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
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- 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
- G01N30/89—Inverse chromatography
-
- 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
- G01N30/50—Conditioning of the sorbent material or stationary liquid
- G01N30/52—Physical parameters
- G01N30/54—Temperature
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
The invention provides a method for determining the content of impurity C in gliquidone, which adopts a high performance liquid chromatography. The detection method provided by the invention has higher specificity, sensitivity and accuracy, is simple and convenient to operate, can quickly and accurately determine the content of the impurity C in the gliquidone, can be used for checking related substances of the gliquidone, and uses the impurity C as a known impurity to be used as a checking item of the related substances of the gliquidone, so that the quality standard of the gliquidone is improved, and the medication safety is guaranteed.
Description
Technical Field
The invention belongs to the technical field of drug analysis, and particularly relates to a method for determining the content of impurity C in gliquidone.
Background
Gliquidone is the second generation oral sulfonylurea hypoglycemic agent, is a high-activity islet-philic beta cell agent, is combined with a specific receptor on an islet beta cell membrane, and can induce to generate a proper amount of insulin so as to reduce the blood sugar concentration. The product can reach the highest blood concentration after being orally taken for 2 to 2.5 hours, and can be completely absorbed quickly. The half-life period of the plasma is 1.5 hours, the metabolism is complete, the metabolite has no hypoglycemic effect, and the majority of the metabolite is excreted through the digestive system of the biliary tract.
The main synthetic route is as follows:
the detection method of the related substances of the gliquidone in the Chinese pharmacopoeia comprises the following steps: octadecylsilane chemically bonded silica is used as a filler, and ammonium dihydrogen phosphate solution (1.725 g of ammonium dihydrogen phosphate is dissolved in 300ml of water, and then the pH is adjusted to 3.5 +/-0.1 with phosphoric acid): acetonitrile (3:5) is used as a mobile phase, and the detection wavelength is 310 nm.
The british pharmacopoeia uses Thin Layer Chromatography (TLC) to detect substances related to gliquidone.
The inventors have discovered a poorly soluble white solid during the refining of the crude gliquidone product. The structure is confirmed, the structure is shown as follows, and is called impurity C for short, and the impurity C is generated by hydrolyzing excessive cyclohexyl isocyanate in the reaction.
The method for detecting the impurity C by using the Chinese pharmacopoeia and the British pharmacopoeia has no response, which indicates that the methods of the Chinese pharmacopoeia and the British pharmacopoeia can not effectively detect the impurity C, and the existing literature and quality standard about the gliquidone do not disclose a quantitative detection means for the impurity C in the gliquidone.
The domestic and foreign documents have no relevant toxicity research data on the impurity C, and the existence of the impurity C can possibly cause serious adverse reaction and even generate toxicity under the condition of no toxicity research data supporting the harmlessness of the impurity C to a human body. Therefore, in order to improve the drug quality of the gliquidone and guarantee the drug safety, a method for determining the content of the impurity C in the gliquidone is urgently needed, the content of the impurity C in the gliquidone can be rapidly and accurately detected, and the quality standard of the gliquidone is further improved.
Disclosure of Invention
The invention provides a method for determining the content of impurities in gliquidone, which is used for solving the problems in the prior art.
The invention focuses on that the preparation process of the gliquidone is unexpectedly found to generate the impurity C, and therefore, the invention provides a method for determining the content of the impurity C in the gliquidone, which comprises the following steps:
step 1, precisely weighing a proper amount of impurity C, dissolving the impurity C by using methanol and diluting the impurity C to prepare a solution with the concentration of about 5 mu g/mL as a control solution;
step 2, taking a proper amount of gliquidone sample, adding methanol to dissolve and diluting the gliquidone sample into a solution containing about 5mg of the sample in every 1mL, and taking the solution as a test sample solution;
and 3, measuring the reference solution and the sample solution by using a high performance liquid chromatography, and calculating the content of the impurity C in the gliquidone by using an external standard method.
According to the detection method provided by the invention, the high performance liquid chromatography uses a reversed phase chromatographic column; the chromatographic column is preferably a chromatographic column with octadecyl bonded silica gel as a filler, a chromatographic column with octadecyl bonded silica gel as a filler and a chromatographic column with phenyl bonded silica gel as a filler; more preferably Agilent ZORBAX Eclipse Plus C18.
Performing gradient elution with an organic phase and an aqueous phase, wherein the organic phase is preferably selected from acetonitrile and methanol, and the aqueous phase is selected from a phosphate aqueous solution or an acetate aqueous solution; more preferably, the elution is carried out in a gradient of methanol and an aqueous solution of phosphate.
Further, the pH value of the aqueous phase solution is 2.0-6.0, and the preferable pH value is 3.0-5.0.
According to the detection method provided by the invention, the detection wavelength of the high performance liquid chromatography is 200-250 nm, preferably 200-220 nm.
According to the detection method provided by the invention, the column temperature of the high performance liquid chromatography is 20-50 ℃, and preferably 30-40 ℃.
According to the detection method provided by the invention, the flow rate of the high performance liquid chromatography is 0.5-1.5 ml/min, and preferably 0.9-1.1 ml/min.
The gradient elution condition is that the volume ratio of the organic phase to the water phase is changed from 40: 60-50: 50 to 65: 35-75: 25 within 15-20 minutes.
In addition, the detection method provided by the invention is used for checking related substances of the gliquidone, and the impurity C is used as a known impurity and is added into a checking item of the related substances of the gliquidone.
The invention has the beneficial effects that: the detection method has the advantages of clear principle, strong specificity, high sensitivity and good repeatability and accuracy of detection results, can quickly and accurately detect the content of the impurity C in the gliquidone, improves the quality standard of the gliquidone and ensures the medication safety.
Drawings
FIG. 1 is a chromatogram of a blank solution of example 1 of the present invention;
FIG. 2 is a chromatogram of a mixed solution of example 1 of the present invention;
FIG. 3 is a chromatogram of a gliquidone localization solution of example 1 of the present invention;
FIG. 4 is a chromatogram of a localization solution of impurity C in example 1 of the present invention;
FIG. 5 is a chromatogram of a localization solution of impurity A in example 1 of the present invention;
FIG. 6 is a chromatogram of a solution for localization of impurity G in example 1 of the present invention;
FIG. 7 is a chromatogram of a solution for localization of impurity J in example 1 of the present invention;
FIG. 8 is a chromatogram of a localization solution of impurity L in example 1 of the present invention;
FIG. 9 is a graph showing the relationship between the peak area of the impurity C and the concentration of the impurity C in example 3 of the present invention.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the accompanying drawings, and it should be understood that the described embodiments are some, but not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
1. Instrumentation and test conditions
Agilent 1260 high performance liquid chromatograph, available from Agilent Inc., available from Agilent ZORBAX Eclipse Plus C18 chromatography column; the detection wavelength is 210 nm; mobile phase: methanol: an aqueous phosphate solution (PH 4.5) changed from 45:55 to 70:30 in 20 minutes; the flow rate is 1 ml/min; the column temperature of the chromatographic column is 35 ℃; the amount of sample was 20. mu.l.
2. Experimental procedure
Taking a proper amount of a mixture consisting of gliquidone, an impurity C, an impurity A, an impurity G, an impurity J and an impurity L, adding methanol to dissolve the mixture, and preparing a mixed solution containing 5mg of gliquidone and 0.05mg of each impurity per 1 ml; and preparing a positioning solution by taking the gliquidone and the standard substance of each impurity as a reference. And (3) injecting the blank solution, the mixed solution and the positioning solution of the gliquidone and each impurity into a liquid chromatograph, and recording a chromatogram, wherein the chromatogram is shown in figures 1-8. Compared with a chromatogram of a positioning solution, the retention time of the gliquidone is 11.930min, and the retention times of the impurity C, the impurity A, the impurity G, the impurity J and the impurity L are 10.237min, 11.930min, 11.930min, 14.760min and 8.605min respectively, so that the impurity C, the gliquidone and other impurities can be well separated, no interference exists in blank, and the specificity of the detection method is good.
Example 2
1. Instrumentation and test conditions
Agilent 1260 high performance liquid chromatograph, available from Agilent Inc., available from Agilent ZORBAX Eclipse Plus C18 chromatography column; the detection wavelength is 210 nm; mobile phase: acetonitrile: an aqueous acetate solution (PH 4.5) changed from 45:55 to 70:30 in 18 minutes; the flow rate is 1 ml/min; the column temperature of the chromatographic column is 35 ℃; the amount of sample was 20. mu.l.
2. Experimental procedure
Taking a proper amount of impurity C, adding methanol for dissolving, preparing a solution containing 1 microgram of impurity C per 1ml, using the solution as a quantitative limit solution, and preparing 2 parts in parallel; taking a proper amount of impurity C, adding methanol for dissolving, preparing a solution containing 0.3 mu g of impurity C per 1ml, using the solution as a detection limit solution, and preparing 2 parts in parallel. The sample introduction and the measurement are carried out in sequence, and the result shows that the detection limit concentration of the impurity C is 0.3 mu g/ml, which is equivalent to 0.006 percent of the concentration of the sample; the limit concentration of the impurity C for determination is 1. mu.g/ml, which corresponds to 0.02% of the sample concentration, indicating that the sensitivity of the detection method is high. The results are shown in Table 1.
TABLE 1 detection Limit and quantitation Limit test results
Example 3
1. Instrumentation and test conditions
Agilent 1260 high performance liquid chromatograph, available from Agilent Inc., available from Agilent ZORBAX Eclipse Plus C18 chromatography column; the detection wavelength is 210 nm; mobile phase: methanol: an aqueous phosphate solution (PH 4.5) changed from 40:60 to 65:35 in 20 minutes; the flow rate is 1 ml/min; the column temperature of the chromatographic column is 35 ℃; the amount of sample was 20. mu.l.
2. Experimental procedure
Taking a proper amount of impurity C, adding methanol for dissolving, preparing a solution containing 40 mu g of impurity C per 1ml, diluting the solution to linear solutions with different concentrations, and sequentially injecting samples for determination. The result shows that the impurity C has good linear relation within the concentration range of 1-40 mu g/ml. The results are shown in table 2, fig. 9.
TABLE 2 results of the Linear experiment
Example 4
1. Instrumentation and test conditions
Agilent 1260 high performance liquid chromatograph, available from Agilent Inc., available from Agilent ZORBAX Eclipse Plus C18 chromatography column; the detection wavelength is 210 nm; mobile phase: methanol: an aqueous phosphate solution (PH 4.5) changed from 45:55 to 70:30 in 17 minutes; the flow rate is 1 ml/min; the column temperature of the chromatographic column is 35 ℃; the amount of sample was 20. mu.l.
2. Experimental procedure
Taking a proper amount of gliquidone, adding methanol for dissolving to prepare a solution containing 5mg of gliquidone per 1ml as a background solution; taking a proper amount of impurity C, adding methanol for dissolving, and preparing a solution containing 5 microgram of impurity C per 1ml as a control solution; taking a proper amount of gliquidone and an appropriate amount of impurity C, adding methanol for dissolving to prepare a solution containing 5mg of gliquidone and 5 mu g of impurity C per 1ml, and taking the solution as a recovery solution, wherein 6 parts of the recovery solution are prepared in parallel. The background solution, the control solution and 6 recovery solutions were sequentially injected, and the experimental results are shown in table 3. The recovery rate of 6 parts of recovery rate solution is 100.93-102.54%, which shows that the method has high accuracy; the RSD value for the 6 recovery solution recovery was 0.53%, indicating good reproducibility of the process.
TABLE 3 recovery rate test results
Example 5
1. Instrumentation and test conditions
Agilent 1260 high performance liquid chromatograph, available from Agilent Inc., available from Agilent ZORBAX Eclipse Plus C18 chromatography column; the detection wavelength is 200 nm; mobile phase: methanol: an aqueous phosphate solution (PH 4.5) changed from 45:55 to 70:30 in 20 minutes; the flow rate is 1 ml/min; the column temperature of the chromatographic column is 35 ℃; the amount of sample was 20. mu.l.
2. Experimental procedure
Taking a proper amount of gliquidone, adding methanol for dissolving to prepare a solution containing 5mg of gliquidone per 1ml as a background solution; taking a proper amount of impurity C, adding methanol for dissolving, and preparing a solution containing 5 microgram of impurity C per 1ml as a control solution; taking a proper amount of the gliquidone and the impurity C respectively, adding methanol for dissolving, and preparing a solution containing 5mg of the gliquidone and 5 mu g of the impurity C per 1ml as a recovery solution. And sequentially injecting the background solution, the control solution and the recovery rate solution, and calculating the recovery rate of the recovery rate solution to be 101.1%.
Example 6
1. Instrumentation and test conditions
Agilent 1260 high performance liquid chromatograph, available from Agilent Inc., available from Agilent ZORBAX Eclipse Plus C18 chromatography column; the detection wavelength is 220 nm; mobile phase: methanol: an aqueous phosphate solution (PH 4.5) changed from 45:55 to 70:30 in 20 minutes; the flow rate is 1 ml/min; the column temperature of the chromatographic column is 35 ℃; the amount of sample was 20. mu.l.
2. Experimental procedure
Taking a proper amount of gliquidone, adding methanol for dissolving to prepare a solution containing 5mg of gliquidone per 1ml as a background solution; taking a proper amount of impurity C, adding methanol for dissolving, and preparing a solution containing 5 microgram of impurity C per 1ml as a control solution; taking a proper amount of the gliquidone and the impurity C respectively, adding methanol for dissolving, and preparing a solution containing 5mg of the gliquidone and 5 mu g of the impurity C per 1ml as a recovery solution. And sequentially injecting the background solution, the control solution and the recovery rate solution, and calculating the recovery rate of the recovery rate solution to be 98.8%.
Example 7
1. Instrumentation and test conditions
Agilent 1260 high performance liquid chromatograph, available from Agilent Inc., available from Agilent ZORBAX Eclipse Plus C18 chromatography column; the detection wavelength is 210 nm; mobile phase: methanol: an aqueous phosphate solution (PH of 3.0) changed from 45:55 to 70:30 in 20 minutes; the flow rate is 1 ml/min; the column temperature of the chromatographic column is 35 ℃; the amount of sample was 20. mu.l.
2. Experimental procedure
Taking a proper amount of gliquidone, adding methanol for dissolving to prepare a solution containing 5mg of gliquidone per 1ml as a background solution; taking a proper amount of impurity C, adding methanol for dissolving, and preparing a solution containing 5 microgram of impurity C per 1ml as a control solution; taking a proper amount of the gliquidone and the impurity C respectively, adding methanol for dissolving, and preparing a solution containing 5mg of the gliquidone and 5 mu g of the impurity C per 1ml as a recovery solution. And sequentially injecting the background solution, the control solution and the recovery rate solution, and calculating the recovery rate of the recovery rate solution to be 100.5%.
Example 8
1. Instrumentation and test conditions
Agilent 1260 high performance liquid chromatograph, available from Agilent Inc., available from Agilent ZORBAX Eclipse Plus C18 chromatography column; the detection wavelength is 210 nm; mobile phase: methanol: an aqueous phosphate solution (PH 5.0) changed from 45:55 to 70:30 in 20 minutes; the flow rate is 1 ml/min; the column temperature of the chromatographic column is 35 ℃; the amount of sample was 20. mu.l.
2. Experimental procedure
Taking a proper amount of gliquidone, adding methanol for dissolving to prepare a solution containing 5mg of gliquidone per 1ml as a background solution; taking a proper amount of impurity C, adding methanol for dissolving, and preparing a solution containing 5 microgram of impurity C per 1ml as a control solution; taking a proper amount of the gliquidone and the impurity C respectively, adding methanol for dissolving, and preparing a solution containing 5mg of the gliquidone and 5 mu g of the impurity C per 1ml as a recovery solution. And sequentially injecting the background solution, the control solution and the recovery rate solution, and calculating the recovery rate of the recovery rate solution to be 101.3%.
Example 9
1. Instrumentation and test conditions
Agilent 1260 high performance liquid chromatograph, available from Agilent Inc., available from Agilent ZORBAX Eclipse Plus C18 chromatography column; the detection wavelength is 210 nm; mobile phase: methanol: an aqueous phosphate solution (PH 4.5) changed from 45:55 to 70:30 in 20 minutes; the flow rate is 0.9 ml/min; the column temperature of the chromatographic column is 35 ℃; the amount of sample was 20. mu.l.
2. Experimental procedure
Taking a proper amount of gliquidone, adding methanol for dissolving to prepare a solution containing 5mg of gliquidone per 1ml as a background solution; taking a proper amount of impurity C, adding methanol for dissolving, and preparing a solution containing 5 microgram of impurity C per 1ml as a control solution; taking a proper amount of the gliquidone and the impurity C respectively, adding methanol for dissolving, and preparing a solution containing 5mg of the gliquidone and 5 mu g of the impurity C per 1ml as a recovery solution. And sequentially feeding the background solution, the control solution and the recovery rate solution, and calculating the recovery rate of the recovery rate solution to be 102.0%.
Example 10
1. Instrumentation and test conditions
Agilent 1260 high performance liquid chromatograph, available from Agilent Inc., available from Agilent ZORBAX Eclipse Plus C18 chromatography column; the detection wavelength is 210 nm; mobile phase: methanol: an aqueous phosphate solution (PH 4.5) changed from 45:55 to 70:30 in 20 minutes; the flow rate is 1.1 ml/min; the column temperature of the chromatographic column is 35 ℃; the amount of sample was 20. mu.l.
2. Experimental procedure
Taking a proper amount of gliquidone, adding methanol for dissolving to prepare a solution containing 5mg of gliquidone per 1ml as a background solution; taking a proper amount of impurity C, adding methanol for dissolving, and preparing a solution containing 5 microgram of impurity C per 1ml as a control solution; taking a proper amount of the gliquidone and the impurity C respectively, adding methanol for dissolving, and preparing a solution containing 5mg of the gliquidone and 5 mu g of the impurity C per 1ml as a recovery solution. And sequentially injecting the background solution, the control solution and the recovery rate solution, and calculating the recovery rate of the recovery rate solution to be 99.2%.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (8)
1. A method for determining the content of impurity C in gliquidone is characterized by comprising the following steps:
step 1, precisely weighing a proper amount of impurity C reference substance, and dissolving and diluting the impurity C reference substance by using methanol to obtain a reference solution;
step 2, taking a proper amount of a gliquidone sample, adding methanol to dissolve and dilute the gliquidone sample to be used as a test solution;
and 3, measuring the reference solution and the sample solution by using a high performance liquid chromatography, and calculating the content of the impurity C in the gliquidone by using an external standard method.
2. The method for determining the content of the impurity C in the gliquidone according to claim 1, characterized in that the high performance liquid chromatography uses a reversed phase chromatographic column, and the gradient elution is carried out by using an organic phase and an aqueous phase; preferably, the organic phase is selected from acetonitrile or methanol; the water phase is selected from phosphate water solution or acetate water solution.
3. The method according to claim 2, wherein the chromatographic column is preferably a chromatographic column using octadecyl bonded silica gel as a filler, a chromatographic column using phenyl bonded silica gel as a filler; more preferably Agilent ZORBAX Eclipse Plus C18.
4. The method of claim 2, wherein the aqueous solution has a PH of 2.0 to 6.0; preferably 3.0 to 5.0.
5. The method for determining the content of the impurity C in the gliquidone according to claim 1, characterized in that the detection wavelength of the high performance liquid chromatography is 200nm to 250 nm; preferably 200nm to 220 nm.
6. The method for determining the content of the impurity C in the gliquidone according to claim 1, wherein the column temperature of the high performance liquid chromatography is 20-50 ℃; preferably 30 to 40 ℃.
7. The method for determining the content of the impurity C in the gliquidone according to claim 1, characterized in that the flow rate of the high performance liquid chromatography is 0.5-1.5 ml/min; preferably 0.9 to 1.1 ml/min.
8. The method according to claim 1, wherein the gradient elution conditions are that the volume ratio of the organic phase to the aqueous phase is changed from 40:60 to 50:50 to 65:35 to 75:25 within 15 to 20 minutes.
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