CN114295740A - Method for analyzing and detecting isomerate of pamixb - Google Patents
Method for analyzing and detecting isomerate of pamixb Download PDFInfo
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- CN114295740A CN114295740A CN202111526248.8A CN202111526248A CN114295740A CN 114295740 A CN114295740 A CN 114295740A CN 202111526248 A CN202111526248 A CN 202111526248A CN 114295740 A CN114295740 A CN 114295740A
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- 238000000034 method Methods 0.000 title claims abstract description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 51
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 14
- 238000001514 detection method Methods 0.000 claims abstract description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 7
- 239000007975 buffered saline Substances 0.000 claims abstract description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 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
- 239000000243 solution Substances 0.000 claims description 38
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 claims description 20
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 11
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 11
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical group [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 11
- 239000012085 test solution Substances 0.000 claims description 4
- 239000000337 buffer salt Substances 0.000 claims 2
- 239000007864 aqueous solution Substances 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000002347 injection Methods 0.000 abstract description 3
- 239000007924 injection Substances 0.000 abstract description 3
- 239000012535 impurity Substances 0.000 abstract 1
- 238000005457 optimization Methods 0.000 abstract 1
- 239000000523 sample Substances 0.000 description 15
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 10
- 238000007865 diluting Methods 0.000 description 8
- 239000011259 mixed solution Substances 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 6
- 230000014759 maintenance of location Effects 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 5
- IJWPAFMIFNSIGD-UHFFFAOYSA-N 4-[3-(3-fluorophenyl)-5,5-dimethyl-4-oxofuran-2-yl]benzenesulfonamide Chemical compound O=C1C(C)(C)OC(C=2C=CC(=CC=2)S(N)(=O)=O)=C1C1=CC=CC(F)=C1 IJWPAFMIFNSIGD-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 229950006009 polmacoxib Drugs 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for detecting an isomer of pamixb by an HPLC method, belonging to the technical field of medicines. The invention adopts an HPLC method to realize the detection of the isomerate of the pamixb, and the chromatographic conditions for determining the isomerate in the pamixb by the HPLC method are as follows: a chromatographic column: pentafluorophenyl bonded silica gel column, mobile phase: methanol and 0.01 to 0.05mol/L of a buffered saline solution, flow rate: 0.5-1.0ml/min, column temperature: 10-30 ℃, detection wavelength: 230nm, sample injection volume: and (3) detecting two isomeric impurities of the pamixib in the synthesized product through a high performance liquid chromatography, and accurately controlling the quality of the pamixib, so that the optimization process is facilitated, and the product quality and the safety are improved.
Description
Technical Field
The invention relates to the technical field of drug analysis, in particular to an analysis and detection method of a pamixb isomer.
Background
Pamipoxib is a selective COX-2 inhibitor, originally developed by the Korea CrystalGenomics company, and first approved in Korea on month 2 in 2015 under the trade name Acelex for use in the treatment of osteoarthritis.
The pamixib article is named as Polmacoxib, the chemical name is 4- [3- (3-fluorophenyl) -5, 5-dimethyl-4-oxo-4, 5-dihydrofuran-2-yl ] -benzenesulfonamide, and the pamixib article has a structure shown in a formula I:
in the synthesis process of the pamixib, two isomers with different fluorine substitution positions on a benzene ring are generated, and the structural formulas of the two isomers are respectively shown as a formula II and a formula III:
due to the existence of isomers, the content and the purity of the pamixib can be influenced. In order to ensure the safety and the effectiveness of clinical medication, the content of isomers in the pamixb is necessary to be controlled. In the prior art, no analytical method for detecting the isomerous body of the pamixib exists. Therefore, in order to improve the safety and the effectiveness of the pamixb, a quantitative detection method of the pamixb isomer, which is simple to operate, high in sensitivity and good in reproducibility, is urgently needed to be established.
Disclosure of Invention
The invention aims to provide a method for detecting an isomer of pamixb by adopting a high performance liquid chromatography. Provides a simple and efficient detection method for controlling the product quality.
The technical scheme of the invention is a method for detecting the Pamifoxib isomer by adopting a high performance liquid chromatography, wherein the chromatographic conditions for detecting the Pamifoxib isomer by adopting the high performance liquid chromatography are as follows:
a chromatographic column: a pentafluorophenyl bonded silica gel column, preferably a Phenomenex Lux 5u Cellulose-3 column (5 μm, 4.6 mm. times.250 mm);
mobile phase: methanol and 0.01-0.05mol/L of a buffered saline solution, the buffered saline solution is preferably potassium dihydrogen phosphate, the pH value of the buffered saline solution is preferably 3.0, and the ratio of methanol to the buffered saline solution is preferably 47.5: 52.5;
flow rate: 0.5-1.0ml/min, preferably 0.7 ml/min; column temperature: 10 ℃ to 30 ℃, preferably 20 ℃; the detection wavelength is 230 nm;
sample introduction volume: 20 μ l.
Compared with the prior art, the invention has the beneficial effects that: through high performance liquid chromatography, two isomers in the pamixb are detected simultaneously, the quality of the pamixb is controlled, and the quality and the safety of products are favorably improved. The present invention will be described in detail with reference to the following examples and accompanying drawings.
Example 1
(1) Experimental materials and experimental conditions: a chromatographic column: phenomenex Lux 5u Cellulose-3 column (5 μm, 4.6 mm. times.250 mm); mobile phase: methanol-0.02 mol/L potassium dihydrogen phosphate solution (pH 3.0 adjusted with phosphoric acid) (47.5: 52.5); flow rate: 0.7 ml/min; column temperature: 20 ℃; detection wavelength: 230 nm; sample introduction volume: 20 mu l of the mixture;
(2) the experimental steps are as follows: taking a proper amount of a pamixib sample, dissolving and diluting the pamixib sample by using methanol to prepare a solution containing about 0.5mg in each 1ml of the pamixib sample as a pamixib solution; dissolving isomer A with methanol, diluting to obtain solution containing about 25 μ g per 1ml as isomer A solution; dissolving isomer B with methanol, diluting to obtain solution containing about 25 μ g per 1ml as isomer B solution; taking a pamixib sample, an isomer A and an isomer B, dissolving and diluting with methanol to prepare a mixed solution containing 0.5mg of pamixib and 25 micrograms of each of the isomer A and the isomer B in each 1ml of the mixed solution, taking the mixed solution as a mixed solution, respectively measuring the pamixib solution, the isomer A solution, the isomer B solution and the mixed solution, respectively injecting into a chromatograph, and recording a chromatogram, wherein the chromatogram is shown in figures 1, 2, 3 and 4;
(3) and (3) analyzing an experimental result: according to the figures 1, 2 and 3, the pamixib has a chromatographic peak with a retention time of about 19.5min, the isomer A has a chromatographic peak with a retention time of about 13.2min, and the isomer B has a chromatographic peak with a retention time of about 18.7 min; according to the figure 4, the separation degrees of the pamixib, the isomer A and the isomer B in the mixed solution are all larger than 1.5, and the isomer A and the isomer B can be completely separated from the pamixib.
Example 2:
(1) experimental materials and experimental conditions: a chromatographic column: phenomenex Lux 5u Cellulose-3 column (5 μm, 4.6 mm. times.250 mm); mobile phase: methanol-0.05 mol/L potassium dihydrogen phosphate solution (pH 3.0 adjusted with phosphoric acid) (45: 55); flow rate: 1.0 ml/min; column temperature: 15 ℃; detection wavelength: 230 nm; sample introduction volume: 20 mu l of the mixture;
(2) taking a proper amount of a pamixb sample containing isomers, dissolving and diluting the pamixb sample with methanol to prepare a solution containing about 0.5mg of the pamixb sample in each 1ml of the pamixb sample, taking the solution as a test solution, measuring the test solution, injecting the solution into a chromatograph, and recording a chromatogram, wherein the chromatogram is shown in figure 5;
(3) according to the analysis of the experimental results, according to the figure 5, the isomer A and the isomer B in the sample solution can be completely separated from the main peak of the pamixb.
Example 3:
under the same conditions (i.e. column: Phenomenex Lux 5u cell lose-3 column (5 μm, 4.6 mm. times.250 mm), mobile phase: methanol-0.02 mol/L potassium dihydrogen phosphate solution (pH 3.0 adjusted with phosphoric acid), flow rate: 0.7ml/min, column temperature: 20 ℃, measurement wavelength: 230nm, injection volume: 20. mu.l.), a series of experimental screenings were carried out for the change of the ratio of the mobile phase methanol-0.02 mol/L potassium dihydrogen phosphate solution, and as a result, it was found that the ratio of the methanol-0.02 mol/L potassium dihydrogen phosphate solution was 45-50: the analysis results are better between 55 and 50, and particularly, the ratio of methanol to 0.02mol/L potassium dihydrogen phosphate solution is 47.5: at 52.5, the chromatographic conditions were optimal, as shown in table 1:
| methanol-buffered saline solution | 45：55 | 47.5：52.5 | 50：50 |
| Degree of separation of three | 12.3、12.3、1.7 | 10.5、10.5、1.8 | 8.5、8.5、1.5 |
| Number of theoretical plates | 14865、18714、11601 | 14569、15255、10304 | 13891、12246、8938 |
| Tailing factor | 1.24、1.15、1.50 | 1.17、1.09、1.40 | 1.22、1.14、1.63 |
In Table 1, the ratios of methanol to 0.02mol/L potassium dihydrogen phosphate solution are 45: 55. 47.5: 52.5, 50: at 50 hours, the resolution of chromatographic peaks of the pamixib, the isomer A and the isomer B, the number of theoretical plates and experimental result parameters of the tailing factor are consistent with the obtained experimental conclusion.
Example 4:
under the same conditions (i.e. column: Phenomenex Lux 5u cell lose-3 column (5 μm, 4.6 mm. times.250 mm), mobile phase: methanol-0.02 mol/L potassium dihydrogen phosphate solution (pH 3.0 adjusted by phosphoric acid) (47.5: 52.5), flow rate: 0.7ml/min, measurement wavelength: 230nm, injection volume: 20 μ L), this example performed a series of experimental screenings for the change of column temperature, and found that the column temperature was between 10-30 deg.C, especially when the column temperature was 20 deg.C, the chromatographic conditions were optimal, as shown in Table 2
| | 10 | 20 | 30℃ |
| Degree of separation of three | 11.8、11.8、1.7 | 10.5、10.5、1.8 | 8.6、8.6、1.6 |
| Number of theoretical plates | 14472、14983、10264 | 14569、15255、10304 | 14952、15376、10428 |
| Tailing factor | 1.20、1.10、1.48 | 1.17、1.09、1.40 | 1.19、1.11、1.45 |
The separation degrees of chromatographic peaks of the pamixib, the isomer a and the isomer B, the number of theoretical plates and experimental result parameters of the tailing factor at 10 ℃, 20 ℃ and 30 ℃ in table 2 correspond to the obtained experimental conclusion.
Example 5: (comparative example)
(1) Experimental materials and conditions
A chromatographic column: a C18 column (5 μm, 4.6 mm. times.250 mm); mobile phase: methanol-0.05 mol/L potassium dihydrogen phosphate solution (pH 3.0 adjusted with phosphoric acid) (45: 55); flow rate: 1.0 ml/min; column temperature: 25 ℃; detection wavelength: 230 nm; sample introduction volume: 20 mu l of the mixture;
(2) experimental procedure
Taking a proper amount of a pamixib sample, dissolving and diluting the pamixib sample by using methanol to prepare a solution containing about 0.5mg in each 1ml of the pamixib sample as a pamixib solution; dissolving isomer A with methanol, diluting to obtain solution containing about 25 μ g per 1ml as isomer A solution; dissolving isomer B with methanol, diluting to obtain solution containing about 25 μ g of isomer B per 1ml, measuring Pamifixib solution, isomer A solution, and isomer B solution, respectively, injecting into chromatograph, and recording chromatogram, as shown in FIGS. 6, 7, and 8.
(3) Analysis of Experimental results
According to fig. 6, 7 and 8, pamixib has a chromatographic peak with a retention time of about 13.2min, isomer a has a chromatographic peak with a retention time of about 13.0min, and isomer B has a chromatographic peak with a retention time of about 13.1 min. The residence times of pamixib, isomer a and isomer B are substantially the same and cannot be completely separated.
From the above results, it can be seen that: the ordinary C18 chromatographic column cannot well separate the isomerate of the pamixb, but the separation effect becomes good after the pentafluophenyl chromatographic column is replaced by the method, the sensitivity is high, the specificity is strong, and the separation degree meets the requirement.
Drawings
FIG. 1 is a chromatogram of a pamixib solution of example 1;
FIG. 2 is a chromatogram of the isomer A solution of example 1;
FIG. 3 is a chromatogram of the isomer B solution of example 1;
FIG. 4 is a mixed solution chromatogram of example 1;
FIG. 5 is a chromatogram of the isomer-containing test solution of example 2;
FIG. 6 is a chromatogram of the pamixib solution of example 5;
FIG. 7 is a chromatogram of the isomer A solution of example 5;
FIG. 8 is a chromatogram of the isomer B solution of example 5.
Claims (5)
1. A method for detecting isomerate of pamixb by an HPLC method is characterized in that: the reagent is used for detecting isomer A and isomer B in the pamixb, wherein the structural formula of the isomer A is as follows:
the structural formula of the isomer B is as follows:
the chromatographic conditions for measuring the isomers in the pamixb by the HPLC method are as follows: a chromatographic column: pentafluorophenyl bonded silica gel column, mobile phase: methanol and 0.01 to 0.05mol/L of a buffered saline solution, flow rate: 0.5-1.0ml/min, column temperature: 10-30 ℃, detection wavelength: 230 nm; sample introduction volume: 20 mul.
2. The method for measuring isomers of pamixb by HPLC method as claimed in claim 1, wherein: the pentafluorophenyl bonded silica gel column is a Phenomenex Lux 5u Cellulose-3 column (5 mu m, 4.6mm multiplied by 250 mm).
3. The method for measuring isomers of pamixb by HPLC method as claimed in claim 1, wherein: the buffer salt in the mobile phase is potassium dihydrogen phosphate, the pH value of the solution is 3.0, and the ratio of methanol to the buffer salt aqueous solution is 47.5: 52.5.
4. the method for measuring isomers of pamixb by HPLC method as claimed in claim 1, wherein: the column temperature was chosen to be 20 ℃.
5. The method for measuring isomers of pamixb by HPLC according to any one of claims 1 to 4, wherein: when preparing the test solution, the test sample is dissolved and diluted with methanol to prepare a solution containing 0.5mg of the test sample per 1ml of the solution.
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| CN101936959A (en) * | 2009-07-03 | 2011-01-05 | 北京京卫燕康药物研究所有限公司 | High performance liquid chromatography (HPLC) for fast separating and analyzing zafirlukast and isomers thereof |
| CN104965041A (en) * | 2015-06-11 | 2015-10-07 | 成都克莱蒙医药科技有限公司 | High performance liquid chromatography detection method for parecoxib sodium isomer |
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-
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- 2021-12-15 CN CN202111526248.8A patent/CN114295740A/en active Pending
Patent Citations (5)
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