CN106908525B - A kind of analysis method measuring SC 69124 intermediate with SC 69124 in relation to substance - Google Patents
A kind of analysis method measuring SC 69124 intermediate with SC 69124 in relation to substance Download PDFInfo
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- CN106908525B CN106908525B CN201710027510.1A CN201710027510A CN106908525B CN 106908525 B CN106908525 B CN 106908525B CN 201710027510 A CN201710027510 A CN 201710027510A CN 106908525 B CN106908525 B CN 106908525B
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Abstract
A kind of analysis method measuring SC 69124 intermediate with SC 69124 in relation to substance, it is characterized in that using high performance liquid chromatography, gradient elution is carried out in the chromatographic column of acid seromucoid bonded silica gel using acetonitrile and acetate buffer as mobile phase with acetonitrile-water mixed solution sample dissolution.This method can effectively measure the related substance in SC 69124 intermediate and SC 69124, especially realize the separation of under same chromatographic condition SC 69124 intermediate, SC 69124 and its isomers, side reaction product, catabolite etc., more efficient within a short period of time separation and the related impurities for identifying SC 69124 intermediate and SC 69124 provide more reliable foundation for the quality control of SC 69124.
Description
Technical field
The invention belongs to Pharmaceutical Analysis technical field, it is related to the related of a kind of measurement SC 69124 intermediate and SC 69124
The analysis method of substance, especially with a kind of high performance liquid chromatography simultaneously to the isomery of SC 69124 intermediate and SC 69124
The method that body, side reaction product and catabolite are measured.
Background technique
SC 69124 intermediate 4- (5- methyl -3- phenyl -4- isoxazolyl) benzsulfamide (FD) and SC 69124 are
Specific C OX-2 inhibitor, SC 69124 are the pro-drug of FD, and the two comes under the analgesia of the former times dry goods in anti-arthritic
Medicine.Clinically SC 69124 is sold as the short medicine of postoperative pain in European market at present, after intermediate FD is because of listing
Interests/Hazard ratio is unsatisfactory and withdraws from from American market.The two synthetic route is similar, it is contemplated that the risk of FD is established exclusive
Strong, the sensitive reliable analysis method of property controls the related substance (being shown in Table 1) of FD and SC 69124, to the matter of SC 69124
Amount control is of great significance.
Summary of the invention
The object of the present invention is to provide a kind of measurement SC 69124 intermediate 4- (5- methyl -3- phenyl -4- isoxazolyls)
The high-efficient liquid phase color of the isomers, side reaction product and the catabolite that are generated in benzsulfamide and SC 69124 synthesis route
Spectral analysis method can be used for study on the synthesis and the control of production process quality of SC 69124.
To achieve the above object, the technical scheme is that
A kind of measurement SC 69124 intermediate (FD) is with SC 69124 in relation to the analysis method of substance, using high-efficient liquid phase color
Spectrometry selects the chiral chromatographic column of acid seromucoid bonded silica gel, with acetonitrile-water mixed solution sample dissolution with acetonitrile-vinegar
Phthalate buffer is that mobile phase carries out gradient elution.
The SC 69124 intermediate (FD) is 4- (5- methyl -3- phenyl -4- isoxazolyl) benzsulfamide, and the pa is auspicious
Former times cloth is N- [[4- (5- methyl -3- phenyl -4- isoxazolyl) phenyl] sulfonyl] propionamide, and related substance is impurity A, impurity
B, impurity C, impurity D, impurity E, impurity F and impurity G (being shown in Table 1).
1 SC 69124 of table, FD and its related structure of matter formula
The eluent gradient elution program is shown in Table 2.
2 eluent gradient elution program of table
In the method, analytical solution is made in the acetonitrile-water mixed solution sample dissolution for being 40:60 with volume ratio.
The chromatographic column is CHIRALPAK AGP, 4mm × 100mm, 5 μm.
The flowing phase composition is acetonitrile-ammonium acetate buffer, and wherein ammonium acetate buffer concentration is 0.01mol/L, pH
4.0。
Chromatographic condition includes: that Detection wavelength is 215nm；Mobile phase elution rate is 0.7mL/min；Chromatogram column temperature is 25
℃；Sample injection volume is 10 μ L.
It is generated in SC 69124 synthesis route the beneficial effects of the present invention are: can effectively measure within a short period of time
Isomers, side reaction product and degradation impurity, have saved the time, reduce testing cost, can be used for SC 69124 study on the synthesis
It is controlled with the quality of production process, the quality of Related product is made to be guaranteed.
Detailed description of the invention
Reference substance liquid chromatogram after the deduction blank operation of Fig. 1 embodiment 1.
Reference substance liquid chromatogram after the deduction blank operation of Fig. 2 embodiment 2.
Test sample liquid chromatogram after the deduction blank operation of Fig. 3 embodiment 2.
In figure: 1- SC 69124；2-FD；3- impurity A；4- impurity B；5- impurity C；6- impurity D；7- impurity E；8- impurity F；
9- impurity G.
Specific embodiment
Technical solution of the present invention is further described below in conjunction with specific embodiment, the embodiment provided is only for illustrating this
Invention, the range being not intended to be limiting of the invention.
This experimental evidence chromatographic column operation instructions are recommended, preferential that isopropanol system, acetonitrile system is selected to carry out investigation examination
It tests.On the basis of considering the Detection wavelength of the durability that chromatographic column uses, measurement ingredient, determine to use acetonitrile system.In second
Each chromatographic peak peak shape is poor after finding sample introduction after testing in nitrile system, and separating degree is bad, therefore considers that buffer salt is added, after test
Preferably 0.01mol/L ammonium acetate solution.
Embodiment 1
(1) instrument and chromatographic condition
High performance liquid chromatograph: 1260 highly effective liquid phase chromatographic system of Agilent and work station.
Chromatographic column: acid seromucoid chromatographic column (CHIRALPAK AGP, 4mm × 100mm, 5 μm).
The ammonium acetate solution for preparing 0.01mol/L is water phase, acetonitrile-water phase in mobile phase with vinegar acid for adjusting pH value to 6.0
Ratio carries out gradient elution by table 3, and setting flow velocity is 0.6mL/min, and Detection wavelength 215nm, column temperature is 25 DEG C.
Table 3
(2) experimental procedure
Take SC 69124, FD, impurity A, B, C, D, E, F, G reference substance appropriate respectively, simultaneously with acetonitrile-water (40:60) dissolution
The mixed solution containing SC 69124, FD, about 2 μ g of each impurity is made in every 1mL in dilution, as reference substance solution.Pa Rui is taken respectively
Former times cloth sample, FD sample, impurity A, B, C, D, E, F, appropriate G, with method prepare in every 1mL containing about SC 69124, FD 0.5mg and
The mixed solution of other each 2 μ g of impurity, as test solution.
(3) measuring method and result
It takes above-mentioned 10 μ L of solution by (1) chromatographic condition sample introduction, runs 46min, record chromatogram, investigate SC 69124, FD
With the separating degree between each impurity, each impurity.The result shows that each impurity separating degree is good (see Fig. 1) in reference substance solution, but supply
SC 69124 chromatographic peak is split point in test sample solution, and impurity is influenced when measuring related substance in SC 69124 and is separated with main peak
Degree.Advanced optimize chromatographic condition such as embodiment 2.
Embodiment 2
(1) instrument and chromatographic condition
High performance liquid chromatograph: 1260 highly effective liquid phase chromatographic system of Agilent and work station.
Chromatographic column: acid seromucoid chromatographic column (CHIRALPAK AGP, 4mm × 100mm, 5 μm).
The ammonium acetate solution for preparing 0.01mol/L is water phase, acetonitrile-water phase in mobile phase with vinegar acid for adjusting pH value to 4.0
Ratio carries out gradient elution by table 4, and setting flow velocity is 0.7mL/min, and Detection wavelength 215nm, column temperature is 25 DEG C.
Table 4
(2) experimental procedure
Take SC 69124, FD, impurity A, B, C, D, E, F, G reference substance appropriate respectively, simultaneously with acetonitrile-water (40:60) dissolution
The mixed solution containing SC 69124, FD, about 2 μ g of each impurity is made in every 1mL in dilution, as reference substance solution.Pa Rui is taken respectively
Former times cloth sample, FD sample, impurity A, B, C, D, E, F, appropriate G, with method prepare in every 1mL containing about SC 69124, FD 0.5mg and
The mixed solution of other each 2 μ g of impurity, as test solution.
(3) measuring method and result
Take above-mentioned 10 μ L of solution by (1) chromatographic condition sample introduction, run 42min, record chromatogram, investigate SC 69124, in
Separating degree between mesosome, each impurity.The result shows that each impurity separating degree of reference substance solution is good (see Fig. 2), test solution
In separating degree is good between each impurity and principal component, each ingredient chromatographic peak peak shape is good (see Fig. 3).
Claims (5)
1. a kind of analysis method of measurement SC 69124 intermediate FD with SC 69124 in relation to substance, characterized in that using efficient
Liquid chromatography is selected the chiral chromatographic column of acid seromucoid bonded silica gel, is made with acetonitrile-water mixed solution sample dissolution
Gradient elution is carried out with acetonitrile-acetic acid ammonium acetate buffer, acetic acid ammonium acetate buffer pH is 4.0, Detection wavelength 215nm；
The SC 69124 intermediate FD is 4- (5- methyl -3- phenyl -4- isoxazolyl) benzsulfamide, and the SC 69124 is
N- [[4- (5- methyl -3- phenyl -4- isoxazolyl) phenyl] sulfonyl] propionamide, related substance is impurity A, impurity B, impurity
C, impurity D, impurity E, impurity F and impurity G:
The eluent gradient elution program is:
2. in analysis method as described in claim 1, characterized in that the acetonitrile-water mixed solution for being 40:60 with volume ratio is molten
Solve sample.
3. in analysis method as described in claim 1, characterized in that the chromatographic column be CHIRALPAKAGP, 4mm ×
100mm, 5 μm.
4. in analysis method as described in claim 1, characterized in that the acetonitrile-acetic acid ammonium acetate buffer, wherein vinegar
Sour ammonium acetate buffer concentration is 0.01mol/L, pH4.0.
5. in analysis method as described in claim 1, characterized in that chromatographic condition includes: that Detection wavelength is 215nm, flowing
Phase elution rate is 0.7mL/min, and chromatogram column temperature is 25 DEG C, and sample injection volume is 10 μ L.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108164521B (en) * | 2018-03-02 | 2020-11-13 | 成都新恒创药业有限公司 | Parecoxib sodium degradation impurity, and preparation method, detection method and application thereof |
| CN108828127A (en) * | 2018-06-21 | 2018-11-16 | 上药东英（江苏）药业有限公司 | Liquid-phase chromatography method in relation to substance in a kind of detection Parecoxib Sodium and synthetic intermediate |
| CN111089931A (en) * | 2019-11-28 | 2020-05-01 | 上海秀新臣邦医药科技有限公司 | Detection method of parecoxib sodium gene genotoxicity impurity |
| CN114441666B (en) * | 2020-11-05 | 2024-02-27 | 成都百裕制药股份有限公司 | Method for detecting impurities in 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride |
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| WO2005065684A1 (en) * | 2003-12-24 | 2005-07-21 | Pharmacia Corporation | Metal salts of parecoxib as prodrugs of the cox-2 inhibitor valdecoxib for the treatment of inflammation, pain and/or fever |
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| CN105651927A (en) * | 2014-11-14 | 2016-06-08 | 泰州复旦张江药业有限公司 | An RT-HPLC detecting method for valdecoxib/parecoxib related substances |
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| WO2005065684A1 (en) * | 2003-12-24 | 2005-07-21 | Pharmacia Corporation | Metal salts of parecoxib as prodrugs of the cox-2 inhibitor valdecoxib for the treatment of inflammation, pain and/or fever |
| CN105651927A (en) * | 2014-11-14 | 2016-06-08 | 泰州复旦张江药业有限公司 | An RT-HPLC detecting method for valdecoxib/parecoxib related substances |
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