CN111077235B - Method for determining 2- [ (2-methyl-5-bromophenyl) methyl ] -5- (4-fluorophenyl) thiophene impurity - Google Patents
Method for determining 2- [ (2-methyl-5-bromophenyl) methyl ] -5- (4-fluorophenyl) thiophene impurity Download PDFInfo
- Publication number
- CN111077235B CN111077235B CN201811224636.9A CN201811224636A CN111077235B CN 111077235 B CN111077235 B CN 111077235B CN 201811224636 A CN201811224636 A CN 201811224636A CN 111077235 B CN111077235 B CN 111077235B
- Authority
- CN
- China
- Prior art keywords
- methyl
- solution
- diluent
- thiophene
- bromophenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- 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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
- G01N2030/065—Preparation using different phases to separate parts of sample
Abstract
The invention provides a method for determining defluorination (BMPT) and o-fluorine (BMOF) impurities of a canagliflozin starting material 2- [ (2-methyl-5-bromophenyl) methyl ] -5- (4-fluorophenyl) thiophene (BMFT). According to the method, a liquid chromatography method is adopted, a pentafluoro-phenyl chromatographic column is used as a stationary phase, acetonitrile-sodium dihydrogen phosphate buffer solution is used as a mobile phase, a starting material BMFT, impurities BMPT and BMOF can be effectively separated, the peak shape of each impurity is good, the column efficiency is high, the specificity is good, and the quality of a canagliflozin starting material (BMFT) is well controlled.
Description
Technical Field
The invention belongs to the field of analytical chemistry, and particularly relates to a method for preparing 2- [ (2-methyl-5-bromophenyl) methyl ] -5- (4-fluorophenyl) thiophene and impurities thereof.
Background
2- [ (2-methyl-5-bromophenyl) methyl group]-5- (4-fluorophenyl) thiophene (hereinafter referred to as "BMFT"), which is a key starting material for the production of canagliflozin, a novel drug for diabetes that improves glycemic control, developed by the young company under the flag of strong united states, is marketed as an inhibitor of sodium-glucose cotransporter 2 (SGLT 2), and is used in combination with dietary control and exercise to improve glycemic control in adult patients with type 2 diabetes. Control of BMPT with two important impurities in BMFT and BMOF with o-fluorine is important, and BMFT has a molecular formula of C 18 H 14 BrFS, a compound of formula (I) having the chemical formula: 2- [ (2-methyl-5-bromophenyl) methyl group]-5- (4-fluorophenyl) thiophene
。
During the synthesis of BMFT, impurities of 2- (5-bromo-2-methylbenzyl) -5-phenylthiophene (BMPT for short) and 2- (5-bromo-2-methylphenyl) -5- (2-fluorophenyl) thiophene (BMOF for short) are generated, wherein the BMPT has a molecular formula of C 18 H 15 BrS the BMOF has the formula C 18 H 14 BrFS of the chemical structural formula
。
Using conventional general C 18 And conventional mobile phase HPLC, it is difficult to separate these two impurities (BMOF, BMPT) from BMFT effectively, peak shape is poor, column efficiency is low, and they are completely coincident.
In order to effectively control the quality of the starting material BMFT of the canagliflozin and ensure the quality of finished canagliflozin, it is necessary to research a measuring method capable of effectively separating the canagliflozin starting material (BMFT) from the two impurities, so that the effective control of the impurities BMOF and BMPT in the canagliflozin starting material (BMFT) is realized, and the method has important significance for the quality control of the canagliflozin bulk drug and the preparation.
Disclosure of Invention
The invention aims to provide a method for separating and measuring 2- [ (2-methyl-5-bromophenyl) methyl ] -5- (4-fluorophenyl) thiophene and impurities thereof, which can effectively separate and measure 2- [ (2-methyl-5-bromophenyl) methyl ] -5- (4-fluorophenyl) thiophene (BMFT) and impurities thereof (BMPT, BMOF), realize quality control of a canagliflozin starting material and ensure quality of a canagliflozin finished product.
In one embodiment, a method of the present invention for the isolation of 2- [ (2-methyl-5-bromophenyl) methyl ] -5- (4-fluorophenyl) thiophene and its impurities, which impurity compounds are 2- [ (2-methyl-5-bromophenyl) methyl ] -5- (2-fluorophenyl) thiophene (BMOF) and 2- [ (2-methyl-5-bromophenyl) methyl ] -5-phenyl) thiophene (BMPT), is a liquid chromatography method comprising: 1) the column is a pentafluoro-phenyl column, preferably a PFP 4.6x250 mm,5 μm column, 2) the mobile phase consists of acetonitrile-buffer, wherein the buffer is sodium dihydrogen phosphate, 3) the volume ratio of acetonitrile to buffer in the mobile phase is: acetonitrile is 50% -60%, and buffer solution is 40% -50%.
Preferably, in the above method of the present invention, the pH value of the buffer solution ranges from 2.0 to 8.0, preferably 2.5; the volume ratio of acetonitrile to buffer in the mobile phase acetonitrile-buffer is 55:45.
The above-described method for separating and measuring 2- [ (2-methyl-5-bromophenyl) methyl ] -5- (4-fluorophenyl) thiophene and its impurities according to the present invention further comprises the steps of:
a) Control solution: accurately weighing 15mg of each of the impurity compounds BMPT and BMOF reference substances, respectively placing into 100ml volumetric flasks, dissolving and diluting to scale with a diluent, shaking uniformly, taking the mixture as a reference substance stock solution, accurately weighing 1ml of the reference substance stock solution, placing into the same 100ml volumetric flask, diluting to scale with the diluent, shaking uniformly, and taking the mixture as a mixed reference substance solution, wherein the sample solution is as follows: taking BMFT 25mg, placing in a bottle with 25ml capacity, dissolving with a diluent, diluting to a scale, and shaking uniformly to obtain a sample solution;
b) Setting the flow rate of the mobile phase to be 1.0-1.5 ml/min, the pH value range of the buffer solution in the mobile phase to be 2.0-8.0, the detection wavelength to be 210-290 nm, the column temperature of the chromatographic column to be 20-35 ℃ and the sample injection amount to be 5-100 mu L;
c) Taking the same volume of the mixed control solution and the sample solution in the step a), respectively injecting the mixed control solution and the sample solution into a liquid chromatograph, recording a chromatogram, and completing the separation and the determination of the canagliflozin starting material BMFT and impurities BMPT and BMOF thereof.
In the above method of the present invention, the diluent in step a) is acetonitrile, the flow rate of the mobile phase in step b) is 1.5ml/min, the detection wavelength is 210nm, the pH value of the buffer solution in the mobile phase is 2.5, the column temperature of the chromatographic column in step b) is 30 ℃, and the sample injection amount is 20. Mu.L.
In a specific embodiment, the method of the invention, the specific chromatographic conditions are preferably as follows:
instrument: agilent 1260 high performance liquid chromatograph
Chromatographic column: PFP, 4.6X105 mm,5 μm;
sample injection amount: 20 μl;
flow rate: 1.5ml/min;
column temperature: 30 ℃;
detection wavelength: 210nm;
a diluent: acetonitrile
Mobile phase: sodium dihydrogen phosphate solution (pH value is adjusted to 2.5 by phosphoric acid) with the concentration of 0.002 mol/L: acetonitrile (45:55V/V).
The method has the beneficial effects that: the method can effectively separate defluorination (BMPT) and o-fluorine (BMOF) impurities of the canagliflozin starting material (BMFT), can accurately measure the defluorination (BMPT) and the o-fluorine (BMOF) impurities of the canagliflozin starting material (BMFT), has symmetrical peak shape and higher column efficiency, and can accurately control the quality of the canagliflozin starting material (BMFT), and the defluorination (BMPT) and the o-fluorine (BMOF) impurities of the canagliflozin starting material (BMFT) can be simply, quickly and accurately separated and detected.
Particularly, the method adopts the pentafluoro-phenyl chromatographic column, and the chromatographic column has low cost, can effectively separate and detect defluorinated (BMPT) and o-fluoro (BMOF) impurities of the canagliflozin starting material (BMFT), and can also reach corresponding requirements on sensitivity. Acetonitrile is selected as a diluent to dissolve the sample, so that the sample is prevented from being separated out in a mobile phase, impurities and the sample can be fully dissolved, and larger solvent peak interference is avoided; the column temperature is 30 ℃, the durability of the column temperature is good, the peak shape is good, and the separation degree can be optimized. The mobile phase was adjusted to pH 2.5 with phosphoric acid in a 0.002mol/L sodium dihydrogen phosphate solution: acetonitrile (45:55) can effectively separate defluorination (BMPT) and ortho-fluorine (BMOF) impurities of a canagliflozin starting material (BMFT), and meanwhile, the working efficiency is improved. The invention solves the problem that defluorination (BMPT) and o-fluorine (BMOF) impurities of the starting material (BMFT) for separating and measuring the canagliflozin are difficult to separate, thereby ensuring the quality controllability of the canagliflozin starting material (BMFT).
Drawings
FIG. 1 is a liquid chromatogram of a blank solvent;
FIG. 2 impurity defluorination (BMPT), ortho-fluorine (BMOF) localization liquid chromatograms (2-1, 2-2);
FIG. 3 is a liquid chromatogram of impurity defluorination (BMPT) and ortho-fluoro (BMOF) control mixtures;
FIG. 4 liquid chromatogram of a canagliflozin starting material (BMFT) mixed with defluorinated (BMPT), ortho-fluoro (BMOF);
FIG. 5 is a liquid chromatogram of a sample solution of canagliflozin starting material (BMFT);
Detailed Description
The following examples serve to further illustrate and understand the spirit of the invention but do not limit the scope of the invention in any way.
Example 1
Instrument and conditions
An Agilent 1260 liquid chromatograph and Instrument workstation in the united states; automatic sample injection;
instrument: agilent 1260 high performance liquid chromatograph
Chromatographic column: PFP, 4.6X105 mm,5 μm;
sample injection amount: 20 μl;
flow rate: 1.5ml/min;
column temperature: 30 ℃;
detection wavelength: 210nm;
a diluent: acetonitrile
Mobile phase: sodium dihydrogen phosphate solution (pH value is adjusted to 2.5 by phosphoric acid) with the concentration of 0.002 mol/L: acetonitrile (45:55).
The experimental steps are as follows:
preparing an impurity stock solution: respectively precisely weighing about 15mg of reference substances of BMOF and BMPT, respectively placing into 100ml volumetric flasks, adding a proper amount of diluent, performing ultrasonic treatment to dissolve, diluting with the diluent to scale, shaking uniformly to obtain impurity stock solution I, precisely weighing 5ml of reference substances, placing into 50ml volumetric flasks, diluting with the diluent to scale, and shaking uniformly to obtain impurity stock solution II.
Preparing a positioning solution: respectively placing 1ml of the above impurity stock solution into different 100ml volumetric flasks, diluting with diluent to scale, and shaking to obtain positioning solutions (see figures 2-1 and 2-2).
Preparing a mixed reference substance solution: and (3) putting 5ml of each impurity stock solution II into the same 50ml volumetric flask, diluting with a diluent to a scale, and shaking uniformly to obtain the final product (see figure 3).
Preparing a sample and mixed impurity reference substance solution: taking 25mg of BMFT sample, precisely weighing, placing into a 25ml volumetric flask, adding 2.5ml of each impurity stock solution II and a proper amount of diluent, performing ultrasonic treatment to dissolve, diluting to scale with the diluent, and shaking uniformly to obtain the final product (see figure 4).
Respectively taking blank solution (diluent), positioning solution, mixed control solution and impurity control solution of sample, performing liquid chromatography according to the above chromatographic conditions, and recording chromatogram; the results are shown in fig. 1, fig. 2, fig. 3 and fig. 4.
The retention time 28.939min in FIG. 2 (2-1) is impurity defluorination (BMPT) and the retention time 30.529min in FIG. 2 (2-2) is chromatographic peak of impurity o-fluorine (BMOF),
fig. 1 shows that the solvent does not interfere with the assay,
FIG. 4 shows that the method can effectively detect impurity defluorination (BMPT) and o-fluorine (BMOF) of the canagliflozin starting material (BMFT), the separation degree is more than 1.5, and the method can be used for measuring the impurity defluorination (BMPT) and the o-fluorine (BMOF) of the canagliflozin starting material (BMFT).
Example 2
Instrument and conditions (same example 1)
An Agilent 1260 liquid chromatograph and Instrument workstation in the united states; automatic sample injection;
instrument: agilent 1260 high performance liquid chromatograph
Chromatographic column: PFP, 4.6X105 mm,5 μm;
sample injection amount: 20 μl;
flow rate: 1.5ml/min;
column temperature: 30 ℃;
detection wavelength: 210nm;
a diluent: acetonitrile
Mobile phase: sodium dihydrogen phosphate solution (pH value is adjusted to 2.5 by phosphoric acid) with the concentration of 0.002 mol/L: acetonitrile (45:55).
The experimental steps are as follows:
the defluorinated (BMPT), ortho-fluoro (BMOF) impurities of the canagliflozin starting material (BMFT) were determined by liquid chromatography.
Taking the BMFT of about 25mg, precisely weighing, placing into a 25ml measuring flask, dissolving with a diluent, diluting to a scale, and shaking uniformly to obtain a sample solution. Preparing a reference substance solution: respectively taking 5ml of the impurity stock solution II, placing into a 50ml volumetric flask, adding diluent to dilute to scale, shaking uniformly, and taking as reference substance solution. The liquid chromatography was performed according to the chromatographic conditions of example 1, and the content of the sample solution was calculated according to the external standard method, except for the solvent peak and the system peak, if there was a chromatographic peak at the position corresponding to the defluorination (BMPT) and the ortho-fluorine (BMOF) impurities, and if there was no chromatographic peak at the position corresponding to the defluorination (BMPT) and the ortho-fluorine (BMOF) impurities, the content was not calculated. The results are shown in FIG. 5.
Comparison experiment:
instrument and conditions
An Agilent 1260 liquid chromatograph and Instrument workstation in the united states; automatic sample injection;
instrument: agilent 1260 high performance liquid chromatograph
Column temperature: 30 ℃;
detection wavelength: 210nm;
a diluent: acetonitrile
Sample injection amount: 20 μl;
flow rate: 1.5ml/min
The steps are as follows:
preparing an impurity stock solution: respectively precisely weighing about 15mg of each of the BMOF and BMPT reference substances, respectively placing into 100ml volumetric flasks, adding a proper amount of diluent, performing ultrasonic treatment to dissolve, diluting with the diluent to a scale, shaking uniformly to obtain an impurity stock solution I, precisely weighing 5ml of the impurity stock solution I, placing into 50ml volumetric flasks, diluting with the diluent to the scale, and shaking uniformly to obtain an impurity stock solution II.
Preparing a mixed reference substance solution: and (3) putting 5ml of each impurity stock solution II into the same 50ml volumetric flask, adding a diluent to dilute to a scale, and shaking uniformly to obtain the product.
Test solution: adding mixed reference substance solution into sample, precisely weighing 25mg of the sample, placing into 25ml volumetric flask, adding 2.5ml of each impurity stock solution II and appropriate amount of diluent, performing ultrasonic treatment to dissolve, diluting to scale with diluent, and shaking.
Taking 20 μl of the sample solution, and testing the sample solution according to different chromatographic columns, buffer solutions and mobile phase proportion conditions in the following table.
TABLE 1 test conditions and test results for test solutions
The experimental results in table 1 show that the technical scheme of the invention can obtain good separation test effect, and well control the quality of the initial materials, thereby ensuring the quality of the finished products. The buffer solution of the C18 chromatographic column and the mobile phase is monopotassium phosphate or the proportion thereof is changed, so that good separation test effect is difficult to obtain, and the quality of the starting materials is not controlled.
Simple substitutions or modifications of the present invention without changing the spirit of the invention also fall within the scope of the invention.
Claims (6)
1. A method for the separation and determination of 2- [ (2-methyl-5-bromophenyl) methyl ] -5- (4-fluorophenyl) thiophene and its impurities, 2- [ (2-methyl-5-bromophenyl) methyl ] -5- (2-fluorophenyl) thiophene and 2- [ (2-methyl-5-bromophenyl) methyl ] -5-phenyl) thiophene, the method being liquid chromatography comprising: 1) the chromatographic column is a pentafluoro-phenyl chromatographic column, 2) the mobile phase consists of acetonitrile-buffer solution, wherein the buffer solution is sodium dihydrogen phosphate buffer solution, the pH value is 2.5,3), and the volume ratio of acetonitrile to the buffer solution in the mobile phase is 55:45.
2. the method of claim 1, comprising the steps of:
a) Control solution: accurately weighing 15mg of each impurity compound reference substance, respectively placing into 100ml volumetric flasks, dissolving with diluent, diluting to scale, shaking up to obtain reference substance stock solution, accurately weighing 1ml, placing into the same 100ml volumetric flask, diluting with diluent to scale, shaking up to obtain mixed reference substance solution, and testing sample solution: taking 25mg of 2- [ (2-methyl-5-bromophenyl) methyl ] -5- (4-fluorophenyl) thiophene, placing in a bottle with a capacity of 25ml, dissolving with a diluent, diluting to a scale, and shaking uniformly to obtain a sample solution;
b) Setting the flow rate of the mobile phase to be 1.0-1.5 ml/min, the pH value of the buffer solution in the mobile phase to be 2.5, the detection wavelength to be 210-290 nm, the column temperature of the chromatographic column to be 20-35 ℃ and the sample injection amount to be 5-100 mu L;
c) Taking the same volume of the mixed control solution and the sample solution in the step a), respectively injecting the mixed control solution and the sample solution into a liquid chromatograph, recording a chromatogram, and completing separation and measurement.
3. The process of claim 2, wherein the diluent of step a) is acetonitrile.
4. The method according to claim 2, wherein the mobile phase in step b) has a flow rate of 1.5ml/min and the detection wavelength is 210nm.
5. The method of claim 2, wherein the column temperature of the chromatographic column in step b) is 30 ℃.
6. The method of claim 2, wherein the sample size in step b) is 20 μl.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811224636.9A CN111077235B (en) | 2018-10-19 | 2018-10-19 | Method for determining 2- [ (2-methyl-5-bromophenyl) methyl ] -5- (4-fluorophenyl) thiophene impurity |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811224636.9A CN111077235B (en) | 2018-10-19 | 2018-10-19 | Method for determining 2- [ (2-methyl-5-bromophenyl) methyl ] -5- (4-fluorophenyl) thiophene impurity |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111077235A CN111077235A (en) | 2020-04-28 |
CN111077235B true CN111077235B (en) | 2023-09-08 |
Family
ID=70308303
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201811224636.9A Active CN111077235B (en) | 2018-10-19 | 2018-10-19 | Method for determining 2- [ (2-methyl-5-bromophenyl) methyl ] -5- (4-fluorophenyl) thiophene impurity |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN111077235B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112730702A (en) * | 2020-12-30 | 2021-04-30 | 南京百泽医药科技有限公司 | Method for determining related substances of 6-acetoxyl-7-methoxy-3H-quinazoline-4-one |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016016852A1 (en) * | 2014-07-31 | 2016-02-04 | Sun Pharmaceutical Industries Limited | Process for the purification of canagliflozin |
CN105319294A (en) * | 2014-06-20 | 2016-02-10 | 重庆医药工业研究院有限责任公司 | Method for separating and testing canagliflozin and matter related to same |
CN108530434A (en) * | 2017-03-03 | 2018-09-14 | 重庆医药工业研究院有限责任公司 | Impurity compound of canagliflozin and preparation method thereof |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2010277556B2 (en) * | 2009-07-31 | 2014-10-09 | Ascendis Pharma As | Biodegradable polyethylene glycol based water-insoluble hydrogels |
ES2711804T3 (en) * | 2014-05-27 | 2019-05-07 | Glenmark Pharmaceuticals Ltd | Process for the preparation of canagliflozin |
-
2018
- 2018-10-19 CN CN201811224636.9A patent/CN111077235B/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105319294A (en) * | 2014-06-20 | 2016-02-10 | 重庆医药工业研究院有限责任公司 | Method for separating and testing canagliflozin and matter related to same |
WO2016016852A1 (en) * | 2014-07-31 | 2016-02-04 | Sun Pharmaceutical Industries Limited | Process for the purification of canagliflozin |
CN108530434A (en) * | 2017-03-03 | 2018-09-14 | 重庆医药工业研究院有限责任公司 | Impurity compound of canagliflozin and preparation method thereof |
Non-Patent Citations (1)
Title |
---|
卡格列净关键中间体合成研究;钟铮 等;《河南科学》;20160831;第1241-1244页 * |
Also Published As
Publication number | Publication date |
---|---|
CN111077235A (en) | 2020-04-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105738489B (en) | method for determining rivaroxaban and impurities thereof by adopting liquid chromatography | |
CN107941936B (en) | Method for separating and determining rivaroxaban and impurities thereof and application | |
CN105588886B (en) | method for determining impurities in apremilast and its preparation by liquid chromatography | |
CN110501446B (en) | Analysis method of oxa-goril sodium raw material and synthetic intermediate thereof | |
CN104965041B (en) | A kind of high-efficiency liquid chromatography method for detecting of Parecoxib Sodium isomer | |
CN110824093A (en) | Method for detecting brivaracetam and related substances thereof | |
CN113049699A (en) | Method for detecting biphenyl anhydride and related substances thereof and application | |
CN111077235B (en) | Method for determining 2- [ (2-methyl-5-bromophenyl) methyl ] -5- (4-fluorophenyl) thiophene impurity | |
CN106706769B (en) | Separation and determination method of empagliflozin and optical isomer thereof | |
CN107525877B (en) | Method for separating and determining brexpiprazole and impurities thereof by adopting liquid chromatography | |
CN107941946B (en) | Detection method of Vonoprazan fumarate | |
CN111707765A (en) | Topiroxostat tablet detection method | |
CN110849994A (en) | Method for separating related substances in rivaroxaban | |
CN103630613A (en) | Separation and detection method for roflumilast and intermediate thereof | |
CN110865130A (en) | Detection method of olopatadine hydrochloride and related substances thereof | |
CN105125520A (en) | Celecoxib preparation and preparing method and control method of celecoxib preparation | |
CN113533539B (en) | Method for measuring related substances peculiar to Apremix | |
CN112834637B (en) | Method for detecting peramivir intermediate I by reversed-phase high performance liquid chromatography | |
CN110579541B (en) | Detection method of lansoprazole related substances | |
CN111077234B (en) | Method for separating and measuring canagliflozin and impurities thereof by liquid chromatography | |
CN107941937B (en) | A kind of method for separating and analyzing of oat alkaloid D and dihydro avenine D | |
CN107884496B (en) | Method for determining content of succinic acid in trelagliptin succinate | |
CN104897818A (en) | UPLC (ultra-high performance liquid chromatography) method for simultaneously determining six related substances in bicalutamide | |
CN104965031A (en) | Content measuring method for compound ketoprofen and omeprazole sustained-release capsules | |
CN104569260A (en) | Method for detecting residual amount of formaldehyde in colistimethate sodium |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |