CN111983124A - Method for detecting 2, 2-dimethyl-1, 3-dichloropropane in ibuprofen - Google Patents
Method for detecting 2, 2-dimethyl-1, 3-dichloropropane in ibuprofen Download PDFInfo
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- CN111983124A CN111983124A CN202010854782.0A CN202010854782A CN111983124A CN 111983124 A CN111983124 A CN 111983124A CN 202010854782 A CN202010854782 A CN 202010854782A CN 111983124 A CN111983124 A CN 111983124A
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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
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/884—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds
Abstract
The invention provides a method for detecting 2, 2-dimethyl-1, 3-dichloropropane in ibuprofen, wherein an ibuprofen intermediate 3 can generate side reaction in the hydrolysis process, 2-dimethyl-1, 3-dichloropropane impurities can be generated, and the 2, 2-dimethyl-1, 3-dichloropropane impurities contain genotoxicity impurity warning groups R-Cl, so that the content of the impurities is checked according to the genotoxicity impurity requirements. According to the method, firstly, 6% of cyanopropylphenyl-94% of dimethylpolysiloxane or a chromatographic column with equivalent energy efficiency is used for pressurizing the chromatographic column by helium, so that the 2, 2-dimethyl-1, 3-dichloropropane in the ibuprofen is separated from other substances, and finally the residual amount of the 2, 2-dimethyl-1, 3-dichloropropane in the ibuprofen can be determined.
Description
Technical Field
The invention belongs to the field of pharmaceutical analytical chemistry, and particularly relates to a method for detecting 2, 2-dimethyl-1, 3-dichloropropane in ibuprofen by a GC-MS (gas chromatography-mass spectrometry) method.
Background
Ibuprofen (CAS number: 15687-27-1) is an antipyretic analgesic, a non-steroidal anti-inflammatory drug, with the English name: ibuprofen, a compound of which the generic name is: 4-isobutyl-a-methylphenylacetic acid. The ibuprofen is used for inhibiting the inducible inflammatory cyclooxygenase (COX 2) to metabolize arachidonic acid into mediator prostaglandin or synthesis of other transmitters, and relieving local tissue congestion, swelling and fever caused by the prostaglandin (PGE 1, PGE2 and PGI 2). By inhibiting leukocyte activity and lysosome release, pain sensitivity of local peripheral nerves to pain-causing substances such as bradykinin is reduced, tissue impulse is reduced, and an analgesic effect is achieved. The medicine is used for treating dysmenorrhea by inhibiting prostaglandin, and has the effects of reducing intrauterine pressure and uterine contraction. Gout is treated by diminishing inflammation and relieving pain, but hyperuricemia cannot be corrected. In addition, the composition also has inhibitory effect on proto-type (physiological) cyclooxygenase (also known as OX 1) such as stomach and kidney, so after the product is taken, symptoms such as increased gastric acid secretion, decreased gastric mucus secretion, decreased tension of stomach and esophagus, and decreased renal blood vessel flow can be caused.
The ibuprofen intermediate 3 can generate side reaction in the hydrolysis process, 2-dimethyl-1, 3-dichloropropane impurities can be generated, and the 2, 2-dimethyl-1, 3-dichloropropane impurities contain genotoxic impurity warning groups R-Cl, so that the content of the impurities is detected according to the genotoxic impurity requirements.
In order to verify the effectiveness and feasibility of the gas chromatography-mass spectrometry combined method, researchers of the company verify the method according to the guidelines of 9101 and ICH-Q2 in the four-part general rules of Chinese pharmacopoeia 2015. The detection method provided by the invention has high system applicability to the detection of 2, 2-dimethyl-1, 3-dichloropropane in ibuprofen, and meets standards in specificity, precision, quantitative limit, detection limit, linearity and range, accuracy and solution stability.
Disclosure of Invention
The invention aims to provide a method for detecting 2, 2-dimethyl-1, 3-dichloropropane in ibuprofen, which comprises the steps of firstly, adopting 6% cyanopropylphenyl-94% dimethylpolysiloxane or a chromatographic column with equivalent energy efficiency to pressurize the chromatographic column by helium so as to separate the 2, 2-dimethyl-1, 3-dichloropropane from other substances in the ibuprofen, and finally, determining the residual amount of the 2, 2-dimethyl-1, 3-dichloropropane in the ibuprofen. The detection of the 2, 2-dimethyl-1, 3-dichloropropane in the ibuprofen is realized by a GC-MS method, and in order to verify the effectiveness and feasibility of the method, the verification is carried out on the aspects of system applicability, specificity, precision, detection limit, quantitative limit, linearity and range, accuracy, durability and the like according to the guidelines of 2015 edition Chinese pharmacopoeia four-part general rule 9101 and ICH-Q2, so that the method completely accords with the guidelines of verification of the Chinese pharmacopoeia method and can be used for quality control of ibuprofen bulk drugs.
A method for detecting 2, 2-dimethyl-1, 3-dichloropropane in ibuprofen comprises the following steps: (1) preparing solutions, namely respectively preparing a blank solution, a 2, 2-dimethyl-1, 3-dichloropropane stock solution, a reference solution, a sensitivity solution and a test solution; the blank solution comprises an acetonitrile solution; the 2, 2-dimethyl-1, 3-dichloropropane stock solution comprises 2, 2-dimethyl-1, 3-dichloropropane and an acetonitrile solution; the reference solution comprises 2, 2-dimethyl-1, 3-dichloropropane and an acetonitrile solution; the sensitivity solution comprises 2, 2-dimethyl-1, 3-dichloropropane and acetonitrile solution; the test solution comprises ibuprofen and acetonitrile solution;
(2) the determination method comprises the following steps: respectively injecting the blank solution, the sensitivity solution, the reference solution and the test solution into a liquid chromatograph, and recording a chromatogram, wherein the chromatogram conditions are as follows: a chromatographic column: the filler is 6% cyanopropylphenyl-94% dimethylpolysiloxane; column temperature: the initial temperature is 40 ℃, the temperature is kept for 5 minutes, the temperature is increased to 100 ℃ at the rate of 10 ℃ per minute, then the temperature is increased to 250 ℃ at the rate of 50 ℃ per minute, and the temperature is kept for 5 minutes; sample inlet temperature: 110 ℃; carrier gas pressure: 13.8 psi; carrier gas: he; sample introduction amount: 0.5 mul; shunting mode: no flow diversion;
the mass spectrometry conditions were as follows:
further, the blank solution is a diluent; the diluent is acetonitrile solution;
the preparation steps of the 2, 2-dimethyl-1, 3-dichloropropane stock solution are as follows: weighing 2, 2-dimethyl-1, 3-dichloropropane reference substances, precisely weighing, placing in a volumetric flask, adding a diluent to dissolve and dilute to a scale, and shaking up; precisely measuring the solution, placing the solution into a volumetric flask, adding a diluent to dilute the solution to a scale, and shaking the solution uniformly to obtain a 2, 2-dimethyl-1, 3-dichloropropane stock solution;
the preparation steps of the reference solution are as follows: precisely measuring a 2, 2-dimethyl-1, 3-dichloropropane stock solution, placing the stock solution into a volumetric flask, adding a diluent to dilute the stock solution to a scale, and shaking up to obtain a reference solution;
the preparation steps of the sensitivity solution are as follows: precisely measuring 1.5ml of reference solution, placing the reference solution in a volumetric flask, diluting the A diluent to a scale, and shaking up to obtain a sensitive solution;
the preparation steps of the test solution are as follows: weighing ibuprofen, placing the ibuprofen in a volumetric flask, adding a diluent to dilute the ibuprofen to a scale, and shaking the ibuprofen uniformly to obtain a test solution.
More further, the preparation steps of the 2, 2-dimethyl-1, 3-dichloropropane stock solution are as follows: weighing about 100mg of 2, 2-dimethyl-1, 3-dichloropropane reference substance, precisely weighing, placing in a 100ml volumetric flask, adding a diluent to dissolve and dilute to a scale, and shaking up; precisely measuring 1.0ml of the solution, putting the solution into a 50ml volumetric flask, adding a diluent to dilute the solution to a scale, and shaking the solution uniformly to obtain a 2, 2-dimethyl-1, 3-dichloropropane stock solution (the concentration of 2, 2-dimethyl-1, 3-dichloropropane is 400 ng/ml);
the acetonitrile is HPLC;
the ultrapure water is HPLC;
the 2, 2-dimethyl-1, 3-dichloropropane is purchased from outsources.
Wherein: rU: testing the peak area of 2, 2-dimethyl-1, 3-dichloropropane in a solution map; rS: 5 average peak areas of 2, 2-dimethyl-1, 3-dichloropropane in a reference solution chromatogram; cS: concentration of 2, 2-dimethyl-1, 3-dichloropropane in a reference solution (μ g/ml); cU: the solution concentration (g/ml) was tested.
The method for measuring the content of the 2, 2-dimethyl-1, 3-dichloropropane also comprises method verification before detection, and the analysis method verifies that the measurement result is as follows:
advantageous effects
The invention aims to provide a method for detecting 2, 2-dimethyl-1, 3-dichloropropane in ibuprofen, which comprises the steps of firstly, adopting 6% cyanopropylphenyl-94% dimethylpolysiloxane or a chromatographic column with equivalent energy efficiency to pressurize the chromatographic column by helium so as to separate the 2, 2-dimethyl-1, 3-dichloropropane from other substances in the ibuprofen, and finally, determining the residual amount of the 2, 2-dimethyl-1, 3-dichloropropane in the ibuprofen. The detection method has high chromatographic peak separation degree of 2, 2-dimethyl-1, 3-dichloropropane in ibuprofen, has high system applicability, and meets standards in specificity, precision, quantitative limit, detection limit, accuracy, linearity, range and durability. In order to confirm the residual quantity of the 2, 2-dimethyl-1, 3-dichloropropane in the ibuprofen, the invention utilizes a convenient and quick GC-MS method, and verifies the method for proving the effectiveness and feasibility of the method, and the detection of the 2, 2-dimethyl-1, 3-dichloropropane in the ibuprofen can be used for monitoring the quality of ibuprofen bulk drugs and preparations. The invention provides the method for detecting 2, 2-dimethyl-1, 3-dichloropropane in ibuprofen for the first time, and the method has the characteristics of high accuracy, high precision, good reproducibility, good stability, strong specificity and the like, and simultaneously greatly improves the detection sensitivity, more effectively controls the product quality and can meet higher quality requirements.
Drawings
FIG. 1 example 2 blank solution chromatogram
FIG. 2 example 2 spectrum of sensitive solution
FIG. 3 spectrum of reference solution of example 2
FIG. 4 spectrum of test solution of example 3
FIG. 5 spectrum of selective solution of example 3
FIG. 6 spectrum of test solution (spiked) in example 4
FIG. 7 spectrum of LOQ solution of example 5
FIG. 8 spectrum of LOD solution of example 6
FIG. 92, 2-dimethyl-1, 3-dichloropropane concentration-peak area Linear relationship
Detailed Description
The invention will be further explained and illustrated by the following specific examples, which are not intended to limit the scope of the invention in any way.
Example 1
(1) Experimental materials and instrumentation conditions
Experimental materials: acetonitrile, manufacturer: merck two ply limited; 2, 2-dimethyl-1, 3-dichloropropane, manufacturer: ladder love (shanghai) into industrial development limited; ibuprofen, manufacturer: hubei Baike Gelai pharmaceuticals, Inc.; ultrapure water, manufacturer: zhuhairun all pharmaceutical Co.
The instrument comprises the following steps: gas chromatography-mass spectrometer: 7890B &7000D GC/MS Triple Quad; electronic analytical balance GR-200, XSE205 DU; a chromatographic column: agilent DB-62430 m.times.0.32 mm, 1.8 μm.
The determination method comprises the following steps: respectively injecting the blank solution, the sensitivity solution, the reference solution and the test solution into a liquid chromatograph, and recording a chromatogram, wherein the chromatogram conditions are as follows: a chromatographic column: the filler is 6% cyanopropylphenyl-94% dimethylpolysiloxane; column temperature: the initial temperature is 40 ℃, the temperature is kept for 5 minutes, the temperature is increased to 100 ℃ at the rate of 10 ℃ per minute, then the temperature is increased to 250 ℃ at the rate of 50 ℃ per minute, and the temperature is kept for 5 minutes; sample inlet temperature: 110 ℃; carrier gas pressure: 13.8 psi; carrier gas: he; sample introduction amount: 0.5 mul; shunting mode: no flow diversion;
(2) experimental procedure
The preparation method of the blank solution (diluent) comprises the following steps: the diluent is acetonitrile solution;
preparing the 2, 2-dimethyl-1, 3-dichloropropane stock solution by the following steps: weighing about 100mg of 2, 2-dimethyl-1, 3-dichloropropane reference substance, precisely weighing, placing in a 100ml volumetric flask, adding a diluent to dissolve and dilute to a scale, and shaking up; precisely measuring 1.0ml of the solution, putting the solution into a 50ml volumetric flask, adding a diluent to dilute the solution to a scale, and shaking the solution uniformly to obtain a 2, 2-dimethyl-1, 3-dichloropropane stock solution (the concentration of 2, 2-dimethyl-1, 3-dichloropropane is 400 ng/ml);
preparing a reference solution (2, 2-dimethyl-1, 3-dichloropropane positioning solution) by the following steps: precisely measuring 1.5ml of 2, 2-dimethyl-1, 3-dichloropropane stock solution, placing the stock solution into a 10ml measuring flask, adding a diluent to dilute the stock solution to a scale, and shaking the stock solution uniformly to obtain a reference solution (the concentration of 2, 2-dimethyl-1, 3-dichloropropane is 60 ng/ml);
the preparation steps of the sensitivity solution are as follows: precisely weighing 1.5ml of reference solution, putting the reference solution into a 10ml measuring flask, adding diluent to dilute the reference solution to a scale, and shaking the reference solution uniformly to obtain a sensitivity solution (the concentration of 2, 2-dimethyl-1, 3-dichloropropane is 9 ng/ml);
the preparation steps of the test solution are as follows: weighing 1.0g ibuprofen sample, precisely weighing, placing in a 10ml measuring flask, adding diluent to dissolve and dilute to scale, and shaking to obtain test solution (ibuprofen concentration: 0.1 g/ml).
The preparation steps of the selective solution are as follows: taking 1.0g (not less than 1.0 g) of ibuprofen sample, precisely weighing, placing in a 10ml measuring flask, and adding an appropriate amount of diluent for dissolving; accurately measuring 1.5ml of 2, 2-dimethyl-1, 3-dichloropropane stock solution, placing the stock solution in the bottle, adding a diluent to dilute the stock solution to a scale, and shaking the stock solution uniformly to obtain a selective solution (the concentration of ibuprofen is 0.1g/ml, and the concentration of 2, 2-dimethyl-1, 3-dichloropropane is 60 ng/ml);
the preparation method of the LOQ solution comprises the following steps: accurately measuring 1.5ml of 2, 2-dimethyl-1, 3-dichloropropane stock solution, placing the stock solution in a 20ml measuring flask, adding a diluent to dilute the stock solution to a scale, shaking the stock solution uniformly to obtain an LOQ solution, and preparing 6 parts of the LOQ solution (the concentration of 2, 2-dimethyl-1, 3-dichloropropane is 30 ng/ml) by the same method;
preparing the LOD solution by the following steps: precisely measuring 3.0ml of LOQ solution, placing in a 10ml measuring flask, adding diluent to dilute to scale, and shaking up to obtain LOD solution (2, 2-dimethyl-1, 3-dichloropropane concentration: 9 ng/ml);
ninthly, the preparation steps of the test solution (adding mark) are as follows: taking about 1.0g of ibuprofen sample, precisely weighing, placing in a 10ml measuring flask, and adding a proper amount of diluent for dissolving; accurately measuring 1.5ml of 2, 2-dimethyl-1, 3-dichloropropane stock solution, placing the stock solution into the bottle, adding a diluent to dilute the stock solution to a scale, shaking the stock solution uniformly to obtain a test solution (labeled), and preparing 6 parts (the concentration of ibuprofen is 0.1g/ml, and the concentration of 2, 2-dimethyl-1, 3-dichloropropane is 60 ng/ml) by the same method.
After the system is stabilized, 1 pin of blank solution, 1 pin of sensitivity solution, 5 pins of reference solution and 1 pin of test solution are added, and the spectrogram is recorded. 2, 2-dimethyl-1, 3-dichloropropane (ppm) = (R)U/Rs)×(Cs/CU) Wherein: rU: testing the peak area of 2, 2-dimethyl-1, 3-dichloropropane in a solution map; rs: 5 average peak areas of 2, 2-dimethyl-1, 3-dichloropropane in a reference solution chromatogram; cs: concentration of 2, 2-dimethyl-1, 3-dichloropropane in the reference solution (μ g/ml); cU: the concentration of the solution (g/ml) was tested.
Example 2 detection method of the invention System suitability test
The applicability of the system is realized by measuring the signal to noise ratio of the 2, 2-dimethyl-1, 3-dichloropropane peak in the sensitivity solution and the RSD of the 2, 2-dimethyl-1, 3-dichloropropane peak area in 5-needle reference solution, wherein the signal to noise ratio of the 2, 2-dimethyl-1, 3-dichloropropane peak in the sensitivity solution is required to be not less than 3, and the RSD of the 5-needle reference solution calculated by the 2, 2-dimethyl-1, 3-dichloropropane peak area is required to be not more than 10.0%.
Blank solution, sensitivity solution and reference solution are prepared as described in example 1, and under the chromatographic conditions described in example 1, blank solution 1, sensitivity solution 1 and reference solution 5 are put into the solution, and the spectra are recorded as shown in fig. 1, fig. 2 and fig. 3, and the results are shown in the following table according to the formula conversion:
example 3 specificity test of the detection method of the invention
The specificity is that the blank solution is determined to have no interference to the detection of the 2, 2-dimethyl-1, 3-dichloropropane; before and after sample loading, the recovery rate of the 2, 2-dimethyl-1, 3-dichloropropane in the selective solution is realized. The blank solution is required to have no interference to the detection of 2, 2-dimethyl-1, 3-dichloropropane; before and after sample loading, the recovery rate of the 2, 2-dimethyl-1, 3-dichloropropane in the selective solution is between 80.0 and 120.0 percent.
Preparing blank solution, 2-dimethyl-1, 3-dichloropropane stock solution, reference solution, test solution and selective solution as described in example 1, after the system is balanced, feeding blank solution 1 needle, reference solution 3 needle, test solution 1 needle and selective solution 3 needle, recording spectrograms, and obtaining specificity detection results as shown in the following table in fig. 1, fig. 3, fig. 4 and fig. 5:
example 4 precision test of the detection method of the invention
Precision is achieved by RSD of 2, 2-dimethyl-1, 3-dichloropropane measurements in 6 parts of test solution (spiked) which are required to meet the acceptance criteria.
Blank solution, 2, 2-dimethyl-1, 3-dichloropropane stock solution, reference solution, test solution (spiked) were prepared as described in example 1. After the system is balanced, 1 needle of blank solution, 1 needle of reference solution and 1 needle of 6 parts of test solution (labeled) are added, chromatogram maps are recorded, as shown in figure 1, figure 3 and figure 6, and the results obtained by conversion according to formulas are shown in the following table:
example 5 quantitation and detection limits of the detection methods of the invention
The detection limit is determined by detecting that its response signal to noise ratio is about 3: 1, the limit of quantitation is determined by the signal-to-noise ratio of about 10: 1, and (b). At the concentration level, 6 parts of quantitative limit test solution are repeatedly examined, and the RSD of the peak area of the unit concentration of 2, 2-dimethyl-1, 3-dichloropropane in the spectrogram obtained 6 times is required to be not more than 10.0 percent so as to confirm that the quantitative limit measurement result has certain precision.
Blank solutions, 2-dimethyl-1, 3-dichloropropane stock solutions, LOQ solutions and LOD solutions were prepared as described in example 1. After the system was equilibrated, 1 pin of blank solution, 1 pin of each of 6 parts of LOQ solution, and 1 pin of LOD solution were introduced, and the spectra were recorded as shown in FIG. 1, FIG. 7, and FIG. 8.
Example 6 accuracy (recovery) of the detection method of the present invention
The accuracy is the degree of closeness of the result measured by the method to the true value or the reference value, and is realized by measuring the recovery rate of the standard solution added into the test solution with different concentrations, the recovery rate of 2, 2-dimethyl-1, 3-dichloropropane is required to be between 80.0% and 120.0% under the limit concentration of LOQ concentration to 150%, and the RSD of the recovery rate is required to be not more than 10%.
Example 7 solution stability of the assay method of the invention
And (3) observing the rule that the detection result changes along with time after the reference solution and the selective solution are placed at room temperature for 0 day, 1 day and 2 days, and providing a basis for the placing time of the reference solution and the test solution during detection. The requirement is that compared with 0 day, the recovery rate of the 2, 2-dimethyl-1, 3-dichloropropane is between 80.0% and 120.0% when the reference solution is placed at room temperature for 2 days, and the reference solution is stable when placed at room temperature for 2 days; compared with the reference solution for 0 day, the recovery rate of the 2, 2-dimethyl-1, 3-dichloropropane of the selective solution is between 80.0 and 120.0 percent within 2 days of placing the selective solution at room temperature, and the selective solution is stable within 2 days of placing the selective solution at room temperature.
Claims (3)
1. A method for detecting 2, 2-dimethyl-1, 3-dichloropropane in ibuprofen is characterized by comprising the following steps: (1) preparing solutions, namely respectively preparing a blank solution, a 2, 2-dimethyl-1, 3-dichloropropane stock solution, a reference solution, a sensitivity solution and a test solution; the blank solution comprises an acetonitrile solution; the 2, 2-dimethyl-1, 3-dichloropropane stock solution comprises 2, 2-dimethyl-1, 3-dichloropropane and an acetonitrile solution; the reference solution comprises 2, 2-dimethyl-1, 3-dichloropropane and an acetonitrile solution; the sensitivity solution comprises 2, 2-dimethyl-1, 3-dichloropropane and acetonitrile solution; the test solution comprises ibuprofen and acetonitrile solution;
(2) the determination method comprises the following steps: respectively injecting the blank solution, the sensitivity solution, the reference solution and the test solution into a liquid chromatograph, and recording a chromatogram, wherein the chromatogram conditions are as follows: a chromatographic column: the filler is 6% cyanopropylphenyl-94% dimethylpolysiloxane; column temperature: the initial temperature is 40 ℃, the temperature is kept for 5 minutes, the temperature is increased to 100 ℃ at the rate of 10 ℃ per minute, then the temperature is increased to 250 ℃ at the rate of 50 ℃ per minute, and the temperature is kept for 5 minutes; sample inlet temperature: 110 ℃; carrier gas pressure: 13.8 psi; carrier gas: he; sample introduction amount: 0.5 mul; shunting mode: no flow diversion;
the mass spectrometry conditions were as follows:
2. the method of claim 1, wherein: the blank solution is a diluent; the diluent is acetonitrile solution;
the preparation steps of the 2, 2-dimethyl-1, 3-dichloropropane stock solution are as follows: weighing 2, 2-dimethyl-1, 3-dichloropropane reference substances, precisely weighing, placing in a volumetric flask, adding a diluent to dissolve and dilute to a scale, and shaking up; precisely measuring the solution, placing the solution into a volumetric flask, adding a diluent to dilute the solution to a scale, and shaking the solution uniformly to obtain a 2, 2-dimethyl-1, 3-dichloropropane stock solution;
the preparation steps of the reference solution are as follows: precisely measuring a 2, 2-dimethyl-1, 3-dichloropropane stock solution, placing the stock solution into a volumetric flask, adding a diluent to dilute the stock solution to a scale, and shaking up to obtain a reference solution;
the preparation steps of the sensitivity solution are as follows: precisely measuring 1.5ml of reference solution, placing the reference solution in a volumetric flask, diluting the A diluent to a scale, and shaking up to obtain a sensitive solution;
the preparation steps of the test solution are as follows: weighing ibuprofen, placing the ibuprofen in a volumetric flask, adding a diluent to dilute the ibuprofen to a scale, and shaking the ibuprofen uniformly to obtain a test solution.
3. The method of claim 2, wherein: the preparation steps of the 2, 2-dimethyl-1, 3-dichloropropane stock solution are as follows: weighing about 100mg of 2, 2-dimethyl-1, 3-dichloropropane reference substance, precisely weighing, placing in a 100ml volumetric flask, adding a diluent to dissolve and dilute to a scale, and shaking up; precisely measuring 1.0ml of the solution, putting the solution into a 50ml volumetric flask, adding a diluent to dilute the solution to a scale, and shaking the solution uniformly to obtain a 2, 2-dimethyl-1, 3-dichloropropane stock solution (the concentration of 2, 2-dimethyl-1, 3-dichloropropane is 400 ng/ml);
the acetonitrile is HPLC;
the ultrapure water is HPLC;
the 2, 2-dimethyl-1, 3-dichloropropane is purchased from outsources.
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| US20110054208A1 (en) * | 2009-08-31 | 2011-03-03 | Florida State University Research Foundation | Method and apparatus for continuous flow synthesis of ibuprofen |
| CN107782820A (en) * | 2016-08-31 | 2018-03-09 | 江苏正大丰海制药有限公司 | The assay method of genetoxic impurity ethyl p-toluenesulfonate in a kind of brufen |
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