CN111879880B - Method for detecting 3 intermediates in ibuprofen - Google Patents
Method for detecting 3 intermediates in ibuprofen Download PDFInfo
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Abstract
The invention provides a method for detecting 3 intermediates in ibuprofen, wherein the intermediate 1, the intermediate 2 and the intermediate 3 are toxic substances containing warning structures, incomplete reaction possibly exists in the reaction process, and the toxic substances are remained in ibuprofen raw material medicines, in order to detect the contents of the intermediate 1, the intermediate 2 and the intermediate 3 in the ibuprofen, the invention provides a high performance liquid chromatography-mass spectrometry combined detection method for the intermediate 1, the intermediate 2 and the intermediate 3 in the ibuprofen, the method is simple, convenient, efficient and accurate, completely accords with the guiding principle of method verification in the four parts 9101 of the guiding principle of ICH Q2 and Chinese pharmacopoeia in the aspects of system applicability, specificity, precision, quantitative limit, detection limit, durability and the like, and can be used for quality control of the ibuprofen raw material medicines.
Description
Technical Field
The invention relates to the technical field of medical analysis, in particular to a method for detecting 3 intermediates in ibuprofen.
Background
Ibuprofen (Ibuprofen) is a non-steroidal anti-inflammatory drug with antipyretic and analgesic effects, is an anti-inflammatory drug without a steroidal structure, and plays roles of antipyresis, analgesia and anti-inflammatory by inhibiting the synthesis of prostaglandin. Ibuprofen is an effective PG synthetase inhibitor and has antipyretic, analgesic and anti-inflammatory effects. Can be used for treating sprain, strain, lumbago, scapulohumeral periarthritis, bursitis, and tenosynovitis. Toothache and postoperative pain, rheumatoid arthritis, osteoarthritis and other seronegative (non-rheumatoid) joint diseases. Can be used for relieving moderate pain, such as arthralgia, myalgia, migraine, headache, toothache, dysmenorrhea, and neuralgia, and relieving fever caused by common cold or influenza. Ibuprofen can stimulate the cellular immune function of human body and experimental animals, increase the activity of natural killer cells and improve the anti-infection capability.
The invention provides a method for detecting an intermediate 1, an intermediate 2 and an intermediate 3 in ibuprofen, wherein the intermediate 1, the intermediate 2 and the intermediate 3 may remain in an ibuprofen finished product due to incomplete reaction, in order to detect the contents of the intermediate 1, the intermediate 2 and the intermediate 3 in the ibuprofen, the detection of the intermediate 1, the intermediate 2 and the intermediate 3 in the ibuprofen is realized according to a high performance liquid chromatography-mass spectrometry combined method independently developed by research and development personnel, and the method is verified by referring to the guidance principle ICH Q2 and the four parts 9101 of Chinese pharmacopoeia.
The patent CN110068633A provides a liquid chromatography detection method for warning structural substances in ibuprofen, wherein a mobile phase used in the method is an acetonitrile-water-phosphoric acid system, the detection method is long in detection time, and the substances to be detected cannot be quickly eluted by an eluent. In order to solve the problems, the invention provides a quicker and more effective detection method.
Disclosure of Invention
The invention aims to provide a method for detecting 3 intermediates in ibuprofen, which is simple, convenient, efficient and accurate, can shorten the detection time and achieve higher efficiency on the premise of not influencing the detection result, conforms to the guidelines of method verification in ICH Q2 and the four parts 9101 of Chinese pharmacopoeia, and can be used for quality control of ibuprofen bulk drugs.
In order to achieve the purpose, the invention provides the following technical scheme:
a method for detecting 3 intermediates in ibuprofen comprises the following steps: (1) preparing solutions, namely preparing a blank solution, a reference solution, a sensitivity solution and a test solution respectively; the blank solution is an acetonitrile solution; the reference solution comprises an intermediate solution and an acetonitrile solution; the sensitivity solution comprises an intermediate solution and an acetonitrile solution; the test solution comprises ibuprofen and acetonitrile solution;
(2) the measuring method comprises the following steps: respectively injecting the blank solution, the reference solution, the sensitivity solution and the test solution into a liquid chromatograph, and recording a chromatogram, wherein the chromatogram conditions are as follows: and (3) chromatographic column: octadecylsilane chemically bonded silica is used as a filling agent; the flow rate is 0.3 mL/min; column temperature: 30 ℃; sample introduction amount: 10 mu l of the mixture; operating time: 15 min; detection wavelength: 230 nm; the mobile phase is a mobile phase A-mobile phase B system, wherein the mobile phase A is formic acid: water =1:100 (volume ratio, V/V), mobile phase B is formic acid: acetonitrile =1:100 (volume ratio, V/V);
the mass spectrometry conditions were as follows:
the invention provides a method for detecting 3 intermediates in ibuprofen, and further comprises the following steps of: the blank solution is acetonitrile solution;
the preparation steps of the reference solution are as follows: precisely measuring a reference substance stock solution, placing the reference substance stock solution in a volumetric flask, adding a diluent to dilute the reference substance stock solution to a scale, and shaking up to obtain a reference substance solution;
the preparation steps of the sensitivity solution are as follows: precisely measuring a reference substance stock solution, placing the reference substance stock solution in a volumetric flask, adding a diluent to dilute the reference substance stock solution to a scale, and shaking up; precisely measuring the solution, placing the solution in a volumetric flask, adding a diluent to dilute the solution to a scale, and shaking up to obtain a sensitive solution;
the preparation steps of the test solution are as follows: taking a test sample, precisely weighing, placing in a volumetric flask, adding a diluent to dissolve and dilute to a scale, and shaking uniformly to obtain a test sample solution;
the diluent is acetonitrile solution;
the blank solution is the diluent;
the formic acid is AR and above;
the ultrapure water and the acetonitrile are subjected to HPLC;
the ibuprofen is purchased externally;
the chromatographic column can be an Agilent Zorbax SB4.6mm multiplied by 150mm, 2.7 mu m or a chromatographic column with equivalent energy efficiency;
the mobile phase gradient process is as follows:
the method for measuring the contents of the 3 intermediates including the intermediate 1 (M1), the intermediate 2 (M2) and the intermediate 3 (M3) further comprises method verification before detection, wherein the method verification is that according to the chromatographic conditions of formal detection, the measurement result is as follows:
advantageous effects
According to the technical scheme, the detection method disclosed by the invention has high chromatographic peak separation degree on the intermediates 1, 2 and 3 in the ibuprofen, has high system applicability, and meets standards in specificity, precision, quantification limit, detection limit, accuracy, linearity, range and durability. In order to confirm the residual quantity of the intermediate 1, the intermediate 2 and the intermediate 3 in the ibuprofen, the method utilizes a convenient and quick high performance liquid chromatography-mass spectrometry combined method, and verifies the effectiveness and feasibility of the method. The detection of the intermediate 1, the intermediate 2 and the intermediate 3 in the ibuprofen can be used for monitoring the quality of ibuprofen bulk drugs and preparations. The invention firstly provides the detection of the intermediate 1, the intermediate 2 and the intermediate 3 in the ibuprofen by using a high performance liquid chromatography-mass spectrometry combined method, and has the characteristics of high accuracy, high precision, good reproducibility, good stability, strong specificity and the like.
Drawings
FIG. 1 is a liquid chromatogram of an empty solution in examples 2, 3 and 4;
FIG. 2 is a liquid chromatogram of the sensitivity solution in example 2;
FIG. 3 is a liquid chromatogram of a control solution of example 2;
FIG. 4 is a liquid chromatogram of a solution of intermediate 1 (M1) in example 3;
FIG. 5 is a liquid chromatogram of a solution of intermediate 2 (M2) in example 3;
FIG. 6 is a liquid chromatogram of a solution of intermediate 3 (M3) in example 3;
FIG. 7 is a liquid chromatogram of the test solution of example 3;
FIG. 8 is a liquid chromatogram of the selective solution of example 3;
FIG. 9 is a liquid chromatogram of the LOQ solution of example 4;
FIG. 10 is a liquid chromatogram of the LOD solution of example 4.
Detailed Description
Example 1
(1) Experimental materials and instrumentation conditions
Experimental materials: acetonitrile, manufacturer: merck shares alliance; formic acid, manufacturer: tianjin Damao chemical reagent plant; ibuprofen, manufacturer: hubei Baike Gelai pharmaceuticals, Inc.; intermediate 1, intermediate 2, intermediate 3, manufacturer: zhuhairun pharmaceutical products, Inc.; ultrapure water, manufacturer: zhuhairun all pharmaceutical Co.
The instrument comprises the following steps: high performance liquid chromatography mass spectrometer: 1290&6470 QQQ; electronic analytical balance XSE205DU, GR-200; a chromatographic column: agilent Zorbax SB4.6mm x 150mm, 2.7 μm.
Respectively injecting the blank solution, the reference solution, the sensitivity solution and the test solution into a liquid chromatograph, and recording a chromatogram, wherein the chromatographic conditions are as follows: a chromatographic column: octadecylsilane chemically bonded silica is used as a filling agent; the flow rate is 0.3 mL/min; column temperature: 30 ℃; sample introduction amount: 10 mu l of the mixture; operating time: 15 min; detection wavelength: 230 nm; the mobile phase is a mobile phase A-mobile phase B system, wherein the mobile phase A is formic acid: water =1:100 (volume ratio, V/V), mobile phase B is formic acid: acetonitrile =1:100 (volume ratio, V/V);
(2) experimental procedure
Preparing intermediate 1, intermediate 2 and intermediate 3 reserve solutions: taking about 50mg of each of the intermediate 1, the intermediate 2 and the intermediate 3 as reference substances, putting the reference substances into a 100ml volumetric flask, adding a diluent to dilute the reference substances 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 stock solutions of an intermediate 1, an intermediate 2 and an intermediate 3; (the stock solution concentrations of the intermediate 1, the intermediate 2 and the intermediate 3 are 10 mug/ml)
Preparing a positioning solution of the intermediate 1, the intermediate 2 and the intermediate 3: taking 1.0ml of intermediate 1, intermediate 2 and intermediate 3 stock solutions, placing the intermediate 1, the intermediate 2 and the intermediate 3 stock solutions in a 50ml volumetric flask, adding a diluent to dilute the intermediate 1, the intermediate 2 and the intermediate 3 stock solutions to a scale, and shaking up the intermediate; precisely measuring 1.0ml of the solution, putting the solution into a 10ml volumetric flask, adding a diluent to dilute the solution to a scale, and shaking the solution uniformly to obtain positioning solutions of an intermediate 1, an intermediate 2 and an intermediate 3; (the concentrations of intermediate 1, intermediate 2 and intermediate 3 in the positioning solution were 20 ng/ml)
Control stock solution: precisely measuring 1.0ml of each of the intermediate 1, the intermediate 2 and the intermediate 3 stock solutions, placing the intermediate 1, the intermediate 2 and the intermediate 3 stock solutions into a 50ml volumetric flask, adding a diluent to dilute the intermediate 1, the intermediate 2 and the intermediate 3 stock solutions to a scale, and shaking the intermediate 3 and the diluent uniformly to obtain a reference product stock solution; (concentration of intermediate 1, intermediate 2 and intermediate 3 in the control stock solution was 200 ng/ml)
Preparing a reference solution: precisely measuring 1.0ml of reference substance stock solution, placing in a 10ml volumetric flask, adding diluent to dilute to scale, and shaking up to obtain reference substance solution; (concentration of intermediate 1, intermediate 2 and intermediate 3 in control solution: 20 ng/ml)
Preparing a sensitive solution: precisely measuring 1.0ml of reference stock solution, placing in a 20ml volumetric flask, adding diluent to dilute to a scale, and shaking up; precisely measuring 3.0ml, putting into a 10ml volumetric flask, adding a diluent to dilute to a scale, and shaking up to obtain a sensitive solution; (the concentration of intermediate 1, intermediate 2 and intermediate 3 in the sensitivity solution was 3 ng/ml)
Sixthly, preparing a test solution: taking about 330mg of a test sample, precisely weighing, placing in a 10ml volumetric flask, adding a diluent to dissolve and dilute to a scale, and shaking uniformly to obtain a test sample solution; (the concentration of ibuprofen in the test solution was 33 mg/ml)
Preparation of a selective solution: precisely weighing about 330mg of a test sample, placing the test sample in a 10ml volumetric flask, precisely weighing 1.0ml of a reference substance stock solution, placing the reference substance stock solution in the volumetric flask, adding a diluent to dissolve and dilute the reference substance stock solution to a scale, and shaking up to obtain a selective solution; (concentration of ibuprofen in the selective solution 33mg/ml, concentration of intermediate 1, intermediate 2, intermediate 3 in the selective solution 20 ng/ml)
Preparation of a limiting stock solution: precisely measuring 1.0ml of each of the intermediate 1, the intermediate 2 and the intermediate 3 stock solutions, placing the intermediate 1, the intermediate 2 and the intermediate 3 stock solutions into a 50ml volumetric flask, adding a diluent to dilute the intermediate 1, the intermediate 2 and the intermediate 3 stock solutions to a scale, and shaking the intermediate 1, the intermediate 2 and the intermediate 3 stock solutions uniformly to obtain quantitative limit stock solutions; (the concentration of intermediate 1, intermediate 2 and intermediate 3 in the quantitative limiting stock solution was 200 ng/ml)
Test solution for self-body (a): precisely measuring 1.0ml of quantitative limit stock solution, placing the quantitative limit stock solution into a 20ml measuring flask, adding a diluent to dilute the stock solution to a scale, and shaking up to obtain a test solution (a);
preparation of LOQ solution: according to the signal-to-noise ratio measured by the test solution (a), the dilution ratio of the sensitivity solution is adjusted to make the signal-to-noise ratio of each component reach the requirement that S/N is approximately equal to 10, and 6 parts of the solution is prepared by the same method.
Preparation of LOD solution: precisely measuring 3.0ml of LOQ solution, placing the LOQ solution into a 10ml measuring flask, diluting the LOQ solution to a scale with diluent, and shaking up to obtain LOD solution.
After the system is stabilized, 1 needle of blank solution, 1 needle of sensitivity solution, 5 needles of contrast solution and 1 needle of test solution are added, and chromatogram is recorded.
Example 2 detection method of the invention System suitability test
The system applicability is realized by the signal to noise ratio of the sensitivity solution and the RSD of the peak area of each component in the 5-pin reference solution, the signal to noise ratio of each component in the sensitivity solution is required to be not less than 3, and the RSD of the peak area of each component in the 5-pin reference solution is not more than 10%.
Preparing blank solution, sensitivity solution and reference solution as described in example 1, and performing chromatogram by using blank solution 1 needle, sensitivity solution 1 needle and reference solution 5 needle under the chromatographic conditions described in example 1, wherein the chromatogram is shown in FIG. 1, FIG. 2 and FIG. 3, and the conversion results according to the formula are shown in the following table:
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; before and after sample adding, the recovery rate of each component in the selective solution is realized, the blank solution is required to have no interference to detection, and before and after sample adding, the recovery rate of each component in the selective solution is required to meet the acceptable standard.
Preparing a blank solution, component positioning solutions, a sample solution, a reference solution and a selective solution as described in example 1, after the system is balanced, feeding a blank solution 1 needle, each component positioning solution 1 needle, a sample solution 1 needle, a reference solution 3 needle and a selective solution 3 needle, recording chromatograms, and obtaining specificity detection results as follows according to fig. 1, fig. 4, fig. 5, fig. 6, fig. 7 and fig. 8:
example 4 quantitation and detection limits of the detection methods of the invention
The lowest detection limit is determined by detecting that its response signal to noise ratio is about 3: 1, the lowest limit of quantitation is achieved by a signal-to-noise ratio of about 10: 1, and (b). Under the level of the limit concentration of quantification, 6 parts of the limit test solution are repeatedly examined, and the RSD of the peak area of the unit concentration of each component in the chromatogram obtained by testing 6 parts of the solution is required to be not more than 10 percent, and the LOQ M1 Should be no more than 20ng/ml (0.6 ppm), LOQ M2 Should be no more than 20ng/ml (0.6 ppm), LOQ M3 Should not be greater than 20ng/ml (0.6 ppm); LOD ≈ 1/3 LOQ.
Blank solution, test solution (a), 6 parts LOQ solution, and LOD solution were prepared as described in example 1. After the system was equilibrated, 1 pin of blank solution, 1 pin of test solution (a), 1 pin of 6 parts of LOQ solution, and 1 pin of LOD solution were entered, and chromatograms were recorded as in fig. 1, 9, and 10. The results obtained are shown in the following table:
example 5 solution stability of the assay method of the invention
And (3) observing the rule that the detection result changes along with time after the control 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 control solution and the test solution during detection.
Claims (2)
1. A detection method for 3 intermediates in ibuprofen, which is characterized in that the 3 intermediates are 2-chloro-p-isobutylpropiophenone, 2- (1-chloroethyl) -2-p-isobutylphenyl-5, 5-dimethyl-1, 3-dioxane and alpha-methyl-p-isobutylphenylacetic acid-3-chloropivalyl respectively, and comprises the following steps: (1) preparing solutions, namely preparing a blank solution, a reference solution, a sensitivity solution and a test solution respectively; the blank solution is an acetonitrile solution; the reference solution comprises an intermediate solution and an acetonitrile solution; the sensitivity solution comprises an intermediate solution and an acetonitrile solution; the test solution comprises ibuprofen and acetonitrile solution; (2) the determination method comprises the following steps: respectively injecting the blank solution, the reference solution, the sensitivity solution and the test solution into a liquid chromatograph, and recording a chromatogram, wherein the chromatogram conditions are as follows: a chromatographic column: octadecylsilane chemically bonded silica is used as a filling agent; the flow rate is 0.3 mL/min; column temperature: 30 ℃; sample introduction amount: 10 mu l of the mixture; operating time: 15 min; detection wavelength: 230 nm; the mobile phase is a mobile phase A-mobile phase B system, wherein the mobile phase A is formic acid with a volume ratio of V/V1: 100: water, and the mobile phase B is formic acid with a volume ratio of V/V1: 100: acetonitrile; the gradient process of the mobile phase is as follows:
the mass spectrometry conditions were as follows:
2. the method of claim 1, wherein: the preparation steps of the blank solution are as follows: the blank solution is acetonitrile solution; the preparation steps of the reference solution are as follows: precisely measuring a reference substance stock solution, placing the reference substance stock solution in a volumetric flask, adding a diluent to dilute the reference substance stock solution to a scale, and shaking up to obtain a reference substance solution; the preparation steps of the sensitivity solution are as follows: precisely measuring a reference substance stock solution, placing the reference substance stock solution into a volumetric flask, adding a diluent to dilute the reference substance stock solution to a scale, and shaking up; precisely measuring the solution, placing the solution in a volumetric flask, adding a diluent to dilute the solution to a scale, and shaking up to obtain a sensitive solution; the preparation steps of the test solution are as follows: taking a test sample, precisely weighing, placing in a volumetric flask, adding a diluent to dissolve and dilute to a scale, and shaking uniformly to obtain a test sample solution; the diluent is acetonitrile solution; the blank solution is the diluent; the formic acid is of AR grade; ultrapure water and acetonitrile are in HPLC grade; the ibuprofen is purchased externally; the chromatographic column is AgilentZorbaxSB4.6mm x 150mm, 2.7 μm.
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| CN109521117A (en) * | 2018-12-07 | 2019-03-26 | 成都倍特药业有限公司 | A kind of detection method of the ibuprofen injection in relation to substance |
| CN110068633A (en) * | 2019-05-24 | 2019-07-30 | 山东新华制药股份有限公司 | The liquid chromatography detecting method of caution structure substance in a kind of brufen |
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| CN106940355A (en) * | 2017-04-24 | 2017-07-11 | 中国药科大学 | A kind of detection method of brufen, its sodium salt and its preparation about material |
| CN109521117A (en) * | 2018-12-07 | 2019-03-26 | 成都倍特药业有限公司 | A kind of detection method of the ibuprofen injection in relation to substance |
| CN110068633A (en) * | 2019-05-24 | 2019-07-30 | 山东新华制药股份有限公司 | The liquid chromatography detecting method of caution structure substance in a kind of brufen |
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