CN112083106B - Method for detecting 3-chloro-2, 2-dimethyl-1-propanol in ibuprofen - Google Patents
Method for detecting 3-chloro-2, 2-dimethyl-1-propanol in ibuprofen Download PDFInfo
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Abstract
The invention provides a method for detecting 3-chloro-2, 2-dimethyl-1-propanol in ibuprofen, wherein the 3-chloro-2, 2-dimethyl-1-propanol is a toxic substance containing a warning structure, incomplete reaction possibly exists in the reaction process, the 3-chloro-2, 2-dimethyl-1-propanol remains in the ibuprofen raw material drug, in order to detect the content of the 3-chloro-2, 2-dimethyl-1-propanol in the ibuprofen, the invention provides a gas chromatography-mass spectrometry combined detection method for the 3-chloro-2, 2-dimethyl-1-propanol in the ibuprofen, the method is simple, convenient, efficient and accurate, and completely accords with the guidelines of the method verification in ICH Q2 and Chinese pharmacopoeia' four-part 9101 guidelines in terms of system applicability, specificity, precision, quantification limit, detection limit, durability and the like, can be used for quality control of ibuprofen bulk drug.
Description
Technical Field
The invention relates to the technical field of medical analysis, in particular to a method for detecting 3-chloro-2, 2-dimethyl-1-propanol in ibuprofen.
Background
Ibuprofen (Ibuprofen) is an antipyretic analgesic non-steroidal anti-inflammatory drug, is an anti-inflammatory drug without a steroidal structure, plays the roles of antipyresis and analgesia by inhibiting the synthesis of prostaglandin, achieves the effects of bringing fever relief to a person with fever, relieving discomfort brought by pain and the like, has no influence on the person with normal body temperature, and does not reduce the body temperature; ibuprofen and naproxen belong to aryl propionic acid antipyretic and analgesic drugs, have obvious effects of resisting inflammation, relieving fever and relieving pain, have the same strength as aspirin, have a certain inhibition effect on platelet function, and can prolong bleeding time. The currently widely adopted production process of ibuprofen in China is an aryl 1, 2-transposition rearrangement method, wherein isobutylbenzene is used as a raw material and is prepared through the steps of parack acylation with 2-chloropropionyl chloride, catalytic ketalization with neopentyl glycol, catalytic rearrangement, hydrolysis, acidification and the like, in the production process, impurity 3-chloro-2, 2-dimethyl-1-propanol is generated, the method for detecting the ibuprofen in the current stage is mainly a gas chromatography area normalization method, the conditions of a chromatographic column are not clear, the product impurities are complex in actual production, and the difference of response factors among components in gas chromatography is large, so that the content of the 3-chloro-2, 2-dimethyl-1-propanol cannot be accurately determined by simply using the area normalization method.
Patent CN111272900A describes that the content of 3-chloro-2, 2-dimethyl-1-propanol is detected by using a gas chromatography method, the used chromatographic column is a quartz capillary chromatographic column with the specification of TG-wax30m × 0.25mm × 0.25 μm, and the used solvent is methanol, the detection method provided in the patent has the defects of time consumption, deviation of detection results and the like, and has the defects of poor detection sensitivity, incapability of more effectively controlling the product quality and capability of meeting higher quality requirements.
The invention provides a method for detecting 3-chloro-2, 2-dimethyl-1-propanol in ibuprofen, wherein 3-chloro-2, 2-dimethyl-1-propanol which is generated due to incomplete reaction can remain in an ibuprofen finished product, and in order to detect the content of 3-chloro-2, 2-dimethyl-1-propanol in the ibuprofen, the invention provides a gas chromatography-mass spectrometry combined method for detecting the content of 3-chloro-2, 2-dimethyl-1-propanol in the ibuprofen, wherein the method is independently developed and realized by research and development personnel, and is verified by referring to ICH Q2 and the four parts 9101 of Chinese pharmacopoeia.
Disclosure of Invention
The invention aims to provide a method for detecting 3-chloro-2, 2-dimethyl-1-propanol 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-chloro-2, 2-dimethyl-1-propanol in ibuprofen comprises the following steps: (1) preparing solutions, namely respectively preparing a blank solution, a 3-chloro-2, 2-dimethyl-1-propanol stock solution, a reference solution, a sensitivity solution and a test solution; the blank solution is an acetonitrile solution; the reference solution comprises a 3-chloro-2, 2-dimethyl-1-propanol solution and an acetonitrile solution; the sensitivity solution comprises a 3-chloro-2, 2-dimethyl-1-propanol 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 gas chromatograph, and recording a chromatogram, wherein the chromatogram conditions are as follows: a chromatographic column: (5% phenyl) -methyl polysiloxane was used as filler; column temperature: the initial temperature is 40 deg.C, maintaining for 5min, heating to 100 deg.C at a rate of 10 deg.C per minute, heating to 250 deg.C at a rate of 50 deg.C per minute, and maintaining for 5 min; sample inlet temperature: 100 ℃; carrier gas pressure: 13.8 psi; carrier gas: he; sample introduction amount: 0.5 mul; sample introduction is not divided;
the mass spectrometry conditions were as follows:
further, the preparation steps of the blank solution are as follows: the blank solution is acetonitrile solution;
the preparation method of the 3-chloro-2, 2-dimethyl-1-propanol stock solution comprises the following steps: weighing 3-chloro-2, 2-dimethyl-1-propanol 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 in a volumetric flask, adding a diluent to dilute the 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 the solution uniformly to obtain a 3-chloro-2, 2-dimethyl-1-propanol stock solution;
the preparation steps of the reference solution are as follows: accurately measuring a 3-chloro-2, 2-dimethyl-1-propanol stock solution, placing the stock solution in a volumetric flask, adding a diluent to dilute the stock solution to a scale, and shaking the stock solution uniformly to obtain a reference solution;
the preparation steps of the sensitivity solution are as follows: precisely measuring a reference solution, placing the reference solution in a volumetric flask, adding a diluent to dilute the reference solution to a scale, and shaking up to obtain a sensitivity 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 ultrapure water and the acetonitrile are HPLC;
the ibuprofen is purchased externally;
the column may be an Agilent HP-5MS 30m × 0.25mm, 0.25 μm, or an energy efficient equivalent.
The method for measuring the content of the 3-chloro-2, 2-dimethyl-1-propanol 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 3-chloro-2, 2-dimethyl-1-propanol 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 3-chloro-2, 2-dimethyl-1-propanol in the ibuprofen, the method is verified by using a convenient and quick gas chromatography-mass spectrometry combined method to prove the effectiveness and feasibility of the method. The detection of 3-chloro-2, 2-dimethyl-1-propanol in ibuprofen can be used for monitoring the quality of ibuprofen bulk drugs and preparations. The invention firstly provides the detection of 3-chloro-2, 2-dimethyl-1-propanol in ibuprofen by using a gas 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 gas chromatogram of an empty white solution in examples 2, 3, 4, 5;
FIG. 2 is a gas chromatogram of the sensitivity solution in example 2;
FIG. 3 is a gas chromatogram of the reference solution in example 2;
FIG. 4 is a gas chromatogram of the test solution in example 3;
FIG. 5 is a gas chromatogram of the selective solution of example 3;
FIG. 6 is a gas chromatogram of the LOQ solution of example 4;
FIG. 7 is a gas chromatogram of the LOD solution of example 4;
FIG. 8 is a gas chromatogram of the test solution (spiked) in example 5;
FIG. 9 is a graph showing the linear relationship between the concentration of 3-chloro-2, 2-dimethyl-1-propanol and the peak area.
Detailed Description
Example 1
(1) Experimental materials and instrumentation conditions
Experimental materials: acetonitrile, manufacturer: merck shares alliance; ibuprofen, manufacturer: hubei Baike Gelai pharmaceuticals, Inc.; 3-chloro-2, 2-dimethyl-1-propanol, manufacturer: tokyo chemical industry co; 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 XSE205DU, GR-200; a chromatographic column: agilent HP-5MS 30 m.times.0.25 mm, 0.25 μm.
Respectively injecting the blank solution, the reference solution, the sensitivity solution and the test solution into a gas chromatograph, and recording a chromatogram, wherein the chromatogram conditions are as follows: a chromatographic column: (5% phenyl) -methyl polysiloxane was used as filler; column temperature: the initial temperature is 40 deg.C, maintaining for 5min, heating to 100 deg.C at a rate of 10 deg.C per minute, heating to 250 deg.C at a rate of 50 deg.C per minute, and maintaining for 5 min; sample inlet temperature: 100 ℃; carrier gas pressure: 13.8 psi; carrier gas: he; sample introduction amount: 0.5 mul; sample introduction is not divided;
the mass spectrometry conditions were as follows:
(2) experimental procedure
Preparing 3-chloro-2, 2-dimethyl-1-propanol stock solution: weighing about 100mg of 3-chloro-2, 2-dimethyl-1-propanol 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, placing the solution in a 50ml volumetric flask, adding a diluent to dilute the solution to a scale, and shaking up; precisely measuring 1.0ml of the solution, placing the solution in a 50ml volumetric flask, adding a diluent to dilute the solution to a scale, and shaking the solution uniformly to obtain a 3-chloro-2, 2-dimethyl-1-propanol stock solution; (the concentration of the 3-chloro-2, 2-dimethyl-1-propanol stock solution is 400 ng/ml);
preparing a reference solution: accurately measuring 1.5ml of 3-chloro-2, 2-dimethyl-1-propanol stock solution, placing the 3-chloro-2, 2-dimethyl-1-propanol stock solution into a 10ml volumetric flask, adding a diluent to dilute the stock solution to a scale, and shaking up to obtain a reference solution; (concentration of 3-chloro-2, 2-dimethyl-1-propanol in the reference solution was 60 ng/ml)
Preparing a sensitivity solution: accurately measuring 1.5ml of reference solution, placing the reference solution in a 10ml volumetric flask, adding diluent to dilute to a scale, and shaking up to obtain a sensitivity solution; (concentration of 3-chloro-2, 2-dimethyl-1-propanol in the sensitivity solution was 9 ng/ml)
Preparation of test solutions: taking about 1.0g of a sample, precisely weighing, placing in a 10ml volumetric flask, adding a diluent to dissolve and dilute to a scale, and shaking up to obtain a test solution; (concentration of ibuprofen in test solution 0.1 g/ml)
Preparing a selective solution: precisely weighing about 1.0g (not less than 1.0 g) of sample, placing in a 10ml volumetric flask, and adding appropriate amount of diluent for dissolving; accurately measuring 1.5ml of 3-chloro-2, 2-dimethyl-1-propanol stock solution, placing the stock solution in the volumetric flask, adding diluent to dilute to a scale, and shaking up to obtain a selective solution; (the concentration of ibuprofen in the selective solution was 0.1g/ml, and the concentration of 3-chloro-2, 2-dimethyl-1-propanol in the selective solution was 60 ng/ml)
Preparing LOQ solution: accurately measuring 1.5ml of 3-chloro-2, 2-dimethyl-1-propanol stock solution, placing the 3-chloro-2, 2-dimethyl-1-propanol stock solution into a 20ml volumetric flask, adding a diluent to dilute to a scale, shaking up to obtain an LOQ solution, and preparing 6 parts of the LOQ solution by the same method; (the concentration of 3-chloro-2, 2-dimethyl-1-propanol in the LOQ solution was 30 ng/ml)
Preparing LOD solution: precisely measuring 3.0ml of LOQ solution, placing in a 10ml volumetric flask, adding diluent to dilute to a scale, and shaking up to obtain LOD solution; (the concentration of 3-chloro-2, 2-dimethyl-1-propanol in the LOD solution was 9 ng/ml)
Preparation of test solutions (spiked): taking about 1.0g of a sample, precisely weighing, placing in a 10ml volumetric flask, and adding a proper amount of diluent for dissolution; accurately measuring 1.5ml of 3-chloro-2, 2-dimethyl-1-propanol stock solution, placing the stock solution in the volumetric flask, 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 by the same method; (ibuprofen concentration 0.1g/ml in test solution (spiked) and 3-chloro-2, 2-dimethyl-1-propanol concentration 60ng/ml in test solution (spiked))
And after the system is stable, feeding a blank solution 1 needle, a sensitivity solution 1 needle, a reference solution 5 needle and a test solution 1 needle, and recording a chromatogram.
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 peak of 3-chloro-2, 2-dimethyl-1-propanol in a sensitivity solution and the RSD of the peak area of 3-chloro-2, 2-dimethyl-1-propanol in 5 needles of reference solutions, wherein the signal-to-noise ratio of the peak of 3-chloro-2, 2-dimethyl-1-propanol in the sensitivity solution is required to be not less than 3, and the RSD of the peak area of 3-chloro-2, 2-dimethyl-1-propanol in 5 needles of reference solutions is required to be not more than 10.0%.
Blank solution, reference solution and sensitivity 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 to obtain chromatograms as shown in fig. 1, fig. 2 and fig. 3, and the results are converted according to the formula as 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 of the 3-chloro-2, 2-dimethyl-1-propanol; before and after sample loading, the recovery rate of the 3-chloro-2, 2-dimethyl-1-propanol in the selective solution is realized. The blank solution should not interfere with the detection of 3-chloro-2, 2-dimethyl-1-propanol; before and after sample adding, the recovery rate of the 3-chloro-2, 2-dimethyl-1-propanol in the selective solution is between 80.0 and 120.0 percent.
Preparing blank solution, 3-chloro-2, 2-dimethyl-1-propanol 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 chromatograms, and obtaining specificity detection results as follows according to the following diagrams in fig. 1, fig. 3, fig. 4 and fig. 5:
remarking: reference solution reference system applicability item 3 first refers to a reference solution.
Example 4 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 the 3-chloro-2, 2-dimethyl-1-propanol 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.
A blank solution, a stock solution of 3-chloro-2, 2-dimethyl-1-propanol, 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 6 parts of LOQ solution, and 1 pin of LOD solution were introduced, and chromatograms were recorded as shown in fig. 1, 6, and 7. The results obtained are shown in the following table:
example 5 solution precision of the assay method of the invention
Precision is achieved by RSD of the 3-chloro-2, 2-dimethyl-1-propanol assay in 6 parts of the test solution (spiked), requiring that RSD of the 3-chloro-2, 2-dimethyl-1-propanol assay in 6 parts of the test solution (spiked) should be no greater than 10.0%.
Blank solutions, 3-chloro-2, 2-dimethyl-1-propanol stock solutions, reference solutions and test solutions (spiked) were prepared as described in example 1. After the system was equilibrated, 1 pin of blank solution, 1 pin of reference solution, 6 parts of test solution (spiked) were added for each 1 pin, and chromatograms were recorded as shown in fig. 1, fig. 3, and fig. 8. The results obtained are shown in the following table:
example 6 solution stability of the assay methods of the invention
And (3) observing the change rule of the detection result with time after the reference solution and the selective solution are placed at room temperature for 0hr, 3hrs and 8hrs, and providing a basis for the placing time of the reference solution and the test solution during detection. Comparing with 0hr, keeping the reference solution at room temperature for 8hrs, and keeping the recovery rate of 3-chloro-2, 2-dimethyl-1-propanol between 80.0% -120.0%, keeping the reference solution at room temperature for 8 hrs; comparing with 0hr, the selective solution is stable within 8hrs at room temperature, and the recovery rate of 3-chloro-2, 2-dimethyl-1-propanol is between 80.0% and 120.0%.
Claims (2)
1. A method for detecting 3-chloro-2, 2-dimethyl-1-propanol in ibuprofen is characterized in that,
the method comprises the following steps:
(1) preparing solutions, namely respectively preparing a blank solution, a 3-chloro-2, 2-dimethyl-1-propanol stock solution, a reference solution, a sensitivity solution and a test solution;
the blank solution is an acetonitrile solution; the reference solution comprises a 3-chloro-2, 2-dimethyl-1-propanol solution and an acetonitrile solution; the sensitivity solution comprises a 3-chloro-2, 2-dimethyl-1-propanol 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 gas chromatograph, and recording a chromatogram, wherein the chromatogram conditions are as follows: a chromatographic column: 5% phenyl-methyl polysiloxane was used as filler; column temperature: the initial temperature is 40 deg.C, maintaining for 5min, heating to 100 deg.C at a rate of 10 deg.C per minute, heating to 250 deg.C at a rate of 50 deg.C per minute, and maintaining for 5 min; sample inlet temperature: 100 ℃; carrier gas pressure: 13.8 psi; carrier gas: he; sample introduction amount: 0.5 mul; sample introduction is not divided;
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 method of the 3-chloro-2, 2-dimethyl-1-propanol stock solution comprises the following steps: weighing 3-chloro-2, 2-dimethyl-1-propanol 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 in a volumetric flask, adding a diluent to dilute the 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 the solution uniformly to obtain a 3-chloro-2, 2-dimethyl-1-propanol stock solution;
the preparation steps of the reference solution are as follows: accurately measuring a 3-chloro-2, 2-dimethyl-1-propanol stock solution, placing the stock solution in a volumetric flask, adding a diluent to dilute the stock solution to a scale, and shaking the stock solution uniformly to obtain a reference solution;
the preparation steps of the sensitivity solution are as follows: precisely measuring a reference solution, placing the reference solution in a volumetric flask, adding a diluent to dilute the reference solution to a scale, and shaking up to obtain a sensitivity 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 for dissolution, diluting to a scale, and shaking uniformly to obtain a test sample solution;
the diluent is acetonitrile solution;
the blank solution is the diluent;
the acetonitrile is of HPLC grade;
the ibuprofen is purchased externally;
the type of the chromatographic column is Agilent HP-5MS 30m multiplied by 0.25mm, 0.25 mu m.
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