CN113219098A - Method for detecting chloroacetyl chloride in diclofenac sodium - Google Patents
Method for detecting chloroacetyl chloride in diclofenac sodium Download PDFInfo
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Abstract
The invention belongs to the technical field of drug analysis, and particularly relates to a method for detecting chloroacetyl chloride in diclofenac sodium, which can be used for solving the problem of detecting chloroacetyl chloride in diclofenac sodium, and provides a convenient, efficient and accurate detection method.
Description
Technical Field
The invention belongs to the technical field of drug analysis, and particularly relates to a method for detecting chloroacetyl chloride in diclofenac sodium.
Background
Diclofenac Sodium (Diclofenac Sodium) with chemical name of 2- [ (2, 6-dichlorophenyl) amino]Sodium phenylacetate, fraction thereofSub-formula is C14H10Cl2NNaO2Molecular weight of 318.13, and the structural formula is as follows:
diclofenac sodium is an antipyretic analgesic and non-steroidal anti-inflammatory drug, is suitable for relieving rheumatoid arthritis, osteoarthritis, spondyloarthropathy, gouty arthritis, rheumatic arthritis and the like, chloroacetyl chloride is a byproduct in the synthesis process of the diclofenac sodium, exists in a diclofenac sodium raw material, has a warning structural group, is a potential genotoxic impurity, possibly has genetic toxicity and carcinogenicity, and is necessary to be controlled in order to ensure the safety and effectiveness of the drug, and a method with strong specificity and high sensitivity is established to control the impurity.
The ICHM7 stipulates that the maximum allowable daily intake of potentially genotoxic impurities is 1.5. mu.g/day for more than 10 years to the lifetime of treatment, and the control limit of chloroacetyl chloride, a genotoxic impurity in diclofenac sodium, is calculated to be not more than 7.5ppm based on the maximum daily dose of 200mg/day for diclofenac sodium. At present, no document discloses a method for detecting the content of chloroacetyl chloride in diclofenac sodium, in particular ultra-trace chloroacetyl chloride.
The invention discloses a method for detecting the chloracetyl chloride of diclofenac sodium for the first time, and provides a convenient, efficient and accurate detection method for solving the problem of detecting the chloracetyl chloride of diclofenac sodium.
Disclosure of Invention
The invention provides a method for detecting chloracetyl chloride of diclofenac sodium, which can detect the content of chloracetyl chloride of diclofenac sodium, thereby effectively ensuring the medication safety and facilitating the quality control of diclofenac sodium, is convenient, efficient and accurate, completely accords with the guidelines of the verification of Chinese pharmacopoeia methods in the aspects of system applicability, repeatability, specificity and accuracy, and can be used for the quality control of the bulk drug of diclofenac sodium.
In order to achieve the purpose, the invention provides the following technical scheme:
a detection method for chloroacetyl chloride in diclofenac sodium comprises the following steps:
(1) preparing a solution, and respectively preparing a blank solution, a reference solution and a test solution.
(2) The determination method comprises the following steps: measuring the content of chloroacetyl chloride in the diclofenac sodium by adopting a gas chromatography, respectively adding a blank solution, a reference solution and a test solution after the system is stable, and recording a chromatogram;
the chromatographic conditions are as follows: the filler is modified polyethylene glycol, and the column temperature is as follows: 60 ℃ for 20 minutes, injection port temperature: 200 ℃, detector temperature: 220 ℃, sample introduction: 3 μ l, carrier gas: n2, split ratio: 2: 1, line rate: 50 cm/sec.
Further, the blank solution is methanol;
the reference solution: placing a proper amount of chloracetyl chloride reference substance into a volumetric flask, adding a proper amount of blank liquid to dissolve and dilute the chloracetyl chloride reference substance to a scale, and shaking up;
the test solution: taking a proper amount of diclofenac sodium sample, placing the diclofenac sodium sample in a volumetric flask, adding the blank solution to dissolve and dilute the diclofenac sodium sample to a scale, and shaking up the solution.
The chromatographic column is Zebron ZB-FFAP 30m multiplied by 0.32mm, 0.5 μm.
More preferably, the measurement method of the present invention comprises the steps of:
(1) preparing a solution: blank solution: methanol;
reference solution: precisely weighing 150mg of chloracetyl chloride reference substance in a 100ml volumetric flask, adding the blank solution to dilute to a scale, and shaking up; taking a 100ml volumetric flask, precisely measuring 10.0ml of the solution, placing the solution in the flask, adding a blank solution to dilute the solution to a scale, and shaking up; taking a 100ml volumetric flask, precisely measuring 1.0ml of the solution, placing the solution in the flask, adding the blank solution to dilute to a scale, and shaking up. (concentration: 1.5. mu.g/ml)
Test solutions: taking a 10ml volumetric flask, precisely weighing about 2g of diclofenac sodium sample, placing the diclofenac sodium sample into the flask, adding a blank solution to dissolve and dilute the diclofenac sodium sample to a scale, and shaking up. (concentration: 0.2 g/ml)
(2) Chromatographic conditions are as follows:
the instrument comprises the following steps: the gas chromatograph is provided with an FID detector, an automatic sample injector and an electronic analytical balance;
a chromatographic column: the filler is modified polyethylene glycol (such as Zebron ZB-FFAP 30m × 0.32mm, 0.5 μm or equivalent polarity chromatographic column)
Column temperature: left at 60 ℃ for 20 minutes.
Sample inlet temperature: detector temperature at 200 ℃: 220 deg.C
Sample introduction amount: 3. mu.l of carrier gas: n2
The split ratio is as follows: 2: 1 line rate: 50 cm/sec.
(3) The determination method comprises the following steps:
and after the system is stable, feeding a blank solution 1 needle, a reference solution 5 needle and a test solution 1 needle, and recording a chromatogram.
Chloroacetyl chloride (ppm) = (Ru/Rs) × (Cs/Cu)
Wherein: ru: testing the peak area of chloracetyl chloride in the solution atlas;
rs: 5 average peak areas of chloroacetyl chloride in the chromatogram of the reference solution;
cs: the concentration of chloroacetyl chloride in the reference solution (. mu.g/ml);
cu: the concentration of the solution (g/ml) was tested. .
Limitation:
the method for detecting chloroacetyl chloride in diclofenac sodium further comprises method verification before detection, wherein the method verification is that according to the chromatographic conditions of formal detection, the determination result is as follows:
the invention discloses a method for detecting chloroacetyl chloride in diclofenac sodium for the first time, provides a convenient, efficient and accurate detection method for solving the problem of detecting chloroacetyl chloride in diclofenac sodium, and can detect the content of chloroacetyl chloride in diclofenac sodium, thereby effectively ensuring the medication safety.
According to the invention, a capillary column with the filler being modified polyethylene glycol is screened out through a large number of experiments, so that the capillary column can be separated and can meet the requirement of the detection limit, and if other fillers are selected, such as a capillary column of 100% dimethyl polysiloxane (such as HP-1) or 5% phenyl-95% methyl polysiloxane (such as HP-5 and SE-30), the detection requirement of the invention cannot be met, or the separation degree requirement cannot be met, or the fillers can be separated but cannot meet the requirement of the detection limit of the invention.
Because the detection limit controlled by the method is low, the inventor screens out a proper solvent as methanol through a large number of experiments, and enables the methanol and the chloracetyl chloride to be effectively separated and meet the detection requirement by controlling experiment parameters, and if other solvents are selected, the separation and detection requirement of the method cannot be met.
Drawings
FIG. 1 is a spectrum diagram of a chloracetyl chloride blank solution in diclofenac sodium
FIG. 2 is a spectrum diagram of chloracetyl chloride reference solution in diclofenac sodium
FIG. 3 is a spectrum diagram of chloroacetyl chloride test solution in diclofenac sodium
FIG. 4 is a diagram of a chloracetyl chloride system applicability solution in diclofenac sodium
FIG. 5 is a spectrum diagram of chloroacetyl chloride selective solution in diclofenac sodium
Detailed Description
The invention is further illustrated by the following examples, which are not to be construed as limiting the invention thereto.
Example 1:
(1) preparing a solution: blank solution: methanol;
reference solution: precisely weighing 150mg of chloracetyl chloride reference substance in a 100ml volumetric flask, adding the blank solution to dilute to a scale, and shaking up; taking a 100ml volumetric flask, precisely measuring 10.0ml of the solution, placing the solution in the flask, adding a blank solution to dilute the solution to a scale, and shaking up; taking a 100ml volumetric flask, precisely measuring 1.0ml of the solution, placing the solution in the flask, adding the blank solution to dilute to a scale, and shaking up. (concentration: 1.5. mu.g/ml)
Test solutions: taking a 10ml volumetric flask, precisely weighing about 2g of diclofenac sodium sample, placing the diclofenac sodium sample into the flask, adding a blank solution to dissolve and dilute the diclofenac sodium sample to a scale, and shaking up. (concentration: 0.2 g/ml)
(2) Chromatographic conditions are as follows:
the instrument comprises the following steps: the gas chromatograph is provided with an FID detector, an automatic sample injector and an electronic analytical balance;
a chromatographic column: the filler is modified polyethylene glycol (such as Zebron ZB-FFAP 30m × 0.32mm, 0.5 μm or equivalent polarity chromatographic column)
Column temperature: left at 60 ℃ for 20 minutes.
Sample inlet temperature: detector temperature at 200 ℃: 220 deg.C
Sample introduction amount: 3. mu.l of carrier gas: n2
The split ratio is as follows: 2: 1 line rate: 50 cm/sec.
(3) The determination method comprises the following steps:
and after the system is stable, feeding a blank solution 1 needle, a reference solution 5 needle and a test solution 1 needle, and recording a chromatogram.
Chloroacetyl chloride (ppm) = (Ru/Rs) × (Cs/Cu)
Wherein: ru: testing the peak area of chloracetyl chloride in the solution atlas;
rs: 5 average peak areas of chloroacetyl chloride in the chromatogram of the reference solution;
cs: the concentration of chloroacetyl chloride in the reference solution (. mu.g/ml);
cu: the concentration of the solution (g/ml) was tested.
Limitation:
example 2: system applicability
The system applicability is realized by measuring the RSD of the chloracetyl chloride peak area in 5-pin reference solution, and the RSD of the chloracetyl chloride peak area in 5-pin reference solution is required to be less than or equal to 10.0%.
Example 3: specificity
The specificity of the method is that the detection of the chloroacetyl chloride is free from interference by measuring a blank solvent; selectivity of the degree of separation between chloroacetyl chloride and adjacent peaks in solution. A blank solvent is required to be free from interference to the detection of chloroacetyl chloride; the separation degree between the chloracetyl chloride and the adjacent peaks in the selective solution is more than or equal to 1.5.
Example 4: selectivity is
The purpose of selectivity is to investigate whether a diclofenac sodium sample generates certain substances under a heating state to influence the detection of chloroacetyl chloride, and the recovery rate of chloroacetyl chloride is required to be between 90.0% and 110.0% before and after sample addition.
Example 5: repeatability of
The precision is realized by testing the RSD of the chloracetyl chloride measuring result in 6 parts of the testing solution, and the RSD of the chloracetyl chloride measuring result in 6 parts of the testing solution is required to be less than or equal to 10.0 percent.
Example 6: quantitative and detection limits
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 to obtain. At this concentration level, 6 parts of the quantitative limit test solution were repeatedly investigated,
example 7: durability
The method is characterized in that the law that a reference solution and a test solution are placed for 0 hour, 8 hours and 16 hours at room temperature and then injected is examined, the change of a detection result along with time is provided for the placing time of the reference solution and the test solution during detection, the requirement is compared with 0 hour, the recovery rate of chloroacetyl chloride after the reference solution is placed for 16 hours is 90.0-110.0%, and the change value of the detection result of chloroacetyl chloride after the test solution is placed for 16 hours at room temperature is within 20% of the limit, so that the solution is stable.
Comparative example the method of example 1 according to the invention was used, the following table conditions were selected, and the other conditions not shown were examined using the method of example 1:
Claims (2)
1. a detection method for chloroacetyl chloride in diclofenac sodium is characterized by comprising the following steps:
(1) preparing solutions, namely respectively preparing a blank solution, a reference solution and a test solution;
(2) the determination method comprises the following steps: measuring the content of chloroacetyl chloride in the diclofenac sodium by adopting a gas chromatography, respectively adding a blank solution, a reference solution and a test solution after the system is stable, and recording a chromatogram;
the chromatographic conditions are as follows: the filler is modified polyethylene glycol, and the column temperature is as follows: 60 ℃ for 20 minutes, injection port temperature: 200 deg.CThe temperature of the detector is as follows: 220 ℃, sample introduction: 3 μ l, carrier gas: n is a radical of2And the split ratio: 2: 1, line rate: 50 cm/sec.
2. The method of claim 1, wherein:
the blank solution is methanol;
the reference solution: placing a proper amount of chloracetyl chloride reference substance into a volumetric flask, adding a proper amount of blank liquid to dissolve and dilute the chloracetyl chloride reference substance to a scale, and shaking up;
the test solution: taking a proper amount of diclofenac sodium sample, placing the diclofenac sodium sample in a volumetric flask, adding a blank solution to dissolve and dilute the diclofenac sodium sample to a scale, and shaking up;
the chromatographic column is Zebron ZB-FFAP 30m multiplied by 0.32mm, 0.5 μm.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116183741A (en) * | 2022-12-03 | 2023-05-30 | 华夏生生药业(北京)有限公司 | Method for detecting chloroacetyl chloride in fluconazole |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108956805A (en) * | 2018-05-31 | 2018-12-07 | 江苏泰洁检测技术股份有限公司 | A kind of derivative quantitative analysis method of chloracetyl chloride |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108956805A (en) * | 2018-05-31 | 2018-12-07 | 江苏泰洁检测技术股份有限公司 | A kind of derivative quantitative analysis method of chloracetyl chloride |
Non-Patent Citations (3)
| Title |
|---|
| MARIE-FRANCE MORISSETTE 等: "Trace level determination of chloroacetyl chloride and degradation products by derivatization gas chromatography", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》 * |
| 唐泰双等: "气相色谱法测定三氯乙酰氯的含量", 《河南化工》 * |
| 潘云雪等: "RP-HPLC法测定双氯芬酸钠注射液的含量和有关物质", 《中国药品标准》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116183741A (en) * | 2022-12-03 | 2023-05-30 | 华夏生生药业(北京)有限公司 | Method for detecting chloroacetyl chloride in fluconazole |
| CN116183741B (en) * | 2022-12-03 | 2023-08-29 | 华夏生生药业(北京)有限公司 | Method for detecting chloroacetyl chloride in fluconazole |
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