CN113984944A - Detection method of Perampanel genotoxic impurities - Google Patents
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Abstract
The invention discloses a detection method of Perampanel genotoxic impurities. The invention has higher system applicability, shows incomparable advantages on specificity, quantitative limit, detection limit, linear range and repeatability, and has higher precision.
Description
Technical Field
The invention belongs to the field of chemical drug analysis and detection, and particularly relates to a detection method of perampanel genotoxic impurities.
Background
Perampanel (Perampanel), chemically known as 3- (2-cyanophenyl) -5- (2-pyridyl) -1-phenyl-1, 2-dihydropyridin-2-one tri-quarter hydrate, is a non-competitive AMPA glutamate receptor antagonist developed by Eisai, approved by the European Union EMA and the U.S. Food and Drug Administration (FDA) at months 7 and 10 of 2012, respectively, for the adjuvant treatment of patients with partial seizure epilepsy over 12 years old, with or without secondary generalized seizures, and is commercially available under the name FYCOMPA. The specifications of the tablet are 2mg, 4mg, 6mg, 8mg, 10mg and 12mg 6 specifications, and the currently imported Perampanel tablet (Weikangtai) is sold at home at 2mg and 4 mg. The known main impurities of Perampanel are impurity A, impurity B, impurity C, impurity D, intermediate III, intermediate IV and the like, and come from intermediates and degradation products, and the structural formula is as follows:
wherein the impurity B is nitrogen oxide and has a genetic toxicity warning structure. According to the guide principle of controlling the genetic toxicity impurities of ICH M7 and the four ministry of communications 9306 of 2020 edition of Chinese pharmacopoeia, the limit of the impurities B is 125ppm calculated according to TTC 1.5 mu g/day. The impurity B in the Perampanel needs to be detected so as to meet the standard requirement.
The limit of genotoxic impurities is low, and most detection methods can also use LC-MS or GC-MS for detection; because LC-MS or GC-MS instruments are expensive, and the large and multiple medicine enterprise QC department does not have the detection conditions of LC-MS or GC-MS, the development of a conventional liquid chromatography method for detecting genotoxic impurities has higher practicability.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a method for detecting the perampanel genotoxic impurities, which completely meets the standards in the aspects of specificity, quantitative limit, detection limit, linear range, repeatability, accuracy and the like and has higher precision.
In order to achieve the purpose, the invention provides the following technical scheme: a method for detecting the genotoxic impurities of the Perampanel comprises the steps of detecting the content of the genotoxic impurities in the Perampanel through a liquid chromatography;
the genotoxic impurity is impurity B, the chemical name is 3- (2-cyanophenyl) -5- (2-N-oxygen pyridyl) -1-phenyl-1, 2-dihydropyridine-2-ketone, and the structural formula is as follows:
preferably, the detection method is capable of quantitatively detecting 6.6ppm of Perampanel genotoxic impurity, impurity B, at the lowest energy.
Specifically, the method for detecting the perampanel genotoxic impurities, provided by the invention, comprises the following steps:
1) preparing test solution
Taking a Perampanel sample of 50mg, precisely weighing, placing in a 10ml measuring flask, adding 1ml of N, N-dimethylformamide, shaking to dissolve, adding 6ml of acetonitrile, diluting with water to a scale, shaking uniformly, and filtering to obtain a subsequent filtrate;
2) preparing reference substance solution
Precisely weighing proper amount of genotoxic impurities, adding diluent to dissolve and dilute into solution containing 12.5 μ g of genotoxic impurities per 1ml, and using the solution as reference mother liquor; precisely measuring a proper amount of reference mother liquor, placing into a measuring flask, and adding blank solution to dilute into a solution containing 0.63 microgram of genotoxic impurities per 1 ml.
3) Respectively and precisely measuring a test solution and a reference solution, injecting the test solution and the reference solution into a liquid chromatograph, recording a chromatogram, and calculating the content of the impurity B in the test solution by adopting an external standard method according to peak areas.
Specifically, the blank solution preparation method in the step 2) comprises the following steps: measuring 1ml of N, N-dimethylformamide and 6ml of acetonitrile, placing the N, N-dimethylformamide and the acetonitrile into the same 10ml measuring flask, diluting the N, N-dimethylformamide and the acetonitrile to the scale with water, and shaking up the N, N-dimethylformamide and the acetonitrile uniformly.
Specifically, the diluent in the step 2) is a mixture of a diluent and a diluent in a volume ratio of 50: 50 of acetonitrile and water.
Specifically, the calculation formula in step 3) is as follows:
wherein:
in the formula: f-response factor; m isS-weighing the impurity B in the control solution; c. CS-the content of impurity B; vS-total diluted volume of impurity B in control solution; a. theSPeak area f of impurity B in chromatogram of control solutionAverage-an average value of the response factors; a. thei-peak area of impurity B in the test sample; m isiWeighing the sample; vi-test article dilution volume.
Preferably, the detection conditions of the liquid chromatography are as follows:
a chromatographic column: an Agela C18 chromatography column, specification 4.6mm x 250mm, 5 μm;
mobile phase A: 0.01mol/L potassium dihydrogen phosphate solution, and adjusting the pH value to 3.0 by phosphoric acid;
mobile phase B: acetonitrile;
and (3) an elution mode: gradient elution;
flow rate: 1.0 mL/min;
column temperature: 30 ℃;
detection wavelength: 220 nm;
sample introduction amount: 20 μ L.
Specifically, during the gradient elution, the elution procedure is:
| time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 80 | 20 |
| 15 | 50 | 50 |
| 20 | 20 | 80 |
| 30 | 20 | 80 |
| 31 | 80 | 20 |
| 40 | 80 | 20 |
Has the advantages that: (1) according to the invention, an acetonitrile-potassium dihydrogen phosphate solution gradient elution system is adopted, so that impurities B, Perampanel and other impurities can be effectively separated, the peak type symmetry is good, the detection of the impurities B is facilitated, and the system applicability is high; (2) the invention has incomparable advantages in specificity, quantitative limit, detection limit, linear range and repeatability, and has high precision.
Drawings
FIG. 1 is a liquid chromatogram for examining a blank solvent;
FIG. 2 is a liquid chromatogram for examining a mixed solution;
FIG. 3 is a liquid chromatogram of an examination control solution;
FIG. 4 is a liquid chromatogram of a test sample solution;
FIG. 5 is a liquid chromatogram of a mixed solution for examining total impurities;
FIG. 6 is a standard curve of impurity B in the control solution.
Detailed Description
For the purpose of enhancing the understanding of the present invention, the present invention will be further described in detail with reference to the following examples and the accompanying drawings, which are only used for explaining the present invention and are not to be construed as limiting the scope of the present invention.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
According to the detection method, the impurity B is mainly detected, and an external standard method is used for calculation.
The instrument and reagent information used in the detection method of the invention in the implementation mode is shown in the following table:
example 1
The embodiment provides a method for detecting a perampanel genotoxic impurity.
1. Chromatographic conditions are as follows:
the instrument comprises the following steps: agilent 1100
A chromatographic column: agela C18 column (4.6 mm. times.250 mm, 5 μm)
Mobile phase A: 0.01mol/L potassium dihydrogen phosphate solution (pH adjusted to 3.0 with phosphoric acid)
Mobile phase B: acetonitrile
Flow rate: 1.0ml/min
Column temperature: 30 deg.C
Detection wavelength: 220nm
Sample introduction amount: 20 μ l
Elution gradient, elution program as shown in table 1:
table 1: gradient elution procedure
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 80 | 20 |
| 15 | 50 | 50 |
| 20 | 20 | 80 |
| 30 | 20 | 80 |
| 31 | 80 | 20 |
| 40 | 80 | 20 |
2. Detection method
(1) Preparing test solution
Taking a Perampanel sample of 50mg, precisely weighing, placing in a 10ml measuring flask, adding about 1ml of N, N-dimethylformamide, shaking to dissolve, adding about 6ml of acetonitrile, diluting with water to a scale, shaking uniformly, and filtering to obtain a subsequent filtrate;
(2) preparing reference substance solution
Precisely weighing an appropriate amount of impurity B, and adding the mixture into a reaction kettle according to a volume ratio of 50: 50 of acetonitrile and water are dissolved and diluted into a solution containing about 12.5 mu g of acetonitrile per 1ml, and the solution is used as a reference mother solution; an appropriate amount of the control mother liquor was precisely measured, placed in a measuring flask, and diluted with water to a solution containing about 0.63. mu.g of impurity B per 1ml after adding about 10% by volume of N, N-dimethylformamide and 60% by volume of acetonitrile to the measuring flask.
(3) Respectively and precisely measuring a test solution and a reference solution, injecting the test solution and the reference solution into a liquid chromatograph, recording a chromatogram, and calculating the content of the impurity B in the test solution by adopting an external standard method according to peak areas.
3. Formula for calculating content of impurity B
(1)
In the formula: f-response factor;
mS is the weighing amount of the impurity B in the reference substance solution;
cS — content of impurity B;
VS — total dilution volume of impurity B in control solution;
AS represents the peak area of the impurity B in the chromatogram of the reference solution.
(2)
In the formula: f mean — mean of response factors;
ai is the peak area of the impurity B in the test sample;
mi is sample weighing of the sample;
vi-dilution volume of test article.
Example 2: specificity test
(1) Blank solution: taking about 1ml of N, N-dimethylformamide and 6ml of acetonitrile, putting the N, N-dimethylformamide and the acetonitrile into the same 10ml measuring flask, diluting the N, N-dimethylformamide and the acetonitrile to the scale with water, and shaking up the N, N-dimethylformamide and the acetonitrile.
(2) Control solution: taking a proper amount of impurity B, precisely weighing, dissolving with 50% acetonitrile solution, and diluting to obtain a solution containing 12.5 μ g of impurity B per 1ml, as reference mother liquor; an appropriate amount of the control mother liquor was precisely measured, placed in a measuring flask, and diluted with water to a solution containing about 0.63. mu.g of impurity B per 1ml after adding about 10% by volume of N, N-dimethylformamide and 60% by volume of acetonitrile in the measuring flask.
(3) Test solution: taking a Perampanel sample of about 50mg, precisely weighing, placing in a 10ml measuring flask, adding about 1ml of N, N-dimethylformamide, shaking to dissolve, adding about 6ml of acetonitrile, diluting with water to a scale, shaking uniformly, filtering, and taking a subsequent filtrate.
(4) Mixing the solution: taking a Perampanel sample of about 50mg, precisely weighing, placing in a 10ml measuring flask, adding about 1ml of N, N-dimethylformamide, shaking to dissolve, adding 0.5ml of a reference product mother solution, adding about 6ml of acetonitrile, diluting with water to a scale, shaking uniformly, filtering, and taking a subsequent filtrate.
(5) Total impurity mixed solution: taking proper amounts of impurity A, impurity B, impurity C, initial raw material IIa, initial raw material IIb, initial raw material IIc, intermediate III, intermediate IV and triphenylphosphine oxide, and dissolving and diluting the proper amounts of impurity A, impurity B, impurity C, initial raw material IIa, intermediate III, intermediate IV and triphenylphosphine oxide by acetonitrile-water (50: 50) to obtain mixed solution containing 0.5mg of each impurity per 1ml as mother solution of each impurity; dissolving appropriate amount of impurity D1 and impurity D2 with methanol, and diluting to obtain solution containing 0.5mg per 1ml as impurity D mother liquor; diluting the impurity mother liquor with acetonitrile-water (50: 50) to obtain mixed mother liquor containing 12.5 μ g of each impurity in 1ml, adding 0.5ml of the impurity mixed mother liquor into a 10ml measuring flask, adding about 1ml of N, N-dimethylformamide and 6ml of acetonitrile, diluting with water to scale, shaking, filtering, and collecting the filtrate.
Blank solution, mixed solution, reference solution, test solution and total impurity mixed solution are respectively injected according to the chromatographic conditions of the embodiment 1, and chromatogram is recorded, which is shown in the attached figures 1-5 and the table 2 of the specification.
Table 2: results of the specificity test
Example 3: limit of quantitation and limit of detection tests
The limit of detection (LOD) and limit of quantitation (LOQ) are determined according to a signal-to-noise ratio method. The control solutions were diluted step by step and the measured signals were compared to baseline noise to calculate the lowest concentration that could be reliably detected, the results are shown in table 3.
Table 3: quantitative limit and detection limit results
The quantitative limit concentration of the impurity B is lower than the quality control limit of the impurity B, and the detection limit concentration is lower than 1/10 of the quality control limit of the impurity B, so that the sensitivity of the invention is proved to be good.
Example 4: linear and range detection
Taking a proper amount of impurity B, precisely weighing, dissolving with acetonitrile-water (50: 50) and diluting to a proper concentration as impurity B mother liquor; taking the impurity B mother liquor, and diluting the impurity B mother liquor into solutions with the concentrations of about 5% (or quantitative limit concentration), 50%, 80%, 100%, 120% and 200% relative to the limit concentration of the impurity B according to a preparation method of a prepared reference substance solution, wherein the solutions are used as test solution with various linear concentrations. The linear relationship is plotted as a function of measured peak area versus analyte concentration and linear regression is performed using the least squares method, requiring that the value of the linear regression coefficient r should be no less than 0.999, and the results are shown in table 4 and fig. 6.
Table 4: results of linear measurement
As is clear from the above results, the detection method of the present invention demonstrated a good linear relationship with respect to impurity B, in which the linear correlation coefficient r was 0.9999 in the range of 6.6ppm (quantitative limit concentration) to 260ppm with respect to the sample concentration.
Example 5: repeatability detection
Perampanel samples were taken and tested 6 times in accordance with the test method of example 1 of the present invention to verify the good precision of the method, the results are shown in Table 5.
Table 5: repeatability test results
| Numbering | Concentration mg/ml | Impurity B (ppm) |
| 1 | 5.026 | ＜ |
| 2 | 4.930 | ＜LOD |
| 3 | 5.078 | ＜ |
| 4 | 5.041 | ＜ |
| 5 | 5.033 | ＜LOD |
| 6 | 5.009 | ＜LOD |
| Mean value | / | ＜LOD |
| RSD(％) | / | / |
As can be seen from the above table, the impurity B was lower than the detection limit in all 6 detections, demonstrating that the method has good precision.
Example 6: accuracy detection
The ratio of the actually measured amount of impurity B in the spiked sample to the theoretical amount (recovery rate), expressed in percent, was determined by spiked recovery, requiring recovery rates between 80% and 115% to confirm the good accuracy of the method, and the results are shown in table 6.
Table 6: accuracy test results
As can be seen from the above table, the recovery rate of the impurity B is 101-106%, and meets the verification requirement (85-110%). The method was confirmed to have good accuracy.
Example 7: intermediate precision detection
Perampanel samples were taken and the ratio (recovery rate) between the actually measured amount and the theoretical amount of impurity B in the spiked samples was determined by a person different from that in example 6 at different times and on different instruments, and the results of the determinations by the two persons were compared for precision, and are shown in Table 7.
Table 7: results of intermediate precision measurement
As can be seen from the table above, the recovery rates of the impurities B in twelve test sample solutions measured by different persons at different times and on different instruments are all in the range of 98-108%, the average value is 101.0%, the RSD is 2.4%, the test method meets the verification requirement (85-110%), and the intermediate precision of the detection method is good.
Example 8: control solution stability testing
And (3) taking the reference substance solution of the impurity B, standing at room temperature, injecting 20 mu l of the reference substance solution after 0h, 4h, 6h, 8h, 10h, 12h and 20h respectively, recording a chromatogram, and calculating the relative standard deviation of the peak area of each impurity B. The results are shown in Table 8.
Table 8: test results of solution stability of control
| Stability of control solutions | Area of impurity B peak |
| 0h | 73161 |
| 4h | 73833 |
| 6h | 73309 |
| 8h | 73093 |
| 10h | 73609 |
| 12h | 73499 |
| 20h | 74098 |
| Average | 73515 |
| RSD(％) | 0.50 |
Example 9: test article solution stability detection
Sampling 20 mu l of Perampanel test solution for 0h, 4h, 6h, 8h, 10h, 12h and 20h respectively, recording a chromatogram, and calculating the relative standard deviation of the peak area of the impurity B, wherein the test result is shown in Table 9.
Table 9: test result of stability of test solution
| Stability of test solution | Area of impurity B peak |
| 0h | Not detected out |
| 4h | Not detected out |
| 6h | Not detected out |
| 8h | Not detected out |
| 10h | Not detected out |
| 12h | Not detected out |
| 20h | Not detected out |
| Average | / |
| RSD(％) | / |
As can be seen from the above table, the test solution was stable without detecting impurity B even after being left at room temperature for 20 hours.
Example 10: durability test
And evaluating the bearing degree of the measurement result which is not influenced when the measurement condition is slightly changed by changing the pH value of the mobile phase A, the proportion of the mobile phase B, the column temperature and the flow rate. The durability results are shown in the following table.
Table 10: chromatographic condition variation parameter
Table 11: effect of different mobile phase ratios on the determination of impurity B
Table 12: effect of different column temperatures on determination of impurity B
Table 13: effect of different pH on determination of impurity B
As can be seen from tables 10 to 13, when the pH value, the initial mobile phase proportion and the column temperature of the mobile phase A are slightly changed, the theoretical plate number of the impurity B in the reference solution is larger than 25000, the separation degree of the impurity B and the adjacent impurities is reduced to 1.5 except when the column temperature is reduced to 25 ℃, the separation degree of the impurity B and the adjacent impurities in the rest conditions is larger than 4, and the recovery rate of the impurity B of each impurity-added sample is in the range of 85-110%, which indicates that the durability of the method is good.
In summary, in the specific test, the blank solvent and each known impurity do not interfere with the detection of the impurity B, and the separation degree between the impurity B and the adjacent impurity peak is greater than 1.5.
In the test of quantitative limit, the quantitative limit concentration of the impurity B is far lower than the quality control limit (125 ppm); the detection limit concentration of the impurity B is 1/10(12.5ppm) which is lower than the quality control limit.
In the linear range test, the impurity B has good linear relation in the range from 6.6ppm (limit of quantitation) to 260ppm relative to the concentration of a test sample, the correlation coefficient r is not lower than 0.999, and the percentage of the y-axis intercept relative to the peak area of the limit concentration reference sample is far less than 25%.
In the accuracy test, the recovery rate of the impurity B is between 85 and 110 percent, and the RSD is less than or equal to 10 percent.
In the repeatability test, the impurity B in 6 samples was less than LOD.
In the test of intermediate precision, six standard samples are respectively measured on different instruments by different testers on different dates, the recovery rate of the detected impurity B in 12 samples meets the verification requirement (85-110 percent), and the RSD is less than or equal to 20 percent.
Therefore, the acetonitrile-potassium dihydrogen phosphate solution gradient elution system is adopted, so that the impurities B, the Perampanel and other impurities can be effectively separated, the peak symmetry is good, the impurity B can be detected easily, and the system has high system applicability. Meanwhile, the method has incomparable advantages in specificity, quantitative limit, detection limit, linear range and repeatability, and has high precision.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the invention.
Claims (7)
1. A detection method of perampanel genotoxic impurities is characterized in that the content of the perampanel genotoxic impurities is detected by a liquid chromatography;
the genotoxic impurity is 3- (2-cyanophenyl) -5- (2-N-oxopyridyl) -1-phenyl-1, 2-dihydropyridin-2-one, and has the following structural formula:
2. the method of claim 1, wherein the assay quantitatively detects 6.6ppm of a perampanel genotoxic impurity.
3. The method according to claim 1 or 2, characterized in that it comprises in particular the steps of:
1) preparing test solution
Taking a Perampanel sample of 50mg, precisely weighing, placing in a 10ml measuring flask, adding 1ml of N, N-dimethylformamide, shaking to dissolve, adding 6ml of acetonitrile, diluting with water to a scale, shaking uniformly, and filtering to obtain a subsequent filtrate;
2) preparing reference substance solution
Precisely weighing proper amount of genotoxic impurities, adding diluent to dissolve and dilute into solution containing 12.5 μ g of genotoxic impurities per 1ml, and using the solution as reference mother liquor; precisely measuring a proper amount of reference mother liquor, placing into a measuring flask, and adding blank solution to dilute into a solution containing 0.63 microgram of genotoxic impurities per 1 ml.
3) Respectively and precisely measuring a test solution and a reference solution, injecting the test solution and the reference solution into a liquid chromatograph, recording a chromatogram, and calculating the content of the genotoxic impurities in the test solution by adopting an external standard method according to peak areas.
4. The method according to claim 3, wherein the blank solution preparation method in the step 2) comprises: measuring 1ml of N, N-dimethylformamide and 6ml of acetonitrile, placing the N, N-dimethylformamide and the acetonitrile into the same 10ml measuring flask, diluting the N, N-dimethylformamide and the acetonitrile to the scale with water, and shaking up the N, N-dimethylformamide and the acetonitrile uniformly.
5. The method according to claim 3, wherein the diluent in the step 2) is a mixture of 50: 50 of acetonitrile and water.
6. The method according to claim 3, wherein the detection conditions of the liquid chromatography are:
a chromatographic column: an Agela C18 chromatography column, specification 4.6mm x 250mm, 5 μm;
mobile phase A: 0.01mol/L potassium dihydrogen phosphate solution, and adjusting the pH value to 3.0 by phosphoric acid;
mobile phase B: acetonitrile;
and (3) an elution mode: gradient elution;
flow rate: 1.0 mL/min;
column temperature: 30 ℃;
detection wavelength: 220 nm;
sample introduction amount: 20 μ L.
7. The method according to claim 6, wherein during the gradient elution, the elution procedure is as follows:
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