CN117723665A - Detection method for sunitinib malate capsule related substances - Google Patents
Detection method for sunitinib malate capsule related substances Download PDFInfo
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- CN117723665A CN117723665A CN202311726575.7A CN202311726575A CN117723665A CN 117723665 A CN117723665 A CN 117723665A CN 202311726575 A CN202311726575 A CN 202311726575A CN 117723665 A CN117723665 A CN 117723665A
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- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 title claims abstract description 54
- 229960002812 sunitinib malate Drugs 0.000 title claims abstract description 53
- 239000002775 capsule Substances 0.000 title claims abstract description 39
- 239000000126 substance Substances 0.000 title claims abstract description 36
- 238000001514 detection method Methods 0.000 title claims abstract description 28
- 239000012535 impurity Substances 0.000 claims abstract description 56
- 230000015556 catabolic process Effects 0.000 claims abstract description 12
- 238000006731 degradation reaction Methods 0.000 claims abstract description 12
- 238000003908 quality control method Methods 0.000 claims abstract description 5
- 239000000243 solution Substances 0.000 claims description 60
- 239000002904 solvent Substances 0.000 claims description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 31
- 150000001204 N-oxides Chemical class 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 27
- 239000012488 sample solution Substances 0.000 claims description 18
- 238000007865 diluting Methods 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 17
- 239000013558 reference substance Substances 0.000 claims description 15
- 239000000706 filtrate Substances 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 239000000523 sample Substances 0.000 claims description 9
- 239000011550 stock solution Substances 0.000 claims description 8
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 7
- 239000005695 Ammonium acetate Substances 0.000 claims description 7
- 229940043376 ammonium acetate Drugs 0.000 claims description 7
- 235000019257 ammonium acetate Nutrition 0.000 claims description 7
- 238000010828 elution Methods 0.000 claims description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 6
- 239000007853 buffer solution Substances 0.000 claims description 6
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 5
- 239000007924 injection Substances 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000004007 reversed phase HPLC Methods 0.000 claims description 4
- 239000003643 water by type Substances 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 3
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 3
- 238000005070 sampling Methods 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000000047 product Substances 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000012467 final product Substances 0.000 abstract description 2
- 238000012360 testing method Methods 0.000 description 47
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 13
- 229960001796 sunitinib Drugs 0.000 description 13
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 13
- 239000002994 raw material Substances 0.000 description 10
- 238000013112 stability test Methods 0.000 description 8
- 238000000926 separation method Methods 0.000 description 6
- 238000007689 inspection Methods 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000000227 grinding Methods 0.000 description 3
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- 238000005259 measurement Methods 0.000 description 3
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- 239000012085 test solution Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 208000033383 Neuroendocrine tumor of pancreas Diseases 0.000 description 2
- 206010067517 Pancreatic neuroendocrine tumour Diseases 0.000 description 2
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ATMPRPNPFMBBBO-ATVHPVEESA-N 1-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethylpyrrole-3-carboxamide Chemical compound CCN(CC)CCN1C(C)=C(C(N)=O)C(C)=C1\C=C/1C2=CC(F)=CC=C2NC\1=O ATMPRPNPFMBBBO-ATVHPVEESA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
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- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
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- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
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- Treatment Of Liquids With Adsorbents In General (AREA)
Abstract
The invention provides a detection method of related substances of sunitinib malate capsules, which can detect degradation impurities in the sunitinib malate capsules, has strong specificity, high accuracy, good durability and more convenient operation, can effectively realize quality control of a production process link of a product, improve the quality of a final product and ensure the safety and effectiveness of clinical medication, and does not interfere with detection of auxiliary material peaks.
Description
1. Technical field
The invention belongs to the technical field of medicine analysis, and particularly relates to a detection method of sunitinib malate capsule related substances.
2. Background art
Sunitinib malate is an oral small molecule multi-target tyrosine kinase receptor inhibitor. Sunitinib malate capsules were approved for sale by the U.S. FDA and european EMA for 1 and 7 months, respectively (trade name) The preparation method is mainly used for treating: (1) inoperable advanced Renal Cell Carcinoma (RCC), (2) failed or intolerable treatment of lmatinib mesylate in gastrointestinal stromal tumor (GIST), (3) unresectable, metastatic advanced pancreatic neuroendocrine tumor (pNET) adult patients. Original grinding productBelonging to the american-type scion company, 90 or more countries including china have been currently approved.
Sunitinib malate, CAS number: 341031-54-7, chemical name (Z) -N- [2- (diethylamino) ethyl ] -5- [ (5-fluoro-2-oxo-1, 2-dihydro-3H-indol-3-ylidene) methyl ] -2, 4-dimethyl-3-carbamoyl-1H-pyrrole malate, structural formula is as follows:
at present, the sunitinib malate capsules and the raw material drug standards thereof are not received in the pharmacopoeias of various countries, so that no relevant legal standard can be referred to, and no reference document capable of effectively controlling various degradation impurities is searched, so that development of a related substance inspection method capable of simultaneously controlling various degradation impurities is very necessary.
3. Summary of the invention
The invention solves the problems existing in the prior art, and provides the detection method for the related substances of the sunitinib malate capsules, which can detect degradation impurities in the sunitinib malate capsules, has strong specificity, does not interfere with detection of auxiliary material peaks, has high accuracy and good durability, is more convenient to operate, can more effectively realize quality control of links in the production process of products, improves the quality of final products, and ensures the safety and effectiveness of clinical medication.
The invention provides a detection method of sunitinib malate capsule related substances, which comprises the following steps: sampling the system applicability solution and the sample solution respectively, detecting according to high performance liquid chromatography conditions, and recording a chromatogram;
the high performance liquid chromatography is reversed phase high performance liquid chromatography, and the chromatographic conditions are specifically as follows: chromatographic column: a chromatographic column using octadecylsilane chemically bonded silica as a filler; mobile phase: mobile phase a: an ammonium acetate buffer solution; mobile phase B: acetonitrile; gradient elution was performed as follows:
further, the elution conditions were:
the related substances are degradation impurities, including impurity A, impurity C, N-oxide and RRT0.93, and the structures are as follows:
the chromatographic conditions further include:
a detector: a UV detector;
flow rate: 1.0ml/min;
column temperature: 40-50 ℃, preferably 45 ℃;
sample injection volume: 50 μl;
detection wavelength: 268nm;
run time: 52 minutes;
the chromatographic column is Waters XBridge Shield RP, 150mm multiplied by 4.6mm and 3.5 mu m;
the concentration of the mobile phase A is 0.05mol/L, and one or more of alkaline reagent such as ammonia water, sodium hydroxide solution and potassium hydroxide solution is used for adjusting the pH value to 8.3-8.7, preferably ammonia water is used for adjusting the pH value to 8.5;
the preparation process of the system applicability solution comprises the following steps: dissolving and diluting an N-oxide reference substance with a solvent, and shaking uniformly to obtain an N-oxide stock solution; taking proper amount of sunitinib malate capsule content, heating, taking out, adding a solvent to dissolve, adding proper amount of N-oxide stock solution, diluting with the solvent, shaking uniformly, filtering, and placing the filtrate to obtain a system applicability solution;
the preparation process of the sample solution comprises the following steps: taking proper amount of sunitinib malate capsule content, adding a solvent to dissolve and dilute, shaking uniformly, filtering, and taking a subsequent filtrate to obtain a sample solution;
wherein the solvent is mobile phase a: acetonitrile=70:30.
The invention further provides a detection method of related substances of the sunitinib malate capsule, which comprises the following steps: sampling the system applicability solution and the sample solution respectively, detecting according to high performance liquid chromatography conditions, and recording a chromatogram;
the high performance liquid chromatography is reversed phase high performance liquid chromatography, and the chromatographic conditions are specifically as follows: chromatographic column: waters XBridge Shield RP18150mm×4.6mm 3.5 μm; mobile phase: mobile phase a: an ammonium acetate buffer solution; mobile phase B: acetonitrile; gradient elution was performed as follows:
the related substances are degradation impurities, including impurity A, impurity C, N-oxide and RRT0.93, and the structures are as follows:
the chromatographic conditions further include:
a detector: a UV detector;
flow rate: 1.0ml/min;
column temperature: 45 ℃;
sample injection volume: 50 μl;
detection wavelength: 268nm;
run time: 52 minutes;
the concentration of the mobile phase A is 0.05mol/L, and the pH value is adjusted to 8.5 by ammonia water;
the preparation process of the system applicability solution comprises the following steps: taking about 2mg of N-oxide reference substance, placing into a 100ml measuring flask, dissolving with solvent, diluting to scale, and shaking to obtain N-oxide stock solution. Taking proper amount of sunitinib malate capsule content (about equivalent to 10mg of sunitinib), placing in a triangular flask with a stopper, adding 5 drops of water, heating at 100 ℃ for 4 hours (degradation generates unknown impurities of impurity C and RRT about 0.93), taking out, completely transferring the mixture into a 50ml measuring flask by using a solvent, adding about 30ml of the solvent, shaking for 20 minutes to dissolve, adding 1ml of N-oxide stock solution, diluting to a scale by using the solvent, shaking uniformly, filtering, taking the natural light condition of the subsequent filtrate, and standing for 5 minutes (degradation generates impurity A) to obtain the sunitinib capsule;
the preparation process of the sample solution comprises the following steps: grinding the content of sunitinib malate capsules, taking a proper amount of fine powder (about 10mg equivalent to sunitinib), placing the fine powder into a 50ml measuring flask, adding about 30ml of solvent, shaking for about 20 minutes to dissolve the sunitinib malate, diluting to a scale with the solvent, shaking uniformly, filtering, and taking a subsequent filtrate to obtain the sunitinib malate capsule;
wherein the solvent is mobile phase a: acetonitrile=70:30.
The invention also provides an application of the detection method of the sunitinib malate capsule related substances in quality control of the sunitinib malate capsule.
The beneficial technical effects of the invention are as follows:
(1) The invention develops a reversed-phase HPLC method which can detect degradation impurities in the sunitinib malate capsules. The detection method has the advantages of strong specificity, no interference of auxiliary material peaks in detection, high accuracy, good durability and more convenient operation, can more effectively realize the quality control of the links in the production process of the product, improves the quality of the final product, and ensures the safety and effectiveness of clinical medication.
(2) The invention provides a system applicability solution preparation method for degrading and generating impurities A, C and RRT0.93 impurities in a sample destruction mode under the condition that an impurity reference substance is difficult to obtain, and solves the problem that the impurities in a related substance sample solution cannot be positioned.
4. Description of the drawings
FIG. 1 is a plot of the test condition 1 method selection overlap of example 1.
FIG. 2 is a plot of the selection of the addition criteria for example 1, test condition 2 method.
FIG. 3 is a graph of the applicability of the test condition 3 system of example 1.
FIG. 4 is an overlay of the specificity test of example 2.
FIG. 5 is an overlay of the accuracy test of example 3.
FIG. 6 is a graph showing the natural light conditions of the solution stability test control solution of example 4.
FIG. 7 is a graph showing the overlap of the solutions of the test control solutions for the solution stability test of example 4 under light-shielding conditions.
FIG. 8 is an overlapping view of the test sample solutions for the solution stability test of example 4 under light-shielding conditions.
FIG. 9 is a linear test diagram of example 5.
FIG. 10 is an overlay of the duplicate solutions of the precision test of example 7.
FIG. 11 is an overlay of solutions for different column systems for example 8 durability tests.
FIG. 12 is an overlay of solutions for different column temperature systems for example 8 durability test.
FIG. 13 is an overlay of the system applicability solutions for different acetonitrile ratios for example 8 durability test.
FIG. 14 is an overlay of solutions for different pH system suitability for the durability test of example 8.
5. Detailed description of the preferred embodiments
The following detailed description of specific embodiments of the invention is provided for purposes of illustration only and is not to be construed as limiting the invention.
Instrument and chromatographic conditions:
instrument: a high performance liquid chromatograph;
a detector: an ultraviolet detector;
chromatographic column: a chromatographic column with octadecylsilane chemically bonded silica as filler, waters XBridge Shield RP18150mm×4.6mm 3.5 μm;
mobile phase: mobile phase a:0.05mol/L ammonium acetate buffer solution; mobile phase B: acetonitrile;
solvent: mobile phase A-acetonitrile (70:30);
flow rate: 1.0ml/min;
column temperature: 45 ℃;
sample injection volume: 50 μl;
detection wavelength: 268nm;
run time: 52 minutes.
Preparing a solution:
preparation of N-oxide stock solution: taking about 2mg of N-oxide reference substance, placing into a 100ml measuring flask, dissolving with solvent, diluting to scale, and shaking.
Preparation of a System suitability test solution: taking proper amount of sunitinib malate capsule content (about equivalent to 10mg of sunitinib), placing into a triangular flask with a plug, adding 5 drops of water, heating at 100 ℃ for 4 hours (degradation generates unknown impurities of impurity C and RRT 0.93), taking out, completely transferring the mixture into a 50ml measuring flask by using a solvent, adding 30ml of the solvent, shaking for 20 minutes to dissolve, adding 1ml of N-oxide stock solution, diluting to a scale by using the solvent, shaking uniformly, filtering, taking the natural light condition of the subsequent filtrate, and standing for 5 minutes (degradation generates impurity A).
Preparation of test solution: taking the content of sunitinib malate capsules, grinding, taking a proper amount of fine powder (about 10mg equivalent to sunitinib), placing into a 50ml measuring flask, adding about 30ml of solvent, shaking for about 20 minutes to dissolve the sunitinib malate, diluting to a scale with the solvent, shaking uniformly, filtering, and taking subsequent filtrate.
Preparation of control solution: precisely measuring 5ml of the sample solution, placing in a 50ml measuring flask, diluting to the scale with a solvent, shaking uniformly, precisely measuring 1ml, placing in a 50ml measuring flask, diluting to the scale with a solvent, and shaking uniformly.
Preparation of a sensitivity solution: precisely measuring 5ml of control solution, placing in a 20ml measuring flask, diluting to scale with solvent, and shaking. Assay:
taking 50 mu l of each of a system applicability test solution and a sensitivity solution, and respectively injecting the solution into a liquid chromatograph, wherein the separation degree between an N-oxide peak and an impurity C peak and the separation degree between a sunitinib peak and an RRT0.93 impurity peak in a system applicability solution chromatogram are not less than 1.5, and the tailing factor of the sunitinib peak is not more than 2.0; the signal to noise ratio of the main peak in the sensitivity solution chromatogram should be not less than 10.
Example 1 selection of chromatographic conditions
Test condition 1:
on the basis of the above instrument and chromatographic conditions, the most applicable chromatographic conditions are continuously screened.
Mobile phase a:0.05mol/L ammonium acetate buffer (pH adjusted to 5.0 with glacial acetic acid); gradient elution procedure:
preparation of a raw material solution: and (3) taking a proper amount of sunitinib malate raw material, and preparing a raw material solution with proper concentration by using a solvent.
Preparation of N-oxide positioning solution: and taking a proper amount of N-oxide reference substance, and preparing a positioning solution with proper concentration by using a solvent.
The raw material solution and the N-oxide positioning solution are precisely measured and 50 mu l of each are sampled under the condition of test condition 1, the result is shown in figure 1, and the result shows that the N-oxide peak coincides with the sunitinib peak.
Test condition 2:
mobile phase a:0.05mol/L ammonium acetate buffer solution (pH value is adjusted to 6.5 by ammonia water); other chromatographic conditions were the same as test condition 1.
N-oxide localization solution: taking a proper amount of N-oxide reference substance, placing the N-oxide reference substance into a measuring flask, adding a solvent for dissolution, and diluting to a scale.
Adding a labeled test sample solution: taking a proper amount of sunitinib malate raw material, placing the sunitinib malate raw material into a measuring flask, adding a proper amount of N-oxide positioning solution after dissolving the sunitinib malate raw material in a solvent, diluting the sunitinib malate raw material to a scale with the solvent, and shaking the sunitinib malate raw material uniformly. The sample is introduced under the condition of the test condition 2, the result is shown in figure 2, and the result shows that the separation degree of the N-oxide peak and the sunitinib peak can be improved by adjusting the pH value of the mobile phase. However, the separation degree of the main peak and the adjacent impurities is less than 1.5, which is not in accordance with the regulations and needs to be optimized continuously.
Test condition 3:
mobile phase a:0.05mol/L ammonium acetate buffer solution (pH value is adjusted to 8.5 by ammonia water); gradient elution procedure:
other chromatographic conditions were the same as test condition 1.
Taking the system applicability solution to sample under the condition of test condition 3, and as a result, as shown in fig. 3, the impurity A, N-oxide, impurity C, RRT 0.73.73, RRT0.93 and sunitinib in the chromatogram of the system applicability solution sequentially form peaks, the separation degree of the sunitinib peak and the adjacent impurity RRT0.93 is 2.72, and the minimum separation degree between the impurities is 5.15. All are larger than 1.5, and meet the regulations. The chromatographic conditions were determined for the examination of the sunitinib malate capsule-related material with test condition 3. The system applicability solution preparation method under the test condition 3 is used as the system applicability solution preparation method for checking the related substances of the sunitinib malate capsules.
Example 2 blank interference test
Preparing a blank auxiliary material solution: weighing about 80mg of blank auxiliary materials, placing into a 50ml measuring flask, adding a proper amount of solvent, shaking for 20min to dissolve, diluting to scale with the solvent, shaking, filtering, and collecting the subsequent filtrate.
And taking the blank auxiliary material solution to carry out measurement under the optimal chromatographic condition of screening.
The results are shown in fig. 4, and the blank auxiliary material is shown to be a peak before 2 minutes (before the relative retention time is 0.2) and is well separated from the impurity peak, so that the blank auxiliary material is proved not to interfere with the inspection of substances related to the sunitinib malate capsules.
Example 3 accuracy test
The accuracy of the method is achieved by examining the accuracy of the different amounts of impurities added to the sample. The concentration of each impurity was examined to determine the limit concentration, 50% of the limit concentration, 150% of the limit concentration. Each concentration is repeated for 3 times, and because the impurity A and the RRT0.93 impurity reference substances are difficult to obtain, only the recovery rate test of the impurity C and the N-oxide is carried out, the average value of the recovery rates is in the range of 80-120%, the relative standard deviation is less than 10%, the method meets the requirements, the accuracy of the method is good, and the results are shown in tables 1-2 and figure 5.
Accuracy was calculated from the measured amount/addition x 100%.
TABLE 1N-oxide recovery test results
TABLE 2 results of impurity C recovery test
Example 4 solution stability test
Control solution stability test:
and placing the reference substance solution under room temperature natural light and under room temperature light-shielding conditions, carrying out sample injection detection at different time points, and comparing with 0 hour to calculate the change value of the peak area. The results are shown in tables 3 to 4 and FIGS. 6 to 7.
The result shows that the change value of the main peak area of the control solution is-37.95 percent, more than 5 percent and unstable when the control solution is placed for 2 hours under the condition of natural light at room temperature, the maximum change value of the main peak area is-3.09 percent, less than 5 percent and meets the acceptance standard when the control solution is placed for 24 hours under the condition of light shielding at room temperature, the control solution is stable within 24 hours under the condition of light shielding at room temperature, sunitinib is sensitive to light irradiation, and the control solution is prepared by light shielding operation.
Table 3 results of stability test of substances examined in control solution (Natural light at room temperature)
Table 4 results of stability test of substances examined in control solution (light-shielding at room temperature)
Test article solution stability:
the sample solutions were placed at room temperature in the dark and were sampled at 0, 2,4, 6, 8, 24 hours, respectively, and the results are shown in Table 5 and FIG. 8.
The result shows that the test sample solution is placed for 24 hours at room temperature in a dark place, the detection amount of N-oxide, impurity C, RRT, impurity and other single impurity impurities is basically unchanged, the detection amount of impurity A is gradually increased (from 0.04% to 0.25%), the detection amount of total impurity is gradually increased (from 0.31% to 0.53%), the test sample solution is unstable under the dark condition, the increase of impurity A is mainly indicated, the preparation of the test sample solution needs to be operated in the dark, and the test sample solution is newly prepared.
Table 5 test results of stability test of test solutions for examination of substances (light-shielding at room temperature)
Example 5 Linear test
The linearity of the method is achieved by examining the linearity of at least 5 solutions of different concentrations. The measured peak area is used for making a curve on concentration, a regression equation, a correlation coefficient and an intercept are calculated by a least square method, and as the impurity A and the RRT0.93 impurity reference substance are difficult to obtain, only the linear test of the impurity C and the N-oxide is carried out, the result shows that the method has good linear relation, and the results are shown in tables 6-8 and figure 9.
TABLE 6 sunitinib malate Linear test results
Note: calculated by sunitinib
TABLE 7N-oxide Linear test results
TABLE 8 results of impurity C Linear experiments
Example 6 quantitative limit and detection limit test
Quantitative limiting solution: and (3) taking proper amounts of sunitinib malate and each impurity reference substance, respectively placing the sunitinib malate and each impurity reference substance into a measuring flask, dissolving the sunitinib malate and each impurity reference substance by using a solvent, and gradually diluting the sunitinib malate and each impurity reference substance until the response value of each component peak is about 10 times higher than that of a noise signal.
Detection limit solution: the quantitative limiting solution is taken and gradually diluted by solvent until the response value of each component peak is measured to be about 3 times as high as that of the noise signal.
And precisely measuring 50 mu l of each of the quantitative limit solution and the detection limit solution, injecting into a liquid chromatograph, and recording a chromatogram. The results are shown in tables 9 to 10.
Table 9 quantitative limit results of substances
Table 10 results of detection limits of substances
EXAMPLE 7 precision test
Precision assays were performed by both method reproducibility and intermediate precision. The method comprises the steps of repeatedly preparing the same batch of sample solution for 6 times, calculating impurity content according to a self-made control method added with correction factors, and calculating the relative standard deviation of 6 times of measurement results; the intermediate precision is verified repeatedly by different analysts and different instruments on different dates; and the relative deviation of the results of the method repeatability and the intermediate precision meets the requirements. The results are shown in Table 11, FIG. 10.
TABLE 11 results of the repeatability and intermediate precision tests of the related substances
Example 8 durability test
The durability of the method is investigated by respectively changing the brand type of the chromatographic column, the column temperature and the acetonitrile proportion in the mobile phase and the pH value of the mobile phase. Only one of the parameters is changed per test, and the result is compared with the measurement result when the parameter is not changed. Compared with standard conditions, the method has the advantages that the brands and batches of chromatographic columns, the column temperature change of +/-5 ℃, the acetonitrile proportion change of +/-5% in a mobile phase and the pH value change of buffer salt in the mobile phase of +/-0.2 are changed, blank auxiliary materials do not interfere with the inspection of related substances, the system applicability test meets the requirements, the change value of each impurity detection amount is less than 0.1% compared with the standard conditions, and the standard conditions are met, so that the inspection method of the related substances of the sunitinib malate capsules under the conditions is good in durability. The results are shown in tables 12 to 13 and FIGS. 11 to 14.
Table 12 results of durability test of substances (System applicability, relative Retention time)
Note: representing standard conditions
TABLE 13 durability test results of substances (impurity detection amount)
Note: representing standard conditions.
Claims (10)
1. The detection method of the sunitinib malate capsule related substances is characterized by comprising the following steps of: sampling the system applicability solution and the sample solution respectively, detecting according to high performance liquid chromatography conditions, and recording a chromatogram; the high performance liquid chromatography is reversed phase high performance liquid chromatography, and the chromatographic conditions are specifically as follows: chromatographic column: a chromatographic column using octadecylsilane chemically bonded silica as a filler; mobile phase: mobile phase a: an ammonium acetate buffer solution; mobile phase B: acetonitrile; gradient elution was performed as follows:
the related substances are degradation impurities, including impurity A, impurity C, N-oxide and RRT0.93, and the structures are as follows:
2. the method for detecting sunitinib malate capsule-related substances according to claim 1, wherein the chromatographic conditions further comprise:
a detector: a UV detector;
flow rate: 1.0ml/min;
column temperature: 40-50 ℃;
sample injection volume: 50 μl;
detection wavelength: 268nm.
3. The method for detecting sunitinib malate capsule related substances according to claim 1, wherein the chromatographic column is Waters XBridge Shield RP, 150mm x 4.6mm 3.5 μm.
4. The method for detecting sunitinib malate capsule-related substances according to claim 1, wherein the mobile phase a concentration is 0.05mol/L.
5. The method for detecting sunitinib malate capsule related substances according to claim 1, wherein the mobile phase a is adjusted to a pH value of 8.3-8.7 with an alkaline reagent.
6. The method for detecting sunitinib malate capsule related substances according to claim 5, wherein the mobile phase a is adjusted to pH 8.5 with ammonia water.
7. The method for detecting sunitinib malate capsule related substances according to claim 1, wherein the gradient elution conditions are as follows:
8. the method for detecting sunitinib malate capsule related substances according to claim 1, wherein the system applicability solution is prepared by the following steps: dissolving and diluting an N-oxide reference substance with a solvent, and shaking uniformly to obtain an N-oxide stock solution; taking proper amount of sunitinib malate capsule content, heating, taking out, adding a solvent to dissolve, adding proper amount of N-oxide stock solution, diluting with the solvent, shaking uniformly, filtering, and placing the filtrate to obtain a system applicability solution; the preparation process of the sample solution comprises the following steps: and taking proper amount of sunitinib malate capsule content, adding a solvent to dissolve and dilute, shaking uniformly, filtering, and taking subsequent filtrate to obtain a sample solution.
9. The method for detecting sunitinib malate capsule-related substances according to claim 9, wherein the solvent is mobile phase a: acetonitrile=70:30.
10. Use of the detection method of sunitinib malate capsule-related substances according to any one of claims 1-9 in quality control of sunitinib malate capsules.
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