CN114076801B - Detection method of related substances in lenalidomide - Google Patents
Detection method of related substances in lenalidomide Download PDFInfo
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- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 title claims abstract description 66
- 229960004942 lenalidomide Drugs 0.000 title claims abstract description 66
- 239000000126 substance Substances 0.000 title claims abstract description 28
- 238000001514 detection method Methods 0.000 title claims abstract description 20
- 239000012535 impurity Substances 0.000 claims abstract description 75
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000012360 testing method Methods 0.000 claims abstract description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 238000000926 separation method Methods 0.000 claims abstract description 8
- 229940079593 drug Drugs 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 7
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 5
- 239000008055 phosphate buffer solution Substances 0.000 claims abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 34
- 239000000243 solution Substances 0.000 claims description 32
- 239000000523 sample Substances 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 16
- 239000011550 stock solution Substances 0.000 claims description 14
- 239000013558 reference substance Substances 0.000 claims description 13
- 238000007865 diluting Methods 0.000 claims description 12
- 239000003085 diluting agent Substances 0.000 claims description 12
- 238000004090 dissolution Methods 0.000 claims description 10
- 230000003044 adaptive effect Effects 0.000 claims description 6
- BXWLVQXAFBWKSR-UHFFFAOYSA-N 2-methoxy-5-methylsulfonylbenzoic acid Chemical compound COC1=CC=C(S(C)(=O)=O)C=C1C(O)=O BXWLVQXAFBWKSR-UHFFFAOYSA-N 0.000 claims description 5
- NTPUVQUUAYGRHK-UHFFFAOYSA-N 4-nitro-3h-2-benzofuran-1-one Chemical compound [O-][N+](=O)C1=CC=CC2=C1COC2=O NTPUVQUUAYGRHK-UHFFFAOYSA-N 0.000 claims description 5
- 239000012490 blank solution Substances 0.000 claims description 5
- 238000010790 dilution Methods 0.000 claims description 5
- 239000012895 dilution Substances 0.000 claims description 5
- 239000012488 sample solution Substances 0.000 claims description 5
- 238000005303 weighing Methods 0.000 claims description 5
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- FCGIVHSBEKGQMZ-UHFFFAOYSA-N methyl 2-(bromomethyl)-3-nitrobenzoate Chemical compound COC(=O)C1=CC=CC([N+]([O-])=O)=C1CBr FCGIVHSBEKGQMZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 4
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical compound O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 claims description 3
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 238000010828 elution Methods 0.000 claims description 2
- 230000014759 maintenance of location Effects 0.000 claims description 2
- OGMCDJBYZAKJTP-UHFFFAOYSA-N methyl 2-(chloromethyl)-3-nitrobenzoate Chemical compound COC(=O)C1=CC=CC([N+]([O-])=O)=C1CCl OGMCDJBYZAKJTP-UHFFFAOYSA-N 0.000 claims description 2
- CRZGFIMLHZTLGT-UHFFFAOYSA-N methyl 2-methyl-3-nitrobenzoate Chemical compound COC(=O)C1=CC=CC([N+]([O-])=O)=C1C CRZGFIMLHZTLGT-UHFFFAOYSA-N 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- 239000008188 pellet Substances 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- 239000007939 sustained release tablet Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 238000003908 quality control method Methods 0.000 abstract description 3
- 208000034578 Multiple myelomas Diseases 0.000 description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- YPQAFWHSMWWPLX-UHFFFAOYSA-N 1975-50-4 Chemical compound CC1=C(C(O)=O)C=CC=C1[N+]([O-])=O YPQAFWHSMWWPLX-UHFFFAOYSA-N 0.000 description 1
- WNTCNOMUJRQWGP-UHFFFAOYSA-N 2-(bromomethyl)-3-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1CBr WNTCNOMUJRQWGP-UHFFFAOYSA-N 0.000 description 1
- VZFCYJWHQZVYDR-UHFFFAOYSA-N 2-(chloromethyl)-3-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1CCl VZFCYJWHQZVYDR-UHFFFAOYSA-N 0.000 description 1
- 101150015280 Cel gene Proteins 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/86—Signal analysis
- G01N30/8675—Evaluation, i.e. decoding of the signal into analytical information
- G01N30/8679—Target compound analysis, i.e. whereby a limited number of peaks is analysed
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Engineering & Computer Science (AREA)
- Library & Information Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a detection method of related substances in lenalidomide. The invention provides a detection method of related substances in lenalidomide, which comprises the following steps: detecting the impurity content in lenalidomide by adopting a high performance liquid chromatography, wherein the test conditions of the high performance liquid chromatography are as follows: octadecylsilane chemically bonded silica chromatographic column Welch Ultimate XB-C18, phosphate buffer solution with pH of 2.0-2.1 as mobile phase A, acetonitrile as mobile phase B, flow rate of 1.0 ml/min-1.1 ml/min, and column temperature of 25-33 ℃. The detection method can detect 6 impurities in lenalidomide simultaneously, has the separation degree higher than 2.5, is simple to operate, and is suitable for quality control of lenalidomide bulk drugs and preparations.
Description
Technical Field
The invention relates to a detection method of related substances in lenalidomide
Background
Lenalidomide (I) is a new generation of antitumor drugs developed by the american new-base (Celgene) biopharmaceutical company and is mainly used for treating myelodysplastic syndrome and multiple myeloma. The FDA approved the lenalidomide capsule developed by the new foundation by the rapid approval procedure on day 12, 27 2005. On month 29 of 2006, FDA approved lenalidomide in combination with dexamethasone for the treatment of patients with multiple myeloma who have previously received at least one treatment. Lenalidomide has gained widespread acceptance by doctors and patients worldwide as a first-line medication for the treatment of multiple myeloma.
According to the journal of Chinese medicinal chemistry, 2014, 24,4, 327-329, there are various impurities generated during the preparation of lenalidomide, such as impurity I (2-bromomethyl-3-nitrobenzoate, CAS: 98475-07-1), impurity II (3- (4' -nitrosoisoindol-1-one) -1-piperidine-2, 6-dione), impurity III (3- (4-hydroxylamine-1-oxo-1, 3-dihydro-isoindol-2-yl) piperidine-2, 6-dione), impurity IV (2-methyl-3-nitrobenzoate, impurity V (2-chloromethyl-3-nitrobenzoate) and impurity VI (4-nitro-3H-isobenzofuran-1-one, CAS: 65399-18-0). However, there has been no analytical method so far that the above six impurities can be detected efficiently.
Therefore, there is an urgent need to develop a method capable of effectively detecting various impurities of lenalidomide to better control the quality of lenalidomide medicines.
Disclosure of Invention
The invention provides a detection method of related substances in lenalidomide which is completely different from the prior art. The detection method can detect 6 impurities (including the impurities I, II, III, IV, V and VI) in lenalidomide simultaneously, has the separation degree as high as more than 2.5, is simple to operate, and is suitable for quality control of lenalidomide bulk drugs and preparations.
The invention provides a detection method of related substances in lenalidomide, which comprises the following steps: detecting the impurity content in lenalidomide by adopting a high performance liquid chromatography, wherein the testing conditions of the high performance liquid chromatography are as follows: octadecylsilane chemically bonded silica gel chromatographic column WelchUltimate XB-C18, phosphate buffer solution with pH of 2.0-2.1 as mobile phase A, acetonitrile as mobile phase B, flow rate of 1.0 ml/min-1.1 ml/min, column temperature of 25-33 ℃; the impurity is impurity I, 2-bromomethyl-3-nitrobenzoic acid methyl ester, CAS:98475-07-1; impurity II,3- (4' -nitrosoisoindol-1-one) -1-piperidine-2, 6-dione; impurity III,3- (4-hydroxylamine-1-oxo-1, 3-dihydro-isoindol-2-yl) piperidine-2, 6-dione; impurity IV, methyl 2-methyl-3-nitrobenzoate; impurity V, 2-chloromethyl-3-nitrobenzoic acid methyl ester; impurity VI, 4-nitro-3H-isobenzofuran-1-one, CAS:65399-18-0; the structures of the impurities I-VI are shown as follows:
in the invention, the lenalidomide comprises lenalidomide bulk drug and a pharmaceutical preparation taking lenalidomide as an active ingredient, such as lenalidomide capsules, lenalidomide tablets, lenalidomide sustained release tablets, lenalidomide pellets and the like.
The high performance liquid chromatography detection described in the present invention is performed in a high performance liquid chromatography analyzer, which is preferably equipped with an ultraviolet detector.
In the invention, the octadecylsilane chemically bonded silica chromatographic column WelchUltimate XB-C18 is preferably a WelchUltimate XB-C18,4.6mm multiplied by 250mm,5 μm chromatographic column.
In the present invention, the column temperature of the octadecylsilane chemically bonded silica chromatographic column WelchUltimate XB-C18 is preferably 28 ℃ to 32 ℃, for example 30 ℃.
In the present invention, the concentration of the mobile phase A is preferably 0.010mol/L to 0.030mol/L, more preferably 0.015mol/L to 0.025mol/L, for example 0.020mol/L.
In the present invention, the pH of the mobile phase a may be 2.0 or 2.1.
In the present invention, the phosphate in the mobile phase a is preferably one or more of potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate and disodium hydrogen phosphate, and more preferably potassium dihydrogen phosphate.
In the present invention, the preparation step of the mobile phase A is preferably as follows: adding phosphoric acid into the phosphate solution, and adjusting the pH to 2.0-2.1.
In the present invention, the detection wavelength for the high performance liquid chromatography is preferably 208nm to 212nm, more preferably 209nm to 211nm, for example 210nm.
In the present invention, the sample amount for the high performance liquid chromatography is preferably 5. Mu.l to 15. Mu.l, more preferably 8. Mu.l to 12. Mu.l, for example, 10. Mu.l.
In the present invention, the run time of the high performance liquid chromatography is preferably 55 to 65 minutes, more preferably 58 to 62 minutes, for example 60 minutes.
In the present invention, the gradient elution gradient of the mobile phase a and the mobile phase B is preferably as follows:
| time (minutes) | Mobile phase a (%) | Mobile phase B (%) |
| 0 | 95 | 5 |
| 20 | 90 | 10 |
| 45 | 25 | 75 |
| 50 | 25 | 75 |
| 50.1 | 95 | 5 |
| 60 | 95 | 5 |
In the invention, the detection method of the related substances in lenalidomide preferably comprises the following steps: preparing a diluent, preparing a sample solution, preparing an impurity control stock solution, preparing a control solution and preparing a system adaptive solution; the steps of the preparation of the solution are not sequential.
The diluent (blank solution) is preferably formulated by the following steps: the volume of dimethyl sulfoxide is fixed by the mobile phase A, wherein the volume of the dimethyl sulfoxide accounts for 15-45% of the total volume of the solution, and more preferably 25-35%, such as 30%.
The sample is preferably prepared by the following steps: and (3) dissolving, diluting and shaking the sample to be tested by using the diluent. The dissolution is preferably ultrasonic dissolution. The dilution is preferably carried out in a measuring flask.
The impurity control stock solution is preferably prepared by the following steps: and respectively taking the impurity I-impurity VI reference substances (the impurity I, the impurity II, the impurity III, the impurity IV, the impurity V and the impurity VI), adding acetonitrile for dissolving, diluting and shaking uniformly. The metering is preferably carried out in a measuring flask. The concentration of the impurity is preferably 10. Mu.g/ml to 20. Mu.g/ml, for example 15. Mu.g/ml.
The reference substance solution is preferably prepared by the following steps: precisely transferring 1ml of the impurity control stock solution, placing in a 50ml measuring flask, adding 15ml of dimethyl sulfoxide, quantitatively diluting to scale with the mobile phase A, and shaking.
The system adaptive solution preparation preferably comprises the following steps: taking 250mg of lenalidomide sample, precisely weighing, placing in a 50ml measuring flask, adding 15ml of dimethyl sulfoxide for ultrasonic dissolution, precisely removing 1ml of the impurity control stock solution, quantifying to scale by using the mobile phase A, and shaking uniformly to obtain the lenalidomide sample.
In the present invention, the method for detecting the related substances in lenalidomide preferably further comprises the following steps:
step 1 diluent formulation (i.e. blank solution formulation): the volume of the dimethyl sulfoxide is fixed by the mobile phase A, wherein the volume of the dimethyl sulfoxide accounts for 15-45 percent of the total volume of the solution, and more preferably 25-35 percent, such as 30 percent;
step 2, preparing a sample: dissolving, diluting and shaking the sample to be tested of the lenalidomide by using the diluent prepared in the step 1; the dissolution is preferably ultrasonic dissolution; the dilution is preferably carried out in a measuring flask;
step 3, preparing impurity control stock solution: respectively taking the impurity I-impurity VI reference substances (the impurities I, II, III, IV, V and VI), adding acetonitrile for dissolving, diluting and shaking uniformly; the volume fixing is preferably carried out in a measuring flask; the concentration of the impurity is preferably 10. Mu.g/ml to 20. Mu.g/ml, for example 15. Mu.g/ml;
step 4, preparing a reference substance solution: precisely transferring 1ml of the impurity control stock solution prepared in the step 3, placing in a 50ml measuring flask, adding 15ml of dimethyl sulfoxide, quantitatively diluting to scale with mobile phase A, and shaking;
step 5, preparing a system adaptive solution: taking 250mg of lenalidomide sample, precisely weighing, placing in a 50ml measuring flask, adding 15ml of dimethyl sulfoxide for ultrasonic dissolution, precisely transferring 1ml of the impurity control stock solution prepared in the step 3, quantifying to scale by using the mobile phase A, and shaking uniformly to obtain the preparation;
and 6, sample injection: after the system is fully balanced, the diluent (namely blank solution) prepared in the step 1 is injected into 1-2 needles; the system applicability solution prepared in the step 5 is 1 needle; the reference substance solution prepared in the step 4 is 5 needles, the test substance solution prepared in the step 2 is 1 needle, and a chromatogram is recorded;
step 7, system adaptability: the blank solution has no interference to each impurity peak in the system applicability solution chromatogram; in the system applicability solution chromatogram, the separation degree of each impurity peak is not less than 1.2; the control solution is continuously injected for 6 times, and the Relative Standard Deviation (RSD) of the main peak area and the retention time is not more than 5.0%;
the sequence of steps 1-5 can be adjusted.
In the method for detecting the related substances in the lenalidomide, the content of the lenalidomide and the related substances is preferably calculated by an external standard method according to the peak area;
m for a pair of : weighing the reference substance, and mg; p (P) For a pair of : the content of the reference substance; a is that For a pair of : peak area of the component to be measured of the reference solution; d (D) For a pair of : dilution of the reference substance; a is that Sample : peak area of the component to be measured in the sample solution; d (D) Sample : dilution of the test sample; m is m Sample : sample is weighed and mg is measured.
The invention relates to a detection method of related substances in lenalidomide, wherein the separation degree of impurities is more than or equal to 2.5.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the detection method of the invention can simultaneously detect 6 impurities (including impurities I, II, III, IV, V and VI) of lenalidomide, has a separation degree as high as more than 2.5, is simple to operate, and is suitable for quality control of lenalidomide bulk drugs and pharmaceutical preparations.
Drawings
FIG. 1 shows a high performance liquid chromatography of lenalidomide prepared in example 1. Wherein 1 represents a chromatographic peak of impurity I; 2 represents a chromatographic peak of impurity II; 3 represents a chromatographic peak of impurity III; 4 represents a chromatographic peak of impurity IV; 5 represents a chromatographic peak of impurity V; 6 represents the chromatographic peak of impurity VI.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Example 1:
the analysis method comprises the following steps:
the test spectrum of the high performance liquid chromatography is shown in figure 1, and the test data is shown in table 1. Therefore, the method can effectively separate the impurity I-impurity VI, and the separation degree is more than 2.5.
TABLE 1 high performance liquid chromatography test data for example 1
Comparative examples
Durability range screening of test conditions for high performance liquid chromatography:
note that: the "-" labeled moiety above illustrates that there is no baseline separation from adjacent chromatographic peaks.
Mobile phase gradient condition screening:
2. chromatographic column screening
Impurity II was not baseline separated from adjacent chromatographic peaks using Waters XSelect Hss C18 (4.6 mm. Times.250 mm,5 μm). The column is not effective in separating the impurities.
Claims (12)
1. The detection method of the related substances in lenalidomide is characterized by comprising the following steps of: detecting the impurity content in lenalidomide by adopting a high performance liquid chromatography, wherein the testing conditions of the high performance liquid chromatography are as follows: octadecylsilane chemically bonded silica chromatographic column Welch Ultimate XB-C18, phosphate buffer solution with pH of 2.0-2.1 as mobile phase A, acetonitrile as mobile phase B, flow rate of 1.0 ml/min-1.1 ml/min, column temperature of 30deg.C; the impurities are as follows: impurity I, methyl 2-bromomethyl-3-nitrobenzoate; impurity II,3- (4' -nitrosoisoindol-1-one) -1-piperidine-2, 6-dione; impurity III,3- (4-hydroxylamine-1-oxo-1, 3-dihydro-isoindol-2-yl) piperidine-2, 6-dione; impurity IV, methyl 2-methyl-3-nitrobenzoate; impurity V, 2-chloromethyl-3-nitrobenzoic acid methyl ester; impurity VI, 4-nitro-3H-isobenzofuran-1-one; the structures of the impurities I-VI are shown as follows:
the concentration of the mobile phase A is 0.010 mol/L-0.030 mol/L; the gradient elution gradient of the mobile phase A and the mobile phase B is as follows:
2. the method for detecting the related substances in lenalidomide according to claim 1, wherein:
the lenalidomide comprises lenalidomide bulk drug and a pharmaceutical preparation taking lenalidomide as an active ingredient.
3. The method for detecting the related substances in lenalidomide according to claim 2, wherein:
the pharmaceutical preparation taking lenalidomide as an active ingredient is a lenalidomide capsule, a lenalidomide tablet, a lenalidomide sustained release tablet or a lenalidomide pellet.
4. The method for detecting the related substances in lenalidomide according to claim 1, wherein:
the high performance liquid chromatography detection is performed in a high performance liquid chromatography analyzer, and the high performance liquid chromatography analyzer is provided with an ultraviolet detector;
and/or the number of the groups of groups,
the octadecylsilane chemically bonded silica column Welch Ultimate XB-C18 is Welch Ultimate XB-C18,4.6mm×250mm,5 μm column.
5. The method for detecting the related substances in lenalidomide according to claim 1, wherein:
the detection wavelength of the high performance liquid chromatography test is 208 nm-212 nm;
and/or the number of the groups of groups,
the sample injection amount of the high performance liquid chromatography is 5-15 mu l;
and/or the number of the groups of groups,
the running time of the high performance liquid chromatography test is 55-65 minutes.
6. The method for detecting the related substances in lenalidomide according to claim 5, wherein:
the detection wavelength of the high performance liquid chromatography test is 209 nm-211 nm;
and/or the number of the groups of groups,
the sample injection amount of the high performance liquid chromatography is 8-12 mu l;
and/or the number of the groups of groups,
the running time of the high performance liquid chromatography test is 58-62 minutes.
7. The method for detecting the related substances in lenalidomide according to claim 1, wherein:
the pH value of the mobile phase A is 2.0 or 2.1;
and/or the number of the groups of groups,
the phosphate in the mobile phase A is one or more of potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate and disodium hydrogen phosphate.
8. The method for detecting the related substances in lenalidomide according to claim 7, wherein:
the concentration of the mobile phase A is 0.015 mol/L-0.025 mol/L;
and/or the number of the groups of groups,
the phosphate in the mobile phase A is potassium dihydrogen phosphate.
9. The method for detecting the related substances in lenalidomide according to claim 1, wherein: the detection method of the related substances in lenalidomide comprises the following steps: preparing a diluent, preparing a sample solution, preparing an impurity control stock solution, preparing a control solution and preparing a system adaptive solution; the steps of the preparation of the solution are not sequential.
10. The method for detecting the related substances in lenalidomide according to claim 9, wherein:
the diluent is prepared by the following steps: the mobile phase A is used for fixing the volume of the dimethyl sulfoxide, wherein the volume of the dimethyl sulfoxide accounts for 15-45% of the total volume of the solution;
and/or the number of the groups of groups,
the sample solution is prepared by the following steps: dissolving, diluting and shaking the sample with the diluent;
and/or the number of the groups of groups,
the impurity control stock solution is prepared by the following steps: respectively taking the impurity I-impurity VI reference substances, adding acetonitrile for dissolving, diluting and shaking uniformly;
and/or the number of the groups of groups,
the reference substance solution is prepared by the following steps: precisely transferring 1ml of the impurity control stock solution, placing in a 50ml measuring flask, adding 15ml of dimethyl sulfoxide, quantitatively diluting to scale with the mobile phase A, and shaking;
and/or the number of the groups of groups,
the system adaptive solution is prepared by the following steps: taking 250mg of lenalidomide sample, precisely weighing, placing in a 50ml measuring flask, adding 15ml of dimethyl sulfoxide for ultrasonic dissolution, precisely removing 1ml of the impurity control stock solution, quantifying to scale by using the mobile phase A, and shaking uniformly to obtain the lenalidomide sample.
11. The method for detecting the related substances in lenalidomide according to claim 1, wherein:
the detection method of the related substances in lenalidomide comprises the following steps:
step 1, preparing a diluent: the mobile phase A is used for fixing the volume of the dimethyl sulfoxide, wherein the volume of the dimethyl sulfoxide accounts for 15-45% of the total volume of the solution;
step 2, preparing a sample solution: dissolving, diluting and shaking the sample to be tested of the lenalidomide by using the diluent prepared in the step 1;
step 3, preparing impurity control stock solution: respectively taking the impurity I-impurity VI reference substances, adding acetonitrile for dissolving, diluting and shaking uniformly;
step 4, preparing a reference substance solution: precisely transferring 1ml of the impurity control stock solution prepared in the step 3, placing in a 50ml measuring flask, adding 15ml of dimethyl sulfoxide, quantitatively diluting to scale with mobile phase A, and shaking;
step 5, preparing a system adaptive solution: taking 250mg of lenalidomide sample, precisely weighing, placing in a 50ml measuring flask, adding 15ml of dimethyl sulfoxide for ultrasonic dissolution, precisely transferring 1ml of the impurity control stock solution prepared in the step 3, quantifying to scale by using the mobile phase A, and shaking uniformly to obtain the preparation;
and 6, sample injection: after the system is fully balanced, the diluent prepared in the step 1 is injected into 1-2 needles; the system applicability solution prepared in the step 5 is 1 needle; the reference substance solution prepared in the step 4 is 5 needles, the test substance solution prepared in the step 2 is 1 needle, and a chromatogram is recorded;
step 7, system adaptability: the blank solution has no interference to each impurity peak in the system applicability solution chromatogram; in the system applicability solution chromatogram, the separation degree of each impurity peak is not less than 1.2; the control solution is continuously injected for 6 times, and the Relative Standard Deviation (RSD) of the main peak area and the retention time is not more than 5.0%; the sequence of steps 1-5 can be adjusted.
12. The method for detecting the related substances in lenalidomide according to claim 11, wherein:
in the step 1, the volume of the dimethyl sulfoxide accounts for 25% -35% of the total volume of the solution;
and/or the number of the groups of groups,
in the step 2, the dissolution is ultrasonic dissolution;
and/or the number of the groups of groups,
in step 2, the dilution is performed in a measuring flask;
and/or the number of the groups of groups,
in the step 1, the constant volume is carried out in a measuring flask;
and/or the number of the groups of groups,
in the step 3, the concentration of the impurities is 10-20 mug/ml.
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