CN113030323A - Method for detecting residual solvent in nilotinib bulk drug - Google Patents
Method for detecting residual solvent in nilotinib bulk drug Download PDFInfo
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- CN113030323A CN113030323A CN202110258832.3A CN202110258832A CN113030323A CN 113030323 A CN113030323 A CN 113030323A CN 202110258832 A CN202110258832 A CN 202110258832A CN 113030323 A CN113030323 A CN 113030323A
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- 239000005536 L01XE08 - Nilotinib Substances 0.000 title claims abstract description 21
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 229960001346 nilotinib Drugs 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title claims abstract description 15
- 239000013557 residual solvent Substances 0.000 title claims abstract description 13
- 239000003814 drug Substances 0.000 title abstract description 12
- 229940079593 drug Drugs 0.000 title abstract description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 51
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 51
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 51
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 34
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000000243 solution Substances 0.000 claims abstract description 11
- 239000013558 reference substance Substances 0.000 claims abstract description 9
- 239000012085 test solution Substances 0.000 claims abstract description 7
- 238000010812 external standard method Methods 0.000 claims abstract description 6
- 238000002347 injection Methods 0.000 claims abstract description 6
- 239000007924 injection Substances 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 238000003988 headspace gas chromatography Methods 0.000 claims abstract description 4
- 238000001514 detection method Methods 0.000 claims description 24
- 239000000523 sample Substances 0.000 claims description 11
- 239000012488 sample solution Substances 0.000 claims description 5
- 239000012159 carrier gas Substances 0.000 claims description 4
- 238000004817 gas chromatography Methods 0.000 claims description 4
- 239000012088 reference solution Substances 0.000 claims description 4
- 238000005070 sampling Methods 0.000 claims description 3
- 239000012490 blank solution Substances 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- -1 polysiloxane Polymers 0.000 claims description 2
- 229920001296 polysiloxane Polymers 0.000 claims description 2
- 238000001228 spectrum Methods 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract 1
- 238000003908 quality control method Methods 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 238000012360 testing method Methods 0.000 description 8
- 238000005303 weighing Methods 0.000 description 7
- 238000011084 recovery Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000007789 gas Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 2
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 2
- 229960002411 imatinib Drugs 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 150000005005 aminopyrimidines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
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- 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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- 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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/30—Control of physical parameters of the fluid carrier of temperature
-
- 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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/32—Control of physical parameters of the fluid carrier of pressure or speed
-
- 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
- G01N30/64—Electrical detectors
- G01N30/68—Flame ionisation 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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/32—Control of physical parameters of the fluid carrier of pressure or speed
- G01N2030/324—Control of physical parameters of the fluid carrier of pressure or speed speed, flow rate
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- 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)
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for determining residual solvent amount in nilotinib bulk drug by headspace gas chromatography, which comprises the following steps: (1) preparing a reference substance solution of the residual solvent to be detected; (2) preparing a test solution; (3) detecting a sample, namely detecting 7 organic solvents of methanol, ethanol, isopropanol, dichloromethane, n-hexane, ethyl acetate and toluene simultaneously by utilizing a hydrogen Flame Ionization Detector (FID) through temperature programming, a headspace sample injection mode and calculation according to an external standard method. The method is simple, sensitive and accurate, and is suitable for quality control of nilotinib raw materials in industrial production.
Description
Technical Field
The invention relates to a method for detecting residual solvents in nilotinib bulk drug, which adopts gas chromatography to detect the contents of methanol, ethanol, isopropanol, dichloromethane, n-hexane, ethyl acetate and toluene in nilotinib according to an external standard method, and belongs to the field of drug analysis and detection.
Background
Nilotinib, an aminopyrimidine derivative, a second generation highly selective tyrosine kinase inhibitor developed by norwalk, switzerland, inhibits the tyrosine kinase activity of both the unmutated and most mutated forms of BCR-ABL1 more effectively and selectively than imatinib. For the treatment of patients with drug-resistant and intolerant Ph + CML chronic phase (CML-CP) and CML acute phase (CML-AP) of previous treatments, including imatinib treatment.
The invention aims at organic solvents used in the synthesis process of nilotinib bulk drug, such as: methanol, ethanol, isopropanol, dichloromethane, n-hexane, ethyl acetate, toluene and the like, and the residual amount of the solvent in the raw materials is accurately determined by adopting headspace gas chromatography so as to ensure the safety, effectiveness and controllable quality of the medicine.
Disclosure of Invention
The invention aims to establish a method for detecting organic residual solvents in nilotinib bulk drug, which utilizes headspace gas chromatography to quickly and accurately detect the residual amounts of 7 organic solvents including methanol, ethanol, isopropanol, dichloromethane, n-hexane, ethyl acetate and toluene in nilotinib. The method has the advantages that: 1. the operation is simple, and the practicability is strong; 2. the method has the advantages of good sensitivity, high accuracy and good separation degree, and can effectively control each impurity in the raw material.
The invention provides a method for detecting residual solvent in nilotinib bulk drug, which comprises the following steps:
(1) taking a proper amount of methanol, ethanol, isopropanol, dichloromethane, N-hexane, ethyl acetate and toluene, precisely weighing, placing in a 100ml measuring flask, adding N, N-dimethylformamide solvent, diluting to scale, shaking up, and preparing into mixed reference substance solutions of about 500, 60, 29, 500 and 89ug/ml of methanol, ethanol, isopropanol, dichloromethane, N-hexane, ethyl acetate and toluene respectively;
(2) accurately weighing 500mg of nilotinib, placing the nilotinib into a 10ml headspace bottle, accurately weighing 5ml of N, N-dimethylformamide, sealing, and gently shaking uniformly to obtain a test solution;
(3) adopting gas chromatography and FID detector, heating, introducing sample via headspace, detecting blank solution, reference solution and sample solution, recording chromatogram, and calculating residual solvent content of methanol, ethanol, isopropanol, dichloromethane, n-hexane, ethyl acetate and toluene according to external standard method.
Further, in the detection method, a polysiloxane capillary chromatographic column is adopted, the initial temperature is 30-50 ℃, the injection port temperature is 180-230 ℃, the detection temperature is 200-250 ℃, the carrier gas is inert gas, the flow rate is 1.0-3.0 ml/min, and the split ratio is 5-20: 1.
furthermore, in the detection method of the invention, the chromatographic column is Agilent DB-624(30m × 0.32mm, 1.8 μm); the initial temperature is preferably 30-40 ℃, and the optimal value is 30 ℃; the temperature of the injection port is preferably 200-210 ℃, and the optimal value is 200 ℃; the detection temperature is preferably 200-220 ℃, and the optimal value is 200 ℃; the carrier gas is N2(ii) a The flow rate is preferably 2.0 ml/min-3.0 ml/min, and the optimal value is 3.0 ml/min; the preferable flow dividing ratio is 10-15: 1, optimal value 5: 1.
compared with the prior art, the invention has the positive effects that:
1. the gas chromatography condition is suitable for detecting the organic solvent residue of the nilotinib bulk drug, and can quickly and accurately detect the content of 7 residual solvents, namely methanol, ethanol, isopropanol, dichloromethane, n-hexane, ethyl acetate and toluene.
2. The detection method provided by the invention is simple to operate, sensitive and accurate, has good reproducibility, and can fully meet the requirement of organic solvent residue determination of nilotinib raw material medicine in industrial production, so that the quality of the product can be effectively controlled.
Drawings
FIG. 1 blank solvent gas chromatogram
FIG. 2 adaptive gas chromatogram of a mixed system of methanol, ethanol, isopropanol, dichloromethane, n-hexane, ethyl acetate and toluene
FIG. 3 gas chromatogram of sample solution
Detailed Description
Examples
1. Instrument and reagent
The instrument comprises the following steps: agilent 7890B gas chromatograph, 7694E headspace sampler, detector FID; an Agilent chromatography workstation;
reagent testing: all the reagents are chromatographically pure; nilotinib (homemade).
2. Chromatographic conditions
A chromatographic column: agilent DB-624(30m × 0.53mm, 3.0 μm);
column temperature: maintaining at 30 deg.C for 6min, increasing to 200 deg.C at 30 deg.C/min, and maintaining for 6 min;
sample inlet temperature: 200 ℃;
detecting the temperature: 200 ℃;
carrier gas: n is a radical of2And the split ratio: 5: 1;
and (3) sample introduction mode: a headspace sampling method;
the balance time is as follows: 30 min;
equilibrium temperature: 80 ℃.
3. Solution preparation
Preparing a mixed reference substance solution: taking a proper amount of methanol, ethanol, isopropanol, dichloromethane, N-hexane, ethyl acetate and toluene, precisely weighing, placing in a 100ml measuring flask, adding N, N-dimethylformamide to dilute to scale, shaking up, and preparing into mixed reference substance solutions of about 500, 60, 29, 500 and 89ug/ml of methanol, ethanol, isopropanol, dichloromethane, N-hexane, ethyl acetate and toluene respectively.
Preparing a test solution: and precisely weighing about 500mg of nilotinib, placing the nilotinib into a 10ml headspace bottle, precisely weighing 5ml of N, N-dimethylformamide, adding, sealing, and gently shaking uniformly to obtain a test solution.
4. Sample assay
Testing applicability of system
Sampling blank solvent (N, N-dimethylformamide), mixed reference solution and test solution, and recording chromatogram. The results show that the components of the mixed control solution are completely separated, R is more than 5, the blank solvent has no interference, and the details are shown in Table 1. The original map is shown in FIGS. 1-3.
TABLE 1 measurement results of retention time and resolution of each component
(ii) precision test
The mixed control solution was injected into the headspace continuously for 6 times with RSD within 5%, see table 2.
Table 2 precision test results (n ═ 6)
③ Linear test
Precisely measuring 1.0, 2.0, 3.0, 5.0, 10.0 and 25.0ml of mixed reference stock solution, respectively placing in a 50ml measuring flask, adding N, N-dimethylformamide for diluting to scale, and shaking uniformly; precisely measuring 5ml, placing into 10ml headspace bottle, sealing, and making into a series of linear mixed control solutions with different concentrations. And (3) introducing a sample into a headspace, performing linear regression by taking the peak area of a reference substance as an ordinate and taking the concentration of reference substance solutions of methanol, ethanol, isopropanol, dichloromethane, n-hexane, ethyl acetate and toluene as an abscissa, and determining results shown in table 3.
TABLE 3 results of the Linear test
Recovery test
Taking 500mg of nilotinib, weighing 9 parts of nilotinib precisely, adding a proper amount of mixed reference substance solution of methanol, ethanol, isopropanol, dichloromethane, N-hexane, ethyl acetate and toluene in three batches respectively, adding N, N-dimethylformamide to dilute to a scale, shaking up, taking the sample solution as a recovery rate sample solution, taking 5ml of headspace sample injection respectively, recording a chromatogram, and calculating the recovery rate according to the following formula. The recovery rates that could be saved were between 90% and 110% (100% + -10%), and the results are shown in Table 4.
TABLE 4 results of recovery test
Detection line and quantitative limit
Calculating a detection line by using the signal-to-noise ratio S/N ═ 3, calculating a quantification limit by using the signal-to-noise ratio S/N ═ 10, sequentially and respectively diluting a mixed reference substance stock solution of methanol, ethanol, isopropanol, dichloromethane, N-hexane, ethyl acetate and toluene, taking 5ml of headspace sample injection, recording a chromatogram, and recording the measurement results of the detection line and the quantification limit in a table 5.
TABLE 5 measurement results of each component detection line and quantitative limit
Sample detection
Precisely measuring 5ml of each of the test solution and the reference solution, introducing a sample in a headspace, recording a chromatogram, and calculating according to an external standard method that the methanol content is not more than 0.5%, the ethanol content is not more than 0.5%, the isopropanol content is not more than 0.5%, the dichloromethane content is not more than 0.06%, the n-hexane content is not more than 0.5%, the ethyl acetate content is not more than 0.5%, and the toluene content is not more than 0.089%.
The organic residue of the sample was determined as described above, with the results: 0.01% of ethanol, and none of the others were detected.
Claims (10)
1. A method for detecting residual solvent in nilotinib raw material comprises the following sample detection steps:
the method comprises the following steps: preparing a reference substance solution of the residual solvent to be detected;
step two: preparing a test solution;
step three: detecting blank solution, reference solution and sample solution by gas chromatography, recording spectra, and calculating residual solvent content of methanol, ethanol, isopropanol, dichloromethane, n-hexane, ethyl acetate and toluene by external standard method.
2. The detection method according to claim 1, wherein the chromatographic column used in the detection method is a polysiloxane capillary chromatographic column.
3. The detection method according to claim 1, wherein the detection method employs a programmed temperature rise.
4. The method of claim 1, wherein the detection method is initiated at a temperature of 30 ℃ to 50 ℃.
5. The detection method according to claim 1, wherein the injection port temperature is 180 ℃ to 230 ℃.
6. The method according to claim 1, wherein the detection temperature is 200 ℃ to 250 ℃.
7. The detection method according to claim 1, wherein the carrier gas is an inert gas and has a flow rate of 1.0 to 3.0 ml/min.
8. The detection method according to claim 1, wherein the flow split ratio is 5-20: 1.
9. the detection method according to claim 1, wherein headspace sampling is employed.
10. The detection method according to claim 1, wherein 7 organic residual solvents of methanol, ethanol, isopropanol, dichloromethane, n-hexane, ethyl acetate and toluene are simultaneously detected by a combined detection method of headspace gas chromatography and external standard method.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113504321A (en) * | 2021-06-29 | 2021-10-15 | 杭州协合医疗用品有限公司 | Method for simultaneously detecting residual cleaning agent n-hexane and ethyl acetate |
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| US20180334449A1 (en) * | 2017-05-16 | 2018-11-22 | F.I.S. - Fabbrica Italiana Sintetici S.P.A. | Process for the preparation of pure nilotinib and its salt |
| CN110208428A (en) * | 2019-07-08 | 2019-09-06 | 苏州天马药业有限公司 | The gas phase detection method of a variety of residual solvents in a kind of bisulfate clopidogrel bulk pharmaceutical chemicals |
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2021
- 2021-03-10 CN CN202110258832.3A patent/CN113030323A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20180334449A1 (en) * | 2017-05-16 | 2018-11-22 | F.I.S. - Fabbrica Italiana Sintetici S.P.A. | Process for the preparation of pure nilotinib and its salt |
| CN110208428A (en) * | 2019-07-08 | 2019-09-06 | 苏州天马药业有限公司 | The gas phase detection method of a variety of residual solvents in a kind of bisulfate clopidogrel bulk pharmaceutical chemicals |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113504321A (en) * | 2021-06-29 | 2021-10-15 | 杭州协合医疗用品有限公司 | Method for simultaneously detecting residual cleaning agent n-hexane and ethyl acetate |
| CN113504321B (en) * | 2021-06-29 | 2023-09-01 | 杭州协合医疗用品有限公司 | Method for simultaneously detecting residual cleaning agent n-hexane and ethyl acetate |
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Application publication date: 20210625 |