CN107490631A - A kind of analyzing detecting method of afatinib intermediate - Google Patents
A kind of analyzing detecting method of afatinib intermediate Download PDFInfo
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- CN107490631A CN107490631A CN201610411393.4A CN201610411393A CN107490631A CN 107490631 A CN107490631 A CN 107490631A CN 201610411393 A CN201610411393 A CN 201610411393A CN 107490631 A CN107490631 A CN 107490631A
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- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 title claims abstract description 55
- 229960001686 afatinib Drugs 0.000 title claims abstract description 55
- 238000000034 method Methods 0.000 title claims abstract description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 54
- 239000000243 solution Substances 0.000 claims abstract description 18
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims abstract description 17
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims abstract description 17
- 235000019799 monosodium phosphate Nutrition 0.000 claims abstract description 17
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims abstract description 17
- 238000001514 detection method Methods 0.000 claims abstract description 16
- 238000010828 elution Methods 0.000 claims abstract description 12
- 239000000337 buffer salt Substances 0.000 claims abstract description 10
- 238000004458 analytical method Methods 0.000 claims abstract description 9
- 239000007788 liquid Substances 0.000 claims description 17
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 14
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 7
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 7
- 239000012488 sample solution Substances 0.000 claims description 6
- 235000019846 buffering salt Nutrition 0.000 claims 1
- 239000003480 eluent Substances 0.000 claims 1
- 239000012071 phase Substances 0.000 abstract description 30
- 239000012535 impurity Substances 0.000 abstract description 7
- 239000007791 liquid phase Substances 0.000 abstract description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 abstract description 4
- 238000003908 quality control method Methods 0.000 abstract description 4
- 230000035945 sensitivity Effects 0.000 abstract description 3
- 239000000945 filler Substances 0.000 abstract description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000377 silicon dioxide Substances 0.000 abstract description 2
- 238000012360 testing method Methods 0.000 description 13
- 238000002474 experimental method Methods 0.000 description 12
- 230000014759 maintenance of location Effects 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 5
- 238000009938 salting Methods 0.000 description 5
- 238000012417 linear regression Methods 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- -1 isoxazoline compound Chemical class 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
Classifications
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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
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
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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)
- Treatment Of Liquids With Adsorbents In General (AREA)
Abstract
The present invention relates to a kind of analyzing detecting method of afatinib intermediate, quality control for afatinib intermediate, it is the chromatographic column (C18 using octadecylsilane chemically bonded silica as filler, 4.6 × 250mm, 3 μm), using the buffer salt solution and acetonitrile of sodium dihydrogen phosphate and disodium hydrogen phosphate as mobile phase, gradient elution, using Detection wavelength as 230nm, column temperature is 25~35 DEG C, carries out high-efficient liquid phase chromatogram technique analysis detection.The analyzing detecting method of the present invention effectively can separate afatinib intermediate and its impurity, and this method has separating degree and a high sensitivity, and repeatability and durability are good, and analysis time is short, simple to operate, it is as a result reliable and stable the advantages of.
Description
Technical field
The present invention relates to the analysis detection side of a kind of HPLC analytical method, especially afatinib intermediate
Method.
Background technology
Afatinib is aniline Kui that isoxazoline compound, be a kind of irreversible EGFR-HER2 dual tyrosine kinases by
Body inhibitor, it irreversible can be combined with EGFR-HER2 EGFR-TKs, suppress its tyrosine kinase activity, and then block
Tumour cell signal transduction leading EGFR-HER2, suppress transfer and the propagation of tumour cell, promote the apoptosis of tumour cell.
N- (the chloro- 4- fluorophenyls of 3-) -6- nitros -7- [[(3S)-tetrahydrochysene -3- furyls] epoxide] -4- quinazoline amine is to close
One of important intermediate into Afatinib, its chemical formula are C18H14ClFN4O4, structural formula is：
The analyzing detecting method of the intermediate not yet disclosed in document, but the analysis detection of the intermediate to reaction controlling and
Yield, which improves, quality that is important, while also directly affecting finished product Afatinib, so establishing a kind of stable
Effective analyzing detecting method carries out quality control to the intermediate and is very important.
The content of the invention
It is an object of the invention to provide a kind of analyzing detecting method of afatinib intermediate, among Afatinib
The quality control of body.
In order to realize the purpose of the present invention, inventor finally obtains following technical scheme by lot of experiments：
A kind of analyzing detecting method of afatinib intermediate, it is the chromatogram using octadecylsilane chemically bonded silica as filler
Post, using buffer salt solution and acetonitrile as mobile phase, gradient elution, comprise the following steps：
A, take afatinib intermediate appropriate, add acetonitrile to dissolve, be configured to every 1ml containing afatinib intermediate 0.071~
0.534mg sample solution；
B, it is 0.8~1.2ml/min to set flow rate of mobile phase, and Detection wavelength 230nm, column temperature is 25~35 DEG C；
C, take a μ l of sample solution 10 to inject liquid chromatograph, perform gradient elution program, complete afatinib intermediate
Analysis detection；
The specification of the chromatographic column is C18,4.6 × 250mm, 3 μm.
The buffer salt solution that it is 2.0 using phosphoric acid tune pH that the mobile phase, which is, is described using acetonitrile as Mobile phase B as mobile phase A
Buffer salt is made up of sodium dihydrogen phosphate and disodium hydrogen phosphate, in mobile phase A the concentration of sodium dihydrogen phosphate be 0.005~
0.015mol/L, the concentration of disodium hydrogen phosphate is 0.005~0.015mol/L；With volume basis, according to the form below carries out gradient elution：
Further, the setting of gradient elution is preferably：
Described sample solution concentration is preferably 0.35mg/ml.
The concentration of sodium dihydrogen phosphate is preferably 0.01mol/L in described mobile phase A, and the concentration of disodium hydrogen phosphate is preferably
0.01mol/L。
The flow velocity of the mobile phase is preferably 1.0ml/min, and column temperature is preferably 30 DEG C.
The method of the present invention is described in detail in embodiment, and method validation has been carried out to the method for the present invention,
As a result prove：Analyzing detecting method of the present invention, effectively afatinib intermediate and its impurity can be separated, and
This method separating degree and high sensitivity, repeatability and durability are good, and analysis time is short, simple to operate, as a result reliable and stable, so as to
Available for the quality control of afatinib intermediate, effective guarantee is provided for the quality of final finished.
Brief description of the drawings
The afatinib intermediate HPLC collection of illustrative plates of Fig. 1 embodiments 1.
The afatinib intermediate HPLC collection of illustrative plates of Fig. 2 embodiments 2.
The afatinib intermediate HPLC collection of illustrative plates of Fig. 3 embodiments 3.
The afatinib intermediate HPLC collection of illustrative plates of Fig. 4 embodiments 4.
The afatinib intermediate HPLC collection of illustrative plates of Fig. 5 embodiments 5.
The afatinib intermediate linear work curve of Fig. 6 embodiments 10.
Embodiment
It is the specific embodiment of the present invention below, technical scheme is further described, but it is of the invention
Protection domain be not limited to these embodiments.It is every to be included in this hair without departing substantially from the change of present inventive concept or equivalent substitute
Within bright protection domain.
Embodiment 1
Instrument and condition：The liquid chromatographic systems of Agilent 1260, chromatographic column：welch Ultimate XB-C18(4.6
× 250mm, 3 μm), Detection wavelength 230nm, 30 DEG C, flow velocity 1.0ml/min of column temperature, mobile phase is that to adjust pH using phosphoric acid be 2.0 to delay
It is mobile phase A to rush salting liquid, and using acetonitrile as Mobile phase B, the buffer salt is made up of sodium dihydrogen phosphate and disodium hydrogen phosphate, flowing
The concentration of sodium dihydrogen phosphate is 0.01mol/L in phase A, and the concentration of disodium hydrogen phosphate is 0.01mol/L；With volume basis, press
Table carries out gradient elution：
Experimental procedure：Afatinib intermediate is dissolved with acetonitrile and quantifies dilution and be made in every 1ml and is contained in Afatinib
Mesosome 0.35mg solution, as need testing solution, precision measures the μ l of need testing solution 10 injection liquid chromatographs, by above-mentioned bar
Part carries out efficient liquid phase chromatographic analysis, records chromatogram, as a result sees accompanying drawing 1.
Accompanying drawing 1 shows, under the chromatographic condition, afatinib intermediate peak and impurity peaks can be kept completely separate, and peak shape
Preferably, separating degree is higher, and the retention time at afatinib intermediate peak is in 28.639min, separating degree 2.33.
Embodiment 2
Instrument and condition：The liquid chromatographic systems of Agilent 1260, chromatographic column：welch Ultimate XB-C18(4.6
× 250mm, 3 μm), Detection wavelength 230nm, 30 DEG C, flow velocity 0.8ml/min of column temperature, mobile phase is that to adjust pH using phosphoric acid be 2.0 to delay
It is mobile phase A to rush salting liquid, and using acetonitrile as Mobile phase B, the buffer salt is made up of sodium dihydrogen phosphate and disodium hydrogen phosphate, flowing
The concentration of sodium dihydrogen phosphate is 0.005mol/L in phase A, and the concentration of disodium hydrogen phosphate is 0.005mol/L；With volume basis, press
Following table carries out gradient elution：
Experimental procedure：With embodiment 1, efficient liquid phase chromatographic analysis is carried out by above-mentioned condition, chromatogram is recorded, as a result sees attached
Fig. 2.
Accompanying drawing 2 shows, under the chromatographic condition, afatinib intermediate peak and impurity peaks can be kept completely separate, and peak shape
Preferably, separating degree is higher, and the retention time at afatinib intermediate peak is in 30.398min, separating degree 2.45.
Embodiment 3
Instrument and condition：The liquid chromatographic systems of Agilent 1260, chromatographic column：welch Ultimate XB-C18(4.6
× 250mm, 3 μm), Detection wavelength 230nm, 30 DEG C, flow velocity 1.2ml/min of column temperature, mobile phase is that to adjust pH using phosphoric acid be 2.0 to delay
It is mobile phase A to rush salting liquid, and using acetonitrile as Mobile phase B, the buffer salt is made up of sodium dihydrogen phosphate and disodium hydrogen phosphate, flowing
The concentration of sodium dihydrogen phosphate is 0.015mol/L in phase A, and the concentration of disodium hydrogen phosphate is 0.015mol/L；With volume basis, press
Following table carries out gradient elution：
Experimental procedure：With embodiment 1, efficient liquid phase chromatographic analysis is carried out by above-mentioned condition, chromatogram is recorded, as a result sees attached
Fig. 3.
Accompanying drawing 3 shows, under the chromatographic condition, afatinib intermediate peak and impurity peaks can be kept completely separate, and peak shape
Preferably, separating degree is higher, and the retention time at afatinib intermediate peak is in 25.184min, separating degree 3.90.
Embodiment 4
Instrument and condition：The liquid chromatographic systems of Agilent 1260, chromatographic column：welch Ultimate XB-C18(4.6
× 250mm, 3 μm), Detection wavelength 230nm, 25 DEG C, flow velocity 1.0ml/min of column temperature, mobile phase is that to adjust pH using phosphoric acid be 2.0 to delay
It is mobile phase A to rush salting liquid, and using acetonitrile as Mobile phase B, the buffer salt is made up of sodium dihydrogen phosphate and disodium hydrogen phosphate, flowing
The concentration of sodium dihydrogen phosphate is 0.005mol/L in phase A, and the concentration of disodium hydrogen phosphate is 0.01mol/L；With volume basis, press
Table carries out gradient elution：
Experimental procedure：With embodiment 1, efficient liquid phase chromatographic analysis is carried out by above-mentioned condition, chromatogram is recorded, as a result sees attached
Fig. 4.
Accompanying drawing 4 shows, under the chromatographic condition, afatinib intermediate peak and impurity peaks can be kept completely separate, and peak shape
Preferably, separating degree is higher, and the retention time at afatinib intermediate peak is in 28.720min, separating degree 2.34.
Embodiment 5
Instrument and condition：The liquid chromatographic systems of Agilent 1260, chromatographic column：welch Ultimate XB-C18(4.6
× 250mm, 3 μm), Detection wavelength 230nm, 35 DEG C, flow velocity 1.0ml/min of column temperature, mobile phase is that to adjust pH using phosphoric acid be 2.0 to delay
It is mobile phase A to rush salting liquid, and using acetonitrile as Mobile phase B, the buffer salt is made up of sodium dihydrogen phosphate and disodium hydrogen phosphate, flowing
The concentration of sodium dihydrogen phosphate is 0.01mol/L in phase A, and the concentration of disodium hydrogen phosphate is 0.005mol/L；With volume basis, press
Table carries out gradient elution：
Experimental procedure：With embodiment 1, efficient liquid phase chromatographic analysis is carried out by above-mentioned condition, chromatogram is recorded, as a result sees attached
Fig. 5.
Accompanying drawing 5 shows, under the chromatographic condition, afatinib intermediate peak and impurity peaks can be kept completely separate, and peak shape
Preferably, separating degree is higher, and the retention time at afatinib intermediate peak is in 28.690min, separating degree 2.40.
Embodiment 6
System suitability is tested
Instrument and condition：With embodiment 1.
Experimental procedure：Take this product appropriate, it is accurately weighed, dissolved and diluted with acetonitrile and be made in every 1ml containing the molten of 0.35mg
Liquid, as need testing solution.Take need testing solution, continuous sample introduction six times, calculate respectively afatinib intermediate peak peak area with
And the relative standard deviation of retention time, experimental result are shown in Table 1.
The afatinib intermediate system suitability experimental result of table 1
As shown in Table 1, the symmetrical factor at afatinib intermediate peak is respectively less than 1.5, and number of theoretical plate is above 3000, peak face
Long-pending relative standard deviation is 0.434% (limit 2.0%), and the relative standard deviation of retention time is 0.107% (limit
1.0%).It can be seen that under the chromatographic condition, afatinib intermediate peak peak shape is preferable, and relative standard deviation is smaller, gained knot
Fruit is reliable and stable.
Embodiment 7
Repeated experiment
Instrument and condition：With embodiment 1.
Experimental procedure：Take this product appropriate, it is accurately weighed, dissolved and diluted with acetonitrile and be made in every 1ml containing the molten of 0.35mg
Liquid, as need testing solution, 6 parts of need testing solutions are prepared with method.Need testing solution is taken, is determined according to this method, by area normalization
Change method calculates afatinib intermediate content, and calculates its relative standard deviation, and experimental result is shown in Table 2.
The afatinib intermediate repeated experiment result of table 2
As shown in Table 2, the content of afatinib intermediate does not have notable difference, relative standard deviation in each need testing solution
For 0.001%, it is seen that the repeatability of this analyzing detecting method is good.
Embodiment 8
Durability is tested
Instrument and condition：The liquid chromatographic systems of Agilent 1260, chromatographic column：welch Ultimate XB-C18(4.6
× 250mm, 3 μm), Detection wavelength 230nm, mobile phase and gradient elution are set with embodiment 1.
Experimental procedure：Take this product appropriate, it is accurately weighed, dissolved and diluted with acetonitrile and be made in every 1ml containing the molten of 0.35mg
Liquid, as need testing solution.Respectively by changing column temperature, flow velocity and pillar batch, the change of afatinib intermediate content is recorded
Change situation (is calculated) by area normalization method, and experimental result is shown in Table 3.
The afatinib intermediate durability experimental result of table 3
As shown in Table 3, after changing column temperature, flow velocity and pillar batch, the measurement result of afatinib intermediate content does not have
Notable difference, it is seen that the good tolerance of analyzing detecting method of the present invention.
Embodiment 9
Test limit
Instrument and condition：With embodiment 1.
Afatinib intermediate about 17.5mg is taken, it is accurately weighed, put and storing solution is used as in 50ml measuring bottles.Acetonitrile is added to dissolve,
Using progressively dilution method, using concentration during S/N ≈ 3 as test limit concentration, now the concentration of afatinib intermediate is
0.01775 μ g/ml, detection are limited to 0.1775ng.It can be seen that the sensitivity of this method and instrument is higher.
Embodiment 10
Linearity and range
Instrument and condition：With embodiment 1.
Experimental procedure：Afatinib intermediate 71.28mg is taken, it is accurately weighed, put in 100ml measuring bottles, add acetonitrile dissolving simultaneously
Scale is diluted to, produces linear storing solution.Precision measures linear storing solution 1.0ml, 2.0ml, 3.0ml, 4.0ml, 5.0ml,
6.0ml, 7.5ml are put in 10ml measuring bottles respectively, add dilution in acetonitrile to shake up, determine in accordance with the law to scale.With the concentration of need testing solution
For abscissa, linear regression is carried out by ordinate of afatinib intermediate peak peak area, it is y=to obtain equation of linear regression
26685x+21.148 it the results are shown in Table 4 and accompanying drawing 6.
The afatinib intermediate linear test result of table 4
From table 4 and accompanying drawing 6, the coefficient R of equation of linear regression2=0.9999, it is seen that under the chromatographic condition,
Afatinib intermediate linear relationship in 0.071~0.534mg/ml concentration range is good.
Claims (5)
1. a kind of analyzing detecting method of afatinib intermediate, analysis detection is carried out using high performance liquid chromatography, its feature
It is to comprise the following steps：
A, take afatinib intermediate appropriate, add acetonitrile to dissolve, be configured to every 1ml containing afatinib intermediate 0.071~
0.534mg sample solution；
B, it is 0.8~1.2ml/min to set flow rate of mobile phase, and Detection wavelength 230nm, column temperature is 25~35 DEG C；
C, take a μ l of sample solution 10 to inject liquid chromatograph, perform gradient elution program, complete point of afatinib intermediate
Analysis detection；
Wherein, chromatographic column：C18,4.6 × 250mm, 3 μm；
The buffer salt solution that it is 2.0 using phosphoric acid tune pH that the mobile phase, which is, is mobile phase A, using acetonitrile as Mobile phase B, the buffering
Salt is made up of sodium dihydrogen phosphate and disodium hydrogen phosphate, and the concentration of sodium dihydrogen phosphate is 0.005~0.015mol/L in mobile phase A,
The concentration of disodium hydrogen phosphate is 0.005~0.015mol/L；With volume basis, according to the form below carries out gradient elution：
2. analyzing detecting method as claimed in claim 1, it is characterised in that described sample solution concentration is 0.35mg/ml.
3. analyzing detecting method as claimed in claim 1, it is characterised in that described flow rate of mobile phase is 1.0ml/min, post
Temperature is 30 DEG C.
4. analyzing detecting method as claimed in claim 1, it is characterised in that the concentration of sodium dihydrogen phosphate is in the mobile phase A
0.01mol/L, the concentration of disodium hydrogen phosphate is 0.01mol/L.
5. analyzing detecting method as claimed in claim 1, it is characterised in that the eluent gradient elution is arranged to：
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113917043A (en) * | 2021-11-04 | 2022-01-11 | 南京安杰新生物医药有限公司 | Detection method of afatinib maleate genotoxic impurities |
| CN115453000A (en) * | 2022-09-30 | 2022-12-09 | 广州艾格生物科技有限公司 | Detection method and application of toxic impurities in tinib drug intermediate |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115453000A (en) * | 2022-09-30 | 2022-12-09 | 广州艾格生物科技有限公司 | Detection method and application of toxic impurities in tinib drug intermediate |
| CN115453000B (en) * | 2022-09-30 | 2023-10-27 | 广州艾格生物科技有限公司 | Detection method and application of toxic impurities in tenib drug intermediate |
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