CN109212048A - The detection method of impurity content in a kind of voriconazole - Google Patents
The detection method of impurity content in a kind of voriconazole Download PDFInfo
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- CN109212048A CN109212048A CN201710549428.5A CN201710549428A CN109212048A CN 109212048 A CN109212048 A CN 109212048A CN 201710549428 A CN201710549428 A CN 201710549428A CN 109212048 A CN109212048 A CN 109212048A
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- G—PHYSICS
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- 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
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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
- G01N30/62—Detectors specially adapted therefor
- G01N30/72—Mass spectrometers
- G01N30/7233—Mass spectrometers interfaced to liquid or supercritical fluid chromatograph
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- G01N30/7266—Nebulising, aerosol formation or ionisation by electric field, e.g. electrospray
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Abstract
The invention discloses a kind of detection methods of impurity content in voriconazole, using high performance liquid chromatography-EFI fog detector joint technology, impurity A, impurity B, impurity C and impurity E are detected, the impurity A be 1- (2,4- difluorophenyl) -2- (1H-1,2,4- triazol-1-yl) ethyl ketone, the impurity B is voriconazole pyrimidine ring defluorinate impurity, and the impurity C is 4- ethyl -5-FU, and the impurity E is (R) -10- camphorsulfonic acid；Described detection method includes the following steps: (1) reference substance solution is prepared；(2) specificity is tested；(3) linear test；(4) sample measures.The detection method can detect impurity A in voriconazole, impurity B, impurity C, impurity E simultaneously, and have many advantages, such as that easy to operate, separating degree is good, high sensitivity, reproducible, data are accurate and reliable.
Description
Technical field
The present invention relates to a kind of detection methods of impurity content in drug measurement techniques field more particularly to voriconazole.
Background technique
Voriconazole (voriconazole) is 2nd generation triazole antifungal agent, is invented within 1991 by Pfizer, then
Tablet and injection are developed, FDA ratifies to list in May, 2002, true for Aspergillosis, the false mould sample of Bo Yide
Bacterium and Scedosporium infection, the treatment of fusarium infection, the product have the characteristics that has a broad antifungal spectrum, antibacterial efficacy are strong,
It is invaded particularly with aggressive Aspergillus and infects good effect caused by profit.Voriconazole mainly has 5 impurity, and structural formula is as follows:
Impurity A is catabolite 1- (2,4 difluorobenzene base) -2- (1H-1,2,4- triazol-1-yl) ethyl ketone；
Impurity B is voriconazole pyrimidine ring defluorinate impurity；
Impurity C is catabolite 4- ethyl -5-FU；
Impurity D is voriconazole chiral isomer；
Impurity E is resolving agent (R) -10- camphorsulfonic acid.
The UV detector detection common using efficient liquid phase (HPLC) of the related substance detecting method of current voriconazole
Impurity A, B, C, and impurity E is without UV absorption, thus Ion-pair chromalography instrument is used, Suppressor conductivity detection device detects (R) -10- camphor tree
Brain sulfonic acid, the not no quasi-instrument of general pharmacy corporation, needs commissioned research mechanism to be detected, detection cycle is long, takes every time
With high.
Therefore, urgent need develops one kind can accurately and reliably detect impurity A in voriconazole, B, C and E method simultaneously.
Summary of the invention
The technical problem to be solved by the present invention is to overcome the deficiencies in the prior art, and Fu Likang can be detected simultaneously by providing one kind
Impurity A, impurity B, impurity C, impurity E in azoles, and it is easy to operate, separating degree is good, high sensitivity, reproducible, data accurately may be used
The detection method of impurity content in the voriconazole leaned on.
In order to solve the above technical problems, the invention adopts the following technical scheme:
The detection method of impurity content in a kind of voriconazole is combined skill using high performance liquid chromatography-EFI fog detector
Art detects impurity A, impurity B, impurity C and impurity E, the impurity A be 1- (2,4- difluorophenyl) -2- (1H-1,2,
4- triazol-1-yl) ethyl ketone, the impurity B is voriconazole pyrimidine ring defluorinate impurity, and the impurity C is that 4- ethyl -5- fluorine is phonetic
Pyridine, the impurity E are (R) -10- camphorsulfonic acid；It is described that detection method includes the following steps:
(1) reference substance solution is prepared: voriconazole reference substance is obtained with mobile phase dissolved dilution to required mass concentration
Reference solution A；Voriconazole reference substance and sodium hydroxide solution are mixed, voriconazole is made to be decomposed into impurity A and C, and with flowing
Dynamic phased soln is diluted to required mass concentration, obtains reference solution B；By impurity B reference substance with mobile phase dissolved dilution to required
Mass concentration obtains reference solution C；It is molten to be obtained into reference to required mass concentration with mobile phase dissolved dilution for impurity E reference substance
Liquid D；
(2) specificity is tested: precision pipettes reference solution A, reference solution B, reference solution C and reference solution D, is configured to
The specificity solution of required mass concentration；Quantitative specificity solution sample introduction, measurement are taken, the standard chromatogram of each reference substance is obtained；
(3) reference solution A, reference solution B, reference solution C, the reference solution D for taking step (1) add mobile phase, dilute respectively
It is interpreted into the reference solution of multiple concentration in gradient；With step (2) under the same conditions sample introduction, measurement；Respectively with voriconazole,
Impurity A, impurity B, impurity E main peak area carry out linear regression to the concentration of voriconazole, impurity A, impurity B, impurity E, obtain
Four regression equations；
(4) sample measures: by sample to be tested mobile phase dissolved dilution to required mass concentration, obtaining test solution；It will
Test solution with step (2) under the same conditions sample introduction, measurement；Record the peak face of voriconazole, impurity A, impurity B, impurity E
Product substitutes into step (3) resulting respective regression equation respectively, calculates respective mass concentration.
Preferably, in the step (2), (3) and (4), EFI fog detector testing conditions are as follows: detector wavelength 210
10~55 DEG C of~288nm, 0.4~1.5MPa of nitrogen pressure, atomization temperature.
Preferably, in the step (2), (3) and (4), the condition of high performance liquid chromatography are as follows: chromatographic column Eclipse
XDB C18、UG120、Luna C18、Nova-Pak C18、Symmetry C18、BDS HYPERSIL C18、ODS-SP C18
In any one, mobile phase be acetonitrile, methanol and pH be 4.0 ammonium formate solution composition mixed solution, flow velocity 1.0-
1.5ml/min；Sampling volume is 20 μ L.
Preferably, the volume ratio for the ammonium formate solution that acetonitrile, methanol and pH are 4.0 is 15~25: 15~45: 35~65.
Preferably, the regression equation of impurity A or C are as follows: y=695187.5310x-21.3208, R2=1.000；The regression equation of impurity B
Are as follows: y=219607.7480x+1325.5292, R2-0.9999；The regression equation of impurity E are as follows: y=435592.9494x+
3492.7250 R2=1.0000.
Preferably, between the step (3) and (4), further includes: according to multiple concentration in gradient of step (3) preparation
Reference solution carries out repeatability measurement test under conditions of step (2).
Preferably, in the step (3), take reference solution A, reference solution B, reference solution C, the reference of step (1) molten
Liquid D, adds mobile phase, is diluted to the reference solution of multiple concentration in gradient respectively specifically: be diluted to concentration gradient be 5 μ g/mL,
The reference solution A of 2 μ g/mL, 1 μ g/mL, 0.5 μ g/mL, 0.25 μ g/mL；Being diluted to concentration gradient is 5 μ g/mL, 2 μ g/mL, 1 μ
The reference solution B of g/mL, 0.5 μ g/mL, 0.25 μ g/mL；Being diluted to concentration gradient is 5 μ g/mL, 2 μ g/mL, 1 μ g/mL, 0.5 μ
The reference solution C of g/mL, 0.25 μ g/mL；Being diluted to concentration gradient is 5 μ g/mL, 2 μ g/mL, 1 μ g/mL, 0.5 μ g/mL, 0.25 μ
The reference solution D of g/mL.
Compared with the prior art, the advantages of the present invention are as follows:
1, the present invention use HPLC- EFI fog detector (CAD) new technology, can detect simultaneously impurity A in voriconazole,
Impurity B, impurity C, impurity E solve the problems, such as that common UV detector can not checked for impurities E (R) -10- camphorsulfonic acid.
2, the present invention has many advantages, such as that easy to operate, separating degree is good, high sensitivity, favorable reproducibility, data are accurate and reliable.
Detailed description of the invention
Fig. 1 is the liquid chromatogram of each reference substance in specificity solution.
Specific embodiment
Below in conjunction with specific preferred embodiment, the invention will be further described, but not thereby limiting the invention
Protection scope.
Embodiment 1:
The detection method of impurity content in a kind of voriconazole of the invention, comprising the following steps:
(1) specificity is tested
Solution is prepared: weighing 10.0mg voriconazole reference substance in 100.0ml volumetric flask, extremely with mobile phase dissolved dilution
Scale, ultrasonic wave degree of being dissolved as reference solution (a)；By 0.050g voriconazole reference substance in 10ml volumetric flask, it is added 5ml's
In 40g/L sodium hydroxide solution, and be diluted to scale with mobile phase, ultrasonic wave dissolution (voriconazole degrade to obtain impurity A and
C).30min is stood, 1ml solution is pipetted in 10.0ml volumetric flask, is diluted to scale with mobile phase, is reference solution (b)；It weighs
10mg voriconazole impurity B reference substance is into 100ml volumetric flask, mobile phase dissolved dilution to scale, is reference solution (c)；Claim
Take 10mg voriconazole impurity E reference substance into 100ml volumetric flask, mobile phase dissolved dilution to scale is reference solution (d).
1.0ml voriconazole reference solution (b), 1.0ml reference solution (c) and 1.0ml reference solution (d) are pipetted respectively to 10ml capacity
In bottle, adds voriconazole reference solution (a) to be diluted to scale, shake up, as specificity solution.
Quantitative specificity solution sample introduction, measurement are taken, each retention time of reference substance is as shown in table 1, the reference colour of each reference substance
Spectrogram is as shown in Figure 1.
In this test, the detector of upper liquid chromatograph used is Corona VeoRS charged aerosol detectors, model
Corona Ultra Ultra UltiMate Edition。
Liquid chromatograph chromatographic condition used are as follows: chromatographic column is BDS HYPERSIL C18 (3 4.6 × 100mm of μ m), stream
Dynamic is mutually acetonitrile: methanol: being 15: 25: 55 (V: V: V), stream with the 1.90g/L ammonium formate solution that anhydrous formic acid adjusts pH to 4.0
Speed: 1.2ml/min, detector wavelength: 35 DEG C of 256nm, nitrogen pressure 0.5MPa, atomization temperature.；Sampling volume: 20 μ L.
Each retention time of reference substance and relative retention time table in the test of 1 specificity of table
| Compound name | Retention time RT/min | Relative retention time RRT |
| Impurity A | 1.001 | 0.07 |
| Impurity B | 8.402 | 0.58 |
| Impurity C | 2.548 | 0.18 |
| Impurity E | 1.310 | 0.09 |
| Voriconazole | 14.497 | 1.00 |
(2) linear and range test
(2.1) solution is prepared:
Voriconazole standard solution: accurately weighing the voriconazole standard items of 50.0mg, set in the volumetric flask of 100ml, uses
Flowing phased soln is simultaneously diluted to scale, shakes up.(500ug/ml)
Voriconazole impurity A Standard Stock solutions: 5.0mg voriconazole impurity A is accurately weighed, the volumetric flask of 100ml is set
In, with mobile phase dissolved dilution to scale, shake up (50ug/ml).(10%)
Voriconazole impurity B Standard Stock solutions: 5.0mg voriconazole impurity B is accurately weighed, the volumetric flask of 100ml is set
In, with mobile phase dissolved dilution to scale, shake up (50ug/ml).(10%)
Voriconazole impurity E Standard Stock solutions: 5.0mg voriconazole impurity E is accurately weighed, the volumetric flask of 100ml is set
In, with mobile phase dissolved dilution to scale, shake up (50ug/ml).(10%)
Voriconazole standard reserving solution: 10ml voriconazole standard solution accurately is pipetted, sets in the volumetric flask of 100ml, adds
Flowing phased soln is simultaneously diluted to scale, shakes up.(10%)
The preparation of 1.0% solution of labelled amount: pipetting above-mentioned each standard reserving solution 10ml in 100ml volumetric flask respectively, uses
Mobile phase is diluted to scale.
The preparation of 0.4% solution of labelled amount: above-mentioned each standard reserving solution 4ml is pipetted respectively in 100ml volumetric flask, with stream
Phase dilution is moved to scale.
The preparation of 0.2% solution of labelled amount: above-mentioned each standard reserving solution 2ml is pipetted respectively in 100ml volumetric flask, with stream
Phase dilution is moved to scale.
The preparation of 0.1% solution of labelled amount: above-mentioned each standard reserving solution 1ml is pipetted respectively in 100ml volumetric flask, with stream
Phase dilution is moved to scale.
The preparation of 0.05% solution of labelled amount: pipetting above-mentioned each standard reserving solution 0.5ml in 100ml volumetric flask respectively,
Scale is diluted to mobile phase.
(2.2) operating procedure:
1) each solution of labelled amount 0.05%: 3 needles
2) each solution of labelled amount 0.1%: 1 needle
3) each solution of labelled amount 0.2%: 6 needles
4) each solution of labelled amount 0.4%: 1 needle
5) each solution of labelled amount 1.0%: 3 needles
With step (1) under the same conditions sample introduction, measurement；Respectively with voriconazole, impurity A, impurity B, impurity E main peak
Area carries out linear regression to the concentration of voriconazole, impurity A, impurity B, impurity E, obtains four regression equations；
Testing result is as follows:
2 impurity A linear test result table of table
3 impurity B linear test result table of table
4 impurity E linear test result table of table
(3) system reappearance test
(3.1) solution is prepared: 0.2% solution under line taking test item；
(3.2) operating procedure: above-mentioned solution is into 6 needles.
5 impurity E reproducible test results table of table
(4) sample measures:
Precision weighs 100.0mg sample to be tested (neat sunshine medicine company production), in 100.0ml volumetric flask, with flowing phased soln
It is diluted to scale, ultrasonic wave is dissolved as test solution；Will test solution with step (1) under the same conditions sample introduction, measurement；Note
The peak area of voriconazole, impurity A, impurity B, impurity E is recorded, is substituted into step (3) resulting respective regression equation respectively, meter
Calculate respective mass concentration.
Calculate content (w/w, %) of the every kind of impurity in voriconazole:
AC,S=sample tests the peak area in relation to substance in solution (a)
AC,RThe main peak area of=reference solution (C)
CC,RThe concentration of=reference solution (C)
CC,SThe concentration of=test solution (a).
Correction factor of the RRF=in relation to substance
Acquired results are as shown in table 6.
6 HPLC-CAD of table combination measures the impurity content table in sample to be tested
| Lot number | Impurity A content | Impurity B content | Impurity C content | Impurity E content |
| 64214001 | 0.0% | 0.03% | 0.01% | 0.05% |
| 64214002 | 0.0% | 0.02% | 0.02% | 0.07% |
| 64215001 | 0.0% | 0.04% | 0.01% | < 0.05% |
Illustrate that HPLC- EFI fog detector (CAD) method of the invention can detect major impurity in voriconazole sample simultaneously
Content.
Three batches of voriconazole samples are used into ion pair chromatography (control methods) and HPLC- EFI provided by the invention respectively
Fog detector (CAD) method is detected, detection data such as table 7:
The impurity E comparison table that 7 ion pair chromatography of table and HPLC-CAD method measure
Conclusion is consistent, and the HPLC-CAD method for illustrating that the present invention uses can be accurately detected impurity E in voriconazole sample
Content.
Be it is necessary to described herein finally: above embodiments are served only for making technical solution of the present invention further detailed
Ground explanation, should not be understood as limiting the scope of the invention, those skilled in the art's above content according to the present invention
The some nonessential modifications and adaptations made all belong to the scope of protection of the present invention.It is it is necessary to described herein finally: with
Upper embodiment is served only for being described in more detail technical solution of the present invention, should not be understood as to the scope of the present invention
Limitation, some nonessential modifications and adaptations that those skilled in the art's above content according to the present invention is made belong to
Protection scope of the present invention.
Claims (7)
1. the detection method of impurity content in a kind of voriconazole, which is characterized in that using high performance liquid chromatography-electron spray detection
Device joint technology detects impurity A, impurity B, impurity C and impurity E, and the impurity A is 1- (2,4- difluorophenyl) -2-
(1H-1,2,4- triazol-1-yls) ethyl ketone, the impurity B are voriconazole pyrimidine ring defluorinate impurity, and the impurity C is 4- ethyl-
5-FU, the impurity E are (R) -10- camphorsulfonic acid；It is described that detection method includes the following steps:
(1) reference substance solution is prepared: voriconazole reference substance is obtained reference to required mass concentration with mobile phase dissolved dilution
Solution A；Voriconazole reference substance and sodium hydroxide solution are mixed, so that voriconazole is decomposed into impurity A and C, and use mobile phase
Dissolved dilution obtains reference solution B to required mass concentration；By impurity B reference substance mobile phase dissolved dilution to required quality
Concentration obtains reference solution C；By impurity E reference substance mobile phase dissolved dilution to required mass concentration, reference solution D is obtained；
(2) specificity is tested: precision pipettes reference solution A, reference solution B, reference solution C and reference solution D, needed for being configured to
The specificity solution of mass concentration；Quantitative specificity solution sample introduction, measurement are taken, the standard chromatogram of each reference substance is obtained；
(3) reference solution A, reference solution B, reference solution C, the reference solution D for taking step (1), add mobile phase, are diluted to respectively
The reference solution of multiple concentration in gradient；With step (2) under the same conditions sample introduction, measurement；Respectively with voriconazole, impurity
A, impurity B, impurity E main peak area carry out linear regression to the concentration of voriconazole, impurity A, impurity B, impurity E, obtain four
Regression equation；
(4) sample measures: by sample to be tested mobile phase dissolved dilution to required mass concentration, obtaining test solution；It will test
Solution with step (2) under the same conditions sample introduction, measurement；The peak area of voriconazole, impurity A, impurity B, impurity E is recorded,
It substitutes into step (3) resulting respective regression equation respectively, calculates respective mass concentration.
2. the detection method of impurity content in voriconazole according to claim 1, which is characterized in that the step (2),
(3) and in (4), EFI fog detector testing conditions are as follows: detector wavelength be 210~288nm, 0.4~1.5MPa of nitrogen pressure,
10~55 DEG C of atomization temperature.
3. the detection method of impurity content in voriconazole according to claim 2, which is characterized in that the step (2),
(3) and in (4), the condition of high performance liquid chromatography are as follows: chromatographic column is Eclipse XDB C18, UG120, Luna C18, Nova-
Pak C18, Symmetry C18, BDS HYPERSIL C18, any one in ODS-SP C18, mobile phase is acetonitrile, first
The mixed solution that the ammonium formate solution that pure and mild pH is 4.0 forms, flow velocity 1.0-1.5ml/min；Sampling volume is 20 μ L.
4. the detection method of impurity content in voriconazole according to claim 3, which is characterized in that acetonitrile, methanol and
The volume ratio for the ammonium formate solution that pH is 4.0 is 15~25: 15~45: 35~65.
5. the detection method of impurity content in voriconazole according to any one of claims 1 to 4, which is characterized in that miscellaneous
The regression equation of matter A or C are as follows: y=695187.5310x-21.3208, R2=1.000；The regression equation of impurity B are as follows: y=
219607.7480x+1325.5292 R2-0.9999；The regression equation of impurity E are as follows: y=435592.9494x+3492.7250,
R2=1.0000.
6. the detection method of impurity content in voriconazole according to any one of claims 1 to 4, which is characterized in that institute
It states between step (3) and (4), further includes: according to the reference solution for multiple concentration in gradient that step (3) are prepared, in step (2)
Under conditions of carry out repeatability measurement test.
7. the detection method of impurity content in voriconazole according to any one of claims 1 to 4, which is characterized in that institute
It states in step (3), takes reference solution A, reference solution B, reference solution C, the reference solution D of step (1), add mobile phase, respectively
It is diluted to the reference solution of multiple concentration in gradient specifically: being diluted to concentration gradient is 5 μ g/mL, 2 μ g/mL, 1 μ g/mL, 0.5
The reference solution A of μ g/mL, 0.25 μ g/mL；Being diluted to concentration gradient is 5 μ g/mL, 2 μ g/mL, 1 μ g/mL, 0.5 μ g/mL, 0.25
The reference solution B of μ g/mL；It is diluted to the ginseng that concentration gradient is 5 μ g/mL, 2 μ g/mL, 1 μ g/mL, 0.5 μ g/mL, 0.25 μ g/mL
Compare solution C；It is diluted to the reference solution D that concentration gradient is 5 μ g/mL, 2 μ g/mL, 1 μ g/mL, 0.5 μ g/mL, 0.25 μ g/mL.
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| CN112461982A (en) * | 2019-09-06 | 2021-03-09 | 扬子江药业集团南京海陵药业有限公司 | Detection method of L-camphorsulfonic acid methyl ester and L-camphorsulfonic acid ethyl ester |
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| CN113341035A (en) * | 2021-07-29 | 2021-09-03 | 湖南沁森高科新材料有限公司 | Detection method of camphorsulfonic acid and sodium dodecyl sulfate |
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