CN109212048B - Method for detecting impurity content in voriconazole - Google Patents
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Abstract
The invention discloses a method for detecting the content of impurities in voriconazole, which adopts a high performance liquid chromatography-electrospray detector combination technology to detect impurities A, B, C and E, wherein the impurity A is 1- (2, 4-difluorophenyl) -2- (1H-1, 2, 4-triazole-1-yl) ethanone, the impurity B is voriconazole pyrimidine ring defluorination impurity, the impurity C is 4-ethyl-5-fluoropyrimidine, and the impurity E is (R) -10-camphorsulfonic acid; the detection method comprises the following steps: (1) preparing a reference substance solution; (2) a specificity test; (3) a linear test; (4) sample measurement. The detection method can detect the impurity A, the impurity B, the impurity C and the impurity E in voriconazole simultaneously, and has the advantages of simplicity and convenience in operation, good separation degree, high sensitivity, good repeatability, accurate and reliable data and the like.
Description
Technical Field
The invention relates to the technical field of drug detection, in particular to a method for detecting impurity content in voriconazole.
Background
Voriconazole (voriconazole) is a 2 nd generation triazole antifungal agent, and is invented by the company of pyroxene in 1991, then tablets and injections are developed, and the FDA is approved to be marketed in the month 5 of 2002 for treating invasive aspergillosis, paeonia suffruticosa and Fusarium infections, and the product has the characteristics of wide antibacterial spectrum and strong antibacterial efficacy, and particularly has good curative effect on infections caused by invasive aspergillosis. Voriconazole has mainly 5 impurities and has the following structural formula:
impurity A is degradation product 1- (2, 4-difluorophenyl) -2- (1H-1, 2, 4-triazol-1-yl) ethanone;
impurity B is voriconazole pyrimidine ring defluorination impurity;
impurity C is degradation product 4-ethyl-5-fluoropyrimidine;
impurity D is voriconazole chiral isomer;
impurity E is resolving agent (R) -10-camphorsulfonic acid.
The existing voriconazole related substance detection method adopts a High Performance Liquid Chromatography (HPLC) common ultraviolet detector to detect the impurity A, B, C, and the impurity E has no ultraviolet absorption, so that an ion pair chromatograph is adopted to inhibit a conductivity detector from detecting (R) -10-camphorsulfonic acid, and common pharmaceutical enterprises do not have the instruments, and each time, a research institution needs to be commissioned for detection, the detection period is long, and the cost is high.
Therefore, there is an urgent need to develop an accurate and reliable method for simultaneously detecting impurities A, B, C and E in voriconazole.
Disclosure of Invention
The invention aims to solve the technical problem of overcoming the defects of the prior art and providing the method for detecting the impurity content in the voriconazole, which can simultaneously detect the impurity A, the impurity B, the impurity C and the impurity E in the voriconazole, and has the advantages of simple operation, good separation degree, high sensitivity, good repeatability and accurate and reliable data.
In order to solve the technical problems, the invention adopts the following technical scheme:
the method for detecting the impurity content in voriconazole adopts a high performance liquid chromatography-electrospray detector combination technology to detect an impurity A, an impurity B, an impurity C and an impurity E, wherein the impurity A is 1- (2, 4-difluorophenyl) -2- (1H-1, 2, 4-triazol-1-yl) ethanone, the impurity B is voriconazole pyrimidine ring defluorination impurity, the impurity C is 4-ethyl-5-fluoropyrimidine, and the impurity E is (R) -10-camphorsulfonic acid; the detection method comprises the following steps:
(1) Preparing a reference substance solution: dissolving and diluting the voriconazole reference substance to the required mass concentration by using a mobile phase to obtain a reference solution A; mixing voriconazole reference substance with sodium hydroxide solution to decompose voriconazole into impurities A and C, and dissolving and diluting to required mass concentration with mobile phase to obtain reference solution B; dissolving and diluting the impurity B reference substance to the required mass concentration by using a mobile phase to obtain a reference solution C; dissolving and diluting the impurity E reference substance to the required mass concentration by using a mobile phase to obtain a reference solution D;
(2) Specificity test: precisely transferring the reference solution A, the reference solution B, the reference solution C and the reference solution D to prepare a specific solution with the required mass concentration; taking quantitative special solution for sample injection and measurement to obtain a standard chromatogram of each reference substance;
(3) Taking the reference solution A, the reference solution B, the reference solution C and the reference solution D in the step (1), adding a mobile phase, and respectively diluting into a plurality of reference solutions with gradient concentration; sampling and measuring under the same conditions as the step (2); linearly regressing the concentrations of voriconazole, impurity A, impurity B and impurity E respectively by using the main peak areas of voriconazole, impurity A, impurity B and impurity E to obtain four regression equations;
(4) Sample measurement: dissolving and diluting a sample to be tested to a required mass concentration by using a mobile phase to obtain a test solution; sampling and measuring the test solution under the same conditions as the step (2); recording peak areas of voriconazole, impurity A, impurity B and impurity E, substituting the peak areas into the regression equations obtained in the step (3) respectively, and calculating the mass concentration of each.
Preferably, in the steps (2), (3) and (4), the detection conditions of the electrospray detector are: the wavelength of the detector is 210-288 nm, the nitrogen pressure is 0.4-1.5 MPa, and the atomization temperature is 10-55 ℃.
Preferably, in the steps (2), (3) and (4), the conditions of the high performance liquid chromatography are: the chromatographic column is any one of Eclipse XDB C18, UG120, luna C18, nova-Pak C18, symmetry C18, BDS HYPERSIL C and ODS-SP C18, the mobile phase is a mixed solution composed of acetonitrile, methanol and ammonium formate solution with pH of 4.0, and the flow rate is 1.0-1.5ml/min; the sample volume was 20. Mu.L.
Preferably, the volume ratio of acetonitrile, methanol and ammonium formate solution with pH of 4.0 is 15-25:15-45:35-65. Preferably, the regression equation for impurity A or C is: y= 695187.5310x-21.3208, r2=1.000; the regression equation for impurity B is: y=219607.7480x+1325.5292, R2-0.9999; the regression equation for impurity E is: y=435592.9494x+3492.7250, r2=1.0000.
Preferably, between the steps (3) and (4), further comprising: and (3) carrying out repeatability measurement test under the condition of the step (2) according to the plurality of concentration gradient reference solutions prepared in the step (3).
Preferably, in the step (3), the reference solution a, the reference solution B, the reference solution C, and the reference solution D in the step (1) are taken, and the mobile phase is added to dilute the reference solutions into a plurality of reference solutions with gradient concentrations respectively, specifically: diluting to obtain a reference solution A with concentration gradient of 5 mug/mL, 2 mug/mL, 1 mug/mL, 0.5 mug/mL and 0.25 mug/mL; diluting to obtain a reference solution B with a concentration gradient of 5 mug/mL, 2 mug/mL, 1 mug/mL, 0.5 mug/mL and 0.25 mug/mL; diluting to obtain a reference solution C with concentration gradient of 5 mug/mL, 2 mug/mL, 1 mug/mL, 0.5 mug/mL and 0.25 mug/mL; diluted to a concentration gradient of 5. Mu.g/mL, 2. Mu.g/mL, 1. Mu.g/mL, 0.5. Mu.g/mL, 0.25. Mu.g/mL of reference solution D.
Compared with the prior art, the invention has the advantages that:
1. the invention adopts a novel technology of an HPLC-electrospray detector (CAD) to simultaneously detect the impurity A, the impurity B, the impurity C and the impurity E in voriconazole, and solves the problem that the common ultraviolet detector cannot detect the impurity E (R) -10-camphorsulfonic acid.
2. The invention has the advantages of simple operation, good separation degree, high sensitivity, good reproducibility, accurate and reliable data and the like.
Drawings
FIG. 1 is a liquid chromatogram of each control in a specific solution.
Detailed Description
The invention is further described below in connection with specific preferred embodiments, but it is not intended to limit the scope of the invention.
Example 1:
the invention relates to a method for detecting impurity content in voriconazole, which comprises the following steps:
(1) Specificity test
Preparing a solution: weighing 10.0mg voriconazole reference substance in a 100.0ml volumetric flask, dissolving and diluting to scale with mobile phase, and ultrasonically dissolving to obtain a solubility reference solution (a); 0.050g voriconazole control was placed in a 10ml volumetric flask, added to 5ml of 40g/L sodium hydroxide solution, diluted to scale with mobile phase and sonicated (voriconazole degraded to give impurities a and C). Standing for 30min, transferring 1ml of the solution into a 10.0ml volumetric flask, and diluting to scale with mobile phase to obtain reference solution (b); weighing 10mg of voriconazole impurity B reference substance into a 100ml volumetric flask, dissolving and diluting a mobile phase to a scale, and obtaining a reference solution (c); 10mg of voriconazole impurity E control is weighed into a 100ml volumetric flask, and the mobile phase is dissolved and diluted to a scale to obtain a reference solution (d). And respectively transferring 1.0ml of voriconazole reference solution (b), 1.0ml of reference solution (c) and 1.0ml of reference solution (d) into a 10ml volumetric flask, and adding the voriconazole reference solution (a) to dilute to a scale, and shaking uniformly to obtain a specific solution.
Taking quantitative special solution, sampling, and measuring, wherein the retention time of each reference substance is shown in table 1, and the standard chromatogram of each reference substance is shown in fig. 1.
In the test, the detector of the liquid chromatograph used in the test is a Corona VeoRS electric fog detector, and the model is Corona Ultra Ultra UltiMate Edition.
The chromatographic conditions of the liquid chromatograph used are: the column was BDS HYPERSIL C (3 μm. Times.4.6X100 mm), the mobile phase was acetonitrile: methanol: 1.90g/L ammonium formate solution adjusted to pH 4.0 with anhydrous formic acid 15:25:55 (V: V), flow rate: 1.2ml/min, detector wavelength: 256nm, nitrogen pressure 0.5MPa and atomization temperature 35 ℃. The method comprises the steps of carrying out a first treatment on the surface of the Sample injection volume: 20. Mu.L.
TABLE 1 retention time and relative retention time table for each control in the specificity test
| Names of Compounds | 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 preparation:
voriconazole standard solution: accurately weighing 50.0mg voriconazole standard, placing into a 100ml volumetric flask, dissolving with mobile phase, diluting to scale, and shaking. (500 ug/ml)
Voriconazole impurity a standard stock solution: accurately weighing 5.0mg voriconazole impurity A, placing into a volumetric flask of 100ml, dissolving with mobile phase, diluting to scale, and shaking (50 ug/ml). (10%)
Voriconazole impurity B standard stock solution: accurately weighing 5.0mg voriconazole impurity B, placing into a volumetric flask of 100ml, dissolving with mobile phase, diluting to scale, and shaking (50 ug/ml). (10%)
Voriconazole impurity E standard stock solution: accurately weighing 5.0mg of voriconazole impurity E, placing into a volumetric flask of 100ml, dissolving with mobile phase, diluting to scale, and shaking (50 ug/ml). (10%)
Voriconazole standard stock: accurately transferring 10ml voriconazole standard solution, placing into a 100ml volumetric flask, adding mobile phase to dissolve and dilute to scale, and shaking. (10%)
Preparation of labeled amount 1.0% solution: 10ml of each standard stock solution was removed separately from the stock solution in a 100ml volumetric flask and diluted to scale with mobile phase.
Preparation of labeling amount 0.4% solution: the standard stock solutions described above were each removed 4ml in 100ml volumetric flasks and diluted to scale with mobile phase.
Preparation of labeling amount 0.2% solution: 2ml of each standard stock solution was removed separately from the flask and diluted to scale with mobile phase.
Preparation of labeling amount 0.1% solution: 1ml of each standard stock solution was removed from each flask and diluted to scale with mobile phase.
Preparation of labeling amount 0.05% solution: 0.5ml of each standard stock solution was removed separately from the stock solution in 100ml volumetric flasks and diluted to scale with mobile phase.
(2.2) operation steps:
1) 3 needles for each solution with a labeling amount of 0.05%
2) 1 needle for each solution with a labeling amount of 0.1%
3) 6 needles for each solution with a labeled amount of 0.2%
4) 1 needle for each solution with a labeling amount of 0.4%
5) 3 needles for each solution with a labeled amount of 1.0%
Sampling and measuring under the same conditions as the step (1); linearly regressing the concentrations of voriconazole, impurity A, impurity B and impurity E respectively by using the main peak areas of voriconazole, impurity A, impurity B and impurity E to obtain four regression equations;
the detection results are as follows:
TABLE 2 impurity A Linear test results Table
TABLE 3 impurity B Linear test results Table
TABLE 4 impurity E Linear test results Table
(3) System reproducibility test
(3.1) preparing a solution, namely taking a 0.2% solution under a linear test item;
(3.2) the above solution was introduced into a 6-needle.
TABLE 5 impurity E reproducibility test results table
(4) Sample measurement:
precisely weighing 100.0mg of a sample to be tested (Ji Hui pharmaceutical industry production), dissolving and diluting to a scale by using a mobile phase in a 100.0ml volumetric flask, and dissolving by using ultrasonic waves to obtain a test solution; sampling and measuring the test solution under the same conditions as the step (1); recording peak areas of voriconazole, impurity A, impurity B and impurity E, substituting the peak areas into the regression equations obtained in the step (3) respectively, and calculating the mass concentration of each.
The content (w/w,%) of each impurity in voriconazole was calculated:
A C,S peak area of related substances in sample test solution (a)
A C,R Main peak area of reference solution (C)
C C,R Concentration of reference solution (C)
C C,S Concentration of test solution (a).
Rrf=correction factor of the substance concerned
The results obtained are shown in Table 6.
TABLE 6 determination of impurity content in samples to be measured by HPLC-CAD combination
| 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％ |
The HPLC-electrospray detector (CAD) method of the invention is described as being capable of simultaneously detecting the content of the main impurity in the voriconazole sample.
Three batches of itraconazole samples were tested by ion-pair chromatography (comparative method) and HPLC-electrospray detector (CAD) methods provided by the present invention, respectively, and the test data are shown in table 7:
TABLE 7 comparison of impurity E results from ion-pair chromatography and HPLC-CAD
The conclusion is consistent, and the HPLC-CAD method adopted by the invention can accurately detect the content of the impurity E in the voriconazole sample.
Finally, what is necessary here is: the above embodiments are only for further detailed description of the technical solutions of the present invention, and should not be construed as limiting the scope of the present invention, and some insubstantial modifications and adjustments made by those skilled in the art from the above description of the present invention are all within the scope of the present invention. Finally, what is necessary here is: the above embodiments are only for further detailed description of the technical solutions of the present invention, and should not be construed as limiting the scope of the present invention, and some insubstantial modifications and adjustments made by those skilled in the art from the above description of the present invention are all within the scope of the present invention.
Claims (4)
1. The method for detecting the impurity content in voriconazole is characterized by detecting an impurity A, an impurity B, an impurity C and an impurity E by adopting a high performance liquid chromatography-electrospray detector combination technology, wherein the impurity A is 1- (2, 4-difluorophenyl) -2- (1H-1, 2, 4-triazol-1-yl) ethanone, the impurity B is voriconazole pyrimidine ring defluorination impurity, the impurity C is 4-ethyl-5-fluoropyrimidine, and the impurity E is (R) -10-camphorsulfonic acid; the detection method comprises the following steps:
(1) Preparing a reference substance solution: dissolving and diluting the voriconazole reference substance to the required mass concentration by using a mobile phase to obtain a reference solution A; mixing voriconazole reference substance with sodium hydroxide solution to decompose voriconazole into impurities A and C, and dissolving and diluting to required mass concentration with mobile phase to obtain reference solution B; dissolving and diluting the impurity B reference substance to the required mass concentration by using a mobile phase to obtain a reference solution C; dissolving and diluting the impurity E reference substance to the required mass concentration by using a mobile phase to obtain a reference solution D;
(2) Specificity test: precisely transferring the reference solution A, the reference solution B, the reference solution C and the reference solution D to prepare a specific solution with the required mass concentration; taking quantitative special solution for sample injection and measurement to obtain a standard chromatogram of each reference substance;
(3) Taking the reference solution A, the reference solution B, the reference solution C and the reference solution D in the step (1), adding a mobile phase, and respectively diluting into a plurality of reference solutions with gradient concentration; sampling and measuring under the same conditions as the step (2); linearly regressing the concentrations of voriconazole, impurity A, impurity B and impurity E respectively by using the main peak areas of voriconazole, impurity A, impurity B and impurity E to obtain four regression equations;
(4) Sample measurement: dissolving and diluting a sample to be tested to a required mass concentration by using a mobile phase to obtain a test solution; sampling and measuring the test solution under the same conditions as the step (2); recording peak areas of voriconazole, impurities A, B and E, substituting the peak areas into the regression equations obtained in the step (3) respectively, and calculating the mass concentrations of the voriconazole, the impurities A, the impurities B and the impurities E respectively;
in the steps (2), (3) and (4), the detection conditions of the electrospray detector are as follows: the nitrogen pressure is 0.4-1.5 MPa, and the atomization temperature is 10-55 ℃; in the steps (2), (3) and (4), the conditions of the high performance liquid chromatography are as follows: the chromatographic column is any one of Eclipse XDB C18, UG120, luna C18, nova-Pak C18, symmetry C18, BDS HYPERSIL C and ODS-SP C18, the mobile phase is a mixed solution composed of acetonitrile, methanol and ammonium formate solution with pH of 4.0, and the flow rate is 1.0-1.5ml/min; the sample injection volume is 20 mu L; the volume ratio of acetonitrile, methanol and ammonium formate solution with pH of 4.0 is 15:25:55.
2. The method for detecting the impurity content in voriconazole according to claim 1, wherein the regression equation of the impurity a or C is: y= 695187.5310x-21.3208, r2=1.000; the regression equation for impurity B is: y=219607.7480x+1325.5292, R2-0.9999; the regression equation for impurity E is: y=435592.9494x+3492.7250, r2=1.0000.
3. The method for detecting the impurity content in voriconazole according to claim 1, wherein between the steps (3) and (4), further comprising: and (3) carrying out repeatability measurement test under the condition of the step (2) according to the plurality of concentration gradient reference solutions prepared in the step (3).
4. The method for detecting the impurity content in voriconazole according to claim 1, wherein in the step (3), the reference solution a, the reference solution B, the reference solution C, and the reference solution D in the step (1) are taken, and the mobile phases are added to dilute the reference solutions into a plurality of reference solutions having gradient concentrations respectively, specifically: diluting to obtain a reference solution A with concentration gradient of 5 mug/mL, 2 mug/mL, 1 mug/mL, 0.5 mug/mL and 0.25 mug/mL; diluting to obtain a reference solution B with a concentration gradient of 5 mug/mL, 2 mug/mL, 1 mug/mL, 0.5 mug/mL and 0.25 mug/mL; diluting to obtain a reference solution C with concentration gradient of 5 mug/mL, 2 mug/mL, 1 mug/mL, 0.5 mug/mL and 0.25 mug/mL; diluted to a concentration gradient of 5. Mu.g/mL, 2. Mu.g/mL, 1. Mu.g/mL, 0.5. Mu.g/mL, 0.25. Mu.g/mL of reference solution D.
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| CN110441460B (en) * | 2019-09-12 | 2022-03-08 | 武汉朗来科技发展有限公司 | Method for detecting trace genotoxicity impurities in voriconazole |
| CN114544842B (en) * | 2020-11-26 | 2023-05-02 | 珠海润都制药股份有限公司 | Method for detecting N-bromosuccinimide in voriconazole |
| 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 |
| CN114280168B (en) * | 2021-10-25 | 2024-05-31 | 郑州市中心医院 | HPLC method for detecting concentration of voriconazole in serum |
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